Textbook of Natural Medicine (2-Volume Set) 2nd edition (September 15, 1999) by Joseph E. Pizzorno (Editor), Michael T. Murray (Editor) By Churchill Livingstone
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Frontmatter Dedication Title Page Copyright Page Contributors Preface Section One - Philosophy of natural medicine Section Two - Supplementary diagnostic procedures Section Three - Therapeutic Modalities Section Four - Syndromes and special topics Section Five - Pharmacology of natural medicines Section Six - Specific health problems Appendix 1: Candida questionnaire Appendix 2: Crohn’s disease activity index Appendix 3: Fasting – patient guidelines Appendix 4: Gluten and gliadin content of selected foods Appendix 5: Healthy exchange lists Appendix 6: Hydrochloric acid supplementation – patient instructions Appendix 7: Patient instructions for measuring basal body temperature Appendix 8: Premenstrual syndrome questionnaire Appendix 9: Rotation diet master chart, plans I and II Appendix 10: Sit and reach test Appendix 11: Vaginal depletion pack
Section One - Philosophy of natural medicine 1 - Functional medicine in natural medicine 2 - History of naturopathic medicine 3 - Philosophy of naturopathic medicine 4 - Placebo and healing 5 - Women in the history of medicine
Section Two - Supplementary diagnostic procedures 6 - Apoptosis assessment 7 - Bacterial overgrowth of the small intestine breath test 8 - Cell signaling analysis 9 - Comprehensive digestive stool analysis 10 - ELISA/ACT test 11 - Erythrocyte sedimentation rate 12 - Fantus test for urine chloride 13 - Fatty acid profiling 14 - Folic acid status assessment 15 - Food allergy testing 16 - Functional assessment of liver phase I and II detoxification 17 - Hair mineral analysis 18 - Heavy metal assessment /table> 19 - Heidelberg pH capsule gastric analysis 20 - Immune function assessment 21 - Intestinal permeability assessment 22 - Laboratory tests for the determination of vitamin status 23 - Lactose intolerance breath test 24 - Mineral status evaluation 25 - Oral manifestations of nutritional status 26 - Rapid dark adaptation test 27 - Serum bile acids assay 28 - Tryptophan load test 29 - Urinary organic acids profiling for assessment of functional nutrient deficiencies, gut dysbiosis, and toxicity 30 - Urinary porphyrins for the detection of heavy metal and toxic chemical exposure 31 - Urine indican test (Obermeyer test) 32 - Zinc status assessment
Section Three - Therapeutic Modalities 33 - Acupuncture 34 - Ayurveda: the science of life and mother of the healing arts 35 - Botanical medicine – a modern perspective 36 - Contemporary homeopathy 37 - Environmental medicine 38 - The exercise prescription 39 - Faith: a powerful force for healing 40 - Glandular therapy 41 - Homeopathy 42 - Hydrotherapy 43 - Manipulation 44 - Nutritional medicine 45 - Peat therapeutics and balneotherapy 46 - Soft tissue manipulation: diagnostic and therapeutic potential 47 - Therapeutic fasting
Section Four - Syndromes and special topics 48 - Chronic candidiasis 49 - Chronic fatigue syndrome 50 - Detoxification 51 - Food allergies 52 - Homocysteine metabolism: nutritional modulation and impact on health and disease 53 - Immune support 54 - Intestinal dysbiosis and dysfunction 55 - Maldigestion 56 - Non-pharmacological control of pain 57 - Role of dietary fiber in health and disease 58 - Rotation diet: a diagnostic and therapeutic tool 59 - Sports nutrition 60 - Stress management
Section Five - Pharmacology of natural medicines 61 - Alkylglycerols 62 - Allium cepa (onion) 63 - Allium sativum (garlic) 64 - Aloe vera (Cape aloe) 65 - Angelica species 66 - Aspergillus oryzae enzyme therapy 67 - Beta-carotene and other carotenoids 68 - Boron 69 - Bromelain 70 - Camellia sinensis (green tea) 71 - Capsicum frutescens (cayenne pepper) 72 - Carnitine 73 - Catechin [(+)-cyanidanol-3] 74 - Centella asiatica (gotu kola) 75 - Cimicifuga racemosa (black cohosh) 76 - Coenzyme Q10 77 - Coleus forskohlii 78 - Commiphora mukul (mukul myrrh tree) 79 - Crataegus oxyacantha (hawthorn) 80 - Curcuma longa (turmeric) 81 - Dehydroepiandrosterone 82 - Echinacea species (narrow-leafed purple coneflower) 83 - Eleutherococcus senticosus (Siberian ginseng) 84 - Ephedra species 85 - Fatty acid metabolism 86 - Fish oils 87 - Flavonoids – quercetin, citrus flavonoids, and HERs (hydroxyethylrutosides) 88 - Ginkgo biloba (ginkgo tree) 89 - Glucosamine 90 - Glycyrrhiza glabra (licorice) 91 - Hydrastis canadensis (goldenseal) and other berberine-containing botanicals 92 - 5-Hydroxytryptophan 93 - Hypericum perforatum (St John’s wort) 94 - Introduction to the clinical use of Chinese prepared medicines 95 - Lobelia inflata (Indian tobacco) 96 - Melaleuca alternifolia (tea tree) 97 - Melatonin 98 - Mentha piperita (peppermint) 99 - Naturally occurring antioxidants 100 - Panax ginseng (Korean ginseng) 101 - Pancreatic enzymes 102 - Phage therapy: bacteriophages as natural, self-limiting antibiotics 103 - Phosphatidylserine 104 - Piper mythisticum (kava) 105 - Probiotics 106 - Procyanidolic oligomers 107 - Pygeum africanum (bitter almond) 108 - Recommended optimum nutrient intakes (RONIs) 109 - Sarsaparilla species 110 - Serenoa repens (saw palmetto) 111 - Silybum marianum (milk thistle) 112 - Soy isoflavones and other constituents 113 - Tabebuia avellanedae (LaPacho, Pau D’Arco, Ipe Roxo) 114 - Tanacetum parthenium (feverfew) 115 - Taraxacum officinale (dandelion) 116 - Taxus brevifolia (Pacific yew) 117 - Uva ursi (bearberry) 118 - Vaccinium myrtillus (bilberry) 119 - Valeriana officinalis (valerian) 120 - Viscum album (European mistletoe) 121 - Vitamin A 122 - Vitamin toxicities and therapeutic monitoring 123 - Vitex agnus castus (chaste tree) 124 - Zingiber officinale (ginger)
Section Six - Specific health problems 125 - Acne vulgaris and acne conglobata 126 - Affective disorders 127 - Alcoholism 128 - Alzheimer’s disease 129 - Angina 130 - Aphthous stomatitis 131 - Ascariasis 132 - Asthma 133 - Atherosclerosis 134 - Atopic dermatitis (eczema) 135 - Attention deficit disorders (hyperactivity and childhood learning disorders) 136 - Autism 137 - Bacterial sinusitis 138 - Benign prostatic hyperplasia 139 - Carpal tunnel syndrome 140 - Celiac disease 141 - Cellulite 142 - Cervical dysplasia 143 - Chlamydial genital infections 144 - Congestive heart failure 145 - Cystitis 146 - Dermatitis herpetiformis 147 - Diabetes mellitus 148 - Epididymitis 149 - Epilepsy 150 - Erythema multiforme 151 - Fibrocystic breast disease 152 - Gallstones 153 - Glaucoma: acute (angle closure) and chronic (open-angle) 154 - Gout 155 - Hemorrhoids 156 - Hepatitis 157 - Herpes simplex 158 - HIV/AIDS: naturopathic medical principles and practice 159 - Hypertension 160 - Hyperthyroidism 161 - Hypoglycemia 162 - Hypothyroidism 163 - Inflammatory bowel disease (Crohn’s disease and ulcerative colitis) 164 - Insomnia 165 - Irritable bowel syndrome 166 - Kidney stones 167 - Leukoplakia 168 - Macular degeneration 169 - Male infertility 170 - Menopause 171 - Menorrhagia 172 - Migraine headache 173 - Multiple sclerosis 174 - Nausea and vomiting of pregnancy 175 - Obesity 176 - Osteoarthritis 177 - Osteoporosis 178 - Otitis media 179 - Pelvic inflammatory disease 180 - Peptic ulcer – duodenal and gastric 181 - Periodontal disease 182 - Pneumonia: bacterial, mycoplasmal, and viral 183 - Premenstrual syndrome 184 - Psoriasis 185 - Rheumatoid arthritis 186 - Rosacea 187 - Seborrheic dermatitis 188 - Senile cataracts 189 - Streptococcal pharyngitis
190 - Trichomoniasis 191 - Urticaria 192 - Vaginitis and vulvovaginitis 193 - Varicose veins 194 - Viral pharyngitis
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This book is dedicated to Dr John Bastyr and all the natural healers of the past and future who bring the virtues of the “healing powers of nature” to all the people of the world. Dr Bastyr, the namesake for Bastyr University, exemplified the ideal physician/healer/ teacher we endeavour to become in our professional lives. We pass on a few of his words to all who strive to provide the best of health care and healing: “Always touch your patients – let them know you care”, and “Always read at least one research article or learn a new remedy before you retire at night”. III
Textbook of Natural Medicine
Second Edition Edited By Joseph E. Pizzorno Jr ND President and Faculty, Bastyr University, Kenmore, Washington, USA
Michael T. Murray ND Faculty, Bastyr University, Kenmore, Washington, USA
EDINBURGH LONDON NEW YORK PHILADELPHIA SYDNEY TORONTO 1999
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For Churchill Livingstone Commissioning Editor: Inta Ozols Head of Project Management: Ewan Halley Project Developmnt: Dinah Thom Design Directions: Judith Wright CHURCHILL LIVINGSTONE An imprint of Harcourt Publishers Limited © J.E. Pizzornao Jr, M.T. Murray amd Bastry Publications 1993 © Textbook of Natural Medicine 2nd edition Harcourt Brace and Company Limited 1999 © Textbook of Natural Medicine 2nd edition Harcourt Publishers Limited 1999
is a registerd trademark of Harcourt Publishers Limited All rights reserved. No part of this publication may be reproduced, stored in a retrival system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without either prior permisson of the publishers (Hartcourt Publishers Limited, Robert Stevenson House, 1–3 Baxter's Place, Leith Walk, Edinburgh EH1 3 AF), or a licence permitting restricted copying in the United Kingdom issued by the copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P Olp. First published 1993 Second edition 1999 Reprinted 1999 Reprinted 2000 (twice) ISBN 0 443 05945 4 British Library Cataloguing in Publication Data A catalog record for this book is available from the British Library. Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Note This is a textbook and references for students and practitioners of natural medicine and other professionals interested in learning about this healing art. For several reasons important reasons, this work should not be viewed as providing a single answer applicable to all individuals. First, the practice of natural medicine is constantly evolving. New research and on going clinical experience continue to give us a better understanding of the human body, its interaction with the physical environment, its reaction to the stresses of modern life, and its response to various forms of therapy and treatment. Second, diagnosis and theraphy are so personalized and individualized that the same promblem for the same person may call for different treatment at different agesor in different settings. Third, all readers need to be aware of the times at which more invasive interventions are more appropriate. The Publisher, the Editors, and the Contributors do not assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this textbook. The reader is advised to check the appropriate literature and the product information currently provided by the manufacturer of each therapeutic substance to verify dosages, the method and duration of adminstration, or contraindications. It is the responsibility of the treating practitioner, reyling on independent experience and knowledge of the patient, to determine dosages and the best treatment for the patient. There is no substitute for individualized diagnosis and treatment. This peronalized approach is at the heart of naturopathic medicine. Theses recommendations are particularly imporant for new forms of treatment and for rare or serious health promblems. Most of the laboratory procedures presented in Section 2 are on the cutting edge of our understanding of the assessment of the physiological function of metabolically inique individuals. As an emerging field, few experts exist and most are employed by the commericals laboratories providing the procedures. The following is a list of the Textbook authors employed by laboratories providing theses test: Stephen Barrie, ND J. Alexander Bralley, PhD Richard S. Lord, PhD Carl P. Verdon, MS, PhD Aristo Vojdani, PhD, MT Printed in China The publisher's policy is to use paper manufactured from sustainable forests
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Contributors
Steve Austin ND Chief Science Officer, HealthNotes Inc, Portland, Oregon, USA Stephen Barrie ND President, Great Smokies Diagnostic Laboratory, Asheville, North Carolina, USA Robert Barry ND Private Practitioner, Seattle, Washington, USA Peter Bennett ND Chief Medical Officer, Helios Clinic, Saanichton, British Columbia, Canada Jeffrey S. Bland PhD Chief Executive Officer of HealthComm International Inc., Tacoma, Washington, USA Jennifer Booker ND Private Practitioner, Olympia, Washington, USA Randall S. Bradley ND DHNAP Private Practitioner, Omaha, Nebraska, USA J. Alexander Bralley PhD Chief Executive Officer, MetaMetrix Clinical Laboratory, Norcross, Georgia, USA Donald J. Brown ND Editor, Quarterly Review of Natural Medicine, Seattle, Washington, USA Qiang Cao MD(China) ND LAc Professor, Acupuncture and Oriental Medicine, Bastyr University, Kenmore, Washington, USA Leon Chaitow ND DO Practitioner and Senior Lecturer, Centre for Community Care and Primary Health, University of Westminster, London, UK Anthony J. Cichoke MA DC Director, Wellness Institute, Portland, Oregon, USA George Wm Cody JD Instructor, Jurisprudence, Bastyr University, Kenmore, Washington, USA Walter J. Crinnion ND Director, Healing Naturally Inc, Kirkland, Washington, USA; Instructor, Department of Environmental Medicine, Bastyr University, Kenmore, Washington, USA Beth DiDomenico ND Federal Way Naturopathy, Federal Way, Washington, USA Patrick M. Donovan ND Naturopathic Staff Physician, Seattle Cancer Treatment and Wellness Center; Private Practitioner, University Health Clinic, Seattle, Washington, USA Cathryn M. Flanagan ND Private Practitioner, Old Saybrook, Connecticut, USA Alan R. Gaby MD Professor, Nutrition, Bastyr University, Kenmore, Washington, USA Kjersten Gmeiner MD
Research Assistant, Bastyr University, Kenmore, Washington, USA Mark D. Groven ND Faculty, Physical Medicine, Bastyr University Natural Health Clinic, Kenmore, Washington, USA Kathi Head ND Senior Editor, Alternative Medicine Review; Technical Advisor, Thorne Research, Dover, Idaho, USA Gregory S. Kelly ND Private Practitioner, Stamford, Connecticut, USA Richard Kitaeff MA ND DAc Naturopathic Physician, Acupuncturist and Director, New Health Medical Center, Edmonds, Washington, USA Allen M. Kratz PharmD Chief Executive Officer, HVS Laboratories Inc, Naples, Florida, USA Elizabeth Kutter PhD Faculty, Evergreen State College, Olympia, Washington, USA Andrew Lange ND Private Practice, Boulder, Colorado, USA Martin J. Lee PhD Lee Research Laboratory, Asheville, North Carolina, USA Buck Levin PhD RD Professor, Nutrition, Bastyr University, Kenmore, Washington, USA Douglas C. Lewis ND Instructor, Physical Medicine, Bastyr University, Kenmore, Washington, USA Richard S. Lord PhD Chief Information Officer, MetaMetrix Inc, Norcross, Georgia, USA Dan Lukaczer ND Director of Clinical Research, Functional Medicine Research Center, HealthComm International, Gig Harbor, Washington, USA Bobbi Lutack MS ND Private Practitioner, Evergreen Natural Health Clinic, Seattle, Washington, USA Stephen P. Markus MD Private Practitioner, Moss Bay Center for Integrative Medicine, Bellevue, Washington, USA Robert M. Martinez DC ND Private Practitioner, Kirkland, Washington, USA Alan L. Miller ND Senior Editor, Alternative Medicine Review; Senior Technical Advisor, Thorne Research, Dover, Idaho, USA Gaetano Morello ND Lecturer, Consultant and Private Practitioner, West Coast Clinic of Integrative Medicine, Vancouver, British Columbia, Canada M. Harrison Nolting ND LAc Associate Professor, Acupuncture and Oriental Medicine, Bastyr University, Kenmore, Washington, USA Lara E. Pizzorno MA (Divinity) Medical Writer and Editor, Seattle, Washington, USA Terry A. Pollock MS Clinical Services Director, MetaMetrix Clinical Laboratory, Norcross, Georgia, USA Dirk Wm Powell ND Private Practitioner, Kent, Washington, USA; Faculty, Bastyr University, Kenmore, Washington, USA
Peter T. Pugliese MD President, Peter T. Pugliese and Associates, Reading, Pennsylvania, USA Paul Reilly ND Private Practitioner, Tacoma; Clinical Staff, Seattle Cancer Treatment and Wellness Center, Seattle, Washington, USA Corey Resnick ND Chief Technology Officer, Tyler Encapsulations, Gresham, Oregon, USA Nancy Roberts ND Private Practitioner, Seattle, Washington, USA Sally J. Rockwell PhD CCN Nutritionist, Seattle, Washington, USA Robert A. Ronzio PhD Laboratory Director, Biotics Research, Houston, Texas, USA John F. Ruhland ND Research Assistant, Bastyr University, Kenmore, Washington, USA Trevor K. Salloum ND Private Practitioner, Kelowna, British Columbia, Canada Alexander G. Schauss PhD Director, Natural and Medicinal Products Research, Life Sciences Division, American Institute for Biosocial and Medical Research, Tacoma, Washington, USA Michael A. Schmidt PhD CNS Visiting Professor, Applied Biochemistry and Clinical Nutrition, Bellingham, Washington, USA David K. Shefrin ND Private Practitioner, Beaverton, Oregon; Chair, Board of Trustees, Southwest College of Naturopathic Medicine and Health Sciences, Tempe, Arizona, USA Virender Sodhi MS(Ayurveda) ND Medical Director, Ayurvedic, Naturopathic Medical Clinic, Bellevue, Washington, USA Nick Soloway LMT DC LAc Private Practitioner, Helena, Massachusetts, USA Leanna J. Standish ND PhD Principal Investigator, Bastyr University AIDS Research Center, Bastyr University, Kenmore, Washington, USA Carl P. Verdon PhD Vice President, Science and Development, MetaMetrix Inc, Norcross, Georgia, USA Aristo Vojdani PhD MT Director of Immunosciences Laboratory Inc, Beverly Hills; Associate Professor, Department of Medicine, Charles Drew University, Compton, California, USA Terry Willard PhD President of Canadian Association of Herbal Practitioners; Director, Wild Rose College of Natural Healing, Calgary, Alberta, Canada
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Preface
The scientific support for the philosophical and therapeutic foundation of natural medicine has evolved remarkably over the past 25 years. Concepts that were once considered “quaint” at best, are now recognized as fundamental to good health and the prevention and treatment of disease. This textbook, with its some 10 000 citations to the peer-review research literature, provides well-documented standards of practice for natural medicine. Based on a sound combination of philosophy and clinical studies, this work provides the astute practitioner with a reliable informational resource to provide health care that identifies and controls the underlying causes of disease, is supportive of the body’s own healing processes, and considerate of each patient’s unique biochemistry. The Textbook is composed of six Sections, each focused on a fundamental aspect of the practice of natural medicine. “Philosophy of natural medicine” covers the history and conceptual basis of natural medicine. “Supplementary diagnostic procedures” provides a primer on diagnostic procedures not commonly taught in conventional medical schools. Diet analysis, food allergy testing, immune function assessment, fatty acid profiling, and hair mineral analysis are examples of these analytical procedures. The next section, “Therapeutic modalities”, provides a descriptive, practical, scientific, and historical review of the common modalities of natural medicine, including botanical medicine, nutritional therapy, therapeutic fasting, exercise therapy, hydrotherapy, counselling, acupuncture, homeopathy, and soft tissue manipulation. “Syndromes and special topics” considers underlying issues relevant to many diseases. “Pharmacology of natural medicines” covers the pharmacognosy, pharmacology and clinical indications for the most commonly prescribed botanical medicines, special nutrients, and other natural agents. Finally, “Specific health problems” provides an in-depth natural medicine approach to over 70 specific diseases and conditions. The comprehensive therapeutic rationales are well documented and based on the pathophysiology and causes of each condition. Kenmore, 1999 Joe Pizzorno Michael Murray
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Section One - Philosophy of natural medicine
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Chapter 1 - Functional medicine in natural medicine Buck Levin PhD RD Michael A. Schmidt PhD CNS Jeffrey S. Bland PhD
PART I: THE PHILOSOPHY OF FUNCTIONAL MEDICINE
INTRODUCTION This textbook bears witness to the remarkable evolution of naturopathic medicine in the USA since Benedict Lust first opened his American School of Naturopathy at the end of the 19th century. During the intervening century, naturopathic physicians have become recognized as primary health care providers in about one-fourth of all states; naturopathic practice has become part of publicly funded clinics, and accredited training has become available in all regions of the country. In addition, naturopathic philosophy has influenced medical philosophy as a whole, including the functional approach which we have espoused in our own work. Naturopathic recognition of key medical principles, including tolle causam (identify and treat the causes), primum non nocere (first do no harm) and docere (doctor as teacher), has helped us clarify our vision of a functional approach to health which derives from a patient-centered, self-care, outcomes-based model. Through functional medicine, we have worked to develop an approach to health care which can be incorporated into the everyday practice of all health care practitioners regardless of training or specialty. Moreover, we have tried to carve out an approach which capitalizes not only upon the foremost accomplishments of basic and applied science, but also upon the strengths of specialty fields and specialized approaches to clinical practice. It is our hope that naturopaths, osteopaths, chiropractors, medical doctors, nutritionists, dietitians, herbalists, homeopaths, acupuncturists, Ayurvedic physicians, and other diversely trained practitioners will be able to find in functional medicine an approach which naturally extends and enhances their current practice. Functional medicine is not an “alternative” approach which requires a change in basic clinical orientation or political allegiance. It requires only a willingness to take
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seriously one’s basic medical philosophy, and to engage the science of our time with the spirit of true discovery, open-mindedness, and due diligence. In this chapter, we specifically address the consequences of such an approach for naturopathy and its clinical practice.
THEORETICAL ASPECTS The philosophy of function in a medical context Most dictionary definitions of “function” indicate that the word is derived from the Greek term ergon, which means “the kind of action or activity proper to a person or thing; the purpose for which something is designed or exists”. [1] This definition tells us the concept of function must be viewed in the same category as the concepts of “purpose” and “design”. It tells us we cannot understand the function of a person or thing without also understanding the purpose for which that person or thing is designed. In early Greek philosophy, the term ergon was frequently contrasted with the term pathemata– things that happened to a person or thing. [2] This comparison focused on the difference between things with the capacity to act ( poiein) and things that were, in contrast, “passive activations” ( pathe).[2] En-ergia – being in activity, or functioning – was considered to be the telos (end purpose) of being alive. Today, when we refer to disease as “pathology-based”, we are actually linking disease, etymologically, to this realm of pathemata and pathe. We are defining disease as something that “happens to” a person, something that is not a part of that person’s purposeful activity. Etymologically, the term “functional medicine” moves us away from this pathological model and aligns us with a medicine that views disease as part of something that is purposeful and is proceeding actively in accordance with some design. The history of philosophy – at least as far back as the writings of Aristotle in the third century BC – has witnessed an ongoing debate between “vitalistic” and “mechanistic” approaches to life and health. Naturopathic medicine has consistently aligned itself with the vitalistic side of this argument. Naturopathy recognizes a vital force – vis medicatrix naturae, or healing power of nature – that is present in all living things, including the human body. For naturopaths, it is this vital force which is ultimately responsible for healing. The functional medicine emphasis on purpose and design is closely related to this recognition of vital force in naturopathy. When functional practitioners recognize purpose and design in physiological events (including “disease of unknown origin”), they are acknowledging that body function is guided by a universal, supra-individual set of principles. They are acknowledging that physiological function originates from an infinite, complex, patterned matrix of occurrences which both precede and transcend individual human experience. The purpose and design of functional medicine therefore echo the spirit of vitalism. This spirit of vitalism does not mean, however, that the healing force is totally mysterious or unapproach-able. While the universal, patterned matrix of events is infinite and cannot be fully understood, it is nevertheless a complex pattern which can be observed and analyzed within the limits of a human perspective. Pursuit of this possibility is essential to a functional approach. The more that can be learned about the patterned matrix of universal events, the better able is the practitioner to support healing. The terms “form” and “function” are probably most familiar to us from the field of architecture. At the turn of the 20th century, US architect Louis Sullivan coined the phrase “form follows function”, recognizing that purpose precedes the blueprint. But in our philosophy of the body’s architecture, how do these terms apply? In the case of several body systems – the musculoskeletal system or the circulatory system, for example – shape and form give an initial hint about function, design, and purpose. It is difficult to observe the body’s skeleton without concluding that it has been designed for structural support. With other physiological systems, these connections are not nearly so obvious. Phrenology, described by English historian J. C. Flugel a century after its origin as “psychology’s greatest faux pas”, argued that the quality of a person’s mental faculties was determined by the size of the brain area upon which those faculties depended, and this quality could be judged by the contours of the skull adjacent to
the area. [3] This literal equating of brain function with brain form, proposed in 1810 in Paris by Francois Joseph Gall and his student J. C. Spurzheim, met with some immediate difficulty in application. After discovering that the skull of French philosopher René Descartes was particularly small in the anterior and superior regions of the forehead, understood to be the seat of a person’s rational faculties, Spurzheim reportedly commented: [3] “Descartes was not so great a thinker as he was held to be.” The inability of phrenologists to make sense of function by reference to form alone is one example of a difficulty that continues to permeate 20th century medicine. Naturopathy has made great strides in linking form with function, by accommodating into its practice long-standing medical traditions which treat function by working with form. Naturopathy’s embrace of physical medicine – from craniosacral therapy and osseous manipulation to hydrotherapy and physiotherapy – has made the connection between form and function more accessible. A final common ground between functional and
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naturopathic medicine involves the very idea of a “medical philosophy”. The need for practical solutions in everyday medical practice is great (so great that most practitioners will not see themselves as having the time – or inclination – to “philosophize”). Yet from a functional and naturopathic perspective, it is impossible to approach health without paying continual attention to one’s philosophy of medicine. In the remainder of this section, we look at several examples of philosophical thinking that we believe continue to represent stumbling blocks for an integrated 21st century medicine. Each of these examples thinks “dualistically” about medical concepts and in so doing, we believe, loses sight of function. Function as a mediator for opposition thinking in the sciences Part/whole
The traditional philosophical dualism of “part/whole” has been directly addressed in the field of holistic health. Two national organizations – the American Holistic Health Association (AHHA), with headquarters in Anaheim, California, and the American Holistic Medical Association (AHMA), located in Raleigh, North Carolina – have each referred to this dualism in defining their field of study. According to the American Holistic Health Association: [4] Rather than focusing on illness or specific parts of the body, holistic health considers the whole person and how it interacts with its environment. It emphasizes the connection of body, mind, and spirit. Holistic Health is based on the law of nature that a whole is made up of interdependent parts. The earth is made up of systems, such as air, land, water, plants, and animals. If life is to be sustained, they cannot be separated, for what is happening to one is also felt by all of the other systems. In the same way, an individual is a whole made up of interdependent parts, which are the physical, mental, emotional, and spiritual. When one part is not working at its best, it will impact all the other parts of that person. Further, this whole person, including all of the parts, is constantly interacting with everything in the surrounding environment. And according to the American Holistic Medical Association: [5] Wellness is defined as a state of well-being in which an individual’s body, mind, emotions, and spirit are in harmony with and guided by an awareness of society, nature, and the universe. … [It] encompasses all safe modalities of diagnosis and treatment, including the use of medications and surgery, emphasizing the necessity of looking at the whole person. On its Internet website, the AHMA states: [6] “Optimal health is much more than the absence of sickness. It is the conscious pursuit of the highest qualities of the spiritual, mental, emotional, physical, environmental, and social aspects of the human experience.” With respect to their characterization of “part” and “whole”, these definitions of holistic medicine are largely compatible with a functional approach. Because the concept of function asks us to consider why a thing is here, i.e., what it is “doing” in the universe, it asks us to be holistic and take into account the holon – which in early Greek philosophy meant both “universe” and “organism”. Wholeness becomes a necessary concept for understanding function, and holistic medicine has done medical philosophy an important service by renewing its focus on the whole. At the same time, we invite supporters of holistic medicine to consider an extension of their philosophy in two ways. First, we invite consideration of a multi-level understanding of wholeness that does not predetermine a frame of reference or specific context in which wholeness is to be evaluated. For example, if we do not presently know whether planetary indices of geomagnetic disturbance – such as sunspot relative number, area, and geomagnetic activity – are as valuable a “whole” or “universe” against which to evaluate and treat cardiovascular disease as homocysteine imbalances (the “whole” or “universe” of the cell) or “heartlessness” and “disheartenment” (a psychological or sociocultural “whole” or “context”), we might expect to benefit by keeping a radical open-mindedness about frames of reference, levels of wholeness, and their ultimate interrelationship in a holistic model. Instead of trying to simplify with three or four frames of reference based on early 20th century psychology (i.e., wholeness as the sum of physical, emotional, mental, and spiritual frames of reference) or a few contexts based on specialty (physical body, immediate external environment, global environment), we might simply postpone such conclusions until we learn more about levels of wholeness and their relationship. From a functional perspective, we suspect this relationship will closely resemble the one described by US engineer, designer, and architect, Buckminster Fuller, in his discussion of “functions” in his 1975 opus, Synergetics:[7] “Functions occur only as inherently cooperative and accommodatively varying subaspects of synergistically transforming wholes.” The relationship of part to whole is a second area in which a holistic perspective could be logically extended. We believe the concept of function necessitates a view of “part” and “whole” that is quite different from the image of a disassembled jigsaw puzzle or a shattered china teacup, which can be reassembled or glued back together to re-establish the “whole” from which it came. In both of these examples, the parts have a visible connection to the whole, but in and of themselves are a diverse array of pieces in all shapes and sizes, bearing no individual resemblance to the whole from which they came. From a functional perspective, we believe this image of part and whole should be changed. Instead of
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a shattered teacup or a disassembled puzzle, we propose a shattered hologram. When a hologram breaks, it does not shatter into discrete pieces with different sizes and shapes that individually bear no resemblance to the original hologram. It splits into separate pieces, each of which visibly contains the complete and original hologram. From a medical perspective, this change means that we would stop assigning partial functions to anatomically distinct body parts or systems and begin treating all parts as visibly containing the original hologram, i.e., whole-body capability. For example, we have traditionally viewed the gastrointestinal (GI) tract, brain, and immune system as separate, identifiable parts unable to carry out each other’s basic functions. In the case of the GI tract, these functions have traditionally been limited to digestion, absorption, secretion, and motility. We now know the GI tract has its own immune system (GALT) and its own brain (memory T-cells disseminated to the intestinal epithelium and lamina propria providing the functional basis for oral tolerance), [8] and that it can carry on functions traditionally reserved for other systems of the body. Similarly, we now recognize that the eye does not simply “see”. We know it helps set the body’s circadian rhythms through the production of melatonin, [9] and that it may therefore coordinate reproductive signaling as well. [10] These findings encourage recognition of the whole inside each part. Equally encouraging have been the many “reflexologies” that have dotted the landscape of alternative medicine, and which have been given open-minded consideration in naturopathy – foot reflexology, iridology, intestinal reflexology in colonics, contact reflex analysis – each pointing toward a “shattered hologram” model in which the unbroken whole is visible in its seemingly separate parts. Inside/outside
The classic debate over nature vs. nurture, heredity/environment, and genetics/experience has had troublesome consequences for a patient-centered approach to well-being. We have seen what can happen when the “insides”, in their purest form, are equated with the chromosomal material inside the nucleus of the cell. What can happen is a philosophy of development that treats the three billion base pairs in the human genome as a largely unalterable blueprint working from the inside to define a person’s potential with respect to the “great taskmaster outside”, i.e., the environment. This extremist view of inside/outside, equating inside – the true “inner sanctum” – with the gene, has given us a national eugenics movement based on misinterpretation of ethnic differences in IQ, a national backlash against elementary school “mainstreaming” based on misinterpretation of learning disorders, and a popular anthropology of racial difference based on misinterpretation of the anthropological facts. Two examples from the history of biology can help place the dualism of “inside/outside” in a more functional context. The first example involves a chapter of a book written by Swiss zoologist Adolph Portmann in 1967. In his chapter, titled “The Outside and the Inside”, Portmann writes: [11] Biologists … have worked from the outside inwards, from what is visible and tangible to what is more and more deeply hidden. … But such probing makes us strangers to the appearance of the living creatures around us. … With a knowledge of the developmental conditions under which, for instance, a feather primordium develops and its pigment is formed, it is only the problem of shape that has been solved. But it still remains to be shown what brings about that special distribution of color in the pattern on the feather germ which is specifically directed towards the whole form in its final condition. In his book, Portmann argues that outsides of animals are in fact expressions of their inwardness, i.e., their developmentally unfolding uniqueness and individuality. He also concludes that the ultimate purpose of this “insides-becoming-outsides” is to help living creatures find each other and “break the ban of isolation”. [11] What we hear in Portmann’s writing is a desire to blur (or even erase) the line between inside and outside. What is innermost “feels a desire” to become outermost, and for the purpose of connecting up with the innermost sanctum of another. As health care practitioners, we are all familiar with the notion of a milieu interieur – an interior, homeostatic, calm harbor maintained in the wake of outside, stormy seas. Pasteur’s contemporary, Claude Bernard, first wrote about this concept in 1865 in his classic text An Introduction to the Study of Experimental Medicine,[12] and it still serves as a cornerstone of our understanding of cellular events. But what we are not familiar with, in this second example, is the extent to which Bernard was forced to dismiss the relevance of purpose and design in positing the milieu interieur:[12] Neither physiologists nor physicians need imagine it their task to seek the cause of life or the essence of disease. That would be entirely wasting one’s time in pursuing a phantom. The words life, death, health, disease have no objective reality. Sickness and death are merely a dislocation or disturbance of the mechanism which regulates the contact of vital stimulants with organic units. It is, of course, the interior milieu that regulates this contact. But by making such an absolute division between inside and outside, Bernard ends up placing all responsibility and focus on this “mechanism” that connects “in” with “out”, and turning his back on the purpose and essence of life/death and health/disease. Both of these examples caution us against drawing
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absolute lines between inside and outside. So does the concept of function itself. When we recognize that function requires purpose – some goal or end-point toward which activity is directed – we are also recognizing that function requires potential, a goal or end-point that is capable of being reached but has not yet been attained in actuality. Without potentiality, there is no function. In functional medicine, no question is more critical than the question of this potentiality and its “location”. To what extent is potential “inside” of us, inside of our cells, our thought, our genes? How are “outside” events related to this potential? In immunology, at least since the end of World War II, we’ve developed a self/non-self model that is forcing us to relabel long lists of diseases as diseases of autoimmunity, diseases in which the distinction between self and non-self has become confused. But from a functional perspective, an absolute division between self and non-self is a too-literal separation of inside from out. Autoimmune diseases cannot be a set of inside, interior dynamics in which “self” mistakes “self” for “non-self” and self-destructs. If this were the case, we wouldn’t be discovering all the risk factors for autoimmune disorders on the outside, removed from the self . Yet that is exactly where we are finding them. The 17-amino acid sequence in bovine serum albumin that travels from cow’s milk formulas to pancreatic beta- cell surface proteins (protein 69) and increases risk for the autoimmune disease we call juvenile-onset diabetes,[13] the links between xenobiotic exposure and systemic lupus erythematosus, [14] and the newly designated “autoimmune polyendocrine syndromes” and their responsiveness to dietary modification are all examples that point to dangers outside the self and their key role in the development of autoimmune disease. But it is not only negative potential that gets locked outside the self when we draw a line too absolutely between inside and out; it is positive potential as well. Function requires purpose. Purpose requires potential. To be “pluri-functioning” organisms, we must also be “pluri-potential”. And because the unbroken whole is visible in the parts, this pluripotential must reside in the parts as well, even in that innermost part we call the human genome, locked away inside the nucleus of the cell. Molecular medicine is teaching us that there is no untouchable inside. Our outside experience – including our dietary intake – continually modifies the expression of our genes. Control of gene expression is highly encrypted, i.e., genes have inducer binding sites and promoter sequences that modify their expression. Numerous nutritional components have been shown to modify that expression, including linoleic and alpha-linolenic acid, isoflavones, quercetin, ellagic acid, vitamin A, and vitamin B6 .[15] The potentiality is ever-present, even when IQ suggests otherwise. At our innermost, genetic selves, we are always also outside of ourselves, linked to wholes through our potential. Cause/effect
In the fourth century BC, in a treatise entitled Physica, the Greek philosopher Aristotle described a doctrine of four causes: formal cause ( eidos), producing in a thing its constitutive essence; material cause ( hyle), providing a thing with its matter and embodiment; efficient cause ( kinoun), initiating change in a thing; and final cause (telos), providing an ultimate purpose for the change. Since the word “cause” has several meanings, Aristotle wrote: “It follows that there are several causes of the same thing (not merely in virtue of a concomitant attribute), e.g., both the art of the sculptor and the bronze are causes of the statue.” [16] What appears treatable or preventable to us as practitioners depends entirely on our philosophy of medicine. Whether dysfunction is treatable or preventable depends on what caused the dysfunction in the first place, i.e., on our concept of causality. Keith Block, MD, medical director of the Cancer Institute at Edgewater Medical Center in Chicago, Illinois, has recently argued that the labeling of any cancer as “terminal” is both scientifically and spiritually unjustifiable. [17] His argument is based on a view of cancer causality that includes an active role for the self in deciphering and acting upon the cosmic event that cancer represents. But the views of Aristotle and Block, welcoming a complex view of causality into our understanding of health, are far from our classic heritage in the sciences. As French Nobel Prize winner Jacques Monod wrote, in his classic 1970 work Chance and Necessity: The cornerstone of the scientific method is … systematic denial that “true” knowledge can be got at by interpreting phenomena in terms of final causes – that is to say of “purpose”. [18] Against this notion, this powerful feeling of destiny, we must be constantly on guard. [18] Monod’s philosophy is our reigning medical philosophy – a philosophy steeped in the Darwinian legacy of a universe with minimal original essence, minimal momentary stability, and an indefinite horizon of possibilities. [19] It is a philosophy that tells us we must be careful when reading purpose into dysfunction, and that we should accept whole categories of disability and death as purposeless, chance events that are essentially not preventable.
Naturopathy, with its focus on prevention, has helped to transform this perspective. Most naturopaths would readily subscribe to the mission statement of the Foundation for Preventive Medicine, based in New York City, when it describes its mission as “enhancing the public’s awareness of recent information indicating that most
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causes of death in our society … are now regarded as potentially preventable”. Preventive, functional, and naturopathic medicine all seem to agree that lack of well-being, lack of vitality, depression, and deficiency in energy are also associated with largely preventable conditions, [20] and that each time we transfer a health condition from the category of “not preventable” to “preventable”, we are honoring our medical philosophy. Energy/matter
As scientists, most of us subscribe to an energy-based view of human function. We believe that healthy function rests on the shoulders of gated ion channels, electrolyte balance, membrane potential, redox, electrochemical gradients, and high-energy phosphate bonds. In our view, the release of heat energy from cells is what makes biological order actually possible in the first place. [21] Yet in spite of its acceptance at a biological and biochemical level, this energy-based paradigm has yet to become fully integrated into our medicine. While electrocardiographic, magnetic resonance, and single photon emission imaging have become standard parts of our diagnostic repertoire, electroacupuncture biofeedback devices, despite their research record and use in many countries, [22] remain unapproved for clinical use in the USA. Once again, naturopathic medicine has provided leadership in this area. Energy-based medicine has been given open-minded consideration in naturopathy, and whole traditions based on principles of energy, including acupuncture and Oriental medicine, have been treated as essential areas for understanding and research. Similarly, acceptance of homeopathy, an energy-based medicine used by a quarter of a million practitioners worldwide, [23] has been nurtured in the USA by the supportive position adopted by naturopaths and naturopathic institutions. From a functional perspective, the rightful place of “energy medicine” in health care approaches is woven into the term “function” itself, which derives from the Greek en-ergia, literally “functioning” or “being in activity”. But clearly, as practitioners, we are just starting to explore this energy–matter relationship in our medical philosophy. In nutrition, for example, we are just beginning to shed our 19th century steam engine model, which perceives the body as a large furnace combusting matter (food) for the sake of extracting caloric energy. In this model, energy is not useful unless extracted out of matter, and matter, once depleted of its energy, is of little use as well. This food-as-fuel model has left us with an under-appreciation of food’s matter and its energy. As raw material for caloric extraction, food becomes most important for its gross, undifferentiated macronutrient content – its 20 g of fat or 100 g of carbohydrate. Subtler distinctions involving omega 3:omega 6 or oligosaccharide:polysaccharide ratio have been slow to evolve. Likewise, food energetics – including the issues of raw food, live food, food enzymes, and active cultures – have been negligibly addressed. Interestingly, we are finding the role of light – in the form of food pigments, including the hemes, chlorophylls, carotenoids, and flavonoids – is slowly revolutionizing our approach to food in the same way that light (and the frame of reference it represented) revolutionized our approach to mass and energy in physics. Body systems from a functional medicine perspective Historical and philosophical perspective
Students of science and medicine in the USA and other Western countries learn anatomy and physiology from a systems approach. They learn to view organ systems, individual organs, tissues, cells, and subcellular spaces as separate entities that interact with one another to create form and function. The better one understands any one system or entity, by this model, the more skilled one will be at treating dysfunction of that entity. This model served well in developing a rational method of inquiry into the etiology of many diseases. Indeed, the advancement of medical science has long been measured by progress made in understanding the mechanisms of disease related to dysfunction in the body’s distinct compartments. Fundamental to the systems model has been the assumption that the more we know about individual organs or systems, the better our medicine will be. Until very recently, this assumption had been widely validated throughout medical history by remarkable progress in diagnosis and treatment of disease, surgical practice, and the development of medications for symptom reduction related to specific diseases. The progress that resulted from this compartmentalizing approach can be compared to advances in biology that followed Linnaeus’s development of a system of taxonomic classification of living organisms in the 18th century. The formalized system of learning allowed for significant advancement in the field of biology. By the 1970s, however, many biologists had become aware of the limitations of description and classification as an epistemology. Their science had outgrown the model. Through advancements in the disciplines of ecology and environmental science, they knew they could classify all the plants and animals in an ecosystem and yet understand nothing about the functioning of the ecosystem as an integrated whole. The need had arisen to address the larger issues of how compartments within the ecosystem interacted to give rise to its function and survival.
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From the perspective of these advancements in biology, one could view medicine as a specialized discipline within the broader field of human ecology. To understand health and disease, one would be required to examine the functional interaction of organ systems with the human environment. Furthermore, one would have to observe the functional interaction between the total human environment and the energy processing and control systems within it. Examining any discipline from a new point of view makes it possible to ask new questions and gain new insights. Looking at human health and medicine from the point of view of interactive function raises questions about the homeodynamic interplay between the external and internal environments of the individual. The functional viewpoint is the longer, larger view; it moves away from the narrow focus on pathology of various parts of the body. It removes the principal focus from diagnosis of pathology and places it on evaluation of genetic pluripotential and its translation into homeodynamic function. It views disease not as an enemy with which to grapple, but as a manifestation of the breakdown of mechanisms that establish control and resilience. To restore these processes, functional medicine uses a broader range of methods than the cut-and-paste tools of compartmentalized medicine. Among others, it employs nutrition, environmental adaptation, lifestyle changes, activity or stress pattern adjustment, or molecular pharmacology, and its selection of tools is based on the unique needs of the individual. The traditional anatomy/physiology model of Western medicine still has great value in diagnosis and treatment, and it has wide application in responding to many specific disease states. This traditional model breaks down, however, when it is applied to chronic conditions that transcend individual organs or organ systems. Among these chronic health problems are inflammation, fatigue, pain, immune dysfunction, and problems of digestion. All of these conditions are characterized, not by end-stage pathologies, but by altered physiological function, and they require a more integrative model to design a therapeutic approach that can improve long-term outcome. This more integrative model is built upon the understanding that dysfunction is not compartment- or organ-specific, but is an alteration in integrated homeodynamic processes. The functional medicine approach incorporates evaluation of antecedents to a health problem, its triggering factors, mediators of altered physiological function, and the relationship to signs and symptoms, to develop an integrated view of the patient’s health status. It focuses less on defining the disease and more on understanding the functions that give rise to the expression of symptoms. A woman may approach her physician complaining of chronic intestinal pain and symptoms of irritable bowel syndrome, for example. A medical history and initial evaluation might uncover other symptoms, including joint pain, headache, low energy, sleep disturbances, and eczema. Rather than coming up with a primary and secondary diagnosis and prescribing symptom-relieving medications, a functional medicine practitioner would delve further in evaluating the source of the inflammation. The practitioner might assess gastrointestinal function, hepatic detoxification ability, and immunological status, and assess their relationship to oxidative stress mediators. Based on this “second tier” of assessments, the practitioner would develop an integrated approach to modify triggers and mediators using specific
biological response modifiers and lifestyle alterations of the individual. Systems integration and functional medicine
The emerging science of today has blurred distinctions among organs, and separation of function into distinct compartments is less useful as a concept. We now know, for example, that identical signalling molecules are released and received by all organ systems, and each influences the function of the others. The view of the body as a collection of separate, interconnected parts is being replaced by an image of the body as a hologram. The endocrine system synthesizes a neurotransmitter that is released by the nervous system and has a receptor site on the white blood cell. A blood cell synthesizes cytokines that are released by the immune system and have receptor cites on the glial cell in the brain. The liver synthesizes steroid hormones that are released by the endocrine system and have immune and nervous system receptors, and vice versa. In other words, all the organs and organ systems of the body are constantly engaging in “cross-communication”, which makes distinctions among them a matter of definition rather than function. In the past 10 years, medicine has witnessed a revolution in molecular biology. We now know, for example, that modifiers of gene expression are produced not only by different organs but also by exposure to various agents in the diet and environment, including chemicals and electromagnetic radiation. We have learned that the processes that give rise to an individual’s health or disease are not controlled by genes alone. Instead, modification of function comes about through alteration in gene expression, transmitting new physiological messages about individual regulation and control. This new view of health focuses on maintaining metabolic and homeodynamic freedom based on interconnectedness, pluripotential, diversity, and redundancy of function. Loss or decline in any of these parameters can be seen as an altered state of health. Altered physiological diversity, for example, translates to a loss of metabolic freedom and a subsequent state of lower
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health reserve. Assessing health, therefore, depends on measuring this reserve rather than evaluating pathology. Functional challenge tests, an integral part of the practice of functional medicine, make it possible to measure specific reserves under conditions of stress. Examples of functional tests include the exercise treadmill test for cardiac function, oral glucose tolerance testing for blood sugar management, and food provocation challenges for food sensitivity. Functional medicine practitioners use the patient as his or her own “universe”, or point of reference in which his or her unique set of interconnections, potentials, diversities, and redundancies is realized. Whether changing conditions involving time, temperature, electro-magnetic energy gradients, infective organisms, or trauma will lower degrees of metabolic freedom is a question that can be answered only in the context of the individual and his or her ability to maintain reserve and avoid reduced stability that comes from lost potential. Functional medicine focuses on maintenance of stability and pluripotential across organ domains. From this perspective, all organ-specific symptoms the patient possesses at any one moment reflect homeodynamic alterations at a broad, “weblike” level and result in new metastable physiological states characterized by lowered stability and reduced degrees of metabolic freedom and efficiency. The more freedom is lost at this “weblike” level, the more symptoms will become manifest, and the more closely they will resemble classical pathology. It is the integrative, homeodynamic, regulatory role of the web that is being altered, however, not a circumscribed set of functions within a specific organ domain. As a diagnostician, a practitioner might look through a focused lens such as an X-ray, blood chemistry, or CAT scan at an isolated, compartmentalized organ system. As a functional medicine practitioner, however, he or she will view alteration in this seemingly distinct compartment as a reflection of change in the web, the whole of which is the individual and his or her unique life experience in the world.
PART II: THE CLINICAL APPLICATION OF FUNCTIONAL MEDICINE
BASIC CONCEPTS IN FUNCTIONAL MEDICINE PRACTICE The practice of functional medicine is guided by three basic concepts: biochemical individuality, health as positive vitality, and life processes as homeodynamic. Biochemical individuality
Each individual is unique. This uniqueness encompasses voluntary activities, such as decision-making, personality development, and emotional response, and involuntary activities like metabolism of nutrients, cellular processing of information, and communications among the body’s organ systems. The concept of biochemical individuality is central to every aspect of the practice of functional medicine, from clinical assessment and diagnosis to the broad spectrum of treatment modalities. As traditionally practiced, medicine and nutrition have given only token consideration to the concept of individuality. In conditions such as phenylketonuria (PKU) or maple sugar urine disease (MSUD), for example, although medicine has long recognized that specific metabolic aberrations alter the afflicted individual’s nutrition and health needs, it has taken the view that these defects are so rare as to be inconsequential. A functional medicine practitioner, on the other hand, considers that all individuals have unique metabolic patterns that affect their nutrition and health needs. In comparing two individuals whose blood levels of B vitamins are nearly identical, for example, one might have five times as high a level of B vitamins in his or her cells as the other. Individuals also respond uniquely to environmental toxins, food additives, and prescription medications. Health as a positive vitality
Functional medicine views health as more than the absence of disease. Health, in the functional medicine model, is the state of positive vitality unique to each individual within his or her life context. Functional medicine employs new assessment tools to help quantify individual well-being and evaluate his or her physiological, cognitive/emotional, and physical function. Functional medicine practitioners cannot narrowly focus on a patient’s symptoms, complaints, or history of illness. They must also evaluate the patient’s history of wellness by asking when in life the individual has felt best and what circumstances would be necessary to make that patient feel truly well again. Although relief of symptoms might be one goal of the application of functional medicine, the broader goal would be to support vitality in the patient’s life experience. Life processes as homeodynamic
Homeodynamics as a principle of functional medicine contrasts with the concept of “homeostasis” in conventional medicine. Homeostasis describes the balance of interconnected components that keep a physical or chemical parameter of the body relatively constant. Homeodynamics posits a similar control system functioning to maintain biochemical individuality. Applied to the body, the term “homeodynamic” describes
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a range of continuously occurring metabolic and physiologic activities that enable an individual to adapt to changing circumstances, stresses, and experiences. The homeodynamics of one’s health are constantly at work to enable a person to function as a unique individual. Supporting health at a homeodynamic level may require one to focus attention on cellular processes or organ function at sites that seem to be far removed from the patient’s area of discomfort, and at levels that may be unusual from a conventional point of view.
ASSESSMENT AND TREATMENT FROM A FUNCTIONAL PERSPECTIVE Healing practices in any society evolve within a cultural context and draw upon the belief systems and resources of the healers within that culture. In traditional societies, the background and support of healing derive from the natural world. In industrialized societies, evolving in a framework erected by Newton and Descartes, medicine formed a different understanding of the body and its function. The term “diagnosis” derives from the Greek word diagnosis, which means, literally, “through gnosis, through the knowledge gained through a perspective”. In conventional Western medicine, diagnosis is defined as “the art of distinguishing one disease from another” or “the determination of the nature of a case of a disease”. Clinical diagnosis is “diagnosis based on symptoms, irrespective of the morbid changes producing them”. Differential diagnosis is “determining which of two or more diseases or conditions a patient suffers from, by systematically comparing and contrasting their symptoms”. Key concepts in these definitions are “disease”, “symptoms”, and “suffers from”, and analysis of these concepts yields clues to the philosophical perspective underlying the Western medical approach to managing health. This underlying perspective is the key factor that differentiates one healing system from another. It is the basis by which we examine patients and develop our plan of action or treatment. A physician whose perspective is oriented toward pharmacology views patients in terms of what drugs are needed. A nutritionist might look for specific nutrients or dietary changes that would benefit patients. A psychotherapist might ask which form of counseling or behavioral intervention is warranted. In each case, the course of action is dictated by the practitioner’s underlying perspective. The underlying perspective of functional medicine is based on process, dynamics, and purpose. Functional medicine focuses on dynamic processes that underlie and precede the pathological state. Acknowledging the existence and necessity to understand pathology, functional medicine focuses on underlying processes and seeks solutions that address these processes. The practice of functional medicine does not focus on diagnosis that compartmentalizes diseases into known entities. Such a system, although it might be useful, is apt to presume that if we can name a disorder we can understand how it came about. Functional medicine practitioners recognize diagnosit categories, but they also investigate underlying dietary, nutritional, lifestyle, environmental, and psychosocial factors that might alter the patient’s state of health and investigate the “purpose” behind the expression of illness. Illness as information
From the traditional medical viewpoint, illness “happens” to a human being; an outside force upsets a system of the body. The clinician then seeks to discover precisely what it was that caused the illness. Although this method remains a useful view in diagnosis (since a number of factors, including food, chemicals, and microorganisms, affect our homeodynamics), it places constraints on both patient and clinician. On the other hand, if we take the view that the human body is an energy-driven, energy-sensitive system that interacts constantly with its surroundings, we can begin to view illness as a form of communication from one level to a level of conscious awareness. Conscious awareness enables the individual to begin to understand the factors that collectively led to the illness. Because it has a purpose, illness can be seen as a functional condition. It may function as an agent for change. It may itself be an epiphenomenon that requires treatment, but paying heed to the “message” that is being communicated by the illness may be what finally enables healing to take place. Both scientific and popular literature often describe cases of recovery from serious illness that occurred as a result of the individual’s paying attention to the message contained in the symptoms. In clinical practice, illness communicates its messages in many ways, including symptoms arising from exposure to chemicals, rashes or breathing difficulties from consuming food allergens, neck pain from repetitive workplace activity, and stress-induced chest pains. Patients who present with these complaints are all getting messages about their bodies’ interactions with their surroundings. In neurology, occurrences of hysterical blindness or hemiplegia are examples of illness as information. In both conditions, physical symptoms arising from deep psychological problems mimic severe organic disease. [24] In making a diagnosis, the functional medicine practitioner must be aware of the message being sent and approach the patient’s illness not as an adversary to be overcome but as information that must be understood and acted upon.
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Treatment decisions
The experienced practitioner of functional medicine knows that illness typically arises from multiple influences, and his or her assessment and treatment take this array of influences into account. In dealing with a problem like migraine headaches, for example, this approach contrasts with the traditional approach of Western medicine. The latter would identify the symptom pattern, rule out vascular and intracranial pathology, and test for the presence of hypertension or renal disease. Treatment would be with drugs like sumatriptan, propranolol, or ergotamine. Biofeedback might be employed as an adjunctive therapy. The functional medicine practitioner, in contrast, would ask the migraine sufferer about dietary, nutritional, genetic, environmental, lifestyle, psychosocial, or spiritual factors that might be interacting in his or her life. The practitioner would inquire into functional changes that might underlie the expression of migraine symptoms. The goal would be to develop a range of potential patient-centered solutions to migraine headache. Remediation of migraine, for example, has been reported with oral magnesium therapy (M. A. Schmidt, unpublished data), essential fatty acid supplementation (S. Baker, personal communication, 1996), removal of food, chemical, and inhalant triggers, [25] sublingual neutralization therapy, [26] spinal manipulation (P. Bolin, personal communication, 1996), acupuncture, homeopathy, and the botanical feverfew ( Tanacetum parthenium).[27] The functional medicine practitioner might employ any one or a combination of these therapies, realizing that no single approach is effective with all migraine sufferers. Rea[25] found that the headache symptoms of 100% of a group of 30 migraine sufferers were triggered by chemicals under controlled challenge, but these were patients who reported chemical sensitivity. A patient-centered approach that recognizes statistical tendencies and diagnostic categories, but is not constrained by them, is desirable. Another example of the value of the functional medicine approach is in assessing microbe-associated illness. The traditional approach to infectious disease regards the organism as an external threat that must be eradicated by intervention that targets that organism specifically. The microbe is the enemy, and drug therapy is the typical weapon. A broader, functional medicine approach would view the microbe as just one (albeit important) factor contributing to poor health. The functional medicine practitioner would consider the state of the host’s defenses and evaluate factors that influence host defenses by examining nutritional, metabolic, environmental, lifestyle, and psychosocial factors that influence immune vigilance. The philosophical basis of functional medicine leads to treatment decisions that are quite different from those typically encountered in an infectious disease model. For example, a patient with Down’s syndrome who suffers from recurrent infection with S. pneumoniae or H. influenzae may experience an increase in IgG 2 and IgG4 production and a reduction in infection susceptibility with selenium supplementation. [28] A child with otitis media with effusion might be treated not with antimicrobials, but with elimination of allergenic foods. [29] An endurance runner who suffers from upper respiratory tract infection associated with heavy training might be given antioxidants. [30] Concept of total load
Total load refers to the sum of influences affecting an individual’s life. Initially advanced by environmental medicine practitioners, the concept is now widely adopted. Included in the total load are chemicals, food, microbes, psychological stressors, and other factors, each of which alone might not give rise to the symptoms of illness. Together, however, the factors that comprise the total load may overwhelm the patient’s metabolic management system. According to Rea [25] , more than 20,000 patients at his Environmental Health Center in Dallas, Texas, experienced relief of symptoms of a range of clinical disorders through reduction of total load. A person’s biochemical individuality affects his or her susceptibility to toxins, and intervention aimed at improving function can help reduce susceptibility or sensitivity. A defective sulfur metabolism pathway, for example, might cause an individual who reacts to sulfur-rich foods to react to other substances in ways that lead to metabolic disturbance. Nutrient modulation might lessen his or her sensitivity to these environ- mental substances. Efforts to reduce total load should be balanced by efforts to restore function, with the long-term goal being reduced susceptibility.
Depth of action
The functional perspective requires the practitioner to examine the processes that give rise to symptoms. Arriving at a diagnosis does not guarantee that we understand what is happening or what the patient needs. For example, we might arrive at a diagnosis of “mood disorder” in a depressed patient and assume that he or she would benefit from a drug like fluoxetine. If the depression arose from a spiritual or relationship crisis, however, the drug therapy might actually interfere with the problem-solving processes that would lead to true healing. Mood and quality of life might appear to improve with drugs, but the patient’s long-term healing would not have been facilitated. A group of epileptic children who were videotaped as they interacted with their families illustrates the
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point. Emotionally fraught family encounters were, in many cases, followed by seizures. When the epileptic patients were later shown films of these episodes, and they saw the relationship between emotional events and seizures, they were able, in many instances, to become almost seizure-free. [31] Granted, drug therapy might have helped these patients to control seizures, but if drugs were the only means of intervention employed, the epileptic children would not have had the opportunity to experience healing at a deeper level. Mechanism and outcome
Understanding biochemical mechanisms enables functional medicine practitioners to apply them in diagnosis and treatment. Understanding the mechanism of homocysteine accumulation, for example, allows them to recommend nutritional strategies like folic acid and vitamin B 12 therapy. By understanding fatty acid synthesis and the arachidonic acid cascade, they can develop nutritional therapies that modify inflammation. Knowing that copper accumulation leads to Wilson’s disease allows them to utilize zinc therapy. Some treatment modalities bring positive outcomes for which the mechanism is not yet well understood. Spinal manipulation in asthmatics admitted to the emergency room, for example, can lessen anxiety and ease breathing. This treatment typically brings about a 25–70% improvement in measurement of peak blood flow. [32] Using pre- and post-manipulation tympanographs, Fallon showed that spinal manipulation in children with otitis media led to normalization of abnormal tympanograms (J. Fallon, personal communication, 1995). Similarly, Fryman (personal communication, 1996) has shown that cranial manipulation normalizes tympanographic measurements in some children. The knowledge that viscerosomatic and somatovisceral reflexes influence the flow of information within the human body suggests the possible mechanism by which manipulation affects visceral function, although the mechanism is not yet clearly understood. Improved function, patient outcome, and quality of life are central to the success of any healing system, however, whether or not we understand the mechanisms of action. Homeopathic medicine is a discipline that is not bound by mechanism, but is rooted in careful analysis and pattern recognition. Reilly [33] demonstrated that asthmatic patients who took homeopathic preparations showed significant improvement in only 1 week compared with those taking placebo. These dramatic results led him to conclude that either homeopathic medicine worked beyond a shadow of a doubt, or the double-blind, placebo-controlled trial, the gold standard of proof upon which modern pharmacology is built, was essentially invalid. Throughout the range of healing arts and sciences, there are numerous examples of positive treatment outcomes that occur even though the mechanism cannot be explained. In functional medicine, the value of understanding mechanisms is in improving human function and patient outcome. Prevention, early detection, and functional medicine
“Prevention” has become a welcome and popular concept in recent years in the practice of medicine. A distinction must be made, however, between true prevention and “early detection”. Although periodic mammography has been heralded as a form of preventive medicine, for example, it is clearly in the realm of early detection. Prevention assumes an understanding of factors that give rise to breast cancer and recommendation/adoption of habits or patterns that prevent disease occurrence. Both prevention and early detection are included in the practice of functional medicine, but the patient’s individuality remains paramount. Functional medicine practitioners work to prevent a specific disorder by managing risk factors, but they also strive to raise the individual’s functional capacity within his or her unique life circumstances. Approach to the patient
Functional medicine is always patient-centered, but it is not the only discipline that fits this description. Naturopathic medicine has helped to pioneer a patient-centered medical approach, not only by making the whole person the center of its practice, but also by incorporating highly patient-centered traditions into its repertoire, including traditional Chinese medicine, Ayur-vedic medicine, homeopathy, chiropractic, and physical therapy, including manipulation and massage. The focus on the patient is important, however, because as methods of data management become more sophisticated, the tendency is to think in terms of probability instead of thinking in terms of the individual patient. Probability is useful in understanding the broad context of health and disease, but clinical practice is filled with so many exceptions that relying on statistics is difficult. Laboratory and instrumental diagnosis from a functional perspective
In assessing a patient’s health, the functional medicine practitioner uses tools that help in understanding how the patient functioned before developing the pathology. These tools also help the practitioner to understand function in the existence of pathology and to assist in predicting preventive measures. Serum glucose measurement is a traditional assessment
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of a fixed analyte at a fixed point in time. Although this measurement yields useful information, it does not reveal how serum glucose will respond under varying dietary conditions. The glucose challenge test, on the other hand, is a functional test that assesses glucose status over time. Similarly, although a resting ECG provides useful information, it does not indicate how the heart would respond to a physical challenge. The stress ECG shows how the heart responds upon exertion. Assessment of magnesium is a third example. Magnesium is an intracellular element, which means that most of the body’s magnesium stores are contained within cells, and only a small amount circulates in blood. A measurement of serum magnesium levels, therefore, does not reflect total body magnesium or the functional status of magnesium. Red cell magnesium is a better indicator of status, although it is a measurement of a fixed analyte at a fixed point in time and has limitations as well. Magnesium loading and subsequently assessing retention by measuring urinary excretion provide a means to assess the functional magnesium status and the unique needs of a particular patient. For functional medicine practitioners, tools that view the body under challenge conditions give a more accurate assessment of body function. This is especially true when one wishes to examine the body’s response to exogenous substances. Some individuals will experience an adverse reaction to any given drug, and these reactions are regarded as atypical and unavoidable. From a different perspective, however, the reactions are not atypical and unavoidable; they are typical and avoidable for that person, and he or she would typically be expected to have an adverse reaction on ingestion of this drug. This understanding comes from developments in understanding the body’s detoxification mechanisms. When a drug or medication is ingested, it is metabolized by the
body and prepared for excretion. The process of detoxification and preparation for excretion takes place in two distinct biochemical phases, known as phase I and phase II. In the biotransformation of a drug or chemical, the agent is progressively converted to a more water-soluble, excretable substance. In phase I, which generally occurs first, a family of isozymes known as cytochrome P450 (cP450) converts the drug or substance into a reactive intermediate, which, although it may be excreted in its present form, typically is further acted upon by phase II processes. In phase II, conjugating substances are attached to the phase I product to facilitate its excretion. Phase II reactions typically take place through glucuronidation, amino acid conjugation, glutathione conjugation, acetylation, and methylation. [34] The phase II process, which depends strongly on adequacy of specific nutrients, must be capable of transforming all of the phase I-generated reactive molecules into excretable compounds. If this process is incomplete, toxic intermediates can build up. Acetaminophen is a typical drug that undergoes conversion for excretion through these two pathways. A common OTC and prescription pain-relieving drug, acetaminophen is a useful model because more than 70,000 incidents of acetaminophen overdose were reported to US poison control centers in 1994. [35] Acetaminophen normally undergoes phase II transformation through the sulfation and glucuronidation pathways, with a small amount being metabolized through glutathione conjugation after conversion in phase I. [36] When the drug is not efficiently converted for excretion, the metabolites that build up can have negative metabolic consequences. Accumulations of one extremely toxic metabolite, NAPQI, may cause liver and nervous system damage. An individual with an adequately functioning detoxification ability that facilitates efficient phase II conversion of acetaminophen is much less likely to have a negative experience than one whose ineffective conversion pathways allow toxic intermediates to accumulate. If one ingests acetaminophen on a regular basis, the sulfur-bearing nutrients glutathione, methionine, and cysteine can be rapidly depleted, with accompanying liver cell damage.[37] Adverse acetaminophen reactions may therefore result from alterations in detoxification pathways. The acetaminophen challenge test effectively assesses the function of these pathways. After the individual has consumed a challenge substance, measurements of acetaminophen metabolites in urine can determine the efficiency of the various conversion processes and provide information about the individual’s unique susceptibility. It may be that alterations in the detoxification pathways of many individuals who have “atypical” drug reactions are making them predictably susceptible to certain kinds of substances. If we can gather this information about them, we may be able to predict their response to drugs, as well as chemicals, foods, and plants. We may be able to understand the functional derangement that underlies the pathology that can result from interaction with the environment; and we may be able to use diet and nutrition to help these individuals restore function in these pathways. Pattern recognition
The next step in the evolution of functional assessment will be to consider human physiology as a dynamic process, involving the interrelationship of multiple systems. Functional assessment of only one pathway or one series of pathways may yield useful information, but it still provides a very limited view. Functional testing will no doubt soon evolve to assess multiple analytes and utilize sophisticated pattern recognition methods.
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Pattern recognition is not new. For centuries, in fact, traditional Chinese medicine has dealt with “patterns of disharmony”. The clinician trained in this discipline learns to recognize the pattern and assign it to a specific diagnostic category. In homeopathic medicine, it was pattern recognition that led to the extensive materia medica. In psychotherapy, an evaluation of the patient’s life events and stories is conducted in an effort to understand the patterns that produce disharmony. In all of these examples, the mechanisms are unimportant; the pattern leads to treatment decisions.
SUMMARY Pattern recognition, depth of action, total load, energetics, information, and patient-centered decisions all describe the early stages of development of the evolving functional approach to assessment and treatment. They also characterize a functional approach with a strong focus on the integrative use of treatment modalities based on recognition of underlying purpose in the transformations viewed by practitioners as they work with individual patients. This is also the integrative paradigm which unites naturopathy with functional medicine.
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Chapter 2 - History of naturopathic medicine George Cody JD
INTRODUCTION “Naturopathy”, as a generally used term, began with the teachings and concepts of Benedict Lust. Naturopathy, or “nature cure”, is both a way of life, and a concept of healing employing various natural means of treating human infirmities and disease states. The earliest mechanisms of healing associated with the term, as utilized by Lust, involved a combination of hygienics and hydropathy (hydrotherapy). The term itself was coined in 1895 by Dr John Scheel of New York City, to describe his method of health care. But earlier forerunners of these concepts had already existed in the history of natural healing, both in America and in the Austro-Germanic European core. Lust came to this country from Germany in 1892 as a disciple of Father Kneipp and as a missionary dispatched by Kneipp to bring hydrotherapy to America. Lust purchased the term “naturopathy” from Scheel in 1902 to describe the eclectic compilation of doctrines of natural healing that he envisioned to be the future of natural medicine. In January of 1902, Lust, who had been publishing the Kneipp Water Cure Monthly and its German language counterpart in New York since 1896, changed the name of the journal to The Naturopathic and Herald of Health and evoked the dawn of a new health care era with the following editorial: Naturopathy is a hybrid word. It is purposely so. No single tongue could distinguish a system whose origin, scope and purpose is universal – broad as the world, deep as love, high as heaven. Naturopathy was not born of a sudden or a happen-so. Its progenitors have for eons been projecting thoughts and ideas and ideals whose culminations are crystallized in the new Therapy. Connaro, doling out his few fixed ounces of food and drink each day in his determined exemplification of Dietotherapy; Priessnitz, agonizing, despised and dejected through the long years of Hydropathy’s travail; the Woerishofen priest, laboring lovingly in his little parish home for the thousands who journeyed Germany over for the Kneipp cure; Kuhne, living vicariously and dying a martyr for the sake of Serotherapy; A.T. Still, studying and struggling and enduring for his faith 18
in Osteopathy; Bernarr Macfadden, fired by the will to make Physical Culture popular; Helen Willmans, threading the mazes of Mental Science, and finally emerging triumphant; Orrison Sweet Maraden, throbbing in sympathy with human faults and failures, and longing to realize Success to all mankind – these and hosts of others have brought into being single systems whose focal features are perpetuated in Naturopathy. Jesus Christ – I say it reverently – knew the possibility of physical immortality. He believed in bodily beauty; He founded Mental Healing; He perfected Spirit-power. And Naturopathy will include ultimately the supreme forces that made the Man of Galilee omnipotent. The scope of Naturopathy is from the first kiss of the new-found lovers to the burying of the centenarian whose birth was the symbol of their perfected one-ness. It includes ideally every life-phase of the id, the embryo, the foetus, the birth, the babe, the child, the youth, the man, the lover, the husband, the father, the patriarch, the soul. We believe in strong, pure, beautiful bodies thrilling perpetually with the glorious power of radiating health. We want every man, woman and child in this great land to know and embody and feel the truths of right living that mean conscious mastery. We plead for the renouncing of poisons from the coffee, white flour, glucose, lard, and like venom of the American table to patent medicines, tobacco, liquor and the other inevitable recourse of perverted appetite. We long for the time when an eight-hour day may enable every worker to stop existing long enough to live; when the spirit of universal brotherhood shall animate business and society and the church; when every American may have a little cottage of his own, and a bit of ground where he may combine Aerotherapy, Heliotherapy, Geotherapy, Aristophagy and nature’s other forces with home and peace and happiness and things forbidden to flat-dwellers; when people may stop doing and thinking and being for others and be for themselves; when true love and divine marriage and pre-natal culture and controlled parenthood may fill this world with germ-gods instead of humanized animals. In a word, Naturopathy stands for the reconciling, harmonizing and unifying of nature, humanity and God. Fundamentally therapeutic because men need healing; elementally educational because men need teaching; ultimately inspirational because men need empowering, it encompasses the realm of human progress and destiny. Perhaps a word of appreciation is due Mr. John H. Scheel, who first used the term “Naturopathic” in connection with his Sanitarium “Badekur,” and who has courteously allowed us to share the name. It was chosen out of some 150 submitted, as most comprehensive and enduring. All our present plans are looking forward some five or ten or fifty years when Naturopathy shall be the greatest system in the world. Actually the present development of Naturopathy is pitifully inadequate, and we shall from time to time present plans and ask suggestions for the surpassing achievement of our world-wide purpose. Dietetics, Physical Culture and Hydropathy are the measures upon which Naturopathy is to build; mental culture is the means, and soul-selfhood is the motive. If the infinite immensity of plan, plea and purpose of this particular magazine and movement were told you, you would simply smile in your condescendingly superior way and straightway forget. Not having learned as yet what a brain and imagination and a will can do, you consider Naturopathy an ordinarily innocuous affair, with a lukewarm purpose back of it, and an ebbing future ahead of it. Such is the character of the average wishy-washy health movement and tumultuous wave of reform. Your incredulous smile would not discomfit us – we do not importune your belief, or your help, or your money. Wherein we differ from the orthodox self-labeled reformer, who cries for sympathy and cringes for shekels. We need money most persistently – a million dollars could be used to advantage in a single branch of the work already definitely planned and awaiting materialization; and we need co-operation in a hundred different ways. But these are not the things we expect or deem best. Criticism, fair, full and unsparing is the one thing of value you can give this paper. Let me explain. Change is the keynote of this January issue – in form, title, make-up. If it please you, your subscription and a word to your still-benighted friends is ample appreciation. But if you don’t like it, say so. Tell us wherein the paper is inefficient or redundant or ill-advised, how it will more nearly fit into your personal needs, what we can do to make it the broadest, deepest, truest, most inspiring of the mighty host of printed powers. The most salient letter of less than 300 words will be printed in full, and we shall ask to present the writer with a subscription-receipt for life. By to-morrow you will probably have forgotten this request; by the day after you will have dropped back into your old ways of criminal eating and foolish drinking and sagged standing and congested sitting and narrow thinking and deadly fearing – until the next progress paper of New Thought or Mental
Science or Dietetics or Physical Culture prods you into momentary activity. Between now and December we shall tell you just how to preserve the right attitude, physical and mental, without a single external aid; and how, every moment of every day, to tingle and pulsate and leap with the boundless ecstasy of manhood consciously nearing perfection.
A BRIEF HISTORY OF EARLY AMERICAN MEDICINE WITH AN EMPHASIS ON NATURAL HEALING To understand the evolutionary history of naturopathic medicine in this country, it is necessary to view the internal development of the profession against the historical, social, and cultural backdrop of American social history. Medicine in America: 1800–1875 In the America of 1800, although a professional medical class existed, medicine was primarily domestically oriented. When an individual fell ill, he was commonly nursed by a friend or family member who relied upon William Buchan’s Domestic Medicine (1769), John Wesley’s Primitive Physic (1747), or John Gunn’s Domestic Medicine (1830). [1] Professional medicine
Professional medicine transferred from England and Scotland to America in pre-revolutionary days. However, 18th- and early 19th-century America considered the
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concept of creating a small, elite, learned profession in violation of the political and institutional concepts of early American democracy.
[1]
The first medical school in the American colonies was opened in 1765 at what was then the College of Philadelphia (later the University of Pennsylvania) and the school came to be dominated by revolutionary leader and physician Benjamin Rush, a signatory to the Declaration of Independence. The proliferation of medical schools to train the new professional medical class began seriously after the war of 1812. Between 1810 and 1820, new schools were established in Baltimore, Lexington and Cincinnati, and even in rural communities in Vermont and Western New York. Between 1820 and 1850, a substantial number of schools were established in the western rural states. By 1850, there were 42 medical schools recognized in the United States, while there were only three in all of France. Generally, these schools were started by a group of five to seven local physicians approaching a local college with the idea of establishing a medical school in conjunction with the college’s educational facilities. The schools were largely apprenticeship-based, and the professors received their remuneration directly from fees paid by the students. The requirements for an MD degree in late 18th- and early 19th-century America were roughly the following: • knowledge of Latin, natural and experimental philosophy • 3 years of serving an apprenticeship under practicing physicians • attending of two terms of lectures and passing of attendant examinations • a thesis. Graduating students had to be at least 21 years of age. [1] The rise of any professional class is gradual and marked by difficulties, and varying concepts existed as to what was the demarcation of a “professional” physician. There were the graduates of medical school versus non-graduates, medical society members versus non-members, and licensed physicians versus unlicensed “doctors”. Licensing statutes came into existence between 1830 and 1850, but were soon repealed, as they were considered “undemocratic” during the apex of Jacksonian democracy. [1] Thomsonianism
In 1822, the rise in popularity of Samuel Thomson and his publication of New Guide to Health helped to frustrate the creation of a professional medical class. Thomson’s work was a compilation of his personal view of medical theory and American Indian herbal and medical botanical lore. Thomson espoused the belief that disease had one general cause – “cold” influences on the human body – and that disease had therefore one general remedy – “heat”. Unlike the followers of Benjamin Rush and the American “heroic” medical tradition who advocated blood-letting, leeching, and the substantial use of mineral-based purgatives such as antimony and mercury, Thomson believed that minerals were sources of “cold” because they come from the ground and that vegetation, which grew toward the sun, represented “heat”. [1] As noted in Griggs’ Green Pharmacy (the best history of herbal medicine to date), Thomson’s theory developed as follows: [2] Instead, he elaborated a theory of his own, of the utmost simplicity: “All diseases … are brought about by a decrease or derangement of the vital fluids by taking cold or the loss of animal warmth … the name of the complaint depends upon what part of the body has become so weak as to be affected. If the lungs, it is consumption, or the pleura, pleurisy; if the limbs, it is rheumatism, or the bowels, colic or cholera morbus … all these different diseases may be removed by a restoration of the vital energy, and removing the obstructions which the disease has generated … Thus the great object of his treatment was always to raise and restore the body’s vital heat: “All … that medicine can do in the expulsion of disorder, is to kindle up the decaying spark, and restore its energy till it glows in all its wonted vigor. Thomson’s view was that individuals could be self-treating if they had a sincere understanding of his “new guide to health” philosophy and a copy of his book, New Guide to Health. The right to sell “family franchises” for utilization of the Thomsonian method of healing was the basis of a profound lay movement between 1822 and Thomson’s death in 1843. Thomson adamantly believed that no professional medical class should exist and that democratic medicine was best practiced by lay persons within a Thomsonian “family” unit. By 1839, Thomson claimed to have sold some 100,000 of these family franchises called “friendly botanic societies”. While he professed to have solely the interests of the individual at heart, his system was sold at a profit under the protection of a patent he had obtained in 1813. The eclectic school of medicine
Some of the botanics (professional Thomsonian doctors) wanted to separate themselves from the lay movement by creating requirements and standards for the practice of Thomsonian medicine. Thomson, however, was adamantly against a medical school founded on his views. Thus, it was not until the decade after Thomson’s death that independent Thomsonians founded a medical college (in Cincinnati) and began to dominate the Thomsonian movement. These Thomsonian doctors, or “botanics”, were later absorbed into the medical sectarian movement known as the “eclectic school”, which originated with the New Yorker, Wooster Beach.
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Wooster Beach was another of medical history’s fascinating characters. From a well-established New England family, he started his medical studies at an early age, apprenticing under an old German herbal doctor, Jacob Tidd, until Tidd died. Beach then enrolled in the Barclay Street Medical University in New York. As noted by
Griggs (p. 180): [2] Beach’s burning ambition was to reform medical practice generally – not to alienate the entire profession by savage attacks from without – and he was convinced that he would be in a stronger position to do so if he were himself a diplomatized doctor. The faculty occasionally listened to criticism from within their own number: against onslaughts of “illiterate quacks” like Samuel Thomson, they simply closed ranks in complacent hostility. After opening his own practice in New York, Beach set out to win over fellow members of the New York Medical Society (into which he had been warmly introduced by the screening committee) to his point of view that heroic medicine was inherently dangerous to mankind and should be reduced to the gentler theories of herbal medicine. He was summarily ostracized from the medical society. To Beach this was a bitter blow, but he soon founded his own school in New York, calling the clinic and educational facility “The United States Infirmary”. However, due to continued pressure from the medical society, he was unable to obtain charter authority to issue legitimate diplomas. He then located a financially ailing, but legally chartered, school, Worthington College, in Worthington, Ohio. He opened there a full-scale medical college; out of its classrooms was launched what became known as the eclectic school of medical theory. As Griggs relates (p. 183): [2] Beach had a new name for his practice: while explaining to a friend his notions of combining what was useful in the old practice with what was best in the new, the friend exclaimed, “You are an eclectic!” to which, according to legend, Beach replied, “You have given me the term which I have wanted: I am an eclectic!” Cincinnati subsequently became the focal point of the eclectic movement and the medical school remained until 1938 (the last eclectic school to exist in America). The philosophies of the sect helped to form the theoretical underpinnings of Benedict Lust’s naturopathic school of medicine.
[1]
Despite his criticism of the early allopathic medical movement (although the followers of Benjamin Rush were not as yet known by this term, reputed to have been coined by Samuel Hahnemann) for their “heroic” tendencies, Thomson’s medical theories were “heroic” in their own fashion. While he did not advocate blood-letting, heavy metal poisoning and leeching, botanic purgatives – particularly Lobelia inflata (Indian tobacco) – were a substantial part of the therapy. The hygienic school of thought
One other forerunner of American naturopathy, also originating as a lay movement, grew into existence at this time. This was the “hygienic” school, which had its genesis in the popular teachings of Sylvester Graham and William Alcott. Sylvester Graham began preaching the doctrines of temperance and hygiene in 1830, and published, in 1839, Lectures on the Science of Human Life, two hefty volumes that prescribed healthy dietary habits. He emphasized a moderate lifestyle, recommending an anti-flesh diet and bran bread as an alternative to bolted or white bread. William Alcott dominated the scene in Boston during this same period, and together with Grahm, saw that the American hygienic movement – at least as a lay doctrine – was well-established. [3] Homeopathy
By 1840, the profession of homeopathy had also been transplanted to America from Germany. Homeopathy, the creation of an early German physician, Samuel Hahnemann (1755–1843), had three central doctrines: • the “law of similars” (that like cures like) • that the effect of a medication could be heightened by its administration in minute doses (the more diluted the dose, the greater the “dynamic” effect) • that nearly all diseases were the result of a suppressed itch, or “psora”. The view was that a patient’s natural symptom-producing disease would be displaced after homeopathic medication by a similar, but much weaker, artificial disease that the body’s immune system could easily overcome. Originally, most homeopaths in this country were converted orthodox medical men, or “allopaths”. The high rate of conversion made this particular medical sect the arch-enemy of the rising orthodox medical profession. (For a more detailed discussion of homeopathy, see Ch. 41. ) The first homeopathic medical school was founded in 1850 in Cleveland; the last purely homeopathic medical school, based in Philadelphia, survived into the early 1930s.[1] The rise and fall of the sects
Although these two non-allopathic sects were popular, they never comprised more than one-fifth of the professional medical class in America. Homeopathy at its highest point reached roughly 15%, and the eclectic school roughly 5%. However, their very existence for many years kept the exclusive recognition desired by
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the orthodox profession from coming within its grasp. Homeopathy was distasteful to the more conventional medical men not only because it resulted in the conversion of a substantial number of their peers, but also because homeopaths generally also made a better income. The rejection of the eclectic school was more fundamental: it had its roots in a lay movement that challenged the validity of a privileged professional medical class. The existence of three professional medical groups – the orthodox school, the homeopaths, and the eclectics – combined with the Jacksonian view of democracy that prevailed in mid-19th century America, resulted in the repeal of virtually all medical licensing statutes existing prior to 1850. But by the 1870s and 1880s, all three medical groups had begun to voice support for the restoration of medical licensing. There are differing views as to what caused the homeopathic and eclectic schools to disappear from the medical scene in the 50 years following 1875. One view defines a sect as follows: [4] A sect consists of a number of physicians, together with their professional institutions, who utilize a distinctive set of medically invalid therapies which are rejected by other sects … By this definition, the orthodox or allopathic school was just as sectarian as the homeopathic and eclectics. Rothstein’s view is that these two 19th century sects disappeared because, beginning in the 1870s, the orthodox school grasped the European idea of “scientific medicine”. Based on the research of such men as Pasteur and Koch, and the “germ theory”, this approach supposedly proved to be the medically proper view of valid therapy and gained public recognition because of its truth. Another view is that the convergence of the needs of the three sects for professional medical recognition (which began in the 1870s and continued into the early 1900s), and the “progressive era”, led to a political alliance in which the majority orthodox school ultimately came to be dominant by sheer weight of numbers and internal political authority. As Starr [1] notes (p. 107): Both the homeopaths and eclectics wanted to share in the legal privileges of the profession. Only afterward did they lose their popularity. When homeopathic and eclectic doctors were shunned and denounced by the regular profession, they thrived, but the more they gained an access to the privileges of regular physicians, the more their numbers declined. The turn of the century was both the point of acceptance and the moment of incipient
disintegration … In any event, this development was an integral part of the drive toward professional authority and autonomy established during the progressive era (1900–1917). It was acceptable to the homeopaths and the eclectics because they controlled medical schools that continued to teach and maintain their own professional authority and autonomy. However, it was after these professional goals were attained that the lesser schools of medical thought went into rapid decline. [1] The American influence From 1850 through 1900, the medical counterculture continued to establish itself in America. From its lay roots in the teachings of the hygienic movement, there grew professional medical recognition, albeit a small minority and “irregular” view, that hygiene and hydropathy were the basis of sound medical thought (much like the Thomsonian transition to botanic and eclectic medicine). Trall
The earliest physician who came to have a significant impact on the later growth of naturopathy as a philosophical movement was Russell Trall MD. As noted in Whorton’s Crusaders for Fitness, [3] he “passed like a meteor through the American hydropathic and hygienic movement” (pp. 138–139): The exemplar of the physical educator-hydropath was Russell Thatcher Trall. Still another physician who had lost his faith in regular therapy, Trall opened the second water cure establishment in America, in New York City in 1844. Immediately he combined the full Preissnitzian armamentarium of baths with regulation of diet, air, exercise and sleep. He would eventually open and or direct any number of other hydropathic institutions around the country, as well as edit the Water-Cure Journal, the Hydropathic Review, and a temperance journal. He authored several books, including popular sex manuals which perpetuated Graham-like concepts into the 1890’s, sold Graham crackers and physiology texts at his New York office, was a charter member (and officer) of the American Vegetarian Society, presided over a short-lived World Health Association, and so on. His crowning accomplishment was the Hygeian Home, a “model Health Institution [which] is beautifully situated on the Delaware River between Trenton and Philadelphia.” A drawing presents it as a palatial establishment with expansive grounds for walking and riding, facilities for rowing, sailing, and swimming, and even a grove for open-air “dancing gymnastics.” It was the grandest of water cures, and lived beyond the Civil War period, which saw the demise of most hydropathic hospitals. True, Trall had to struggle to keep his head above water during the 1860’s, but by the 1870’s he had a firm financial footing (being stabilized by tuition fees from the attached Hygeio-therapeutic College). With Trall’s death in 1877, however, the hydropathic phase of health reform passed. As will be seen later in this chapter, this plethora of activity is very similar to that engaged in by Benedict Lust between 1896 and his death in 1945, when he worked to establish naturopathic medicine. The Hygeian Home and later “Yungborn” establishments at Butler, New Jersey, and Tangerine, Florida, were very similar to European nature cure sanitariums, such as the original
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Yungborn founded by Adolph Just and the spa/ sanitarium facilities of Preissnitz, Kneipp and Just. Trall gave a famous address to the Smithsonian Institution in Washington, DC, in 1862, under the sponsorship of the Washington Lecture Association. “The true healing art: or hygienic vs drug medication”, a 2.5 hour lecture purported to have received rapt attention, was devoted to Trall’s belief in the hygienic system and in hydropathy as the true healing art. The address was reprinted by Fowler and Wells (New York, 1880) with an introduction written by Trall, prior to his death in 1877. Trall also founded the first school of natural healing arts in this country to have a 4-year curriculum and the authorization to confer the degree of MD. It was founded in 1852 as a “hydropathic and physiological school” and was chartered by the New York State Legislature in 1857 under the name “New York Hygio-Therapeutic College”, with the legislature’s authorization to confer the MD degree. In 1862, Trall went to Europe to attend the International Temperance Convention. At this meeting of reformers, he took prominent part, specifically relating to the use of alcohol as a beverage and as a medicine. He eventually published more than 25 books on the subjects of physiology, hydropathy, hygiene, vegetarianism, and temperance, among many others. The most valuable and enduring of these was his Hydropathic Encyclopedia, a volume of nearly 1,000 pages that covered the theory and practice of hydropathy and the philosophy and treatment of diseases advanced by older schools of medicine. At the time of his death, according to the December 1877 Phrenological Journal cover article featuring a lengthy obituary of Trall, this encyclopedia had sold more than 40,000 copies since its original publication in 1851. For more than 15 years, Trall was editor of the Water-Cure Journal (also published by Fowler and Wells). During this period, the journal went through several name changes including the Hygienic Teacher and The Herald of Health. When Dr Lust originally opened the American School of Naturopathy, an English-language version of Kneipp’s Water-cure (or in German Meine Wasser-kurr) being unavailable, he used only the works and writings of Russell Trall as his texts. By 1871, Trall had moved from New York to the Hygeian Home on the Delaware River. His water-cure establishment in New York became The New Hygienic Institute. One of the co-proprietors there was Martin Luther Holbrook, who later replaced Trall as the editor of The Herald of Health. As noted by Professor Whorton (pp. 139–140):[3] But Holbrook’s greatest service to the cause was as an editor. In 1866 he replaced Trall at the head of The Herald of Health, which had descended from the Water-Cure Journal and Herald of Reforms (1845–1861) by the way of the Hygienic Teacher and Water-Cure Journal (1862). Under Holbrook’s direction the periodical would pass through two more name changes ( Journal of Hygiene Herald of Health, 1893–1897, and Omega, 1898–1900) before merging with Physical Culture. Trall and Holbrook both advanced the idea that physicians should teach the maintenance of health rather than simply provide a last resort in times of health crisis. Besides providing a strong editorial voice espousing vegetarianism, the evils of tobacco and drugs, and the value of bathing and exercise, dietetics and nutrition along with personal hygiene were strongly advanced by Holbrook and others of the hygienic movement during this era. As described, again by Whorton (pp. 143–144): [3] The orthodox hygienists of the progressive years were equally enthused by the recent progress of nutrition, of course, and exploited it for their own ends, but their utilization of science hardly stopped with dietetics. Medical bacteriology was another area of remarkable discovery, bacteriologists having provided, in the short space of the last quarter of the 19th century, an understanding, at long last, of the nature of infection. This new science’s implications for hygienic ideology were profound – when Holbrook locked horns with female fashion, for example, he did not attack the bulky, ground-length skirts still in style with the crude Grahamite objection that the skirt was too heavy. Rather he forced a gasp from his readers with an account of watching a smartly dressed lady unwittingly drag her skirt “over some virulent, revolting looking sputum, which some unfortunate consumptive had expectorated.” Holbrook expanded on the work of Graham, Alcott and Trall and, working with an awareness of the European concepts developed by Preissnitz and Kneipp, laid further groundwork for the concepts later advanced by Lust, Lindlahr and others: [3] For disease to result, the latter had to provide a suitable culture medium, had to be susceptible. As yet, most physicians were still so excited at having discovered the causative agents of infection that they were paying less than adequate notice to the host. Radical hygienists, however, were bent just as far in the other direction. They were inclined to see bacteria as merely impotent organisms that throve only in individuals whose hygienic carelessness had made their body compost heaps. Tuberculosis is contagious, Holbrook acknowledged, but “the degree of vital resistance is the real element of protection. When there is no preparation of the soil by heredity, predisposition or lowered health standard, the individual is amply guarded against the attack.” A theory favored by many others was that germs were the effect of disease rather than its cause; tissues corrupted by poor hygiene offered microbes, all harmless, an environment in which they could thrive. (p. 144) In addition to introducing the works of Father Kneipp and his teachings to the American hygienic health care movement, Holbrook was a leader of the fight against
vivisection and vaccination: [3] Vivisection and vaccination were but two of the practices of medicine criticized in the late 19th century. Therapy also continued to be an object of protest. Although the heroism of 23
standard treatment had declined markedly since mid-century, a prescription was still the reward of any visit to the doctor, and drugless alternatives to healing were appearing in protest. Holbrook published frequent favorable commentaries on the revised water cure system of Germany’s Father Kneipp. A combination of baths, herbal teas, and hardening exercises, the system had some vogue in the 1890’s before flowering into naturopathy. Holbrook’s journal also gave positive notices to osteopathy and “chiropathy” [chiropractic] commending them for not going to the “drugstore or ransack[ing] creation for remedies nor load[ing] the blood with poison.” But though bathing and musculoskeletal manipulation were natural and nonpoisonous, Holbrook preferred to give the body complete responsibility for healing itself. Rest and proper diet were the medicines of this doctor who billed himself as a “hygienic physician” and censured ordinary physicians for being engrossed with disease rather than health. (pp. 146–147) The beginnings of “scientific medicine” While the hygienic movement was making its impact, the orthodox medical profession, in alliance with the homeopaths and eclectics, was making significant advances. The orthodox profession, through the political efforts of the AMA, had first tried to remove sectarian and irregular practitioners by segregating them from the medical profession altogether. It did so by formulating and publishing its first national medical code of ethics in 1847. (In 1846, the orthodox profession formed the American Medical Association to represent their professional views.) The code condemned proprietary patents (even carrying over into a physician’s development of surgical or other medical implements, which led to its greatest criticism); encouraged the adoption of uniform rules for payment in geographical areas; condemned the practice of contract work, prohibited advertising and fee-sharing even among specialists and general practitioners; eliminated blacks and women; and, most significantly, prohibited any consultation or contact with irregulars or sectarian practitioners. As the code stated: [5] … no one can be considered as a regular practitioner, or a fit associate in consultation, whose practice is based on an exclusive dogma, to the rejection of the accumulated experience of the profession, and of the aids actually furnished by anatomy, physiology, pathology, and organic chemistry. (pp. 234–279) In the late 1870s and into the 1880s, the major sects – the orthodox, or allopathic school, the homeopaths and the eclectics – began to find more reason to cooperate to obtain common professional goals. These included the enactment of new licensing laws and the creation of a “respectable” medical educational system. Also at this time, the concept of “scientific medicine” was brought to America. (Although Starr differs with Rothstein about the cause of the death of the homeopathic and eclectic sectarian schools, he notes that Rothstein clearly documents the transition, during the 19th century, of medicine to a recognized professional class composed of both the minority sects and the orthodox school.) This transition from conflict between the major sects resulted in the erosion of the implementation of the code of ethics, the cooperation among the sects to revive medical licensing standards, the admission of sectarian physicians to regular medical societies and, ultimately, a structural reorganization of the American Medical Association, which took place between 1875 and 1903. [1] [4] Once the cooperation between the three medical views had begun, the medical class as dominated by the regular school came fully into power. And the homeopathic and eclectic schools of thought met their demise, which was finally brought about by two significant events: the rapid creation of new medical educational standards between 1900 and 1910, culminating in the publication of the famous “Flexner Report” (1910); and the effective infusion of millions of dollars into selected allopathic medical schools by the newly created capitalistic philanthropic foundations, principally the Carnegie and Rockefeller foundations. The foundations
The impact of the monies from the Carnegie and Rockefeller foundations has been clearly documented [6] and is described in detail, albeit for the advancement of a particular political point of view, in Brown’s Rockefeller Medicine Men. The impact of the monies from these foundations, as contributed to medical schools that met the AMA’s view of medical education and philosophy, cannot be underestimated. This process has been well documented. [1] [6] [7] [8] As discussed by Burrows,[8] this educational reform allowed the AMA to form a new alliance with legislators, and push quickly for medical licensing designed to reward the educational and medical expertise of the new orthodox “scientific medicine”, and the exclusion of all others.[8] Medical education in transition
Based upon the rising example of scientific medicine and its necessary connection to research, the educational laboratory, and a more thorough scientific education as a preamble to medical practice, Harvard University (under the presidency of Charles Elliott) created a 4-year medical educational program in 1871. The primal modern medical educational curriculum was devised and set in motion over 20 years later at Johns Hopkins University under the leadership of William Osler and William Welch, using the resources from the original endowment of the hospital and university from the estate of Johns Hopkins. [1] Other schools followed suit. By the time the American Medical Association set up its Council on Medical
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Education in 1904, it was made up of five members from the faculties of schools modeled on the Johns Hopkins prototype. This committee set out to visit and rate each of the (160) medical schools then in operation in the country. The ratings used were class “A” (acceptable), class “B” (doubtful), and class “C” (unacceptable). Eighty-two schools received a class “A” rating, led by Harvard, Rush (Chicago), Western Reserve, the University of California and, notably, Johns Hopkins. Forty-six received a class “B” rating, and thirty-two a class “C” rating. The class “C” schools were mostly in rural areas and many of them proprietary in nature. Flexner report
Subsequently to the AMA ratings, the Council on Medical Education applied to the Carnegie Foundation to commission an independent report to verify its work. Abraham Flexner, a young, energetic and noted educator was chosen for this task by the Carnegie Foundation and accompanied by the secretary (Nathan Colwell MD) of the Council on Medical Education, who had participated in all of the committee site visits. Flexner visited each of the 162 United States medical schools then operating. The publication of the “Flexner Report”, which was widely publicized, put the nails in the coffins of all schools with class “C” ratings and many with class “B” ratings. Significantly, the educational programs of all but one eclectic school (in Cincinnati) and one homeopathic school (in Philadelphia) were eliminated by 1918. The eclectic medical schools, in particular, were severely affected by the report. According to Griggs (p. 251):
[ 2]
Of the eight Eclectic schools, the Report declared that none had “anything remotely resembling the laboratory equipment which is claimed in their catalogs.” Three of them were under-equipped; the rest “are without exception filthy and almost bare. They have at best grimy little laboratories … a few microscopes, some bottles containing discolored and unlabeled pathological material, in an incubator out of commission, and a horrid dissecting room.” The Report found them more culpable than a regular school for these inadequacies: “… the Eclectics are drug-mad; yet, with the exception of the Cincinnati and New York schools, they are not equipped to teach the drugs or drug therapy which constitutes their sole reason for existence.”
The other regular schools that had conducted homeopathic or eclectic programs had by that time phased them out in the name of “scientific medicine”. Pharmaceutical industry
During this same period of time, the American Medical Association, through several of its efforts, began a significant alliance with the organized pharmaceutical industry of the United States, shaping that industry in a manner acceptable to the allopathic profession. [1] [7] [9] The new “sects” The period from 1890 through 1905 saw the rise of three new medical sects and several other smaller “irregular” schools which replaced those soon to pass away. In Missouri, Andrew Taylor Still, originally trained as an orthodox practitioner, founded the school of medical thought known as “osteopathy”, and in 1892 opened the American School of Osteopathy in Kirksville, Missouri. In 1895, Daniel David Palmer, originally a magnetic healer from Davenport, Iowa, performed the first spinal manipulation, which gave rise to the school he termed “chiropractic”. He formally published his findings in 1910, after having founded a chiropractic school in Davenport, Iowa. And, in 1902, Benedict Lust founded the American School of Naturopathy in New York. Although some of the following discussion will be devoted to the schools of healing called osteopathy and chiropractic, only that portion of their histories related to the history of naturopathy will be mentioned. [10] (A full study of osteopathic medicine in America may be found in The D.O.’s by Gevitz[11] , and a reasonable sketch of chiropractic medicine may be found in Ronald Lee Kapling’s chapter in Salmon. [10] ) As noted by Starr,[1] these new sects, including Christian Science, formulated by Mary Baker Eddy (see Silberger [12] for further discussion), either rose or fell on their own without ever completely allying with orthodox medicine. Starr theorized that these sects arose late enough that the orthodox profession and its political action arm, the AMA, had no need to ally with them and would rather battle with them publicly. This made these sectarian views separate and distinct from the homeopathic and eclectic schools.
THE FOUNDING OF NATUROPATHIC MEDICINE Benedict Lust Benedict Lust came to the United States in 1892 at the age of 23. He had suffered from a debilitating condition in his late teens while growing up in Michelbach, Baden, Germany, and had been sent by his father to undergo the Kneipp cure at Woerishofen. He stayed there from mid-1890 to early 1892; not only was he “cured” of his condition, but he also became a protégé of Father Kneipp. Dispatched by Kneipp to bring the principles of the Kneipp water cure to America, he emigrated to New York City. By making contact in New York with other German Americans who were also becoming aware of the Kneipp principles, Lust participated in the founding of the first “Kneipp Society”, which was organized in Jersey City, New Jersey, on 3 October 1896. Lust was also present at the first organizational
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meeting (in the middle of October 1896) of the Kneipp Society of Brooklyn, and subsequently, through Lust’s organization and contacts, Kneipp Societies were founded in Boston, Chicago, Cleveland, Denver, Cincinnati, Philadelphia, Columbus, Buffalo, Rochester, New Haven, San Francisco, the state of New Mexico, and Mineola on Long Island. The members of these organizations were provided with copies of the Kneipp Blatter, and a companion English publication Lust began to put out called The Kneipp Water-Cure Monthly. The first “sanatorium” using Kneipp’s principles was organized in this country shortly before Lust’s arrival. Charles Lauterwasser, an earlier student of Kneipp’s who called himself a hydrophic physician and natural scientist, opened the Kneipp and Nature Cure Sanatorium in Newark, New Jersey, in 1891. In 1895, the Brooklyn Light and Water-Cure Institute was established in Brooklyn, New York, by L. Staden and his wife Carola, both graduates of Lindlahr’s Hygienic College in Dresden, Germany. According to their advertising, they specialized in natural healing, Kneipp water treatment, Kuhne’s and Preissnitz’s principles (including diet cure and electric light baths – both white and blue – electric vibration massage, Swedish massage and movements, and Thure-brandt massage). In 1895, Lust opened the Kneipp Water-Cure Institute in New York City, listing himself as the owner and a Dr William Steffens as the residing physician. At the same address (on 59th Street) in October of that year, Lust opened the first “Kneipp store”. In the originating November 1896 edition of The Kneipp Water-Cure Monthly and Kneipp Blatter, he advertised his store and sanitarium as personally authorized by Father Kneipp. Father Kneipp died in Germany, at Woerishofen, on 17 June 1897. With his passing, Lust was no longer bound strictly to the principles of the Kneipp water cure. He had begun to associate earlier with other German American physicians, principally Dr Hugo R. Wendel (a German-trained Naturarzt) who began, in 1897, to practice in New York and New Jersey, as a licensed osteopathic physician. In 1896, Lust entered the Universal Osteopathic College of New York, graduated in 1898, and became licensed as an osteopathic physician. In 1897, Lust became an American citizen. Once he was licensed to practice as a health care physician in his own right, Lust began the transition toward the concept of “naturopathy”. Between 1898 and 1902, when he adopted the term “naturopath”, Lust acquired a chiropractic education and changed the name of his Kneipp store to “health food store” (the original facility to utilize that name and concept in this country), specializing in providing organic foods and the materials necessary for drugless cures. He also began the New York School of Massage (listed as established in 1896) and the American School of Chiropractic, all within the same facility – Lust’s Kneipp Institute. Photographs of this facility taken between 1902 and 1907, when the facility moved to another location, show a five-story building listing “Benedict Lust – Naturopath, Publisher, Importer”. In the first part of 1896, just prior to his organizing of various Kneipp Societies around the New York area, Lust returned to Woerishofen to study further with Father Kneipp. He returned again in 1907 to visit with Dr Baumgarten, Kneipp’s medical successor at the Woerishofen facility, which was then run, in cooperation with Baumgarten, by the Reverend Prior Reily, the former secretary to Father Kneipp and his lay successor at Woerishofen. As directed by Kneipp, Reily had completed, after Kneipp’s death, Kneipp’s master work Das grosse Kneipp – Buch. Lust was to maintain contact with the partnership of Reily and Baumgarten throughout the early part of the 20th century. In 1902, when he purchased and began using the term naturopathy and calling himself a “naturopath”, Lust, in addition to his New York School of Massage and American School of Chiropractic, his various publications and his operation of the Health Food Store, began to operate the American School of Naturopathy, all at the same 59th Street address. By 1907, Lust’s enterprises had grown sufficiently large that he moved them to a 55 room building. It housed the Naturopathic Institute, Clinic and Hospital; the American Schools of Naturopathy and Chiropractic; the now entitled “Original Health Food Store”; Lust’s publishing enterprises; and New York School of Massage. The operation remained in this four-story building, roughly twice the size of the original facility, from 1907 to 1915. In the period of 1912 through 1914, Lust took a “sabbatical” from his operations to further his education. By this time he had founded his large estate-like sanitarium at
Butler, New Jersey, known as “Yungborn” after the German sanitarium operation of Adolph Just. In 1912, he attended the Homeopathic Medical College in New York, which, in 1913, granted him a degree in homeopathic medicine and, in 1914, a degree in eclectic medicine. In early 1914, Lust traveled to Florida and obtained an MD’s license on the basis of his graduation from the Homeopathic Medical College. Thereafter, he founded another “Yungborn” sanitarium facility in Tangerine, Florida, and for the rest of his life, while continuing his publications, engaged in active lecturing. He also continued to maintain a practice in New York City, and operated the sanitariums at Tangerine, Florida, and Butler, New Jersey. His schools were operated by Hugo R. Wendel. From 1902, when he began to utilize the term naturopathy, until 1918, Lust replaced the Kneipp Societies
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with the Naturopathic Society of America. Then, in December 1919, the Naturopathic Society of America was formally dissolved due to its insolvency and Lust founded the “American Naturopathic Association”. Thereafter, the association was incorporated in some additional 18 states. In 1918, as part of his effort to replace the Naturopathic Society of America (an operation into which he invested a great deal of his funds and resources in an attempt to organize a naturopathic profession) and replace it with the American Naturopathic Association, Lust published the first Universal Naturopathic Directory and Buyer’s Guide (a “yearbook of drugless therapy”). Although a completely new version was never actually published, in spite of Lust’s announced intention to make this volume an annual publication, annual supplements were published in either The Naturopath and Herald of Health or its companion publication, with which The Naturopath at one time merged, Nature’s Path (which commenced publication in 1925). The Naturopath and Herald of Health , sometimes printed with the two phrases reversed, was published from 1902 through 1927, and from 1934 until after Lust’s death in 1945. This volume documents the merging of the German and American influences which influenced Lust in his development of the practice of naturopathy. The voluminous tome, which ran to 1,416 pages, is dedicated to: … the memory of all those noble pioneers and discoverers who have died in the faith of Naturopathy, and to their courageous successors in the art of drugless healing, all of whom have suffered persecution for saving human lives that medical autocracy could not save, this work is respectfully dedicated by its editor Benedict Lust, N.D., M.D., “The Yungborn”, Butler, New Jersey, U.S.A., April 1, 1918. Lust’s introduction is reprinted here in its entirety to show the purpose of the directory and the status of the profession in the early 1900s: Introduction To the Naturopathic Profession, the Professors of Natural Healing in all its branches, the Professors of Scientific Diet, Hydrotherapy, Heliotherapy, Electrotherapy, Neuropathy, Osteopathy, Chiropractic, Naprapathy, Magnetopathy, Phytotherapy, Exercise, Swedish Movements, Curative Gymnastics, Physical and Mental Culture, Balneopathy, and all forms of Drugless Healing, the Faculties of all Drugless Colleges, Institutions, Schools, and all Professors of Hygiene and Sanitation; Manufacturers of Naturopathic Supplies; Publishers of Health Literature, and Natural Healing Societies, GREETINGS: I have the honor to present to your consideration and goodwill, this Volume, No. 1, Year 1918–1919, of the Universal Naturopathic Directory, Year Book of Drugless Healing, and Buyers’ Guide. For twenty-two years past, the need of a directory for Drugless Therapy has been felt. The medical world is in a condition of intense evolution at the present time. It is evolving from the Drugging School of Therapy to the Drugless School. People by the million have lost confidence in the virtues of Allopathy and are turning with joyful confidence to the Professions of Natural Healing until it has been estimated that there are at least forty thousand practitioners of Naturopathic healing in the United States. The motto that IN UNITY THERE IS STRENGTH is the foundation of the present enterprise. Hitherto, the drugless profession has lacked that prestige in the eyes of the public, which comes from the continuous existence of a big institution, duly organized and wielding the immense authority which is derived no less from organization and history than from the virtues of the principles that are held and practiced by such institutions. The public at large instantaneously respects an institution that is thoroughly organized and has its root earthed in history. The time has fully arrived when the drugless profession should no longer exist in the form of isolated units, not knowing one another and caring but little for such knowledge. Our profession has been, as it were, as sheep without a shepherd, but the various individuals that constitute this movement so pregnant with benefits to humanity, are now collected for the first time into a Directory and Year-Book of Drugless Healing, which alone will give immense weight and dignity to the standing of the individuals mentioned therein. Not only will the book add to the prestige of the practitioner in the eyes of his patients, but when the scattered members of our profession in every State desire to obtain legislative action on behalf of their profession and themselves, the appeal of such a work as our directory will, in the eyes of legislators, gain for them a much more respectful hearing than could otherwise be obtained. Now, for the first time, the drugless practitioner finds himself one of a vast army of professional men and women who are employing the most healthful forces of nature to rejuvenate and regenerate the world. But the book itself throws a powerful light upon every phase of drugless healing and annihilates time and distance in investigating WHO IS WHO in the realm of Drugless Therapy. A most sincere effort has been made to obtain the name and address of every adherent of the Rational School of Medicine who practices his profession within the United States, Canada and the British Isles. It is impossible at this stage of Naturopathic history, which is still largely in the making, to obtain the name and address of every such practitioner. There were some who, even when appealed to, refused to respond to our invitation, not understanding the object of our work. Many of even the most intelligent members have refused to advertise their professional cards in our pages. But we can only attribute these drawbacks to the fact that every new institution that has suddenly dawned upon human intelligence will find that a certain proportion of people who do not understand the nature of the enterprise because the brain cells that would appreciate the benefits that are sought to be conferred upon them, are undeveloped, but a goodly proportion of our Naturopaths have gladly responded to the invitation to advertise their specialty in our columns. These, of course, constitute the brightest and most successful of our practitioners and their examples in this respect should be followed by every practitioner whose card does not appear in this book. We take it for granted that every one of the forty thousand practitioners of Naturopathy is in favor of the enterprise represented by this Directory. This work is a tool of his trade and not to possess this book is a serious handicap in the race for success.
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Here will be found an Index of by far the larger number of Naturopaths in the country arranged in Alphabetic, Geographic and Naturopathic sections. Besides this, there is a classified Buyers’ Guide that gives immediate information regarding where you can find special supplies, or a certain apparatus, or
a certain book or magazine, its name, and where it is published. The list of Institutions with the curriculum of each will be found exceedingly useful. Natural healing, that has drifted so long, and, by reason of a lack of organization, has been made for so many years the football of official medicine, to be kicked by any one who thought fit to do so, has now arrived at such a pitch of power that it has shaken the old system of bureaucratic medicine to its foundations. The professors of the irrational theories of life, health and disease, that are looking for victims to be inoculated with dangerous drugs and animalized vaccines and serums, have begun to fear the growth of this young giant of medical healing that demands medical freedom, social justice and equal rights for the new healing system that exists alone for the betterment and uplifting of humanity. I want every Professor of Drugless Therapy to become my friend and co-worker in the great cause to which we are committed, and those whose names are not recorded in this book should send them to me without delay. It will be of far greater interest and value to themselves to have their professional card included amongst those who advertise with us than the few dollars that such advertisement costs. It will be noted that there are quite a number of Drugless Healers belonging to foreign countries (particularly those of the Western Hemisphere) represented in this Directory. The profession of medicine is not confined to any race, country, clime or religion. It is a universal profession and demands universal recognition. It will be a great honor to the Directory, as well as to the Naturopathic profession at large to have every Naturopathic practitioner, from the Arctic Circle to the furthest limits of Patagonia, represented in the pages of this immense and most helpful work. I expect that the Directory for the year 1920 will be larger and even more important than the present Directory and that it will contain the names of thousands of practitioners that are not included in the present work. The publication of this Directory will aid in abolishing whatever evils of sectarianism, narrow-mindedness and lack of loyalty to the cause to which we are devoted, that may exist. That it will promote a fraternal spirit among all exponents of natural healing, and create an increase of their prestige and power to resist the encroachments of official medicine on their constitutional rights of liberty and the pursuit of happiness, by favorably influencing Legislators, Law courts, City Councils and Boards of Health everywhere, is the sincere belief of the editor and publisher. Having introduced the volume, Lust leads off with his article entitled “The principles, aim and program of the nature cure system”. Again, this relatively brief article is reproduced here in its entirety, so that one can see the merging of influences: The principles, aim and program of the nature cure system Since the earliest ages, Medical Science has been of all sciences the most unscientific. Its professors, with few exceptions, have sought to cure disease by the magic of pills and potions and poisons that attacked the ailment with the idea of suppressing the symptoms instead of attacking the real cause of the ailment. Medical science has always believed in the superstition that the use of chemical substances which are harmful and destructive to human life will prove an efficient substitute for the violation of laws, and in this way encourages the belief that a man may go the limit in self indulgences that weaken and destroy his physical system, and then hope to be absolved from his physical ailments by swallowing a few pills, or submitting to an injection of a serum or vaccine, that are supposed to act as vicarious redeemers of the physical organism and counteract life-long practices that are poisonous and wholly destructive to the patient’s well-being. From the earliest ages to the present time, the priests of medicine have discovered that it is ten times easier to obtain ten dollars from a man by acting upon his superstition, than it is to extract one dollar from him, by appealing to reason and common sense. Having this key to a gold mine within their grasp, we find official medicine indulging at all times in the most blatant, outrageous, freakish and unscientific methods of curing disease, because the methods were in harmony with the medical prestige of the physician. Away back in pre-historic times, disease was regarded as a demon to be exorcized from its victim, and the medicine man of his tribe belabored the body of his patient with a bag in which rattled bones and feathers, and no doubt in extreme cases the tremendous faith in this process of cure that was engendered in the mind of the patient really cured some ailments for which mental science and not the bag of bones and feathers should be given credit. Coming down to the middle ages, the Witches’ Broth – one ingredient of which was the blood of a child murderer drawn in the dark of the moon – was sworn to, by official medicine, as a remedy for every disease. In a later period, the “docteur a la mode”, between his taking pinches of snuff from a gold snuff box, would order the patient bled as a remedy for what he denominated spirits, vapors, megrims, or miasms. Following this pseudo-scientific diagnosis and method of cure, came the drugging phase in which symptoms of disease were unmercifully attacked by all kinds of drugs, alkalis, acids and poisons which were supposed, that by suffocating the symptoms of disease, by smothering their destructive energy, to thus enhance the vitality of the individual. All these cures have had their inception, their period of extensive application, and their certain desuetude. The contemporary fashion of healing disease is that of serums, inoculations and vaccines, which, instead of being an improvement on the fake medicines of former ages are of no value in the cure of disease, but on the contrary introduce lesions into the human body of the most distressing and deadly import. The policy of expediency is at the basis of medical drug healing. It is along the lines of self-indulgence, indifference, ignorance and lack of self-control that drug medicine lives, moves and has its being. The sleeping swineries of mankind are wholly exploited by a system of medical treatment, founded on poisonous and revolting products, whose chemical composition and whose mode of attacking disease, are equally unknown to their originators, and this is called “Scientific medicine.” Like the alchemist of old who circulated the false belief that he could transmute the baser metals into gold, in like manner the vivisector claims that he can coin the agony of animals into cures for human disease. He insists on cursing animals that he may bless mankind with such curses. To understand how revolting these products are, let us just refer to the vaccine matter which is supposed to be an efficient preventive of smallpox. Who would be fool enough 28
to swallow the putrid pus and corruption scraped from the foulest sores of smallpox that has been implanted in the body of a calf? Even if any one would be fool enough to drink so atrocious a substance, its danger might be neutralized by the digestive juices of the intestinal tract. But it is a far greater danger to the organism when inoculated into the blood and tissues direct, where no digestive substances can possibly neutralize its poison. The natural system for curing disease is based on a return to nature in regulating the diet, breathing, exercising, bathing and the employment of various forces to eliminate the poisonous products in the system, and so raise the vitality of the patient to a proper standard of health. Official medicine has in all ages simply attacked the symptoms of disease without paying any attention to the causes thereof, but natural healing is concerned far more with removing the causes of disease, than merely curing its symptoms. This is the glory of this new school of medicine that it cures by removing the causes of the ailment, and is the only rational method of practicing medicine. It begins its cures by avoiding the uses of drugs and hence is styled the system of drugless healing. It came first into vogue in Germany and its most famous exponents in that country were Priessnitz, Schroth, Kuhne, Kneipp, Rickli, Lahmann, Just, Ehret, Engelhardt, and others. In Sweden, Ling and others developed various systems of mechano-therapy and curative gymnastics. In America, Palmer invented Chiropractic; McCormick, Ophthalmology. Still originated Osteopathy; Weltmer, suggestive Therapeutics. Lindlahr combined
the essentials of various natural methods, while Kellogg, Tilden, Schultz, Trall, Lust, Lahn, Arnold, Struch, Havard, Davis, Jackson, Walters, Deininger, Tyrell, Collins and others, have each of them spent a lifetime in studying and putting into practice the best ideas of drugless healing and have greatly enlarged and enriched the new school of medicine. Life Maltreated by Allopathy The prime object of natural healing is to give the principle of life the line of least resistance, that it may enable man to possess the most abundant health. What is life? The finite mind of man fails to comprehend the nature of this mysterious principle. The philosopher says “Life is the sum of the forces that resist death,” but that definition only increases its obscurity. Life is a most precious endowment of protoplasm, of the various combinations of oxygen, hydrogen, carbon and nitrogen, and other purely mineral substances in forming organic tissues. As Othello says, referring to Desdemona’s life, which he compares to the light of a candle – “If I quench thee thou flaming minister, I can thy former light restore Should I repent me; but once put out THY light, I know not whence is that Promethean heat That can thy light relume.” The spark of life flickers in the sockets of millions and is about to go out. What system of medicine will most surely restore that flickering spark to a steady, burning flame? Will [it be] the system that employs poisonous vaccines, serums and inoculations, whose medical value has to be supported by the most mendacious statements, and whose practitioners are far more intent on their emoluments and fame, than they are in the practice of humanity? The Allopathic system, which includes nine-tenths of all medical practitioners, is known by its fruits, but it is an appalling fact that infant mortality, insanity, heart disease, arteriosclerosis, cancer, debility, impoverished constitutions, degeneracy, idiocy and inefficiency have enormously increased, particularly during the last twenty-five years, that is, during the regime of inoculations, serums and vaccines. Naturopathy, on the other hand, so far as it has been developed, and so far as official medicine will allow it to act, leaves no such trail of disease, disaster and death behind it. Natural healing is emancipation from medical superstition, ignorance and tyranny. It is the true Elixir of Life. The Allopaths have endeavored to cure sick humanity on the basis of the highly erroneous idea that man can change the laws of nature that govern our being, and cure the cause of disease by simply ignoring it. To cure disease by poisoning its symptoms is medical manslaughter. Dr. Schwenninger of Germany says: “We are suffering under the curse of the past mistakes of our profession. For thousands of years medical doctors have been educating the public into the false belief that poisonous drugs can give health. This belief has become in the public mind such a deep-seated superstition, that those of us who know better and who would like to adopt more sensible, natural methods of cure, can do so only at the peril of losing practice and reputation. “The average medical man is at his best but a devoted bigot to this vain school-craft, which we call the Medical Art and which alone in this age of science has made no perceptible progress since the days of its earliest teachers. They call it recognized science! Recognized ignorance! The science of to-day is the ignorance of to-morrow. Every year some bold guess lights up as truth to which but the year before the schoolmen of science were as blind as moles.” And Dr. O.W. Holmes, Professor of Anatomy in Harvard University, states: “The disgrace of medicine has been that colossal system of self-deception, in obedience to which mines have been emptied of their cankering minerals, entrails of animals taxed for their impurities, the poison bags of reptiles drained of their venom, and all the inconceivable abominations thus obtained thrust down the throats of human beings, suffering from some fault of organization, nourishment, or vital stimulation.” And these misguided drug doctors are not only not ashamed of their work, but they have induced subservient legislators to pass laws that perpetuate the age-long scandal of allopathic importance, and the degenerative influence of the poisons, and to actually make it a crime on the part of nature doctors to cure a man of his ailment. The brazen effrontery of these medical despots has no limits. They boast of making the State legislators their catspaw in arresting, fining and imprisoning the professors of natural healing for saving human life. Legislators have no right to sit in judgment over the claims of rival schools of healing. They see tens of thousands of sick people go down to their graves by being denied the cures that the employers of nature’s forces alone can give them. It is their business to provide for the various schools of medicine a fair field and no favor. A citizen has an inalienable right to liberty in the pursuit of happiness. Yet the real saviors of mankind are persecuted by the medical oligarchy which is responsible for compulsory vaccination, compulsory medical inspection of public school children, and the demands for State and Federal departments of health, all for the ostensible good of the people, but in reality for the gain of the Medical Trust.
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The Naturopaths The Naturopaths are desirous of freedom for all schools of medicine. They are responsible practitioners who are willing to be examined by an impartial council, appointed by and acting for the State, who will testify to the life and character of every drugless physician before he is entitled to practice medicine. Not one invidious discrimination should be made between the different schools of medicine. The state should see to it that each school should have a full opportunity to do its best for the up-lifting of its citizens. The Program of Naturopathic Cure 1. ELIMINATION OF EVIL HABITS, or the weeds of life, such as over-eating, alcoholic drinks, drugs, the use of tea, coffee and cocoa that contain poisons, meat eating, improper hours of living, waste of vital forces, lowered vitality, sexual and social aberrations, worry, etc. 2. CORRECTIVE HABITS. Correct breathing, correct exercise, right mental attitude. Moderation in the pursuit of health and wealth. 3. NEW PRINCIPLES OF LIVING. Proper fasting, selection of food, hydropathy, light and air baths, mud baths, osteopathy, chiropractic and other forms of mechano-therapy, mineral salts obtained in organic form, electropathy, heliopathy, steam or Turkish baths, sitz baths, etc. Natural healing is the most desirable factor in the regeneration of the race. It is a return to nature in methods of living and treatment. It makes use of the
elementary forces of nature, of chemical selection of foods that will constitute a correct medical dietary. The diet of civilized man is devitalized, is poor in essential organic salts. The fact that foods are cooked in so many ways and are salted, spiced, sweetened and otherwise made attractive to the palate, induces people to over-eat, and over eating does more harm than under feeding. High protein food and lazy habits are the cause of cancer, Bright’s disease, rheumatism and the poisons of auto-intoxication. There is really but one healing force in existence and that is Nature herself, which means the inherent restorative power of the organism to overcome disease. Now the question is, can this power be appropriated and guided more readily by extrinsic or intrinsic methods? That is to say, is it more amenable to combat disease by irritating drugs, vaccines and serums employed by superstitious moderns, or by the bland intrinsic congenial forces of Natural Therapeutics, that are employed by this new school of medicine, that is Naturopathy, which is the only orthodox school of medicine? Are not these natural forces much more orthodox than the artificial resources of the druggist? The practical application of these natural agencies, duly suited to the individual case, are true signs that the art of healing has been elaborated by the aid of absolutely harmless, congenial treatments, under whose ministration the death rate is but five per cent of persons treated as compared with fifty per cent under the present allopathic methods. The Germanic influence The philosophical origins of naturopathy were clearly Germanic. The most significant influences, except those of Russell Trall and the Osteopathic concepts of A. T. Still (at this time strictly the correction of spinal lesions by adjustment), and the chiropractic principles of D. D. Palmer, were all Germanic. (This is well documented in the January 1902 editorial of Water Cure Monthly.) The specific influences drawn upon by Lust for his work, in order of their chronological contributions to the system of naturopathy, are the following: 1. 2. 3. 4. 5. 6. 7. 8.
Vincent Preissnitz (1799–1851) Johann Schroth (1798–1856) Father Sebastian Kneipp (1821–1897) Arnold Rickli (1823–1926) Louis Kuhne (c. 1823–1907) Henry Lahman (no dates known) F. E. Bilz (1823–1903) Adolph Just (?–1939).
Also of note were Theodor Hahn and Meltzer, who, in the 1860s, were well-known for their work in the movement called, in German, Naturatz or “naturism”. In photographs accompanying his article “The principles, aim and program of the nature cure system”, Lust described each of these thinkers as follows: 1. VINCENT PREISSNITZ, of Graefenberg, Silesia. Founder of Hydropathy. Born October 4, 1799. A pioneer Naturopath, prosecuted by the medical authorities of his day, and convicted of using witchcraft, because he cured his patients by the use of water, air, diet and exercise. He took his patients back to Nature – to the woods, the streams, the open fields – treated them with Nature’s own forces and fed them on natural foods. His fame spread over the whole of Europe, and even to America. His cured patients were numbered by the thousands. The Preissnitz compress or bandage is in the medical literature. Preissnitz is no more, but his spirit lives in every true Naturopath. 2. JOHANN SCHROTH, a layman, not described in Lust’s directory, but often talked of in later works and prominently mentioned for his curative theories in Bilz’s master work The Natural Method of Healing. Schroth smashed his right knee in an accident with a horse and it remained stiff in spite of repeated medical treatment. At last, a priest told Schroth that Preissnitz’s methods might help, and Schroth decided to give them a try. In order to avoid frequent changing of the packs that were directed by Preissnitz, he placed several packs on top of one another, wrapping the whole portion with a woolen cloth. He left this pack on the injured knee for several hours and produced a moist heat which he theorized to cause the poisonous toxins to dissolve and be swept away. These packs are still used as part of the “Schroth cure” and have reportedly become famous for their blood-cleansing effect. (From an article in the March 1937 Naturopath and Herald of Health by Dr. T.M. Schippel.) As noted by Bilz, the Schroth cure, called by Bilz “the regenerative treatment,” was developed for treatment of chronic diseases through the use of an extreme diet following total fasting by withdrawing of all food and drink and then the use of totally dry grain products and the eventual reintroduction of fluids. 3. FATHER SEBASTIAN KNEIPP, of course, is much described and the photos include one of Kneipp lecturing to the multitudes at Wandelhale at Woerishofen, attending Pope Leo XIII in 1893, noting this is the only consultation on health care matters that Kneipp ever consented to outside of Woerishofen, though many famous and aristocratic individuals desired his counsel, and a picture of Kneipp with 30
the Archdukes Joseph and Francis Ferdinand of Austria walking barefoot in new-fallen snow for purposes of hardening the constitution. It was noted that the older Archduke was cured by Father Kneipp of Bright’s disease in 1892, and it noted that the Archduke Joseph, in appreciation of this cure, donated a public park in the town of Woerishofen at a cost of $150,000 florens. The Archduke Francis Ferdinand, the son of Archduke Joseph, was the individual whose murder precipitated World War I. There is a further picture of Father Kneipp surrounded by “Doctors” from different parts of the world while he gave consultation to numerous patients. 4. ARNOLD RICKLI, founder of the light and light and air cures (atmospheric cure). Dr. Rickli was one of the foremost exponents of natural living and healing. In 1848, he established at Veldes, Krain, Austria, the first institution of light and air cure or as it was called in Europe the “atmospheric cure”. In a limited way (rather very late) his ideas have been adopted by the medical profession in America for the cure of consumption. He was an ardent disciple of the vegetarian diet and exemplified the principles of natural living in his own life. The enclosed photo shows him at the age of 97, when he was still active and healthy. He has since passed on, but his work still lives as a testimonial of his untiring efforts. He was the founder and for over 50 years the President of the National Austrian Vegetarian Association. 5. LOUIS KUHNE wrote, in 1891, The New Science of Healing, the greatest work of basic principles in natural healing. In the tradition of Natural Healing and prevention, Kuhne has been described as one who “… advocated sun, steam baths, a vegetarian diet, and whole-wheat bread …” in these relatively early days”. His renowned work constitutes the only true scientific philosophy for the application of all Drugless Methods. He was the first to give to the world the comprehensible idea of pathology and the first to proclaim the doctrine of the “unity of cure.” His book Facial Expression gives the means of diagnosing a patient’s pathological condition and determining the amount and location of the systemic encumbrance. He is the founder and first Master of Naturopathy. 6. DR. H. LAHMAN. When the University of Leipzig expelled H. Lahman for his spreading medical sedition among the students, it added a staunch advocate to natural healing. Dr. Lahman finished his medical education in Switzerland and returned to Germany to refute in practice the false ideas of medical science. He later founded the largest Nature Cure institution in the world at Weisser Hirsch, near Dresden, Saxony. He was a strong believer in the “Light and Air” cure and constructed the first appliances for the administration of electric light treatment and baths. He was the author of several books on Diet, Nature Cure and Heliotherapy. As noted in Other Healers, Other Cures: “Heinrich Lahmann came along to stress no salt on foods and no water with meals …”* His works on diet are authoritative and his “nutritive salts theory” forms the basis of rational dietetic treatment. This work has but recently come to light in America, and progressive dietitians are forsaking their old, worn-out, high protein, chemical and caloric theories for the “organic salts theory.” Carque, Lindlahr, McCann, and other wide awake food scientists have adopted it as a basis for their work. Dr. Lahman was a medical nihilist. He denounced medicine as unscientific and entirely experimental in its practice and lived to prove the saneness of his ideas as evidenced by his thousands of cured patients. 7. PROFESSOR F.E. BILZ. That real physicians are born, not made, is well illustrated in the case of Dr. Bilz, who achieved his first success in healing as a lay practitioner. As a mark of gratitude, a wealthy patient presented him with land and a castle in which to found a Nature Cure sanitarium… The Bilz institution at Dresden-Rdebeul, Germany, became world renowned and was long considered the center of the Nature Cure movement. Professor Bilz is the author of the first Naturopathic encyclopedia, The Natural Method of Healing, which has been translated into a dozen languages, and in German alone has
run into 150 editions. He has written many works on Nature Cure and Natural Life, among them being The Future State, in which he predicted the present World War, and advocated a federation of nations as the only logical solution of international problems. 8. ADOLPH JUST, famous author of Return to Nature and founder of original ‘Yungborn’ in Germany. Both Adolph Just’s Return to Nature and Louis Kuhne’s The Natural Science of Healing were translated into English by Lust and released through his publication house. The convergence with American influences The Universal Naturopathic Directory was truly eclectic in its compilation and composition. Besides the Lust article noted previously, the volume included: “How I became acquainted with nature cure” by Henry Lindlahr MD ND (which has been reproduced in large part in the introduction to volume 1 of Lindlahr [13] ); “The nature cure” by Carl Strueh MD ND; “Naturopathy” by Harry E. Brook ND; “The present position of naturopathy and allied therapeutic measures in the British Isles” by J. Allen Pattreiouex ND; “Why all drugless methods?” by Per Nelson; and “Efficiency in drugless healing” by Edward Earle Purinton (a reprint of the 1917 publication, referred to earlier, which was composed of a series of articles published in The Herald of Health and Naturopath between August 14 and February 1916). The volume also contained Louis Kuhne’s “Neonaturopathy (the new science of healing)” in the first publication of the translation by Lust, and articles on electrotherapy, neuropathy, dietology, chiropractic, mechanotherapy, osteopathy, phytotherapy, apyrtropher, physical culture, optometry, hydrotherapy, orthopedics, pathology, natural healing and living, astroscopy, phrenology, and physiology – all of which were specially commissioned for the directory from practitioners and authors considered expert in these subjects. The volume also included the directory of drugless physicians in alphabetical order, geographically arranged, and itemized by profession; biographical notes on American contributors of note; the naturopathic book catalog; a guide to natural healing and natural life books and periodicals; a classified list of medical works, a series of book reviews; a buyer’s guide for naturopathic supplies; and, in addition to extensive indexes, a “parting word” by Lust. * See Kruger.[ 16]
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In addition, the volume contained numerous advertisements for naturopathic schools, sanitariums and individual practices, and closed with the following note: This, then, completes Volume 1 of the Naturopathic Directory, Drugless Yearbook and Buyer’s Guide for the years 1918 and 1919. Into it, has been placed the conscientious labor of many willing hearts, hands and minds. It is their contribution to the noble cause of natural healing. It will stand as a monument to their endeavors, as well as a memorial to the great souls, the fathers of natural healing, who have passed on. Let this, then, herald a new era – the era wherein man shall recognize the omniscience of Nature, and shall profit through conforming to her laws. In the biographical section, it becomes apparent that Lust owed a great deal of the feeling of camaraderie in the nature cure movement to some varied American practitioners. The most prominent of these have had their biographical sections as contained in the 1918 directory. Two of them deserve specific note and attention: Palmer and Still. Lust met A. T. Still in 1915 in Kirksville, Missouri, shortly before Still’s death. From their meetings, Lust noted later in the Naturopath and Herald of Health (June 1937) that Still believed that osteopathy by “… compromising with medicine … is doomed as the school that could have incorporated all the natural and biological healing arts …”. Lust wanted naturopathy to fill this void. Lust also had lengthy acquaintance with B. J. Palmer (the son of D. D. Palmer, the founder of chiropractic), who, following in his father’s footsteps, put Davenport, Iowa, and the Palmer Chiropractic College on the map. Lust also became connected with Henry Lindlahr MD ND of Chicago, Illinois (as noted in the autobiographical sketch contained in the directory [14] and reprinted in the volume 1 of Lindlahr [13] ). Lindlahr was a rising businessman in Chicago with all the bad habits of the “gay nineties” era. Only in his 30s, he had begun to be chronically ill. He had gone to the orthodox practitioners of his day and received no relief. Then he was exposed to Schroth’s works, and in following them began to feel somewhat better. Subsequently, he liquidated all his assets and went to Germany to stay in a German sanitarium to be cured and to learn nature cure. He then came back to Chicago and enrolled in the Homeopathic/Eclectic College of Illinois. In 1903, he opened a sanitarium, which included a residential sanitarium, located in Elmhurst, Illinois, a “transient” clinic (office) on State Street in Chicago, and “Lindlahr’s Health Food Store”. Shortly thereafter he founded the Lindlahr College of Natural Therapeutics, which included hospital internships at the sanitarium. The institution became one of the leading naturopathic colleges of the day. In 1908, he began to publish Nature Cure Magazine and began publishing his series of Philosophy of Natural Therapeutics, with volume 1 (“Philosophy”) in 1918. This was followed by volume 2 (“Practice”) in 1919, volume 3 (“Dietetics”; republished with revisions as it had originally been published in 1914), and, in 1923, volume 6 (“Iridiagnosis”). The intended volumes 4 and 5 were in production at the time of Lindlahr’s death in 1927. As described in Other Healers, Other Cures: Henry Lindlahr, another American, is remembered for his conviction that disease did not represent an invasion of molecules, but the body’s way of healing something. In other words, he viewed symptoms as a positive physiological response-proof that the body is fighting whatever’s wrong. Accordingly, a fever is a “healthy” sign and one should be let alone, unless it is dangerously high, of course. The impact of all of these gentlemen on the development of naturopathy in America, under Lust’s guidance, was profound. From these beginnings, the naturopathic movement gathered strength and continued to grow through the 1920s and 1930s, having a major impact on natural healing and natural lifestyle in the United States. Along the way, Lust was greatly influenced by the writings of John H. Tilden MD (largely published between 1915 and 1925). Tilden was originally a practicing physician in Denver, Colorado, who became disenchanted with orthodox medicine and began to rely heavily on dietetics and nutrition, formulating his theories of “auto-intoxication” (the effect of fecal matter remaining too long in the digestive process) and “toxemia”. Lust was also greatly influenced by Elmer Lee MD, who became a practicing naturopath in about 1910, and whose movement was called the “hygienic system”, following the earlier works of Russell Trall. Lee published Health Culture for many years. In addition to John Tilden MD and Elmer Lee MD, another medical doctor, John Harvey Kellogg MD, who turned to more nutritionally based natural healing concepts, was greatly respected by Lust. Kellogg was renowned through his connection with the Battle Creek Sanitarium. The sanitarium itself was originally founded in the 1860s as a Seventh Day Adventist institution designed to perpetuate the Grahamite philosophies of Sylvester Graham and William Alcott. The sanitarium was on the verge of being closed, however, due to economic failure, when in 1876 Kellogg, a new and more dynamic physician-in-chief, was appointed. Kellogg, born in 1852, was a “sickly child” who, at the age of 14, ran across the works of Graham and converted to vegetarianism. At the age of 20 he studied for a term at Trall’s Hygio-Therapeutic College and then earned a medical degree at New York’s Bellevue Medical School. He maintained an affiliation with the regular schools of medicine during his lifetime, due more to his practice of surgery, than his beliefs in the area of health care. [3]
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Kellogg designated his concepts, which were basically the hygienic system of healthful living, “biologic living”. Principally, Kellogg defended vegetarianism, attacked sexual misconduct and the evils of alcohol, and was a prolific writer through the late 19th century and early 20th century. He produced a popular periodical, Good Health, which continued in existence until 1955. When Kellogg died in 1943 at the age of 91, he had had more than 300,000 patients through the Battle Creek Sanitarium (which he had renamed from Western Health Reform Institute shortly after his appointment in 1876), including many celebrities, and the “San” became nationally well known. Kellogg, along with Tilden and Elie Metchnikoff (director of the prestigious Pasteur Institute and winner of the 1908 Nobel Prize for a contribution to immunology), wrote prolifically on the theory of “auto-intoxication”. Kellogg, in particular, felt that humans, in the process of digesting meat, produced a variety of intestinal self-poisons that contributed to “auto-intoxication”. As a result, Kellogg became a near fanatic on the subject of helping humans to return to a more healthy natural state by returning to the naturally designed usage of the colon. He felt that the average modern colon was devitalized by the combination of sedentary living, the custom of sitting rather than squatting to defecate, and the modern civilized habit of ignoring “nature’s call” out of an undue concern for politeness. Further, Kellogg concentrated on the fact that the modern diet had insufficient bulk and roughage to stimulate the bowels to proper action. Kellogg was also extremely interested in hydrotherapy. In the 1890s, he established a laboratory at the San to study the clinical applications of hydrotherapy. This led, in 1902, to his writing Rational Hydrotherapy. The preface espoused a philosophy of drugless healing that came to be one of the bases of the hydrotherapy school of medical thought in America. Tilden, as mentioned, was of a similar mind. Indeed, he had to have been to have provided natural health care literature with his 200-plus page dissertation entitled “constipation”, with a whole chapter devoted to the evils of not responding when nature called. This belief in the “evils” drawing away from the natural condition of the colon was extremely important to Kellogg’s work. New Dietetics (1921) became one of the bibles of naturopathic literature. [15]
[3]
Because of Lust’s interest, Kellogg’s The
Lust was also influenced by the works of Sidney Weltmer, the father of “suggestive therapeutics”. The theory behind Professor Weltmer’s work was that whether it was the mind or the body that first lost its grip on health, the two were inseparably related. When the problem originated in the body, the mind nonetheless lost its ability and desire to overcome the disease because the patient “felt sick”, and consequently slid further into the diseased state. Alternatively, if the mind first lost its ability and desire to “be healthy” and some physical infirmity followed, the patient was susceptible to being overcome by disease. Weltmer’s work dealt specifically with the psychological process of desiring to be healthy. Lust enthusiastically backed Weltmer’s work and had him on the program at various of the annual conventions of the American Naturopathic Association (which commenced after its founding in 1919). Lust was also personal friends with and a deep admirer of Bernarr MacFadden. MacFadden was the founder of the “physical culture” school of health and healing, also known as “physcultopathy”. This school of healing gave birth across the country to gymnasiums at which exercise programs, designed to allow the individual man or woman to maintain the most perfect state of health and human condition possible, were developed and taught. [3] As described in Other Healers, Other Cures (p. 182): [16] The next Naturopathic star, after Kellogg, was Bernarr MacFadden, the physical culturist who built a magazine-publishing empire (his first magazine was Physical Culture founded in 1898.) MacFadden proselytizes for exercise and fresh vegetables, hardly eccentric notions. But his flamboyant efforts to publicize them and his occasional crack-pot ideas (like freezing the unemployed, then thawing them out when the Depression was over) alienated many people. Still, he was his own best advertisement. He fathered nine children by four wives and was parachuting from planes in his 80s. One of MacFadden’s admirers was that arch-foe of the medical profession, George Bernard Shaw, the longevous eccentric in his own right … Lust was also very interested in, and helped to publicize “zone therapy”, originated by Joe Shelby Riley DC, a chiropractor based in Washington, DC, and one of the early practitioners of “broad chiropractic”. Zone therapy was an early forerunner of acupressure as it related “… pressures and manipulations of the fingers and tongue, and percussion on the spinal column, according to the relation of the fingers to certain zones of the body …”. [14] Several other American drugless healers contributed to a broad range of “-opathies” that Lust merged into his growing view of naturopathy as the eclectic compilation of methods of natural healing. The Universal Directory also contained a complete list of osteopaths and chiropractors as drugless healers within the realm of Lust’s view of naturopathic theory. His other significant compatriots at the time of the publication of the directory were Carl Stueh, described by Lust as “… one of the first medical men in this country who gave up medicine and operation for natural healing”, F. W. Collings MD DO DC, an early graduate of the American School of Naturopathy (1907) who went on to graduate from the
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New Jersey College of Osteopathy (1909) and the Palmer School of Chiropractic (1912), another “broad chiropractor”, Anthony Matijaca MD ND DO, the naturopathic resident expert in electrotherapy and an associate editor of the Herald and Health Naturopath (the inverted name of the Lust journal at the time of the directory), and Carl Schultz ND DO MD, president and general manager of the Naturopathic Institute and Sanitorium of California, essentially the second school in the country to pursue the education of physicians under the name of “naturopathy.”
EARLY 20th-CENTURY MEDICINE The metamorphosis of orthodox medicine In many ways, the progressive health era of 1900–1917 not only marked the formative years of naturopathy, but were also its halcyon days. In many jurisdictions, modern licensing laws, crafted during this time, were not yet in effect, so varied views of health care could be openly practiced. By 1920, however, the American world of medicine had undergone a sharp transition, culminating four decades of change. A look at the structure of early medical care in the United States, even as practiced and dominated by the orthodox school, is instructive, when one notes the changes occurring between 1875 and 1920. In 1875 the following was generally true of American medical practice: • The practice, even in urban areas, sent the doctorto the patient; the “house call” was the norm. • There was little modern licensing regulation. • Hospitals were charitable institutions where persons too poor to otherwise receive health care were usually sent when ill. • The AMA, although formed in 1846, and generally representative of the professional goals of the regularor orthodox school of medicine, had scarcely begun to make any political inroads at all. • Medical schools required little or no college education for entrance, and were largely apprenticeship-based and proprietary in nature, having changed little throughout the century. • Although some doctors had begun to specialize, to do so was far from the norm. The major recognized specialties were surgery, obstetrics and gynecology. • There were many different types of doctors and society’s recognition of the profession neither recognized specific expertise nor necessarily rewarded professionals in medical practice well. • Although the orthodox school made up roughly 80% of the professional medical practitioners, the homeopaths and the eclectics were visible and respected
intheir own communities for their abilities and expertise, and much of the public relied on other “irregular” practitioners. By comparison, in 1920, total metamorphosis of medicine as a profession had occurred: • By 1920, practices had become office- and clinic-oriented. • Modern licensing principles had become fully developed, and physicians and surgeons were licensedin all jurisdictions. Most other health care providershad some licensing restrictions placed upon them if they were recognized at all. • Due largely to the introduction into surgery of the practice of antiseptic techniques and aseptic procedures, and a correspondent decline in operative mortality, institutional care in the hospital became increasingly accepted. Also, clinical pathology and diagnostic laboratory procedures had become well developed, the hospital had become a major training and clinical research facility, and generally more acceptable to the patient. • The AMA was approaching the peak of its political power, having exercised, through its Council on Medical Education and its Council of Pharmacy and Chemistry, major effects on medical schools and the pharmaceutical industry. • The transition to research and education-based medical schools, instead of practitioner apprenticeships and proprietary education, had become complete. All recognized medical schools had a 4-year curriculum,with an undergraduate degree or substantial undergraduate study required as a prerequisite. In addition, most schools, in conjunction with most licensing statutes, required a year’s internship. • Specialization was becoming well developed, and the number of specialty groups had increased considerably. This would continue through the 1930s andinto the early 1940s. • Professional authority and autonomy had undergone a substantial transition; and the allopathic physician was now recognized as the medical expert. • By 1922, the last eclectic school was on the vergeof closure, and in the early 1930s the last of the homeopathic schools in the United States was also on the verge of closure. The influence of these sects on orthodox medicine had dwindled to almost nothing. Naturopaths and other alternative health care practitioners had adopted the areas of expertise previously considered the territory of homeopaths and eclectics. The halcyon years of naturopathy In 1924, Morris Fishbein succeeded George Simmons as editor of the Journal of the American Medical Association (JAMA). Fishbein had joined the editorial staff of JAMA under Simmons immediately following his graduation
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from Chicago’s Rush Medical School in 1913. As Campion points out: [7] Over the years Fishbein not only established himself as the gifted editor of the most widely read medical journal in the United States; he also learned how to extend his editorial position, how to project his opinions nationwide. He became, as the saying went in those years, a “personality.” TIME referred to him as “the nation’s most ubiquitous, the most widely maligned, and perhaps most influential medico.” In addition to his development of JAMA as an editorial and personal voice, Fishbein also continually railed against “quackery”. Lust, among others, including MacFadden, became Fishbein’s epitome of quackery. When MacFadden became a wealthy man, after his publishing company included popular magazines like True Confessions and True Detective, he began campaigning for the 1936 Republican presidential nomination. In response, a physician submitted, under the initials “K.G.”, a tongue-in-cheek listing of the cabinet that would exist under MacFadden, including the newly created “Secretary of Aviation” for Benedict Lust. Lust was a popular figure by this time who conducted such a busy lecture schedule and practice, alternating between the “Yungborns” in Butler, New Jersey, and Tangerine, Florida, that he had become almost as well known as an airline traveler. Lust devoted a complete editorial in Nature’s Path to a response. If Fishbein had JAMA as a personal editorial outlet, Lust had his own publications. Commencing with the Naturopath and Herald of Health in 1902 (which changed its name to Herald of Health and Naturopath in 1918), Lust continually published this and other monthly journals. In 1919, it became the official journal of the American Naturopathic Association, mailed to all members. Each edition contained the editorial column “Dr Lust speaking”. In the early 1920s, the “health fad” movement was reaching its peak in terms of public awareness and interest. As described, somewhat wistfully, in his June 1937 column, Lust announced the approach of the 41st Congress of Natural Healing under his guidance: The progress of our movement could be observed in our wonderful congresses, in 1914 Butler, N.J., 1915 Atlantic City, 1916 in Chicago, 1917 Cleveland, 1918 New York, 1919 Philadelphia, 1920 and 1921 again New York, and 1922 in Washington, D.C., where we had the full support and backing of the Congress of the United States. President Harding received the president and the delegates of our convention and we were the guests of the City of Washington. Through the strenuous efforts of Dr. T.M. Schippel, Hon. Congresswoman Catherine Langley of Kentucky, and eight years of hard work financed and sustained by Dr. Schippel and her powerful friends in Congress, Naturopathy was fully legalized as a healing art in the District of Columbia and the definition was placed on record and the law affirmed and amended by another act which has been fully published over and over again in the official journal of the A.N.A., Naturopath. In 1923 in Chicago, with the help and financing of the great and never-to-be forgotten Dr. Henry Lindlahr, we had a great convention. Not only were all the Naturopaths there but even to an extent our congress was recognized and acknowledged as official and of great importance by the medical people, particularly by the Health Commissioner of Chicago. We held a banquet, and there were discussions covering all platforms of the healing art. It was the first congress in the United States where medicine and Naturopathy in all its branches such as the general old-time Nature Cure, Hydrotherapy and Diet, Osteopathy, Naprapathy, Chiropractic, Neuropathy and Physiotherapy were represented on the same platform. The speakers represented every modern school of healing and the movement at that time was in the direction of an entirely recognized and independent school of healing. There were two camps, official medicine and official Naturopathy, the medical camp having all that is good and bad in medicine and surgery and all the other schools of healing that had sold their birthright and trusted to the allurement of organized medicine, such as Homeopaths, Eclectics, Physio-medics, and the Osteopaths to a large extent. The Osteopaths were always in the wrong camp when they went on mixed boards and Dr. Andrew Taylor Still, the father of Osteopathy, told me in 1915 that by compromising with medicine Osteopathy is doomed as the school that could have incorporated all of the natural and biological healing arts. The year following we had the great congress in Los Angeles which has never been duplicated. We had to meet in two hotels because the crowds ran over 10,000. The glorious banquet will never be forgotten and the congress celebrated and demonstrated that the initial and first intent of the A.N.A. to teach the public Natural Living and Nature Cure was realized. We will never forget the glorious week in Los Angeles where the authorities and the whole city joined us. The success of that congress was largely due to the talent of Dr. Fred Hirsch, the successor to Prof. Arnold Ehret and the noble and generous Naturopaths of the A.N.A. of Cal. There was never a second congress like that. Then we had the great congresses of New York in 1925, Indianapolis 1926, Philadelphia 1927, Minneapolis 1928, Portland, Oregon 1929, New York 1930, Milwaukee 1931, Washington, D.C., 1932, Chicago 1933, Denver 1934, San Diego 1935, and Omaha 1936. In 1925, Lust began to try to reach more of the general populace through the lay publication Nature’s Path. The Naturopath and Nature’s Path were later merged because the self-supporting advertising and subscription monies were more available by publication to the general populace than to the members of the association (The Naturopath, 1902–1927; Nature’s Path, 1925–1927; merged 1927–1933; separated 1934–1938; Nature’s Path, 1939–?). In January of 1934, Lust commenced republication under the title Naturopath and Herald of Health in addition to Nature’s Path. Each of the volumes opened with his column, which was different for each publication. Both publications were issued continuing through 1938, when the Nature’s Path again became the sole publication until Lust’s death in 1945. Although, after the Universal Directory, Lust continued to write volumes on naturopathic principles, he was more of a synthesizer, organizer, lecturer, and essayist than a lasting scientific author of naturopathic articles.
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His most enduring contributions remain his early translations of Kuhne’s and Just’s works. During the 1920s and up until 1937, Lust’s brand of “quackery”, as labeled by Fishbein, was in its most popular phase. Although the institutional markings of the orthodox school had gained ascendancy, prior to 1937 it had no real solutions to the problems of human disease. Instructive in this regard is Louis Thomas’ interesting work The Youngest Science. Thomas compares his education and internship as a physician to his father’s life as a physician. His father believed that bedside manner was more important than any actual medication offered by the physician. Indeed, his father went into general surgery so that he could offer some service to his patients that actually made some change in their condition. Thomas points out that the major growth of “scientific medicine” up until 1937 advanced diagnosis rather than offering any hope of cure. During this period of time, Lust’s naturopathic medicine, and both chiropractic and osteopathic medicine, continued to be on the outside looking in. Practitioners of all three groups were continually prosecuted for practicing medicine without a license, although they often won their cases by establishing before juries that their practices were, even according to the testimony of medical men, not the same at all. Additionally, because the orthodox practitioners could offer little or no actual hope of cure for many diseases, the “health food and natural health” movement was generally popular. During the 1920s, Gaylord Hauser, later to become the health food guru of the Hollywood set, came to Lust as a seriously ill young man. Lust, through application of the nature cure, removed Hauser’s afflictions and was rewarded by Hauser’s lifelong devotion. His regular columns in Nature’s Path became widely read among the Hollywood set. As noted in Other Healers, Other Cures (p. 183):[16] The last big name in Naturopathy was Gaylord Hauser, a Viennese-Born food scientist (as one of his early books identified him) turned to Naturopathy in his later years. He is best remembered for advising the eating of living foods, not dead foods, and for escorting Greta Garbo around. In addition to fresh fruits and vegetables, Hauser’s “Wonder Foods” were skinned milk, brewers yeast, wheat germ, yogurt, and black strap molasses. In 1937, however, all this began to change. The change came, as both Thomas and Campion note in their works, with the era of “miracle medicine”. Lust recognized this and his editorializing became, if anything, even more strident. From the introduction of sulfa drugs in 1937 to the Salk vaccine’s release in 1955, the American public became used to annual developments of miracle vaccines and antibiotics. Benedict Lust died in September of 1945 in residence at the Yungborn facility in Butler, New Jersey, preparing to attend the 49th Annual Congress of his American Naturopathic Association. On 30 August 1945, for the official program of that congress which was held in October 1945 just after his death, he dictated the following remarks: What is the present condition of Naturopathy? What is its future? I can give my opinion in a very few words. For fifty years I have been in the thick of the fight to bring to the American people the Nature Cure. During that period I have had an opportunity to judge what Naturopathy has done, and can accomplish and the type of men and women, past and present, who make up the Naturopathic ranks. Let us take the present situation first. What is Naturopathy accomplishing? The answer to that is: “Everything.” Naturopathy holds the key for the prevention, alleviation and cure of every ailment, to man and beast alike. It has never failed in the hands of a competent Naturopath. Whatever the body can “catch” – that same body, with proper handling, can eliminate. And that takes in cancer, tumors, arthritis, cataract and the whole gamut of “incurable medical” disease and ailments. During my years of practice I, personally, have seen every type of human ailment and so-called serious “disease” give way to the simple, proven Naturopathic methods. I make no exception to that statement. Now let us see the type of men and women who are the Naturopaths of today. Many of them are fine, upstanding individuals, believing fully in the effectiveness of their chosen profession – willing to give their all for the sake of alleviating human suffering and ready to fight for their rights to the last ditch. More power to them! But there are others who claim to be Naturopaths who are woeful misfits. Yes, and there are outright fakers and cheats masking as Naturopaths. That is the fate of any science – any profession – which the unjust laws have placed beyond the pale. Where there is no official recognition and regulation, you will find the plotters, the thieves, the charlatans operating on the same basis as the conscientious practitioners. And these riff-raff opportunists bring the whole art into disrepute. Frankly such conditions cannot be remedied until suitable safeguards are erected by law, or by the profession itself, around the practice of Naturopathy. That will come in time. Now let us look at the future. What do we see? The gradual recognition of this true healing art – not only because of the efforts of the present conscientious practitioners but because of the bungling, asinine mistakes of orthodox medicine – Naturopathy’s greatest enemy. The fiasco of the sulpha drugs as emphasized disastrously in our armed forces is just one straw in the wind. The murderous Schick test – that deadly “prevention” of diphtheria – is another. All these medical crimes are steadily piling up. They are slowly, but inevitably, creating a public distrust in all things medical. This increasing lack of confidence in the infallibility of Modern Medicine will eventually make itself felt to such an extent that the man on the street will turn upon these self-constituted oppressors and not only demand but force a change. I may not be here to witness this revolution but I believe with all my soul that it is coming. Yes, the future of Naturopathy is indeed bright. It merely requires that each and every true Naturopath carry on – carry on – to the best of his and her abilities. May God bless you all. The naturopathic journals of the 1920s and 1930s are instructive. Much of the dietary advice focused on poor eating habits, including the lack of fiber in the diet and
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an overreliance upon red meat as a protein source. Over half a century later in the 1980s, the pronouncements of the orthodox profession, the National Institute of Health and the National Cancer Institute finally became aware of the validity of the early assertions of the naturopaths that such dietary habits would lead to degenerative diseases, including cancers associated with the digestive tract and the colon. The December 1928 volume of Nature’s Path was the first American publication of the works of Herman J. DeWolff, a Dutch epidemiologist who was one of the first individuals to assert, based on studies of the incidence of cancer in the Netherlands, that there was a correlation between exposure to petrochemicals and various types of cancerous conditions. He saw a connection between chemical fertilizers and their usage in some soils (principally clay) that led to their remaining in vegetables after they had arrived at the market and were purchased for consumption. Again, it was 50 years later before orthodox medicine began to see the wisdom of such assertions. The emerging dominance of AMA medicine The introduction of “miracle medicine”, the impact of World War II on health care, and the death of Benedict Lust in 1945, all combined to cause the decline of naturopathic medicine and natural healing in the United States. (During the war, the necessity for crisis surgical intervention techniques for battlefront wounds encouraged use of morphine and sulfa drugs, and penicillin for diseases not previously encountered by American citizens. This resulted in rapid development of high-technology approaches to medicine and highly visible successes.) The effects of these events on osteopathy and chiropractic, however, were completely different. In the early days of osteopathy, there was a significant split between the strict drugless systems advocated by A. T. Still, and the beliefs of many MDs who were converted to osteopathy because of its therapeutic value. The latter group did not want to abandon all of the techniques they had previously learned and all of the drugs they had previously used when those therapy techniques were sometimes effective. Ultimately, most schools of osteopathy, commencing with the school based in Los Angeles, California, converted to more of an imitation of modern orthodox medicine. These developments led to more of an accommodation between the California osteopaths and the members of the California Medical
Association. (This developing cooperation between the California Osteopathic and Medical Association was one of the major issues leading to the downfall, in 1949, of Fishbein’s editorial voice in JAMA.) Thus, osteopathy found a place in professional medicine, at the cost of its drugless healing roots and therapies. [7] The effect on chiropractic of the post-war years was somewhat different. Because of educational recognition under the G.I. Bill, the number of chiropractors in the country grew substantially, and their impact on the populace grew accordingly. The sect eventually grew powerful enough in terms of numbers and economic clout that it could pose a legal challenge to the orthodox monopoly of the AMA. However, in the immediate post-war years, the American Medical Association gained tremendous political clout. Combined with the American Legion and the National Board of Realtors, [17] these three groups posed a powerful political triumvirate before the United States Congress. These years, called the years of the “great fear” in Caute’s book by that name, [18] were the years during which to be unorthodox was to be “un-American”. Across the country, courts began to take the view that naturopaths were not truly doctors, as they espoused doctrines from “the dark ages of medicine” (something American medicine had apparently come out of in 1937) and that drugless healers were intended by law to operate without “drugs” (which became defined as anything a person would ingest or apply externally for any remedial medical purpose). In this regard, the Washington State Supreme Court case of Kelly vs. Carroll (the defendant being Otis G. Carroll of Spokane, Washington, a long-time follower, with his brother Robert V. Carrol, Sr, of Lust), and the Arizona State Supreme Court case of Kuts-Cheraux vs. Wilson document how significant limitations were placed on naturopaths under the guise of calling them “drugless healers”. In the state of Tennessee, as a reaction to the 1939 publication of the book Back to Eden by herbalist Jethro Kloss, court action initiated by the Tennessee State Medical Association led first to the publishers being forbidden to advertise the book for any therapeutic purpose. They were allowed only to acknowledge that it was in stock. The Tennessee State Legislature then declared that the practice of naturopathy in the state of Tennessee would be considered a gross misdemeanor, punishable by up to 1 year in jail. Although it was under considerable public pressure in those years, the American Naturopathic Association undertook some of its most scholarly work, coordinating all the systems of naturopathy under commission. This resulted in the publication of a basic textbook on naturopathy ( Basic Naturopathy published in 1948 by the ANA [19] ) and a significant work compiling all the known theories of botanical medicine (as commissioned by the ANA’s successor after its 1950 name change to the American Naturopathic Physicians and Surgeons Association), the Naturae Medicina published in 1953. [20] Naturopathic medicine began splintering when Lust’s ANA was succeeded by six different organizations in the mid 1950s.
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The primary organizations among these were the successor to the ANA, which underwent a name change in 1950 to the American Naturopathic Physician and Surgeon’s Association, and subsequently changed to the American Association of Naturopathic Physicians in 1956, and the International Society of Naturopathic Physicians formed under the leadership of M. T. Campenella of Florida shortly after Lust’s death, with its American offshoot, the National Association of Naturopathic Physicians. By 1955, the AANP, as it ultimately became known, had recognized only two schools of naturopathic medicine, the Central States College of Physiatrics in Eaton, Ohio, under the leadership of H. Riley Spitler, and Western States College of Chiropractic and Naturopathy located outside Portland, Oregon, under the leadership of R. A. Budden. Budden was a Lindlahr graduate and among the group which took over control of the Lindlahr College after Lindlahr’s death in the 1920s. He moved west after World War II when the north-west States, including Oregon, became the last bastion of naturopathic medicine in this country.
THE MODERN REJUVENATION After the counter-culture years of the late 1960s and America’s disenchantment with organized institutional medicine, which began after the miracle era faded and it became apparent that orthodox medicine had its limitations, alternative medicine began to gain new respect. Naturopathic medicine underwent an era of rejuvenation. As succinctly described in Cassedy’s Medicine in America: A Short History, [21] this phenomenon, which is not limited to naturopathic medicine, is consistent with the modern, and continuing, “search for health beyond orthodox medicine” (pp. 147–148): It should not have been surprising to anyone that certain organized therapeutic sects continue to exist in mid-twentieth century America as successful and conspicuous alternatives to regular medicine. This is not to say that they offer the same threats to the medical establishment or play the same roles as their nineteenth-century counterparts had, as complete therapeutic systems. But they do continue to hold a strong collective appeal for individuals who mistrust or are somehow disenchanted with main line medicine. They have appealed also to anti-authoritarian sentiments that flourish throughout society. Moreover, as earlier, they satisfy a variety of needs that regular medicine continues to neglect or ignore. The same author, in describing the post-World War II decades and the changing fortunes of such healing theories as naturopathic medicine, observed as follows: The period also brought about the renewal or updating of certain previously widely used therapies and considerable experimentation with others, some of them exotic. To an extent this trend represented the rediscovery by trained physicians, nurses, and other regular health professionals of certain values and older styles of therapy. The participation of such professionals proved to be an essential ingredient in the rebirth of several such therapies. However, the major reason for the new successes was the wide-spread active interest and involvement of America’s literate lay people in the search for more personal or humane forms of treatment. As another author, John Duffy, has observed in From Humors to Medical Science (p. 350):[22] Since health is too closely related to cultural, social, and economic factors to be left exclusively to doctors, American lay people have always engaged in do-it-yourself medicine, resorted to “irregulars and quacks”, and supported health movements. As a result of the current fad for physical fitness, our streets are beset by sweat-suited individuals of all ages doggedly jogging their way to health and long life. In addition, stores selling “natural” foods are flourishing, physical fitness salons have become a major business, and anti-smoking and weight-loss clinics and workshops are attracting thousands of individuals bent on leading cleaner and leaner lives. And those for whom physical activity in itself is not enough are seeking physical and mental well-being through faith healing, yoga, and a host of major and minor gurus. When neither mental effort nor physical exercise can solve medical problems, the sceptics of modern medicine can always turn to the irregulars. A recent estimate places a number of Americans who have relied on an irregular practitioner at some time in their lives at 60 million, and, aided by the high cost of orthodox medicine, irregular medical practice appears to be on the rise … At the beginning of this period of rejuvenation, the profession’s educational institutions had dwindled to one, the National College of Naturopathic Medicine (which had branches in Seattle, Washington, and Portland, Oregon) which was created after the death of R. A. Budden and the conversion of Western States College to a straight school of chiropractic. As described in Other Healers, Other Cures, c. 1970 (p. 183): [16] Today, Naturopaths in seventeen states are licensed to diagnose, treat, and prescribe for any human disease through the use of air, light, heat, herbs, nutrition, electrotherapy, physiotherapy, manipulations, and minor surgery. At present, one can earn an D.N. [a misnomomer, actually – N.D.] degree at the National College of Naturopathic Medicine in Seattle and Emporia, Kansas, [where, by contract, the first two years of the four year medical education were then taught], or the new North American Naturopathic Institute in North Arlington New Jersey [there is also a school in Montreal]. The four-year curriculum covers many standard medical courses – anatomy, bacteriology, urology, pathology, physiology, X-ray reading etc. – but also includes botanical medicine, hydrotherapy, electrotherapy, and manipulative technique … The public, by the late 1970s, was particularly ripe for another rejuvenation of naturopathy’s brand of “alternative” health care. As described in Murphy’s Enter The Physician: The Transformation of Domestic Medicine, 1760–1860, when discussing this cyclical rejuvenation in the mid-20th century (pp. 226–227): [23]
Contemporary crusaders still stress prevention as the lay 38
person’s primary duty, but a growing chorus is calling for every person to assume the newly proactive role in his or her own health care. This is essential, say the analysts, because both lay people and doctors have placed far too much faith in the power of medicine and technology to work miracles. For a host of different reasons and from a variety of different perspectives, health advocates are calling on each person to “accept a certain measure of responsibility for his or her own recovery from disease or disability.” What would this entail? There are probably as many answers to this question as there are respondents, but it is striking to note how many of the solutions would have been familiar to our ancestors who lived between 1760 and 1860. One recurring idea, for instance, is that each person knows his or her own constitution history the best, and therefore has a duty to communicate that knowledge to medical personnel. Another is a refurbished concept of vis, medicatrix, naturae, the belief that many diseases are self-limiting and therefore do not require much medical intervention – and certainly not the amount or the sort to which contemporary Americans are accustomed. Most significantly, today’s analysts are calling on professionals and non professionals to build and nurture a health-care partnership very much like that envisioned by nineteenth-century health publicists: a partnership based on mutual respect, clear understanding and faithful execution. In that scenario, both as it originally evolved and in its updated version, it is the doctor who directs treatment, but crucial to a successful outcome are the informed and responsible actions of the patients, other care givers, and the patient’s family and friends. In 1978, the John Bastyr College of Naturopathic Medicine was formed in Seattle, Washington, by Joseph E. Pizzorno, Jr, ND (founding president), Lester E. Griffith ND, and William Mitchell ND (all graduates of the National College of Naturopathic Medicine), who felt that it was necessary to have more institutions devoted to naturopathic care and the teaching of naturopathic therapeutics. During the late 1970s, other naturopathic doctors also recognized this need and naturopathic colleges were established in Arizona (the Arizona College of Naturopathic Medicine), Oregon (the American College of Naturopathic Medicine) and California (the Pacific College of Naturopathic Medicine). Unfortunately, none of these three survived. However, the current status of naturopathic medicine, as represented by Bastyr University and National College of Naturopathic Medicine, and now joined by the Southwest College of Naturopathic Medicine and Health Sciences in Arizona and a program in naturopathic medicine at the University of Bridgeport in Connecticut, is that of growth and presumably a solid future. There are currently favorable commentaries on the state of naturopathic medicine, and its continuing efforts to reinvest various diverse theories of “natural healing” with modern vigor. In Other Healers, Unorthodox Medicine In America (edited by Norman Gevitz, the author of The D.O.’s), [24] a volume which was written to provide “a scholarly perspective on unorthodox movements and practices that have arisen in the United States” (from the editor’s preface), part of this effort is described by Author Martin Kauffman, (from the Department of History at Westfield State College,) a modern expert on homeopathy (pp. 116–117): In addition to the revival of classical homeopathy, a major development in recent times has been the teaching of homeopathy at naturopathic colleges on the West coast. In Seattle, John Bastyr, a Naturopath and Homeopath who had been practicing for fifty years, readied the move in 1956 to establish the national college of Naturopathic Medicine, which was later moved to Portland, Oregon. The College’s four-year curriculum includes a required third-year course in homeopathy, with homeopathic electives being available to third and fourth year students. In 1978, three naturopathic practitioners in Seattle founded the John Bastyr College of Naturopathic Medicine. During the sixth quarter all students at that school are required to take 44 hours of course work in homeopathy, after which they may elect another 66 hours and up to 238 hours of clinical homeopathic instruction. The significance of the naturopathic schools to the resurgence of homeopathy is demonstrated by the fact that “about one third of the graduating class specialized in homeopathic practice, a total of about 50 each year in all” (citing the American Homeopath in italics). And, as described in the Encyclopedia of Alternative Health Care by Olsen (pp. 209–210): [25] Today in Germany, the nature care movement in herbal remedies tradition has matured into a well-established health care practice, with about 5,000 professionals throughout the country. … One Kneipp practitioner, Benedict Lust, emigrated to America to begin teaching and practicing naturopathy here. By 1902, he had founded the American School of Naturopathy in New York City. The practice quickly spread across the United States (California was the first State to pass a law regulating natural medicine, in 1919.) Numerous schools offering a variety of training cropped up and disappeared. The movement peaked in America around 1950 and nearly died out by the early 1960’s. The legal climate for naturopathy turned cold in many States, in the face of the powerful modern medical establishment. While naturopathy medicine is now legal (in several states) many naturopaths practicing in other states are old-timers, practicing under their original “drugless therapy” licenses, issued before laws prohibiting new naturopathic practices went into effect. Today, there are only two schools in naturopathic medicine in the United States: the National College in Portland Oregon, and John Bastyr College in Seattle, Washington. The American Association of Naturopathic Physicians is beginning to organize and unify the profession, with its own definition and philosophy of modern naturopathic medicine. Alaska, Arizona, Connecticut, Oregon, Washington, and Hawaii recognize naturopathy as a primary medicine with specific licensing laws, as do the Canadian provinces of British Columbia, Manitoba, Ontario, and Saskatchewan. In other states, efforts are under way to gain licensure for naturopaths (this description was cerca in 1989). And the movement continues to grow. And so, the impact of natural healing has come full circle. In an era where the statistical number of persons born who are expected to contract cancer, now recognized as a
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degenerative disease, has increased rather than declined, and the incidence of other degenerative diseases (arthritis, arteriosclerosis, atherosclerosis, etc.) has increased in direct relation to the lengthening of life expectancies produced by improved sanitation and nutrition (although speciously claimed by AMA medicine to be the result of their therapies), the early teachings of Lust, Lindlahr, et al appear to have more validity than ever. REFERENCES 1. Starr
P. Social transformation of American medicine. New York: Basic Books. 1983
2. Griggs
B. Green pharmacy. London: Jill, Norman, & Hobhouse. 1981
3. Whorton
J. Crusaders for fitness. Princeton, NJ: Princeton Press. 1982
4. Rothstein 5. Haller
W. American physicians in the 19th century. Baltimore, MD: Johns Hopkins Press. 1972
J. American medicine in transition, 1850–1910. Urbana, IL: University of Illinois Press. 1981: p 234–279
6. Rosen
G. The structure of American medical practice. Philadelphia: University of Pennsylvania. 1983
7. Campion 8. Burrows
F. AMA & US Health Policy Since 1940. Chicago, IL: AMA Publishers. 1984
J. Original medicine in the progressive era. Baltimore, MD: Johns Hopkins Press. 1977: p 31–51
9. Coulter
H. Divided legacy, vol II. Washington, DC: Wehawken Books. 1973: p 402–423
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Salmon JW. Alternative medicines. NY: Tavistock. 1984: p 80–113
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Gevitz N. The D.O.’s. Baltimore, MD: Johns Hopkins Press. 1982
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Silberger J. Mary Baker Eddy. Boston, MA: Little Brown. 1980
Lindlahr H. Philosophy of natural therapeutics, vol. I. Maidstone, England: Maidstone Osteopathic. 1918. (Vol II – Practice: 1919; Vol III – Dietetics: 1914; Reprints: CW Daniel Co, Essex, England, 1975, 1981, 1983) 13.
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Lust B. Universal directory of naturopathy. Butler, NJ: Lust. 1918
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Kellogg JH. New dietetics. Battle Creek, MC: Modern Medical Publications. 1923
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Kruger, H. Other healers, other cures. A guide to alternative medicine. New York: Bobbs-Merrill. 1974
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Goulden J. The best years. New York, NY: Athenium. 1976
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Caute D. The great fear. New York, NY: Simon & Schuster. 1978
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Spitler HR. Basic naturopathy. Des Moines, IA: ANA. 1948
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Kuts-Cheraux AW. Naturae medicina. Des Moines, IA: ANPSA. 1953
21.
Cassedy JH. Medicine in America: a short history. Baltimore: Johns Hopkins University Press. 1991
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Duffy J. From humors to medical science: a history of American medicine, 2nd edn. Urbana, IL: University of Illinois Press. 1993
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Murphy LR. Enter the physician: the transformation of domestic medicine, 1760–1860. University of Alabama Press. 1991
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Gevitz, N. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Press. 1988
25.
Olsen KG. The encyclopedia of alternative health care. NY: Pocket Books. 1989
FURTHER READING General Barrett S, Herbert V. The vitamin pushers: how the health food industry is selling America a bill of goods. NY: Prometheus Books. 1994 Barrett S, Jarvis W. The health robbers: a close look at quackery in America. NY: Prometheus Books. 1993 Berlinger H. A system of medicine: philanthropic foundations in the Flexner era. NY: Tavistock Publishers. 1985 Breiger G. Medical America in the 19th century. Baltimore, MD: Johns Hopkins Press. 1972 Brown ER. Rockefeller medicine men. CA: University of California Press. 1978 Burrows J. Organized medicine in the progressive era. Baltimore, MD: Johns Hopkins Press. 1977 Campion F. AMA & U.S. health policy since 1940. Chicago, IL: AMA Publishers. 1984 Cassedy JH. Medicine in America: a short history. Baltimore: Johns Hopkins University Press. 1991 Coulter H. Divided legacy, vol. III. Washington, DC: Wehawken Books. 1973 Coward R. The whole truth: the myth of alternative health. London: Faber and Faber. 1989 Duffy J. The healers. Urbana, IL: University of Illinois Press. 1976 Duffy J. From humors to medical science: a history of American medicine, 2nd edn. Urbana, IL: University of Illinois Press. 1993 Gevitz N. The D.O.’s. Baltimore, MD: Johns Hopkins University Press. 1982 Gevitz, N. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Press. 1988 Dr Goodenough’s Home Cures & Herbal Remedies. Crown. 1982 Green H. Fit for America: health, fitness, sport & American society. NY: Pantheon Books. 1986 Griggs B. Green pharmacy. London, UK: Jill, Norman & Hobhouse. 1981 Haller J. American medicine in transition, 1850–1910. Urbana, IL: University of Illinois Press. 1981 Inglis B, West R. Alternative health guide. New York, NY: Knopf. 1983 Kruger H. Other healers, other cures: a guide to alternative medicine. NY: Bobbs-Merrill. 1974. Ludmerer K. Learning to heal. NY: Basic Books. 1985 Manger LN. A history of medicine. NY: Marcel Dekker. 1992 McKeown T. The role of medicine: dream, mirage, or nemesis? London, UK: Nuffield Provincial Hospitals Trust. 1976 Murphy LR. Enter the physician: the transformation of domestic medicine, 1760–1860. Tuscaloosa, AL: University of Alabama Press. 1991
Rosen G. The structure of American medical practice: 1875–1941. Philadelphia: University of Pennsylvania. 1983 Rosenberg C. The care of strangers: the rise of America’s hospital system. NY: Basic Books. 1987 Rothstein W. American physicians in the 19th century. Baltimore, MD: Johns Hopkins Press. 1972 Salmon JW. Alternative medicines. New York: Tavistock. 1984 Serrentino J. How natural remedies work. B.C.: Hartley & Marks. 1991 Silberger J. Mary Baker Eddy. Boston, MA: Little Brown. 1980 Starr P. Social transformation of American medicine. New York: Basic Books. 1983 Thomas L. The youngest science. Boston, MA: Viking. 1983 Whorton J. Crusaders for fitness. Princeton, NJ: Princeton Press. 1982 Wirt A. Health & healing. New York, NY: Houghton Mifflin. 1983 Wohl S. Medical industrial complex. New York, NY: Harmony. 1983 A naturopathic bibliography Abbot JK (MD). Essentials of medical electricity. Philadelphia, PA: WB Saunders. 1915 Altman N. The chiropractic alternative: how the chiropractic health care system can help keep you well. Los Angeles, CA: J.P. Tarcher. 1948 Barber ED (DO). Osteopathy complete. Kansas City, MO: Private 1896 Baruch S (MD). An epitome of hydro-therapy. Philadelphia, PA: WB Saunders. 1920
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Benjamin H (ND). Everybody’s guide to nature cure, 7th edn. England: Thorsons. 1981 Bennet HC (MD). The electro-therapeutic guide. Lima, OH: National College of Electro-therapeutics. 1912 Bilz FE. The natural method of healing (2 vols). (English translation) New York, NY: Bilz, International News Co. 1898 Dejarnette MB (DC). Technic & practice of bloodless surgery. Nebraska City, NB: Private. 1939 Downing CH (DO). Principles & practice of osteopathy. Kansas City, MO: Williams. 1923 Filden JH (MD). Impaired health (its cause & cure), 2nd edn. Denver, CO: Private. 1921 Finkel H (DC, ND). Health via nature. New York, NY: Barness Printing & Society for Public Health Education. 1925 Foster AL (DC, ND). Foster’s system of non-medicinal therapy. Chicago, IL: National Publishing Association. 1919 Fuller RC. Alternative medicine and American religious life. NY: Oxford University Press. 1989 Goetz EW (DO). Manual of osteopathy. Cincinnati, OH: Nature’s Cure. 1909 Gottsschalk FB (MD). Practical electro-therapeutics. Hammond, IN: Frank Betz. 1904 Olsen KG. The encyclopedia of alternative health care. NY: Pocket Books. 1989 Graham RL (MD). Hydro-hygiene. New York, NY: Thompson – Barlow Co. 1923 Inglis B. Natural medicine. Great Britain: William Collins. 1979 Johnson AC (DC, ND, DWT). Principles & practice of drugless therapeutics. Los Angeles, CA: Chiropractic Education Extension Bureau. 1946 Kellogg JH (MD). New dietetics. Battle Creek, MI: Modern Medical Publications. 1923 Kellogg JF. Rational hydrotherapy. Battle Creek, MI: Modern Medical Publications. 1901, 1902 King FX. Rudolf Steiner and holistic medicine. York Beach, MA: Nicolas-Hays. 1987 Kuhne L. Neo-naturopathy (new science of healing). (Translated by B Lust), Butler, NJ: Lust Publ. 1918 Kuts-Cheraux AW (MD, ND). Naturae medicina. Des Moines, IA: ANPSA. 1953 Just A. Return to nature. (Translated by B Lust), Butler, NJ. Lust Publ. 1922 Lust B (ND). Universal directory of naturopathy. Butler, NJ: Lust Publ. 1918 Lindlahr H (MD). Philosophy of natural therapeutics, vol. I. Maidstone, England: Maidstone Osteopathic. 1918. (Vol II – Practice: 1919; Vol III – Dietetics: 1914; Reprints: CW Daniel Co, Essex, England, 1975, 1981, 1983) MacFadden B (ND). Building of vital power. NJ: Physical Culture Publications. 1904 MacFadden B (ND). Power & beauty of superb womanhood. NJ: Physical Culture Publications. 1901
Murray CH (DO). Practice of osteopathy. Elgin, IL: Private. 1909 Murray MT (ND), Pizzorno JE (ND). Encyclopedia of natural medicine. Rocklin, CA: Prima. 1998 Pizzorno JE (ND). Total wellness. Rocklin, CA: Prima. 1996 Richter JT (DC, ND). Nature – the healer. Los Angeles, CA: Private. 1949 Spitler HR (MD, ND, PhD). Basic naturopathy. Des Moines, IA: ANA. 1948 Trall RT (ND). Hydropathic encyclopedia (3 vols). New York, NY: SR Wells. 1880 Turner RN (ND, DO, Bac, MBNOA). Naturopathic medicine: treating the whole person. Great Britain: Thorsons. 1984 Weltmer E. Practice of suggestive therapeutics. Nevada, MO: Weltmer Institute. 1913
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Chapter 3 - Philosophy of naturopathic medicine Randall S. Bradley ND DHANP
INTRODUCTION This chapter examines the philosophical foundation of naturopathic medicine and its modern applications. Unlike most other health care systems, naturopathy is not identified by any particular therapy or modalities. In fact, there is a wide variety of therapeutic styles and modalities found within the naturopathic community (see Table 3.1 ). For example, there are still practitioners who adhere to the strict “nature cure” tradition and focus only on diet, “detoxification”, lifestyle modification, and hydrotherapy. There are also those who specialize in homeopathy, acupuncture or natural childbirth. At the other end of the spectrum are found naturopathic physicians who extensively use natural medicinal substances to manipulate the body’s biochemistry and physiology. Finally, there is the majority who practice an eclectic naturopathic practice that includes a little of everything. From its inception 100 years ago, naturopathic medicine has been an eclectic system of health care. This has allowed it to adopt many of this century’s more effective elements of natural and alternative medicine, as well as to adopt conventional medicine’s basic and clinical sciences and diagnostics (see Ch. 2 for further discussion). Through all of this eclecticism, it has always identified the Latin expression vis medicatrix naturae (the healing power of nature) as its philosophical linchpin. TABLE 3-1 -- Naturopathic modalities Naturopathic physicians are trained to use a number of diagnostic and treatment techniques. These modalities include: • Diagnosis – all of the conventional clinical laboratory, physical diagnosis, and imaging (i.e. X-ray, etc.) techniques, as well as holistic evaluation techniques • Counseling – lifestyle, nutritional and psychological • Natural medicines– nutritional supplements (i.e. all food constituents), botanical medicine, and homeopathy • Physical medicine– hydrotherapy, naturopathic manipulative therapy, physiotherapy modalities, exercise therapy and acupuncture • Family practice – natural childbirth, minor surgery, natural hormones, biologicals, and natural antibiotics
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However, the expression vis medicatrix naturae, by itself, does not provide a clear picture of naturopathic medical philosophy, or an understanding of the practice of naturopathic medicine in all of its varied forms. With the profession’s history of eclecticism, no two practitioners will treat any individual patient exactly alike. While this has its advantages (i.e. individualization of each patient’s care, more therapeutic options, etc.), it also makes it difficult to perceive the profession’s philosophic cohesiveness. Another major disadvantage of this eclecticism is the difficulty in developing consistent practice standards. To attempt to solve this problem, the modern profession has articulated a general statement of naturopathic principles expanding on vis medicatrix naturae (see Table 3.2 ). However, this statement of principles is probably still not adequate to address the issues that concern modern students of naturopathic medicine or other professionals. Therefore, in order to gain a more in-depth understanding of naturopathic medicine, it is necessary to discuss medical philosophy in general.
MEDICAL PHILOSOPHY The issues fundamental to medical philosophy have changed little since naturopathy first appeared as a distinct profession at the end of the 19th century. What has changed is the level of understanding of the biological process and the language of science. Most people who study the early writers on naturopathic medical philosophy quickly get lost in the archaic language and arguments used to justify the theories. This chapter translates these concepts and issues into modern terms. Vitalism vs. mechanism Historically, there have been two main medical philosophies, those of vitalism and mechanism. Their origins can be traced to the Hippocratic writings of ancient Greece. Throughout history, the line separating these two schools of thought has not always been clear, but their philosophical perspectives have generally been in opposition. The conflicting goals and philosophical foundations of these two concepts remain relevant as the modern practices of conventional and alternative physicians come into conflict. As will be seen, the foundations of naturopathic medical philosophy are found in vitalism. However, naturopathy also recognizes the practical value of the mechanistic approach to health care. Mechanism
Up to the early part of the 20th century, there was considerable debate over the issue of vitalism vs. mechanism in the field of biology. The mechanists, or materialists, maintained that the phenomenon of life could be explained exclusively as the product of a complex series of chemical and physical reactions. They denied the possibility that the animate had any special quality that distinguished it from the inanimate. It was their contention that the only difference between life and non-life is the degree of complexity of the system. Mechanism has several other distinctive characteristics. Its most obvious is that it is reductionistic. In fact, “reductionism” is often used as a synonym of mechanism. Mechanistic science is also characterized by an emphasis TABLE 3-2 -- The principles of naturopathic medicine • The healing power of nature: vis medicatrix naturae Nature acts powerfully through healing mechanisms in the body and mind to maintain and restore health. Naturopathic physicians work to restore and support these inherent healing systems when they have broken down, by using methods, medicines, and techniques that are in harmony with natural processes. • First do no harm:primum non nocere Naturopathic physicians prefer non-invasive treatments that minimize the risks of harmful side-effects. They are trained to know which patients they can treat safely, and which ones they need to refer to other health care practitioners. • Find the cause:tolle causam Every illness has an underlying cause, often in aspects of the lifestyle, diet or habits of the individual. A naturopathic physician is trained to find and remove the underlying cause of a disease.
• Doctor as teacher: docere A principal objective of naturopathic medicine is to educate the patient and emphasize self-responsibility for health. Naturopathic physicians also recognize and employ the therapeutic potential of the doctor–patient relationship. • Treat the whole person Health or disease comes from a complex interaction of physical, emotional, dietary, genetic, environmental, lifestyle, and other factors. Naturopathic physicians treat the whole person, taking these factors into account. • Preventive medicine The naturopathic approach to health care can prevent minor illnesses from developing into more serious or chronic degenerative diseases. Patients are taught the principles with which to live a healthy life; by following these principles they can prevent major illnesses.
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on linear causality. Without its emphasis on reductionism and linear causality, Western science and medicine would probably have not been so successful. As the 20th century advanced, each new discovery in biological and medical science reinforced the arguments for mechanism, until by the middle of the 20th century, the biology community had almost exclusively embraced the philosophy of mechanism. Mechanism is the philosophical foundation of biomedical science and conventional medicine. Mechanistic medicine identifies disease and its accompanying signs and symptoms as simply the result of a disruption of normal chemical reactions and physical activities. Such disruptions are caused by the direct interference in these reactions and activities of a “pathogenic agent”. (For the purposes of this discussion, the general expression “patho-genic agent” refers to any known or unknown etiological agent or condition. Examples include microbial agents, autotoxins, genetic defects, environmental toxins, non-end-product metabolites, and physical and emotional stress and trauma.) A living organism, then, is simply a very complex machine which, due to external agents and “wear and tear”, breaks down. Because the signs and symptoms of disease are thought to be due only to these mechanical disruptions and interference with reactions, they are considered to be completely destructive phenomena and are therefore to be eliminated. Disappearance of the signs and symptoms indicates that the pathogenic agent and its resulting disease have been eradicated, or at least controlled. The goals of mechanistic medicine tend to be the quick removal of the signs, symptoms, and the pathogenic agent. Mechanistic medicine is being practiced in cases where the intention of the therapy is to intervene in the perceived mechanism of the disease and/or relieve the symptoms. Examples would be the use of antihistamines to relieve rhinitis, vitamin B 6 to help PMS, surgery and emergency care for traumatic injuries, coronary bypass surgery, anti-inflammatory agents in systemic lupus erythematosus (SLE), or insulin in juvenile onset diabetes. Mechanism is also being used when an identified pathogenic agent is directly attacked or eliminated. Instances of this would be the use of antibiotics or the isolation of a patient from a particular allergen. Clearly, mechanistic medicine can be very effective in achieving its goals. In the face of modern medical technology, it is easy to see how this philosophy came to dominate biology, medicine, and the attention of the public. However, the unsolved problems of mechanistic medicine – particularly those of chronic degenerative disease, authoritarianism which alienates patients from responsibility for their own health, and the increasing cost of health care – suggest that there are limits to the mechanistic perspective and explain why vitalism has not disappeared and is, in fact, in resurgence. Vitalism
The philosophy of vitalism is based on the concept that life is too well organized to be explained simply as a complex assemblage of chemical and physical reactions (i.e. a living system is more than just the sum of its parts). This is in contrast to the mechanist’s contention that “the only difference between life and non-life is the degree of complexity”. Throughout the 19th century, the debate between vitalism and mechanism was mostly carried on by biologists whose interests were mainly in the study of the organism’s specific cellular activities, such as morphological development. These activities were argued to be “vital” and, therefore, not explainable by mechanistic science. The tendency was to infer a metaphysical quality to this concept. As can be imagined, these earlier debates lurched from one specific argument to the next as modern biology unraveled the secrets of cellular metabolism. Fortunately, the debate has now shifted back to the relevant and holistic general concepts. While modern vitalism is inherently holistic in its view and has an emphasis on circularity as its causality (i.e. feedback loops), there is no conflict with the findings of biomedical science. Eventually, all of the individual chemical and physical reactions that are found in the processes of life will probably be identified. What is significant is not the individual reaction, but the fact that they are all coordinated to such a degree as to produce the special activities of a living organism. An organism’s unique complexity – as demonstrated by its ability to grow and develop, respond to stimuli, reproduce, and repair itself – requires a level of organization and coordination that suggests a distinct quality that is not readily explained by mechanism. This organization and coordination has been identified as “homeostasis” by physiology. All organisms, up to the point of death, are attempting to return to this ideal state when injured or ill. As there is no inanimate counterpart to this level of complexity and organization, this is the most dramatic general argument in favor of vitalism. A less dramatic argument used to support the vitalistic perspective is the “problem of entropy”. Entropy is the tendency of any closed system to find equilibrium, i.e. the state of least organization. In other words, systems tend to run down and become less complex over time. In defiance of this universal rule, life, up until the point of death, consistently creates more complex systems out of simple ones. To do this, life actively pursues external matter and energy to incorporate into itself, while at the same time selectively eliminating by-products from its utilization of this matter and energy. When the problem of entropy is examined on the molecular level, the same individual chemical processes and elements may be found in both animate and inanimate systems. In the inanimate system, however, there is a
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constant move toward a state of chemical equilibrium. This type of system cannot maintain an unstable chemical state and always seeks stabilization. Even after the addition of external exciting energy, the system will return to the simplest, least reactive state possible. The animate system is virtually the opposite. It is continuously in a state of dynamic chemical instability, actively seeking energy to maintain this instability, and consistently moving to more complex and organized states (and back again). It is only at the onset of death that an animate system begins to move towards equilibrium. The third general argument in favor of a vitalistic view of life is evolution. For evolution to exist as a force in nature, generations of living organisms have to survive long enough to grow, reproduce and then evolve. In order for this survival to take place, the organisms’ homeostatic and repair processes must be consistently directed towards maintaining a state of balance with the external environment (i.e. health). Any organisms that did not behave biochemically and physiologically in this manner would have died and not evolved. Thus the phenomenon of evolution, as the action of countless living organisms over eons, multiplies life’s anti-entropic quality and is incompatible with a mechanistic view of living systems. These easily observable examples of life’s “special quality” suggest an “organizing force” that goes beyond what is possible from mere chemistry. This quality that makes life unique should not be mistaken as a metaphysical concept, although is not intended to argue here for or against such concepts. The point is only that vitalism is a medical philosophy based on observable scientific phenomena. Unfortunately, a definitive definition of this quality (in the old literature called the “vital force”, defense mechanism, or simply “Nature”) will have to wait for more research. At this point in the discussion, not many mechanistic practitioners would have reason to be uncomfortable, as the ideas proposed are relatively non-controversial and just follow generally accepted physiological principles. Interestingly, many of these practitioners probably have personal belief systems that are quite compatible with this stage of the vitalistic argument. However, the conflict becomes evident upon examination of the premises upon which the practice of vitalistic medicine is based. What truly separates vitalism from mechanism, and makes it useful as a medical philosophy, is its perspective on disease and the associated symptoms.
Meaning of disease Vitalism maintains that the pathogenic agent does not directly cause the symptoms accompanying disease; rather, they are the result of the organism’s intrinsic response or reaction to the agent and the organism’s attempt to defend and heal itself. Symptoms, then, are part of a constructive phenomenon that is the best “choice” the organism can make, given the circumstances at any particular point in time. These symptoms can be further described as arising from two situations. The first and most common situation is when they are from a “healing reaction”, which is the organism’s concerted and organized attempt to defend and heal itself. These healing reactions produce what can be called “benign symptoms”. Examples include fever and inflammation in infections, almost any reaction of the immune system, and many of the symptoms of chronic disease. This interpretation of symptoms is generally ignored by mechanism. Instead, it views them as the result of a destructive process and focuses on intervening by relieving the symptom or manipulating the pathological mechanism. Mechanistic medicine is therefore most often working contrary to homeostasis and the organism’s healing attempt (in fact, this is usually its intent). When this therapeutic approach is effective, vitalists call the result a “suppression” (see Table 3.3 ). This approach to health care is so pervasive that most people, lay and professional alike, today routinely suppress mild fevers with antipyretics. In contrast, vitalism considers these symptoms to be the product of a constructive phenomenon and therapeutically stimulates and encourages this directed healing process. Rather than simply trying to eliminate a pathogenic agent, as mechanistic therapy might, vitalism focuses more on augmenting the organism’s resistance to that agent. That is not to say that vitalists object to removing the agent, only that it should be done in the context of simultaneously increasing resistance (in other words, decreasing susceptibility). The importance of this approach becomes evident when one recognizes that disease is only possible when both a pathogenic agent and a susceptibility to that agent are present. Healing reactions can take several forms, as shown in Table 3.4 . In the first type, an organism’s response to a TABLE 3-3 -- Cure, suppression and palliation When symptoms improve following treatment (regardless of the therapeutic system), it is for one of three reasons: • Cure. The symptoms go away and the patient’s overall health improves. In this case the treatment can be discontinued and the patient continues to do well. • Suppression. The symptoms go away but overall the patient becomes less healthy. The treatment can be discontinued and the symptoms will stay away, but the patient feels worse generally (i.e. deceased sense of well-being, energy or moods), or new, often more limiting, symptoms eventually develop (e.g. suppressed eczema leading to asthma). • Palliation. The symptoms are improved but only as long as the treatment is continued. At best, palliation is something that is done while a curative treatment is given time to work. In and of itself, palliation will never lead to a cure, but unfortunately, continued palliation may eventually lead to suppression.
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TABLE 3-4 -- The four types of healing reactions Reaction
Description
Acute, asymptomatic
Organism easily defends itself
“Healing crisis”
Relative strength of pathogenic agent and organism similar; symptoms of body defending itself apparent
Vigorous but unsuccessful
Pathogenic agent stronger than organism; death if no intervention
Chronic, mildly symptomatic
Healing reaction feeble, but adequate to maintain life; progressive degeneration
pathogenic agent does not produce symptoms. When it is capable of easily defending itself from the agent, no symptoms will be perceivable. This is a common homeostatic process and is demonstrated when a potential pathogen, such as beta-hemolytic streptococcus, is cultured from a healthy person’s throat. However, when the organism is more susceptible or the relative strength of the pathogenic agent is greater, a threshold is reached and symptoms become perceivable. Successful healing reactions of this type would include vigorous acute diseases that quickly resolve. The early naturopaths would have called these acute reactions “healing crises”. As the susceptibility of the organism increases relative to the strength of the pathogenic agent, there is a greater likelihood that the healing attempt will not be successful. When such a reaction is unsuccessful but vigorous, death may result, unless there is timely application of vitalistic or mechanistic therapy. Examples of this situation might be acute bacterial meningitis or cholera. When the healing attempt is feeble and therefore ineffective, it usually goes into the “chronic disease” stage of the reaction. Vitalists observe that suppression seems to increase the likelihood that the reaction will be forced to go into such a chronic stage. In this situation the reaction is “smoldering”, and most often the organism cannot overcome the pathogenic agent unassisted. It just “holds its own”, and if the organism’s general health decreases over the years, the reaction gradually degenerates, producing symptoms that become less benign as it moves to an end-stage pathology. If the organism can be therapeutically stimulated to produce a more vigorous healing reaction, it can often successfully complete the original healing attempt. This augmented reaction is another example of a naturopathic healing crisis and would also be called an “aggravation” by the vitalists who practice homeopathic medicine. Intervening in the mechanism of disease by relieving symptoms does little to stimulate or encourage the healing response; in fact it usually actually inhibits the healing response. In contrast, vitalistic therapies can be very effective in helping these healing reactions, because their goals are precisely the same as those of the organism. Thus, it is thought that vitalistic medicine works because, by honoring this process and thereby strengthening the whole organism, it encourages a more effective healing effort. Ideally, the organism is then able to accelerate and complete its reaction against the pathogenic agent, leading to the permanent disappearance of the symptoms as it returns to a state of health. It would be naive to say that every stage of the healing reaction is positive and in the best interest of the organism, or that no symptoms should be palliated. The modern vitalist acknowledges that intervention is sometimes necessary. On the other hand, it is important to note that routine intervention can encourage its own worst-case scenarios. When mechanistic therapies successfully suppress an organism’s chosen healing reaction, a less effective and less desirable response is often produced. Therefore, when suppression occurs, it can lead to a more complicated medical situation. Consequently, the very practice of mechanistic medicine tends to reinforce its practitioner’s conviction that intervention is usually necessary. It should be noted, however, that not all intervention leads to suppression. It happens less often when the pathogenic agent can be readily eliminated, such as in non-recurring acute bacterial infections, or when relatively non-invasive therapies are used, such as natural medicines. The second type of symptom-producing situation occurs when the organism produces symptoms in response to an organic lesion that arises from the direct pathological influence of a pathogenic agent. These can be called “morbid symptoms” and examples would include symptoms from the mass of an invasive tumor, shortness of breath from emphysema, and pain of an injury or MI. It should be mentioned that even these symptoms are the result of the organism’s overall effort to maintain homeostasis; benign symptoms are also often present. In addition, a morbid symptom is not necessarily produced for a negative reason. For instance, pain is valuable as an indication of tissue damage. As can be seen, many, if not most, of these situations involve “end-stage” pathology. Here mechanistic therapies can be very positive when the goals of the therapy do not conflict with those of the organism. There are instances when invasive intervention will probably be required to save “life and limb”. These include such conditions as birth and genetic defects, serious traumatic injuries, crisis situations, overwhelming infections, and many malignancies. Unfortunately, conventional intervention does not guarantee a successful outcome either. Even in these situations, however, the effectiveness of vitalistic and natural therapy should not be underestimated, and their concurrent use will certainly augment any mechanistic intervention. Although the concept of benign and morbid symptoms can be a useful tool to help understand the healing and disease process, in many situations it may not be
possible
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to categorize the type of symptoms produced. A rough rule of thumb, however, would be that virtually all symptoms accompanying “reversible” or functional pathology are benign. On the other hand, many of the symptoms associated with traumatic injury and end-stage pathology would be morbid symptoms. Changing society After this discussion of vitalism’s perspective on disease, the question that comes to mind is: “If most health problems are likely to respond to vitalistic medicine, then why is mechanism dominant?” The best answer is probably found in examination of the general attitudes held by society during the Industrial Age just ending. Mechanism came into dominance during this period because it neatly fit into the Industrial Age’s world-view. This is the “man conquers nature” view that holds humanity as above and separate from the world in which it lives. It follows that nature is simply a resource that technology will eventually subdue or subjugate and put into order. Although this perspective is still very strong in Western society, there has been a dramatic change within the last 30 years. Attitudes are now shifting in favor of the ecological integration of humanity into the environment. This “new” world-view holds that humanity is part of an orderly nature and that to ignore this creates situations that eventually become problems. Most ecological disasters are excellent examples of the results of the old view. In addition, the new view contends that if an effort is made to understand how nature functions and an attempt is made to work within that understanding, humanity’s needs can be more efficiently met. Mechanistic medicine, as part of the “old” world-view, generally sees disease as something to conquer and put into order. Vitalistic medicine, on the other hand, looks at the order that is already present and attempts to integrate its therapy into that orderly process. As a result, vitalism is becoming increasingly popular as society shifts from the old to the new world-view. The belief systems of many mechanistic practitioners recognize this order. However, due to education and peer pressure, these personal beliefs are rarely translated into clinical practice. The mechanistic view is still relatively pervasive in society, and because mechanism is convenient (e.g. taking aspirin for a headache), vitalistic practitioners can generally shift their perspective and successfully use mechanistic therapy (although their therapeutic goals may be different). On the other hand, since mechanists dispute the premises upon which vitalistic medicine is based, they generally have great difficulty when attempting to practice or research a vitalistic therapy and frequently cannot demonstrate its efficacy. Scientific medicine While mechanism and vitalism represent opposing perspectives, the systems of medicine that represent these philosophies can be successfully tested and examined with the scientific method. * That is not to say that the philosophy of vitalism has been unquestionably proven – only that the validity of vitalistic interventions can be scientifically demonstrated. If a therapy can be proven effective, then that implies the accuracy of the philosophy upon which it is based. Unfortunately, very few of the vast resources of the 20th century biomedical community have been directed toward investigating vitalistic medicine. Conventional medicine, as the dominant health care system and a representative of mechanism, has claimed for itself the title of “scientific medicine”. However, it is inherently no more or less scientific than vitalistic medicine. A system is scientific only when it has met the criteria of the scientific method. This method requires the collection of data through observation and experimentation, and the formulation and testing of hypotheses. Non-prejudicial science can effectively study any system, but the researcher must understand the system’s particular paradigm. Experiments on a vitalistic therapy based on a reductionistic and mechanistic model are going to be less than satisfactory. The criteria of the scientific method can be met by vitalistic medicine, but only when the researchers recognize that it cannot be studied as though it is reductionistic or based on a simplistic model of linear causality. When the experimental model acknowledges the complexity of a living system in a social context (i.e. holism and circularity), vitalistic medicine proves to be both verifiable and reproducible, and thus scientific. Unfortunately, due to conventional medicine’s current political and economic dominance, it is in the position to dictate (through economic and publication control) that research, and therefore the scientific method, will primarily be applied to itself. The result is that most conventional practitioners dismiss vitalistic medicine, along with all alternatives, as unscientific. This is unfortunate because most vitalistic physicians also have extensive training in mechanistic and/or conventional medicine. Generally, they are capable of practicing mechanistically, and do so to greater or lesser * A thorough review of all health care modalities in use today reveals a category that could be called “esotericia”. While this category is not historically relevant to this discussion of medical philosophy, and its brief mention is not intended as an argument for or against “legitimacy”, esotericia would include such things as prayer, faith healing, psychic healing, Healing Touch, Touch for Health and medical dowsing. Generally speaking, the actual operator of the therapy must call on God or have some special endogenous skill or “power” that goes beyond intellectual knowledge. These modalities are all “operator-dependent” and cannot be examined separate from the practitioner – thus greatly increasing the difficulty of their scientific verification.
47
degrees. The conflict between the practitioners of these different systems is very often due to a lack of constructive dialog. This can be attributed to two general causes: the first is simply that each system defines the world of “correct” medicine in terms of its own principles; the second is the issue of who controls the economic and political power.
NATUROPATHIC PHILOSOPHY Historically, naturopathy is a vitalistic system of medicine. However, over the last 100 years it has also incorporated a number of therapies that can function mechanistically. What makes them acceptable, given naturopathic medicine’s vitalistic foundation, is that they are natural therapies. Natural medicines and therapies, when properly used, generally have low invasiveness and there is little evidence that they cause suppression or side-effects. When used mechanistically, they allow some intervention while still allowing the organism’s healing abilities the opportunity to continue unopposed, especially when used to support the body’s own healing processes. Vis medicatrix naturae Naturopathic physicians assert that all true healing is a result of vis medicatrix naturae (the healing power of nature). Unfortunately, some people in the field of alternative medicine (including some naturopathic physicians and students) have mistakenly translocated this concept to the therapy. These practitioners tend to operate as though this “healing power” is an intrinsic property of the natural therapy or medicinal substance itself. In contrast, vitalism and naturopathic medicine have always understood that the “healing power of nature” is an inherent property of the living organism. Vis medicatrix naturae is the living organism’s “desire” and ability to heal itself. The application of this principle in practice is, of course, dependent upon the patient’s needs. Ideally, it involves only the use of therapies that support the organism and encourage its intrinsic healing process to work more effectively. It also avoids the use of medicines and procedures that interfere with natural functions or have harmful side-effects. Natural medicines and therapies are therefore preferred, since, when used properly and in appropriate circumstances, they are the least harmful, least invasive, and best able to work in harmony with the natural healing process. Since the total organism is involved in the healing attempt, the most effective approach to diagnosis and treatment is to consider the whole person. In addition to physical and laboratory findings, important consideration is given to the patient’s attitude, psychological and spiritual state, social circumstances, lifestyle, diet, heredity, and environment. Careful attention to each person’s unique individuality and susceptibility to disease is critical to the proper evaluation and treatment of any health problem.
Naturopathic physicians contend that most disease is the direct result of the ignorance and violation of what would be traditionally called “natural living laws”. These general lifestyle (including diet) rules are based on the concept that there is an environment (both internal and external) that optimizes the health of an organism. Analysis of the lifestyles of Paleolithic and healthy primitive and modern cultures gave naturopathic physicians and their progenitors many clues as to what a healthy lifestyle should include. Throughout most of modern history, biomedical science has focused primarily on researching the sick. Recently it has finally begun to evaluate what makes for a healthy lifestyle. To no-one’s surprise, this lifestyle looks like the same one advocated by naturopaths for the last 100 years. A healthy lifestyle could be generalized to include: the consumption of natural unrefined foods; getting adequate amounts of exercise and rest; living a moderately paced lifestyle; having constructive and creative attitudes; avoiding toxins and polluted environments; and the maintaining of proper elimination. During illness, it is also important to control these areas in order to remove as many unnecessary stresses as possible and to optimize the chances that the organism’s healing attempt will be successful. Therefore, patient education and responsibility, lifestyle modification and preventive medicine are fundamental to naturopathic practice. While the practice of naturopathic medicine is grounded in vis medicatrix naturae, it also recognizes that intervention in the disease process is sometimes efficacious and, at times, absolutely necessary. Naturopathic physicians treat patients using a wide variety of therapeutic modalities. Some of these are vitalistic and some mechanistic. It is the goal of the therapy that ultimately determines which approach is utilized. Naturopathic physicians have a long-standing tradition of integrating the best aspects of traditional, alternative, and conventional medicine in the interest of the patient. As appropriate, patients are referred to other health care practitioners. Whenever possible, every effort is made to use all treatment techniques in a manner that is harmonious with the naturopathic philosophy. Natural medicines and therapies The medicines administered and prescribed by naturopathic physicians are primarily natural and relatively unprocessed. Although it is recognized that some situations may require the use of synthesized medicines, their use is considered less desirable. Some of the arguments in favor of natural medicinal substances have already been discussed. In addition to the reasons noted above,
48
natural agents are preferred because their constituents have been encountered in nature for millions of years. This long period of exposure has enabled the body to develop metabolic pathways capable of effectively utilizing, processing, and detoxifying these medicines. Four categories of natural medicines can be defined. The first includes substances found in nature that have been only minimally processed. Examples would include, but are not limited to, foods, clean air and water, and whole herbs. The early “nature cure” practitioners used this category primarily. The second category includes agents extracted or made from naturally occurring products. Although these have undergone pharmacological processing, the constituents of the medicines are still in the form found in the original natural substance. These first two types of natural medicinal substances have synergistic constituents that allow their use at lower doses with a resultant broader and safer therapeutic index. Examples of this category include tinctures and other botanical extracts, homeopathic medicines, glandulars and other substances of animal origin. The third type of natural medicines are those highly processed medicinal substances that are derived from a natural source. These often have everything removed but the identified active ingredient and no longer have any synergistic constituents. Examples include many new phytotherapeutic agents, constituents of biochemical pathways, enzymes, amino acids, minerals, vitamins, and other food extracts. The fourth category that may be considered “natural” are those manufactured medicines which are presumed to be identical to naturally occurring substances. These have the advantage of being less expensive and are typically available in higher concentrations. However, their use is less desirable due to: • the difficulty of determining whether they are indeed the equivalent of the natural product • their lack of natural synergistic components • the inclusion of contaminates from the manufacturing process. These contaminates are often chemically and structurally similar to the desired medicine, but generally interfere with the normal pathways rather than enhance them. Examples of these manufactured “natural” medicines include hormones, synthetic vitamins and analogs of plant and animal constituents. Increasingly, medicines of the types identified in cate-gories three and four are being grown “synthetically” by microorganisms specially engineered to produce the desired medicinal substance. It is difficult to say which of these categories best describes this situation. There are also potential problems with this kind of manufacturing process as evidenced by the tryptophan disaster of several years ago. Naturopathic physicians also use many natural therapies. What makes a therapy “natural” is that it is derived from a phenomenon of nature and is used to stimulate the body to heal itself. Examples of these phenomena are air, light, heat, electricity, sound and mechanical force. Some of these natural therapies include mechanical and manual manipulation of the bony and soft tissues (naturopathic manipulative therapy), physiotherapy modalities (e.g. electrotherapy and ultrasound), hydrotherapy, and exercise therapy. Naturopathic physicians also use lifestyle modification, counseling and suggestive therapeutics. These therapies are all discussed in more detail in other chapters. Family and specialty practice Naturopathic physicians, like other types of primary care providers, develop practices that meet their personal interests and skills. While most are engaged in general and family practice, many have also specialized in particular therapeutic modalities and/or types of health problems. However, in all situations the emphasis is still on treating the whole person. The practice of family medicine requires the use of some techniques and devices that are not, in the strict sense of the word, natural therapies, but belong among the comprehensive family practice services offered by the naturopathic profession. Included in family practice are such services as the prescription and fitting of birth control devices, first aid, and minor surgery. Minor surgery includes the repair of minor wounds and lesions and the removal of growths and foreign bodies from superficial tissues. When necessary, it includes the use of local anesthetics and appropriate first aid procedures. First aid includes the treatment of ambulatory acute injuries and conditions that are routinely seen and handled in general practice. Many naturopaths have also developed advanced expertise in different natural therapeutic modalities. These practitioners have usually invested in postgraduate training, such as that available through residencies. Three therapeutic specialties that merit mention are natural childbirth, acupuncture, and homeopathy.
THE PHILOSOPHICAL CONTINUUM When the various healing systems are examined and placed on a philosophical continuum, mechanism and vitalism are on different ends of the same health care spectrum. Both ends of this health care continuum have their strengths and weaknesses. Mechanistic medicine is effective for trauma, crisis care, end-stage pathology and many acute diseases. It is essentially a failure with chronic disease. In fact, conventional medicine considers most chronic diseases incurable. Vitalistic medicine, on the other hand, has its most dramatic successes with
49
chronic disease and is effective with many kinds of acute disease. It is not very effective with trauma and crisis care and end-stage pathology, although it can be a very useful complement to conventional medicine. As can be seen, both ends of the health care spectrum are necessary if every patient’s health care needs are going to be met.
Although aspects of naturopathic (e.g. constitutional hydrotherapy) and conventional medicine (e.g. chemotherapy) represent the archetypes of vitalism and mechanism, the area between the ends of this spectrum is a gray area within which both naturopathic and conventional physicians operate on a continual basis. While naturopathic physicians integrate vitalistic therapies with some mechanistic therapies, it is not possible for everyone to be experts in everything. The vast majority of naturopathic or conventional physicians are not going to be able to learn and competently practice all types of health care. Consequently, to effectively meet society’s health care needs, it is necessary to create an integrated health care system. Such an integrated system would have both vitalistic and mechanistic practitioners working together in the same clinical settings. The trends of popular culture and a biomedical science that is finally beginning to study alternative medicine suggest that the creation of an integrated health care system is now underway. However, it takes no great skill for a mechanistic medical doctor to switch from giving a synthetic drug for a disease to giving a natural medicinal substance. If naturopathic medicine becomes just another mechanistic system using natural medical substances to treat disease (instead of a system identified with treating the whole person vitalistically), it will lose its unique niche in an integrated health care system. For naturopathic medicine to survive and thrive in this new environment, it will need to keep its vitalistic roots. With a thorough grounding in vis medicatrix naturae, modern naturopathic medicine will flourish and achieve a leadership position as the dominant health care paradigm shifts to the integrated medicine of the future.
CONCLUSION The practice of naturopathic medicine can be summarized most simply as helping the body/mind heal itself in the least invasive, most fundamentally curative manner possible. This approach is not tied to any particular therapy or modality, but rather is oriented to a rational blend of vitalistic and mechanistic principles working with the whole person, and educating the patient in the ways of health. As naturopathic knowledge of health and disease grows, new therapies and approaches to health care will be added as they satisfy the principle of vis medicatrix naturae. As the larger health care system becomes more integrated, naturopathic medicine’s place is assured as the profession that truly understands each unique human being’s power to heal. FURTHER READING Baer HA. The potential rejuvenation of American naturopathy as a consequence of the holistic health movement. Medical Anthropology 1992; 13:369–383 Coulter HL. Divided legacy. Richmond, CA: North Atlantic Books. 1975 (vol. 1), 1977 (vol. 2), 1982 (vol. 3), 1994 (vol. 4) Coulter HL. Homeopathic science and modern medicine. Richmond, CA: North Atlantic Books. 1980 Dubos R. Mirage of health: utopias, progress, and biological change. New York: Harper & Row. 1959: p 131 Kirchfeld F, Boyle W. Nature doctors: pioneers in naturopathic medicine. Portland, OR: Medicina Biologica. 1994 Lindlahr H. Philosophy of natural therapeutics. Reprinted by the Maidstone Osteopathic Clinic. 1975 McKee J. Holistic health and the critique of western medicine. Soc Sci Med 1988; 26(8): 775–784 McKeown T. The role of medicine: dream, mirage or nemesis? Oxford: Basil Blackwell. 1979 Payer L. Medicine and culture. New York: Henry Holt. 1988 Schubert-Soldern R. Mechanism and vitalism. University of Notre Dame Press. 1962 Selys H. The stress of life. McGraw-Hill. 1956 Sinnott E. The bridge of life. Simon and Schuster. 1966 Spitler HR. Basic naturopathy. American Naturopathic Association. 1948 Zeff JL. The process of healing: a unifying theory of naturopathic medicine. J Nat Med 1997; 7(1)
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Chapter 4 - Placebo and healing Peter Bennett ND
INTRODUCTION The thoughts of a patient’s mind and the physician’s therapeutic intention on the patient have a profound effect on the health of the patient. The ability of the patient’s mind to affect the process of virtually every disease has been well documented, [1] [2] and the internal mechanisms and pathways by which the mind can positively or negatively affect the immune and healing processes has been investigated in the scientific literature of psychoneuroimmunology. [3] [4] As the body of knowledge documenting the critical importance of the patient’s psyche on the therapeutic environment has grown, it has become increasingly important for all schools of medicine to teach the healing potential of the human mind. The potential of the mind to influence human healing has been explored to the greatest depth in medical literature discussing the placebo effect. The “power of placebo” draws upon the innate ability of the body to spontaneously heal itself, a fundamental principle of naturopathic medicine. This point separates the care delivered by naturopathic physicians from the pharmaceutical and surgical approaches of current medical “standard of care” procedures. If common medical texts on internal medicine or ambulatory care are examined, the word “healing” is not found in the index. Except for the diagnositic evaluation of “self-limiting diseases” and “spontaneous regression”, the ability of the human organism to self-right and repair from a state of acute or chronic disease does not get explored in modern medicine except under the designation of “placebo response”. The placebo response therefore represents all the “unknown” variables which conspire to heal a patient, in spite of pharmaceutical and surgical intervention. Placebo response Placebo response is the power of the mind through intention, to effect: • a change in oneself 52
• a change in those around us • a change in the environment we live in. Intention has been seen to affect machines [5] and remote biological systems. [6] Distantly influenced systems include another person’s electrodermal activity, blood pressure, and muscular activity; the spatial orientation of fish; the locomotor activity of small mammals and the rate of hemolysis of human red blood cells. Prayer, an example of intention, has been extensively studied as a therapeutic healing modality. [7] One study showed a dramatic result in cardiac ICU recovery when patients were prayed for by someone at a distant location. [8] Patients in this study were five times less likely to require antibiotics, three times less likely to develop pulmonary edema, 12 times less likely to require endotracheal intubation and less likely to suffer cardiac mortality. Our biological systems must conform to the laws of physics. Modern physics has investigated the effect of an observer on the system observed. It has been shown that an electron will acquire a definite axis of measurement in the process of measurement. Bell’s theorem supports the idea that our universe consists of particles unified instantly as an indivisible whole; our biological homeostatic systems cannot be analyzed in terms of independent parts. The interconnected nature of our biological systems has been known for thousands of years; the ancient Buddhist concept of “interdependent phenomena” accurately describes this paradigm. Our current medical system has not shifted with the developments in modern physics. These modern ideas of biological systems are diametrically opposed to Cartesian paradigms that our internal and external environments consist of separate parts joined by local connections. Medicine must take a “quantum leap” to catch up with the knowledge we possess about our environment through quantum physics. We can see clearly that it is impossible for a doctor to observe a patient and not have that observation affect the health of the patient. Pierre Teilhard de Chardin postulated, and Rupert Sheldrake proved, that the possibility of a “morphogenetic field” for the subliminal communication to all members of our species is possible. [9] The effect of human thought on other members of society has been described in human society since the beginning of our earliest cultures. Naturopathic physicians believe that the body has a powerful ability to maintain health and repair to a healthy state after disease by virtue of its inherent power of vitality. This homeostatic healing mechanism has been selected by Nature in the same way that other organs which we consider to be vital to our survival have been selected. Healing occurs unaided by simply maintaining an environment that does not obstruct the path of cure. Because placebo literature documents the philosophical foundations of the naturopathic health care model, it is important to review the full scope of this subject. Integrating known placebo initiators in clinical practice is essential for good patient care. Why study the placebo effect? For hundreds of years, physicians have watched their patients respond to therapies with a wide range of results. Some patients recover fully, while others, with apparently identical diseases and therapies, wither and die. Today, a skilled physician can correctly diagnose the condition of a patient by applying the sophisticated techniques of modern medicine. Then, an appropriate therapy, the efficacy of which has been thoroughly proven in research and clinical trials, can be prescribed. Through this process the patient will have received the best care available through current medical technology. But if the diagnosis, therapy, and therapeutic interaction do not stimulate the hope, faith, and belief of the patient, the chances of success are measurably diminished. It has been repeatedly demonstrated in the literature on the placebo effect, [10] psychoneuroimmunology,[3] and psychosomatic,[11] behavioral, [12] [13] and psychiatric [14] medicine that the beliefs of both the patient and the doctor, and their trust in each other and the process, generate a significant portion of the therapeutic results. [15] The placebo and its effect are not separate from any aspect of the therapeutic interaction, nor are they “nuisance variables” muddying a clear clinical picture. Rather, they send the physician a strong message: it is a patient’s own belief systems that mobilize the inherent healing powers of the mind. By studying the placebo effect, a physician is better able to fully harness this power to trigger internal healing mechanisms. Yet, despite the amount of documentation, the placebo effect remains one of the most misunderstood areas in modern medicine. The physician should always strive to stimulate self-healing, or the placebo effect, as fully as possible to maximize its potential for healing. Someday the physician will be able to explore the deepest recesses of the unconscious to directly access therapies that assist the body in the restoration of internal homeostasis. The optimal model for health care is the marriage of appropriate medical technology with the factors that have been shown to generate the placebo effect. This exciting scenario shines on the horizon as the health care of the future. Since the doctor/patient relationship is such fertile ground for stimulating the healing response,
[ 16] [17] [18]
it serves a physician well to comprehend the nature of the
placebo phenomena in order to fully realize this potential for healing.
HISTORY OF PLACEBO The modern physician and the primitive medicine men and shamans of the past have both used ineffective therapies
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to stimulate healing in their patients. As Shapiro notes: “… the true importance of placebo emerges with a review of the history of medical treatment”. [19] It has been noted that the historic therapies of the medical profession and traditional healers, “… purging, puking, poisoning, puncturing, cutting, cupping, blistering, bleeding, leeching, heating, freezing, sweating, and shocking”, [20] worked because of the placebo effect. Although in retrospect these practices might seem ludicrous, all of these therapies were once considered effective. As an embarrassing epilogue, placebo literature has shown that ineffective procedures are just as pervasive in modern medicine as in the jungle hut of the shaman. We must therefore ask ourselves the following question: how can unfounded medical therapies survive peer review literature and centuries of cultural acceptance? The power of the patient’s belief in the potential for cure has been consistently observed throughout history. Both Galen and Hippocrates recognized the strong effect of the mind on disease and recommended that faith, treatment ritual, and a sound doctor/patient relationship could provide important therapeutic results. [21] Recognition of the power of positive expectation was recorded frequently in the medical literature of the 17th and 18th centuries. It was in the 18th century that placebo was first defined as a “… commonplace method of medicine”. [22] As the importance of drug therapy grew in the 19th century, the term placebo became identified with medicines involving substances that resembled drugs. But in the 1940s, because of the increase in double-blind research, it became associated with inert substances that were used to replace active medication. Origin of the term placebo The original Latin meaning of placebo is “I shall please”. [23] Although the term had a purely medical application in the first half of the 20th century, its meaning has been subject to various interpretations throughout the last several hundred years. Before the 1940s, placebos were pharmacologically inactive substances, such as saline or lactose pills, used to satisfy patients that something was being done for them, i.e. the doctor was “pleasing” the patient. In the 1940s and 1950s, there was an explosion of the use of double-blind experimental procedures to evaluate the growing number of new drugs and medical procedures. Suspicion arose that all medical therapies contained an element of placebo phenomena. [24] This new understanding pressed the scientific community to offer new, far broader definitions. Shapiro offered the classic definition of a placebo: [25] Any therapeutic procedure (or that component of any therapeutic procedure) which is given deliberately to have an effect, or unknowingly has an effect on a patient, symptom, syndrome, or disease, but which is objectively without specific activity for the condition being treated. The therapeutic procedure may be given with or without the conscious knowledge that the procedure is a placebo, may be an active (non-inert) or inactive (inert) procedure, and includes, therefore, all medical procedures no matter how specific – oral and parenteral medications, topical preparations, inhalants, and mechanical, surgical, and psycho-therapeutic procedures. The placebo must be differentiated from the placebo effect which may or may not occur and which may be favorable or unfavorable. The placebo effect is defined as the changes produced by placebos. The placebo is also used to describe an adequate control in research. A more accurate definition of placebo would be: Placebo effect is the process of a physician working with the self-healing processes of a patient. Placebo response means healing that results from the patient’s own natural survival and homeostatic defense mechanisms. Modern placebo definitions extend to its nature, properties, and effects. Placebo can be known or unknown, active or inactive, and positive or negative in results (placebo effect vs. nocebo effect), and can extend to all forms of diagnostic or therapeutic modalities, which are further defined in Table 4.1 .
CLINICAL OBSERVATIONS OF “KNOWN” PLACEBO THERAPY One of the more dramatic examples of the placebo effect reported in the medical literature involved a patient with advanced lymphosarcoma, which Klopfer was
[ 27]
reported
TABLE 4-1 -- Types of placebo Placebo type Definition Known placebo
Placebo used in a single-blind experiment. The doctor knows it is a placebo but the patient does not
Unknown placebo
Double-blind placebo use. Neither the doctor nor the patient knows that the medication is a placebo
Active placebo
Any substance that has an intrinsic physiological effect that is irrelevant to the ensuing placebo effect. The vasodilating effect of niacin would make it a good active placebo
Inactive placebo
Any substance that is used with medicinal intent but which has no inherent physiological effect. Except for the glucose effect in a sugar pill (or, to complicate things, an allergic reaction to some component of the supposedly inert substance), it has no physiological effect
Placebo effect
Any changes that occur in a patient as the result of placebo therapy
Nocebo effect Any changes that occur as a result of placebo therapy that are perceived as negative or counterproductive to the path of cure
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highly susceptible to the patient’s faith in an experimental drug called Krebozion. When the patient was placed on the drug, his enthusiasm was so intense that “the tumor masses had melted like snowballs on a hot stove, and in only a few days, they were half their original size!”. The injections were continued until the patient was discharged from the hospital and had regained a full and normal life, a complete reversal of his disease and its grim prognosis. Within 2 months of this recovery, reports that the drug Krebozion was ineffectual were leaked to the press. Learning of this, the patient quickly began to revert to his former condition. Suspicious of the patient’s relapse, his doctors decided to take advantage of the opportunity to test the dramatic regenerative capabilities of the mind; a single-blind study was done on the patient using pure placebo. He was told that a new version of Krebozion had been developed which overcame the difficulties described in the press, and some was promised to him as soon as it could be procured: [27] With much pomp and ceremony saline water placebo was injected, increasing the patient’s expectations to a fevered pitch. Recovery from his second near terminal state was even more dramatic than the first. Tumor masses melted, chest fluid vanished, he became ambulatory, and even went back to flying again. At this time he was certainly the picture of health. The water injections were continued, since they worked such
wonders. He then remained symptom-free for over two months. At this time the final AMA announcement appeared in the press – “nationwide tests show Krebiozen to be a worthless drug in the treatment of cancer”. Within a few days of this report, Mr. Wright was readmitted to the hospital in extremis. His faith now gone, his last hope vanished, and he succumbed in less than 2 days. Other famous placebo case studies include one reported by Cannon on belief causing “voodoo death”, [28] and one reported by Kirkpatrick, [29] who documented the spontaneous regression of lupus erythematosus resulting, in part, from the patient’s belief in the removal of a curse. Other clinical observations Belief sickens, belief kills, belief heals [30]
Evans [31] and Beecher [32] reviewed, between them, 26 double-blind studies on the efficacy of active analgesic drugs in the treatment of pain. Independently, they concluded that 35% of patients suffering from pain experienced a 50% reduction in their symptoms following placebo medication. These are particularly remarkable results when viewed in the context of Evans’ observation that with a standard dose of morphine only 75% of the patients will get a 50% reduction in pain. In calculating the efficiency index of placebo analgesia, a method often used to determine the relative efficiency of drugs, placebo efficacy compared with a standard dose of morphine was 0.56 as effective. This prompted Evans to remark: “Thus, on TABLE 4-2 -- Symptoms and side-effects of placebo response • Anger[33] • Anorexia[34] • Behavioral changes [35] • Depression [33] • Dermatitis medicamentosa[34] • Diarrhea [34] • Drowsiness[36] • Epigastric pain [34] • Hallucinations [37] • Headache[38] • Lightheadedness [34] • Palpitation[34] • Pupillary dilation [32] • Rash [39] • Weakness[34] average, placebo is not a third as effective as a standard injection of morphine in reducing severe clinical pain of various kinds but is in fact 56% as effective.”
[ 31]
As discussed above, placebo has been evaluated in a wide variety of clinical settings besides pain management (see Table 4.2 ). When a phenomenon such as placebo has been observed to be active in diverse clinical situations, such as surgery, drug therapy, psychotherapy, and biofeedback, and over a range of physical and mental symptoms, the conclusion that it must be a factor in all aspects of medicine is inescapable. In addition to the variety of positive effects that placebo produces are the nocebo effects, perceived as counterproductive to the therapeutic goals. These side-effects frequently are consistent with the medication that patients think they are getting. For example, the studies that measure the effects of a supposed aspirin usually show nocebo effects of ulcer-like pain. [40] In homeopathy, aggravations and ameliorations are commonly seen when a placebo is given to fend off a patient’s need to take a medication while the homeopathic physician is waiting to see if a high-potency remedy will effect a cure. Homeopathic doctors report that placebos can cause anxiety and loneliness, as well as calmness and immediate relief from insomnia. [41]
PLACEBO MYTHS Investigation of the understanding of placebo found in the current medical literature reveals the misconceptions that prevail about the nature of placebo therapy and its effectiveness.[42] A study undertaken to examine doctors’ and nurses’ attitudes about placebo efficacy and use revealed that both groups underestimated the number of patients who could be helped by placebo. [42] Physicians showed a consistent pattern of placebo use: • Placebos were used to prove the patient wrong by diagnosing psychogenic symptoms in patients who were thought to be exaggerating, imagining, or faking their symptoms. 55
• Placebos were used in the treatment of alcoholic, psychotic, and demanding patients who were disliked by the staff of the hospital. • In situations where standard treatments had failed or the patient was getting worse, placebos were used as treatment. These misconceptions regarding the nature of the placebo have accounted for its widespread misuse for patients who are perceived as uncooperative or who are suspected of malingering. Myths about placebos continue to hinder a full understanding about the power inherent in this aspect of health care. The most common are discussed below.
[ 43]
Myth 1
Since placebos tend to be physiologically inert, it is not possible for them to have an effect on physiological homeostasis. Fact. Research shows that placebos have a wide range of effects (see Table 4.3 ) that are found throughout all aspects of human physiology. Myth 2
Placebos are only useful with symptoms that are associated with psychological or psychosomatic complaints. Patients who need a placebo are hypochondriacs with vivid imaginations and need to be palliated with something “to please them”. Fact. Placebos have been shown to be effective in the care of all types of patients, with a consistent level of positive results for a wide variety of accurately diagnosed
diseases. TABLE 4-3 -- Physiologic changes induced by placebo • Heart —improved exercise tolerance[44] [45] —decreased serum lipoproteins [46] —improved T-waves[47] —decreased pulse rate and arterial pressure [48] • Sympathetic stimulation —decreased tremulousness, sweating, and tachycardia [34] • Claudication —increased walking distance [49] —addictive drug withdrawal [50] • Post-surgical trauma —decreased facial swelling [51] • Diabetic blood sugar dyscrasias (NIDDM) —lowered fasting blood sugar [52] [53] • Gastrointestinal secretion and motility —decreased gastric acid secretion
[54]
—changes in gastric motility [55] [56] —healing of duodenal ulcers [57] • Hypertension —lowered blood pressure [58] [59] [60] —reduced urinary catecholamines
[ 61]
• Motor dysfunction —improved tremor magnitude [62]
Beecher was one of the first to compile a listing of the therapeutic effectiveness of placebo, thereby uncovering the wide range of therapeutic applications that were previously thought to be limited to only pain control. [15] He concluded: … there is too little scientific as well as clinical appreciation of how important unawareness of these placebo effects can be and how devastating to experimental studies as well as to sound clinical judgement lack of attention to them can be. The large and ever-growing number of studies on placebo and double-blind research (see Table 4.4 ) supports the assertion made by Beecher 30 years ago: [15] Many “effective” drugs have power only a little greater than that of placebo. To separate out even fairly great true effects above those of placebo is manifestly difficult to impossible on the basis of clinical impression. Many a drug has been extolled on the basis of clinical impression when the only power it had was that of a placebo. Myth 3
The placebo effect is only found in substances that are inert. Fact. Placebo phenomena have been observed across a wide spectrum of medical disciplines, including surgery,
[103]
drug therapy,
Myth 4
The patient who responds to placebo can be characterized as someone who is of a typical neurotic disposition. [42] Fact. Although many studies have tried to infer a TABLE 4-4 -- Conditions that have been shown to respond to placebo [ 44] [63] [64] [65] [66]
• Angina
• Anxiety[67] [68] [69] • Arthritis [40] [70] [71] • Asthma[72] [73] [74] [75] • Behavioral problems [76] • Claudication, intermittent [49] • Common cold[77] [78] [79] [80] • Cough[81] • Depression [82] [83] • Diabetes (NIDDM) [52] [53] • Drug dependence[55] • Dysmenorrhea[84] • Dyspepsia[85] • Gastric ulcers [86] • Hayfever[87] [88] • Temporal and vascular headaches [89] [90] [91] • Hypertension [92] [93] • Labor and postpartum pain [94]
[104]
and biofeedback.[93]
• PMS[95] • Ménière’s disease
[96]
• Nausea of pregnancy[34] • Pain[97] [98] • Psychoneuroses[99] [100] • Rhinitis [101] • Sleep disturbances[102] • Tremor[62]
56
personality type, disposition, [105] [106] or certain epidemiological class of patient, [107] this has yet to be well demonstrated since, given the right circumstances, any person can become a placebo reactor. [108] [109] After reviewing the bulk of the research on this subject, Bush [110] and Wolf & Pinsky [34] concluded that the attempts to pigeonhole personalities into a clinical profile ignored the complexity of the human mind. Gliedman et al [99] similarly reported that age, sex, marital status, social class, and intelligence are unimportant factors in determining a patient’s response to placebo. Wolf summarized that attempts to identify placebo reactors need to: [104] … identify the nature of the symptom being treated, the motivation of the patient and physician, the nature of the test agent, its mode of administration and the life situation of the subject at the time he is tested. The significant point here is not the apparently conflicting findings of investigators with respect to placebo reactors, but rather that in any given situation, responses to a placebo may vary as compared to any other situation and the significance of situations to human subjects cannot be precisely duplicated.
PHARMACODYNAMICS The physiological response of the “inert and inactive” placebo extends into the realm of drug pharmacodynamics. Dose–response time curves, cumulative effects (increasing therapeutic efficacy with repeated doses), [111] variable strengths of analgesia based on a patient’s drug expectation, [63] drug interactions, [34] [112] and carry-over effects [37] [106] have all been demonstrated. The effects of placebo are so pronounced that some observers have suggested that they can exceed those attributable to potent pharmacological agents. [34] Packaging and delivery
Several studies have found that the effectiveness of a placebo therapy is dependent on the mode of delivery. [47] For example, one study found that green tablets improved anxiety and yellow tablets improved depression, [113] while another study found that blue capsules were more sedative and pink capsules were more stimulating.[48] Placebo injections appear to be more effective than oral administration after oral placebo has failed to relieve the symptoms. [40] Placebo interactions
Benson[114] writes that the patient’s belief is also a powerful force in determining the degree of relief afforded by the placebo. An increase in patient expectation enhances the physician’s ability to elicit a placebo response. Even if patients know that they are receiving placebos, the expectation and relief brought about by the therapeutic interaction provides positive results. [115] The importance of expectation is further demonstrated by the observation that the greater the stress level of the patient and the greater his or her need for assistance, the greater the effectiveness of placebo. [36] This is even seen in patient response to psychotropic drugs: LSD-25 can have no effect if the patient is told that the drug is a placebo. [105] [116] Patients, such as war heroes, who have severe injuries but do not have great mental suffering attached to their pain need less pain medication than similar injuries in persons who have pain that engenders anxiety and connotes disaster. [117]
PLACEBO HEALING MECHANISMS Where animals or humans can react to their own deviations from homeostasis and where these deviations set off restorative processes, therapeutic intervention, including placebo, has an already existing substrate of recovery for exploitation. [12] A human being has an intrinsic ability to “self-right” – vis medicatrix naturae. This is the keystone of a philosophy that has been held for thousands of years by naturally oriented physicians (see Ch. 3 ). The concept of a homeostatic, self-regulating mechanism is central to the understanding of basic concepts of physiology: negative feedback loops control virtually all systems of the body. According to Guyton: [118] … the body is actually a social order of about 75 trillion cells organized into different functional structures … each cell benefits from homeostasis and in turn each cell contributes its share towards the maintenance of homeostasis. The body can maintain health and re-establish a healthy state after disease by virtue of its inherent vitality. This is part of the definition of a homeostatic mechanism; it has been selected by nature in the same way that organs vital to our survival have been selected. The surviving species are those most fitted and best able to cope with dysfunction. Those organisms that can tolerate the greatest stresses and still maintain a normal physiology are the hardiest survivors and ensure the species’ ability to increase the limits of its adaptation. Therefore, given that an organism is self-maintaining when in an environment that it has been selected for, healing happens unaided by simply maintaining an environment that does not obstruct the path of cure. As Norman Cousins observed: [119] … without any help, the human body is able to prescribe for itself. It does so because of a healing system that is no less real than the circulatory system, the digestive system, the nervous system, or any of the other systems that define human beings and enable them to function. The role of emotions
Reviews of studies that explore how specific emotions can increase cancer susceptibility, [120] [121] examine the effect
57
of emotions and recovery from cancer, [122] examine the increased incidence of sudden and rapid death during psychological stress, [123] and monitor the changes in immune function during emotional stress [124] [125] all confirm that emotions play a powerful role in the prognosis of a patient. Cannon and Tregear document dramatic case histories of pioneering anthropologists who witnessed the power of taboos and curses to kill strong healthy men and women in Third World cultures throughout Africa, South America, and the South Pacific: “I have seen a strong young man die the same day he was tauped; the victims die under it as though their strength ran out as water.”[126] The
vis medicatrix naturae
The healing process described as vis medicatrix naturae demonstrates the significant power and potential of the self-generated healing capacity. For a physician,
there is no more powerful stimulator of this healing mechanism, the placebo effect, than a strong doctor/patient interaction. Just by walking through the door of the physician’s office, a patient’s internal homeostatic mechanisms are nudged into seeking higher levels of health, healing, and adaptation. The placebo effect is a result or effect of the patient seeking the assistance of the doctor’s ability to heal and cure. As Benson noted: [114] When we dissected the placebo effect a number of years ago, we found three basic components: one, the belief and expectation of the patient; two, the belief and expectation of the physician; and three, the interaction between the physician and the patient. When these are in concert, the placebo effect is operative. … Perhaps nothing is being transmitted from the healer to the patient, but rather it’s the belief the patient has in the healer that’s helpful. Conscious control over homeostasis
The body has two internal forces to maintain homeostasis: a lower and a higher drive. The lower drive is the inherent internal healing mechanism, the vital force, or primitive life support and repair mechanism that can operate even in a person who is asleep, unconscious, or comatose. The higher drive is the power of the mind and emotions to intervene and affect the course of health and disease by depressing or stimulating the internal healing capacities. This can be seen in the clinical observation of patients who move toward spontaneous remission of a life-threatening disease through positive emotional support [10] [122] or in patients who fail to express emotions compatible with the body’s attempts to survive. [122] In any disease process, the consciousness of the patient decides the effectiveness of any therapy. Experiments in remote intention generated healing and prayer show that the intention of others is a factor in the homeostatic capabilities of the mind and body. The fact that the homeostatic mechanism can sense and respond to these remote intentions is a reflection of the power of the human mind. Some authors feel that there is a physiological basis for the unlimited possibility of human voluntary control. [127] The ultimate control of psyche over soma demonstrates the priority of the conscious mind over physiologic processes such as immunity and pain control. [128] This puts an enormous responsibility on the physician. He or she must take full account of a patient’s mental and emotional states when treating chronic or life-threatening disease. Physiological mechanisms Identification of a biochemical mechanism for placebo analgesia has done more to change the image of placebo than any amount of arguing about the importance of beliefs and the mind.[129] The mechanisms of placebo response have been suggested to be a mixture of psychological interactions mediating physiological responses. [14] Psychological components of the patient’s placebo effect have been shown to include the decreased anxiety and the increased relaxation, [63] conditioning, [13] expectation,[18] and well-being generated by the establishment of a sound doctor/patient relationship. [130] [131] The physiologic mechanisms of the placebo effect have been suggested to include chemicals, catalysts, and enzymes. It is believed that steroids, catecholamines, [10] the autonomic nervous system,[14] [132] neuropeptides, and endorphins [133] are also involved. These physiologic mechanisms interrelate synergistically and are presently being researched under the rapidly developing field of psychoneuroimmunology, [4] through which the links between depression, affective disorders, emotions, and the immune and central nervous systems are being explored. Susceptibility to depression and sensitivity to pain have now been found to be mediated through neurotransmitters such as catecholamines, serotonin, and dopamine. The current model for explaining the mechanism by which emotions, mood, and psychological stress suppress immune function involves cerebral-hypothalamic and pituitary interaction which translates stress and anxiety into an autonomic-endocrine response. This response adversely affects the immune function, particularly after chronic stimulation. Stressful stimulation is received in the sensory cortex of the brain and is then referred to the limbic system and the hypothalamus. This interface of the higher brain functions and homeostatic regulating centers provides the communication link between the psyche and soma. According to Rossi: “The hypothalamus is thus the major output pathway of the limbic system. It integrates the sensory-perceptual, emotional, and cognitive function of the mind with the biology of the body.” [14] In the hypothalamus are the nerve centers which
58
control both branches of the autonomic nervous system, parasympathetic and sympathetic, nerve cells that secrete endocrine-releasing factors, and neural pathways that release hormones directly into the posterior pituitary. The corticosteroids and catecholamines from sympathetic stimulation are key factors in altering disease susceptibility in response to stress. Corticosteroids inhibit the function of both macrophages and lymphocytes, as well as lymphocyte proliferation. [134] Corticosteroids also cause the thymic and lymphoid atrophy noted by Hans Selye in his experiments on stress-induced immune dysfunction. The autonomic release of catecholamines stimulates receptors on the surface of lymphocytes, thereby increasing their maturation rate. When in a mature state, the lymphocytes’ ability to kill bacteria and cancer cells and produce interferon seems to become paralyzed. [135] Thus a population of mature lymphocytes develops, ready to defend the body from infection and inflammation yet remaining paralyzed until the “red alert” signal of sympathetic fight or flight is turned off, signaling the appropriate time to rest and repair. A number of other peptides, E-type prostaglandins, somatotropin, histamine, insulin, endorphins, ADH, and PTH, all have receptor sites on lymphocytes and can stimulate the same cAMP-mediated response resulting in lymphocyte maturation and inhibition. [134] A study of the effect of catecholamines on the human immune system showed that when a physiologic dose of epinephrine is injected into a healthy volunteer there is an increase in the number of circulating T-suppressor lymphocytes and a decrease in the number of circulating T-helper lymphocytes (changes similar to those found in AIDS). [134] Placebo and stress physiology
Stress “let-down” of a patient in the therapeutic environment is one of the mechanisms producing the placebo effect. This results from the patient’s perception that a transition from a stressful situation to a non-stressful situation has occurred. Mowrer [135] observed that with a decrease in anxiety there is a concomitant increase in hope, signifying that the period of suffering is over. Certain familiar images and signals, such as white coats, syringes, behavioral procedures, and clinical protocol, create a conditioned response – relief, now that help has arrived. Evans similarly observed that “… the reduction of fear through the shared expectations that the doctor’s medicine will work – even if unknown to the patient it is placebo – mediates powerful therapeutic effects”. [63] The placebo effect in the clinical environment transforms the emotional and mental stress of the patient. These effects, also observed and described by Franz Alexander,[11] Hans Selye,[136] George Solomon,[137] and Walter Cannon, [138] allow the patient to escape the “fight and flight” response that can cause, and maintain, the state of illness. Physiologic and psychologic stress
Selye[139] demonstrated that physiologic stress can have a dramatic effect on the immune and endocrine systems of the body. Laudenslager [140] went on to show that it is not just stress that creates these physiologic changes, but also the perception that stress is “inescapable” that is critical to the response. More recently, studies on the effects of psychological stress have demonstrated significant changes in immune capability. Maladjustment to “life-change stress” correlates with reduced activity of natural killer cells, [141] decreased T- and B-cell responsivity, [124] and decreased lymphocyte cytotoxicity. [142] For example, Riley [143] observed increased tumor activity in a controlled stress environment and concluded: Emotional, psychosocial, or anxiety-stimulated stress produces increased plasma concentrations of adrenaline, corticosteroids and other hormones through well-known neuroendocrine pathways. A direct consequence of these increased corticoid concentrations is the injury to elements of the immunological apparatus, which may leave the subject vulnerable to the action of the latent oncogenic viruses, newly transformed cancer cells, or other
incipient pathological processes that are normally held in check by an intact immune system. Current reviews of the literature relating psychological stress and immune dysfunction support the hypothesis that the homeostatic immune mechanisms, both humoral and cellular, are significantly impaired by both natural and experimental stress. [2] [134] [115] [144] Hypertension, [145] common colds,[146] coronary artery disease, [147] and myocardial ischemia [148] have been linked to adverse stress physiology. Stress even has the ability to increase permeability of the blood–brain barrier. [149] The implication of stress altering the blood–brain barrier exposes important insights into enigmatic diseases like chronic fatigue syndrome and stress-induced neurological disorders. Endorphins, hormones and neuropeptides
… one rapidly activated psychoneuroendocrine mechanism through which a placebo stimulus may reduce both depression and pain is produced by stimulating the endorphin system. [13] Research on endorphins is a relatively new area of study in the field of psychoneuroimmunology. Original research by Levine et al [97] suggested that the pain relief noted in placebo studies could be explained by the simple mechanism of endorphin-mediated actions. The original emphasis on endorphins and enkephalins was plausible considering their known modulation of pain and mood functions. This position was further supported by later observations that depression increases chronic clinical pain [150] and that decreased activity in endogenous opioids may be part of the pathophysiology of depression. [151] With the information that placebo can stimulate endorphins,
59
Levine et al felt that an explanation for the action of placebos had finally been found. However, this hypothesis failed to account for the broad spectrum of placebo effects, nor did it account for the fact that the analgesia associated with hypnosis is not affected by an opioid antagonist. [152] [153] It is important to note that recent literature suggests that Levine et al were not entirely wrong in implicating the role of endorphins with the placebo mechanism. Rather, they were right for the wrong reason. Endorphins are mainly derived from three precursor proteins (by separate biochemical processes). [154] These opioid peptides are released from central and peripheral areas in response to pain, stress, and emotions and perform many physiological functions, of which analgesia is but one. [155] However, it is becoming evident that the boundaries between the central nervous system and the immune system are not as clear as once thought. The several known effects of endorphins on immune system function are listed in Table 4.5 . [156] When the functions of neurotransmitters such as endor-phins are found to have such an intimate relationship with immune integrity, the paradigm of a body with functions performed independently by its parts – a Newtonian type of thinking – begins to lose credibility. To further blur the already hazy distinction between the central nervous system and the immune system, research has demonstrated that endorphins and peptide hormones such as ACTH, TSH, HCG, and LH are produced by lymphocytes.[156] It is clear that the demarcation between the central nervous system and the immune system is impossible to distinguish. Both the brain and the immune system are the only tissues in the body which have a memory, and the level of communication between the two argues a taxonomy which identifies them as one. Evidence of the innervation of the thymus gland, bone marrow, spleen, and lymph nodes supports the finding that the immune system is subject to efferent CNS information. [156] In addition, studies demonstrating the atrophy of the thymus and lymphatic tissues in the absence of growth hormone, [157] corticotropin (ACTH), and increased steroid production by adrenal cells after interferon stimulation indicate that “… in the future it will be difficult to distinguish the receptors and signals that are used within and between the neuroendocrine and immune system”.[156] TABLE 4-5 -- Effects of endorphins on the immune system Increased and decreased
Lymphocyte production Chemotaxis
Increased
T-cell sensitivity to PGE 2
Increased
Antibody production
Increased and decreased
Complement
Binding of fractions C 5B –C 9
T-cell proliferation
Modulation of
NK-cell function
Modulation of
B-cell differentiation
Modulation of
CLINICAL APPLICATION A physician with an interest in the psychopharmacologic treatment which also can be expensive, elaborate, detailed, time-consuming, esoteric, and dangerous will usually generate a strong placebo response. He or she will be interested in the symptoms of the patient, the differential response to various drugs and will be careful to observe side-effects which may be dangerous. The physician may encourage the patient to call at any time if side-effects develop. [21] The application of placebo phenomena in clinical practice should not be a vague attempt to replace the skill of the medically trained physician with obscure “hand waving”, incantations, and inert lactose pills. In primary care and specialty clinical practice, the physician’s intent should be to optimize patient care through engaging restorative defense mechanisms. To effectively apply current placebo research, several principles (listed in Table 4.6 and discussed below) must be understood. Prima non nocerum: prioritize a treatment program and establish a hierarchy of care Prima non nocerum is the Hippocratic injunction dictating that a physician care for the patient so that self-healing mechanisms can engage. This ancient phrase means, “don’t disturb the organism’s ability to heal itself”. The body must be given the full range of possibilities in allowing the power of homeostasis, vis medicatrix naturae, to have its optimum capability. Doing no harm means that a patient is supplied with the level of medical intervention that is appropriate to their ability to maintain life support. The job of the physician is to determine when homeostasis or defense mechanism has lost the ability to respond to disease. Acute traumatic swelling and inflammation and shock are examples of the human defense mechanism responding in a way that threatens the health of the organism. It is most interesting that the organism would make choices, as in shock and inflammation, that could end up killing itself. To practice the principle of prima non nocerum a physician must learn when to act and when to let the body heal itself. This is the highest art of medicine; each case and situation will be different and it is up to the physician to interpret the needs of the moment. TABLE 4-6 -- Six principles of optimizing placebo response in clinical practice • Prima non nocerum – prioritize a heirarchy of therapeutic intervention • Tollum causum – remove the obstacles • Support the therapeutic relationship • Enhance positive emotional states • Implement therapeutic conditioning or learning
• Utilize altered states of consciousness
60
By implication, the physician who seeks to apply this principle understands the principles of physiology upon which human life depends for homeostasis. Doing no harm means that a patient is supplied with the level of intervention that is appropriate to his or her own ability to maintain life support. Prima non nocerum does not necessarily mean that a physician withholds invasive therapy: it is the physician’s responsibility to determine when the body is unable to re-establish homeostasis and therapy is indicated. If an arm must be severed to save the patient’s life, there is no violation of prima non nocerum. However, to enhance the principle of prima non nocerum, a physician sometimes must withhold therapies and be content to leave the patient to self-heal. Hippocrates understood the wisdom of letting the body heal on its own, implicit in the “do no harm” injunction. The treatment of Charles II is a case in point: [158] A pint of blood was extracted from his right arm and a half pint from his left shoulder, followed by an emetic, two physics, and an enema comprised of fifteen substances; the royal head was shaved and a blister raised; then sneezing powder, more emetics, and bleeding, soothing potions, a plaster of pitch and pigeon dung on his feet, poisons containing ten different substances, chiefly herbs, finally forty drops of extract of human skull and an application of bezoar stone; after which his majesty died. When this treatment is compared with modern procedures such as mammary artery ligation for the relief of angina – a procedure which has no benefit when compared with sham artery ligation – it appears that throughout the centuries physicians have continued to rely on the placebo effect for the care and cure of their patients. Since it plays such an important role in health care, simple, non-invasive, and effective treatments should be the goal of all therapeutic approaches. Robert Burton wrote in 1628: “… an empiric oftentimes, and a silly chirurgeon, doth more strange cures than a rational physician … because the patient puts confidence in him.” [159] The rational physician will also recognize that healing and curing are not necessarily the same. If a patient is helped in any way by the doctor, with or without the use of placebo, the path of cure has been assisted, although the specific pathology may not have responded. Not all patients can be cured but most patients can be helped. Tollum causum: remove the cause of disease Tollum causum is the principle that seeks to remove the obstacles to cure. The forces “inhibiting the floodgates of health from opening” must be removed for the full force of the patient’s beliefs to effect the path of cure. This concept is fundamental to the philosophy of naturopathic medicine with its strong emphasis on diet, detoxification, and a pattern of living that is consistent and compatible with the context in which humans evolved. Obstacles to cure are defined as blocks to the self-healing capacity of the organism. Contamination with heavy metals and xenobiotics (see Ch. 37 ), focal infections, electromagnetic pollution, scar tissue, genetic metabolic abnormalities, and parenchymal organ damage defeat the best therapeutic intentions and must be addressed. The patient’s habitat is an important aspect of the therapeutic protocol, not only in the diagnosis and care of internal mental and physiological dysfunction, but also in determining which environmental factors may be contributing to dysfunction and disease. These factors might include diet, lifestyle, and living environment. It is of the utmost importance to remove a patient from surroundings that are associated with illness or to assist the patient in creating an environment more conducive to health. Factors which provide conditioning that reinforce the disease process can be associated directly or indirectly with one’s environment. For example, if animals are returned to situations where their experimental neuroses were induced, their pathological behavior reactivates. [160] When a patient leaves the offending environment to receive treatment from a physician, the prognosis is correspondingly more favorable. [12] The physician has the added advantage of a patient’s heightened expectation during an office visit – a patient’s positive associations with the “healing” environment increases their receptivity to treatment. [161] If the home or work environment is a source of “dis-ease”, and an obstacle to cure, then providing an alternative environment may be a most helpful way to remove the obstacles to cure. Support the therapeutic relationship Confidence should surround all aspects of the therapeutic interaction. The patient must have confidence in the doctor’s ability to assist a cure, the doctor must have confidence in the efficacy of his or her therapy, [162] and there must be an understanding or relationship between the doctor and the patient which is mutually conducive to respect, trust, and compassion. The quality of the doctor/patient relationship is paramount. The therapeutic approach to a patient which optimizes the confidence of the patient in the skill of the doctor stimulates the inherent self-regulating healing mechanisms by relaxing the anxiety the patient has about their illness. Anxiety is a well-known immunosupressant and aggravates the body’s defense mechanism. An optimum therapeutic relationship when combined with the clinical skill to remove the cause of homeostatic dysfunction is the height of therapeutic acumen. As Lewith so accurately states: [163] The general practitioner may therefore wish to employ all his knowledge, enthusiasm, consultation technique and 61
sympathy, to create the best possible atmosphere in which to elicit a placebo response from the patient. Current research on factors contributing to the genesis of the placebo effect consistently documents the importance of the doctor/patient relationship. [164] [165] [166] The healing power of the therapeutic interaction has been demonstrated by the commencement of the placebo effect even before the actual administration of the pill. [167] The physician facilitates the cultivation of a sound relationship through developing good communication skills. The art of bedside manner has been recognized throughout history as the primary skill a successful physician needs. [168] Indeed, the history of medicine is as much a history of the relationship between doctor and patient as it is the evolution of medical technology and techniques. Through centuries when doctors were doing more harm than good, little more than the esteem of their clientele sustained the medical profession. But however little real help the doctor had to offer, it was to him that people turned when illness struck. [169] Bedside manner has been found in clinical studies to entirely alter the course of double-blind studies and the quality of a therapeutic encounter to facilitate or disrupt the efficacy of a treatment. [170] Listening to the patient, [170] verbal and non-verbal communication of the physician, amount of time spent with the patient, [171] patient education, [172] demeanor of the physician, [173] and interview skills [171] have been suggested as factors and components of effective physician communication skills. Touch is an important form of communication and is sometimes forgotten as a key aspect of the doctor/patient relationship. Highly skilled clinicians with many years of experience, such as the late Dr John Bastyr (whose remarkable healing abilities inspired the founding of Bastyr University by those privileged to have been his students), frequently impressed upon clinicians the importance of always using diagnostic and therapeutic touch during a patient visit. The doctor’s touch can be diagnostic, therapeutic, and, perhaps most important, a means of communicating that he or she is deeply attuned to the problems, needs, and fears of the patient. [174] Touch can heal by increasing tissue mobility and fluid exchange (as in massage), and by relieving pain, as demonstrated in research on healers who use their hands.[175] Touch has also been documented in well-designed double-blind research to extend an unusual healing power which can be transmitted through the hands to plants and animals.[176] Regarding other methods of enhancing confidence between the doctor and patient, the setting in which a doctor provides therapy to a patient will also determine its effectiveness. The doctor’s office setting is very important for optimum and effective treatment: tools and support systems are more accessible, and a heightened patient response results from seeking out the “healing” environment. In a clinical trial with hypertensive patients, placebo alone was not as effective as when it was administered in conjunction with hospitalization. The visit to the physician represents a search for changes that cannot be found through “self-care” or over-the-counter medicines. According to Frank: [177]
In short, it appeared that the placebo situation relieved chiefly anxiety and depression, that the degree of relief was unrelated to personality and autonomic measures, and that the patients who responded strongly to a placebo at one time might not at another. In conjunction, these results suggest that the extent of responsiveness to a placebo depends on the interaction of the patient’s state at a particular time with certain properties of the situation. The finding that administration of tests and questionnaires seemed to have at least as beneficial an effect as had the pill implies that any interaction between patient and situation that heightens expectations of help may lead to symptom reduction and improvement in mood. The aspects of the situation producing this effect include not only presentation of a symbol of the physician’s healing powers (a pill), but any attention and interest shown by professional personal. This phenomenon was also observed in industry and termed the “Hawthorne effect”. As a direct result of the increased attention factory workers received during investigation, the quality of their work improved. [178] In conclusion, the importance of a doctor/patient relationship and the confidence that this engenders shows that all human beings need to share their feelings and experience the therapeutic benefits of touch: the doctor/patient relationship provides an ideal way to meet these fundamental needs. Enhance positive emotional states Love in all its subtleties is nothing more and nothing less than … the psychical convergence of the universe upon itself. (The Phenomenon of Man, Pierre Teilhard de Chardin) For optimum enhancement of the psychoneuroimmune system, the physician must assist the patient in developing practices that amplify positive emotional states and reduce negative emotional states. A negative mental state (anxiety, stress, panic, anger, depression, neurotic behavior, self-deprecation, self-destructive feelings and tendencies, and a weak will to live) hinders the ideal functioning of the psycho-neuro-immune-endocrine axis, disrupting homeostasis. Engle has termed this the giving-up/given-up complex: [179] Study of the life settings in which patients fall ill reveals that illness is commonly preceded by a period of psychological disturbance, during which the individual feels unable to cope. This has been designated the giving-up/given-up complex and has the following five characteristics: a feeling of giving up, experienced as helplessness or hopelessness; a depreciated image of the self; a sense of loss of gratification from relationships or roles in life; a feeling of disruption of the sense of continuity between past, present, and future; and a reactivation of earlier periods of giving-up. It is proposed that this state reflects the temporary failure of the mental coping 62
mechanisms with a consequent activation of neurally regulated biological emergency patterns. Changes in body economy so evoked may alter the organism’s capability to deal with concurrent pathogenic processes, permitting disease to develop. The importance of reducing negative mental states in acute and chronic conditions has been discussed extensively. cause various forms of cardiopulmonary dysfunction, even death. [115]
[123]
Acute psychological stress is documented to
Chronic mental and emotional strain causes immune system breakdown and disease. The homeostatic processes become overwhelmed by autoimmune, microbial, or neoplastic invasion. Major authors on the subject of acute and chronic stress emphasize the high priority of managing the physiologically and immunologically destructive effects of the human body’s response to stress. Pelletier [180] lists hypertension, arteriosclerosis, migraine headache, cancer, chronic bronchitis, emphysema, asthma, and arthritis as disease processes which are caused or exacerbated by stress physiology. A study researching the relationship between resistance to streptococcal infections in families and stress load in the family found a positive correlation. [181] Another study on the psychosomatic susceptibility to infectious mononucleosis found that psychosocial factors of high motivation and poor academic performance significantly increased the risk of “disease” infection. [182] In yet another study, anticipation of mood and menstrual discomfort were positively correlated and manipulated, thereby supporting the suspicion that expectations act as a determinant of mood.[183] The conclusion that there is no acute, chronic, or degenerative disease that is not affected by a patient’s mental and emotional state must be drawn from the pervasive immunoendocrine effects generated by the mind and emotions. Wolf [184] and Cousins [185] write of the power of panic as a factor in myocardial infarction, Marbach & Dworkin [150] describe depression as a component in myofascial pain dysfunction, and Shekelle [186] notes, in a 17-year follow-up study, a twofold increase in the incidence of cancer in depressed patients. The clinical scenarios these observers describe infer that the placebo effect can control the onset and advance of a disease by shutting down the destructive thoughts, images, and feelings that mediate stress. Enhancing positive emotions is the corollary of controlling the damaging effects of negative mental and emotional states. Laughter, [187] hope,[188] acceptance,[117] and the reduction of suffering [189] have been shown to speed the course of healing and reduce the level of pain and distress reported by patients. Although pain is sometimes the only language nature can use to adequately communicate to the patient that something is in need of healing: “… the relief of suffering and the cure of disease must be seen as twin obligations of a medical profession that is truly dedicated to the sick”. [189] Acceptance has been observed to be a key factor that assists patients in greater understanding of their pain. [117] Acceptance does not mean complacency in the face of disease, but a rational understanding of the situation and the limitations that can sometimes accompany a disease process. The importance of cultivating hope in a patient also cannot be underestimated. [190] The fact that a patient seeks the help of a physician or “care giver” already implies a substrate of hope and is a signal that the patient can visualize the potential for recovery. The treatment needs to merely stimulate this willingness to envision a future of health. Hope is an embodiment of the patient’s and the doctor’s ability to visualize an image of healing and recovery. This process is a recurrent theme in imagery therapy, [191] visualization therapy, [192] therapeutic touch,[193] and psychic healing. [194] Hope is both an active and a passive placebo. Passive hope placebo is that brought with the patient as the act of seeking help generates a level of unspoken faith in an image or potential for cure. Active hope placebo is generated by the physician, who consciously instills a vision or image of cure in the patient as an adjunct to therapy. Frank performed a double-blind study where patients were divided into control and induction groups. hope was strengthened to conform with the expectations of the therapist: [177]
[ 195]
The induction group was led through a process whereby their
It introduces some perceptual clarity into the process of treatment; and to the extent that all our therapists adhered roughly to the insight model of therapy, it helped to bring the patient’s expectations in line with what actually occurred in treatment, and also helped him behave in accordance with the therapist’s expectations of a good patient. The induction group were actually being consciously strengthened to a level of optimal response, while not being led into false expectations. This type of patient education or active placebo is a necessary and useful tool for framing and directing a positive outlook and prognosis. If a patient can conceive of a state of wellness, then that state of wellness can be achieved. It is the job and domain of the physician to discover those images, emotions, and perceptions which reside in the conscious and subconscious mind of the patient that block the image of a positive state of health. He or she must actively work to control these with the same level of intent as with any presenting gross complaint or physiological dysfunction. Finding these dysfunc-tional mental substrates and working with the patient to try and change them is fundamental to treating the true cause of disease (see Tollum causum on p. 60 ). Research has demonstrated the importance of positive and negative thinking in heart disease and cancer, the two areas of disease which cause the highest death rate. Doctors’ health care management protocols should reflect
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this research in the same way that attention to proper diet is a part of a management approach to high serum cholesterol. It is now clearly established, for instance, that even low levels of stress trigger the onset of myocardial ischemia. [196] We also know from the work of Steven Greer et al [197] and David Spiegel[198] that the attitude
and emotional exploration are critical to breast cancer survival. Knowing these scientific facts, it is imperative that every doctor have strategies for helping their patients explore the areas of stress management, group therapy and support groups and skills in building positive attitude. Implement therapeutic conditioning or learning Those who remain at least dimly aware that everything they say or do to a patient conveys a major or minor, positive or negative, helpful or harmful psychological impact are likely to be more effective physicians. [199] Conditioning of the mind has been suggested as a mechanism by which the placebo effect becomes a learned response. [12] [14] [177] The future of therapeutic application of placebo will probably hinge primarily on the use of conditioning. A doctor who can understand this will pay close attention to the stimuli of his patients and modify these stimuli in a scientific way to help treat immune and neurological related diseases. Modern psychology acknowledges two models of conditioning or reinforcement of learning behavior: operant and classical conditioning. Operant conditioning is a behavior response that theoretically occurs in the presence of some stimulus that is a positive reinforcement, e.g. a rat will learn to press a conditioning bar if a food pellet is dispensed as a result. Classical conditioning is a behavior response created by the simultaneous pairing of unconditioned and conditioned stimuli prior to an evoked response. This is best illustrated by the experiments of Pavlov and his “salivating dog”. In Pavlov’s experiment with the conditioning of a dog’s salivary response to the ringing of a bell, the bell ring is the conditioned stimuli, the food the unconditioned stimuli. The salivation is the unconditioned response to the food that becomes the conditioned response. When the dog finally associates the bell ring with the food, the ringing alone causes salivation, the conditioned response. The principle of classical conditioning has far-reaching implications for the diagnosis and treatment of disease because of the pervasive and permeating implications that conditioning has in all the sensory stimuli of daily existence, in sickness and in health: [200] Pavlov’s teachings, concepts and basic notions afford the real and ultimately scientific basis for the recognition of the potentialities of medical science attacking diseases from both the psychic and somatic sides. For the purposes of this discussion, recognize that classi-cal conditioning happens randomly in our environment and is closely linked to health and healing phenomena. Subconsciously, we note random events and associate them with previous events and observations, independent of an intended learning behavior. Operant conditioning happens in the context of reward, and classical conditioning happens in the context of associated stimuli. There is a much greater predominance and range of associated stimuli (classical conditioning) than operant conditioning for the genesis of the placebo effect. This is because the operant depends on reward, although operant conditioning can happen in the medical mode: “Pain killing drugs which I have taken in the past kills pain therefore this capsule which is a painkiller will kill my pain.” Gliedman et al [12] note that drugs that affect the CNS are readily conditioned, whereas drugs that affect the peripheral nervous system and are secretory stimulators (e.g. atropine and pilocarpine) do not result in the establishment of a conditioned response. The primary importance of psychological states to central nervous system excitation demonstrates that the pivotal loci of command for conditioning resides within the hypothalamus and the limbic system. Therefore, a doctor who can induce a state of central excitation in the patient can encourage and condition this patient to make those changes that are deemed necessary for the recovery of health. The conditioning of a patient to a placebo response is modified by learning stimuli associated with the illness, the stimuli of the doctor and the therapeutic setting, the stimuli of the therapy, previous health, medical therapy, and authority-related experiences. [201] The way that all of these factors interact in the psyche of the patient determines the nature of the placebo response that is achieved. Satiation obscures the conditioned response, while situa-tions of increased stress seem to potentiate the responsiveness of the placebo effect. conditioning, and learning may therefore be subject to the nature of central excitatory states as well as to levels of stress and distress.
[117]
Placebo,
The physiological breadth of the placebo response in humans can now be understood in terms of the variety of interactions and effects that drugs, therapeutic procedures, and sensory phenomena of the medical environment have on the psychosomatic matrix of a patient’s consciousness. Rossi [14] notes that this complicated web of sensory processing reveals how any facet of therapy: … that alters any aspect of the body’s sensory, perceptual or physiological responsiveness on any level can disrupt the more or less fragile state-dependent encoding of symptoms and thereby evoke a “nonspecific” but real healing effect that we call the placebo response. In fact, the scientific basis of therapeutic applications of psychoneuroimmunology is based on classical conditioning. This research was done by Ader & Cohen
[202]
to
64
show that the immune system could be conditioned for therapeutic purposes. Ader & Cohen conditioned immuno-suppression in rats by injecting them with a conditioned stimulus of cyclophosphamide (a potent immunosuppressing agent) while feeding them a saccharine solution as an unconditioned stimulus. The idea of conditioning for immunomodulation in human patients is therefore a promising therapeutic modality. Applying conditioning techniques for the treatment of systemic lupus erythematosus resulted in a delay in the development of the disease using a dosage that normally had minimal results. [203] To fully account for the extent of previous and future conditioning in a patient, the physician must take a complete and exhaustive history in order to explore the influences of family, work, accidents, emotional predispositions, past medical history, and neutral stimuli as contributing factors during the onset of an illness. Lifestyle and emotional, behavioral, or physiological factors might contribute to maintaining the state-dependent learning pattern of disease and dysfunction or give clues for a successful therapeutic intervention. A good example of this is Batterman & Lower’s [204] demonstration of increased analgesic effectiveness based on similar previous therapy. A physician who knows which therapies succeeded, and which failed, can take advantage of the patient’s conditioning and encourage biochemical pathways that the body has learned. Drug or therapeutic interventions are not procedures that can be predicted in the same way as can in vivo experimental results. The variables involved in human responses to therapy are clearly underestimated in the current rush of research-oriented therapeutic evaluation. [55] Therefore, a patient who has been treated by a number of physicians or practitioners for a complaint and received no results or relief has been conditioned to believe that consultation and treatment by a physician will provide no positive changes. When the patient visits the next practitioner, even if this practitioner can offer a diagnosis and treatment that are correct answers to the long-sought cure, there are very real patient conditioning factors that must still be considered. Consider the case of a young woman who was undergoing treatment for breast cancer and the clinical course of the ensuing metastases. Each time that she had a positive response to therapy, she experienced a subsequent remanifestation of the cancer. The result of this conditioning was that she came to equate each new course of chemotherapy as a herald of some new manifestation: “… she was torn between a desire to live and the fear that allowing hope to emerge again would merely expose her to misery if the treatment failed.” [205] The parameters of conditioning in a clinical setting extend to all aspects of the patient’s sensory perceptions. Consciously, or unconsciously, the physician is providing an environment for patient learning. Lipkin [206] points out that every drug, every apparatus, every injection, and every piece of information or advice carries a suggestion of help and hope, regardless of the physiological effects that may accompany it. It is important to realize that the patients are taking in all the information about the surroundings, interactions, and therapy, and making associations that can potentially affect the course of their responsiveness to therapy. Mower[135] observed that the “safety signals” of syringes, laboratory coats, and behavioral procedures are all retained in the patient’s psyche for future association. A physician can skillfully take advantage of these by encouraging and cultivating response generalization or by associating previous therapeutic situations with subse-quent treatments with unconditioned stimuli such as office music, odors, and images. Giving patients some sort of unconditioned stimulus that can be taken home allows them to associate with the conditioned response, eliciting the memory of the therapeutic interaction while away from the doctor’s office. These
unconditioned stimuli or placebos can be given in multiples at one time, [131] changed for more powerful stimuli,[70] and delivered at the end of an induction, suggestion, or imagery procedure. They should not be limited to pills or other ap-parent medicaments, but should extend to sounds, smells, visualizations, and feelings. It should be remembered that therapeutic conditioning depends on a perceived physiological shift or change in the patient as described in the theory and research of biofeedback. [207] This shift can be experienced as a sense of relaxation, increased warmth or circulation, altered autonomic tone, or change in some sensory perception. Patients know immediately when there is no change in their disease or dysfunction after they have been given placebo. [208] Therefore some patients will need a more active form of therapeutic management that allows for some level of perceived change. Ideally this perception would be a sense of being free from pain, or a state of abnormal physiologic function altered to a state of improved physiologic function. Acupuncture, spinal manipulation, drug therapy, physiotherapy, hydrotherapy, and surgery are all therapies that can create an immediate biochemical impact perceived by the patient. The optimum model to apply to the concept of conditioning therapy and the selection of an appropriate therapy or modality was proposed by Greene & Laskin [209] in their evaluation of myofascial pain dysfunction (MPD). During an 11-year follow-up study of MPD patients, they concluded that, when comparing the effectiveness of a wide variety of reversible and non-reversible (surgical) therapies, conservative and reversible therapies were the most important and appropriate treatment factors for the patient’s health and well-being. Focusing on patient communication, educating patients regarding reversibility
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of the condition and the nature of muscle dysfunction as it relates to stress–pain–spasm, developing a therapeutic strategy based on increasing patient awareness and self-management skills, and selecting a flexible treatment strategy were all found to be essential for achieving a good initial response which could lead to long-term wellness. The specifics of which therapy was most indicated was not felt to be as important as the need to focus on the nature of presenting musculoskeletal problems and the factors and complexity of the treatment environment. Routine use of active pharmacological substances reinforces the relationship between conditioned and unconditioned stimuli. However, routine use of unconditioned stimuli in the absence of a conditioned response weakens the therapeutic efficacy of the practitioner and has been described as “placebo sag”. [13] Therefore, the learning of a conditioned response from unconditioned stimuli could diminish if the conditioned stimuli fail to produce an adequate or reliable conditioned response. Without the intermittent demonstration of active strength, the placebo effect will get weaker and weaker. The implications of placebo sag for practitioners of alternative medicine, who try to work with the body’s own defense mechanisms without overwhelming medical intervention, are that periodic use of perceptually active therapy is needed to support a patient who is not able to respond to, or responds too slowly to, a gentler therapeutic nudge. In this case, the physician must recondition the vital force to open a path to homeostasis. In a sense, this may be a paradigm of the therapeutic situation where changes towards health are induced in the patient by a doctor who is able to cultivate a basic state of arousal, presumably central in nature. This state of arousal causes the patient to become accessible to the doctor’s expectations of him. [12] The typical placebo burst, where a therapy is initially effective after a short period, but then wanes, is now understood in terms of the placebo sagging from lack of effective unconditioned stimuli to maintain the conditioned framework. [70] Physicians who lack the ability to extract themselves from a series of unsuccessful therapies risk eventual placebo sag: [13] … therapists who primarily use their active strengths (or unconditioned stimuli) paradoxically will get stronger placebo effects than quacks, will enjoy escalating credibility, and will seem as miracle men – when in fact perhaps only half their miracles can be traced to their active ingredients while the other half is a function of the anticipatory (or conditioned) response elicited by their conditioned features. Since the visit to a physician is often initiated by the physical pain of the patient, it stands to reason that skillful pain management is a high priority in establishing a therapeutic conditioned response. Pain management by hypnosis, TENS, therapeutic touch, direct or indirect manipulation, imagery, acupuncture, meditation, [210] and an understanding that aims to elicit the nature of suffering [205] can all be valuable therapeutic adjuncts to establishing a therapeutic environment that conditions the patient for full potentiation of their healing capabilities (see Ch. 56 for a full discussion of these techniques.) With the recent development of standardization, research, and concentration of the active components of plant medicines, vitamins, and biochemical precursors, naturopathic medicine (and other forms of alternative medicine) stands on a stronger therapeutic base because of an ever-growing verification of their pharmaceutical and therapeutic armamentarium. These therapeutic modalities are characterized by safe, yet physiologically active, substances and procedures; therefore they provide some defense against placebo sag. Utilize altered states of consciousness Since ancient times, aboriginal humans have recognized the tremendous therapeutic power that lies dormant in the subconscious mind. For thousands of years, shamans and medicine men have used trance states to engage the most subtle aspects of the patient’s subconscious to effect factors in disease pathogenesis and prognosis. [211] In modern medicine, it has been documented that shamanistic healing involving altered states can offer dramatic “spontaneous remissions”; [29] the mechanisms of this process have been explored in the theory and application of hypnosis. [1] [128] Most currently accepted techniques employed to trigger the subconscious to effect positive changes in somatic or psychic health involve hypnosis. Placebo effect has been linked with hypnosis, or “low arousal states”, which are therefore believed to be critical factors in the evaluation of the mechanisms and perimeters of placebo. [200] A review of the literature documenting the potency of hypnosis and the observed results of placebo clearly demonstrates that these two areas yield remarkably similar clinical results. The inquiry into hypnosis grew out of the simple intent to validate the effectiveness of the mind in healing processes, whereas most placebo literature grew out of the intent to demonstrate a certain percentage of chance, fluke, spontaneous remission, or psychosomatic illness as a factor to be ruled out in the delivery of intelligent, scientific health care. Using these antiquated definitions of placebo and hypnosis, one is led to believe that hypnosis describes a process of healing based on the skillful guidance of a qualified practitioner, while placebo describes a process based on chance, regardless of the professional circumstances. On closer inspection, the distinction between the two blurs: they appear to be much the same process. Illness, healing, and health states constantly shift in the homeostatic system, a system affected by stimuli
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received through the different levels of awareness, and can be accessed, investigated, and modified by a variety of techniques. These include placebo, hypnosis, and induced altered states of consciousness. Rossi [14] notes that since memory is dependent and limited to the level of awareness in which the memory was acquired, it is “state bound information”: State dependent memory, learning, and behavior phenomena are the missing link in all previous theories of mind body relationships. … The major thrust of these hypotheses is that mind-body information and state-dependent memory, learning and behavior mediated by the limbic-hypothalamic system, are the two fundamental processes of mind-body communication and healing. … The new approach to mind-body healing and therapeutic hypnosis may be conceptualized as processes of accessing and utilizing state-dependent memory, learning and behavior systems that encode symptoms and problems and then reframing them for more integrated levels of adaptation and development. Some psychosomatic phenomena are coded into the behavior of an individual through state-induced patterning. Until the patient can access the state in which somatic complaints are induced, possibly through hypnosis or other methods which break the sympathetic dominance of “encoded” shock, [212] the psyche cannot clear them from the soma: [14] A person in a traumatic car accident experiences an intense rush of the alarm reaction hormones. His detailed memories of the accident are intertwined with the complex psychophysiological state associated with these hormones. When he returns to his usual or “normal” psychophysiological states of
awareness a few hours or days later, the memories of the accident become fuzzy or, in really severe cases … the victim may be completely amnesic. The memories of the accident have become “state-bound” – that is, they are bound to the precise psychophysiological state evoked by the alarm reaction, together with its associated sensory-perceptual impressions. In accessing these psychosomatic state-dependent areas of homeostatic dysfunction, the physician must use techniques that relax the conscious mind and allow access to subconscious content for reframing. The nature of the visit to a physician encourages a patient into more accessible unconscious states, as demonstrated by higher placebo effects when patients present to a hospital setting. [161] These labile states of consciousness are quite natural; humans constantly cycle in and out of different consciousness states. [161] These cycles, or ultradian rhythms, are described as alternating cycles of hemispherical dominance that change every 1.5 hours. When these cycles are interrupted by behavioral stress, psychosomatic behavioral responses such as ulcers, gastritis, asthma attacks, and skin rashes develop. [213] A change in these rhythms manifests as a period of psychic repose. If an individual is in the midst of performing a task, day-dreaming or the felt need for a rest or coffee break may be the external manifestation of an internally sensed signal of a change in rhythm. This is also a period when one is highly susceptible to hypnotic suggestion. Because these rhythms are very flexible and labile, they can be invoked through hypnosis or, if the physician senses a natural lull indicating a hemispherical switch, a “natural” trance can be induced. Centuries ago in India, practitioners of hatha yoga observed the effect of mental states on the breathing patterns of an individual. With anger, frustration, and mental instability, the breath reflected a short, arrhythmic pattern which mirrored the disturbed psyche of the person. Conversely, when a person is in a peaceful, relaxed, deep meditative state, the breath is long, rhythmic, and barely perceptible. Their discovery formed the basis for the development of breathing exercises called pranayama (literally, regulation or restraint of the vital energy), which aimed to calm the breath so that deep states of meditation and focused concentration could be attained. Current research has affirmed the powerful effect these exercises have on asthma, diabetes, chronic gastrointestinal disorders, and psychosomatic and psychiatric dysfunction. [214] Therapeutic exercises which use somatic stimuli to effect changes in the psyche create fertile environments for stimulating the placebo response. A breathing technique used to decrease sympathetic tone or alter nostril predominance for causing shifts in hemispherical activity, [215] an exercise to release fascial muscle tension and thereby effect mood-enhancing blood flow in the brain, [216] [217] or a biofeedback treatment that aids in slowing the heart rate and decreasing negative emotional states [207] are all examples of how the psyche can be accessed by the soma. The whole process of eliciting the placebo response involves an attempt to marshal all the reserves and potential for healing through a doctor/patient interaction, engaging both the patient’s mind and body to re-establish homeostatic equilibrium. Health care professionals can use the wisdom of psychosomatic therapies as a central part of their therapeutic protocol. In addition to the specific therapeutic regimen, treatment of the whole patient can be achieved through these harmonious techniques. If physicians could persuade patients to care daily for their emotions, minds, and spirits the way they care for their hair or teeth, the effectiveness of any prescribed treatment would be greatly enhanced. As a primary therapeutic adjunct and important basis for preventive medicine, this line of treatment is all too often ignored.
ETHICS It is important to remember that there are two forms of “conscious” placebo used by the physician. The use of placebo as a gentle therapeutic agent by a practitioner is very different from the use of placebo in a controlled
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trial where the possibility of a known therapy is withheld in a treatment group. Some authors feel that the use of placebo in clinical trial breeches the Declaration of Helsinki which states that every patient should be assured of the best proven diagnostic and therapeutic method. [218] The ethical problems of delivering health care in a research design where there is a possibility of favorable outcome and having half of the group be denied access to this possible favorable outcome is a troubling ethical issue. The ethical use of placebo has also been questioned in an attempt to determine if a physician should be deceiving patients in the process of healing. [219] Although there are some authors who advocate a restricted use of pure and impure placebo because of its “deceptive” nature, [207] it becomes clear in a brief review of the current literature [4] that any argument for or against the use of placebo assumes that there are medical procedures that are free of potential placebo effect. Brody [24] concludes that placebo can be called the “lie that heals”. However, on closer examination it can be seen that it is not the lie that does the healing, but rather the relationship between the patient and doctor which stimulates a natural self-healing mechanism via psychologic, symbolic, and biologic intervention: For some time, medical science has looked almost exclusively at technical means of diagnosis and treatment; the doctor/patient relationship that forms the setting for their application has been naively viewed as a non contributory background factor, relegated to the amorphous realm of the “art of medicine,” or simply ignored. In this setting, the placebo effect has inevitably been viewed as a nuisance variable, interfering with our ability to elicit “clean data” from clinical trials; and deception in medicine has been seen either as an unimportant side issue or as a tolerated means toward an end. But as the doctor/patient relationship is rediscovered as a worthy focus for medical research and medical education, the placebo effect assumes center stage as one approach to a more sophisticated understanding of this relationship. [24] While it has been observed that a physician’s correct understanding of the nature of placebo therapy can coexist with its inaccurate use and abuse, recommended that: [219]
[42]
it has been
• Pure placebo should not be prescribed unless the physician has examined the exact indications even more carefully than when prescribing specific therapy. • To avoid missing disease process that can be easily treated with an empirically proven protocol (e.g. vitamin B 12 -deficient peripheral neuropathy), the physician should not relax a diagnostic protocol because a patient seems to be responding to placebo.
CONCLUSION Health practitioners need to be equipped with a better understanding of placebo therapeutics. [6] [220] For many years now, the study of placebo has been recommended to doctors and health care professionals. The ideal environment for the dissemination of the therapeutic implications of the doctor/patient relationship is in medical schools as a required part of the curriculum. After finding a pattern of misuse and misunderstanding about the nature and efficacy of placebo, Goodwin [42] recommended that better education might result in more effective placebo use. In 1938, Houston [168] wrote of the need to reaffirm the art of medicine because he perceived a trend in medicine that invested in a concept of the therapeutic doctor/patient interaction as “undisciplined thought”. Houston’s remedy for the intellectual bias that viewed medicine as a “tight, fast-set science” was to emphasize the importance of psychobiology in medical schools: [168] One of the most hopeful moves in medical education is teaching to first-year students the elements of psychobiology. A system of belief is implanted best in the young. It would be my suggestion that psychobiology be taught in the premedical years, that the doctor/patient relationship be the beginning of medical studies. A deep insight into this fundamental philosophy is a chief concern of the internist.
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Chapter 5 - Women in the history of medicine Jennifer Booker ND
INTRODUCTION Traditionally, women have been the healers, caring for their families and neighbors and helping each other through childbirth. Over centuries, women developed and utilized herbal remedies, poultices, diet therapies, water treatments, and techniques for bone setting and the suturing of wounds. Their methods were passed down to form not only the basis of naturopathic medicine, but also much of what is allopathic medicine. Women have always been at the forefront in providing humane health care, from the venerated women healers of ancient Greece, to the persecuted medieval women lay healers, to the pioneering women of North America. The witch burnings of medieval Europe, the persecution of midwives in the 18th, 19th and 20th centuries, and the discrimination experienced by women in medicine today are all part of the history and development of medicine. To be unaware of women’s role in medical history is to be ignorant of half the story of medicine. Today, health care is primarily in the hands of men, with women playing helpmate roles. The history of women as primary health care givers has been almost completely obliterated. Information about women healers is not part of mainstream knowledge; the interested reader must seek out books specifically about women healers which, until recently, have been generally unavailable. Indeed, women are generally excluded from history books, not only those concerned with medicine (see Spender[1] for further discussion). This dearth of information is a reflection of the pervasive sexism of our civilization. It is the author’s intent to reclaim here part of the history of women in medicine. Today, 93% of allopathic physicians are male. Through-out the industrialized world there are still only few women physicians: England has 24% [2] and Canada 10%. [3] This phenomenon is the culmination of events that date back to early Greece. This chapter investigates the chrono-logical events that have resulted in a medical system dominated by white, middle- and upper-class males.
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FROM ANCIENT GREECE TO 13th-CENTURY ROME Trotula lived in the 11th century and studied and taught in Salerno. Her gynecological work De Mulerium Passionibus (On the Suffering of Women), the earliest known compendium of women’s health care, includes the treatments used by Greek, Roman and Arab physicians. During the following 300 years, this text was used across most of Europe. First typeset in 1544, it was reprinted many times in several languages. [4] Unfortunately, in allowing women into medical schools and careers, Italy was an exception. The faculty of medicine at the University of Paris absolutely opposed female physicians. Since, in 1220, anyone who was not a faculty member was strictly prohibited by law from the practice of medicine, women were effectively eliminated. There was little need to enforce the law until 1322 when Jacoba Felicie, along with several other women, was charged with examining sick persons, prescribing remedies, curing patients and receiving fees without a license. Although many of Jacoba’s patients testified in her favor, and she demonstrated her procedures were the same as those used by licensed physicians, she was still charged and fined. This discrimination continued in France, without remittance, until 1868 (600 years later), when the first woman was allowed entry into the Paris Medical School. Generally, the tradition of women healers which had begun in the ancient world continued until around the 13th century. Surgery was commonly undertaken by nuns at the local convents or by the “lady of the manor” in wealthy homes as a charitable duty. Some women healers received payment for their skills. Cecelia of Oxford, designated wise woman of the village, was employed as court surgeon by Queen Phillippa, wife of Edward III (1327–1377). In the 13th century, contact with Arabian scholars stimulated a revival of interest in learning which resulted in two major developments that directly led to excluding women from the healing professions: the appearance of medical schools in universities and the formation of barber-surgeon guilds. [4] With the incorporation of medicine into universities, only licensed doctors were given the legal right to practice with the title of physician. With the exception of Italy, all European universities were closed to women. Official recognition of their medical skills was no longer available. The development of universities and medicine was strictly controlled by church doctrine, and innovation suppressed. Medical students studied Plato, Aristotle, and Christian theology. Medical theory was restricted to Galen and the study of the “complexions” and “tempera-ments” of men. Students rarely, if ever, saw patients, and human dissection was outlawed by the church. Surgery was considered degrading and menial. Treatment consisted of bleeding, leeches and quasi-religious rituals. For example, the physician to Edward II, an Oxford graduate, prescribed writing “in the name of the Father, the Son and the Holy Ghost, Amen,” on the patient’s jaw for a toothache. [5] In contrast, the women healers of this era, practicing illegally, followed the healing methods of Trotula and St Hildegarde of Bingen, Germany. Hildegarde (1098– 1179) wrote a compendium of natural healing methods entitled Liber Simplicis Medicine. In it, at a time when male physicians had no use for such advice, she lists the healing properties of 213 plants and 55 trees and asserts the importance of cleanliness for proper treatment. [6] Although the natural healing methods of these women resulted in their being persecuted and burned at the stake as witches in the Middle Ages, many of these methods continue to be used in naturopathic medicine today. Viewed from the perspective of the late 20th century, church doctrine was disturbingly misogynist. Pain in labor was perceived as the Lord’s just punishment for Eve’s original sin. In the 13th century, St Thomas Aquinas wrote: [2] As regards the individual nature, woman is defective and misbegotten, for the active power in the male seed tends to the production of a perfect likeness according to the male sex; while the production of women comes from defect in the active power, or some material indisposition.… ( Summa Teleologica) This attitude towards women climaxed in the 15th century with the burning of witches or lay healers (discussed below). The second development of the 13th century which served to exclude women from the healing professions was formation of barber-surgeon guilds. These guilds laid down regulations for apprenticeship and membership. In return for guaranteeing standards of practice, members were given exclusive rights to their home town’s needs for surgical care and could prosecute non-guild members who dared to perform surgery. Those most affected were the midwives. Forceps, a surgeon’s invention, could only be legally used by guild members; therefore, a midwife was required to call in a barber-surgeon during a difficult delivery. The surgeon would either remove the infant piecemeal by hooks and perforators or perform caesarian section once the mother was dead. [7] Occasionally women were allowed admittance into barber-surgeon guilds by patrimony or apprenticeship, but numbers were small. By the end of the 14th century, organized medicine had effectively excluded women. The church joined in with witch-hunts in the 15th century, and the long tradition of
women healers was almost completely eradicated.
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THE 14th THROUGH 17th CENTURIES By the 14th century, professional, university-trained physicians were in demand by the wealthy. Middle- and upper-class educated women healers were eliminated by excluding them from universities and licensing. This left only the women lay healers of the peasant class as competition. The medical profession appealed to the church for help, and the church responded by persecuting women in one of the most vicious rampages in history. There were two reasons for this victimization: the witch-healer was an empiricist in direct opposition to church doctrine, and women represented sexuality, a betrayal of faith through sensory awareness and alignment with the devil. The church believed women to be the conduit of all evil. All pleasure was condemned, as the devil was considered the source. Women were associated with sex, and lust in either husband or wife was blamed on the woman. A newborn was immediately baptized by a male priest in order to ensure salvation of its soul, which had been exposed to the wickedness of the woman for 9 months while in the womb. Upon resurrection, it was believed that all humans would be reborn as men. [8] Women healers had sins to atone for other than their sex. The so-called witches relied upon their senses and observation in treating their patients. The church believed that to trust one’s senses was wrong – the senses were the devil’s playground and used by the devil to lure men into the conceits of the intellect, delusions of carnality, and away from the faith. [8] The methods of the witch-healer were based on years of experience. She maintained an attitude of active inquiry, learning through trial and error, cause and effect. Her repertoire included herbal remedies such as clary, hyssop, lily, ergot, belladonna and digitalis – many still used by naturopathic physicians today. Codified in the written works of Hildegarde of Bingen and Trotula of Italy, her approach was scientific according to today’s standards. Even established medicine referred to these works for centuries.[8] The approach of medical doctors, deeply anti-empirical with no concern for the material world and empirical observation, was more consistent with church doctrine. They did not search for the natural laws governing physical phenomena but instead abided by the belief that the Lord created the world anew each moment, and hence there was no point in questioning one’s surroundings. The witch-hunts During the 14th through 17th centuries, witch-hunts spread across Europe. Thousands of executions, usually live burnings at the stake, were carried out, first in Germany and Italy and later in France and England. In 1484, a witch-hunting manual, the Malleus, was written by reverends Kramer and Sprenger, beloved sons of Pope Innocent VIII. It contained specific instructions for conducting witch-hunts and methods of torture for extracting confessions and names of other witches. Witchcraft was defined as political subversion, religious heresy, lewdness, and blasphemy. Women were accused of every conceivable sex crime against men. They were accused of being organized, of having magical healing powers, and of harming with magic. According to the Malleus: “All witchcraft comes from carnal lust which in women is insatiable.… And blessed be the highest who so far has preserved the male sex from so great a crime.…”[8] Women were often charged and burned at the stake simply for possessing medical knowledge and obstetrical skills. “If a woman dare to cure without having studied, she is a witch and must die” (Malleus). [8] Of course, women could not officially study as they were not allowed into medical schools. English physicians complained to Parliament about the “worthless and presumptuous women who usurped the profession” and requested that fines and long imprisonment be the punishment for any woman “who dared to use the practice of Fisyk”. [9] King Henry VIII heard their plea and secured nationwide regulation of medicine and surgery with the Act of 1512, which installed a system of licensing that approved practitioners and punished and suppressed all others. [7] In Europe, the church was given the responsibility of implementing the program to eliminate women healers and “witchcraft”. In several German cities, approximately 600 burnings occurred each year, two each day except Sundays. Over 900 “witches” were executed in 1 year in the Wertzberg area and over 1,000 in the area of Como. In Toulouse, 400 women were put to death in 1 day. In the Bishopric of Trier in 1585, so many woman were killed that two villages were left with only one woman each. It has been estimated that the total number of executed witches (85% of whom were women) was in the millions. [8] The persecution of women healers greatly strengthened the relationship between the church and the medical profession. The doctor was considered the medical expert, providing an aura of authority to the witch-hunt as he decided whether the accused was a witch and what afflictions were the results of witchcraft. The dogma was that if a woman effected a cure, it was with the help of the devil, while if a male priest or doctor effected a cure, it was with the help of God – the Lord worked through male priests and doctors, not through women. [2] The majority of witches were the general practitioners of the peasant population. The poor did not have access to hospitals or university-trained physicians and were bitterly afflicted with poverty and disease. The church upheld a double standard in terms of who should receive health care. For the upper classes and nobility, it was a given. For the poor, life experience in the world was
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fleeting and unimportant and so was their suffering. The peasants were offered little in the form of relief or even words of comfort from the church:
[8]
You have sinned and God is afflicting you. Thank him and you will suffer so much less the torment in the life to come. Endure, suffer, die. Has not the church its prayer for the dead? The witch-hunts deprived the peasantry of the health care that was available to them and helped establish the dominance of a technological and rather violent male-dominated medical profession by eliminating the last of their competition. Not only during the medieval period in Europe, but also until about 1875, university-trained doctors depended on blood-letting and purgatives. Calomel, a mercury salt and the most popular purgative and cure-all medical remedy, was used in large doses for acute problems. [10] Through the 17th century, they derived their prognoses from astrology and the theory of “complexions and temperaments”, partially treating their patients with incantations and quasi-religious rituals. A common treatment for leprosy was a soup made of black snake caught on dry land among stones.[5] In contrast, the approach of the medieval woman healer emphasized the role played by the patient’s innate power of healing – a view still held in naturopathic medicine today. Illness was regarded as part of the life process and an attempt on the part of the organism to regain homeostasis. Her methods included herbs, diet therapy, massage, water cures, poultices, and other gentle health-promoting approaches. [11] Women healers used their extensive knowledge of physiology, anatomy and herbs gained through experience and observation. Their superior healing abilities were acknowledged by Paracelsus who, in 1527, burned his texts on pharmaceuticals, confessing he “had learned from the Sorceress all he knew”. [5] The witch-hunts, however, branded women healers as superstitious and potentially malevolent and so thoroughly discredited women healers among the emerging middle class that, in the 17th and 18th centuries, devastating inroads were made into their last preserve, midwifery. Discrediting the midwives
The English Act of 1512, which ultimately controlled the licensing of physicians, made no mention of midwives, probably on the basis that midwifery was considered part of surgery. [7] The system of licensing that did develop for midwives was concerned mainly with social and religious functions, for there was no way for a woman to become educated and therefore no possibility of achieving legitimate status through government licensing. Medical schools and universities were closed to women everywhere in Europe except Italy. The majority of midwives were peasants and could not afford to travel abroad to study. As a result, midwives lacked the knowledge of Latin and Greek necessary to read texts or communicate their knowledge of female anatomy and physiology. The few midwives who did manage to educate themselves, by witnessing dissections and reading medical works, still remained legally unqualified as they could not attain a university degree. [7] Midwives in England organized in the mid-18th century to protest the Act of 1512 and the intrusion of male doctors into their realm. They charged doctors with commercialism, damaging infants’ skulls with dangerous overuse of forceps, and causing undue harm to mothers. But as midwives did not know proper medical terminology and many of their members were being burned as witches even as they spoke, their protests were easily dismissed as “old wives’ tales” based on ignorance and superstition. So much was their skill and tradition discredited that they lost claim to their own techniques. For example, when Ambroise Pare (1510–1590), surgeon to the King of France, developed an interest in childbirth, he laid claim to discovery of podalic version, the method utilized and described by the woman physician Aspasia of second century Rome.[4] The male medical profession could now boast of their superior obstetrical methods. By the early 1600s, male “midwives” began to establish themselves in earnest. They were called in for difficult cases, often with disastrous results. Nevertheless, by the end of the 18th century, throughout Europe childbirth had become the province of male physicians. [7] Conclusion The persecution of witches was a major exercise in medical and social control, eliminating women healers and removing the peasants’ only source of health care. World-views that conflicted with church doctrine, i.e. that recognized the nature principle and the holistic quality of human life, were exorcised from the healing arts, not to be revived until the women’s movement in North America in the 1700s and 1800s. Perhaps most significant was the effect the witch-hunts had on society’s perception of women, firmly establishing suspicion of evil, black magic and immoral sexuality of women in general, and women healers specifically.
THE BATTLE OF THE SECTS IN 19th-CENTURY AMERICA Rise of the medical establishment In early colonial America, the responsibility for healing was in the hands of women as was general family care. University-trained physicians, i.e. allopaths, did not emigrate to the colonies until the late 1700s, and then only a
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few came. In the New World, formal education, including medicine, was not available at the university level. In New Jersey, for example, medical practice, except in extraordinary cases, was mainly in the hands of women as late as 1818. [12] Colonial women brought centuries of healing lore with them handed down from the “witch” healers of medieval Europe. Knowledge of indigenous herbs learned from the American Indians was combined with the European traditions of massage, hydrotherapy, botanicals, and midwifery. Medical practice was open to anyone who could demonstrate healing skills, regardless of formal training, race, or sex. Then, in the early 1800s, American university-trained doctors, modeled after the established European allopaths, began to become available. The four medical schools established by the turn of the century were far below European standards, and programs were only a few months in length. Most schools lacked clinical facilities and did not require even high school diplomas for entry. As the number of formally trained doctors grew, it became clear that much needed to be done before they could achieve the prestige and economic status of European medical doctors. One of their first tasks was to distinguish themselves from lay healers. Allopaths were already easily identified as they were male, middle- and upper-class and almost always more costly. Their clientele consisted of middle- and upper-class citizens who could afford the prestige of being under their care. It was fashionable among upper-class women, for example, to employ male doctors for obstetrical care, much to the horror of the general populace who considered it immoral for a woman to expose herself in such a manner to a man. [12] The allopaths, however, had little to offer in terms of theory or practice that was superior to what was avail-able through folk medicine. Women healers used gentle botanical medications, offered dietary advice based on generations of experience, and, perhaps most importantly, did little or no harm. Allopathic doctors distinguished themselves by doing a great deal of harm in the form of “heroic medicine”. Benjamin Rush has been credited with playing a central role in establishing heroic medicine. Along with a small group of elite American medical doctors, he completed his medical education with a few years of study in Great Britain. Here they developed the style of the genteel, highly paid European physicians, and aspired to establish a similar medical model in the New World. To accomplish this, they had to convince the general public that the allopaths were able to offer medical care superior to the inexpensive and efficacious care provided by lay healers and midwives. An all-encompassing theory and system of therapeutics was developed which resulted in immediate, although extremely dangerous, results. The purpose was to produce the strongest possible visible response in the patient. The stronger a drug or procedure, the greater its therapeutic value was purported to be. Blood-letting, purgatives, laxatives, enemas and blistering were among the most common treatments. A patient was bled until he either fainted or his pulse was no longer palpable. In 1847, one physician, after observing that extensive blistering of children often led to convulsions, gangrene or even death, concluded that blistering “ought to be held in high rank” in the treatment of childhood diseases. [10] Not all physicians were in agreement with these methods, however. Douglas observed that: [10] Frequently there is more danger from the physician than from the Distemper … but sometimes not withstanding the Male Practice, Nature gets the better of the Doctor and the patient recovers. Aside from the lack of effective therapeutic techniques, there was a total void where medical theory should have been. Air was considered the carrier of disease, and getting wet was thought to enhance susceptibility to disease. Those who listened lived in fear of bathing, sunlight, and breezes. Drinking water was kept from the ill, and windows were kept shut and covered with heavy drapes. Women were advised to keep themselves covered from the sun at all times with parasols and veils. Heroic medicine gave regular doctors the appearance of being able to keep back disease, winning the “battle” against disease even if it killed the patient. Some of these doctors became very wealthy and gained much influence with statesmen and other influential members of the upper classes. Politically, this was essential to subsequent events in the development of allopathic dominance in North America. Professions are the creation of the ruling class. To become sole providers of health care and succeed with the sham of heroic medicine, allopaths needed patronage from the ruling class. According to sociologist Elliot Friedson: [2] A profession attains and maintains its position by virtue of the protection and patronage of some elite segment of society which has been persuaded that there is some special value in it’s work. Between 1800 and 1820, allopaths used their newly acquired influence to pressure 17 states into passing licensing laws restricting the practice of medicine to their own kind. In 10 states, practicing without a license meant imprisonment. [13] Two major unforeseen political problems, however, appeared to disrupt the allopaths’ plans. First, the general populace and lower classes did not accept the hazards and pretensions of heroic medicine, preferring the more effective and much less painful and expensive health care provided by lay healers. The second problem was
enforcement of licensing laws. The general populace was
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not prepared to persecute their own trusted healers, often the women of their own families or a well-known neighbor. The new laws incited public outrage. Fanned by the labor rebellion against upper class elitism and exploitation of burgeoning industrialization, the popular health movement emerged. The popular health movement In the early 1800s, the industrial revolution created a deep economic division between the upper and lower classes. Factory employees and unskilled laborers lived in abject poverty on the edge of starvation while working long hours for ridiculously low wages. Single family farmers and owners of small businesses were exploited by banks whose financial manipulations often pushed them into ruin. Upper class industrialists flaunted wealth gained at the expense of the lower classes. From this setting arose the labor movement with its membership of farmers, artisans and factory workers. At the same time, the women’s movement began to take greater hold among working-class women. In early industrialized society, many women were thrown together, free of the company of men. Women were either confined to home and church or worked in all-women factories such as those in the New England mill towns. Discovering their common aversion to heroic male medicine, women began to develop alternatives.[14] Among the hundreds of benevolent associations, charitable institutions and mutual support groups was the “Ladies Physiological Society”, a feminist health care group. At society meetings, women learned about female anatomy, physiology and personal hygiene; old-time home remedies were recultivated and exchanged; and the lore of botanical healing and other techniques used by the pioneer women healers were recovered. In opposition to the dangerous therapies of allopathic doctors, they emphasized preventive care: frequent bathing, loose-fitting clothing, whole grains, and fresh air – all in direct opposition to the medical dogma of the day. The women’s health movement was at the forefront of general social upheaval, a radical assault on medical elitism, and an affirmation of traditional “peoples’” medicine. Women’s outrage against allopathic medicine, shared by working-class men, resulted in a mass movement against medical professionalism and “expertism” of all forms. It was a class war, and the allopathic doctors were on the side of the aristocratic upper class. Regular doctors, with their claim to educational superiority, were denounced, along with the universities that trained them. It was popularly believed that students learned in the universities to look upon labor as “servile and demeaning”.[11] By the 1830s, the labor and feminist movements had converged into the popular health movement. According to historian Richard Shryock: [10] This crusade for women’s health was related both in cause and effect to the demand for women’s rights in general and the health and feminist movement became indistinguishable at this point. The health movement was concerned with women’s rights, and the women’s movement was concerned with health care and access to medical training for women. However, it took a male voice to repeat what women had already said and done before any change took place. Samuel Thomson is credited with laying the foundation of a theory (see Chs 2 and 35 ) and practice of folk medicine for the working class and feminists. A poor New Hampshire farmer, he had watched his wife and mother die at the hands of allopathic doctors. Outraged by their violent methods, he began to reconstruct the folk medicine he had learned from a woman healer and midwife named Mrs Benton. According to Thomson: [13] The whole of her practice was with roots and herbs applied to the patient, or given in hot drinks, to produce sweating which always answered the purpose. … By her attention to the family, and the benefits they received from her skill, we became very much attached to her; and when she used to go out and collect roots and herbs, she would take me with her, and learn me their names, with what they were good for. Thomson’s methodology systemized Mrs Benton’s methods, which she in turn had learned from native American Indians and the tradition of women healers before her. In 1822, he published A New Guide to Health, which described what was basically her entire healing system. His intention was to provide the public with self-sufficient health care and to remove healing as a commodity from the marketplace. (Although less toxic and more natural then the medical therapies of the day, Thomson’s were not always particularly gentle. For example, lobelia was given as an emetic to cleanse the stomach and followed with capsicum to induce fever. He also used steam baths (his followers were often called “steamers”) and sought to restore equilibrium through the use of Myrica cerifera (bayberry), Nymphea odorata (pond lilly), Pinus canadensis (spruce), and Rhus glabrum (sumac).)[15] The Thomsonian Movement was in full swing by 1835, claiming just under one-quarter of the entire US population. There were five Thomsonian journals which included articles concerned with health, women’s rights, and affronts to female health inflicted by “heroic” obstetrical practices. He felt that women were natural healers, and strongly believed that doctors, who graduated without ever having witnessed a delivery, should leave obstetrics to midwives. His son, John Thomson, wrote: [14] We cannot deny that women possess superior capacities for the science of medicine, and although men should reserve for themselves the exclusive right to mend broken limbs and fractured skulls, and to prescribe in all cares for their own sex, they should give up to women the office of attending upon women.
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These ideas were in direct opposition to those of regular doctors, who felt that women had no place in medicine and continued to put much effort into keeping them out. Women were still not allowed into regular medical schools, and the new licensing laws forbade anyone who was not licensed and university educated from practicing the healing arts. Perhaps an extreme example of discrimination against women is that of Henrietta Faber who studied and practiced medicine in Havana, Cuba, disguised as a man. When, in 1820, she revealed her true sex in order to marry, she was sentenced to 10 years in prison. [16] It wasn’t until 1849 that the first woman, Elizabeth Blackwell, entered a United States medical school. (When she was applying to the 42 all-male medical schools, a well-meaning professor at Jefferson Medical College recommended she attend classes disguised as a man.) Healing systems similar to Thomson’s grew in the radical climate of the 1830s. Sylvester Graham founded a movement of physiologically based healing called the Hygienic Movement. The Grahamites were so anti-medicine they rejected the use of botanicals as well as drugs. Instead, the system encouraged a vegetarian diet of raw fruits and vegetables and whole grains, while allopaths held that uncooked produce was injurious to your health and white bread was a status symbol. Both the Thomsonians and the hygienists upheld that health care and healing skills belonged to the people and should not be a marketable commodity. Followers of Thomson and Graham fought the new licensing laws for physicians alongside the feminists and working-class activists: [17] Any system that teaches the sick that they can get well only through the exercise of the skill of someone else, and that they remain alive only through the tender mercies of the privileged class, has no place in nature’s scheme of things, and the sooner it is abolished, the better off mankind will be. (It should be noted, however, that while the Thomsonians and the hygienists actively recruited women and strongly believed in the importance of women improving their health and that of their families, they were not particularly supportive of feminism.) By the mid-1830s, every state with restrictive licensing laws had either softened or repealed them. Some states, like Alabama and Delaware, exempted Thomsonians and Grahamites from any restrictions. [13] Regular doctors now became recognized as just another sect and were revealed as the sect that had attempted to monopolize health care at the expense of the working class. Unfortunately, however, the popular health movement began to decline shortly after its greatest victory. By the late 1830s, some of the Thomsonian and Grahamian practitioners wanted professionalism and to establish schools and licensing for their graduates, seeking
what they had fought so hard against and reversing some of the original tenets of the movement. In-fighting began over the loss of basic principles. Much competition developed between their schools for students, creating a larger rift. Along with these events occurred a loss of public support. Feminists turned away from health issues and refocused their efforts on women’s rights in a world controlled by men. The radicalism of the working class trailed off toward Andrew Jackson’s Democratic Party and away from socialist revolution. During the lull, allopaths began adopting enough of the principles of natural healing to appear credible. The reputation of medical doctors was in a terrible state. Their professionalism had been significantly undermined, and uncontrollable growth of their ranks, from a few thousand in 1800 to over 40,000 in 1850, resulted in decreased medical fees and lowered economic status. [13] Many of the graduates, unable to make a living from their practice, chose to open schools of their own. Allopaths were also experiencing stiff competition from herbalists, hydropaths, midwives, homeopaths, and the eclectics who mixed natural healing with allopathy. Each healing art had its own schools, journals, and dedicated following. Homeopaths were particularly threatening as they appealed to the upper class, the patient population most coveted by allopathic physicians. In 1847, a small group of allopathic doctors formed the American Medical Association (AMA). Upon surveying their affairs, they concluded:
[13]
No wonder the profession of medicine has measurably ceased to occupy the elevated position which once it did; one wonders that the merest pittance in the way of remuneration is scantily doled out even to the most industrious of our ranks. One of the first acts of the newly formed AMA was to extend the length of required study from 4 to 6 months and to require 2 years of approved preceptorship. However, practically all hospitals barred women from internship programs. In 1857, Elizabeth Blackwell, after being barred from all New York hospitals (despite her degree), opened the first woman-dominated hospital in the world, the New York Infirmary for Women. Internships for women continued to be very limited (in the early 1940s, 607 of 712 hospitals would not accept women) until World War II when the shortage of male doctors opened the doors for women. The problems for women were further aggravated by the AMA’s Consultation Clause which barred women from membership in the AMA and prohibited members from providing consultations for irregular doctors. Although the Consultation Clause was effective, it was not until the early 1900s that allopathic medicine was able to establish supremacy and essentially eliminate women allopaths and natural healers of both sexes from the field. This was accomplished through their adoption of the new religion of “science” and the infusion by the chemical and drug industry (primarily through the
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Rockefeller and Carnegie foundations) of millions of dollars into their drug-oriented schools. The threat of women doctors From the 1850s through the turn of the century, allopathic doctors relentlessly attacked their competition: the sectarian or irregular and women practitioners. The natural healing-oriented groups were attacked for allowing women among the ranks, and women doctors were attacked for their sectarian methods. But the worst was yet to come. By mid-century, middle- and upper-class women were aspiring to become regular doctors. They too were motivated by reform, as were the women of the popular health movement, but their spirit of reform was moral rather than social. Middle- and upper-class women were outraged by the implicit indecency of the male doctor treating a female patient. Catherine Beecher, a well-known doctor and journalist of her time, publicly raised charges of seduction and sexual abuse by male doctors. A women’s society in Philadelphia made it quite clear that “the Bible recognizes and approves only women in the sacred office of midwife”. [19] A popular women’s magazine, Godey’s Lady’s Book, argued strongly in favor of women physicians: [19]
[18]
We would, in all deference, suggest that, first of all, there will be candor in the patient to the female physician, which would not be expected when a sense of native delicacy and modesty existed to the extent of preferring to suffer rather than divulge the symptoms. Women began to force their way into allopathic medical schools. Elizabeth Blackwell gained admission into Geneva Medical College in upstate New York in 1849 after having been turned down by 16 other schools. After her graduation, Geneva College quickly passed a resolution barring entry of women. [19] In the same year, Harriet Hunt was admitted to Harvard Medical College, but the decision was reversed when the all-male student body threatened to riot. Instead, she attended and graduated from an irregular school. [19] Emily Howard Jennings returned to Canada from the New York Medical College for Women in 1867 to become the first recognized Canadian woman doctor. [20] Ironically, the first woman doctor to practice in Canada was actually James Barry, who posed as a man right up to her death. Even in death her sex went unreported by the embalmer; only when her grave was exhumed did her sex become known. The truth had been too embarrassing for the male embalmer to reveal, since women were not believed to have the intellect required to become physicians let alone study (see Shyrock [10] ), yet Barry had become chief military doctor for the country. Through the efforts of the sisters Augusta Jennings Kimball and Ella Jennings, the second and third Canadian women doctors, and those who followed, by 1900 there were approximately 5,000 women doctors in the US and Canada. Over 1,500 women were enrolled in medical colleges exclusively for women: seven in the United States[19] and two in Canada [20] (Toronto Women’s Medical College and Queens Women’s Medical College). One of the strongest women physicians at the turn of the century, both as a feminist and leader of the natural health movement, was Dr Aloysia Stroebele. In the early 1890s, Stroebele, originally from Sigmaringen, Germany, opened the Bellevue Sanitarium in Butler, New Jersey, a nature cure retreat. As the personal aide to Lady Cooke, the famed suffragist leader, she became a strong advo-cate of “feminine independence and the emancipation of women”. [21] During the several years she spent with Lady Cooke, she made three trips around the world, and in the process met with several natural healers, one of whom, Rikli, influenced her greatly. Her accomplishments were many: co-founding the first naturopathic college, co-founding the famed Yungborn sanitarium, funding the journal Naturopath, and authoring several articles and books. She married Benedict Lust, the founder of naturopathic medicine, in 1901 and changed her name to Louisa Lust. Her most telling contribution, besides her famous cures at “the Bellevue” through her integration of diet therapy, hydrotherapy, and the Rickli air cure, were the funds she contributed to fight 17 legal actions taken against practitioners of naturopathy. [22] The male medical profession understood all too well the economic threat of these women physicians. Any middle- or upper-class woman who found the idea of revealing herself to a male doctor too repulsive could turn to a woman who was a regular, allopathic physician – still the preferred healers of the upper classes. She no longer had to quibble over going to see “irregular” women physicians. Male physicians fought back with all the misogynous slander they could muster. They argued that women were too frail to practice medicine, incapable of operating while menstruating, and unable to survive the vulgarities of anatomy class or the shocking truths of reproduction. [19] The idea that women were too delicate and modest to survive medical training, let alone desire it, meant that women who insisted upon their rights were not really women at all. Alfred Stille, president of the AMA in 1871, explained the phenomenon of women in medicine in his presidential address:[10] Certain women seek to rival men in manly sports … and the strange-minded ape them in all things, even in dress. In doing so they may command a sort of admiration such as all monstrous production inspires, especially when they tend towards a higher type of their own. The editor of the Buffalo Medical Journal was more explicit: [17] If I were to plan with malicious hate the greatest curse I could conceive for women, if I could estrange them from the 81
protection of men, and make them as far as possible loathsome and disgusting to man, I would favor the so-called reform which proposes to make doctors
of them. In other words, women who became physicians, or even desired to become physicians, were not only less than women, they were less than human. In addition to public slander, male MDs and medical students did all they could to make the lives of women aspiring to medical careers as miserable as possible. In class they were harassed with insolent and offensive language, and missiles of tobacco quid and garbage were thrown at them. Anatomy teachers often refused to lecture if women were present. [19] An 1848 obstetrics textbook explained how: “She (woman) has a head almost too small for intellect but just big enough for love.” [10] Once graduated, women doctors were allowed into few hospitals, and internships were almost non-existent. Nor were women doctors allowed to join medical societies or to publish in medical journals. Not until 1915 did the AMA admit its first female physician. The entry of women into medicine was fiercely resisted by male doctors, not only because of their deeply rooted misogyny dating from the beginnings of Christianity and the economic threat they posed, but also because of their association with the popular health movement. The integrity of allopaths had been assaulted by the general public and the popular health movement in which women and feminism played a central role. The irregular schools of nature cure continued to welcome women students, and many of the irregular doctors were women providing a gentle and viable alternative to the dangers of regular health care. During the late 18th and early 19th centuries, women applying to medical school were considered guilty by association of being in opposition to regular medicine and of being feminists.
[ 2]
Hydrotherapy: a haven for women In terms of women’s liberation and medical thought, the most revolutionary alternative system of healing was the hydrotherapy movement, or hydropathy as it was known in 19th century America. The original system consisted of using hot and cold water for bathing, wrapping, douching, and spritzing (spraying all or parts of the body). Allopathic medicines were excluded. Instead, a vegetarian diet, fresh air, exercise, regular bathing with cold water, and drinking numerous glasses of pure water were considered the pathways to health. Later, the principles of hydrotherapy were combined with those of the hygienic, Graham, and eclectic systems to form naturopathic medicine. The formal practice of hydrotherapy began with Vincent Priessnitz who opened a water cure clinic in Graefenburg, Germany, in 1829. [23] A medical doctor, Joel Shew, and his wife, Mary Louise Shew, introduced hydrotherapy to the United States in 1843, where the cause was most visibly carried forward by Mary Gove Nichols and Russell Thatcher Trall. [23] Women played a major role in hydrotherapy as practitioners, educators, and leaders in health reform and women’s rights. Many women worked alongside husbands or male professionals, specializing in the care of obstetric and gynecological patients. Most prominent was Mary Gove Nichols who, in 1846, opened her own water cure establishment in New York. [23] In 1851, she and her physician husband Thomas Nichols opened a medical school based on water cure principles in New York. Other prominent water cure partners included Racheal Brooks Gleason and her physician husband Silas Gleason, James Jackson and Thodoria Gilbert (who opened the Glen Haven Water Cure), and Harriet Austin who later worked with Jackson. [23] The concept of women as protectors of the family’s health and morality was one of the major tenets guiding the hydrotherapist’s insistence that women take control of their own health and personal power. They believed that by developing a healthy lifestyle and independence, women could work alongside men to improve society. These ideas were in direct opposition to the dominant social ethics and medical thought of the day. Allopaths viewed puberty, menses, pregnancy, childbirth, and menopause as a series of potentially dangerous pathological events. Women were relegated to the domestic sphere due to their supposed weak physical and intellectual nature. In the home, they could be protected by the man. [24] In contrast, the hydropaths viewed women’s physiology and reproductive functions as normal, healthy processes. Water cure establishments provided a haven where women could receive sympathetic care, find relief from constant pregnancies, and receive psychological and emotional support. [24] Women were inspired to achieve beyond the domestic realm, and many went on to become hydropaths themselves. Taking the cure at the hydrotherapy establishments became fashionable amongst the wealthy during the late 19th century. Between 1843 and 1900, 213 water cure sanitariums opened. [23] Numerous journals, books, and magazines devoted to the tenets of water cure and a natural lifestyle were published during this time. They became forums for disseminating hydropathic ideals of the perfect society where women no longer wore tight corsets, long dresses, or suffered the ill effects of the allopaths’ over-medication with mercury (for postpartum hemorrhage), lead (for dyspepsia), opium, leeches, and blood-letting. Women were encouraged to avoid the meat-, salt- and stimulant-rich diet of the day. In the vision of the hydropaths, women were free to pursue any career they chose, with hydrotherapy and medicine being the most noble. [23] [24] [25]
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Thomas Nichols’ statement in the Water Cure Journal clearly states their intent: “Never has woman had such an opening for usefulness and influence as this. No water cure establishment is complete without a qualified woman physician.” [26] Mary Gove Nichols, in her inaugural address at the opening to the American Hydropathic Institute, professed: “Women are peculiarly fitted to the art of healing because of their tenderer love, the sublime devotion, the never to be wearied patience and kindness of woman.” [27] Women comprised between 30 and 50% of the graduates from the hydrotherapy schools. They worked diligently as the heads of the ladies’ departments of the water cure establishments, attending to all facets of women’s and children’s health care. They provided prenatal care where allopaths had little to offer, recommending a diet of fruit, vegetables, whole grains, and milk. Loose clothing, daily exercise, and cold baths were recommended to tone the body in preparation for childbirth. [23] After the birth, women were encouraged to get out of bed within days, if not the same day, thus decreasing the risk of postpartum blood clots and pulmonary embolism. Women were taught to experience childbirth as an empowering, natural and holy function, rather than as an event to be dreaded as risking imminent death. Hydrotherapy, more than any other 19th century medical sect, had the strongest connection with the women’s movement. Victory for a male profession Until the early 20th century, allopaths had little to offer that was superior to the other types of health care practices. They had neither economic dominance nor elevated social status over the irregular or natural health care practitioners. In spite of the AMA’s valiant attempts to establish allopathy as the only legitimate form of healing, only 8,000 out of 125,000 doctors in the United States were members of the AMA at the turn of the century. [28] European allopaths had better success in establishing themselves among the upper class. With the introduction of the germ theory by French and German scientists came the first scientifically demonstrable basis for disease prevention and treatment. European medical men were the first to adopt scientific methodology into medical practice and education. This served to further enhance their already elevated status. Science had become the new religion of the general public and was held up as the answer to all social, economic and health problems. The new religion was received in North America with tremendous enthusiasm. Science in North America became a national moral value; any discipline which wanted to justify its existence had to adopt scientific doctrine. Social work, philanthropy, housekeeping, child-rearing, business management, public administration, law, and medicine all began to search for a scientific basis. The adoption of scientific principles was synonymous with reform. [2] In the late 19th century, a small group of American doctors traveled to German and French medical universities for further training and returned determined to install an elite medical educational system that would elevate their professional status. In 1893, they founded Johns Hopkins University, the first medical school in North America with laboratories and full-time professors. Eight years later, the Rockefeller Institute for Medical Research was opened. The institute was, and is still today, solely concerned with pure research and helped to exalt the mystery of European scientism. One of the founders of the institute and a close friend of the Rockefellers,
described the place as “a theological seminary, presided over by the Reverend Simon Flexner, M.D.”. [29] Having finally created a credible academic and research model for medical education, the AMA began to effectively utilize economic and political pressure to ensure that all schools providing a medical education either ascribed to the model provided by the Rockefeller Institute and Johns Hopkins University or were closed. This was accomplished through a cooperative effort between the AMA’s Council on Medical Education (made up of faculty from the medical schools modeled on the Johns Hopkins prototype) and the Carnegie and Rockefeller Foundations. The Carnegie Foundation ostensibly agreed to conduct a study of the educational institutions found in the various healing professions. The results were then utilized to determine which schools and sects were to receive a portion of $150 million in endowments. The study was conducted by Abraham Flexner, brother of the director of the Rockefeller Institute, Simon Flexner MD, a graduate of Johns Hopkins University. In the survey, schools such as Harvard were seen to be conforming to the new scientific model quite well, as they had the money (granted them by the foundations) to employ full-time professors and install expensive laboratories. These schools were given large endowments. The smaller, poorer schools, which provided medical education for women, blacks and those interested in natural healing, did poorly in meeting allopathic requirements and hence received no funds from the Rockefeller and Carnegie foundations. According to Flexner’s report, these schools were not worth saving and their closure would be no loss. Despite the 10 medical colleges in existence at the time that provided medical education solely for women, Flexner also decided that few women doctors were needed. He perceived a lack of “any strong demand for women physicians or any strong ungratified desire on the part of women to enter the profession”! [30] Flexner did deduce that some black doctors were needed, but only enough to check the spread of disease from black to white
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neighborhoods for “ten millions of them live in close contact with sixty million whites”. [30] Due to both economic and philosophical reasons, the irregular schools, which had been a haven for women, and women’s medical colleges did not conform to the new allopathic model and were discredited by the Flexner report. From 1904 to 1915, 92 medical schools closed or merged: five out of seven all-black medical schools closed, seven out of 10 medical schools for women shut their doors, and the majority of the alternative medical schools were eliminated. As a direct result, the number of women graduates from allopathic medical schools dropped from 4.3 to 3.2%. In the meantime, from 1910 to 1930, over $300 million was poured into the medical schools that ascribed to the Johns Hopkins model. [31] Not only women and blacks were affected by these events, for scientism became the domain of the upper classes. The reforms which ruled the existence of medical schools included an entrance requirement of 2 years of university training. This effectively made a medical career impossible for all but the middle and upper classes due to the expense. Medical schools that had been economically accessible to the working class ceased to exist, and the entrance of blacks into medical schools was limited by racial discrimination. Women suffered sex discrimination in their attempts to enter the remaining medical colleges, [2] with percentages steadily shrinking until the 1970s and the resurgence of feminism. [32] The medical profession had become an institution composed almost entirely of white, middle- and upper-class males confirmed in their opposition to women and natural healing methods. It is true that turn-of-the-century medicine needed some form of standardization of education and health care. However, in the fervor of scientism, sexism, racism, and the allopaths’ rush for economic control, the alternatives to allopathic medicine were effectively eliminated. Despite the new reforms, the quality of medical care was not necessarily improved. The new system of lengthy scientific training did not guarantee that physicians were any more effective or humanely empathic than the irregular healers they replaced – in fact quite the opposite appears to have been the case (see Ivan Illich, Limits to Medicine [33] and other chapters of this textbook). While the scientific method has much to offer, it is arguable that, in the context of the stifling, one-dimensional philosophy and male elitism of the medical profession, the use of the banner of scientism to establish political and economic protection from competing ideas actually inhibited the development of health care in this country. Midwives: the last of the women healers to fall In 1900, approximately 50% of all births in North America were attended by midwives. [2] Middle- and upper-class women had their babies delivered by licensed MDs. Lower-class blacks and European immigrants could not afford MDs, nor did they want them. Midwifery was a respected tradition held in high esteem, particularly by Africans and Europeans. This meant fewer obstetrical cases for teaching medical students, as upper-class women certainly did not want a room full of men, medical students or not, witnessing their birthing efforts. Therefore, it was said that midwives, by providing affordable and readily available obstetrical care to the lower class, were depriving medical students of valuable learning experiences. To remedy the situation, medical schools began to associate themselves with local charity hospitals, offering medical trainees as staff in return for patients they could learn on. In the meantime, the medical profession put considerable energy into making midwifery illegal. An editorial in the Journal of the American Medical Association by Charles Ziegler stated the situation: [11] It is at present impossible to secure cases sufficient for the proper training in obstetrics, since 75% of the material otherwise available for clinical purposes is utilized in providing a livelihood for midwives. The “material,” of course, was the bodies of pregnant women. A campaign was launched to rally support among members of the profession to outlaw midwifery by appealing to their sense of what was best for medical education and by portraying midwives as “hopelessly dirty, ignorant and incompetent relics of a barbaric past” who could do only harm to mother and child: [34] They may wash their hands, but oh what myriads of dirt lurk under their fingernails. Numerous instances could be cited and we might well add to other causes of pyosalpinx “dirty midwives.” She is the most virulent bacteria of them all and she is truly a micrococcus of the most poisonous kind. An obvious solution to the problem of the “dirty and ignorant midwives” would have been to educate them in hygiene, in the use of an eyedropper to prevent gonococcal eye infections in the newborn, and in the use of forceps in difficult births. However, the medical profession wanted obstetrical “material”, not to train midwives to further increase their effectiveness and legitimacy. Through cooperation with them, the MDs could have learned much about childbirth and improved their own reputations. The medical doctors’ version of childbirth was dangerous. If the labor was going too slowly for his schedule, he used forceps and caesarian section with considerable risk to mother and child. [7] In teaching hospitals, there was a definite bias in favor of surgery to provide experience for students in abnormal deliveries. [11] In fact, a 1912 study by Johns Hopkins University found the majority of American doctors less competent than the midwives they had replaced. According to the study, they were less
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experienced, less observant and less likely to be present at the critical moment. [35] It appears that the MDs realized they could not fill the void of service left if midwives were eliminated. One obstetrician in 1915 admitted that of all births in New York State, 25% would be entirely deprived of assistance once midwifery was eliminated. [34] Yet between 1900 and 1930, midwives were almost totally eliminated from North America. With the demise of the midwife, American women lost their last independent role as healers. More than one historian has referred to the years from 1900 to 1965 as the Dark Ages in terms of the progress of women in the healing arts. [36] Although there were women allopathic physicians, their numbers were small. In 1900, women comprised 5% of all physicians of all sects, and by 1926, they made up only 2%. Not until the 1970s, with the resurgence of feminism, did the number of women in allopathic medical schools approach even 6%. [32] The remaining irregular schools had continued accepting women students without discrimination, although the numbers were not as high as they are now. In the early 1970s, the naturopathic student body was
approximately 33% female.
WOMEN IN MEDICINE TODAY Today’s dominant form of medicine is a refined form of the heroic techniques of turn-of-the-century allopaths, and women have only recently begun to make real progress in entering the ranks of male-dominated technological medicine. From 1968 to 1978, the number of women enrolled in regular medical schools has increased dramatically, from 7 to 25%. At McMaster Medical School in Hamilton, Ontario, more than 50% of the 1978 graduating class were women – the first time in North America that the number of women in an allopathic medical school was greater than that of men. [37] Discrimination against women in medicine persists, however. According to a 1985–86 survey conducted by the AMA, women earn 62% of the salary of their male colleagues. [38] Women also fill less than 3% of administrative positions in medical schools, and, as of 1987, only two American medical colleges have a female dean. Academic ranking also shows discrimination as women make up 23.6% of assistant professors as compared with only 6% of full professors. [38] [39] Barriers to admitting women into medical schools have been lowered considerably for several reasons: the adoption of civil rights and affirmative action legislation, and resolutions on equal opportunity in the United States and Canada. The women’s movement has encouraged women to seek non-traditional careers and to assert their rights to pursue them. [40] Although the number of women in medicine is increasing, sexist attitudes seem to have changed little since the turn of the century. Ramey, referring to the scarcity of women in administrative positions, commented in 1980 that “women are prone to emotions, verbosity, pettiness and pregnancy”. [41] In this author’s opinion, the final proof of the continued existence of discrimination against women in allopathic medicine is this statistic: women comprise only 10% of practicing allopathic physicians. In contrast, they comprise 40% of practicing naturopathic physicians. Continuing discrimination against women in medicine has manifested itself in many ways: [41] [42] [43] [44] • There is no school-supported recruitment of women such as there is for minority students. • There is a reluctance to admit married women, as they may become pregnant and, if they have families, may not utilize their education. • There is overt discrimination in the classroom, including baiting, hostility, and derogatory comments. It has been documented that lecturers, in dealing with problems in medical practice, direct all of their questions and comments to male students. [43] [45] The prevalence of stereotyping women as sex objects within the profession is exhibited by the number of female students who have been sexually embarrassed, harassed or abused by their male instructors. Reports of such incidents at a conference on women in medicine in Toronto in 1985 were too frequent to be considered extraordinary. [42] A 1988 study of the gender climate in medical school found that 80% of women students reported discrimination by faculty and other physicians, with faculty displaying subtle to blatant sexism.[43] Another recent study at a Midwest medical school indicated that gender discrimination increased in intensity as the women moved closer to graduation and licensing. [43] The types of discrimination reported included sexual remarks, jokes and innuendoes relegating women into stereotyped roles, sexual advances by married mentors, and blatant sexual manipulation. [44] The same study also found that two-thirds of practicing male physicians admitted they did not accept women as professional peers. A prevalent argument used to justify reluctance in allowing women into allopathic medical school is that women MDs are less productive. [36] Evidence, however, suggests the opposite is true. The January 1976 Bulletin of the Professional Corporation of Physicians of Quebec indicated that although women doctors work only 66% of the hours that male doctors do, they provide 92% of the patient care that male doctors provide. While it is true that not all women physicians continue to practice throughout the entire span of their potential working years, it is also true that women doctors are still expected to carry on with traditional family roles – a continuing societal problem. A study of women doctors in Detroit indicated that only 59% had worked without interruption since graduation and that 76% of women physicians are
85
still doing all of the cooking, shopping, housekeeping, and childcare. [44] [46] Women’s advancement within the profession is inversely related to marital status and family size.[36] As a direct result of carrying the lion’s share of family responsibility, and the discrimination they experience in obtaining an education and competing for career opportunities, women allopathic physicians are severely underrepresented in private practice, surgical specialties, and administrative and policy-making positions. Still, the future of women in allopathic medicine looks brighter since their numbers are increasing. It has been predicted that women will make up 35% of the medical profession within the next decade or two. [42] As to the types of medicine women will be practicing, it seems that women are returning to their traditional role of providing preventive health care. According to Spiro: [47] The long standing interest of women in preventive medicine, and the current public dissatisfaction with crisis-oriented care have led still others to predict that one contribution of women may be a more ‘health-oriented’ medical practice. When one considers the percentage of women in naturopathic medicine, his statement is irrefutable. The return of women to their role as primary providers of humane, holistic health care can be attributed to several events: • the resurgence of irregular and naturopathic medicine in North America and Europe as indicated by the increasing number of colleges and institutions providing training in massage, herbal medicine, midwifery, acupuncture, homeopathy, and naturopathy • the revival of the feminist movement since the late 1960s • the increasing interest women are taking in self-health care as reflected by the growing number of women’s organized health information groups • the growing dissatisfaction of the general public with allopathic medicine, recognizing it as expensive and potentially dangerous to one’s health. (For further discussion, see Illich, [33] Mendelsohn,[48] and McKowen.[49] ) These events and social conditions have created an atmosphere similar to the one in which the popular health movement became successful in the early 1800s. Now, as during that time, there is considerable public discontent with heroic medicine and a recultivation of folk medicine, with women at the forefront of the revolution in health care. Today, women make up over 50% of the student bodies at Bastyr College and National College of Naturopathic Medicine. Much of the philosophy and therapeutic approach of naturopathic medicine has been derived from the work of women healers dating back to ancient Greece and the Roman empire. History seems to be repeating itself, with women once again playing a major role in providing preventive holistic health care.
CONCLUSION The history of women in medicine is not well known outside of their traditional roles as helpmates and nurses to male physicians. It is not generally known that women have been primary health care providers from ancient Greece through the beginning of the 19th century. Many factors have created the low percentage of women in the medical profession today. Throughout the ages, women have been intensively persecuted for practicing medicine: Aspasia by Roman law, women folk healers of medieval times who were burned as witches, English midwives who were legislated out of practice in 1512, and women healers of all kinds in early America who were virtually barred from entering allopathic medical schools in North America until the end of the 19th century, and then allowed only in very limited numbers. Today, women have made substantial progress in breaking into the allopathic medical profession despite continuing discrimination. The real changes for women in medicine may come with recent trends towards natural therapies and preventive health care, and the resurgence of midwifery and naturopathic medicine. Along with increasing public interest in irregular medicine and the resurgence of colleges providing credible training in alternative health care, an increasing number of primary health care givers are, once again, women.
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Shryock RH. Medicine and society in America: 1660–1860. Ithaca, NY: Great Seal Books. 1960
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Kaufman M. Homeopathy in America. Baltimore, MD: Johns Hopkins Press. 1971: p 19
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Beecher C. On female health in America. In: Cott N, ed. Roots of bitterness: documents of the social history of American women. New York, NY: EP Dutton. 1972
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Hacker C. The indomitable lady doctors. Toronto, Ontario: Irwin. 1974
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Lust B. Autobiography. Bastyr University Press. 1998, in press
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Kirchfield F, Boyle W. Pioneers in naturopathic medicine. Buckeye Naturopathic Press: Medicina Biologica. 1994
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Donegan JB. Hydropathic highway to health: women and water-cure in antebellum America. Westport, CN: Greenwood Press. 1986
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Wevis HB, Kemble HR. The great American water cure craze, a history of hydrotherapy in the United States. Trenton, NJ: The Past Times Press. 1967
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Nichols TL. Medical education. The American hydropathic institute. Water-Cure J 1851; 12: 66 (from Cayleff
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Brown RE. Rockefeller medicine men: medicine and capitalism in the progressive era. Berkeley, CA: University of California Press. 1979
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Section Two - Supplementary diagnostic procedures
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Chapter 6 - Apoptosis assessment Aristo Vojdani PhD MT
INTRODUCTION Apoptosis is a distinct form of cell death controlled by an internally encoded suicide program. It is believed to take place in the majority of animal cells. It is a distinct event that triggers characteristic morphological and biological changes in the cellular life cycle. It is common during embryogenesis, normal tissue and organ involution, and cytotoxic immunological reactions and occurs naturally at the end of the life span of differentiated cells. Apoptosis can also be induced in cells by the application of a number of different agents, including physiological activators, heat shock, bacterial toxins, oncogenes, chemotherapeutic drugs, a variety of toxic chemicals, and ultraviolet and gamma radiation. When apoptosis occurs, the nucleus and cytoplasm of the cell often fragment into membrane-bound apoptotic bodies which are then phagocytized by neighboring cells. Alternatively, during necrosis, cell death occurs by direct injury to cells, resulting in cellular lysing and release of cytoplasmic components into the surrounding environment, often inducing an inflammatory response in the tissue. A landmark of cellular self-destruction by apoptosis is the activation of nucleases and proteases that degrade the higher-order chromatin structure of the DNA into fragments of 50–300 kilobases and subsequently into smaller DNA pieces of about 200 base-pairs in length. Using fluorescent-labeled reagents, it is possible to tag the DNA break and identify the percentage of apoptotic cells with a high degree of accuracy. [1] [2] [3] [4] [5] [6] Measurable features of apoptosis
One of the most easily measured features of apoptotic cells is the break-up of the genomic DNA by cellular nucleases. These DNA fragments can be extracted from apoptotic cells and result in the appearance of DNA laddering when the DNA is analyzed by agarose gel electrophoresis. The DNA of non-apoptotic cells, which remains largely intact, does not display this laddering
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on agarose gels during electrophoresis. The large number of DNA fragments appearing in apoptotic cells results in a multitude of 3´-hydroxyl termini of DNA ends. This property can also be used to identify apoptotic cells by labeling the DNA breaks with fluorescent-tagged deoxyuridine triphosphate nucleotides (F-dUTP). The enzyme terminal deoxynucleotidyl transferase (TdT) catalyzes a template-independent addition of deoxyribonucleotide triphosphates to the 3´-hydroxyl ends of double- or single-stranded DNA. A substantial number of these sites are available in apoptotic cells, providing the basis for the single-step fluorescent labeling and flow cytometric method. Non-apoptotic cells do not incorporate significant amounts of the F-dUTP owing to the lack of exposed 3´-hydroxyl DNA ends. Apoptosis can also be characterized by changes in cell membrane structure. During apoptosis, the cell membrane’s phospholipid asymmetry changes – phosphatidylserine (PS) is exposed on the outer membrane, while membrane integrity is maintained. Annexin V specifically binds phosphatidylserine (PS), whereas propidium iodide (PI) is a DNA-binding fluorochrome. When a cell population is exposed to both reagents, apoptotic cells will stain positive for annexin V and negative for PI; necrotic cells will stain positive for both and live cells will stain negative for both. [3] This process of apoptosis and its analysis by flow cytometry are shown in Figures 6.1 and 6.2 .
Figure 6-1 Detection of apoptosis using damaged membrane or DNA single-strand break and flow cytometry.
Figure 6-2 Separation of cells by flow cytometry and detection of apoptotic population. Different stages of apoptosis
The process of apoptosis is divided into three different stages: • induction • sensing or triggering • execution. These stages of apoptosis are depicted in Figure 6.3 . Induction represents the initial events that signal a cell so that apoptosis may begin. This induction phase may
Figure 6-3 Various stages of “inside out” cell death or apoptosis.
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be induced by a variety of physical agents such as toxic chemicals, radiation, chemotherapy agents, hormones and CD95 or Fas ligation. However, in a series of our recent experiments, we demonstrated that this induction stage of apoptosis is prevented by many antioxidants (vitamin C, beta-carotene and vitamin E) and also by a variety of biological response modifiers, including lentinan, thymic hormones, viral antigens and cytokines. The induction stage is followed by a decision on whether or not the cell will undergo apoptosis. The decision to die is under the control of a number of different pathways or cellular sensors that induce the apoptosis signal which then triggers the central mechanisms. During this stage, several enzymes, such as IL 1 -ß* converting enzymes, serine protease, cysteine protease, granzymes and cyclin-dependent kinases, become activated. Once activated, these enzymes dismantle the cell and trigger the cell surface changes that cause direct cell recognition and engulfment of the dying cells by phagocytes. These central events are prevented by a variety of antioxidants and biological response modifiers. Apoptosis is induced by chemicals to control malignancy
Many chemicals have the capacity to bind to DNA, form DNA adducts or cause DNA single-strand breaks, possibly leading to cancer. However, the body is equipped with many factors, enzymes, suppressor genes and cellular sensors, all with the capacity to prevent this action of chemicals on DNA by activating apoptosis-inducing signals. The role of apoptosis in regulating tissue growth is readily apparent in the simple equation in which the rate of growth is equal to the difference between the rates of cell proliferation and cell death. Thus, tissues expand if the rate of proliferation exceeds the rate of cell death. This is one of the reasons for suggesting that defects in apoptosis may contribute to the transformed state. An important prediction of the relevance of apoptosis to malignancy is that the rate of apoptosis versus mitosis should influence the behavior of a tumor. Recently, the relationship between the apoptotic and mitotic indices in a tumor was demonstrated predictive of outcome: higher ratios correlate with positive prognosis. Further, it was found that this is not simply a function of cell death per se. Tumors with a high incidence of necrosis rather than apoptosis were correlated with poor prognosis. It therefore follows that treatments or conditions that favor apoptosis should have desirable effects, and that defects in the pathway(s) leading to apoptosis are likely to play important roles in the process of oncogenesis. [4] [5] Many reactive chemicals and drugs, such as acetaminophen, diquat, carbon tetrachloride, quinones, cyanide, polyhydroxyl polyether, methyl mercury, organotin and others, have been implicated in apoptosis (programmed cell death) and necrosis (toxic cell death). [7] [8] [9] [10] [11] [12] [13] [14] Most of the research on chemical induction of apoptosis is carried out with primary cultures of cell lines (neurons, thymocytes, carcinoma cells, leukemia cells, neuroblastoma, breast cancer cells, lymphoma and others); little has been published on the in vivo effects of chemicals on apoptotic cells in animal models and none in humans. Therefore, it was of interest to examine the effects of exposure to low levels of benzene, as well as through drinking water concentrations of up to 14 ppb on the apoptotic cell population, and to examine possible changes in the cell-cycle progression. [7] There is sufficient evidence for the carcinogenicity of benzene in humans; therefore, there is no safe level of exposure to this chemical or its metabolites. Published case reports, a case series, epidemiological studies, and both cohort and case–control studies have shown statistically significant associations between leukemia and occupational exposure to benzene and benzene-containing solvents. [15] [16] It is indicated that possibly 800,000 persons are exposed to benzene from coke oven emissions at levels greater than 0.1 ppm, and 5 million may be exposed to benzene from petroleum refinery emissions at levels of 0.1–1.0 ppm. Since then, numerous chemicals have been implicated in apoptosis (or programmed cell death) which arises from damage to DNA. We hypothesized that in individuals with a certain genetic make-up, benzene or its metabolites act as haptens, which may induce programmed cell death. The study involved a group of 60 male and female subjects who were exposed to benzene-contaminated water (at concentrations up to 14 ppm for a period of 3–5 years). For comparison, we recruited a control group consisting of 30 healthy males and females with a similar age distribution and without a history of exposure to benzene. Peripheral blood lymphocytes of both groups were tested for percentage of apoptotic cell population, using flow cytometry. When exposed individuals were compared with the control group, statistically significant differences between each mean group were detected (27.5 ± 2.4 and 10 ± 2.6, respectively), indicating an increased rate of apoptosis in 86.6% of exposed individuals ( P < 0.0001, Mann–Whitney U-test). Flow cytometry analysis of apoptosis in a healthy control and a patient with CFS is shown in Figure 6.4 . We have already shown that benzene induction of apoptosis is caused by a discrete block of the cell cycle progression. Since it was shown that the ratio of apoptosis to mitosis is predictive of tumor growth, with increased apoptosis favoring positive prognosis, we analyzed our data and expressed them in terms of this ratio. [5] As shown in Table 6.1 , about 10% of the chemically exposed individuals demonstrated a rate of mitosis
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Figure 6-4 Enhanced apoptotic cell population in benzene-exposed CFS individuals. Flow cytometry analysis of apoptotic cell population in negative control cells (HL-60 leukemic cell line), positive control cells (HL-60 leukemic cells treated with the apogen camptothecin), control subjects and benzene-exposed individuals. PBL were isolated, cultured for 12 hours paraformaldehyde-fixed, F-dUTP-labeled and analyzed for apoptosis by flow cytometry.
greater than that of apoptosis, which is predictive of cancer development. Therefore, the tendency of normal cells to commit suicide when deprived of their usual growth factors, or of physical contact with their neighbors due to chemical exposure, is probably a built-in defense against metastasis. Prompt activation of apoptosis in tumor cells that leave their native tissue presumably eradicates many metastatic cells before they have a chance to proliferate. In cancer, it is tumor cells that neglect to sacrifice themselves or forget to die. Indeed, researchers increasingly describe cancer as a disease involving both excessive proliferation of cells and abandonment of their ability to die. Cancer develops after a cell accumulates mutations in several genes that control cell growth and survival. When a mutation seems irreparable, the affected cell usually kills itself rather than risk becoming deranged and potentially dangerous. But if the cell does not die, it or its progeny may live long enough to accumulate mutations that enable it to divide uncontrollably and metastasize, to break away from the original tumor and establish masses at distant sites. In many tumors, genetic damage apparently fails to induce apoptosis because the constituent cells have inactivated the gene that codes for the P53 protein. This protein, it will be recalled, can lead to activation of the cell’s apoptotic machinery when DNA is injured by environmental agents such as benzene or its metabolites. Therefore, it is very important to study cell suicide in health and diseases.
CLINICAL APPLICATIONS Apoptosis in autoimmune diseases
In cancer, it is the tumor cells that forget to die – in autoimmunity, immune cells fail to die when they are supposed to. Virtually all tissues harbor apoptotic cells at one time or another. Damaged cells usually commit suicide for the greater good of the body; when this does not occur, disease may develop. Autoimmunity occurs when the antigen receptors on immune cells recognize specific antigens on healthy cells and cause the cells bearing those particular substances to die. But true autoimmune diseases that involve apoptosis do exist. Under normal conditions, the body allows a certain number of self-reactive lymphocytes to circulate. These cells normally do little harm, but they can become overactive
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TABLE 6-1 -- Ratio of apoptosis to mitosis in patients exposed to a carcinogenic chemical (benzene). In patients 11 and 14, the rate of mitosis is twice that of apoptosis, yielding a ratio of apoptosis to mitosis very close to 0.5. Others present ratios close to 1, which indicates normal homeostasis Sample no. Percentage apoptosis Percentage mitosis Ratio of apoptosis/mitosis 1
34
18.3
1.9
2
29
25
1.2
3
48
46
1.05
4
47
52
0.9
5
20
18
1.1
6
42
17
2.5
7
23
17
1.35
8
26
19
1.37
9
35
13
2.7
10
44
19
2.3
11
18
33
0.54
12
19
15
1.26
13
32
12
2.66
14
19
35
0.54
15
27
16
1.68
16
29
19
1.52
17
28
27
1.03
18
24
19
1.26
19
7
6
1.16
20
10
11
0.9
through several processes. For instance, if these reactive lymphocytes recognize some foreign antigen such as microbes on food and haptenic chemicals, then exposure to that antigen causes them to become excited. If, due to molecular mimicry, these antigens are similar to normal tissues, the activated cells may expand their numbers and attack the healthy tissue, thus causing an autoimmune disease. [1] [17] [18] Autoimmune reactions usually are self-limited – they disappear when the antigens that originally set them off are cleared away. In some instances, however, the autoreactive lymphocytes survive longer than they should and continue to induce apoptosis in normal cells. Some evidence in animals and humans indicates that extended survival of autoreactive cells is implicated in at least two chronic autoimmune syndromes – systemic lupus erythematosus and rheumatoid arthritis. In other words, the lymphocytes undergo too little apoptosis, with the result that normal cells undergo too much. [19] [20] Apoptosis during viral infection
Disturbance in the regulation of apoptosis participates in a variety of diseases. Viral illnesses are among the diseases caused by apoptosis dysregulation. After entering a cell, viruses attempt to shut down the cell’s ability to make any proteins except those needed to produce more virus. This act of stalling host protein synthesis is enough to induce many kinds of cells to commit suicide. If the host cell dies, the virus is also eliminated. Therefore, certain viruses have evolved ways to inhibit apoptosis in the cells they infect. Epstein–Barr virus, which causes mononucleosis and has been linked to lymphomas in humans, uses a mechanism that has been seen in other viruses. It produces substances that inhibit apoptosis. Other viruses, such as P53, inactivate or degrade the induced apoptosis. Papillomavirus, a major cause of cervical cancer, is one example. Cowpox virus, a relative of which is used as the smallpox vaccine, is another. Both elaborate a protein that prevents proteases from carrying out the apoptotic program. Investigators interested in antiviral therapy are now exploring ways to block the activity of the anti-apoptotic molecules manufactured by viruses. [19] Apoptosis in AIDS
Induction of apoptosis by viruses in healthy cells is believed to contribute to the immune deficiency found in AIDS patients. In these patients, infection with human immunodeficiency virus (HIV) causes T-helper cells to die. As T-helper cells gradually disappear, cytotoxic cells, such as NK cells, perish as well through apoptosis, since they cannot survive without the growth signals produced by T-helper cells. When the number of T-cells dwindles, so does the body’s ability to fight infections, especially viral and parasitic. Researchers have shown that many more helper cells succumb than are infected with HIV. It is also highly probable that a large number of the cells probably die through apoptosis. Apparently, Fas plays a crucial role in this process. Normally, T-cells make functional Fas only after they have been active for a few days and are ready to die. But helper cells from AIDS patients may display high amounts of functional Fas even before the cells have encountered an antigen. This display of Fas would be
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expected to cause the cells to undergo apoptosis prematurely whenever they encounter Fas ligand on other cells (such as on T-cells already activated against HIV or other microbes). In addition, if the primed cells encounter the antigen recognized by their receptors, they may trigger their own death. It is also possible that oxygen free radicals trigger the suicide of virus-free T-cells. These highly reactive substances are produced by inflammatory cells drawn to infected lymph nodes in HIV patients. Free radicals can damage DNA and membranes in cells. They will cause necrosis if they do extensive damage, but they can induce apoptosis if the damage is more subtle. In support of the free-radical theory, researchers have found that molecules capable of neutralizing free radicals will
prevent apoptosis in T-cells obtained from AIDS patients. [19] [20] Therapies with anti-apoptotic medication, such as Trolox, a water-soluble analog of vitamin E which prevents oxidative stress, and pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kB (NF-kB), are now the focus of AIDS and autoimmune disease studies. [21] [22] Apoptosis in the heart and brain
In contrast to cancer, where cells forget to die and insufficient apoptosis occurs, excessive apoptosis accounts for much of the cell death that follows heart attacks and strokes. In the heart, vessel blockage decimates cells that were fully dependent on the vessel. Those cells die by necrosis, partly because they are catastrophically starved of the oxygen and glucose they need to maintain themselves and partly because calcium ions, which are normally pumped out of the cell, rise to toxic levels. Over the course of a few days, cells surrounding the dead zone – which initially survive because they continue to receive nourishment from other blood vessels – can die as well. Later on, however, many cells die by necrosis after being overwhelmed by the destructive free radicals that are released when inflammatory cells swarm into the dead zone to remove necrotic tissue. The less injured cells commit suicide by apoptosis. If the patient is treated by restoring blood flow, still more cells may die by necrosis or apoptosis, because reperfusion leads to a transient increase in the production of free radicals. Similarly, in strokes due to inflammation, release of such neurotransmitters as glutamate lead to necrosis and apoptosis. Understanding of the factors that lead to the tissue death accompanying heart attack, stroke, and reperfusion has led to new ideas for treatment. Notably, cell death might be limited by drugs and other agents that block free-radical production or inhibit proteases. Apoptosis also accounts for much of the pathology seen in such diseases as Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis (Lou Gehrig’s disease), which are marked by the loss of brain neurons. Elevated apoptosis in these neurological diseases seems to be related to lack of production of the nerve growth factor and to free radical damage. It seems likely that a combination of such factors could cause many cells to destroy themselves. Manipulation of this process of cell killing may help in treating these neurological diseases. In fact, studies in animal models imply that long-term delivery of nerve growth factors could protect against programmed cell death in these conditions. Therefore, a greater understanding of the mechanisms involved in cell death should greatly enhance those important steps. [17] [21] [23]
CONCLUSIONS Apoptosis and cell proliferation play an important role in development, differentiation, homeostasis, and aging. [2] [3] [4] [5] [6] The balance established between these two processes depends on a variety of growth and death signals which are influenced by diet, nutrition, lifestyle and other environmental factors. When the equilibrium between life and death is disrupted by aberrant signals (e.g. low levels of antioxidants in the blood or tissue cells), either tissue growth or atrophy occurs. Under normal conditions with optimal nutritional factors, tissue homeostasis is sustained by balancing the effects of mitosis and apoptosis. The importance of this
Figure 6-5 Balance or imbalance between the rate of apoptosis and mitosis determines tissue homeostasis, atrophy, cell proliferation, and development of cancer.
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balance can clearly be seen when one of these processes becomes predominant (see Fig. 6.5 ). During viral or chemical exposure and in pre-neoplastic tissue, the number of cells undergoing apoptosis increases, possibly to compensate for an increase in proliferation. As the cell loses functional tumor-suppressor genes (the P53), the propensity to undergo apoptosis decreases and the population of tumor cells grows. Inefficient immune function such as low NK activity due to stress or antioxidant deficiencies may contribute further to this mitosis and apoptosis imbalance, which results in additional tumor cell growth.
REFERENCES 1. Wyllie
AH, Kerr JF, Currie AR. Cell death. the significance of apoptosis. Int Rev Cytol 1980; 68: 251
2. White
E. Life, death and the pursuit of apoptosis. Genes Dev 1996; 10: 1
3. Jarvis
WD, Kolesnick RN, Fornari FA et al. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci USA 1994; 91: 73
4. Green
DR, Martin SJ. The killer and the executioner: how apoptosis controls malignancy. Current Opinion Immunol 1995; 7: 694
5. Arends
MJ, McGregor AH, Wyllie AH. Apoptosis is inversely related to necrosis and determines net growth in tumors bearing constitutively expressed myc, ras and HPV oncogenes. J Pathol 1994; 144: 1045 6. Marchetti
P, Hirsch T, Zamzami M et al. Mitochondrial permeability triggers lymphocyte apoptosis. J Immunology 1996; 157: 4830
7. Vojdani
A, Mordechai E, Brautbar N. Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water. Human Exp Toxicol 1997; 16: 485–494 8. Walker 9. Brown
PR, Smith C, Youdale T et al. Topoisomerase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Cancer Res 1991; 51: 1078–1085 DB, Sun XM, Cohen GM. Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J Biol Chem 1993; 268: 3037
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Reynolds ES, Kanz MF, Chicco P, Moslen MT. 1.1-Dichloroethylene: an apoptotic hepatotoxin? Environ Health Perspect 1984; 57: 313
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Aw TY, Nicotera P, Manzo L, Orrenius S. Tributyltin stimulates apoptosis in rat thymocytes. Arch Biochem Biophys 1990; 283: 46
12.
Rossi AD, Larsson O, Manzo L et al. Modification of Ca 2+ signaling by inorganic mercury in PC12 cells. FASEB 1993; 7: 1507
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Kunimoto M. Methyl mercury induces apoptosis of rat cerebellar neurons in primary culture. Biochem Biophys Res Commun 1994; 204: 310
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Vivian B, Rossi AD, Chow SC, Nicotera P. Organotin compounds induce calcium overload and apoptosis in PC12 cells. Neurotoxicology 1995; 16: 19
15.
Ledda-Columbano GM, Coni P, Curto M et al. Induction of two different modes of cell death, apoptosis and necrosis in rat liver after a single dose of thioacetamide. Am J Pathol 1991; 139: 1099
16.
ATSDR (Agency for Toxic Substances and Disease Registry) Toxicological profile for benzene, draft report. Atlanta, GA: Department of Health and Human Services, Agen. 1987
National Institute of Environmental Health Sciences. Sixth annual report on carcinogens. Benzene Case No. 71–43–2: 35. Research, 1991. Triangle Park, NC: National Institute of Environmental Health Sciences. 1991 17.
18.
Golstein P, Ojcius DM, Ding-E Young J. Cell death mechanisms and the immune system. Immunol Rev 1991; 121: 29
19.
Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Ann Rev Immunol 1992; 10: 267
20.
Duke RC, Ojcius DM, Ding-E Young J. Cell suicide in health and disease. Scientific American 1996; 275: 80
21.
Martin SJ, Green DR. Protease activation during apoptosis: death by a thousand cuts. Cell 1995; 82: 349
22.
Forrest VJ, Kang Y, McClain DE et al. Oxidative stress-induced apoptosis prevented by Trolox. Free-radical Biol Med 1994; 16: 675–684
23.
Schreck R, Meier B, Mannel DN et al. Dithiocarbamates as potent inhibitors of nuclear factor kB activation in intact cells. J Exp Med 1992; 175: 1181
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Chapter 7 - Bacterial overgrowth of the small intestine breath test Stephen Barrie ND
INTRODUCTION Bacterial overgrowth of the small intestine is a serious digestive disorder that is treatable after proper diagnosis. Although widespread, it is frequently unsuspected in cases of chronic bowel problems and carbohydrate intolerance because its symptoms often mimic other disorders. [1] The incidence of bacterial overgrowth of the small intestine increases with age, particularly in people aged 80 years and more. [2] Elderly patients may develop mal-absorption secondary to bacterial overgrowth. It has been suggested as the major cause of clinically significant malabsorption in the elderly and linked to the “failure to thrive syndrome” seen in older patients. [3] Breath testing is a very useful procedure for distinguishing bacterial overgrowth of the small intestine from other problems with similar symptoms. Symptoms of bacterial overgrowth By inhibiting proper nutrient absorption, bacterial overgrowth of the small intestine can lead to systemic disorders such as altered permeability, anemia and weight loss, osteomalacia and vitamin K deficiency. [3] Bacterial overgrowth of the small intestine may also contribute to maldigestion and malabsorption. It frequently is a complication of parasitic infection. Patients with pancreatic insufficiency secondary to chronic pancreatitis are prone to developing bacterial overgrowth of the small intestine. [4] As can be seen from Table 7.1 , the signs and symptoms TABLE 7-1 -- Symptoms of bacterial overgrowth • Abdominal cramps • Bloating • Diarrhea • Gas • Steatorrhea • Vitamin B12 malabsorption and deficiency • Weight loss
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of bacterial overgrowth are commonly seen in a clinical practice. Causes of bacterial overgrowth Normally, far fewer bacteria inhabit the small intestine than the ample growth found in the colon. Gastric acid secretion and intestinal motility keep the small intestine relatively free of bacteria. A wide range of abnormalities and malfunctions, however, can encourage bacteria to multiply in the small intestine. The most common causes relate to a decrease in the production of hydrochloric acid or pancreatic enzymes, thereby creating an unsterile environment for the small intestine. Other causes of bacterial overgrowth of the small intestine include intestinal obstructions caused by Crohn’s disease, adhesions, radiation damage and lymphoma (see Table 7.2 ). Many years may pass between the development of diverticula and symptoms of bacterial overgrowth. [5] [6]
EFFECTS ON THE BODY Bacterial flora function as small biochemical factories, which explains most of the effects of bacterial overgrowth of the small intestine. [7] The flora contain very high concentrations of different enzymes which act upon substrates presented through the diet. Some of these enzymes produce toxic fermentation products normally not found in the small intestine. Gut flora metabolize biliary steroids, which contribute to the diarrhea common in bacterial overgrowth and which may contribute to colon cancer. As can be seen in Table 7.3 , overgrowth of flora in the small intestine can have a wide variety of damaging effects to the intestines and health.
TESTING METHODS While intubation and culture of intestinal aspirates are the standard for determining bacterial overgrowth of the TABLE 7-2 -- Causes of bacterial overgrowth of the small intestine • Achlorhydria, hypochlorhydria or drug-induced hypoacidity • Crohn’s disease • Diabetes mellitus • Giardiasis and other parasitic infections • Immunodeficiency syndromes (particularly sIgA) • Intestinal adhesions • Systemic lupus erythematosus • Malnutrition • Chronic pancreatitis
• Reduced motility in elderly patients • Scleroderma • Stasis due to structural changes – diverticulitis, blind loops, radiation damage
TABLE 7-3 -- Health effects of floral overgrowth in the small intestine • Inactivate pancreatic and brush border digestive enzymes due to production of proteases • Destroy dietary flavonoids, which serve as important natural antioxidants but are rapidly broken down and hydrolyzed by gut flora • Hydrogenate polyunsaturated fatty acids • Deconjugate bile salts • Consume vitamin B12 • Produce vitamin B12 antagonists • Produce nitrosamines small intestine, the less invasive breath trace-gas analysis is an attractive and effective alternative.
[5] [8] [ 9] [ 10]
Endoscopy and intestinal fluid culture have the advantages of providing a definitive diagnosis, but the method is expensive and requires invasive intubation. In addition, it assesses only one or a few sites and may miss flora elsewhere, leading to false-negative results. On the other hand, hydrogen/methane breath tests are simple to administer and offer greater patient comfort and convenience. In addition, these breath tests have good sensitivity and specificity. However, hydrogen/methane breath tests are not effective in patients who don’t produce hydrogen or methane in response to carbohydrate challenge dose (less than 5%). The bacterial overgrowth of the small intestine breath test uses a challenge dose of lactulose or glucose that the patient takes after an overnight fast. If bacteria exist in the small intestine, the bacteria will ferment the challenge substance and produce increases in breath hydrogen and methane. Each substance has advantages and disadvantages. Lactulose challenge Lactulose, a synthetic disaccharide not absorbed by the digestive system, produces hydrogen after contact with bacteria in the gut. patients collect a fasting breath sample, drink a 10g lactulose solution, and collect breath samples every 15 minutes for 2 hours. [1]
[11]
In the lactulose challenge test,
Advantages
• Good sensitivity, because the challenge dose is carried farther toward the jejunum than glucose, so it checks for bacterial overgrowth farther down the intestinal tract • Good specificity for bacterial overgrowth of the small intestine • Suitable for patients with diabetes, hypoglycemia, and other blood sugar disorders because lactulose isn’t absorbed.
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Disadvantages
• Some difficulty in interpretation due to the possible late peak of colonic fermentation of lactulose • Possible mild discomfort or diarrhea in some patients, although usually at higher doses than those used in the breath test. Glucose challenge Glucose is normally absorbed before it reaches the large intestine. If bacteria are present in the small intestine, the bacteria will metabolize glucose before it can be absorbed, producing breath gases. This test requires ingestion of a 75g glucose solution. Advantages
• Good sensitivity and specificity • Easy to interpret because patients who don’t have bacterial overgrowth of the small intestine absorb glucose and don’t produce an increase in breath gases • Can be performed at the same time as a glucose tolerance test (if both are medically indicated). Disadvantages
• Test is not suitable for patients with diabetes, hypoglycemia, or other blood sugar disorders • If the presence of yeast in the colon is regarded as a medical condition, ingestion of sugar may be inadvisable due to its potential for promoting yeast growth • Sensitivity is reduced for distal ileum activity of bacterial overgrowth. [12] Interpreting the results Baseline responses
The typical fasting breath sample contains less than 10 ppm of breath hydrogen or methane. A high breath hydrogen or methane level greater than 20ppm is likely in patients with bacterial overgrowth. Because the fasting breath hydrogen level can be suppressed by methanogenic bacteria, testing for both hydrogen and methane is more sensitive than testing for hydrogen only.[1] Lactulose response
The lactulose challenge typically causes a two-phase response. During the test, hydrogen increases early as lactulose comes into contact with bacteria in the small intestine. This rapid response distinguishes bacterial overgrowth from normal colonic flora, which produce a later, more prolonged increase in breath hydrogen. [1] [12] The test monitors breath gas during the first 2 hours, so colonic fermentation either is not detected or is seen as a rise in the final breath specimens. A breath hydrogen peak greater than 12 ppm above the fasting level within 30 minutes of ingesting lactulose and preceding the colonic excretion response by 15
minutes is considered indicative of bacterial overgrowth of the small intestine.
[1] [ 12] [13]
Glucose response
With the glucose challenge, a rise of 12 ppm in breath hydrogen within 1 hour suggests bacterial overgrowth. [1] The 1 hour period avoids confusion between an increase in breath hydrogen due to bacterial fermentation and early colonic generation of breath hydrogen due to rapid transit. [14] Combining the observation of elevated fasting breath hydrogen (greater than 20ppm) and a positive hydrogen response (greater than 15ppm) reduces the chance of false-positive responses. [1] False-positives
The majority of false-positives reported in bacterial overgrowth of the small intestine breath test can be eliminated if patients follow proper instructions and preparation. [1] Typical problems include: • Eating high-fiber foods within 24 hours of the test. This elevates the level of fiber in the colon at the beginning of the test and increases breath hydrogen production. No starches except rice should be eaten the night before the test. A protein and rice meal, such as beef, poultry, fish or tofu, should be eaten the night before. Fiber supplements should be discontinued 24 hours before the test. • Smoking. Smoking in the area of the test produces high hydrogen levels and unstable baseline results. Breath samples should not be collected where patients are exposed to tobacco smoke. • Sleeping. Sleeping during the test increases both hydrogen and methane levels due to the slow-down in removal of breath trace gases from blood. False-negatives
False-negative results can be caused by severe diarrhea or recent use of an antibiotic, laxative, or enema. Any of these may inhibit bacterial fermentation of carbohydrates and thus production of breath trace gases. [15] [16] [17] [18] [19] To reduce the possibility of false-negative results, patients should wait at least 1 week following completion
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of antibiotic treatment or after recovery from severe diarrhea to re-establish colonic flora. Hyperacidic colon contents do not affect the lactulose challenge because the test reports bacterial fermentation in the small intestine. [1]
CLINICAL APPLICATION Once bacterial overgrowth of the small intestine has been diagnosed, two steps are necessary: • treat the overgrowth symptoms • investigate the underlying causes to keep bacterial overgrowth from recurring. Antimicrobials While tetracycline (250mg four times daily) is the traditional antibiotic choice, research indicates that up to 60% of patients with bacterial overgrowth no longer respond to it. [5] Several broad-spectrum antibiotics have been used effectively. Augmentin (250–500mg three times daily) is generally effective and well tolerated. Acceptable alternatives include the cephalosporin Keflex (250mg four times daily) and Flagyl (250 mg three times daily). [5] Antimicrobials such as penicillin, ampicillin, neomycin, kanamycin, and oral aminoglycosides are ineffective in treating bacterial overgrowth because of their poor activity against anaerobes. A non-absorbable rifamycin derivative, Rifaximin, has been used effectively against anaerobic intestinal bacteria in Italy. [20] Several natural antimicrobials may be useful in the treatment of bacterial overgrowth syndromes. These include: • bismuth, a broad-spectrum antimicrobial absorbed in the gut • bentonite, which inhibits bacterial growth and activity, absorbing many by-products that bacteria produce • berberine, an alkaloid from Hydrastis canadensis, with antimicrobial, antifungal and antiprotozoan activity • herbal mixtures containing gentian and sanguinaria, which have very strong broad-spectrum antimicrobial activity. Nutrition
A low-starch or low-sugar diet may be helpful in reducing diarrhea and steatorrhea. Whether starch or sugar needs to be restricted depends on the location of bacterial overgrowth. If bacteria are in the jejunum, patients tend to be more intolerant of sugars. If bacteria are in the ileum, starch may affect patients more. Soluble fiber may exacerbate abnormal gut ecology. A diet free of cereal grains is generally helpful. Potential deficiencies of nutrients such as vitamin B and calcium should be considered (see Ch. 19 ). [5]
12 ,
vitamin K,
Treatment of underlying causes Bacterial overgrowth of the small intestine may recur if the root causes are not eradicated ( Table 7.2 ). Hypochlorhydria and achlorhydria limit the body’s ability to utilize nutrients from food and supplements. With low gastric acid, ingested food is not adequately sterilized, and normal colonic bacteria may move upstream into the small intestine, causing the return of bacterial overgrowth. Numerous studies have shown that acid secretion decreases with age, possibly due to atrophy of various digestive functions (see Ch.19 ). Betaine hydrochloride may be useful in replacing hydrochloric acid in patients not producing sufficient amounts. A sluggish digestive tract keeps food lingering in the intestinal system. Reduced motility may be caused by inadequate water intake, a low-fiber diet, or aging. Addition of insoluble fiber helps to create bulk and encourage motility.
SUMMARY Bacterial Overgrowth of the Small Intestine Breath Test is a useful procedure for patients with chronic gastrointestinal problems. Table 7.4 lists the most appropriate clinical indications. TABLE 7-4 -- Clinical conditions for the bacterial overgrowth of the small intestine breath test • Patient has abdominal gas, bloating or diarrhea, usually within 1 hour of eating • Patient cannot tolerate carbohydrates or starchy foods, fiber supplements and/or friendly flora supplements • Evidence of hypochlorhydria and/or low transit time as indicated by patient history or the comprehensive digestive stool analysis
• When CDSA indicates maldigestion or malabsorption, patient is treated but symptoms persist. Also, when the CDSA suggests alkaline pH or dysbiosis • Lactose intolerance is suspected but ruled out by lactose intolerance breath test • Patient has abdominal symptoms coupled with unexplained symptoms such as vitamin B12 deficiency, chronic weight loss or chronic skin problems
REFERENCES 1. Hamilton 2. Riordan
LH. Breath testing and gastroenterology. QuinTron Division, The EF Brewer Company: Menomonee Falls, WI. 1992
SM, McIver CJ, Duncombe VM, Bolin TD. The association between small intestinal bacterial overgrowth and aging [abstract]. Gastroenterology 1994; 106: A266
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3. Saltzman
JR, Russell RM. Nutritional consequences of intestinal bacterial overgrowth. Compr Ther 1994; 20: 523–530
4. Salemans 5. Toskes
JMJI, Nagengast FM, Jansen JBMJ. The 14C-xylose breath test in chronic pancreatitis: evidence for small intestinal bacterial overgrowth [abstract]. Gastroenterology 1994; 106: A320
PP. Bacterial overgrowth of the gastrointestinal tract. Adv Int Med 1993; 38: 387–407
6. Herlinger 7. Galland 8. Corazza
H. Enteroclysis in malabsorption: can it influence diagnosis and management? Radiologe 1993; 33: 335–342
L. Clinical applications of breath testing. Great Smokies Diagnostic Laboratory Seminar, Greenwich, CT. 1994 GR, Menozzi MG, Strocchi A. The diagnosis of small bowel bacterial overgrowth. Reliability of jejunal culture and inadequacy of breath hydrogen testing. Gastroenterology 1990; 98:
302–309 9. King
CE, Toskes PP. Comparison of the 1-gram [14C] xylose, 10-gram lactulose-H2, and 80-gram glucose-H2 breath tests in patients with small intestine bacterial overgrowth. Gastroenterology 1986; 91: 1447–1451 10.
Kerlin P, Wong L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 1988; 95: 982–988
Davidson GP, Robb TA, Kirubakaran CP. Bacterial contamination of the small intestine as an important cause of chronic diarrhea and abdominal pain: diagnosis by breath hydrogen test. Pediatrics 1984; 74: 229–236 11.
12.
Rhodes JM, Middleton P, Jewell DP. The lactulose hydrogen breath test as a diagnostic test for small bowel bacterial overgrowth. Scand J Gastroenterol 1979; 14: 333–336
13.
Rhodes JM. Lactulose hydrogen breath test in the diagnosis of bacterial overgrowth. Gastroenterology 1990; 98: 1547
14.
Corazza G, Sorge M, Strocchi A. Glucose-H 2 breath test for small intestine bacterial overgrowth. Gastroenterology 1990; 98: 254
15.
Lerch MM, Rieband HC, Feldberg W. Concordance of indirect methods for the detection of lactose malabsorption in diabetic and non-diabetic subjects. Digestion 1991; 48: 81–88
16.
Gilat T, Ben Hur H, Gelman-Malachi E. Alterations of the colonic flora and the effect on the hydrogen breath test. Gut 1978; 19: 602
17.
Solomons NW, Garcia R, Schneider R. H 2 breath tests during diarrhea. Acta Paediatr Scand 1979; 88: 171
18.
Vogelsang H, Ferenci P, Frotz S. Acidic colonic microclimate – possible reason for false negative hydrogen breath test. Gut 1988; 29: 21–26
19.
Perman JA, Modler S, Olson AC. Role of pH in production of hydrogen from carbohydrates by colonic bacterial flora. Studies in vivo and in vitro. J Clin Invest 1981; 67: 643
20.
Corazza GR, Ventrucci M, Strocchi A. Treatment of small intestine bacterial overgrowth with rifaximin, a non-absorbable rifamycin. J Internat Med Res 1988; 16: 312–316
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Chapter 8 - Cell signaling analysis Aristo Vojdani PhD MT
INTRODUCTION Signaling pathways in normal cells consist of growth and controlling messages from the outer surface deep into the nucleus. In the nucleus, the cell cycle clock collects different messages, which are used to determine when the cell should divide. Cancer cells often proliferate excessively because genetic mutations cause induction of stimulatory pathways and issue too many “go ahead” signals, or the inhibitory pathways can no longer control the stimulatory pathways. [1] Over the past 5 years, impressive evidence has been gathered with regard to the destination of stimulatory and inhibitory pathways in the cell. These pathways converge on a molecular apparatus in the cell nucleus that is often referred to as the cell cycle clock. The clock is the executive decision-maker of the cell; apparently, it runs amok in virtually all types of human cancer. In a normal cell, the clock integrates the mixture of growth-regulating signals received by the cell and decides whether the cell should pass through its life cycle. If the answer is positive, the clock leads the process.
THE CELL CYCLE A scheme of the classical cell cycle is shown in Figure 8.1 . The cell cycle compartments are drawn such that their horizontal position reflects their respective DNA content. Cells that contain only one complement of DNA from each parent (2C) are referred to as diploid cells. Cells that have duplicated their genome, and thus have 4C amounts of DNA, are called tetraploid cells. The cell cycle is classically divided into the following phases: • G0 • G1 •S • G2 • M.
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Figure 8-1 Stages of cell cycle (G 0 , G1 , S, G 2 , and M phases) (A) and DNA histogram (B) generated by flow cytometry.
The cell cycle phase of G 1 was historically considered to be a time when diploid (2C) cells had little observable activity. Since this time precedes DNA synthesis, the term Gap 1 (G1 ) was coined. We now know that there is quite a bit of transcription and protein synthesis during this phase. At a certain point in the cell’s life, the DNA synthetic machinery turns on. This phase of the cell’s life is labeled “S” for synthesis. As the cell proceeds through this phase, its DNA content increases from 2C to 4C. At the end of S, the cell has duplicated its genome and now is in the tetraploid state. After the S phase, the cell again enters a phase that was historically thought to be quiescent. Since this phase is the second gap region, it is referred to as G 2 . In the G2 phase, the cell is producing the necessary proteins that will play a major role in cytokinesis. After a highly variable amount of time, the cell enters mitosis (M). DNA content remains constant at 4C until the cell actually divides at the end of telophase. The enlarged parent cell finally reaches the point where it divides in half to produce its two daughters, each of which is endowed with a complete set of chromosomes. The new daughter cells immediately enter G 1 and may go through the full cycle again. Alternatively, they may stop cycling temporarily or permanently. [2] [3] [4]
FLOW CYTOMETRY TO ASSESS CELL CYCLE STATUS Flow cytometry is a method of measuring cell properties as they “flow” through a detector while being illuminated with intense light. Tissues are generally disaggregated into single-cell suspensions and stained with one or more fluorescent dyes. The cells are forced to flow within a sheath of fluid, eventually being intersected and interrogated by an intense light source such as a laser beam. As the cell enters the laser beam, it scatters light in all directions. The measurement of light scattered in the forward direction yields information on the particle’s size. Scattered light at right-angles to the incident light beam provides information on the internal granularity of the cell. If the cell has been stained with one or more fluorescent dyes, a correlated measurement of more than one cellular parameter can be achieved.
CLINICAL APPLICATION Patients exposed to carcinogenic chemicals and patients with chronic fatigue syndrome
To determine whether peripheral blood lymphocytes (PBL) isolated from chronic fatigue syndrome (CFS) individuals and chemically exposed patients represent a discrete block in cell cycle progression, PBL isolated from CFS and control individuals were cultured, harvested, fixed, PI-stained, and analyzed by flow cytometry. The non-apoptotic cell population in PBL isolated from CFS individuals consisted of cells arrested in the late S and G 2 /M boundaries, as compared with healthy controls. The arrest was characterized by increased S and G 2 /M phases of the cell cycle (from 9 to 33% and from 4 to 21%, respectively) ( Table 8.1 , Fig. 8.2 ) at the expense of G0 /G1 . Such an abnormality in cell cycle progression is an indication of abnormal mitotic cell division in patients who have been exposed to chemicals and who suffer from chronic fatigue syndrome. From these results, we concluded that PBLs of patients with chemical exposure
Phase G0 /G1 88.6 ± 1.4
TABLE 8-1 -- Percentage of different phases of cell cycle in healthy controls and patients exposed to chemicals Healthy controls Chemically exposed 51.7 ± 2.4
S
8.6 ± 1.2
33.2 ± 4.3
G2 /M
3.6 ± 0.82
21.0 ± 2.6
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Figure 8-2 Cell cycle analysis of peripheral blood lymphocytes from healthy controls (A) and patients exposed to benzene (B). Note that in patients’ samples, the majority of cells switched from G 0 /G 1 to S and G 2 /M phases.
and chronic fatigue syndrome grow inappropriately, not only because the signaling pathways in cells are perturbed, but also because the cell cycle clock becomes deranged and stimulatory messages become greater than the inhibitory pathways. [5] [6] However, in order to limit cell proliferation and avoid cancer, the human body equips cells with certain back-up systems that guard against runaway division. One such back-up system present in lymphocytes of CFS patients provokes the cell to undergo apoptosis. This programmed cell death occurs if some of the cell’s essential components are deregulated or damaged. For example, injury to chromosomal DNA can trigger apoptosis. [1] [5] [6]
REFERENCES 1. Weinberg
RA. How cancer arises. Scientific American 1996; 275: 62
2. Wheeless
LL, Coon JS, Cox C et al. Precision of DNA flow cytometry in inter-institutional analyses. Cytometry 1991; 12: 405
3. Wersto
RP, Liblit RL, Koss LG. Flow cytometric DNA analysis of human solid tumors: a review of the interpretation of DNA histograms. Hum Pathol 1991; 22: 1085
4. Shankey 5. Vojdani 6. Vojdani
TV, Rabinovitch PS, Bagwell B et al. Guidelines for implementation of clinical DNA cytometry. Cytometry 1993; 14: 472
A, Ghoneum M, Choppa PC et al. Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. J Intern Med 1997; 242: 465–478
A, Mordechai E, Brautbar N. Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water. Human Exp Toxicol 1997; 16: 485–494
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Chapter 9 - Comprehensive digestive stool analysis Stephen Barrie ND
INTRODUCTION Nutrition and digestion are undeniably important to good health. We are, essentially, what we eat and then absorb. Over the long haul, excellent health is impossible without good nutrition. However, without adequate breakdown and assimilation, even the best diet offers little help. Additionally, incomplete or faulty digestive processes may lead to a variety of chronic disorders. Gastrointestinal (GI) disorders have a major impact on health. One recent study found that, during a 3 month period, nearly 70% of American households experienced one or more gastrointestinal symptoms.[1] Maldigestion, malabsorption and abnormal gut flora and ecology, as well as many complex chronic illnesses and symptoms, lie at the root of most common GI complaints. Thus, nutrition and digestive processes are central to long-term health. The comprehensive digestive stool analysis (CDSA) provides clinicians with a critical tool for evaluating the status of the GI tract. This assay helps to pinpoint imbalances, to provide clues about current symptoms and to warn of potential problems should the imbalances progress. With an accurate assessment, custom-tailored treatment can be easily applied, greatly increasing the chances for therapeutic success. The CDSA is used in the evaluation of various gastrointestinal symptoms or systemic illnesses that may have started in the intestine. Because illnesses are often not discernible from symptoms, the CDSA is a valuable screen for all patients and frequently reveals critical imbalances previously unsuspected.
THE GASTROINTESTINAL TRACT As most food molecules cannot be absorbed or utilized in their native state, a primary function of the gastrointestinal system is to break down complex molecules and absorb nutrients. This is a complex process, taking place primarily in the gastrointestinal mucosa, where the
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battle for health – to absorb nutrients and exclude toxins – is fought. The gastrointestinal mucosa does this through a combination of physical barriers to diffusion, mucosal fluids and active immune processes. [2] The digestive process Mouth
Teeth break up food and mix it with saliva. Saliva in turn helps to form a bolus and protects the pharyngeal and esophageal mucosa, primarily with secretory IgA antibodies. Saliva also helps to remineralize the teeth with calcium salts. The enzymes lingual lipase, salivary amylase and ptyalin initiate fat and starch digestion.
[ 3]
Stomach
The stomach mechanically churns food, breaks up and emulsifies fats and exposes molecules to additional enzymes. In doing this, it produces 1–2 L of gastric juices per day. [4] Gastric juice has several components: • Hydrochloric acid is secreted by the parietal cells. It activates pepsinogens to convert to pepsin and renders some minerals (e.g. calcium and iron) more absorbable. Stomach acid all prevents bacterial overgrowth by creating an essentially sterile environment (a potential exception is Helicobacter pylori). • Mucus forms an acid- and pepsin-resistant coating of the stomach lining. • Gastric lipase begins the hydrolysis of fats. Small intestine
Most digestion and absorption takes place in the small intestine and is mediated by pancreatic enzymes and bile.
[4]
The process involves several steps:
1. Secretion of pancreatic juices (about 2.5 L/day), which is controlled by the vagus nerve and the duodenal hormones secretin and cholecystokinin. Hormone production, in turn, is stimulated by the presence of fat, protein and acid chyme. 2. Secretion of bicarbonate which neutralizes stomach acid. 3. The proteases trypsinogen, chymotrypsinogen and procarboxypeptidase are activated to trypsin, chymotrypsin and carboxypeptidase. These enzymes digest proteins to oligopeptides and amino acids. 4. Amylase splits starch to maltose. 5. Lipase hydrolyzes diglycerides and triglycerides, producing long-chain fatty acids. 6. Bile secreted by the liver (about 700 ml daily) is stored in the gall bladder. Bile salts solubilize and emulsify fats, enabling enzymatic hydrolysis. The crypts of Lieberkühn of the intestinal mucosa also produce immunoglobulins (which protect the gastric mucosa from microbes) and small amounts of digestive enzymes such as peptidase and disaccharidases. Large intestine
A primary role of the large intestine is the absorption of water, about 1 L daily. The large intestine also provides an environment for microbial fermentation of soluble fiber, starch, and undigested carbohydrates. Anaerobic colonic fermentation results in the production of short-chain fatty acids (SCFAs), the main energy source for colonic epithelial cells. It is these SCFAs, in combination with amines derived from protein degradation, that provide buffering and create the slightly acidic pH of fecal matter. Absorption of specific nutrients [5]
Carbohydrate digestion
Salivary amylase initiates starch digestion in the mouth. However, this activity is short-lived as the enzyme is denatured by low gastric pH. In the duodenum, oligosaccharides and starch polymers undergo hydrolysis by pancreatic amylase. Specific disaccharides are hydrolyzed by brush border enzymes (lactase, maltase, sucrase) located on the enterocyte microvilli. Resulting monosaccharides are absorbed by specific sodium-dependent transport carrier mechanisms. Protein digestion
Gastric acid and pepsin initiate the digestion of dietary protein. This is followed in the duodenum by hydrolysis into oligopeptides and amino acids by proteolytic pancreatic enzymes. Final protein digestion is accomplished by intestinal brush border peptidases. Dipeptides, tripeptides, free amino acids, and other short-chain peptides are then absorbed. Fat digestion
Processing of dietary fat is the most complex of the digestive and absorptive processes. Fat is water-insoluble, so the GI tract must transform large water-insoluble particles into a soluble, absorbable form. Digestion begins in the mouth with secretion of lingual lipases. The stomach disperses fat globules into an evenly divided phase, called chyme. Pancreatic enzymes then split triglycerides into fatty acids and monoglycerides, which then combine with bile acids and phospholipids to form micelles. This process transforms water-insoluble lipids into a water-soluble form absorbed in the proximal small intestine.
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After absorption, fatty acids and other lipids are re-esterified in the intestinal cell to form chylomicrons, which are then secreted into the lymphatic system. Medium-chain triglycerides can be absorbed directly in the jejunum without forming chylomicrons.
DIGESTIVE ABNORMALITIES[ 6]
[7] [8]
As discussed in Chapters 19 and 55 , inadequate digestion and absorption of nutrients is a far more common problem than is generally recognized by clinicians. Not only does ingestion of even the best nutritional substances provide little benefit when breakdown and assimilation are inadequate, but also incompletely digested macromolecules can be inappropriately absorbed into the systemic circulation. This can lead to food allergy, immune complex deposition diseases, and toxic overload of the liver. Maldigestion Hypochlorhydria
Gastric acid secretion is a fundamental step in digestion and assimilation. Many clinical conditions originate with decreased gastric acidity ( Tables 9.1 and 9.2 ). Acid secretion decreases with age, and low stomach acidity is found in more than 50% of patients over the age of 60. [22] [23] Researchers speculate that malabsorption of nutrients in the elderly is due to atrophy of various digestive organs because of hypochlorhydria. [24] Gastric acid has a fundamental role in activating pancreatic proenzymes and converting them from inactive precursors (chymotrypsinogen, trypsinogen, etc.) to their active forms (chymotrypsin, trypsin). Intestinal peristalsis and gastric acid secretion normally prevents excessive growth of bacteria in the small intestine. Bacterial overgrowth appears to interfere with fat digestion and irritate the intestinal mucosa. Pancreatic exocrine insufficiency
Inadequate delivery of pancreatic lipases and proteases to the small intestine can lead to inadequate breakdown TABLE 9-1 -- Symptoms of low gastric acidity[9] [10] • Bloating, belching, burning, and flatulence immediately after meals • Sense of fullness after eating • Indigestion, diarrhea, or constipation • Systemic reactions after eating • Nausea after taking supplements • Rectal itching • Weak, peeling or cracked fingernails • Dilated capillaries in cheeks and nose (in non-alcoholics) • Post-adolescent acne • Iron deficiency • Chronic intestinal infections, parasites, yeast, bacteria • Undigested food in stool
TABLE 9-2 -- Diseases linked to low gastric acidity [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] • Addison’s disease • Asthma • Celiac disease • Chronic autoimmune disorders • Dermatitis herpetiformis • Diabetes mellitus • Eczema • Food allergies • Gall bladder disease • Gastric carcinoma • Gastritis
• Graves’ disease • Hepatitis • Lupus erythematosus • Osteoporosis • Pernicious anemia • Psoriasis • Rosacea • Thyrotoxicosis • Urticaria • Vitiligo of fats and protein. The net effect is a failure to obtain nourishment from protein, carbohydrate and fiber foods and an unhealthy environment for the flora of the large colon. It has been argued that even small decreases in pancreatic output can contribute substantially to maldigestion and have far-reaching effects in chronically ill patients. Malabsorption Malabsorption is characterized by abnormal fecal excretion of fat (steatorrhea) and variable malabsorption of fats, fat-soluble vitamins, other vitamins, proteins, carbohydrates, minerals and water. Common causes are listed in Table 9.3 . Important clinical diseases strongly associated with and possibly causal of mucosal malabsorption are listed in Table 9.4 . TABLE 9-3 -- Common causes of malabsorption • Defective protein, fat, or carbohydrate breakdown • Inadequate solubility of fatty acids (inadequate bile salts) • Rapid transit (e.g. diarrhea), which doesn’t allow sufficient time for absorption • Mucosal cell abnormality and inadequate surface area • Intestinal infection
TABLE 9-4 -- Diseases associated with mucosal malabsorption • Sprue • Whipple’s disease • Crohn’s disease • Giardiasis • Cryptosporidiosis • Lactose intolerance • Eosinophilic gastroenteritis
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Clinical considerations of malabsorption
The signs and symptoms of malabsorption, which increases with age, are varied. [25] Amino acids, carbohydrates, fats, vitamins, and trace elements may be absorbed by different processes, so an individual may suffer malabsorption of one nutrient but not of others. In fat malabsorption, essential fatty acid deficiency may result in addition to the loss of the highest dietary source of calories.
MICROBIOLOGY Bacteria
Because the oxygen content of the colon is low, the vast majority of bacteria are anaerobes. There are, however, hundreds of varieties of anaerobic flora in vastly different concentrations, all growing very slowly. The significance of most of these flora remains largely unknown. Most researchers, therefore, utilize the aerobic flora as an indication of bacterial health. Two frequently identified organisms, Lactobacilli sp. and Escherichia coli, are employed as indicators of eubiosis or healthy overall flora. Many researchers believe these two organisms have intrinsic benefit and aid digestion while helping to prevent overgrowth of abnormal flora. Bacterial cultures also identify and show potential pathogens. The term “potential pathogens” is used because individuals may harbor traditional pathogens and appear healthy, while others harbor weak or questionable pathogens and have gastrointestinal complaints. While not necessarily causing acute GI tract disturbances, some intestinal bacteria may be involved in the etiology of various chronic or systemic problems. These include Klebsiella, Proteus, Pseudomonas and Citrobacter. These organisms may be involved, through molecular mimicry, in various autoimmune diseases. This has been reported in diabetes mellitus, meningitis, thyroid disease, ulcerative colitis, arthritis, ankylosing spondylitis and systemic lupus. [26] [27] Some potential pathogens may cause clinical and subclinical malabsorption of nutrients and increase bowel permeability to large macromolecules. A number of clinicians speculate that this is directly related to the etiology of food and chemical sensitivity and intolerance. Whipple’s disease, although rare, presents an interesting model of the interaction of bacterial infection, absorptive processes and systemic health. This disease is known to be caused by an unusual bacteria which resists attempts to culture it in vitro. Symptoms include severe alterations in intestinal permeability and chronic fatigue. [28] There is strong scientific support for the profound relation between GI tract flora, malabsorption, permeability changes and overall health. Yeast
In the last few years, colonic yeast infections have TABLE 9-5 -- Diseases associated with Candida albicans overgrowth [30] [31] [32] [33] [34] [35] • Food allergy • Migraine headache • Irritable bowel syndrome • Asthma
• Indigestion and gas • Depression related to PMS • Vaginitis • Chronic fatigue attracted attention and controversy as a possible cause of chronic complex illness. [29] Many investigators suggest that an intestinal overgrowth of Candida albicans (and other intestinal yeast) may be involved in several diseases, as listed in Table 9.5 . Although others have dismissed these claims as speculation, part of the problem is focusing on the terms “pathogen” and “commensal”. It may be more accurate to use the terms “strong pathogen” and “weak pathogen”. While it is obvious that yeasts are not strong pathogens, large amounts of weak pathogens are also a problem. A significant and surprising amount of peer-reviewed literature supports yeast as a weak pathogen. [36] [37] [38] While the normal GI tract harbors small amounts of yeast, overgrowth may occur as a consequence of the wide use of antibiotics, corticosteroids, birth control pills and increased dietary carbohydrates. [39] Odds’ text on Candida summarized more than 20 published studies which found that patients had a frequency of C. albicans in their feces more than twice as often as normal controls. [40] One study reported that chronic diarrhea and abdominal cramps may be caused by large numbers of dead or damaged yeast, as found in feces. [41] Other research indicates Candida as a cause of colitis in patients with AIDS, neoplastic disease and renal transplants. [42] [43] [44]
While the yeast pathogenicity debate continues, high-quality laboratory work is essential. Yeast may be observed directly via a microscope or indirectly through a culture. Both are necessary for proper analysis. Dysbiosis Dysbiosis is the state of disordered microbial ecology that causes disease. It may exist in the oral cavity, gastrointestinal tract or vaginal cavity. In dysbiosis, organisms of low intrinsic virulence, including bacteria, yeasts and protozoa, induce disease by altering the nutrition or immune responses of their host. [45] The major causes of intestinal dysbiosis are given in Table 9.6 . The concept of intestinal flora having a major impact on human health has increasingly gained support, particularly as the widespread use of antibiotics has been observed to disrupt the normal flora ( Fig. 9.1 shows the microecology relationships). Published research has implicated
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Figure 9-1 Microecology relationships.
TABLE 9-6 -- Major causes of intestinal dysbiosis [45] [46] [47] • Poor diet/nutritional status (high fat, simple carbohydrates) • Stress • Antibiotic/drug therapy • Decreased immune status • Decreased gut motility • Maldigestion • Intestinal infection • Presence of xenobiotics • Increased intestinal pH intestinal dysbiosis as contributing to vitamin B 12 deficiency, steatorrhea, irritable bowel syndrome, inflammatory bowel disease, autoimmune arthropathies, colon and breast cancer, psoriasis, eczema, cystic acne and chronic fatigue. [48] [49] [50] [51] [52] [53] GI tract and arthritis
Researchers increasingly acknowledge that there is a link between digestive processes and arthritis. In patients with altered bowel anatomy, chronic bacterial overgrowth can lead to the formation of circulating immune complexes and synovitis. [54] Changes in bowel permeability due to local gut inflammation may expose the host immune system to microbial or food antigens and even bacterial translocation. [55] [56] In some cases, toxins derived from enteric organisms (e.g. Clostridium difficile) may play a direct role in the induction of arthritis. Food allergy
Food allergy is a well-documented problem, although its prevalence, testing methods and treatment modalities are controversial. Some researchers have proposed that food allergy is not an immunological disease but a disorder of bacterial fermentation in the colon. The combined mechanisms of reduced gut enzyme concentrations, imbalanced bacterial flora and increased permeability may account for many cases of food intolerance. [57] Four patterns of dysbiosis Leo Galland MD has advanced the idea of four interlocking patterns of bacterial dysbiosis: putrefaction, fermentation excess, deficiency and sensitization. Putrefaction
This is the Western degenerative disease pattern which results from diets high in fat and meat and low in insoluble fiber. This type of diet produces increased concentrations of Bacteroides sp. and induces bacterial urease and beta-glucuronidase activity. These enzymes may then metabolize bile acids to tumor promoters and deconjugate excreted estrogens, raising the plasma estrogen level. The fecal pH may increase as a result of increased ammonia production. Epidemiologic data implicates this type of dysbiosis in the pathogenesis of colon cancer and breast cancer. It is usually corrected by decreasing dietary fat and animal flesh, increasing fiber consumption and consuming probiotic preparations.
Fermentation excess
This is a condition of carbohydrate intolerance induced by an excess of normal bacterial fermentation usually resulting from small bowel or fecal bacterial overgrowth. Abdominal distention, flatulence, diarrhea, constipation and feelings of malaise are commonly described. In small bowel bacterial overgrowth, degradation of intestinal brush-border and pancreatic enzymes by bacterial proteases may cause maldigestion. Fecal short-chain fatty acids may be elevated. Patients with fermentation excess are usually intolerant of fiber supplements and often benefit from a reduction of carbohydrate consumption and antimicrobials. Deficiency
Exposure to antibiotics or a diet depleted of soluble fiber may create a deficiency of normal fecal flora, including Bifidobacteria, Lactobacillus sp., and E. coli. Direct evidence of this condition is seen in stool cultures when concentrations of any of these organisms are reduced. This condition has been described in patients with irritable bowel syndrome and food intolerance. Deficiency and putrefaction dysbiosis often occur together and respond to the same treatment. Probiotic supplementation as well as fructo-oligosaccharides are often helpful in re-establishing a normal flora.
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Sensitization
Abnormal immune responses to components of the normal indigenous intestinal microflora may contribute to the pathogenesis of inflammatory bowel disease, spondyloarthropathies, and other connective tissue diseases or skin disorders such as psoriasis or acne. Endotoxins may activate the alternative complement pathway and sensitization may complement fermentation excess. Similar treatments may benefit both conditions.
THE CDSA MARKERS The comprehensive digestive stool analysis provides diagnostic tools for analysis of digestion, colonic environment and absorption. Digestion The Great Smokies Diagnostic Laboratory (GSDL) has developed unique detergent extraction and enzymatic analysis procedures that allow quantitative, precise, and accurate measurements of digestion efficacy. [58] [59] These methods give physicians the tools for differential diagnosis of digestive conditions as they relate to acute and chronic illness. Triglycerides
Triglycerides are the major dietary fat component. Elevated fecal amounts reflect incomplete fat hydrolysis and suggest pancreatic insufficiency. Chymotrypsin
Fecal chymotrypsin is a sensitive, specific measure of proteolytic enzyme activity. [60] [61] Decreased values suggest diminished pancreatic output (pancreatic insufficiency), hypoacidity of the stomach, or cystic fibrosis. Elevated chymotrypsin values suggest rapid transit time, or, less likely, a large output of chymotrypsin from the pancreas. Iso-butyrate, iso-valerate and n-valerate
New research suggests that these short-chain fatty acids (SCFAs) can be produced through bacterial fermentation of protein, thus reflecting the presence of undigested protein in the bowel. In a healthy colon, these SCFAs constitute less than 10% of the total concentrations of SCFAs due to the sparse amounts of polypeptides present in the large intestine compared with undigestible carbohydrates. However, an increase in the load of protein in the colon will alter these concentrations. Causes may include pancreatic insufficiency (insufficient proteases), malabsorption or gastrointestinal disease, leading to mucosal desquamation.
[62]
Meat and vegetable fibers
These are microscopic, qualitative, indirect indicators of maldigestion from either gastric hypoacidity or diminished pancreatic output. Several studies report that fecal meat fibers were equal to other methods for non-specific maldigestion. [60] [63] [64] One study reported a correlation between excessive fecal meat fibers and hypochlorhydria or achlorhydria as measured by direct radiotelemetry. [65] Absorption Total fecal fat
This parameter is the sum of all the lipids except short-chain fatty acids. Elevation can be indicative of maldigestion or malabsorption. Elevated long-chain fatty acid levels may reflect malabsorption, and elevated triglyceride levels reflect maldigestion. Long-chain fatty acids
These free fatty acids are readily absorbed by healthy mucosa. In cases of malabsorption, however, they accumulate and reach substantially elevated levels in the feces. Elevation can also indicate pancreatic insufficiency. Cholesterol
Fecal cholesterol comes from both dietary sources and mucosal epithelial cell breakdown. Some of this cholesterol is absorbed, stored and used by the body, but some is excreted. The fecal cholesterol level remains surprisingly constant during fluctuating exogenous intake. An elevated cholesterol level in feces is abnormal and may reflect mucosal malabsorption. Total short-chain fatty acids
A special property of colonic bacteria is their fermentation of soluble fibers to short-chain fatty acids (acetate, propionate, butyrate and valerate). [66] These molecules are normally readily absorbed so that fecal levels reflect a balance between production and absorption. SCFAs provide up to 70% of the energy for colonic epithelial cells. [67] SCFA production may be an important factor in establishing and maintaining a balanced ecosystem in the colon and may prevent establishment of pathogenic microbes such as Salmonella and Shigella spp. One interesting report suggests that diversion colitis might be successfully treated with rectal irrigations of SCFAs. [68] Elevated levels of the four main SCFAs may reflect colonic malabsorption or bacterial overgrowth. Elevated levels are also found in active colitis. [69] Decreased levels may reflect insufficient dietary fiber or disruption of the normal colonic flora.
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Microbiology Beneficial bacteria
Healthy amounts of Lactobacilli, Bifidobacteria and E. coli are essential to the maintenance of a healthy colon. Lactobacilli and Bifidobacteria spp., in particular, have long been noted for their contributions to intestinal health – from the inhibition of gut pathogens and carcinogens, control of intestinal pH and the reduction of cholesterol to the synthesis of vitamins and disaccharidase enzymes. In a healthy gut, these organisms make up a substantial portion of the 400-plus species of bacteria; Bifidobacteria alone comprises up to one-quarter of the total flora in a healthy adult. Reduced numbers of these organisms, resulting from the use of broad-spectrum antibiotics, chronic maldigestion or bacterial overgrowth, leave the intestine susceptible to invasion by pathogens and production of carcinogens. Low levels may indicate the need to supplement with “friendly bacteria” to restore these important properties. While E. coli do not share some of these direct beneficial effects, clinical observation suggests that ample amounts of these organisms are present in healthy intestines. [70] Additional bacteria
Bacteriology cultures quantitate normal flora ( Lactobacilli, Bifidobacteria, E. coli and other frequently isolated organisms), imbalanced flora and potential pathogens. Serotyping for toxigenic E. coli and Campylobacter cultures is performed on diarrhetic specimens (see Tables 9.7 and 9.8 ). Mycology
The CDSA includes a mycology culture that identifies and quantitates fecal yeast. Some of the more commonly TABLE 9-7 -- Common potential pathogens • Aeromonas • Bacillus cereus • Campylobacter • Citrobacter • Klebsiella • Proteus • Pseudomonas • Salmonella • Shigella • Staphylococcus aureus • Vibrio
TABLE 9-8 -- Common imbalanced flora • Beta-hemolytic streptococcus • Enterobacter • Hafnia alvei • Hemolytic E. coli • Mucoid E. coli identified species are C. albicans, C. tropicalis, Rhodotorula and Geotrichum. Broth dilution sensitivity analyses are performed on all yeast cultures of 2+ or greater, utilizing both pharmaceutical and natural substances. Quantitative MIC analysis determines the relative potency of differing antimycotic agents. This provides more information on the effective agents and dosages for each yeast. Metabolic markers n-Butyrate
Butyric acid is a key SCFA because it is the main energy source for colonic epithelial cells. Adequate amounts are necessary for healthy metabolism of the colonic mucosa. A possible mechanism for the anticancer action of dietary fiber is the increased fermentation of fiber to butyrate. It has been suggested that failure to use butyric acid by colonic mucosal cells or inadequate amounts available in the colon could be a primary factor in the etiology of ulcerative colitis, inflammatory bowel disease and colon cancer. [66] [71] [72] Beta-glucuronidase
Beta-glucuronidase is a bacterial enzyme, the activity of which serves as a valuable marker of cancer risk. This enzyme is elaborated by several microorganisms, including E. coli, Bacteroides and Clostridium. Via the uncoupling of glucuronides (compounds detoxified through the hepatic glucuronidation pathway), this enzyme catalyzes reactions which may result in the formation of carcinogens in the bowel as well as the persistence of certain hormones and drugs in the body. Thus, excess beta-glucuronidase activity correlates with increased cancer risk, including estrogen-related cancers through the enhanced enterohepatic recirculation of estrogen in the body. The activity of this enzyme is strongly influenced by diet, levels of Lactobacilli and Bifidobacteria, intestinal pH and nutrients such as calcium glucarate. [73] [74] [75] [76]
pH
Fecal pH appears to be an indicator of the health or status of the colonic digestive processes. Abnormally acidic or alkaline pH usually reflects an abnormality in either acid production or absorption. There is increasing evidence that fecal pH is a useful indicator of risk for colon cancer. [77] [78] [79] There appears to be a correlation between alkaline pH and decreased short-chain fatty acids (particularly butyrate). [80] Elevated fecal pH and diminished SCFAs suggest inadequate digestion of fiber and/or inadequate intake of dietary fiber. Short-chain fatty acid distribution
Adequate amounts and proportions of the different
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SCFAs reflect the basic status of intestinal metabolism. The ratios of the individual SCFAs remain relatively constant in healthy colons, but become imbalanced in various disease states. Imbalanced ratios of the SCFAs reflect imbalanced metabolic processes due to disordered bowel flora. Researchers are beginning to identify unique SCFA “fingerprints” with specific bacterial infections. [71] The ratio among SCFAs has diagnostic value as a screening test for intestinal infections. [72] A significantly higher ratio of acetate/total SCFAs and a lower ratio of butyrate/total SCFAs have been found in the feces of patients with large bowel adenomas and cancer compared with control groups. [71] Immunology Fecal sIgA
Secretory IgA, derived from lymphoid tissue within the intestinal mucosa, acts as the first line of immunological defense against microbes and antigens in the GI tract. SIgA works by binding with pathogenic microorganisms, allergenic food proteins and carcinogens to form immune complexes which prevent them from binding to the surface of absorptive cells. SIgA has been demonstrated to prevent the adhesion of Vibrio cholerae to mucosal epithelium, to neutralize cholera toxin and polio virus, and to reduce the absorption of ovalbumin and other allergenic food proteins. In patients with selective IgA deficiency, high titers of antibodies against food antigens can be detected. Depressed sIgA has also been observed in healthy, asymptomatic individuals, presumably from high antigenic exposure. Over time, this decreased resistance can lead to dysbiosis and increased risk for infection and allergy. [81] [82] [83] [84] [85] Macroscopic observations The color of feces provides important insight into various conditions, as listed in Table 9.9 . The presence of mucus or pus can indicate irritable bowel syndrome, intestinal wall inflammation (caused TABLE 9-9 -- Clinical interpretation of fecal color Probable significance
Color Light brown to brown
Normal
Yellow or green
Diarrhea or a bowel sterilized by antibiotics
Black
Upper GI tract bleeding
Tan or gray
Blockage of the common bile duct, pancreatic insufficiency (greasy stool) or steatorrhea
Red
Beets in diet; lower tract bleeding
by infection – typhoid, Shigella or amoebic), diverticulitis or other intestinal abscess. Absence of mucus and pus is normal. The CDSA also includes an occult blood test. Although a positive result might be due to hemorrhoids or eating too much red meat, occult blood is a possible indicator of colon cancer. Follow-up is recommended, perhaps a second test using a meat-free diet or a sigmoidoscopic exam. Dysbiosis index Intestinal dysbiosis is marked by many indicators. Relevant results are weighed and an index is calculated to provide a quick assessment of the patient’s GI tract. Factors used to determine the index include metabolic and microbiological markers.
SUMMARY The CDSA’s battery of integrated tests evaluates digestion, colonic environment, and absorption. It enables therapeutic intervention based not only on single test results, but also on patterns and relationships. The CDSA provides clinical insights not available with other diagnostic procedures, insights not limited to the gastrointestinal system. According to Mitch Kaminski MD: “More than 50% of the immune system takes its signals from the gut. Immune modulation, the cytokines, commonly produce oxidative stress. Free radicals cause aging and chromosomal damage associated with cancers.”
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Chapter 10 - ELISA/ACT test Patrick M. Donovan ND
INTRODUCTION Antigens from the enteric environment are among the most common and constant challenges to our immune defense and repair systems, and hence to overall health and vitality. [1] [2] [3] [4] [5] Challenges can be from enteric organisms and seemingly innocuous, commonly encountered substances such as foods, chemicals, and microbial toxins (endo- and exotoxins). Maldigestion and increased intestinal permeability increase such exposure. [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [ 30] [31] [ 32] [33] [ 34] [35] [ 36] [37] [38] [39] [40] [41]
The adaptive mechanisms for human immune defense and repair can be overwhelmed by these reactive substances. This enhances susceptibility to both infectious disease and hypersensitivity reactions. Clinically important immune overload dysfunction can then occur and present as recurrent infections, multisystem chronic inflammation, and/or autoimmune syndromes.[36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] Identifying the commonly encountered substances (foods, food additives, soaps, detergents, environmental chemicals, and pharmaceuticals) that cause delayed hypersensitivity reactions in an individual is often clinically challenging due to the time-delayed or late-phase reactions they elicit. The individual may slowly adapt to the impaired function and reduced performance caused by daily onslaught of reactive substances without being fully aware of the tax on his/her inner economy. [41] The identification of these reactive substances and their mitigation or elimination is the first step in preventing or correcting immune overload dysfunction and chronic inflammatory, degenerative or autoimmune diseases. A comprehensive, and clinically useful test for identifying such foreign reactants is the enzyme-linked immunosorbant assay. [50] [51] [52] Reducing immunologic load allows an individual’s physical economy to move from a state of “red alert” and hyperactivity to one of balance, regeneration, and repair. This shift is essential to the restoration of health.
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REACTANTS AND THE IMMUNE RESPONSE Chemical reactants are usually antigens, i.e. compounds that induce an immune response. The criteria are that the reactant be:
[1] [2] [3] [ 4]
• identified by the host organism as foreign • of large enough molecular weight to be detected by the immune system • of sufficient chemical complexity to induce a reaction. Foreignness. Generally, the immune system does not respond to the body’s own normal tissues (i.e. self-antigens), but it does respond to those antigenic compounds identified by the body as non-self or foreign. Autoimmune conditions are the exception where normally sequestered self-antigens are exposed to the immune system and treated as foreign. This is usually due to tissue damage significant enough to breach normal compartmentalization, decreased tissue repair, and increased tissue permeability which exposes antigens normally restricted from the circulation in states of health. High molecular weight. A compound must have a certain molecular size to be antigenic. Low molecular weight compounds, such as many drugs and chemicals, can only be antigenic when they bind with a high molecular weight carrier such as a protein (haptenization). Chemical complexity. There also must be a certain degree of structural and chemical complexity for a compound to be antigenic. Classes of antigens There are four major classes of antigens: • polysaccharides • lipids • nucleic acids • proteins. These four are usually combined in reactive antigens, e.g. lipopolysaccharides, glycopeptides, nucleoproteins, etc. Polysaccharides are part of more complex molecules found on the surface of most animal and human cells. They are also a major constituent in the cell walls of plants and microorganisms. Lipids are not antigenic of themselves. They are only antigenic when combined with other molecules such as polysaccharides, forming lipopolysaccharides (LPS). Lipopolysaccharides are products of many bacterial (endotoxins), fungal, and plant cell walls which can activate the immune system. Nucleic acids are also usually not themselves antigenic, but can become so when combined with protein carriers (histones). Proteins, especially glycopeptides, are the most antigenic of all compounds; virtually any protein can induce an immune response given the appropriate circumstances. When an antigen enters the body, the healthy immune system is stimulated to respond. White blood cells such as macrophages, neutrophils, eosinophils, basophils, and lymphocytes, e.g. helper or natural killer (NK) cells, respond by phagocytosing and processing the antigen. Proinflammatory compounds and immunostimulating chemicals (interferons, interleukins, cytokines, and other growth factors and cellular modulators) play essential roles in modulating the immune response. Antibodies are produced from activated B-class lymphocytes which attack/bind to the antigen and stimulate complement amplification of the response. Immune complexes occur when humoral response exceeds cellular processing capacity. The reticuloendothelial system (RES), especially the Kuppfer cells of the liver, is responsible for removing immune complexes or cells with bound/absorbed immune complexes from the circulation.[1] [2] [3] [4] Hypersensitivity reactions An amplified immune response to an antigen can occur, resulting in hypersensitivity reactions. [1] [2] [3] [4] [5] [25] [31] [34] [41] [49] In a hypersensitive reaction or condition, the normally beneficial immune response becomes inappropriately over-responsive to normally innocuous, commonly encountered antigens, causing inflammation and tissue damage through the release of proinflammatory compounds. This can cause acute crises or lead to chronic allergies, asthma, autoimmune and inflammatory diseases, as well as other “environmentally sensitive” conditions. These reactions are increasingly common in the industrialized world where chemical dependence, environmental pollution, restructured diet patterns, and habitual distress are endemic. [5] [28] [34] [37] [39] [40] [41] [48] [49]
There are four basic types of hypersensitivity (allergic) responses (defined by Gel & Coombs in the 1960s). These responses are mediated by the release of proinflammatory compounds induced either by an antigen–antibody, cell-cytotoxic, or T-cell-mediated response. Delayed-type reactions (types II–IV) are not as easily identified clinically nor as closely linked to disease conditions due to their delayed nature and the variety and chronicity of the symptoms they cause. Type I reactions are typically readily identified as the reactions are immediate. Type I: immediate hypersensitivity or immediate
This reaction is mediated by immunoglobulin E (IgE) which binds to the antigen and causes the release of pharmacologically active amines and cytokine compounds, most notably histamine. The classic allergic reaction of itchy eyes, runny nose, swelling and edema,
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hives, and bronchoconstriction, or more severe responses such as asthmatic attacks and anaphylaxis, can occur. It happens immediately (within minutes) on exposure to the antigen and can be life-threatening. Type II: antibody-dependent cytotoxic hypersensitivity
This reaction occurs when antibodies (IgA, IgG, or IgM) are provoked against cellular antigens (this can be an antigen on an individual’s own cells) leading to cell/tissue destruction via the activation of immune cells and proinflammatory compounds. This delayed reaction may take hours or days to develop. ABO and Rh incompatibility reactions, drug-induced reactions (via haptenization with cellular and/or circulating blood proteins), and many autoimmune conditions are examples. Type III: immune complex-mediated hypersensitivity
This reaction occurs when immune complexes are formed when antibodies (IgG, IgM, or IgA) and antigens coalesce. These complexes deposit in the tissues causing the release of immunologically active cells and proinflammatory chemicals that damage those tissues. This delayed reaction may take hours or days to develop. The classic Arthus reaction, serum sickness, and autoimmune/infection-associated immune complex diseases (rheumatoid arthritis, rheumatic fever, glomerulonephritis, etc.) are examples of this type of reaction. Type IV: T-cell-mediated hypersensitivity
This reaction is mediated by T-cells which have been previously sensitized to a specific antigen. The T-cells release lymphokines (interleukins) which induce an inflammatory reaction. This type of reaction is seen in the TB skin test, contact dermatitis, and tissue or organ rejection reactions. The classic delayed reaction can take days to develop. Cross-reactive, cytotoxic antibodies, and disease An antibody-dependent cytotoxic reaction directed against self-antigens can be initiated and propagated by environmental antigens (viruses, bacteria, food protein, chemical, etc.), similar enough to self-antigens to stimulate crosss-reactive antibodies to self. When this occurs, chronic exposure to the environmental antigen can potentiate this self-directed immune response by provoking continual production of cross-reactive antibodies – hence, the possible relationship between environmental antigens and autoimmune diseases. [1] [2] [3] [4] [41] [53] [54] [55] Immune complex-mediated diseases High levels of circulating immune complexes can result in their deposition in susceptible tissues. This deposition can damage these tissues and organs and result in: • metabolic dysfunction • inflammation • pain • swelling • fibrosis • exposure of normally sequestered self-proteins to immunological recognition • release of free radical and acidic oxidative products. Chronic antigen exposure and systemic antigen load resulting in a delayed hypersensitivity response and immune complex deposition can often lead to autoimmune and chronic diseases, accelerated aging, and organ dysfunction and failure, if not corrected. [1] [2] [3] [4] [56] [57] [58] [59] [60] [61] These diseases/pathologies can be placed broadly into three groups (see Table 10.1 ) according to the source of the antigen and the organs most frequently affected.[3] Persistent infection
When a low-grade persistent infection occurs with a weak antibody response, chronic immune complex formation can result. These complexes may then deposit in various tissues, producing such conditions as endocarditis, hepatitis, glomerulonephritis, and arthritis. Autoimmunity
Immune complex-mediated inflammatory disease is a frequent complication of autoimmune disease. Such autoimmune diseases include rheumatoid arthritis and TABLE 10-1 -- Immune complex-mediated diseases Antigen Sites of complex deposition
Cause Persistent infection
Microbial antigen
Infected organ(s), kidneys, joints, heart
Autoimmunity
Self-antigen
Kidneys, joints, arteries, muscles, brain, lungs, liver, skin, bowel, connective tissue
Extrinsic or exogenous source
Environmental antigen (food, drugs, chemicals, etc.)
Generally the same as for autoimmunity
Modified from Roit et al [2] (p. 21).
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other inflammatory joint diseases, systemic lupus, polyarteritis, vasculitis, polymyositis, glomerulonephritis, multiple sclerosis, colitis, Crohn’s, and many of the mixed connective tissue diseases.
Extrinsic or exogenous antigens
Environmental antigens are generally contacted by the skin and mucosal surfaces (inhaled or ingested) and form immune complexes either at the body surfaces or in the tissues after absorption. Such antigens may include chemicals, drugs, endotoxins, food proteins, and antigenic material from moulds, plants, or animals. Prolonged immune complex formation and the production of cross-reactive autoantibodies may occur from chronic daily exposure to reactive environmental antigens leading to overload of the reticuloendothelial system and tissue deposition.
INTESTINAL ANTIGENS AND TOXICANTS The most common portals of entry for foreign antigens are the skin and mucosal surfaces of the genitourinary, respiratory, and gastrointestinal tracts. Of primary clinical importance is the gastrointestinal tract because of its constant contact with a plethora of dietary materials, proteins, chemicals, and bacteria. [1] [2] [3] [4] [6] [7] [8] [9] [10] [27] [32] [ 34] [36] [ 37] [38] [ 39]
Observations by clinicians since the time of Hippocrates and reports in the current scientific literature document the role of the colon and bowel in the etiology and propagation of many diseases and pathological conditions. This is due to the local and systemic effects of bowel antigens (“toxicants”) in different tissues and organs, often mediated through a delayed hyperreactive mechanism. [6] [26] [28] [29] [32] [41] [49] [56] [57] [58] [59] [60] [61] There is a significant release of toxicants from the bowel into systemic circulation when: • colon health is compromised in any way (infection, irritation, inflammation, or ulceration) • the microfloral homeostatic environment is disturbed (dysbiosis) resulting in overgrowth of pathogenic organisms • there exists a hospitable environment for parasitic infection • putrefaction occurs as a result of prolonged fecal transit time (constipation) • prolonged distress has compromised normal protective mechanisms such as secretory IgA. This release results in immune activation, delayed hypersensitivity, inflammation, and host disposition to chronic disease. Antigenic bowel toxicants include dietary macromolecules (undigested or partially digested food proteins and other by-products of incomplete digestion), various food additives and chemicals, and microbial toxicants (bacterial lipopolysaccharides). [6] [7] [8] [9] [10] [13] [19] [32] [34] [36] [37] [38] [39] [54] [55] [56] [58] [62] The bowel is partially permeable to these toxicants and many, particularly food, macromolecules can traverse the normal intestine in sufficient quantities to exceed the lymphatic system’s surveillance capacity, resulting in their immunological recognition as foreign invaders. [6] [7] [8] [9] [10] [32] [56] [58] [62] This recognition causes activation of the body’s immune mechanisms, particularly the activation of lymphocytes, resulting in the production of anti-bodies (IgA, IgG, IgE, IgM), the formation of immune complexes, and delayed hypersensitive reactions. Food antigens Normally, the digestive process completely breaks down foods into their component amino acids, tiny peptides, glycerides, and saccharides. All too often, however, digestion is not complete. In fact, appreciable quantities of these digestion remnants can penetrate the normal intestinal mucosal barrier and enter systemic circulation, where they provoke immune response. [6] [7] [8] [9] [10] [32] [56] [58] [62] Individuals with allergic conditions, gastrointestinal disease, poor digestive functions (especially low hydrochloric acid activity in the stomach and pancreatic insufficiency), constipation, and diets high in refined foods can absorb significant amounts of these food antigens, with resultant delayed hypersensitivity reactions. These reactions are becoming more common. [28] Some researchers claim that they are the leading cause of many undiagnosed symptoms, and that at least 60% of the American population suffers some degree of disability from associated symptoms. Diet-induced hypersensitivity reactions are associated with: [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [18] [19] [ 20] [62] [ 63] [64] [ 65] [66] [ 67] [68] [69] [70] [71] [72] [73] [ 74] [75] [ 76] [77] [ 78] [79] [ 80]
• migraine headache • eczema • arthritis • systemic lupus erythematosus • inflammatory bowel disease • gall bladder disease • asthma • irritable bowel syndrome • childhood hyperactivity • disturbances of behavior • sinus congestion • indigestion • intestinal gas • diarrhea/constipation • general fatigue. Primary protective mechanisms against systemic antigen overload from the bowel Secretory immunoglobulin A (sIgA)
Secretory IgA is found primarily in bodily secretions
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(saliva, tears, breast milk, and gastrointestinal and respiratory mucus). Secretory IgA acts as a major protective mechanism in these areas by neutralizing biologically active antigens such as viruses, bacteria, enzymes, and toxins. It binds antigens crossing the mucosal barrier and mediates their transport from portal circulation through the liver into the bile for elimination, thus limiting the immunological response. [81] [82] [83] [84] Any deficiency of sIgA, transient or chronic, either from decreased production (immunodeficiency) or from overwhelming the sIgA system by repeated antigen exposure, can cause an influx of bowel antigens into the portal circulation. This influx, if prolonged and sufficient, can overwhelm the second line of defense: the liver’s phagocytosis of these substances. When this occurs, the toxins enter systemic circulation and initiate both immediate and delayed reactions, immune complex deposition, complement activation, inflammation, tissue damage, and disease. [85] [86] [87] [88] The increased levels of antibodies to dietary antigens found in patients with IgA deficiency (which occurs in one of 600 individuals of European origin) [53] further support the importance of this class of immunoglobulin in limiting the absorption of food macromolecules.[88] It is important to note that sIgA deficiency is the most common primary immunodeficiency. Liver
The liver plays a crucial role by filtering the portal circulation and preventing antigen and immune complex entrance into systemic circulation. The Kuppfer cells of the liver, with the help of sIgA, phagocytize, process, and eliminate these toxins in the bile. However, if the liver is compromised in any way, either from (1) inflammation (e.g. hepatitis), (2) fatty infiltration and degeneration (e.g. cirrhosis), (3) excessive alcohol consumption, (4) drugs, and/or (5) chronic toxin overload, then these bowel antigens will more readily enter systemic circulation and generate disease. [81] [82] [83] [84] [89]
IDENTIFYING THE ANTIGENIC TOXICANTS OF DELAYED HYPERSENSITIVITY The classic way of testing for delayed reactions to food and other environmental antigens is by the subjective method of provocative challenge. [5] [25] [31] [34] Exposure to the reactive substance (food, chemical, etc.) will elicit various signs and symptoms. Often, as in the case of foods, it is necessary to eliminate the suspicious substance from the individual’s immediate environment for 4 or more days, keeping all other variables constant, before reintroducing it (challenge). When multiple foods and other substances are suspected (as is usually the case), this process can be time-consuming and painfully frustrating to both patient and doctor. In such a case, an objective laboratory test may be the best method; however, no “gold standard” test has been developed which consistently recognizes all delayed reactions. The tests currently available for delayed hypersensitivity reactions include: • the modified radioallergosorbent test (RAST) – a solid-phase radioimmunoassay classically used to detect IgE (type 1) reactions modified for IgG • the radioallergosorbent procedure (RASP) – a variant of the RAST, this is also a solid-phase radioimmunoassay classically used to detect IgE (type I) reactions but thought to be more sensitive to IgG reactions than the classic RAST • the food immune-complex assay (FICA) – a solid-phase radioimmunoassay specific for IgG allergens and immune complexes • the IgG ELISA – a solid-phase, monoclonal antibody test for an IgG subclass (IgG 4 ) reaction utilizing the ELISA technique (see below) • the ELISA/ACT – a modification of the ELISA method which combines enzyme amplification with lymphocyte blastogenesis. Of these tests, the ELISA/ACT appears to be the only one capable of testing for all (types II–IV) delayed hypersensitive reactions (see Fig. 10.1 ). [4] [5] [25] [31] [34] [50] [51] [52]
The ELISA method The ELISA method of immunologic testing is a solid-phase immunoassay (as are radioimmunoassays such as the RAST) which employs an enzyme-linked reactant (classically an anti-immunoglobulin). Positive results are obtained when the enzyme is activated in the presence of a substrate producing a measurable color change. The intensity of the color change can also be read to determine the strength of reaction. According to Benjamini & Leskowski: [4] The ELISA method is rapidly replacing many assays in which a radioactive label is used because it is less expensive. Also, it does not require the special precautions for the handling of radioactivity, and it is, in general, just as sensitive. ELISA/ACT The ELISA/ACT is a modification of the ELISA method. It combines enzyme amplification with lymphocyte blastogenesis (instead of monoclonal or anti-antibody binding) in an autologous environment (whole plasma, as opposed to serum, with all the immunologic constituents intact and inducible) to test for all phases (types II–IV) of delayed reactivity (see Fig. 10.1 ). [50] [51] It is, in a sense, an ex vivo window on the immune system which can provide an “immunologic fingerprint” of an
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Figure 10-1 The immune response pie.
TABLE 10-2 -- ELISA/ACT categories tested • Environmental chemicals • Food preservatives • Dairy products • Fish/crustaceans/mollusks • Fowl • Fruit • Grains • Meat • Oils • Nuts/seeds • Spices/seasoning • Sugars • Vegetables individual’s delayed reactivity via the pattern of reactivity to a large number of substances (see Tables 10.2 and 10.3 ). One of the key advantages of this procedure over other laboratory methods is its ability to measure IgG 4 antibodies. Although initially thought to act as a blocking antibody, thereby exerting protective effects against allergy, it now appears that IgG 4 antibodies are actually involved in producing allergic symptoms. [52] As shown in Table 10.3 , a positive result on the TABLE 10-3 -- Meaning of positive results • Immune recognition • Contaminant recognition • Contingent recognition • Cross-reaction to: —gut pathogen (identical epitope) —related food family (identical epitope) —patient’s tissue (identical epitope) ELISA/ACT test (lymphocyte blastogenic reaction) can be due to one of four causes:
• immune recognition of a particular antigen specific to the compound tested • immune recognition of a contaminant (such as a pesticide) not normally a constituent of the specific compound tested • immune recognition contingent upon the presence of a specific hapten • immune recognition of an identical epitope to another antigen. While the common serum-based ELISA test, through several steps, builds up a molecular sandwich to improve the detection of small amounts of reactive substance, the ELISA/ACT is a one-step procedure taking unique advantage of the reactive cell surface on which enzymes become active when a substance is recognized as foreign. This reduction in steps contributes to greater precision. [50] [51] [52] Lymphocyte blastogenesis
Lymphocyte blastogenesis occurs during the early phase of all delayed hypersensitivity reactions. It represents lymphocyte activation from antigen/cytokine (see Table 10.4 ) stimulation where the lymphocytes are in a state of hyperactive metabolism resulting in a rapid increase in size and synthesis of DNA, RNA, and protein. By linking the enzyme reaction to lymphocyte blastogenesis (release of membrane-sequestered compound during the blastogenic reaction), the ELISA becomes an activated cell test (ACT) specific for all delayed responses. [52] A blastogenic reaction can take place within hours as demonstrated by a change in the rate of protein formation. The measurement of such a reaction has traditionally taken up to 4–5 days using tests for thymidine and uptake of radiolabeled purine and pyrimidine. Because of a new technique, ELISA/ACT measures blastogenesis within hours, allowing for much quicker evaluation of sensitivity. [50] [51] [52] Validity, reproducibility, sensitivity, and specificity
The classic way of determining the validity (the degree to which the results of a measurement correspond to TABLE 10-4 -- Substances capable of eliciting a lymphocyte blastogenic response (positive result) • Antigen • Hapten • Oxidant • Lectin • Other
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the true state of the phenomenon being measured) [89] of a test is by comparing the observed measurement or results to some accepted, objective, physical standard (the “gold standard”). However, there is no such standard for determining delayed hypersensitivity reactions. Therefore, validity must be established by showing that the test results are predictive of or are directly related to clinically measurable or observable phenomena (signs and symptoms). [89] To determine its validity (based on the predictive value of clinical phenomena), the ELISA/ACT was performed on a very refractory population: 81 patients suffering from an autoimmune or chronic viral syndrome for more than 5 years that had been progressive and had not responded more than briefly to any of several therapeutic interventions. Each patient filled out two symptom questionnaires (the Cornell Medical Index Questionnaire and a questionnaire prepared by Serammune Physicians’ Laboratory) and rated the intensity of their primary symptoms on a scale of 1–100 prior to beginning the recommended ELISA/ACT program based on their test results. At 6–30 months after beginning the program, they again rated the intensity of their primary symptoms (these data are based on follow-up results regardless of how carefully the person followed the recommendations). The results showed a primary symptom intensity of 77.4 ± 14.5 before and 26.4 ± 18.2 after following
Figure 10-2 Response of autoimmune syndromes to ELISA/ACT – patient report (6–36 month follow-up)
the program (p < 0.0001), demonstrating a significant improvement (see Fig. 10.2 ). [90] These results suggest a strong correlation between the reduction of symptom intensity and the elimination of the reactive foods and substances (as determined by the ELISA/ACT), and incorporation of the ELISA/ACT program, supporting the validity of the ELISA/ACT test and program. During the 3 year development phase of the ELISA/ACT, two procedures were utilized to establish relia-bility (the extent to which repeated measurements of a relatively stable phenomenon fall closely to each other): [89] 1. In over 100 separate instances, multiple samples were taken at the same time, from the same subject, and analyzed with the technician blinded. Results replicated with R > 0.999 with only occasional differences where a strong reaction was read as an intermediate or a marginal intermediate was read as not reactive. 2. Many of the more than 3,000 different subjects tested were retested weekly, sometimes for months at a time. The results replicated with an R = 0.998. [91] Determination of sensitivity (the proportion of positive reactions that are confirmed as truly positive – the greater the sensitivity, the fewer the false-positives) specificity (the proportion of negative reactions that are
[89]
and
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TABLE 10-5 -- Measures to reduce error Sources of error
Measures to reduce error
Glass contact
Sample drawn and shipped in plastic
Vacuum draw of sample
Sample drawn slowly using syringe
Tissue thromboplastin activated
Initial 3 ml of blood discarded
Heat
Sample refrigerated and shipped with ice pack
Leukopenia (14 µmol/L by their definiion) in a group of 1,160 elderly (ages 67–96) individuals, in the Framingham Heart Study, to be 29.3%. The study also indicated that plasma homocysteine levels increase with age. [38] Homocysteine facilitates the generation of hydrogen peroxide. [44] By creating oxidative damage to LDL cholesterol and endothelial cell membranes, hydrogen peroxide can then catalyze injury to vascular endothelium. [44] [46] Nitric oxide and other oxides of nitrogen released by endothelial cells (also known as endothelium-derived relaxing factor, or EDRF) protect endothelial cells from damage by reacting with homocysteine, forming S-nitrosohomocysteine, which inhibits hydrogen peroxide formation. However, as homocysteine levels increase, this protective mechanism can become overloaded, allowing damage to endothelial cells to occur. [45] [46] [47] Because of the role of sulfate compounds in the formation of amino sugars needed to form the basement membrane of blood vessels, high levels of homocysteine are likely to contribute to the formation of blood vessels which are more susceptible to oxidative stress. [47] The end result of the combination of oxidative damage and endothelial collagen instability can be the formation of atherosclerotic plaques. Decreased plasma folate levels are correlated with increased levels of homocysteine, and a subsequent increased incidence of CAD. In a 15 year Canadian study of CAD mortality in 5,056 men and women aged 35–79 years, lower serum folate levels were correlated with a significantly increased risk of fatal CAD. [48] In a cohort from the Framingham Heart Study, concentrations of folate and P5P were inversely correlated with homocysteine levels and the risk of extracranial carotid-artery stenosis. [38] Low P5P and low vitamin B12 have also been linked with hyperhomocysteinemia and a significantly increased risk of CAD. [35] Re-methylation of homocysteine and the subsequent formation of SAM is critical for biosynthesis of L-carnitine, CoQ 10 , and creatine. Similarly, the trans-sulfuration pathway must be functioning properly for optimal biosynthesis of cysteine, GSH, pantethine, and taurine. All of these nutrients are used clinically to reduce oxidative stress, improve risk factor markers, or treat heart disease. Peripheral vascular disease Elevated homocysteine levels have been established as an independent risk factor for intermittent claudication
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(IC) and deep vein thrombosis. Elevated homocysteine levels corresponded with an increased incidence of intermittent claudication and decreased serum folate levels in a study of 78 patients with IC. [49] A fourfold increase in risk of peripheral vascular disease was noted in individuals with hyperhomocysteinemia compared with those with normal homocysteine levels. [50] A group of researchers in the Netherlands found high homocysteine levels to be a significant risk factor for deep-vein thrombosis, with a stronger relationship among women than men. [51] An increased risk of peripheral vascular occlusion has been noted in women taking oral contraceptives, which might be linked to the significantly increased homocysteine levels in women so affected. It is already known that oral contraceptives can cause declines or deficiencies in vitamins B 6 , B12 , and folate, nutrients integral to the processing of homocysteine. Laboratory assessment of plasma homocysteine levels may be helpful to detect women who may be predisposed to peripheral vascular occlusion while on oral contraceptives. [52] Stroke Stroke patients have significantly elevated homocysteine levels compared with age-matched controls, [53] with a linear relationship between risk of stroke and homocysteine levels, [54] and a significant decrease in blood folate concentrations in those with elevated homocysteine. [55] Pregnancy Biochemical enzyme defects and nutritional deficiencies are receiving increasing attention for their role in causing neural tube defects (NTD) as well as other negative pregnancy outcomes, including spontaneous abortion, placental abruption (infarct), pre-term delivery, and low infant birth weight. Recent evidence has suggested that derangement of methionine-homocysteine metabolism could be the underlying mechanism of pathogenesis of neural tube defects and might be the mechanism of prevention observed with supplementation of folic acid. [56] [57] It has been firmly established that a low dietary intake of folic acid increases the risk for delivery of a child with a NTD, and that periconceptional folic acid supplementation reduces the occurrence of NTD. [58] [59] [60] [61] [62] [63] [64] Research also indicates that supplemental folic acid intake results in increased infant birth weight and improved Apgar scores, along with a concomitant decreased incidence of fetal growth retardation and maternal infections. [65] [66] [67] [68] A derangement in methionine-homocysteine metabolism has also been correlated with recurrent miscarriage and placental infarcts (abruption). [69] The amino acid homocysteine, when elevated, might be a teratogenic agent contributing to congenital defects of the heart and neural tube. Evidence from experimental animals lends support to this belief. When avian embryos were fed homocysteine to raise serum homocysteine to over 150 nmol/ml, dysmorphogenesis of the heart and neural tube, as well as of the ventral wall, was observed. [70] Because homocysteine metabolism, through the re-methylation and trans-sulfuration pathways, affects several biochemical pathways involving the production of
nutrients which are essential to the optimal functioning of the cardiovascular, skeletal, and nervous systems, it is not surprising that these other nutrients have been linked to complications of pregnancy in animal models and humans. Low plasma vitamin B 12 levels have been shown to be an independent risk factor for NTD. [71] [72] Methionine has been shown to reduce the incidence of NTD by 41% in an animal model when administered on days 8 and 9 of pregnancy. [73] [74] This evidence indicates that a disturbance in the remethylation pathway with a subsequent decrease in SAM may be a contributing factor to these complications of pregnancy. Phosphatidylcholine, due to its role as a precursor to acetylcholine and choline, is acknowledged as a critical nutrient for brain and nerve development and function. [75] [76] [77] Since the metabolic pathways of choline (via betaine), methionine, methylcobalamin and 5-methylTHF are interrelated, intersecting at the regeneration of methionine from homocysteine, a disturbance in the metabolism of either of these two methyl-donor pathways, due to limited availability of key nutrients or decreased enzyme activity, will have a direct impact on the body’s ability to optimize levels of SAM. Evidence suggests that women with a history of NTD-affected pregnancies have altered folic acid metabolism. [78] [79] [80] [81] Patients with a severe congenital deficiency of the enzyme MTHFR, which is needed for the formation of 5-methylTHF, have reduced levels of both methionine and adenosylmethionine in the cerebrospinal fluid and show demyelination in the brain and degeneration of the spinal cord. [2] [82] Because of its direct impact in the activation of folic acid to its methyl derivative, a milder version of this enzyme defect is also strongly suspected to increase the incidence of NTD. [83] It is established that high vitamin A intake during the first 2 months of pregnancy is associated with a several-fold higher incidence of birth defects. [84] [85] Although the mechanism of action remains to be elicited, in an animal model the activity of hepatic MTHFR is suppressed with high vitamin A levels, suggesting that its teratogenic effect during early pregnancy may be associated with a subsequent derangement in the remethylation of homocysteine. [86] Since a more significant correlation has been found between high homocysteine levels in women experiencing placental abruption, infarction, and spontaneous abortion than in control women, and since homocysteine and CoQ 10 synthesis are both dependent upon the
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methionine-SAM-homocysteine pathway, it is possible that low CoQ 10 and elevated homocysteine independently found in complicated pregnancy may also in fact be found to be related conditions. [87] [88] Nutritional intervention with the cofactors required for optimal metabolism of the methionine-homocysteine pathways offers a new integrated possibility for primary prevention of NTD and several other complications of pregnancy. Supplementation with betaine, and the active forms of cobalamin and folic acid, such as methylcobalamin and folinic acid, along with riboflavin-5'-phosphate (because of its role as a cofactor for the MTHFR enzyme), may play a significant role in reducing or preventing these emotionally devastating outcomes. Neurological and mental disorders In addition to the known impact of homocysteine on the cardiovascular system and micronutrient biochemical pathways, numerous diseases of the nervous system are correlated with high homocysteine levels and alterations in B 12 , folate, or B6 metabolism, including depression, schizophrenia, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and cognitive decline in the elderly. Methylation reactions via SAM, including methylation of DNA and myelin, are vitally important in the CNS. The neurologic complications of vitamin B 12 deficiency are thought to be due to a reduction of activity of the B 12 -dependent enzyme methionine synthase, and the subsequent reduction of SAM production. The CNS lacks the alternate betaine pathway of homocysteine remethylation; therefore, if methionine synthase is inactivated, the CNS has a greatly reduced methylation capacity. [89] Other causes of reduced methionine synthase activity include folic acid deficiency and nitrous oxide anesthesia exposure. [90] Homocysteine has also been found to be a neurotoxin, especially in conditions in which glycine levels are elevated, including head trauma, stroke, and B 12 deficiency. [91] Homocysteine interacts with the N-methyl-D-aspartate receptor, causing excessive calcium influx and free radical production, resulting in neurotoxicity. [91] The neurotoxic effects of homocysteine and/or reduced methylation reactions in the CNS contribute to the mental symptomatology seen in B 12 and folate deficiency. Increased homocysteine levels can also be seen in schizophrenics. [92] Significant deficiencies in B 12 and folate are common in the elderly population, and can contribute to a decline in cognitive function. [93] [94] [95] An investigation of cognitive ability in older men (aged 54–81) found poorer spatial copying skills in those individuals with higher homocysteine levels. Better memory performance was correlated with higher vitamin B 6 levels. [96] B12 deficiency and increasing severity of cognitive impairment have been seen in Alzheimer’s disease (AD) patients compared with controls and patients with other dementias.[97] In a study of 52 AD patients, 50 hospitalized non-demented controls, and 49 elderly subjects living at home, patients with AD were found to have the highest homocysteine levels and the highest methylmalonic acid (an indicator of B 12 deficiency) levels. [98] In a study of 741 psychogeriatric patients, high plasma homocysteine levels were found in demented and non-demented patients; however, only demented patients also had lower blood folate concentrations compared with controls. Patients with concomitant vascular disease had significantly higher plasma homocysteine than those without diagnosed vascular disease. Significantly higher homocysteine levels, compared with controls, have also been found in Parkinson’s patients. [99] Homocysteine’s effects on neurotransmitter metabolism, along with its potential reduction of methylation reactions, could be a contributing factor to the etiology of depression. Folate and B 12 deficiency can cause neuropsychiatric symptoms including dementia and depression. Although no studies have been performed to date investigating depression, folate and B 12 deficiency and homocysteine levels, with what is known about these deficiencies and methionine synthase inhibition, it is suggestive that this connection will be revealed in the future. We do know that SAM is used therapeutically as an antidepressant in Europe and is the third most popular antidepressant treatment in Italy in 1995. [100] [101] As yet, SAM is not available as a supplement in the US. Methylation of myelin basic protein is vital to the maintenance of the myelin sheath. The worst-case scenario of folate and B 12 deficiency includes demyelination of the posterior and lateral columns of the spinal cord, a disease process called subacute combined degeneration of the spinal cord (SCD). [89] SCD can also be precipitated by nitrous oxide anesthesia, which causes an irreversible oxidation of the cobalt moiety of the B 12 molecule and the subsequent inhibition of methionine synthase activity, a decrease in homocysteine remethylation, and decreased SAM production. [90] This has been treated using supplemental methionine, which further supports the theory of a nitrous oxide-induced biochemical block at methionine synthase. [102] Particularly at risk for this condition are B 12 -deficient individuals who then visit their dentist and receive nitrous oxide. [90] [103] Abnormal methylcobalamin metabolism is one of the proposed mechanisms for the pathophysiology of the demyelinating disease multiple sclerosis. Deficiency of vitamin B12 has been linked to some cases of multiple sclerosis, and it is suggested that dietary deficiency, or more likely, a defect in R-protein-mediated absorption or methylation of B12 , might be a significant contributor to the pathogenesis of MS. [104]
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Diabetes mellitus Homocysteine levels appear to be lower in individuals with type 1 diabetes mellitus. Forty-one type 1 diabetic subjects (age 34.8 ± 12 years, duration of illness: 10.7 ± 11.1 years) were compared with 40 age-matched control subjects (age 34.2 ± 9.1 years). Following an overnight fast, homocysteine was significantly ( P = 0.0001) lower in the diabetic group (6.8 ± 2.2) than in the controls (9.5 ± 2.9). This difference was apparent in male and female subgroups. [105] However, increased levels of homocysteine have been reported in type 1 diabetics with proliferative retinopathy [106] and nephropathy. [106] [107]
Evidence to date suggests that metabolism of homocysteine is impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). Following a methionine load, hyperhomocysteinemia occurred with significantly greater frequency in patients with NIDDM (39%) as compared with age-matched controls (7%). The area under the curve over 24 hours, reflecting the total period of exposure to increased homocysteine, was also elevated with greater frequency in patients with NIDDM and macrovascular disease (33%) as compared with controls (0%). The authors concluded that hyperhomocysteinemia is associated with macrovascular disease in a significant proportion of patients with NIDDM. [108] Other researchers have reported a correlation between increased homocysteine levels and the occurrence of macroangiopathy in patients with NIDDM. Intramuscular injection of 1,000 µg methylcobalamin daily for 3 weeks reduced the elevated plasma levels of homocysteine in these individuals. [109] Elevated homocysteine levels appear to be a risk factor for diabetic retinopathy in individuals with NIDDM. This might be due to a point mutation on the gene for the enzyme MTHFR.[110] [111] A significantly higher percentage of diabetics with retinopathy exhibit this mutation. [112] Elevated homocysteine levels cause cell injury to the small vessels, which may contribute to the development of retinopathy as well as macroangiopathy in the cardiovascular system. [110] Rheumatoid arthritis Elevated total homocysteine levels have been reported in patients with rheumatoid arthritis. Twenty-eight patients with rheumatoid arthritis and 20 healthy age-matched control subjects were assessed for homocysteine levels, while fasting and in response to a methionine challenge. Fasting levels were 33% higher in rheumatoid arthritis patients than in controls. Four hours following the methionine challenge, the increase in plasma homocysteine concentration was also higher in patients with rheumatoid arthritis. [112] Another study found statistically significant increases in homocysteine in RA patients ( P = 0.003), with 20% of the patients having homocysteine levels above the reference range. [113] A mechanism for this increased homocysteine in RA patients has not been elucidated. Penicillamine, a common sulfhydryl-containing arthritis treatment, has been found to lower elevated homocysteine levels in vivo. [114] Further investigation into both the prevalence of hyperhomocysteinemia and the mechanism of action impacting rheumatoid arthritis is needed. Kidney failure Because homocysteine is cleared by the kidneys, chronic renal failure, as well as absolute or relative deficiencies of 5-methylTHF, methylcobalamin, P5P, or betaine, results in increased homocysteine levels. In 176 patients with end-stage renal disease on peritoneal or hemodialysis, homocysteine concentrations averaged 26.6 ± 1.5 µmol/L in patients with renal failure as compared with 10.1 ± 1.7 µmol/L in normals. Abnormal values exceeded the 95th percentile for normal controls in 149 of the patients with renal failure. [115] Data also indicate that plasma homocysteine values represent an independent risk factor for vascular events in patients on peritoneal and hemodialysis. Patients with a homocysteine concentration in the upper two quintiles (> 27.8 µmol/L) had an independent odds ratio of 2.9 (CI, 1.4–5.8; P = .007) of vascular complications. Vitamin B levels were also lower in patients with vascular complications than in those without. [116] Alcoholism and ethanol ingestion Chronic alcoholism is known to interfere with one-carbon metabolism. Because of this, it is not surprising to find that mean serum homocysteine levels are two times higher in chronic alcoholics than in non-drinkers ( P< 0.001). Beer consumers have lower concentrations of homocysteine compared with drinkers of wine or spirits ( P = 0.05). In chronic alcoholics, serum P5P and red blood cell folate concentrations have been shown to be significantly lower than in control subjects. [10] Plasma homocysteine is significantly higher, compared with controls, in 42 active alcoholics hospitalized for detoxication. In another group of 16 alcoholics, abstaining from ethanol ingestion, plasma homocysteine did not deviate from that of controls. [11] Feeding ethanol to rats produces prompt inhibition of methionine synthase as well as a subsequent increase in activity of betaine homocysteine methyltransferase. Despite the inhibition of methionine synthase, the enhanced betaine homocysteine methyltransferase pathway utilizes hepatic betaine pools to maintain levels of SAM.[117] Results indicate that ethanol feeding produces a significant loss in SAM in the first week, with a return to normal SAM levels in the second week. Betaine
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feeding enhances hepatic betaine pools in control as well as ethanol-fed animals; attenuates the early loss of SAM in ethanol-fed animals; produces an early increase in betaine homocysteine methyltransferase activity; and generates increased levels of SAM in both control and ethanol-fed groups. [118] It has been shown that minimal supplemental dietary betaine at the 0.5% level increases SAM twofold in control animals and fivefold in ethanol-fed rats. Concomitant with the betaine-generated SAM, ethanol-induced hepatic fatty infiltration was ameliorated. [117] Betaine supplementation also reduces the accumulation of hepatic triglyceride produced after ethanol ingestion. [118] Gout Although homocysteine levels have been positively correlated with increased uric acid levels, [2] [119] [120] no studies exist to date which have investigated homocysteine levels in gout patients. It is possible the increased uric acid levels in gout are due to decreased SAM production because of the reduction in homocysteine recycling. The excess adenosine, which would have reacted with methionine to form SAM, is degraded to form uric acid as its end product. Niacin is contraindicated in gout, as it competes with uric acid for excretion. [121] Animal studies have shown that increased levels of S-adenosylhomocysteine (SAH), and thus homocysteine, cause significant reductions in SAM-dependent methylation reactions. [12] Therefore, since degradation of the niacin-containing coenzyme nicotinamide adenine dinucleotide (NAD) is dependent on methylation by SAM, and SAM activity is severely reduced in hyperhomocysteinemia, niacin levels might be higher in these people, resulting in less uric acid excretion, higher uric acid levels and increased gout symptoms in susceptible individuals. This possibility and its mechanism need further investigation. Osteoporosis Homocystinuria due to cystathionine synthase deficiency is an autosomal recessive error of sulfur amino acid metabolism characterized clinically by lens dislocation, mental retardation, skeletal abnormalities and thromboembolic phenomena. [122] Individuals with this enzyme deficiency have decreased concentrations of cysteine and its disulfide form, cystine. In children with homocystinuria, osteoporosis is a common presenting symptom. [123] Because of the role of sulfur compounds in the formation of sulfated amino sugars, disturbed cross-linking of collagen has been proposed as a possible mechanism of action. One group of researchers studying 10 patients with homocystinuria found normal synthesis of collagen, but a significant reduction of cross-links. [124] Because of the correlation between homocystinuria and osteoporosis in children with this amino acidopathy, and because of the increase in homocysteine concentrations in postmenopausal women, several authors have implied that elevated homocysteine levels contribute to postmenopausal osteoporosis. To date, no evidence is available which demonstrates that homocysteine levels are higher in postmenopausal women with osteoporosis than in age-matched controls.
DIAGNOSTIC CONSIDERATIONS Many of the studies cited herein have used a reference range, with 12–16 µmol/L being the upper limit of the normal range. We will probably see this level drop, as we did with cholesterol testing, as researchers have found a highly significant increase in relative risk of atherosclerotic cardiovascular disease and other disease processes as homocysteine levels increase, even within the “normal” range. A number of clinical laboratories currently perform plasma homocysteine determinations, by itself or within a cardiovascular panel.
THERAPEUTIC CONSIDERATIONS If a dietary deficiency or an increased demand, resulting from genetic biochemical individuality exists for 5-methylTHF, methylcobalamin, P5P, or betaine, treatment with these micro-nutrients should reduce homocysteine levels. Several studies utilizing folic acid, B 6 , B12 , and betaine, either alone or in combination, have demonstrated the ability of these nutrients to normalize homocysteine levels. [21] [39] [41] [125] [126] In a recent placebo-controlled clinical study of 100 men with hyperhomocysteinemia, oral therapy with 650 mcg folic acid, 400 mcg vitamin B 12 , 10 mg vitamin B6 , or a combination of the three nutrients was given daily for 6
weeks. Plasma homocysteine was reduced 41.7% (P < 0.001) during folate therapy and 14.8% ( P < 0.01) during B 12 therapy, while 10 mg B 6 did not reduce plasma homocysteine significantly. The combination worked synergistically to reduce homocysteine levels by 49.8%. [127] In 68 patients with recent myocardial infarction, 18% had increased plasma homocysteine. Oral folate therapy (2.5 mg) reduced this hyperhomocysteinemia in 94% of treated patients (mean decrease 27%). [36] In a group of 48 patients with peripheral atherosclerotic vascular disease, 50% had abnormally high fasting plasma homocysteine levels, while 100% had abnormal plasma homocysteine after a methionine load. Treatment with 5 mg folic acid and 250 mg pyridoxine for 12 weeks normalized 95% of the fasting levels and 100% of post-load homocysteine levels. [39] Other studies confirm that oral folate supplementation will almost always lower high homocysteine, while B 6 and B12 will
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lower homocysteine only in those with a genetic metabolic defect and/or dietary deficiency in those nutrients.
[125] [128]
A deficiency of the P5P dependent enzyme cystathione synthase is the most common genetic abnormality affecting the trans-sulfuration pathway of homocysteine breakdown. Fortunately, B 6 supplementation stimulates this enzyme and, in combination with betaine, corrects the hyperhomocysteinemia in these individuals. [21] [125] Therapeutic approach Supplements
• Folinic acid: 800 mcg t.i.d. • Methylcobalamin: 800 mcg t.i.d. • Pyridoxal 5´-phosphate: 20 mg t.i.d. • Betaine (trimethylglycine): 1,200 mg t.i.d. • N-acetylcysteine: 500 mg t.i.d.
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Chapter 53 - Immune support Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION The immune system is a complex integration of synergistic segments that are continuously barraged by stimuli. Immunology is a rapidly developing field with concepts being continually devised and revised. For the physician interested in assessing and maintaining a patient’s health, the development of a thorough understanding of the immune system and the many factors which enhance and/or inhibit normal function is essential. The immune system is truly “wholistic”, as evidenced by the close association of psychological, neurological, nutritional, environmental, and endocrinologic factors with immune function. Supporting the immune system is critical to good health. Conversely, good health is critical to supporting the immune system. The best approach to supporting immune function is a comprehensive plan involving lifestyle, stress management, exercise, diet, nutritional supplementation, glandular therapy, and the use of plant-based medicines.
PSYCHONEUROIMMUNOLOGY Psychoneuroimmunology is a term used to describe the interactions between the emotional state, nervous system function, and the immune system. The growing body of knowledge documenting the mind’s profound influence on physiology in health and disease necessitates a fundamental change in the way physicians perceive their patients. An important step is the study of nervous system response to environmental or intra-psychic perceptions that activate endocrine processes which, in turn, influence the immune system. A complete and detailed account of the many facets of psychoneuroimmunology (PNI), or behavioral immunology, is beyond the scope of this chapter. Instead, we will concentrate on the effects of stress and neurotransmitters on the immune response.
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Stress
The term stress-induced illness is certainly not a misnomer, since many clinical and experimental studies have clearly demonstrated that stress, personality, attitude, and emotion are etiologic or contributory in many diseases. [1] Reaction to stressful stimuli is entirely individual, reinforcing the fact that people differ significantly in their perceptions and responses to various life events. The variations in response help to account for the wide diversity of stress-induced illnesses. Stress-induced increases in corticosteroids and catecholamines lead to an immunosuppressed state, leaving the host susceptible to infectious and carcinogenic illnesses. This immunosuppression is proportional to the level of stress and, although the effects are numerous, they appear to involve a common mechanism: an increase in intracellular cyclic AMP. Other mechanisms are also significant, with thymic involution and suppressed lymphopoiesis being perhaps the most important. Cyclic nucleotides and immune function
In many systems of the body, cholinergic and beta-adrenergic stimulation mediate diametrically opposed actions. On the cellular level, this antagonism is mediated via cyclic AMP and cyclic GMP. Beta-adrenergic stimulation of responsive target tissues causes a rise in intracellular cAMP, whereas acetylcholine acting on muscarine receptors leads to increased levels of cGMP. The immune system is also affected by this yin–yang balance, although it appears to be much more complex than in other systems. Cyclic AMP and GMP have shown antagonistic effects in all immune functions studied to date. The immune effects of cGMP include:
[2] [3] [ 4] [ 5] [ 6] [7]
• enhanced lymphocyte mediated cytotoxicity • stimulation of T-cell rosette formation (a measure of thymus-derived lymphocyte activity) with inhibition of B-cell rosette formation • enhanced lymphoid cell and lymphocyte proliferation • increased lymphocyte lysosomal enzyme release • increased leukocyte chemotaxis. From this information, it is apparent that cGMP usually serves to enhance immune function during infection and carcinogenesis. In contrast, cAMP appears to inhibit white cell proliferation and functional response, thus possibly serving to modulate the immune system. While there are many conditions where enhancing cGMP activity and inhibiting cAMP activity is contraindicated (e.g. autoimmune disease, atopy, gout, and psoriasis), in acute or chronic infection the cGMP:cAMP ratio should be enhanced. Although many exogenous TABLE 53-1 -- Lifestyle practices associated with higher natural killer cell activity • Not smoking • Increased intake of green vegetables • Regular meals • Proper body weight • More than 7 hours of sleep • Regular exercise • A vegetarian diet compounds alter the cGMP:cAMP ratio, paramount in any treatment plan is adequate rest and elimination of stressful activity. This promotes an increase in cholinergic activity while concurrently lowering beta-adrenergic activity. In addition, other cAMP promoting factors should be eliminated (e.g. caffeine and its analogs) while increasing cGMP stimulators (e.g. ascorbic acid). [6] [7]
LIFESTYLE A healthy lifestyle goes a long way in establishing a healthy immune system. This benefit is perhaps most obvious when looking at the effects of lifestyle on natural
killer cell activity. [8] [9] Table 53.1 lists the lifestyle practices which are associated with higher natural killer cell activity.
NUTRITIONAL FACTORS The health of the immune system gland is greatly impacted by a person’s nutritional status. Dietary factors which depress immune function include nutrient deficiency, excess consumption of sugar, consumption of allergic foods and high cholesterol levels in the blood. Dietary factors which enhance immune function include all essential nutrients, antioxidants, carotenes, and flavonoids. Consistent with good health, optimal immune function requires a healthy diet that: • is rich in whole, natural foods, such as fruits, vegetables, grains, beans, seeds, and nuts • is low in fats and refined sugars • contains adequate, but not excessive, amounts of protein. On top of this, individuals are encouraged to drink five or six 8-ounce glasses of water per day (preferably pure). These dietary recommendations along with a positive mental attitude, a good high potency multivitamin-mineral supplement, a regular exercise program, daily deep breathing and relaxation exercises (meditation, prayer, etc.), and at least 7 hours of sleep daily will go a long way in helping the immune system function at an optimum level.
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Nutrient deficiency Nutrient deficiency is the most frequent cause of a depressed immune system. Although, historically, research relating nutritional status to immune function has concerned itself with severe malnutrition states (i.e. kwashiorkor and marasma), attention is now shifting towards marginal deficiencies of single or multiple nutrients and the effects of overnutrition. The plethora of clinical and experimental data has made inevitable the conclusion that a single nutrient deficiency can profoundly impair the immune system. Given the widespread problem of subclinical nutrient deficiency in Americans, it can be concluded that many are suffering from impaired immunity amenable to nutritional supplementation. This statement is particularly true in the elderly. Numerous studies have shown that most elderly Americans are deficient in at least one nutrient. Likewise, there are numerous studies which show that taking a multiple vitamin and mineral supplement enhances immune function in elderly subjects (whether they suffer from overt nutritional deficiency or not). General factors Protein
The importance of adequate protein intake to proper immune function has been extensively studied. [10] The most severe effects of protein-calorie malnutrition (PCM) are on cell-mediated immunity, although all facets of immune function are ultimately affected. PCM is not, however, usually a single nutrient deficiency. It is normally associated with multiple nutrient deficiencies, and some immune dysfunctions attributed to PCM are most likely due to these other factors. Partial deficiencies of dietary vitamins produce a comparatively greater depression in the natural and inducible levels of cytotoxic activities than do partial protein deficiencies. Nonetheless, adequate protein is essential for optimal immune function. Sugar
The oral administration of 100 g portions of carbohydrate as glucose, fructose, sucrose, honey, and orange juice all significantly reduces neutrophil phagocytosis, while starch has no effect. As can be seen in Figure 53.1 , effects start within less than 30 minutes, last for over 5 hours, and typically show a 50% reduction in phagocytic activity at the peak of inhibition (usually 2 hours after ingestion). [11] [12] Since PMNs constitute 60–70% of the total WBC and are a major portion of the defense mechanism, impairment of phagocytic activity leads to an immune-compromised state. Oral administration of increasing
Figure 53-1 The effects of sugar on white cell phagocytic activity.
amounts of glucose progressively lowers neutrophil phagocytosis, with maximal inhibition corresponding to maximal blood glucose levels. Oral ingestion of 75 g of glucose has also been shown to depress lymphocyte response to mitogens, apparently due to the elevation of insulin levels. parameters of immune function are also undoubtedly affected by sugar consumption.
[ 13]
Other
It has been hypothesized that the ill effects of high glucose levels are a result of elevation of insulin levels and competition with vitamin C for membrane transport sites.[14] [15] This is based on evidence that vitamin C and glucose appear to have opposite effects on immunological function and the fact that both require insulin for membrane transport into many tissues. Considering that the average American consumes 125 g of sucrose, plus 50 g of other refined simple sugars, each day, the inescapable conclusion is that most Americans have chronically depressed immune systems. It is clear, particularly during an infection, that the consumption of simple sugars, even in the form of fruit juice, is deleterious to the host’s immune status. Short-term fasting could be encouraged, particularly during the first 24–48 hours of an acute infectious illness, since this results in a significant (up to 50%) increase in phagocytic index. [11] The fast should not be continued for an excessive period, since eventually the leukocyte’s energy sources will become depleted. Obesity
Obesity is associated with decreased immune status, as evidenced by the decreased bactericidal activity of leukocytes, and increased morbidity and mortality from infections. [16] Cholesterol and lipid levels are usually elevated in obese individuals, which may explain their impaired immune function (see below). Lipids
Increased levels of cholesterol, free fatty acids, triglycerides,
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and bile acids inhibit various immune functions, including: • lymphoproliferation • response to mitogens
[17] [18] [19] [ 20]
• antibody response • PMN chemotaxis • phagocytosis. Optimal immune function is therefore dependent on control of these serum components. Interestingly, L-carnitine, even at minimal concentrations, has been shown to neutralize lipid-induced immunosuppression. [20] This is probably due to carnitine’s role as a rate-limiting factor in the removal of fat emulsion from the blood. [21] Alcohol
Alcohol increases the susceptibility to experimental infections in animals; and alcoholics are known to be more susceptible to pneumonia. Studies of human polymorphonuclear leukocytes show a profound depression in the rate of mobilization into the traumatized skin of nutritionally normal people. Alcohol does not, however, alter phagocytosis or cytotoxic activity. [22] Vitamins Vitamin A
Vitamin A plays an essential role in maintaining the integrity of the epithelial and mucosal surfaces and their secretions. These systems constitute a primary non-specific host defense mechanism. Vitamin A has been shown to stimulate and/or enhance numerous immune processes, including: [23] [24] [25] [26] • induction of cell-mediated cytotoxicity against tumors • natural killer cell activity • lymphocyte blastogenesis • mononuclear phagocytosis • antibody response. These effects are not due simply to reversal of vitamin A deficiency, since many of them are further enhanced by the administration of (supposedly) excessive levels of vitamin A.[26] In addition, vitamin A prevents and reverses stress-induced thymic involution, while added vitamin A can actually promote thymus growth. [27] Retinol also demonstrates potent viricidal activity. [28] Carotenes
Carotenes have demonstrated a number of immune-enhancing effects. [29] In addition to being converted into vitamin A, carotenes function as antioxidants. Since the thymus gland is so susceptible to free radical damage, beta-carotene may be more advantageous in enhancing the immune system than retinol. For more information, see Chapter 121 . Vitamin C
Vitamin C (ascorbic acid) plays an important role in the natural approach to immune enhancement. Although vitamin C has been shown to be antiviral and antibacterial, its main effect is via improvement in host resistance. Many different immunostimulatory effects have been demonstrated, including enhancing lymphoproliferative response to mitogens and lymphotrophic activity and increasing interferon levels, antibody responses, immunoglobulin levels, secretion of thymic hormones, and integrity of ground substance. [23] [24] [25] [26] [27] [28] [29] [30] Vitamin C also has direct biochemical effects similar to interferon. [31] Numerous clinical studies support the use of vitamin C in the treatment of infectious conditions. In addition to its well-known effects in reducing the frequency, duration, and severity of the common cold, vitamin C has also been shown to be useful in other infectious conditions. [30] [32] [33] [34] [35] [36] Vitamin C levels are quickly depleted during the stress of an infection. [37] It is useful to supplement vitamin C concurrently with flavonoids since these compounds raise the concentration of vitamin C in some tissues and potentiate its effects, as well as exerting their own effects. [38] Vitamin E
Vitamin E enhances both humoral and cell-mediated immunity. A vitamin E deficiency results in lymphoid atrophy and decreased lymphoproliferative response to mitogens, splenic plaque-forming colonies, antibody response, and monocyte function. [23] [24] Vitamin E supplementation (30–150 IU) has been shown to: [39] • increase lymphoproliferative response to mitogens • prevent free radical-induced thymus atrophy • enhance helper T-cell activity • increase splenic plaque-forming colonies, serum immunoglobulins, antibody response, PMN phagocytosis, and reticuloendothelial system activity. Elderly subjects may benefit from even higher dosages of vitamin E. A recent study sought to determine the effect of vitamin E supplementation at different dosages on immune function in 88 patients over the age of 65 years. [40] To determine the effect of vitamin E on immune function, the researchers measured T-cell function by assessing delayed-type hypersensitivity (DTH) skin response; antibody response to hepatitis B, tetanus, and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin. Vitamin E was given at either 60, 200, or 800 IU for
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235 days. While the placebo group only experienced an 8% increase in DHT, the 60 IU group had a 20% increase in DTH; the 200 IU group had a 58% increase in DTH; and the 800 IU group had a 65% increase in DTH. With regard to antibody production, the best results were observed in the patients receiving 200 IU daily. No effect was noticed on autoimmune antibodies. No adverse effects were observed at any of the three dosage schedules of vitamin E. Pyridoxine
A pyridoxine deficiency results in depressed cellular and humoral immunity, lymphoid tissue atrophy, leukopenia, reduction in quantity and quality of antibody production, depressed lymphoproliferative response to mitogens, and decreased thymic hormone activity. [23] [24] Factors predisposing to deficiency are low dietary intake, excess protein intake, consumption of hydralazine (yellow) dyes, and alcohol and oral contraception use. Folic acid and vitamin B 12
The megaloblastic state induced by a deficiency of vitamin B 12 and/or folate results in improper WBC production and abnormal lymphocyte responses. Folic acid deficiency (the most common vitamin deficiency in the US) has been shown to result in lymphoid atrophy and decreased lymphoproliferative response to mitogens, splenic plaque-forming colonies, and antibody production. A B 12 deficiency, besides producing a deficiency in folate conversion to its active tetrahydrofolate form, leads to impaired PMN phagocytosis and bactericidal action. [23] [24] Other B vitamins
Thiamin, riboflavin, and pantothenic acid deficiencies lead to reduced antibody response, decreased splenic plaque-forming colonies, and lymphoid atrophy.
[25]
Minerals Iron
Iron deficiency is a commonly encountered isolated nutritional deficiency which causes immune dysfunction in large numbers of patients. Marginal iron deficiency, even at levels that do not lower hemoglobin values, can influence the immune system. Lymphoid tissue atrophy, decreased lymphoproliferative response to mitogens, defective macrophage and neutrophil function, and decreased proportion of T-cell to B-cell ratios are common experimental and clinical findings. [23] [24] Iron is an important nutrient to bacteria as well as humans. During infection, one of the body’s non-specific defense mechanisms to limit bacterial growth is to reduce plasma iron, and in vitro studies have shown that the bacteriostatic and some of the bactericidal effects of serum are eliminated by the addition of iron to the serum. [41] As temperature rises, plasma iron levels drop, and when temperature is raised to fever levels, the growth of bacteria is inhibited, but not at high iron concentrations. These observations lead us to the conclusion that iron supplementation is probably contraindicated during acute infection, especially in patients with low transferrin levels. However, in patients with impaired immune function, chronic infections, and subnormal iron levels, adequate supplementation is essential. Trace minerals Trace minerals primarily function as activators of enzyme-metal-substrate complexes in which they are loosely bound cofactors. The role of these elements in these metaloenzymes is either structural, in which they influence the reactivity of the protein by stabilizing strained configurations of binding ligands about the metal atom, or catalytic, in which they act as centers of positive charge. Zinc
The hereditary zinc deficiency disease, acrodermatitis enteropathica (AE), offers an excellent model for understanding the role of zinc in immunity. In AE, the number of T-cells is reduced, lymphoproliferative response to mitogens is reduced, thymic hormone levels are lower, delayed cutaneous hypersensitivity is decreased, and PMN phagocytosis, chemotaxis, and cytotoxic activities are impaired. All of these effects are reversible upon adequate zinc administration and absorption. [42] Zinc serves a vital role in many immune system reactions, e.g. it promotes the binding of complement (C1q) to immune complex, acts as a protectant against iron-catalyzed free radical damage, acts synergistically with vitamin A, is required for lymphocyte transformation, acts independently on lymphocytes as a mitogen, and is a necessary cofactor in activating serum thymic factor. [43] [44] Zinc inhibits, in vitro, the growth of several viruses including rhino, picorna and toga viruses, and herpes simplex and vaccinia virus. [45] Adequate zinc nutriture is particularly important in the elderly, and zinc supplementation in elderly subjects results in increased numbers of T-cells and enhanced cell-mediated immune responses. [46] Throat lozenges containing zinc became popular in the treatment of the common cold as a result of a double-blind clinical trial in 1984 which demonstrated that zinc-containing lozenges significantly reduced the average duration of common colds by 7 days. [47] The lozenges used in this study contained 23 mg of elemental zinc, which
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the patients were instructed to dissolve in their mouths every 2 waking hours after an initial double dose. After 7 days, 86% of the 37 zinc-treated subjects were symptom-free, compared with 46% of the 28 placebo-treated subjects. Additional studies have confirmed these results. [48] Because high doses of zinc can actually impair immune function, a daily intake of greater than 150 mg of zinc for longer than 1 week cannot be recommended. Selenium
Selenium in its vital role in glutathione peroxidase affects all components of the immune system including the development and expression of all white blood cells. Selenium deficiency results in depressed immune function, whereas selenium supplementation results in augmentation and/or restoration of immune functions. Selenium deficiency has been shown to inhibit resistance to infection as a result of impaired white blood cell and thymus function, while selenium supplementation (200 mcg/day) has been shown to stimulate white blood cell and thymus function. [49] [50] [51] The ability of selenium supplementation to enhance immune function goes well beyond simply restoring selenium levels in selenium-deficient individuals. For example, in one study selenium supplementation (200 mcg/day) to individuals with normal selenium concentrations in their blood resulted in a 118% increase in the ability of lymphocytes to kill tumor cells and an 82.3% increase in the activity of natural killer cells. [50] These effects were apparently related to the ability of selenium to enhance the expression of the immune-enhancing compound interleukin-2 and, consequently, the rate of white blood cell proliferation and differentiation into forms capable of killing tumor cells and microorganisms. The supplementation regimen did not produce significant changes in the blood selenium levels of the participants. The results indicated that the immune-enhancing effects of selenium in humans require supplementation above the normal dietary intake.
ENHANCING THYMUS FUNCTION Perhaps the most effective method in re-establishing a healthy immune system is employing measures to improve thymus function. Promoting optimal thymus gland activity involves: • prevention of thymic involution or shrinkage by ensuring adequate dietary intake of antioxidant nutrients • use of nutrients that are required in the manufacture or action of thymic hormones • using botanical medicines or glandular products containing concentrates of calf thymus tissue to enhance thymus activity. Antioxidants
The thymus gland shows maximum development immediately after birth. During the aging process, the thymus gland undergoes a process of shrinkage or involution. The reason for this involution is that the thymus gland is extremely susceptible to free radical and oxidative damage caused by stress, radiation, infection, and chronic illness. Many patients with impaired immune function as well as conditions associated with impaired immunity (e.g. chronic fatigue syndrome, cancer, AIDS, etc.) suffer from a state of oxidative imbalance characterized by a greater number of pro-oxidants in their system than antioxidants. This situation is quite detrimental to thymus function. One of the primary ways in which antioxidants impact the immune system, particularly cell-mediated immunity, may be via protecting the thymus gland from damage. The antioxidant nutrients most important for protecting the thymus include the carotenes, vitamin C, vitamin E, zinc, and selenium. Nutrients
Many nutrients function as important cofactors in the manufacture, secretion and function of thymic hormones. A deficiency of any one of these nutrients results in decreased thymic hormone action and impaired immune function. Zinc, vitamin B 6 , and vitamin C are perhaps the most critical. Supplementation with these nutrients has been shown to increase thymic hormone function and cell-mediated immunity.
Zinc is perhaps the critical mineral involved in thymus gland function and thymus hormone action. Zinc is involved in virtually every aspect of immunity. When zinc levels are low, the number of T-cells is reduced; thymic hormone levels are lower, and many white blood functions critical to the immune response are severely lacking. All of these effects are reversible upon adequate zinc administration and adsorption. [52] [53] Thymus extracts
A substantial amount of clinical data now supports the effectiveness of orally administered calf thymus extracts in restoring and enhancing immune function. [54] [55] The effectiveness of thymus extracts is reflective of broad-spectrum immune system enhancement presumably mediated by improved thymus gland activity. This effect fits in nicely with one of the basic concepts of glandular therapy, i.e. that the oral ingestion of glandular material of a certain animal gland will strengthen the corresponding human gland. The result is a broad general effect indicative of improved glandular function. Thymus extracts may provide the answer to chronic viral infections and low immune function. The ability
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of thymus extracts to treat and then reduce the number of recurrent infections was studied in groups of children with a history of recurrent respiratory tract infections. Double-blind studies revealed not only that orally administered thymus extracts were able to effectively eliminate infection, but also that treatment over the course of a year significantly reduced the number of respiratory infections and significantly improved numerous immune parameters. [56] Thymus extract has been shown to normalize the ratio of T-helper cells to suppressor cells whether the ratio is low or high.
[ 54] [55]
BOTANICALS Many herbs have been shown to have antibacterial, antiviral, and immunostimulatory effects, and a complete discussion is outside the scope of this chapter (several immune-enhancing botanicals are discussed in depth in Section 5). This chapter focuses on two of the most popular immune-enhancing botanicals – Echinacea and Astragalus. These two herbs were selected based on their ability to exert broad-spectrum effects on immune functions. They stimulate the body‘s natural defense mechanisms via slightly different mechanisms and are in many ways the prototypes of the hundreds of plants with known antimicrobial and immunological activity. Echinacea
sp.
Perhaps the most widely used Western herb for enhancement of the immune system is echinacea. The two most widely used species are Echinacea angustifolia and Echinacea purpurea. Both have been shown to exert profound immune-enhancing effects. Several classes of constituents contribute to this action. [57] One of the most important immune-stimulating components of Echinacea are large polysaccharides, such as inulin, that activate the alternative complement pathway (one of the immune system’s non-specific defense mechanisms) and increase the production of immune chemicals that activate macrophages. The result is increased activity of many key immune parameters: production of T-cells, macrophage phagocytosis, antibody binding, natural killer cell activity, and levels of circulating neutrophils. [57] Echinacea strengthens the immune system even in healthy people. For example, oral administration of an E. purpurea root extract (a dose of 30 drops three times daily) to healthy males for 5 days resulted in a remarkable 120% increase in leukocyte phagocytosis. [58] In another study of healthy volunteers aged 25–40 years, the fresh-pressed juice of E. purpurea extract was found to increase the phagocytosis of Candida albicans by 30–40%; it also increased the migration of white cells to the scene of battle by 30–40%.[59] Besides immune support, Echinacea also exerts direct antiviral activity and helps prevent the spread of bacteria by inhibiting a bacterial enzyme called hyaluronidase. This enzyme is secreted by bacteria in order to break through the body’s first line of defense, the protective membranes such as the skin or mucous membranes, so that the organism can enter the body. Echinacea is discussed fully in Chapter 82 . Astragalus membranaceus
The root of Astragalus is a traditional Chinese medicine used for viral infections. Clinical studies in China have shown it to be effective when used prophylactically against the common cold.[60] It has also been shown to reduce the duration and severity of symptoms in acute treatment of the common cold as well as to raise white blood cell counts in chronic leukopenia. Research in animals has shown that Astragalus apparently works by stimulating several factors of the immune system, including enhancing phagocytic activity of monocytes and macrophages, increasing interferon production and natural killer cell activity, enhancing T-cell activity, and potentiating other antiviral mechanisms. [60] [61] Astragalus appears particularly useful in cases where the immune system has been damaged by chemicals or radiation. In immunodepressed mice, astragalus has been found to reverse the T-cell abnormalities caused by cyclophosphamide, radiation, and aging. [62] Like Echinacea, the polysaccharides contained in the root of Astragalus membranaceus contribute to the immune-enhancing effects.
THERAPEUTIC APPROACH A major challenge to the discerning clinician is to determine which of the above factors is the key to reactivating or supporting a patient’s immune system. The regimen listed below is meant as a general approach and must be tailored to the patient’s specific needs in order to maximize the desired effects and limit unnecessary treatment. General measures • Rest (bed rest better) • Drink large amount of fluids (preferably diluted vegetable juices, soups, and herb teas) • Limit simple sugar consumption (including fruit sugars) to less than 50 g a day. Supplements • High potency multiple vitamin and mineral formula • Vitamin C – 500 mg every 2 hours • Bioflavonoids – 1,000 mg/day 486
• Vitamin A – 5,000 IU/day; or beta-carotene – 25,000 IU/day • Zinc – 30 mg/day • Thymus extract – the equivalent to 120 mg pure polypeptides with molecular weights less than 10,000 or roughly 500 mg of the crude polypeptide fraction. Botanicals
All dosages to be three times/day. sp.
Echinacea
• Dried root (or as tea): 0.5–1 g • Freeze-dried plant: 325–650 mg • Juice of aerial portion of E. purpurea stabilized in 22% ethanol: 2–3 ml • Tincture (1:5): 2–4 ml • Fluid extract (1:1): 2–4 ml • Solid (dry powdered) extract (6.5:1 or 3.5% echinacoside): 150–300 mg. Astragalus membranaceus
• Dried root (or as decoction): 1–2 g • Tincture (1:5): 2–4 ml • Fluid extract (1:1): 2–4 ml • Solid (dry powdered) extract (0.5% 4-hydroxy-3-methoxy isoflavone): 100–150 mg.
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Chapter 54 - Intestinal dysbiosis and dysfunction Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION Overgrowth of inappropriate bacteria in the various segments of the intestines is becoming recognized as a significant, but rarely recognized, cause of chronic disorders not only of the intestines but also of other systems of the body. Although widespread, it is frequently unsuspected because its symptoms often mimic other disorders. Environmental exposure, widespread antibiotic use and a low-fiber diet, as well as digestive disorders, have resulted in increasing incidence of intestinal dysbiosis and dysfunction with age. Further discussion of the substantive role of the digestive tract in health and disease can be found in Chapters 7 , 9 , 19 , 21 , 23 , 31 , 57 , 131 , 163 and 165 . The length of the list in itself indicates the wide-ranging effects of intestinal dysbiosis. This chapter provides some overview and fills in the gaps between the above listed chapters.
SMALL INTESTINE Bacterial overgrowth The upper portion of the human small intestine is normally relatively free of bacteria. Overgrowth of organisms in this area results in carbohydrate fermentation which produces excessive gas, bloating, and abdominal distention, and protein putrefaction which produces vasoactive amines. [1] For example, bacteria and yeast contain decarboxylases which can convert the amino acids histidine to histamine and tyrosine to tyramine, ornithine to putrescine and lysine to cadaverine. All of these compounds cause constriction and relaxation of blood vessels by acting on their smooth muscle. In the intestinal tract, excessive vasoactive amine synthesis can lead to increased gut permeability (i.e. the “leaky gut” syndrome), abdominal pain, altered gut motility, and pain (see Ch. 21 ). Diagnosis of small intestinal overgrowth involves comprehensive digestive and stool analysis (see Ch. 9 ) and breath tests which measure the hydrogen and methane
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after the administration of lactulose and glucose (see Ch. 7 ). Symptoms of small intestinal bacterial overgrowth are similar to those generally attributed to achlorhydria and pancreatic insufficiency – indigestion and sense of fullness (bloating) – but may also include symptoms generally associated with Candida overgrowth (discussed below), nausea, diarrhea, and arthritis. This latter association is quite important as many patients with rheumatoid arthritis exhibit small intestinal bacterial overgrowth, the degree of which correlates with the severity of symptoms and disease activity.[2] Several protective measures prevent bacterial overgrowth in the small intestine: digestive enzymes, liver secretions, peristalsis and immunological factors. [3] [4] [5] [6] [7] Hydrochloric acid, bile and pancreatic enzymes play a critical role in preventing significant numbers of bacteria from transiting through the stomach or migrating up the small intestine. [4] [5] Decreased motility of the small intestine due to a motility disorder (e.g. systemic sclerosis) or a meal high in refined sugar can also contribute to small intestinal bacterial overgrowth. [6] [7] The mechanism by which a high sugar meal decreased mobility is simple: when blood sugar levels rise too rapidly, the feedback system inhibits gastrointestinal peristalsis. Since glucose is primarily absorbed in the duodenum and jejunum, inhibition of this portion of the gastrointestinal tract is the strongest. Low immune function, food allergies, stress, and other factors which reduce the level of secretory IgA can also contribute to bacterial overgrowth in the small intestine ( Table 54.1 ). Finally, a weak ileocecal can lead to overpopulation of the small intestinal tract with bacteria from the colon. A weak ileocecal valve is most often the consequence of long-term constipation or straining excessively at defecation. In both of these cases, a low-fiber diet is most often responsible. An overgrowth in the gastrointestinal tract of the usually benign yeast Candida albicans is now becoming recognized as a complex medical syndrome known as the yeast syndrome or chronic candidiasis (see Ch. 48 ). TABLE 54-1 -- Factors associated with small intestinal bacterial overgrowth • Decreased digestive secretions —achlorhydria —hypochlorhydria —drugs which inhibit hydrochloric acid —pancreatic insufficiency —decreased bile output due to liver or gall bladder disease • Decreased motility —scleroderma (progressive systemic sclerosis) —systemic lupus erythematosus —intestinal adhesions —sugar-induced hypomotility —radiation damage • Low secretory IgA • Weak ileocecal valve The overgrowth of Candida is believed to cause a wide variety of symptoms in virtually every system of the body, with the gastrointestinal, genitourinary, endocrine, nervous, and immune systems being the most susceptible. Eventually this syndrome will be replaced by a more comprehensive term to include small intestinal bacterial overgrowth and the leaky gut syndrome. Treatment
Obviously, addressing the cause of the small intestinal bacterial overgrowth is the first step. The subject of decreased digestive secretions is discussed in Chapter 55 . The decreased motility is usually addressed by decreasing sugar consumption while increasing dietary fiber (see Ch. 57 for more in-depth discussion). [7] Restoring secretory IgA to normal levels involves eliminating food allergies (see Ch. 51 ) and enhancing immune function (see Ch. 53 ). Stress is particularly detrimental to secretory IgA. This effect offers an additional explanation as to why stressful events tend to worsen gastrointestinal function and food allergies. Pancreatic enzymes and botanical medicines containing berberine can be used to inhibit the bacteria growing in the small intestinal overgrowth. In addition to exerting broad-spectrum antibiotic activity (including activity against Candida albicans), berberine has been shown to inhibit the bacterial decarboxylase enzyme which converts amino acids into vasoactive amines. [8] Pancreatic enzymes, in addition to enhancing protein digestion, are largely responsible for keeping the small intestine free from bacteria as well as parasites (pathogenic bacteria, yeast, protozoa, and helminths). [9] A lack of proteases or other digestive secretions greatly increases an individual’s risk of having an intestinal infection including chronic Candida infections of the gastrointestinal tract.
COLON The large intestine is not significantly involved in digestion but does play a role in the absorption of water and electrolytes and provides temporary storage for waste products and the formation of stool. The health of the colon is largely determined by amount of dietary fiber and the proper elimination of waste products. (Irritable bowel syndrome is discussed in Ch. 165 , and Crohn’s disease and ulcerative colitis are fully covered in Ch. 163. ) Constipation An old-time naturopathic belief was that “disease begins in the colon”. There appears to be great wisdom in that statement: improper elimination of waste products has
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Dietary Physical inactivity
TABLE 54-2 -- Causes of constipation Highly refined and low-fiber foods, inadequate fluid intake Inadequate exercise, prolonged bed rest
Pregnancy Advanced age Drugs
Anesthetics, antacids (aluminum and calcium salts), anticholinergics (bethanechol, carbachol, pilocarpine, physostigmine, ambenonium), anticonvulsants, antidepressants (tricyclics, monoamine oxidase inhibitors), antihypertensives, anti-Parkinsonism drugs, antipsychotics (phenothiazines), beta-adrenergic blocking agents (propanolol), bismuth salts, diuretics, iron salts, laxatives and cathartics (chronic use), muscle relaxants, opiates, toxic metals (arsenic, lead, mercury)
Metabolic abnormalities
Low potassium stores, diabetes, kidney disease
Endocrine abnormalities
Low thyroid function, elevated calcium levels, pituitary disorders
Structural abnormalities
Abnormalities in the structure or anatomy of the bowel
Bowel diseases
Diverticulosis, irritable bowel syndrome (alternating diarrhea and constipation), tumor
Neurogenic abnormalities
Nerve disorders of the bowel (aganglionosis, autonomic neuropathy), spinal cord disorders (trauma, multiple sclerosis, tabes dorsalis), disorders of the splanchnic nerves (tumors, trauma), cerebral disorders (strokes, Parkinsonism, neoplasm)
Enemas (chronic use) serious health repercussions. Constipation regularly affects over 4 million people in the United States. [10] This high incidence translates to over $500 million in annual sales of laxatives. There are a number of possible causes of constipation, but the most common cause is a low-fiber diet ( Table 54.2 ). Treatment
While constipation will usually respond to a high-fiber diet, plentiful fluid consumption, and exercise, many sufferers of chronic constipation do not avail themselves of these healthful approaches and use laxatives instead. It is well accepted that increasing dietary fiber is an effective treatment of chronic constipation. High levels of dietary fiber increase both the frequency and quantity of bowel movements, decrease the transit time of stools, decrease the absorption of toxins from the stool, and appear to be a preventive factor in several diseases. Particularly effective in relieving constipation are bran and prunes. The typical recommendation for bran (oat preferable to wheat) is half a cup of bran cereal, increasing to 1.5 cups over several weeks. Whole prunes as well as prune juice possess good laxative effects. Eight ounces is usually an effective dose. Be sure that patients are consuming enough liquids. Prescribe the drinking of at least six to eight glasses per day. In addition, recommend the consumption of 25–35 g of fiber. When patients need additional support, consider using fiber formulas. These formulas act as bulking agents. They can be composed of natural plant fibers derived from psyllium seed, kelp, agar, pectin, and plant gums like karaya and guar. They can also be made from purified semi-synthetic polysaccharides like methyl-cellulose and carboxymethyl cellulose sodium. Psyllium-containing laxatives are the most popular and usually the most effective. If patients have been using stimulant laxatives, even natural ones like Cascara sagrada (Rhamnus purshiana) or senna (Cassia senna), they will need to “retrain” their bowels. Table 54.3 lists the recommended rules for re-establishing bowel regularity. The recommended procedure will take 4–6 weeks. Diverticular disease Most often the presence of diverticula is without symptoms; however, if the diverticula becomes inflamed, perforated, or impacted, symptomatic diverticulitis results. Only about 20% of people with diverticulosis develop diverticulitis. Symptoms of diverticulitis include episodes of lower abdominal pain and cramping, changes in bowel habits (constipation or diarrhea), and TABLE 54-3 -- Rules for bowel retraining • Find and eliminate known causes of constipation • Never repress an urge to defecate • Eat a high-fiber diet, particularly fruits and vegetables • Drink six to eight glasses of fluid per day
• Sit on the toilet at the same time every day (even when the urge to defecate is not present), preferably immediately after breakfast or exercise • Exercise for at least 20 minutes, three times per week • Stop using laxatives (except as discussed below to re-establish bowel activity) and enemas • Week 1: Every night before bed take a stimulant laxative containing either cascara or senna. Take the lowest amount necessary to reliably ensure a bowel movement every morning • Weekly: Each week decrease dosage by 50%. If constipation recurs, go back to the previous week’s dosage. Decrease dosage if diarrhea occurs
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a sense of fullness in the abdomen. In more severe cases, fever may be present along with tenderness and rigidity of the abdomen over the area of the intestine involved. Treatment
Treatment of diverticular disease involves the recommendation of a high-fiber diet. In severe cases of diverticulitis, an antibiotic may be warranted. Dysbiosis The microecology of the human gastrointestinal tract is an incredibly complex ecosystem as there are at least 500 different species of microflora that are part of the “normal” intestinal flora. [11] There are nine times as many bacteria in the gastrointestinal tract as there are cells in the human body. The type and number of gut bacteria play an important role in determining health and disease. A state of altered bacterial flora in the gut has become popularly known as “dysbiosis”. The term was first used by noted Russian scientist Elie Metchnikoff to reflect a state of living with intestinal flora that has harmful effects. He theorized that toxic compounds produced by the bacterial breakdown of food were the cause of degenerative disease. [12] There is a growing body of evidence that is supporting and refining Metchnikoff’s theory. The major causes of dysbiosis are listed in Table 54.4 . Obviously, treatment begins with addressing these major causes. In addition, it is important to re-seed the gastrointestinal tract with probiotics. The most important healthful bacteria are Lactobacillus acidophilus and Bifidobacterium bifidum (see Ch. 105 for a full discussion). The symbiosis or pathogenicity of the 500 normal microbial inhabitants of the human digestive tract is largely determined by the environment in which they live and the balance between the various types. Candida albicans is an example of an organism that, under normal circumstances, lives in harmony with the host, but if Candida overgrows and is out of balance with other gut microbes it can result in problems. In general, parasites TABLE 54-4 -- Causes of intestinal dysbiosis • Dietary disturbances —high protein —high sugar —high fat —low fiber —food allergies • Lack of digestive secretions • Stress • Antibiotic/drug therapy • Decreased immune function • Malabsorption • Intestinal infection • Altered pH cause most of their problems by interfering with digestion and/or damaging the intestinal lining, either of which can lead to increased mucous secretion and/or diarrhea. One of the most intriguing hypotheses explaining the balance and growth of the various organisms is the type of level of digestion of carbohydrates in the diet. The research in this area and clinical applications of modification of dietary carbohydrates are covered in a very interesting book, Breaking the Vicious Cycle, by nutritionist Elaine Gottschall. [13] The presence of undigested and unabsorbed carbohydrates within the small intestine and/or colon result in increased fermentation and overgrowth of certain, toxic species of bacteria. Not only is the production of gas increased, but so also is the production of short-chain organic acids, such as lactic acid, which are damaging to the intestinal mucosa. The damage to the intestinal mucosa aggravates the problem by decreasing the level of disaccharides (lactase, sucrase, isomaltase and, less often, maltase) in the lining cells, thus further increasing the levels of undigested disaccharides. As the gastrointestinal tissues become more damaged, mucous secretion increases, further separating complex carbohydrates from their digestive sites. Treatment involves the “specific carbohydrate diet”, which breaks the vicious cycle by only allowing carbohydrates that are either predigested or easily digested and virtually totally absorbed in the duodenum, making them unavailable to more distal bacteria. Basically, all disaccharides (e.g. lactose, sucrose), all grain starches (e.g. wheat, rice, corn syrup), and starchy vegetables (e.g. potatoes) are eliminated, as are most legume starches. Simple sugars such as glucose and fructose (found in honey, fruits, and some vegetables) and lactose-hydrolyzed milk products are allowed. Interestingly, although not acknowledged (all historic references are to conventional medical practitioners), several of these concepts were first promulgated by TABLE 54-5 -- Common protozoa and helminths Protozoa • Ameba • Giardia • Trichomonas • Cryptosporidium • Dientamoeba fragilis • Iodamoeba butschlii • Blastocystis • Balantidium coli • Chilomastix
Helminths • Roundworm (Ascaris lumbricoides) • Pinworm (Enterobius vermicularis) • Hookworm (Necator americanus) • Threadworm (Strongyloides stercoralis) • Whipworm (Trichuris trichiura) • Tapeworms (various species)
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Organism
TABLE 54-6 -- Incidence of parasites in 200,000 stool samples [14] Incidence Notes
Protozoa Giardia lamblia
7.2%
Significant increase from the 4% found in 1979; more than 9% of the specimens were located around the Great Lakes or in the north-west of the United States
Entamoeba coli and Endolimax 4.2% nana Blastocystis hominis
2.6%
Entamoeba histolytica
0.9%
Cryptosporidium species
0.2%
Nematodes Hookworm
1.5%
Trichuris trichiura
1.2%
Ascaris lumbricoides
0.8%
Clonorchis and Opisthorchis species
0.6%
Strongyloides stercoralis
0.4%
Hymenolepis nana
0.4%
Enterobius vermicularis
0.4%
Taenia species
0.1%
Tape tests positive for 11.4% of 9,597 specimens
“Professor” Arnold Erhardt at the turn of the century in his book The Mucousless Diet. Parasites Diarrheal diseases caused by parasites still constitute the greatest single worldwide cause of illness and death. The problem is more severe in underdeveloped countries with poor sanitation, but even in the United States diarrheal diseases are the third major cause of sickness and death. Furthermore, the ease and frequency of worldwide travel and increased migration to the United States is resulting in growing numbers of parasitic infections. In addition to normal inhabitants of the gastrointestinal system acting as parasites, there are also significant diarrheal diseases associated with protozoa and helminths ( Table 54.5 ). (One parasite, Ascaris lumbricoides is discussed in more detail in Ch. 131. ) The apparent incidence of the various parasites are listed in Table 54.6 . These data come from state diagnostic laboratories which evaluated over 200,000 stool specimens in 1987. Parasites were found in 20.1% of the stool samples. While the most commonly reported symptoms of parasitic infection are diarrhea and abdominal pain, these symptoms do not occur in every case ( Table 54.7 ). In fact, there appears to be a growing number of individuals experiencing milder than usual gastrointestinal symptoms due to parasitic infections and/or symptoms not traditionally considered to be linked to parasitic infections. For example, in many cases of the irritable bowel syndrome, indigestion, and poor digestion, parasites may be causing the symptoms. In addition, parasitic infections are often an unsuspected cause of chronic illness and fatigue. TABLE 54-7 -- Signs and symptoms of parasitic infections • Abdominal pain and cramps • Constipation • Depressed secretory IgA • Diarrhea • Fatigue • Fever • Flatulence • Food allergy • Foul-smelling stools • Gastritis • Headaches • Hives • Increased intestinal permeability • Indigestion • Irregular bowel movements • Irritable bowel syndrome • Loss of appetite • Low back pain • Malabsorption
• Weight loss
Treatment
A number of natural compounds can be useful in helping the body rid itself of parasites. However, before selecting a natural alternative to an antibiotic in parasitic infections, the underlying factors which may have been responsible for setting up the internal terrain for a parasitic infection, e.g. achlorhydria, decreased pancreatic enzyme output, etc., must be controlled. Proper treatment with either an antibiotic or a natural alternative requires monitoring by repeating multiple stool samples 2 weeks after therapy (see Ch. 131 for a more detailed therapy). The treatment of parasitic infections typically utilizes high dosages of pancreatic enzymes (10 × USP 750–1,000 mg, 10–20 minutes before meals) and berberine-containing
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plants such as Hydrastis canadensis, Berberis vulgaris, Berberis aquifolium, and Coptis chinensis. When using these plants, the dosage should be based on berberine content. As there is a wide range of quality, standardized extracts are preferred. Three times a day dosages are as follows: • dried root or as infusion (tea): 2–4 g • tincture (1:5): 6–12 ml (1.5–3 tsp) • fluid extract (1:1): 2–4 ml (0.5–1 tsp) • solid (powdered dry) extract (4:1 or 8–12% alkaloid content): 250–500 mg. These dosage recommendations result in a berberine dosage of 25–50 mg three times daily or a daily dosage of up to 150 mg. This dosage is consistent with the dosage range in the positive clinical studies in various parasitic infections (see Ch. 91 ). For children a dosage based on body weight is appropriate. The daily dosage would be the equivalent to 5–10 mg of berberine/kg body weight.
REFERENCES 1. Sawada
Y, Periera SP, Murphy GM, Dowling RH. Polyamines in the intestinal lumen of patients with small bowel bacterial overgrowth. Biochem Soc Trans 1994; 22: 392(S)
2. Henriksson 3. Sarker
SA, Gyr R. Non-immunological defense mechanisms of the gut. Gut 1990; 33: 1331–1337
4. Saltzman
JR, Kowdley KV, Pederosa MC et al. Bacterial overgrowth without clinical malabsorption in elderly hypochlorhydric subjects. Gastroenterol 1994; 106: 615–623
5. Rubinstein 6. Husebye 7. Russo
AEK, Blomquist L, Nord CE et al. Small intestinal bacterial overgrowth in patients with rheumatoid arthritis. Ann Rheum Dis 1993; 52: 503–510
E, Mark Z, Hasple J et al. Antibacterial activity of the pancreatic fluid. Gastroenterol 1985; 88: 927–932
E. Gastrointestinal motility disorders and bacterial overgrowth. J Intern Med 1995; 237: 419–427
A, Fraser R, Horowitz M. The effect of acute hyperglycemia on small intestinal motility in normal subjects. Diabetologia 1996; 39: 984–989
8. Watanabe
A, Obata T, Nagashima H. Berberine therapy of hypertyraminemia in patients with liver cirrhosis. Acta Med Okayama 1982; 36: 277–281
9. Rubinstein
E, Mark Z, Hasple J et al. Antibacterial activity of the pancreatic fluid. Gastroenterol 1985; 88: 927–932
10.
Sonnenberg A, Koch TR. Epidemiology of constipation in the United States. Dis Colon Rectum 1989; 32: 1–8
11.
Hentges DJ, ed. Human intestinal microflora. In: Health and disease. New York, NY: Academic Press. 1983
12.
Metchnikoff E. The prolongation of life. New York, NY: Arna Press. 1908 (1977 reprint)
13.
Gotschall E. Breaking the vicious cycle. Kirkton, Ontario: Kirkton Press. 1994
14.
Results of testing for intestinal parasites by state diagnostic laboratories, United States, 1987. Morbid Mortal Weekly Rep 1992; 40(SS-4): 25–30
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Chapter 55 - Maldigestion Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION Proper digestion, absorption, and elimination are necessary in order to gain the nutritional benefits from foods. Any disruption of these processes causes substantial, and usually progressive, health problems throughout the body. As discussed in several chapters in this textbook (e.g. Chs 7 , 21 , 31 , 57 , 131 , 163 , and 165 ), intestinal dysfunction is a common, yet inadequately recognized, problem. This chapter provides some overview of digestive dysfunction and ways to improve digestion. Intestinal dysfunction, independent of digestive dysfunction, is discussed in Chapter 54 . A full discussion of the various laboratory procedures for evaluation of digestive function can be found in Chapters 9 , 19 , and 23 .
THERAPEUTIC CONSIDERATIONS Indigestion The term indigestion is often used by patients to describe a feeling of gaseousness or fullness in the abdomen. It can also be used to describe “heartburn”. Indigestion can be attributed to a great many causes, including not only increased secretion of acid but also decreased secretion of acid and other digestive factors and enzymes. Indigestion is commonly treated with antacids and histamine (H 2 )-receptor antagonists either self-prescribed by patients or prescribed by medical practitioners. The use of these agents will typically raise the gastric pH above 3.5, effectively inhibiting the action of pepsin, the enzyme involved in protein digestion that can be irritating to the stomach. Although raising the pH can reduce symptoms, it also substantially impairs protein digestion and mineral disassociation. In addition, the change in pH can adversely effect gut microbial flora including the promotion of an overgrowth of Helicobacter pylori. Finally, most nutrition-oriented physicians believe that lack of acid, not excess, is the true culprit for most patients.
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According to surveys, most people use antacids to relieve symptoms of reflux esophagitis. [1] However, reflux esophagitis is most often caused by overeating, not excessive acid production. Other common causes include: • obesity • cigarette smoking • chocolate • fried foods • carbonated beverages • alcohol • coffee. These factors either increase intra-abdominal pressure or they decrease the tone of the esophageal sphincter. Chronic heartburn may also be a sign of a hiatal hernia. However, while 50% of people over the age of 50 have hiatal hernias, only 5% of patients with hiatal hernias actually experience reflux esophagitis. Perhaps the most effective treatment of chronic reflux esophagitis and symptomatic hiatal hernias is to utilize gravity. The standard recommendation is to simply place 4-inch blocks under the bedposts at the head of the bed. This elevation of the head is very effective in many cases. Another recommendation to heal the esophagus, is using deglycyrrhizinated licorice (DGL). Hypochlorhydria In the patient with chronic indigestion, rather than focus on blocking the digestive process with antacids, the natural approach to indigestion focuses on aiding digestion. Although much is said about hyperacidity conditions, a more common cause of indigestion is a lack of gastric acid secretion. There are many symptoms and signs that suggest impaired gastric acid secretion, and a number of specific diseases have been found to be associated with insufficient gastric acid output. [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] These are listed in Tables 55.1 and 55.2 . Several studies have shown that the ability to secrete gastric acid decreases with age. [13] [15] [16] Some studies found low stomach acidity in over half of those over the age TABLE 55-1 -- Common signs and symptoms of low gastric acidity • Bloating, belching, burning, and flatulence immediately after meals • A sense of “fullness” after eating • Indigestion, diarrhea, or constipation • Multiple food allergies • Nausea after taking supplements • Itching around the rectum • Weak, peeling, and cracked fingernails • Dilated blood vessels in the cheeks and nose • Acne • Iron deficiency • Chronic intestinal parasites or abnormal flora
• Undigested food in stool • Chronic candida infections • Upper digestive tract gassiness
TABLE 55-2 -- Diseases associated with low gastric acidity • Addison’s disease • Asthma • Celiac disease • Dermatitis herpetiformis • Diabetes mellitus • Eczema • Gall bladder disease • Graves’ disease • Chronic autoimmune disorders • Hepatitis • Chronic hives • Lupus erythematosus • Myasthenia gravis • Osteoporosis • Pernicious anemia • Psoriasis • Rheumatoid arthritis • Rosacea • Sjögren’s syndrome • Thyrotoxicosis • Hyper- and hypothyroidism • Vitiligo of 60. The best method of diagnosing a lack of gastric acid is the Heidelberg gastric analysis ( Ch. 19 ). [17] It has been suggested by Wright [18] that the response to a bicarbonate challenge during Heidelberg gastric analysis, not simply resting pH, is the true test of the functional ability of the stomach to secrete acid. Since the Heidelberg gastric acid analysis is not widely available, a clinical trial of HCl supplements can be used as described in Appendix 7 . Etiology
Like peptic ulcer disease, achlorhydria and hypochlorhydria have been linked to the overgrowth of the bacteria Helicobacter pylori. Approximately 90–100% of patients with duodenal ulcers, 70% with gastric ulcers, and about 50% of people over the age of 50 test positive for H. pylori.[19] The presence of H. pylori is determined by measuring the level of antibodies to H. pylori in the blood or saliva, or by culturing material collected during an endoscopy as well as measuring the breath for urea. More recently, a breath test has become available for assessment of current H. pylori activity. Low gastric output is thought to predispose to H. pylori colonization and H. pylori colonization increases gastric pH, thereby setting up a positive feedback scenario and increasing the likelihood for the colonization of the stomach and duodenum with other organisms. [20] Interestingly, there has been only scant research into the effects of antacids and H 2 -receptor antagonists on promoting H. pylori overgrowth.[21] Although the typical conventional medicine approach is to focus only on the infective agent, as usual host defense factors are equally or more important. Unfortunately,
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the research has focused on eradicating the organism and there is little information on protective factors against infectivity. Proposed protective factors against H. pylori-induced intestinal damage are maintaining a low pH and ensuring adequate antioxidant defense mechanisms. [22] [23] [24] Low levels of vitamin C and vitamin E and other antioxidant factors in the gastric juice not only appear to lead to the progression of H. pylori colonization, but also contribute to the ulcer formation since the mechanism by which H. pylori damages the stomach and intestinal mucosa is via oxidative damage. [25] Furthermore, antioxidant status and gastric acid output appear to explain the observation that most people infected with H. pylori do not develop peptic ulcer disease or gastric cancer. Deglycyrrhizinated licorice
Deglycyrrhizinated licorice (DGL) may prove useful for both eradicating the organism and stimulating increased host defense factors. DGL has shown good results in healing both duodenal ulcers and gastric ulcers (discussed more fully in Ch. 180 ). Rather than inhibit the release of acid, DGL stimulates the normal defense mechanisms that prevent ulcer formation. Specifically, DGL: [26] [27] • improves both the quality and quantity of the protective substances which line the intestinal tract • increases the life span of the intestinal cell • improves blood supply to the intestinal lining. The active components of DGL are believed to be flavonoid derivatives. These compounds have demonstrated impressive protection against chemically induced ulcer formation in animal studies. Several similar flavonoids have also been shown to inhibit H. pylori in a concentration-dependent manner. [28] In addition, unlike antibiotics, the flavonoids were also shown to augment natural defense factors which prevent ulcer formation. The activity of flavone, the most potent flavonoid in the study, was shown to be similar to that of bismuth subcitrate. Bismuth
Bismuth is a naturally occurring mineral that can act as an antacid as well as exert activity against H. pylori.[29] The best known and most widely used bismuth preparation is bismuth subsalicylate (e.g. Pepto-Bismol). However, bismuth subcitrate has produced the best results against H. pylori and in the treatment of nonulcer-related indigestion as well as peptic ulcers. [30] [31] In the United States, bismuth subcitrate preparations are available through compounding pharmacies (contact the International Academy of Compounding Pharmacists: 1-800–927–4227).
One of the key advantages of bismuth preparations over standard antibiotic approaches to eradicating H. pylori is that while the bacteria may develop resistance to various antibiotics it is very unlikely to develop resistance to bismuth. The usual dosage for bismuth subcitrate is 240 mg twice daily before meals. For bismuth subsalycilate the dosage is 500 mg four times daily. Bismuth preparations are safe when taken at prescribed dosages. Bismuth subcitrate may cause a temporary and harmless darkening of the tongue and/or stool. Bismuth subsalicylate should not be given to children recovering from the flu, chickenpox, or any other viral infection as it may mask the nausea and vomiting associated with Reye’s syndrome, a rare but serious illness. Pancreatic insufficiency Both physical symptoms and laboratory tests can be used to assess pancreatic function. Common symptoms of pancreatic insufficiency include abdominal bloating and discomfort, gas, indigestion, and the passing of undigested food in the stool. For laboratory diagnosis, the comprehensive stool and digestive analysis (discussed in Ch. 9 ) is quite useful. The most severe level of pancreatic insufficiency is seen in cystic fibrosis. Although cystic fibrosis is quite rare, mild pancreatic insufficiency is thought to be a relatively common condition, especially in the elderly. Pancreatic enzyme supplements
Pancreatic enzyme products are an effective treatment for pancreatic insufficiency and are widely used. Most commercial preparations are prepared from fresh hog pancreas (i.e. pancreatin) (see Ch. 101 for a full discussion). The dosage of pancreatic enzymes is based on the level of enzyme activity of the particular product as defined by the United States Pharmacopoeia (USP). A 1× pancreatic enzyme (pancreatin) product has in each milligram not less than 25 USP units of amylase activity, not less than 2.0 USP units of lipase activity, and not less than 25 USP units of protease activity. Pancreatin of higher potency is given a whole number multiple indicating its strength. For example, a full-strength undiluted pancreatic extract that is 10 times stronger than the USP standard would be referred to as 10× USP. Full-strength products are preferred to lower potency pancreatin products because lower potency products are often diluted with salt, lactose, or galactose to achieve desired strength (e.g. 4× or 1×). The dosage recommendation for a 10× USP pancreatic enzyme product is typically 350–1,000 mg three times/day immediately
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before meals when used as a digestive aid and 10–20 minutes before meals or on an empty stomach when anti-inflammatory effects are desired. Enzyme products are often enteric-coated. However, numerous studies have shown that non-enteric-coated enzyme preparations actually outperform enteric-coated products if they are given prior to a meal (for digestive purposes) or on an empty stomach (for anti-inflammatory effects). For vegetarians, bromelain, papain and enzymes extracted from Aspergillus oryzae can substitute for pancreatic enzymes.
REFERENCES 1. Graham 2. Bray
DY, Smith JL, Patterson DJ. Why do apparently healthy people use antacid tablets. Am J Gastroenterol 1983; 78: 257–260
GW. The hypochlorhydria of asthma in childhood. Br Med J 1930; i: 181–197
3. Rabinowitch 4. Carper 5. Rawls
WM, Butler TJ, Kilby JO, Gibson MJ. Gallstones, gastric secretion and flatulent dyspepsia. Lancet 1967; i: 413–415
WB, Ancona VC. Chronic urticaria associated with hypochlorhydria or achlorhydria. Rev Gastroent 1950; Oct: 267–271
6. Gianella 7. De
IM. Achlorhydria and its clinical significance in diabetes mellitus. Am J Dig Dis 1949; 18: 322–333
RA, Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections. Ann Int Med 1973; 78: 271–276
Witte TJ, Geerdink PJ, Lamers CB. Hypochlorhydria and hypergastrinaemia in rheumatoid arthritis. Ann Rheum Dis 1979; 38: 14–17
8. Ryle
JA, Barber HW. Gastric analysis in acne rosacea. Lancet 1920; ii: 1195–1196
9. Ayres
S. Gastric secretion in psoriasis, eczema and dermatitis herpetiformis. Arch Derm 1929; Jul: 854–859
10.
Dotevall G, Walan A. Gastric secretion of acid and intrinsic factor in patients with hyper and hypothyroidism. Acta Med Scand 1969; 186: 529–533
11.
Howitz J, Schwartz M. Vitiligo, achlorhydria, and pernicious anemia. Lancet 1971; i: 1331–1334
12.
Howden CV, Hunt RH. Relationship between gastric secretion and infection. Gut 1987; 28: 96–107
13.
Rafsky HA, Weingarten M. A study of the gastric secretory response in the aged. Gastroent 1946; May: 348–352
15.
Davies D, James TG. An investigation into the gastric secretion of a hundred normal persons over the age of sixty. Br J Med 1930; i: 1–14
16.
Baron JH. Studies of basal and peak acid output with an augmented histamine meal. Gut 1963; 3: 136–144
17.
Mojaverian P, Ferguson RK, Vlasses PH et al. Estimation of gastric residence time of the Heidelberg capsule in humans. Gastroenterology 1985; 89: 392–397
18.
Wright J. A proposal for standardized challenge testing of gastric acid secretory capacity using the Heidelberg capsule radiotelemetry system. J John Bastyr Col Nat Med 1979; 1: 2: 3–11
19.
Berstad K, Berstad A. Helicobacter pylori infection in peptic ulcer disease. Scand J Gastroenterol 1993; 28: 561–567
20.
Sarker SA, Gyr K. Non-immunological defense mechanisms of the gut. Gut 1992; 33: 987–993
21.
Stockbruegger RW, Seeberg S, Hellner L et al. Intragastric nitrites, nitrosamines, and bacterial overgrowth during cimetidine therapy. Gut 1982; 23: 1048–1054
22.
Shibata T, Imoto I, Taguchi Y et al. High acid output may protect the gastric mucosa from injury caused by Helicobacter pylori in duodenal ulcer patients. J Gastroenterol Hepatol 1996; 11: 674–680
23.
Rokkas T, Papatheodorou G, Karameris A et al. Helicobacter pylori infection and gastric juice vitamin C levels. Digestive Dis Sci 1995; 40: 615–621
24.
Phull PS, Price AB, Thorniley MS et al. Vitamin E concentrations in the human stomach and duodenum – correlation with Helicobacter pylori infection. Gut 1996; 39: 31–35
25.
Baik SC et al. Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. Cancer Res 1996; 56: 1279–1282
26.
van Marle J, Aarsen PN, Lind A, van Weeren-Kraner J. Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium. Eur J Pharmacol 1981; 72: 219–225
27.
Johnson B, McIssac R. Effect of some anti-ulcer agents on mucosal blood flow. Br J Pharmacol 1981; 1: 308
28.
Beil W, Birkholz C, Sewing KF. Effects of flavonoids on parietal cell acid secretion, gastric mucosal prostaglandin production and Helicobacter pylori growth. Arzneim Forsch 1995; 45: 697–700
29.
Kang JY, Tay HH, Wee A et al. Effect of colloidal bismuth subcitrate on symptoms and gastric histology in non-ulcer dyspepsia. A double blind placebo controlled study. Gut 1990; 31: 476–480
Marshall BJ, Valenzuela JE, McCallum RW et al. Bismuth subsalicylate suppression of Helicobacter pylori in non-ulcer dyspepsia: a double-blind placebo-controlled trial. Dig Dis Sci 1993; 38: 1674–1680 30.
31.
Lambert JR, Midolo P. The actions of bismuth in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 1997; 11(suppl 1): 27–33
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Chapter 56 - Non-pharmacological control of pain Richard Kitaeff MA ND DAc
INTRODUCTION Pain in its myriad forms is one of the most common symptoms for which patients seek relief. Acute pain is an unpleasant experience primarily associated with tissue injury, and the protective response patients have to pain provides the clinician with valuable diagnostic information. The reaction to pain is highly subjective and, as a function of higher centers, is extremely variable. It is influenced by many factors depending on the individual patient and his or her situation. When pain becomes chronic, the multifactorial influences (e.g. anxiety; depression; social, cultural, and economic factors; and secondary gain) play an even larger role. When treating a patient for pain, it is essential first to determine the primary cause, the pathogenesis, and secondary or contributing factors. The relief of pain may then be achieved by removal of the primary cause (e.g. cure of an infection), neutralization of the effect of the stimulus (e.g. emollients for an ulcer), relief of discomfort (e.g. biofeedback), suppression of the disease process (e.g. anti-inflammatory agents), and dulling or obliterating the sense of pain (e.g. analgesics or acupuncture). [1] Although the medical profession has chosen to emphasize the pharmacological methods of pain control, many non-pharmacological options are available. Their applicability and efficacy are documented below. (Although this chapter liberally utilizes childbirth pain control, the examples and concepts are generalizable to any situation involving acute and/or chronic pain.)
THE EXPERIENCE OF PAIN A psychological model Pain is generally acknowledged to be a complex physiological/psychological phenomenon. It involves motivational and emotional components and conceptual interpretation, which may or may not have their basis in actual nociception. Verbal reports of pain and associated
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behavioral responses are controlled, at least in part, by psychological, cultural, and situational factors. For acute pain, such as that of childbirth, in which the painful experience can be directly related to nociceptive input, a multiprocess feedback model can be considered. However, one must keep in mind the complexity of the psychological processes intervening between sen-sory event and observable response, ranging from the physiological to the social aspects of personality. These include: • elements of information processing • performance ability • attention • memory • expectancy • attitudes and beliefs • secondary gain • self-concept • designated sick roles. In the psychological model, the brain infers information from bodily signs and integrates this with existing personal and situational variables to direct behavior. When consideration must also be given to the interactions with interested observers, such as physicians, family members and birth attendants, who influence the interpretation with their own experiences and attitudes about pain, the complexity becomes even greater. According to this model, which does not differ in essence from a general model of stress, a primary appraisal of the personal danger or threat posed by the painful stressor is followed by a secondary appraisal of one’s ability to cope, based on emotional feedback, and contributions of situational and sociocultural response factors. On this basis, a woman in labor could choose to consider pain as “positive”, “functional”, or “creative”; “pain with a purpose”; or, alternatively, “part of a process involving injury”. [2] This conceptualization of painful stress suggests that intervention could be successful at several levels: cognitive patterning, physiological arousal associated with emotional stress, and control of environmental stimuli. Examples of appropriate strategies could be: cognitive coping skills such as restructuring and utilization of preparatory information and attention shifts; muscular relaxation, physical or electrical stimulation, and biofeedback techniques; and structuring of the environment in a way conducive to effective coping (such as by making it non-threatening and comfortable). [3] Neuropsychological mechanisms of pain According to research on the mechanisms of pain, pain can be treated not only by anesthetic blocks, surgical intervention and the like, but also by influencing the motivational-affective and cognitive factors as well. [4] The traditional specificity theory of pain, first enunciated by Descartes in the 17th century, holds that pain messages are conducted from specific pain receptors at the periphery through discrete pathways to pain centers in the brain. However, there are individual differences in pain responses, pain is not consistently stopped by cutting or blocking the “pain pathway”, and it is now known that non-painful types of stimulation will activate the A-delta and C fibers that are associated with pain. Therefore, later modifications of pain theory took into account patterning of nerve impulses over time to reflect differences in degree and intensity of stimuli and summation of signals from an extended area. [5] The currently accepted view of pain is the gate control theory of Melzack & Wall [6] , which they formulated in 1965. Based on neurological data and a categorization of the words used to describe pain, this theory conceptualizes the pain experience as having sensory-discriminative, motivational-affective, and cognitive-evaluative components or modalities, corresponding to different patterns of nervous impulses. Neurologically, a specialized cluster of nerve cells in the substantia gelatinosa of the spinal column is thought to operate like a valve or gate, controlling nerve signals before they evoke the perception of, and response to, pain. Besides this monitoring of sensory data in the central nervous system, gating is also influenced by the relative amount of activity in large-diameter (A-beta) and small-diameter (A-delta and C) nerve fibers. The large fibers tend to inhibit transmission, or close the gate, preventing pain, and the small fibers tend to facilitate transmission, or open the gate, resulting in pain. The fact that large fibers are activated by pressure, touch, massage, and vibration suggests a mechanism for such pain control techniques as acupressure, acupuncture, and transcutaneous electrical nerve stimulation (TENS). Such stimulation apparently closes the spinal gate via the large-fiber system. Melzack & Casey[4] expanded this theory by proposing the possibility of a higher level gate, in the reticular or limbic structures of the brain, that
probably mediates the drive to escape from unpleasant stimuli. At central nervous system levels, the biochemical mechanisms of gate control may involve the endorphins, natural morphine-like substances that have been implicated in the pain-controlling effects produced by acupuncture. [7] Pain in childbirth A psychological/social learning approach to pain emphasizes control of motivation, expectation, focus of attention, stress, and feelings of anxiety, depression and helplessness. Factors specifically operative in labor pain include these as well as social support and the physiological factors of hunger, rest, and muscular tension.
[8]
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All of these can contribute to the interpretation of pain being placed on the nociceptive message provided by uterine contractions. The influence of motivation on labor pain was effectively demonstrated in a prospective study of maternal attitudes toward pregnancy in 8,000 American women. One of the factors found to be strongly related to maternal attitude toward having a baby was the need for analgesics in labor. [9] Cultural conditioning may also be fundamental to the labeling of childbirth as painful. Throughout most of the world, analgesics are not required for labor; in fact, a Japanese anesthesiologist suggests that the idea of “painless delivery” is a strange one to his culture. [10] American women, on the other hand, “live through a largely self-fulfilling prophecy of birth as a painful, terrifying ordeal, and/or as a medical, drugged process over which they have no control”. [8] This relates to body fantasies of injury, brought about in a hospital environment where distress is an expected response to the expulsive reflex. [2]
PAIN CONTROL Moderating variables and psychological techniques Psychological strategies
The psychological strategies recommended for control of labor pain, many of them part of prepared childbirth programs, generally aim to provide control, communication, relaxation, attention focus, and support, as well as physical counter-stimuli. There is considerable psychological research supporting the use of these in the development of pain tolerance. The significance of various characteristics of an individual’s psychological profile has been studied by evaluating the effects on pain perception of such parameters as: • introversion-extroversion [11] [12] [13] • augmenters-reducers [14] • field dependence [15] [16] • repression-sensitization. [17] [18] [19] For example, on the repression-sensitization axis, repressors may be characterized as those who avoid having to cope with pain, while sensitizers have an obsessive need to cope. They like to be informed in advance about the situation and to have control over it. The superior initial tolerance exhibited by repressors in response to heat and pressure stimuli disappears in repeated trials, showing that the sensitizers’ predilection for challenge enables them to endure long-term pain better. The importance of individual difference variables is also illustrated by the observation that one-third of patients undergoing surgical operations do not request pain-killing medication. [20] This common ability to suppress pain indicates that not all surgical patients consider themselves passive victims. In fact, during the postoperative period, pain persists longer for those who accept medication. Cognitive strategies
The impetus for devising cognitive strategies to promote tolerance of pain has been particularly supported by investigations showing that pain tolerance increases with greater predictability and perception of control. [21] [22] [23] [24] [25] Similarly, preparatory communications and information received prior to the onset of experimental or surgical pain consistently decreases the subjects’ perception of pain. [26] [27] [28] [29] Animal studies have demonstrated higher rates of instrumental responses when painful shocks are signaled than when they are unsignaled. [30] Kanfer & Seidner[31] found that subjects who could advance slides of travel pictures at their own rate tolerated ice-water immersion of the hand longer than yoked subjects whose slides were changed by the experimenter. When surgery patients are given a sense of control by providing them with preparatory information concerning postsurgery discomforts and operative care, in combination with training in rehearsal of realistic, positive aspects of the surgical experience, they showed a significant reduction in postsurgical anxiety (as indicated by nurses’ observations), requests for sedatives, and length of hospital stay. [32] Furthermore, preparation for repeated peridontal surgery by auditory and visual messages classified as “control enhancement” was associated with reduction of pain after a second surgery. [33] Subjects who could cognitively redefine a threat of electric shocks as interesting new physiological sensations also reduced stress to a greater extent than subjects not provided with this coping strategy. [34] Meichenbaum and Turk developed a procedure utilizing “stress inoculation”. [35] It begins with an educational phase (in which subjects are given a conceptual framework for understanding the nature of their stressful reactions), followed by rehearsal of behavioral and cognitive coping skills, based on a set of coping self-statements generated by the client in collaboration with the therapist. Such cognitive-behavioral techniques, sometimes in combination with EMG biofeedback control, have been found successful in treatment of chronic low back pain. [36] [37] [38] Also, cognitive-behavioral strategies have been effective in alleviating the pain of irritable bowel syndrome, [39] temporomandibular joint syndrome,[40] cancer, [41] migraine headaches, [42] and rheumatic conditions. [43] This emphasis on conceptualization, preparatory information, and cognitive transformation seems to have been incorporated into the Read method of natural childbirth, which replaces fear with knowledge about birth. [8] Sheila
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Kitzinger, [2] in her method of prepared childbirth, similarly emphasizes the necessity of “acquiring knowledge and understanding of what labor involves, the terminology used by obstetricians and midwives, and information about what happens in hospitals”. A study by Stevens & Heide[35] conducted at the University of Wisconsin used ice-water to test perception and endurance of pain in subjects who had been taught methods used in childbirth education classes. The controls for this training and an additional control group offered only distraction during the tests. Those who had been taught the techniques reported only about half the pain of the controls and endured it 2.5 times longer. The prepared childbirth strategies improved with practice, were effective for pain lasting longer than most contractions in labor, and were more effective than distraction techniques. [44] However, this later finding introduces some confusion, since some prepared childbirth methods include either distraction techniques or some other deliberate disposition of one’s attention. Attention-focusing
Distraction of focused attention, mostly utilizing the rhythms of the breath, is essential to the Lamaze method, the most popular prepared childbirth program in America, and important in the Bradley and other methods. Sheila Kitzinger describes the controlled attention focusing as: [2] … concentration on what is happening, one’s response to it as a task, and visualization of what is being achieved by the work of the uterus during contractions. The focus may be on the fantasy of the contractions as a shape provided by actual objects (furniture, architectural details, flowers, a painting)
in the room, or a combination of these factors. Stevens & Heide [44] found that attention-focusing functions effectively as an analgesia for labor pain. Such strategies are strongly supported by much psychological research. The focus may be on a competing response, as in the Kanfer & Goldfoot [45] study showing that when attention was directed to self-presented external slides, individuals were able to increase their tolerance of the pain of cold water. Focus on a competing response is also shown in the use of hypnosis as an analgesic and in the meditative states of Raj yogis, who pinpoint attention on the tip of their nose or a point on the back of their skull, and then do not react physiologically to cold water, bright lights, or sudden sounds. [46] [47] Other adepts in unusual feats of pain tolerance, such as having spikes stuck through their skin, either maintain an unfocused attitude, without evaluation, or pinpoint attention totally on the pain, but without evaluation. [48] In such cases, the attitude of detachment from the pain can be reflected by an undisturbed EEG pattern of alpha or beta waves throughout performance of the feat. Relaxation training
Relaxation training is another essential element of pain control, and is found in all childbirth training programs. A considerable body of literature supports its importance in pain control, since a state of lowered autonomic arousal is incompatible with anxiety. While progressive muscular relaxation, systematic desensitization, and autogenic training are all well-established physiological approaches to muscular relaxation, meditation traditions provide quicker methods to achieve what Benson[49] has called, the “relaxation response”. One of the simplest meditation practices – maintaining a focal awareness of the flow of the breath – is taught by Rahima Baldwin in Special Delivery and is identical to the ancient Buddist practice of vipassana or insight meditation. Hypnosis
Hypnosis or auto-hypnosis is another method utilized to induce deep relaxation for pain control. It incorporates many of the therapeutic elements already referred to – focused attention, positive expectation, and a supportive or permissive attitude – in making suggestions that alleviate anxiety. Thus, its success in pain management may be viewed from a cognitive-behavioral perspective. [50] In one technique, “glove anesthesia” is induced in one hand and the “numb, heavy wooden feeling” so produced is transferred to the other hand, the face, and eventually to the abdomen in order to “relieve the discomfort” of uterine contractions (the word “pain” is never used, as this would be countersuggestive). [51] Control of environmental stress
Kitzinger[2] cites animal research to show how environmental stress can interfere with the physiological processes of labor and delivery. Education for childbirth therefore promotes verbal and non-verbal support from husband, obstetrician, midwife or anyone else who is part of the birthing environment. Touch relaxation and coaching techniques combine the essential elements of relaxation, massage counter-stimulus, and the direct supportive communication of a partner. [8] Several studies agree that comfort in labor is also enhanced by a more vertical position such as the squatting posture that is adopted in many other cultures.
[52] [53] [54]
Counter-stimulus methods: massage, acupuncture, TENS The hand reflexology method of grasping combs during labor to activate points on the fingertips and balls of the hand that relate to uterine functioning is one example of counter-stimulus strategy. [8] Foot reflexology, acupressure,
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acupuncture and transcutaneous electrical nerve stimulation (TENS) might also share a common autonomic nervous mode of operation. Transcutaneous electrical nerve stimulation (TENS)
The use of TENS to control pain during delivery has been evaluated by several studies. The method used in a Swedish study, which was subsequently replicated in Germany and Britain, was originally developed in the US by Shealy for the control of acute and chronic pain. [55] [56] Generally, the electrodes are placed over the painful area in order to stimulate the cutaneous nerves in that area. For use in labor, four electrodes are placed on either side of the midline of the spine to stimulate the posterior primary rami of the spinal segments (T11–L1 and S2–S4) receiving the painful stimuli during labor (it is interesting to note that these are the loci of acupuncture points (BL-20, BL-27, and BL-28) which are traditionally thought to reflect female reproductive function). The selection of this area for stimulation is based on Bonica’s account of the neurological mechanism of delivery pain. [57] During the first stage, pain receptors are assumed to be activated by contractions of the uterus and dilation of the cervix. The evoked impulses are mediated in afferents which run in the hypogastric nerves and reach the spinal cord via the dorsal roots T10–L1. The pain is referred to large areas of the abdomen and back. During the second stage, pain is also caused by distension and stretching of the delivery canal, the pelvic floor, the vulva, and the perineum. The pain is localized, and the impulses reach the spinal cord mainly via the pudendal nerves and the dorsal roots S2–S4. The pain during the first stage is characterized as an ache considered to be mediated in small-diameter C fibers. During the second stage, the pain has the more localized intensive nature usually identified with the delta-afferent fibers. [57] [58] In the typical application of this technique for control of pain during labor, low-intensity stimulation is given continuously and a high-intensity stimulation could be initiated by the parturient herself whenever pain increased. Stimulation via the thoracic electrodes is maintained throughout the delivery at an amplitude that is maximal for a pleasant sensation, whereas sacral stimulation is added from the later part of the first stage. Table 56.1 summarizes the uniformly good results which have been reported. It has been especially appreciated by those patients who complained of backache. An Austrian study compared the analgesic effects of TENS, pethidine and placebos on labor pain in 30 parturient women during the first stage of labor. No significant difference was found between the placebo, unspecific TENS, and control groups in the increase in pain during the test period. TABLE 56-1 -- The results of the use of TENS for pain control in labor Study
n
Good(%) Moderate(%) None(%)
Augustinsson et al [55]
147 44
44
12
Andersson et al [59]
27
48
37
15
Kanfer & Goldfoot [45]
35
20
62
18
Stewart[60]
67
31
56
13
Kubista et al[61]
102 55
24
21
Bundsen et al [62]
347 47
42
11
Patients who had received pethidine and those who had been given TENS experienced considerable relief of pain. [63] It is curious that apart from a passing reference by Shealy to its use in labor, no research on its obstetric application appeared for many years in any of the US literature. A 1996 review of 30 studies on TENS stimulation of acupuncture points in labor substantiated the conclusions of earlier research. [64] In view of the relatively good results and lack of complications, the consensus of all the above studies is that the TENS method is recommended as a primary pain-relieving measure, to which conventional methods can be added as needed. Robson [65] comments that TENS is non-invasive and is believed to be safe for both mother and baby. It is easy to apply and can be operated throughout labor by doctor, midwife, father, or mother. Augustinsson et al [55] were most impressed by the lack of complications, since the conventional methods, including analgesic and sedative drugs, N 2 O inhalation, epidural anesthesia and local blockades, all possess a varying degree of potential risks. [55] Another advantage is that TENS, since it does not give complete analgesia, does not eliminate pain as a diagnostic tool; it can be interrupted whenever needed for clinical evaluation. More importantly, perhaps, from the point of view of the woman in labor is the fact that her consciousness is
not altered to the point of excluding her own active participation in, and experience of, the delivery. Both Stewart [60] and Augustinsson et al[55] reported the method to be inadequate alone for analgesia in the second stage of labor. Augustinsson et al see this difference as possible support for the assumption that Cfiber-mediated pain is more amenable to blocking by electrical stimulation than is A fiber-mediated pain. Stewart mentions simply that many patients did not wish to use the stimulator at that time as it proved a distraction from their efforts to bear down. In this connection, it is interesting to note that “those who were well prepared and keen on natural childbirth were not always the most enthusiastic and, in fact, two of the early failures were patients who had been to relaxation classes.” [60] Robson [65] explains that TENS could distract some patients from their breathing or other focus of attention learned in courses.
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A related issue in the TENS literature is introduced by the comment of Andersson et al [59] that there was a correlation between the degree of hypnotisability and pain relief in their subjects. Such a correlation may, of course, imply only a susceptibility to any type of therapeutic effect. Neumark et al [63] tested this effect by including a placebo group that was given no current through the electrodes, and found that the result for the placebo group was not different from TENS applied non-specifically (i.e. incorrectly), but was significantly different from the effect of TENS placed over the relevant nerve distribution and from that of pethidine. Robson, [65] while making no attempt to assess a patient’s degree of susceptibility to hypnosis, switched off the machine for at least two contractions. All patients asked for it to be switched on again, indicating that the technique was providing pain relief. Augustinsson et al [55] consider the suggestive effect, if it occurs, to be of minor significance, since several investigators have found the pain-reducing effect of TENS to be achieved through demonstrable neurophysiological mechanisms. Stewart [60] points out that the increased personal contact between patient and attendant essential to the use of this method may introduce an element of suggestibility or distraction affecting the pain experience. Acupuncture
Hundreds of studies have investigated the efficacy and mechanisms of acupuncture analgesia for acute and chronic pain, in surgical operations, and in childbirth. In a review article of 24 studies, Lewith & Machin [66] found that the typical clinical trial showed a 70% efficacy when compared with placebo treatment. Reichmanis & Becker[67] found similar results in a review of 17 studies of acupuncture analgesia in experimentally induced pain. At the same time, somatosensory EEG-evoked potential studies have provided objective evidence of the analgesic effect of acupuncture. [68] [69] [70] Hyodo & Gega [10] of the Osaka Medical College have reviewed the literature (summarized in Table 56.2 ) on acupuncture anesthesia and analgesia in normal delivery and found mixed results. For example, Wallis et al [72] reported that while 19 of the 21 volunteer parturients
Study
TABLE 56-2 -- Results of acupuncture analgesia in the control of labor pain n Good(%) Poor or none(%)
Hyodo & Gega[10] Primapara
16 62.5
37.5
Multipara
16 93.7
7.3
Ito[71]
80 85
15
Wallis et al [72]
9–33
67–91
Abouleish & Depp[73]
80.5
19.5
considered acupuncture unsuccessful in providing analgesia for labor, one-third of them indicated that they would choose acupuncture analgesia in labor again. Some authors criticize the technique as being inconsistent, unpredictable, incomplete, time-consuming, and interfering with movement and electronic monitoring. In their own study, Hyodo & Gega [10] tested 32 patients, equally divided between primaparas and multiparas. Low-frequency electrical current was introduced through needles at LI-4, ST-36, and SP-6, a standard therapeutic repertory for sedation of the reproductive organs. The result, as assessed by relief noted by the patient as well as by the obstetrician’s observation, was 62.5% finding good or excellent effect on the subjective scale, and 62.6% good or excellent on the objective scale among the primapara; and 93.8% subjective relief, and 93.7% objective relief among the multipara. Overall, 90% of the cases experienced relief of pain within 20 minutes of initiation of acupuncture anesthesia. They noted the considerable disparity in reports of effectiveness of acupuncture from Japan and America, and explained it as a novelty effect: It is natural that in Japan, where no analgesic methods are normally used, the scoring in favor of acupuncture will be high compared with that in America. They concluded that it is useful for delivery, especially because of its safety, despite more erratic and less potent results than conventional anesthetic techniques.
[10]
A considerable amount of research has focused on determining a mechanism for acupuncture analgesia. A 1995 review of studies on acupuncture effects in pain and disease pointed out that, like exercise, acupuncture produces rhythmic discharges in nerve fibers and causes the release of endogenous opioids and oxytocin. Furthermore, “experimental and clinical evidence suggests that acupuncture may affect the sympathetic system via mechanisms of the hypothalamic and brain-stem levels”. [74] Animal studies continue to demonstrate that acupuncture analgesia is mediated in the central and peripheral nervous systems by opioid peptides. [75] [76] [77] The cortex and hippocampus appear to participate in the modulation of chronic pain, and the analgesic action of electroacupuncture seems to operate along this pathway.[76] A study carried out on dogs seems to verify the traditional theory of points of tonification and sedation, by differential production of sympathomimetic and parasympathomimetic effects on the cardiovascular system upon stimulation of different points. In a study of labor induction and inhibition by electroacupuncture, Tsuei et al [78] utilized SP-6 and SP-4 points, located in the territory of the L-4 dermatome. The spleen meridian, to which these loci belong, runs across the dermatomes of L-4, L-5, L-2, and L-1, and then upward from T-12 to T-5. Since the sympathetic nerve controlling the uterus through the pelvic plexus receives
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preganglionic fibers from T-5 to L-4, Tsuei et al concluded that it is highly possible that stimulation of the electropermeable loci within this area may alter the physiologic function of the uterus. [78] The LI-4 points of the upper extremities, often added to the spleen meridian points in the acupunctural control of labor pain, perhaps represent the central approach to the autonomic nervous system, since these loci control pain to the head and neck. It should be noted, however, that Motoyama[79] has attempted to verify the traditional subtle anatomy of meridian pathways through tests of electrocutaneous resistance at meridian points, and claims that these effects cannot be adequately explained in terms of the conventional sympathetic dermatomes, but imply an alternative bioelectric transmission system. The discovery of the Head McKenzie sensory zones has shown the possible mediation of the invisible meridians and points of traditional Eastern medicine between internal organs and corresponding skin areas. Nakatani [80] was able to detect the electropermeable line as an apparent viscerocutaneous autonomic nerve reflex when organic diseases are involved. Hyodo [81] has explained acupuncture stimulation as the transmission of impulses centrally from the reactive electropermeable loci, via a sympathetic afferent fiber, and the autonomic nerve in the viscera is stimulated to response by the reverse of the McKenzie theory.
CONCLUSION This chapter has presented many of the current non-pharmacological strategies for control of pain. Since the mechanism of pain perception has been shown to involve both physiological and psychological components, the optimal treatment might combine psychological factors of preparatory information, attention focus, relaxation, and supportive communication, in conjunction with the physical stimuli of transcutaneous electrical nerve stimulation or acupuncture. In fact, such a multidisciplinary approach to patients with chronic back pain was evaluated following a 4 week program which included back schooling, psychological intervention,
and treatment by acupuncture, chiropractic, the Alexander technique and a pain specialist. Significant improvement was maintained for a period of 6 months. [82] The selection, balance, and application of these treatment components should be based on consideration of an individual’s coping styles. Such a treatment program could be developed to provide a more consistently effective analgesia than the individual components can provide separately. Relieving the pain of childbirth, for example, without diminishing or distorting the full consciousness of the experience for the mother, would be consistent with the goals of the contemporary physician of natural medicine.
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Chapter 57 - Role of dietary fiber in health and disease Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION The appreciation of the role of diet in determining the level of health continues to grow. A substantial body of research has now well established that certain dietary practices cause, as well as prevent, a wide range of diseases. In addition, the research is now showing that certain diets and foods can provide immediate therapeutic benefit. This chapter discusses the major diseases of Western society and how they relate to one key component of the diet: dietary fiber. The dietary fiber hypothesis has two basic components: • a diet rich in foods which contain plant cell walls(i.e. whole grains, legumes, fruits, and vegetables) is protective against a wide variety of diseases, in particular those that are prevalent in Western society • a diet providing a low intake of plant cell walls is a causative factor in the etiology of these diseases and provides conditions under which other etiological factors are more active. The term “Western diet” is used throughout this chapter, as well as in many other parts of the textbook. It refers to the typical diet of Western peoples, also referred to as “foods of commerce”. It consists of a high intake of refined carbohydrates, saturated fats, processed foods, salt and cholesterol, and an extremely low intake of dietary fiber. The primitive diet
Detailed anatomical and historical evidence suggests that humans evolved as “hunter-gatherers” i.e. humans appear to be omnivores capable of surviving on both gathered (plant) and hunted (animal) foods. [1] However, while the human gastrointestinal tract is capable of digesting both animal and plant foods, there are indications that it functions better with plant foods. [2] There is a tremendous amount of evidence showing that
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deviating from a predominantly plant-based diet is a major factor in the development of heart disease, cancer, strokes, arthritis, and many other chronic degenerative diseases. It is now the recommendation of many health and medical organizations that the human diet should focus primarily on plant-based foods – vegetables, fruits, grains, legumes, nuts, seeds, etc. Such a diet is thought to offer significant protection against the development of chronic degenerative disease. [3] [4] [5]
DIETARY FIBER AND CHRONIC DEGENERATIVE DISEASE The belief in the beneficial effects of fiber in the diet goes back to at least 1585. However, the link between dietary fiber and chronic disease in the medical literature originated to a great extent from the work of two medical pioneers, Denis Burkitt MD and Hugh Trowell MD, authors of Western diseases: their emergence and prevention, which was first published in 1981. [3] Based on extensive studies examining the rate of diseases in various populations (epidemiological data) and his own observations of primitive cultures, Burkitt formulated the following sequence of events: • First stage. The primal diet of plant eaters contains large amounts of unprocessed starch staples; there are few examples of chronic degenerative diseases like osteoarthritis, heart disease, diabetes, and cancer. • Second stage. Commencing Westernization of diet, obesity and diabetes commonly appear in privileged groups. • Third stage. With moderate Westernization of the diet, constipation, hemorrhoids, varicose veins, and appendicitis become common complaints. • Fourth stage. Finally, with full Westernization ofthe diet, chronic degenerative diseases like osteoarthritis, rheumatoid arthritis, gout, heart disease, cancer, etc. are extremely common. Although now extremely well-recognized, the work of Burkitt and Trowell is actually a continuation of the landmark work of Weston A. Price, a dentist and author of Nutrition and physical degeneration. [6] In the early 1900s, Dr Price traveled the world observing changes in teeth and palate (orthodontic) structure as various cultures discarded traditional dietary practices in favor of a more “civilized” diet. Price was able to follow individuals as well as cultures over periods of 20–40 years, and carefully documented the onset of degenerative diseases as their diets became more Westernized. It is now well documented that diet is the major factor responsible for many chronic degenerative diseases. In 1984, the National Research Council’s Food and Nutrition Board established the Committee on Diet and Health and undertook a comprehensive analysis on diet and
Metabolic
TABLE 57-1 -- Diseases highly associated with a low-fiber diet Obesity, gout, diabetes, kidney stones, gallstones
Cardiovascular Hypertension, cerebrovascular disease, ischemic heart disease, varicose veins, deep vein thrombosis, pulmonary embolism Colonic
Constipation, appendicitis, diverticulitis, diverticulosis, hemorrhoids, colon cancer, irritable bowel syndrome, ulcerative colitis, Crohn’s disease
Other
Dental caries, autoimmune disorders, pernicious anemia, multiple sclerosis, thyrotoxicosis, dermatological conditions
major chronic diseases. [5] It is the Food and Nutrition Board which develops the Recommended Dietary Allowance (RDA) guidelines on the desirable amounts of essential nutrients in the diet. Their findings, as well as those of the US Surgeon General and other research groups, have brought to the forefront the need for Americans to change their eating habits to reduce their risk for chronic disease. Table 57.1 lists diseases with convincing links to a diet low in dietary fiber and plant foods. Many of these now common diseases were extremely rare before the 20th century. Trends in US food consumption During this century, food consumption patterns have changed dramatically: total dietary fat intake has increased from 32% of the calories in 1909 to 43% in 1985; overall carbohydrate intake dropped from 57 to 46%; and protein intake has remained fairly stable at about 11%. [5] Compounding these detrimental changes are the individual food choices accounting for the changes. There has been a rise in the consumption of meat, fats and oils, and sugars and sweeteners, in conjunction with the decreased consumption of non-citrus fruits, vegetables, potatoes, and grain products. These changes have resulted in the percentage of calories from starches or complex carbohydrates, as found naturally occurring in grains and vegetables, to drop from 68% in 1909 to 47% in 1980. Currently, more than half of the
carbohydrates being consumed are in the form of sugars (sucrose, corn syrup, etc.) being added to foods as sweetening agents. High consumption of refined sugars is linked to many chronic diseases, including obesity, diabetes, heart disease, and cancer.
DEFINITION AND COMPOSITION OF DIETARY FIBER Generally, the term “dietary fiber” refers to the components of plant cell wall and non-nutritive residues. Originally, the definition was restricted to substances that are not digestible by the endogenous secretions of the human digestive tract. This latter definition is specious, since it depends on an exact understanding of what exactly is not digestible.
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TABLE 57-2 -- Dietary fiber constituents of the food groups Main dietary fibers
Food group Fruits and vegetables
Cellulose, hemicellulose, lignin, pectic substances, cutin, waxes
Grains
Cellulose, hemicellulose, lignin, phenolic esters
Seeds (other than grains)
Cellulose, hemicellulose, pectic substances, guar endosperm
Seed husk of Plantago ovata
Arabinogalacturonosyl-phamno-xylan (mucilage)
Food additives
Gum arabic, alginate, carrageenan, carboxymethylcellulose
TABLE 57-3 -- Classification of dietary fiber Plant part Food sources
Fiber class
Chemical structure
I. Cellulose
Unbranched 1–4-beta- D-glucose polymer
Physiological effect
Principal plant wall Wheat bran component
Increases fecal weight and size
Plant cell walls
Oat bran
Increases fecal weight and size, binds bile acids
Karaya, gum arabic
Laxative
Guar, legumes, psyllium
Hydrocolloids that bind steroids and delay gastric emptying, heavy metal chelation
II. Non-cellulose polysaccharides A. Hemicelluloses
Mixture of pentose and hexose molecules in branching chains
B. Gums
Branched chain uronic acid containing polymers
C. Mucilages
Similar to hemicelluloses
D. Pectins
Mixture of methyl esterified galacturan, galactan, and arabinose in varying proportions
Citrus rind, apple, onion skin
As above
E. Algal polysaccharides
Polymerized D-mannuronicacid and L-glucuronic acid
Algin, agar, carrageenan
As above
III. Lignins
Non-carbohydrate polymeric phenylpropene
Endosperm of plant seeds
Woody part of plant
Wood (40–50%), wheat (25%), Antioxidants, anti-carcinogenic apple (25%), cabbage (6%)
The composition of the plant cell wall varies according to the species of plant. Typically, the dry cell wall contains 35% cellulose, 45% non-cellulose polysaccharides, 17% lignins, 3% protein, and 2% ash. [7] [8] [9] It is important to recognize that dietary fiber is a complex of these constituents, and supplementation of a single component does not substitute for a diet rich in high-fiber foods. However, in some clinical conditions the use of specific components is a useful adjunct to a healthy diet. Tables 57.2 and 57.3 summarize the classifications of dietary fibers. Cellulose
The best known dietary fiber component is cellulose. This unbranched 1–4-beta- D-glucose polymer ranges in size from 3,000 to 100,000 glucose units. It is a relatively insoluble, hydrophilic material. This ability to bind water accounts for its effect of increasing fecal size and weight. Although undigestible by humans, it is partially degraded by the microflora of the gut. This anaerobic process (fermentation) occurs in the colon, results in the degradation of about 50% of the cellulose, and is an important source of short-chain fatty acids (SCFAs). [7] [8] SCFAs have very important properties in the colon, as discussed below. Non-cellulose polysaccharides
The majority of polysaccharides in the plant cell wall are a non-cellulose type, i.e. they are water-soluble and posses diverse properties. Included in this class are hemicelluloses, gums, mucilages, algal polysaccharides, and pectin substances. [7] [8] [9] Hemicelluloses
These compounds contain a mixture of pentose and hexose molecules in branched-chain configurations of much smaller size than cellulose. Their ability to increase fecal weight is dependent on the pentose fraction. The hemicelluloses are also an important source of SCFAs via bacterial degradation. [7] [8] [9] Pectin and pectin-like substances
Pectins are found in all plant cell walls as well as in the outer skin and rind of fruits and vegetables. For example,
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the rind of an orange contains 30% pectin; an apple peel 15%; and onion skins 12%. The gel-forming properties of pectin are well known to anyone who has made a jelly or jam. These same gel-forming qualities are responsible for the cholesterol-lowering effects of pectins. Pectins lower cholesterol by binding the cholesterol and bile acids in the gut and promoting their excretion. [7] [8] [9] Gums
Plant gums are a complex group of water-soluble, branched-chain, uronic acid-containing polymers. They are produced by the plant in response to injury, and are commercially produced by incising a plant or tree and collecting the fluid extract. Gums are used as emulsifiers, thickeners, and stabilizers by the food industry and as laxatives in pharmaceuticals. [7] [8] [9]
Mucilages
Structurally, mucilages resemble the hemicelluloses, but they are not classed as such due to their unique location in the seed portion of the plant. They are generally mixed with the endosperm of the plant seeds, where they retain water, preventing seed desiccation. Guar gum, found in leguminous plants, is the most widely studied mucilage. It is isolated from the endosperm of Cyamopsis tetragonolobus, a plant cultivated in India for livestock feed. It is used commercially as a protective colloid, stabilizer, thickening and film-forming agent for paper sizing, cheese, salad dressings, ice cream, soups, toothpaste, pharmaceutical jelly, lotion, skin cream, and tablets. It is also used as a laxative. Guar gum and other mucilages are perhaps the most potent cholesterol-lowering agents of the gel-forming hydrocolloids, including pectin and glucomannan. Guar gum has been shown to reduce fasting and postprandial glucose and insulin levels in both healthy and diabetic subjects; and it has decreased body weight and hunger ratings when taken with meals by obese subjects. Psyllium seed husk (Plantago ovata) is another example of a mucilage which is widely used as a bulking and laxative agent. [7] [8] Algal polysaccharides
Included in this category are alginic acid, agar, and carrageenan. Marine-derived polysaccharides are used extensively by the food industry. Alginate has been shown to inhibit heavy metal uptake in the gut, as do other gel-forming fibers. Agar is used as a thickening agent and as a gel for holding microbiological media. It has laxative and fecal bulk-increasing activity. [7] [8] Carrageenan is used in milk and chocolate products due to its ability to react with milk proteins. However, unlike other plant polysaccharides, it adversely affects the intestinal mucosa. [7] [8] It has been shown in rats to induce ulcer formation in the cecum, due to the promotion of mucosal macrophage release of lysosomal enzymes. Other rat studies have shown carrageenan to enhance carcinogen induction of neoplasia, colerectal carcinoma, birth defects, and hepatomegaly. [10] Lignins and lignans
Lignins are composed of aromatic polymers of conyiferyl, para-coumaryl, and sinapyl alcohols in varying ratios. Vanillin (artificial vanilla) and other aromatic chemicals are synthesized from lignins. Lignans are fiber compounds related to lignins that are typically composed of cinnamic acid, cinnamyl alcohol, propenylbenzene, and allylbenzene precursor units. Many plant lignans show important properties, such as anticancer, antibacterial, antifungal, and antiviral activity. Plant lignins are metabolized by the gut flora into the animal lignins enterolactone and enterodiol, both of which posses anti-estrogenic activity and are believed to be protective against cancer. [11] Phytic acid
In the plant, phytic acid (inositol hexaphosphoric acid) is responsible for storing minerals such as calcium, phosphorus, magnesium, and potassium. There is some concern that phytates can adversely affect the uptake and utilization of many minerals, including calcium, iron, and zinc. The major sources of phytate in the diet are cereal grains and legumes (see Table 57.4 ). Phytate is destroyed by heat and by the enzyme phytase during the leavening of bread. [7] [8] Phytic acid exerts impressive antioxidant and antitumor effects. [12] [13] [14] When administered in drinking water or injected, phytic acid has demonstrated a consistent antitumor effect in animals against colon cancer and fibrosarcomas. Clinical trials in humans are in preparation.
Plant phytic acid
TABLE 57-4 -- Occurrence of phytic acid in plant tissues Percentage dry weight
Soybeans
1.4
Wheat
0.9
Corn
1.1
Rice
0.9
Peanuts
1.9
Sesame seeds
5.4
Lima beans
2.5
Barley
1.0
Oats
0.8
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TABLE 57-5 -- Beneficial effects of dietary fiber • Decreased intestinal transit time • Delayed gastric emptying resulting in reduced postprandial hyperglycemia • Increased satiety • Increased pancreatic secretion • Increased stool weight • More advantageous intestinal microflora • Increased production of short-chain fatty acids • Decreased serum lipids • More soluble bile
PHYSIOLOGICAL EFFECTS OF DIETARY FIBER It is beyond the scope of this chapter to detail all known effects of dietary fiber on humans. Instead, we will cover effects of greatest clinical significance (stool weight, transit time, digestion, colon function, short-chain fatty acids, and colon flora). Beneficial effects of dietary fiber are given in Table 57.5 . Stool weight and transit time
Fiber has long been used in the treatment of constipation. Dietary fiber, particularly the water-insoluble, hydrophilic fibers such as cellulose (e.g. bran), increases stool weight as a result of their water-holding properties. [7] [8] [9] Transit time, the time taken for passage of material from the mouth to the anus, is greatly reduced on a high-fiber diet. Cultures consuming a high-fiber diet (100–170 g/day) usually have a transit time of 30 hours and a fecal weight of 500 g. In contrast, Europeans and Americans who eat a typical, low-fiber diet (20 g/day) have a transit time of greater than 48 hours and a fecal weight of only 100 g. [3] [15] Interestingly, when fiber is added to the diet of subjects with abnormally rapid transit times (less than 24 hours) it causes slowing of the transit time. [7] [8]
Dietary fiber’s effect on transit time is apparently directly related to its effect on stool weight and size. A larger, bulkier stool passes through the colon more easily, requires less intraluminal pressure, and subsequently less straining. [1] [2] [3] [4] It has been hypothesized that the decreased intraluminal pressure (due to the greater leverage the colon mucosa has on a larger stool) results in less hydrostatic stress on the colon wall and therefore avoids the ballooning effect, which results in diverticuli. The increased intestinal transit time associated with the Western diet allows prolonged exposure of various compounds, both natural and man-made, to the intestinal flora, resulting in increased conversion to potential carcinogens. [3] [4] [7] [8] Digestion
Although dietary fiber increases the rate of transit through the GI tract, it slows gastric emptying, thus reducing postprandial hyperglycemia in both normal and diabetic subjects.[7] [8] Pancreatic enzyme secretion and activity also increase in response to fiber, although excessive levels of fiber (greater than 10% of the meal by weight) have a converse effect. [16] A number of research studies have examined the effects of fiber on mineral absorption. Although the results have been somewhat contradictory, it now appears that large amounts of dietary fiber may result in impaired absorption and/or negative balance of some minerals. While fiber as a dietary component does not appear to interfere with the minerals in other foods, supplemental fiber, especially hemicelluloses, may result in a negative mineral balance. [2] [3] [4] Short-chain fatty acids (SCFAs)
The fermentation of dietary fiber by the intestinal flora produces three main end products: • short-chain fatty acids • various gases • energy. The SCFAs, acetic, proprionic, and butyric acids, are the main anions in the large intestine and have many important physiological functions. For every 20 g of fiber consumed each day, approximately 200 mmol of SCFAs will be produced, of which 62 will be acetate, 25 proprionate, and 16 butyrate. [8] Proprionate and acetate are transported directly to the liver and utilized for energy production, while butyrate provides an important energy source for the colonic mucosa. In fact, butyrate is the preferred substrate for energy metabolism in the distal colon. [7] [8] Butyrate production may also be responsible for the anti-cancer properties of dietary fiber. [7] [8] [17] Even at extremely low concentrations, butyrate has been shown, in vitro, to profoundly affect gene expression and other nucleic processes, such as DNA synthesis, resulting in suppressed cell proliferation in both normal and malignant cells. Butyrate causes trophic effects on normal colonocytes, stops the growth of neoplastic colonocytes, inhibits the pre-neoplastic hyperproliferation induced by certain tumor promoters in vitro, inhibits the expression of certain protooncogenes and causes differentiation of colon cancer cell lines. [18] Some of these effects are due to the acetylation of histones and the stabilization of the chromatin structure. Short-chain fatty acids are exhibiting impressive anti-cancer results in both animal and human experiments. [17] Butyrate is also being used in enemas in the treatment of ulcerative colitis. Certain fibers appear to be more effective than others in increasing the levels of SCFAs in the colon. Pectins (both apple and citrus, guar gum and other legume fibers) and vegetable fiber isolates produce more SCFAs than wheat fiber, corn fiber or oat bran. [7] [8]
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Intestinal bacterial flora
Dietary fiber appears to improve all aspects of colon function. Of central importance is the role it plays in maintaining a “suitable” colonic bacterial flora. A low-fiber intake is associated with both an overgrowth of Enterobacteriaceae and other endotoxin-producing bacteria and a lower percentage of Lactobacillus and other acidophilic bacteria. [7] [8] A diet high in dietary fiber promotes acidophilic bacteria through the increased synthesis of colonic SCFAs, which reduces the colon pH, a condition conducive to the growth of beneficial bacteria.
DISEASES ASSOCIATED WITH A LOW-FIBER DIET Because of the important physiological effects of dietary fiber, a diet low in dietary fiber will obviously lead to altered physiology or disease. The diseases with the strongest correlation with a lack of dietary fiber are diseases of the colon and gastrointestinal tract, heart disease and gallstones, obesity, and diabetes. Each of these will be briefly discussed below. Diseases of the colon and gastrointestinal disorders
The epidemiological and experimental data documenting the protective effect of dietary fiber on colon cancer are overwhelming. There is evidence for similar strong links with other common diseases of the colon – diverticulitis, diverticulosis, irritable bowel syndrome, ulcerative colitis, and appendicitis as well as hemorrhoids, peptic ulcers, and hiatal hernia. [3] [4] [7] [8] Furthermore, these very same diseases will often respond to a high fiber diet. Heart disease and gallstones
Dietary fiber has been shown to be quite protective against heart disease and gallstones. A diet high in dietary fiber is known to reduce total cholesterol and triglyceride levels while increasing HDL-cholesterol levels and the production and storage of less saturated bile acids. [3] [4] [7] [8] The binding of bile acids and micellar components to various grains, food fibers, and isolated fiber compounds results in the reduction of the enterohepatic circulation of bile salts and cholesterol. Loss of cholesterol and bile salts through the feces is the major pathway for elimination of these compounds from the body. Dietary fiber also decreases cholesterol biosynthesis and increases the conversion of cholesterol to the bile acids via activation of the vitamin C-dependent enzyme 7-alpha-hydroxylase, the rate-limiting step in bile acid synthesis. [7] [8] This enhancement of bile acid synthesis and excretion is the result of dietary fiber’s preferential binding of deoxycholic acid, resulting in a compensatory increase in circulating levels of chenodeoxycholic acid. Chenodeoxycholic acid has been shown to inhibit cholesterol absorption and synthesis at its rate-limiting enzyme HMG-CoA reductase. [8] Binding of chenodeoxycholic acid by dietary fiber results in an increase in the taurocholate to glycocholate ratio. The ultimate result of these alterations in bile salt concentrations and ratios is a less saturated bile which solubilizes cholesterol more effectively and is resistant to stone formation. Obesity
A dietary fiber-deficient diet is an important etiological factor in the development of obesity.
[3] [ 4] [ 7] [ 8]
Dietary fiber plays a role in preventing obesity by:
• increasing the amount of necessary chewing, thus slowing the eating process • increasing fecal caloric loss • altering digestive hormone secretion • improving glucose tolerance • inducing satiety by increased gastric filling, stimulation of cholecystokinin release, and intestinal bulking action. Other effects of dietary fiber on obesity are discussed below under diabetes mellitus – 60–90% of type II diabetics are obese.
Diabetes mellitus
Epidemiological and experimental data show diabetes mellitus to be one of the diseases most clearly related to inadequate dietary fiber intake. [3] [4] [7] [8] Clinical trials that have demonstrated the beneficial therapeutic effect of dietary fiber on diabetes have further substantiated this association (discussed below). Dietary fiber’s prevention and modulation of diabetes is due to its effects on glucose and, subsequently, insulin levels. A high-complex carbohydrate, high-fiber diet reduces postprandial hyperglycemia (largely by delaying of gastric emptying and thereby reducing insulin secretion) and increases tissue sensitivity to insulin (how, or if, this relates to chromium uptake and metabolism has not been determined). [7] [8] Fermentation products of fiber, chiefly SCFAs, enhance hepatic glucose metabolism and may further contribute to the ameliorating effects of dietary fiber on diabetes.
CLINICAL USE OF DIETARY FIBER The best and most cost-effective way of using dietary fiber in a clinical setting is via encouraging a diet rich in plant foods (see Table 57.6 for the dietary fiber content of selected foods). A good goal for dietary fiber intake
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Food
TABLE 57-6 -- Dietary fiber content of selected foods Serving
Calories Grams of fiber
Fruits Apple (with skin)
1 medium
81
3.5
Banana
1 medium
105
2.4
Cantaloupe
¼ melon
30
1.0
Cherries (sweet)
10
49
1.2
Grapefruit
½ medium
38
1.6
Orange
1 medium
62
2.6
Peach (with skin)
1
37
1.9
Pear (with skin)
½ large
61
3.1
Prunes
3
60
3.0
Raisins
¼ cup
106
3.1
Raspberries
½ cup
35
3.1
Strawberries
1 cup
45
3.0
Bean sprouts
½ cup
13
1.5
Celery (diced)
½ cup
10
1.1
Cucumber
½ cup
8
0.4
Lettuce
1 cup
10
0.9
Mushrooms
½ cup
10
1.5
Pepper (green)
½ cup
9
0.5
Spinach
1 cup
8
1.2
Tomato
1 medium
20
1.5
Asparagus (cut)
1 cup
30
2.0
Beans (green)
1 cup
32
3.2
Broccoli
1 cup
40
4.4
Brussels sprouts
1 cup
56
4.6
Cabbage (red)
1 cup
30
2.8
Carrots
1 cup
48
4.6
Cauliflower
1 cup
28
2.2
Corn
½ cup
87
2.9
Kale
1 cup
44
2.8
Parsnip
1 cup
102
5.4
Potato (with skin)
1 medium
106
2.5
Potato (without skin)
1 medium
97
1.4
Spinach
1 cup
42
4.2
Sweet potatoes
1 medium
160
3.4
Zucchini
1 cup
22
3.6
Baked beans
½ cup
155
8.8
Dried peas (cooked)
½ cup
115
4.7
Kidney beans (cooked)
½ cup
110
7.3
Lima beans (cooked)
½ cup
64
4.5
Lentils (cooked)
½ cup
97
3.7
Navy beans (cooked)
½ cup
112
6.0
1 muffin
104
2.5
Vegetables (raw)
Vegetables (cooked)
Legumes
Rice, breads, pastas, and flour Bran muffins
Bread (white)
1 slice
78
0.4
Bread (whole wheat)
1 slice
61
1.4
Crisp bread, rye
2 crackers
50
2.0
Rice, brown (cooked)
½ cup
97
1.0
Rice, white (cooked)
½ cup
82
0.2
Spaghetti (reg. cooked)
½ cup
155
1.1
Spaghetti (whole wheat, cooked)
½ cup
155
3.9
All-Bran
½ cup
71
8.5
Bran Chex
? cup
91
4.6
Corn Bran
? cup
98
5.4
Cornflakes
1¼ cup
110
0.3
Grape Nuts
¼ cup
101
1.4
Oatmeal
¾ cup
108
1.6
Raisin Bran-type
? cup
115
4.0
Shredded Wheat
? cup
102
2.6
Breakfast cereals
Nuts Almonds
10 nuts
79
1.1
Filberts
10 nuts
54
0.8
Peanuts
10 nuts
105
1.4
is 25–35 g daily. This can easily be achieved if the dietary focus is on whole, unprocessed, plant foods. In addition to the well-known use of dietary fiber as a laxative, the principle use of supplemental dietary fiber is in the treatment of irritable bowel syndrome and other functional disturbances of the colon, elevated cholesterol levels, and obesity. The best fiber sources for non-laxative effects are psyllium, guar gum, glucomannan, gum karaya, and pectin, because they are rich in water-soluble fibers. While there are many fiber supplements to choose from, the most clinically effective are those that are rich in water-soluble fiber and low in added sugar or other sweeteners. Irritable bowel syndrome
The treatment of irritable bowel syndrome (IBS) by increasing the intake of dietary fiber has a long, although irregular, history. In general, consuming a diet rich in complex carbohydrates and dietary fiber while avoiding sugar and refined foods is effective in many cases. The most effective fiber supplements are the water-soluble forms. However, the type of fiber often used in both research and clinical practice is wheat bran. [1] As wheat is among the most commonly implicated foods in malabsorptive and allergic conditions, the use of wheat bran is usually not indicated in individuals with symptoms of IBS since food allergy is a significant causative factor in this condition. In addition, while patients with constipation are likely to respond to wheat bran, those with diarrhea may actually worsen their symptoms. Elevated cholesterol levels
A recent review article concluded that soluble-fiber supplementation was very effective in lowering cholesterol levels. [19] Specifically, a significant reduction in the level of serum total cholesterol was found in 68 of the 77 (88%) studies reviewed. The effect of soluble fiber supplementation was clearly dose-dependent. In other words, the higher the intake of soluble fiber, the greater the reduction in serum cholesterol. The average doses and reductions noted in clinical trials are shown in Table 57.7 . Many of the studies utilized oat bran or oatmeal as
Fiber Oat bran (dry)
Dosage (g)
TABLE 57-7 -- Cholesterol-lowering effects of various fibers Typical reduction in total cholesterol
50–100
20%
Guar gum
9–15
10%
Pectin
6–10
5%
Psyllium Vegetable fiber
10–20 27
10–20% 10%
514
the source of fiber. The overwhelming majority of these studies demonstrated that individuals with high cholesterol levels will experience significant reductions with frequent oatmeal or oat bran consumption. In contrast, individuals with normal or low cholesterol levels will experience little change. In individuals with high cholesterol levels (above 220 mg/dl) the consumption of the equivalent of 3 g of soluble oat fiber lowers total cholesterol by 8–23%. This is highly significant as with each 1% drop in serum cholesterol level there is a 2% decrease in the risk of developing heart disease. Three grams of fiber would be provided by approximately one bowl of ready-to-eat oat bran cereal or oat meal. Although oatmeal’s fiber content (7%) is less than that of oat bran (15–26%), it has been determined that the polyunsaturated fatty acids contribute as much to the cholesterol-lowering effects of oats as the fiber content. Although oat bran has a higher fiber content, oatmeal is higher in polyunsaturated fatty acids. In practical terms, the dosage level for dry oat bran would be ?–1 cup; for dry oatmeal 1–1? cups. [19] [20] Obesity
When taken with water before meals, water-soluble fiber sources bind to the water in the stomach to form a gelatinous mass that makes an individual feel full. As a result, they will be less likely to overeat. However, the benefits of fiber go well beyond this mechanical effect. Fiber supplements have been shown to enhance blood sugar control and insulin effects, as well as actually reduce the number of calories absorbed by the intestines. [7] In some of the clinical studies demonstrating weight loss, fiber supplements were shown to reduce the number of calories absorbed by 30–180 calories/day. Over the course of a year, this could result in a reduction of 3–18 pounds. The most impressive results in weight loss studies have been achieved with guar gum, a water-soluble fiber obtained from the Indian cluster bean ( Cyamopsis tetragonoloba). In one study, nine women weighing between 160 and 242 pounds were given 10 g of guar gum immediately before lunch and dinner. They were told not to consciously alter their eating habits. After 2 months, the women reported an average weight loss of 9.4 pounds – over 1 pound/week. Reductions were also noted for cholesterol and triglyceride levels. [21] It is estimated that a person will lose 50–100% more weight by supplementing their diet with fiber than by simply
restricting calories alone (see Table 57.8 for information on clinical studies of the treatment of obesity with dietary fiber supplements). Cancer prevention
The body of research documenting the cancer-preventing effects of a high-fiber diet has continued to accumulate. In addition to the epidemiological associations, researchers have now also performed prospective and supplementation studies. Virtually every study has shown a significant protective effect of dietary fiber for a wide range of cancers. Several recent studies have shown benefit for prevention of breast cancer. One representative study evaluated the association between breast cancer and dietary intake in two Chinese populations (Shanghai and Tianjin) who are at low risk for breast cancer. These populations have one-fifth the rate of breast cancer of US white women. There were two case-controlled studies. In the 834 women studied, the intake of crude fiber, carotene and vitamin C showed a strong significant inverse association with breast cancer risk. The effect was closely associated with the intake of green vegetables. The women in the lowest tertile intake of crude fiber intake and the highest tertile intake of fat intake had a 2.9-fold increased risk for breast cancer relative to those in the highest tertile of crude fiber intake and the lowest tertile of fat intake. [33] The same protective effect has also been found in
Fiber
Number of subjects
TABLE 57-8 -- Clinical studies of the treatment of obesity with dietary fiber supplements Length of Dosage Calorie Average weight loss (fiber) Average weight loss study (g/day) Restriction (lbs) (placebo)
Guar
9
2 months
20
None
9.4
No placebo group
21
Guar
7
1 year
20
None
61.9
No placebo group
22
Guar
21
2.5 months
20
None
15.6
No placebo group
23
Guar
33
2.5 months
15
None
5.5
0.9 lbs
24
Glucomannan 20
2 months
3
None
5.5
Weight gain of 1.5 lbs
25
Glucomannan 20
2 months
3
None
8.14
0.44 lbs
26
Citrus Pectin
14
4 weeks
5.56
Yes
12.8
No placebo group
27
Mixture A
60
12 weeks
5
Yes
18.7
14.7 lbs
28
Mixture A
89
11 weeks
10
Yes
13.9
9.2 lbs
29
Mixture B
45
3 months
7
Yes
13.6
9 lbs
30
Mixture B
97
3 months
7
Yes
10.8
7.3 lbs
31
Mixture B
52
6 months
7
Yes
12.1
6.1 lbs
32
Reference
Mixture A, 80% fiber from grains/20% fiber from citrus; mixture B, 90% insoluble/10% soluble fiber from beet, barley, and citrus fibers.
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fibrocystic disease of the breast. In a study of the diet of 354 women with benign proliferative epithelial disorders of the breast who were compared with 354 matched controls and 189 unmatched controls, an inverse association between dietary fiber and the risk of benign, proliferative, epithelial disorders of the breasts was observed.[34] The protective effects of supplemental dietary fiber have now been demonstrated, even in those with previous colon cancer. A total of 411 patients with colorectal adenomas were placed on a 25% fat content diet, supplemented with 25 g of wheat bran daily, and a capsule of 20 mg of beta-carotene daily. Patients with the combination of a low-fat diet and added wheat bran had zero large adenomas at both 2 and 4 years, a statistically significant effect compared to the control group.
[35]
DOSAGE RECOMMENDATIONS When using dietary fiber supplements, encourage patients to start out with a small dosage and increase gradually. Since water-soluble fibers are fermented by intestinal bacteria, a great deal of gas can be produced. If the patient is not accustomed to a high-fiber diet, an increase in dietary fiber can lead to increased flatulence and abdominal discomfort. Start out with a dosage between 1 and 2 g before meals and at bedtime and gradually increase the dosage to 5 g.
POSSIBLE ADVERSE EFFECTS Mineral malabsorption
A number of research studies have examined the effects of fiber on mineral absorption. Although the results have been somewhat contradictory, it now appears that large amounts of dietary fiber may result in impaired absorption and/or negative balance of some minerals. Fiber as a dietary component does not appear to interfere with the minerals in other foods. However, supplemental fiber, especially wheat bran, may result in a mineral deficiencies. Fiber supplements may also inhibit the absorption of certain drugs. A good recommendation would be for the patient to take the fiber supplement away from medications. Safety
If a patient has a disorder of the esophagus, fiber supplements in a pill form are contraindicated as they may expand in the esophagus and lead to obstruction. [36] Fiber supplements in capsules appear to be slightly better tolerated than tablets, but should still be used with caution. The difference is in how the tablets and capsules interact with water. One study showed that fiber (glucomannan) tablets swelled to seven times their original size within 1 minute of coming into contact with water. [37] In contrast, fiber-filled gelatin capsules took 6 minutes to begin to swell. One very important recommendation is to consume amounts of water with the fiber supplement.
SUMMARY A diet high in plant foods is associated with a decreased incidence of most of the degenerative diseases of Western society. While this is largely due to increased levels of dietary fiber, such a diet is also high in other important nutrients, most of which are also deficient in the Western diet. It is clear from the literature that the best source of dietary fiber is from whole foods, although fiber supplements do have a place in the treatment phase of specific diseases. It must be stressed that even with a diet high in dietary fiber, when as little as 18% of the total calories are in the form of refined carbohydrates, many of the beneficial effects of dietary fiber are greatly reduced. There is no substitute for a healthy diet, i.e. a diet composed of foods as close to their original form as possible.
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1. Eaton 2. Ryde
SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. New Engl J Med 1985; 312: 283–289
D. What should humans eat? Practitioner 1985; 232: 415–418
3. Trowell
H, Burkitt D. Western diseases: their emergence and prevention. Harvard University Press. 1981; Trowell H, Burkitt D, Heaton K. Dietary fibre, fibre-depleted foods and disease. New York, NY: Academic Press. 1985 4. US
Dept of Health and Human Services. The Surgeon General’s report on nutrition and health. Rocklin, CA: Prima. 1988
5. National 6. Price
Research Council. Diet and health. Implications for reducing chronic disease risk. Washington, DC: National Academy Press. 1989
W. Nutrition and physical degeneration. La Mesa, CA: Price-Pottinger Foundation. 1970
7. Spiller
GA. Dietary fiber in health and nutrition. Boca Raton, FL: CRC Press. 1994
8. Vahouny
G, Kritchevsky D. Dietary fiber in health and disease. New York, NY: Plenum Press. 1982
9. Selvendran
RR. The plant cell wall as a source of dietary fiber: chemistry and structure. Am J Clin Nutr 1984; 39: 320–337
10.
Watt J, Marcus R. Harmful effects of carrageenan fed to animals. Canc Det Prev 1981; 4: 129–134
11.
Setchell KDR. Discovery and potential clinical importance of mammalian lignans. In: Flaxseed in human nutrition. Chaimpaign, IL: AOCS Press. 1995: p 83–98
12.
Graf E, Empson KL, Eaton JW. Phytic acid. A natural antioxidant. J Biol Chem 1987; 262: 11 647–11 650
13.
Vucenik I, Tomazic VJ, Fabian D et al. Antitumor activity of phytic acid (inositol hexaphosphate) in murine transplanted and metastatic fibrosarcoma, a pilot study. Cancer Lett 1992; 65: 9–13
14.
Graf, Eaton JW. Suppression of colonic cancer by dietary phytic acid. Nutr Cancer 1993; 19: 11–19
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15.
Physicians Committee for Responsible Medicine, P.O. Box 6322, Washington, DC, 20015
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Sommer H, Kasper H. Effect of long-term administration of dietary fiber on the exocrine pancreas in the rat. Hepato-gastroenterology 1984; 31: 176–179
17.
Royall D, Wolever TM, Jeejeebhoy KN et al. Clinical significance of colonic fermentation. Am J Gastroenterol 1990; 85: 1307–1312
18.
Velazquez OC, Lederer HM, Rombeau JL. Butyrate and the colonocyte. implications for neoplasia. Dig Dis Sci 1996; 41: 727–739
19.
Glore SR, Van Treeck D, Knehans AW et al. Soluble fiber and serum lipids. A literature review. J Am Diet Assoc 1994; 94: 425–436
20.
Ripsin CM, Keenan JM, Jacobs DR et al. Oat products and lipid lowering, a meta-analysis. JAMA 1992; 267: 3317–3325
21.
Krotkiewski M. Effect of guar on body weight, hunger ratings and metabolism in obese subjects. Clin Sci 1984; 66: 329–326
22.
Krotkiewski M, Smith U. Dietary fibre in obesity. In: Leeds AR, Avenell A, eds. Dietary fiber perspectives. Reviews and bilbiography. London: John Libbey. 1985: p 61
23.
Krotkiewski M. Effect of guar gum on body-weight, hunger ratings and metabolism in obese subjects. Br J Nutr 1984; 52: 97–105
24.
Anonymous. Better than oat bran. Science News 1994; 145: 28
25.
Walsh DE, Yaghoubian V, Behforooz A. Effect of glucomannan on obese patients. A clinical study. Int J Obesity 1984; 8: 289–293
26.
Biancardi G, Palmiero L, Ghirardi PE. Glucomannan in the treatment of overweight patients with osteoarthrosis. Curr Ther Res 1989; 46: 908–912
27.
El-Shebini SM. The role of pectin as a slimming agent. J Clini Biochem Nutr 1988; 4: 255–262
Solum TT, Ryttig KR, Solum E et al. The influence of a high-fibre diet on body weight, serum lipids and blood pressure in slightly overweight persons. A randomized, double-blind, placebo-controlled investigation with diet and fibre tablets (DumoVital). Int J Obesity 1987; 11(1): 67–71 28.
Ryttig KR, Larsen S, Haegh L. Treatment of slightly to moderately overweight persons. A double-blind placebo-controlled investigation with diet and fibre tablets (DumoVital). Tidsskr Nor Laegeforen 1984; 104: 989–991 29.
30.
Rossner S, von Zweigbergk D, Ohlin A et al. Weight reduction with dietary fibre supplements. Results of two double-blind studies. Acta Med Scand 1987; 222: 83–88
Ryttig KR, Tellnes G, Haegh L et al. A dietary fibre supplement and weight maintenance after weight reduction. A randomized, double-blind, placebo-controlled long-term trial. Int J Obesity 1989; 14: 763–769 31.
Rigaud D, Ryttig KR, Angel LA et al. Mild overweight treated with energy restriction and a dietary fiber supplement. A 6-month randomized, double-blind, placebo-controlled trial. Int J Obesity 1990; 14: 763–769 32.
33.
Yuan JM, Wang QS, Ross RK et al. Diet and breast cancer in Shanghai and Tianjin, China. Br J Cancer 1995; 71: 1353–1358
34.
Baghurst PA, Rohan TE. Dietary fiber and risk of benign proliferative epithelial disorders of the breast. Int J Cancer 1995; 63: 481–485
35.
MacLennan R, Macrae F, Bain C et al. Randomized trial of intake of fat, fiber, and beta-carotene to prevent colorectal adenomas. J Natl Cancer Inst 1995; 87: 1760–1766
36.
Halama WH, Maudlin JL. Distal esophageal obstruction due to a guar gum preparation. South Med J 1992; 85: 642–646
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Henry DA, Mitchell AS, Aylward J et al. Glucomannan and risk of oesophageal obstruction. Br Med J 1986; 292: 591–592
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Chapter 58 - Rotation diet: a diagnostic and therapeutic tool Sally J. Rockwell PhD CNN
INTRODUCTION Food allergy/intolerance is a common component of many chronic diseases (see Ch. 51 ). However, it is often not recognized as problematic because conventional laboratory diagnosis is not very sensitive for food allergies and most allergists dismiss the concept of delayed hypersensitivity reactions to foods (see Chs 10 and 15 ). A time-honored effective approach to both diagnosis and treatment of food sensitivities is an elimination/rotation diet. This approach has the advantage of being low-cost, but the techniques must be followed assiduously to ensure clinical efficacy. Table 58.1 lists the typical indications for an elimination diet.
THE ELIMINATION DIET The first step in the elimination diet is to remove from the diet all of the most common allergenic foods – i.e. wheat and other glutinous grains, dairy products, eggs, corn, soy and tofu, peanuts, citrus fruits, yeast and refined sugars – and other often problematic substances such as highly processed foods, chemicals, additives, preservatives, artificial colorings, flavorings, caffeine (coffee, tea, cola drinks, chocolate), and alcohol. The object is to avoid all suspect foods and substances for at least 5 days, or long enough to clear all traces of those foods from the digestive tract. The omitted foods are then reintroduced into the diet one at a time. By keeping an accurate food and symptom diary, the offending foods can be identified and eliminated; then, TABLE 58-1 -- Indications for the use of the elimination diet • Documented or suspected food allergies/intolerances • Chronic complaints that have not subsided with treatment • Symptomatic patients whose tests results are all “normal” • Patients suspected of mental health problems due to lack of significant progress • Children and teens who are labeled ADD, hyperactive, or autistic, or who have behavior problems
518
depending upon the severity of the initial test response, the foods can be retested and added back into the diet within 3–6 months. While some recommend eliminating only one food at a time, clinicians in this area have found that multiple allergies are the rule, not the exception. Eliminating only one allergen may not improve symptoms enough to allow the improvement to be recognized. The advantages of eliminating all major allergens in the beginning include rapid clearing, minimal adverse reactions, and accurate test results. When symptoms clear rapidly, the patient is inspired and eager to continue with the testing. As Dr Doris Rapp explains: If there are several tacks in the bottom of a shoe, the whole foot hurts; removing only one tack will make little or no difference. But remove all the tacks, let the foot heal, then add back one tack at a time and the source of pain is isolated and easily identified. If only one tack (or food) is removed, no significant difference will be noted. Variations of the elimination diet range from the most stringent plan – i.e. elimination of all the major allergens, refined foods and toxic substances – to a more lenient approach – elimination of only wheat, dairy and refined sugars. Consideration of the patient’s lifestyle, age, weight, general health, food preferences, attitude and family system will determine the approach. For children and pregnant or lactating women, the amount of calories or carbohydrates should not be restricted; simply omit the major allergens. Variations of the elimination diet As can be seen in Table 58.2 , all elmination/challenge diets are simply variations on the same theme: 1. 2. 3. 4.
Eliminate suspect foods for at least 5 days Introduce/test by challenge ingestion Carefully record reactions Rotate foods, avoiding those shown to cause disagreeable reactions.
TABLE 58-2 -- Elimination diet variants Type
Protocol
Water fast
Water-only fast for 5 days, reintroduce foods
Dilute juice fast
Dilute fruit juice fast for 5 days, reintroduce omitted foods
Fruit, melon and vegetable plan Only fruits, melons and vegetables for 5 days, reintroduce omitted foods Cave man (person) plan
Proteins, nuts, seeds, legumes, fruits and vegetables for 5 days – reintroduce omitted foods. Eat only natural, unprocessed foods
Water fast
Water fast should only be done under the close guidance of a health professional experienced in supervising fasts. A lifetime of accumulated toxins can be released in a short period of time, creating unwarranted discomfort and complications which overwhelm the patient and interfere with testing (see Ch. 47 for a complete description of fasting methodologies).
The dilute juice fast
Less severe than water fasting, and more acceptable to patients, is the dilute juice fast. The diluted juices provide a modest amount of calories, stabilize blood sugar levels and decrease the adverse detoxification–withdrawal reactions which may occur while eliminating all common allergens. The basic procedure is to use three parts distilled or mineral water to one part of fresh, sugar-free juice. The dilute juices are sipped throughout the day. Ideally, a different juice is used each day: celery, carrot, papaya, cranberry, berry, apple, pineapple, and other fruits or vegetables that have not been consumed on a daily basis. Citrus fruits should be avoided. Low-allergen protein supplements, e.g. Ultra Clear, Medi Pro Protein Powder, pure free-form amino acids, N Foods, or Vivonex, may be added after the third day. In addition, liberal amounts of pure water should be consumed throughout the day in order to dilute and flush out toxic substances. Note. This works for most Candida patients as the juice is so dilute that it rarely creates a problem. However, commercially prepared juices (especially tomato and citrus juice) often contain molds which can be problematic. Fruit and/or vegetable plan
The patient consumes unlimited amounts of clean fresh fruit and melons and raw, steamed, or baked vegetables throughout the day. If Candida overgrowth is severe, or if weight loss is desired, vegetables should be emphasized over fruits. The cave man (person) plan
When the major allergenic foods are eliminated, what’s left are the basic foods that the cave man consumed: vegetables, fruits, berries, honey, nuts, seeds, beans, peas, sprouts, roots, gourds, poultry, fish, seafood, and wild game. Procedure Beginning the elimination diet
An ideal elimination diet begins with: 1. 2 days of the dilute juice, then 2. Fruits and vegetables for the next 2 days, then 519
3. 2 days of the cave person diet, or until symptoms clear. Any one, or combination of, the above elimination plans will clear the patient of allergenic substances. If after 5 days the patient’s symptoms have not diminished (or disappeared), continue for another 5 days. If not clear in 10 days, begin to rotate, as they may be reacting to a food or substance they are consuming every day. (Unsuspected environmental allergens may be contributing to the symptoms also – see “Helpful hints and suggestions”, p. 52.) Testing by challenge ingestion
Introduce one suspect food every other day. The object is to provide the patient with sufficient calories, build a reliable list of safe foods, and delay unpleasant reactions for as long as possible. Begin with rarely ingested foods as they are least likely to cause adverse reactions. Do not test foods which are known to cause severe reactions. Suggested testing sequence
Reintroduce back into the diet in the following order whenever possible: vegetables, fruits, melons, beans, nuts and seeds, yeasts, dairy products and finally grains. When adding dairy, test goat products first: plain yogurt, cheeses, and then milk. Repeat the same process with cow’s milk. Test grains in the following order: quinoa, amaranth, buckwheat, wild rice, brown rice, millet, barley, spelt, kamut, teff, oats, rye, corn and wheat last (gluten-containing grains are in italics). Also test dietary supplements one at a time. Food and symptom diary
Have the patient record chronologically in a notebook all foods, liquids, supplements, moods, symptoms and reactions. The foods eaten throughout the day should be noted in pencil, or blue or black ink. Highlight or circle symptoms using colored ink so that those adverse reactions will stand out clearly. In 2–3 weeks a repetitive pattern of symptoms will be clearly visible, which allows for identification and elimination of the problematic foods or food combinations causing symptoms. In the beginning, a patient may not be able to describe in exact words how he or she feels, and so a numbering system may be useful to note general moods throughout the day. Number from 1 (poor) to 10 (excellent). Feeling sort of medium, neither poor nor excellent, would be recorded as a 5. In general, depending on the patient’s health and motivation, foods causing a mild reaction should be avoided for 3 months, and those causing a severe reaction are best avoided for at least 6 months before being reintroduced. Testing children
Play a game with children – make testing fun. Have them draw a picture of how they feel or write their name before and after testing a substance. Note the differences.
THE DIVERSIFIED ROTATION DIET The basic concept of the diversified rotation diet is to: • eliminate all major allergenic substances • eat the remaining foods once every 4 days • allow 2 or 4 days between food families. Rotation can be simplified by using a template – the “master chart” – with foods correctly arranged according to their botanical family classifications. The spacing of the foods, and food families, are pre-organized into four columns, one for each day, so the patient simply chooses foods from the appropriate column each day. A color-coding system further simplifies the process of choosing the correct foods. The master chart, plan I (see Appendix 10 ) is the most liberal of the two plans. It provides 4 days between specific foods and only 2 days between food families. The master chart, plan II is used for severely sensitive individuals (see Appendix 10 ). It incorporates 4 days between specific foods and 4 days between food families. If necessary, it can be easily adapted to a 7 day rotation. Using the master charts
Use a pencil to cross out the major allergens, plus any known or suspected problem foods, in each of the four columns. The patient may eat the remaining foods from the appropriate column throughout the day. The foods which are not crossed out are what they are allowed to eat. The arrows on the chart (?) indicate a food which is essentially the only food of a family and which is not cross-reactive with other foods. Therefore, it is not restricted to any one particular day, and can be moved to another column if additional food choices are needed. Those who will be rotating for any length of time will welcome the benefits of using the color-coding system. A color is assigned to each day. Each column represents a day – day 1: green, column one; day 2: yellow, column two; day 3: blue, column three; and day 4: red, column four. After day 4, rotate back to day 1 and repeat the process. Food containers are labeled and color-coded to coordinate with the color of the day. The color-coding system enables the entire family to see at a glance which foods are permitted on each of the days. Example. The first column of the master chart is day 1, green day; place green labels, green twist-ties or green rubber bands on all appropriate food containers for day 1, and so on.
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Modifications for vegans The master charts can be used for vegans by simply crossing out all foods of animal origin. After the initial elimination phase, proceed with the food challenges. Legumes (beans and peas) are generally an important part of the vegan diet; so test each legume, one at a time, beginning with the least allergenic, rarely eaten beans, then soy and tofu, and test peanuts last. Depending upon the allergic response to legumes, the patient may be able to tolerate legumes daily, as long as a different legume is eaten each day. In other words, while the four days between foods rule continues to be honored, the one day between food families rule may be safely ignored for some patients. Food preparation For testing purposes, use fresh, organic foods whenever possible. Otherwise frozen or dehydrated foods are a better choice than canned goods. Most vegetables are best raw, steamed, or baked. Fish, poultry, and meat are best poached, steamed, sautéed, baked or simmered in a crock pot. Soups and stews are fine. Use only sea salt for seasoning; all spices and flavorings need to be avoided until they are individually tested. Stabilize blood sugar levels by advising the patient to eat small, frequent meals throughout the day. Using hypoallergenic foods, prepare four mixtures of “trail mix” – nuts and dried fruits – for each day. Refer to the master chart for specific food choices. Maintain a supply of healthy snacks everywhere: home, school, office and automobile. Helpful hints and suggestions Control of withdrawal symptoms and allergenic reactions. Ascorbates buffered with calcium, potassium and/or magnesium are suggested as a daily source of vitamin C for allergenic individuals. They help to balance an acidic body pH, and are valuable for neutralizing unpleasant allergic reactions. Stabilizing pH eases the symptoms of withdrawal from allergenic foods, and the cravings which occur when breaking an addiction – whether it’s sugar, wheat, coffee, cigarettes, alcohol or a drug. For daily use, determine an individual’s requirement for vitamin C. Begin with ? tsp of buffered ascorbate in ½ glass of water 3 times a day (between meals and at bedtime). Gradually increase by an additional ? tsp per dose every 2 days until they reach bowel tolerance: loose stool, gas or diarrhea. Reduce dosage. As the patient improves, their vitamin C requirement will likely decrease and the dosage may need to be decreased again. Note. Buffered C should not be taken with meals as it will neutralize stomach acid, which is often deficient in patients with food allergy/intolerance (see Ch. 19 ). For temporary relief of symptoms or to neutralize an adverse reaction, mix and drink a ½ teaspoon of buffered vitamin C in ½ glass of water or dilute juice. Available commercial products include Klaire Labs Bi-carbs, Cardiovascular’s Tri-salts and Alka Seltzer Gold label (not the blue label). If all of the above are unavailable, ½ teaspoon of baking soda in ½ glass of water can be useful. Environmental allergies. If the patient doesn’t respond in a timely fashion, and all other possibilities have been ruled out, suspect environmental and/or chemical sensitivities. Step one is to eliminate all scented toiletries, room sprays and cleaning solutions in the home and work place. * Ensure adequate protein intake. As the most allergenic foods also tend to be those highest in protein, care must be taken to ensure the patient is consuming enough protein. Patients with large numbers of food allergies should be referred to a competent nutritionist to help them develop an adequately balanced diet. Be patient. Be especially patient and supportive of those who have experienced long-term conventional treatment only. You may be the first physician to remind them that symptoms are the body’s way of communicating and that learning to pay attention to what they eat and drink, and the possible adverse symptoms, is a vital part of getting well again. Allergy-free cook books. Recipes, plus dozens of helpful hints and suggestions can be found in specialty cook books. The author has published several self-help books and tapes, including The rotation game, complete with instructions, colored visual aids, recipes, etc. Utilization of the rotation diet can be greatly assisted through the use of a commercial product developed by the author: The rotation game (see address in footnote, below; a free copy of Allergy Alert newsletter is available on request). * Contact S. J. Rockwell at the following address for a patient “how-to” checklist: PO Box 31065, Seattle, WA 98013 (tel: (206) 547 1814; fax: 547 7696; e-mail:
[email protected]).
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Chapter 59 - Sports nutrition Gregory S. Kelly ND*
INTRODUCTION The increased focus on fitness and subsequent research in the exercise field have expanded the role of nutrition in sports performance. Because there is widespread belief among athletes that special nutritional practices will enhance their achievements in competition, the use of supplements has become common. This chapter reviews the efficacy of some of supplements currently promoted to athletes. The topic has been divided into two broad categories: sports nutrition for strength athletes; and sports nutrition for endurance athletes. This division is to a degree arbitrary, so some of the supplements discussed might be applicable for athletes in both of these categories.
SPORTS NUTRITION FOR STRENGTH ATHLETES Creatine monohydrate Creatine monohydrate has become one of the most popular supplements in the history of body-building. It is used primarily to increase strength and lean body mass and has shown consistent results in promoting these effects in experimental subjects. In humans, over 95% of the total creatine content is located in skeletal muscle. Approximately one-third is in its free form as creatine, also known as methylguanidinoacetic acid, while the remainder is present in a phosphorylated form as creatine phosphate (also called phosphocreatine). Creatine phosphate is utilized within skeletal muscle storing high energy phosphate bonds. Creatine is formed in the liver, kidney, and pancreas. Initially, arginine and glycine combine to produce guanidinoacetate. A methyl group from S-adenosylmethionine (SAM) is then transferred, resulting in the formation of creatine. The by-product of this reaction, S-adenosylhomocysteine, is subsequently hydrolyzed into homocysteine * Reprinted with permission from Alternative Medicine Review 1997; 2(4): 282–295
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and adenosine. In order to optimize endogenous production of creatine, the amino acids arginine, glycine, and methionine must be available as substrates. Additionally, magnesium is required as a cofactor to form SAM from methionine, and B 12 , folic acid and betaine are required to recycle the homocysteine to methionine for reuse as SAM. While creatine can be synthesized endogenously as described above, it is also found in a variety of foods in varying concentrations. The richest source is considered to be wild game, but in domesticated animals, beef (lean red meat) is the richest source; 1.1 kg of fresh uncooked steak contains about 5 g of creatine. [1] Fish is also a good source, especially herring, salmon, and tuna. However, it is believed that creatine in foods may be destroyed or reduced significantly by cooking. Creatine is transported to muscle tissue where it exists in equilibrium with creatine phosphate. Creatine phosphate spontaneously converts to creatinine (estimated to be at a rate of about 2 g/day for a 150 pound male) and is then excreted in the urine. [2] While part of this turnover can be replaced through dietary sources of creatine, especially meat and fish, the remainder must be supplied by endogenous synthesis. Because of this, there is a constant drain on arginine, glycine, methionine, and nutritional cofactors to maintain a supply of creatine and creatine phosphate. In vegetarians, daily needs must be met exclusively by endogenous synthesis. When dietary creatine is high, the synthetic pathway is correspondingly regulated downward. [3] In addition to its use in skeletal muscle, some creatine is used by cardiac muscle. Chronic heart failure patients might have decreased stores of creatine and have been shown to have improved exercise capacity following administration of creatine. [4] One week of creatine (20 g/day) supplementation to patients with chronic heart failure increased skeletal muscle energy-rich phosphagens and performance for both strength and endurance. [4] Creatine phosphate produces energy in the form of ATP in muscle cells for about 10 seconds of activity. After it is depleted, the muscle shifts to anaerobic glycolysis for fuel. It is thought skeletal muscles are capable of storing significantly more creatine than is generally supplied by the diet and by endogenous synthesis. Because of this, increased serum creatine, following an oral dose of creatine monohydrate, will be available for storage in muscle tissue. Over time, this increased dietary consumption can allow the muscle to become saturated with creatine. When the muscle has this extra creatine, it should theoretically be able to delay fatigue and refuel itself more quickly during high-intensity, short-duration exercise, and so should be capable of greater work. When muscle absorbs creatine, it is hypothesized that it also brings water intracellularly with it, so the muscle becomes more “hydrated”. It is estimated that muscles are about 70% water, so this results in a larger, fuller muscle. Evidence suggests when a cell is well hydrated it might accelerate its synthesis of new proteins and might also minimize protein degradation. [5] One gram of creatine monohydrate or less in water produces only a modest rise in plasma creatine concentration; however, a 5 g oral dose has been shown to significantly increase plasma creatine concentration. Repeated dosing with 5 g of creatine monohydrate every 2 hours sustains the plasma concentration at around 1,000 mmol/L.[1] Recent studies have shown that feeding large amounts of creatine (typically 20–30 g/day for 5 days) increases muscle total creatine (and phosphocreatine) content. [1] [6] The extent of the increase normally observed is inversely related to the pre-supplementation level. [ 1] [6] Vegetarians, because they have a very low dietary creatine intake and low to normal total creatine content, would be expected to show large increases. [1] Muscle creatine uptake appears to be augmented substantially in individuals adhering to a program of repeated high-intensity exercise during the period of supplementation. [1] Resynthesis of phosphocreatine following 1 minute of recovery from intense muscular contraction is accelerated in individuals consuming creatine. [6] Adequate vitamin E status might also be needed to optimize creatine uptake. [7] In one study of eight subjects, biopsy samples were taken after 5 days of ingestion of 20 g creatine/day. In five of the eight subjects, there was substantially increased muscle total creatine concentration and creatine phosphate resynthesis during recovery. In the remaining subjects, creatine supplementation slightly increased total creatine concentration but did not increase creatine phosphate resynthesis. [6] In three subjects measured, uptake into muscle was greatest during the first 2 days of supplementation, accounting for 32% of the total 30 g of creatine monohydrate given orally per day. In these subjects, renal excretion was 40, 61 and 68% of the creatine dose over the first 3 days, respectively. Approximately 20% or more of the creatine taken up was measured as phosphocreatine, while no changes were observed in the muscle ATP content. [1] Oral creatine monohydrate supplementation has also been shown, in a patient with extrapyramidal movement disorder and extremely low creatinine concentrations in
serum and urine, to significantly increase brain creatine levels. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine phosphate before oral substitution of creatine and a significant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patient’s neurologic symptoms. Oral substitution of arginine, a substrate for creatine synthesis, was unable to elevate cerebral creatine levels. [8] Creatine supplementation has been shown to improve performance in situations where the availability of creatine phosphate is important, such as very high-intensity
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exercise, especially where repeated bursts of energy are required with short recovery periods. [9] [10] [11] [12] [13] Several studies have documented creatine monohydrate’s effect on muscle size and strength. Typically, after a 5–7 day loading dose, there is an increase in the amount of work done in repeated bouts of maximal exercise and a gain in body mass of between 0.5 and 1.0 kg. [10] [12] One group of researchers reported 28 days of supplementation (20 g/ day) producing a fat-free mass increased by 1.7 kg.[9] While creatine supplementation increased performance in sprint-trained cyclists, it does not appear to improve endurance performance. [14] One study actually reported a worsening in performance during prolonged continuous exercise following creatine supplementation. This finding remains unexplained, although the authors believe the increase in body mass due to supplementation might be a contributing factor. [15] Research shows that creatine supplementation has no measurable effect on respiratory gas exchange and blood lactate concentrations during either incremental submaximal exercise or recovery, suggesting that creatine phosphate produces energy in the form of ATP in muscle cells for about 10 seconds of activity. After it is depleted, the muscle must shift to anaerobic glycolysis for fuel. Creatine supplementation does not influence substrate utilization during and after this type of exercise. [16] Results from an unpublished human trial indicate that insulin might be a potent upregulator of a muscle’s ability to take in creatine. This has resulted in many users supplementing creatine monohydrate with a simple carbohydrate (such as glucose, dextrose, or maltose) which simultaneously causes a release in insulin. In a 4 week trial, a large increase in speed, anaerobic power, and lean body mass, along with a decrease in body fat, was reported in individuals receiving doses of 20 g/day of creatine for the first 5 days, followed by 10 g/day for the remainder of the 4 weeks. An even greater response in these parameters was reported in the athletes using a creatine/carbohydrate mix, which contained creatine monohydrate, dextrose, taurine, disodium phosphate, magnesium phosphate, and potassium phosphate. Dosage
Typically, dosing of creatine monohydrate follows a loading and a maintenance cycle. During the loading period, larger doses of creatine monohydrate are ingested for 5–7 days. A typical dose for individuals weighing less than 225 pounds is 5 g q.i.d, while heavier individuals might take up to six doses per day. The maintenance dose would be 0.03 g/kg body weight. [17] [18] Larger doses are probably not of any greater benefit since the capability of muscle to take in and store creatine is finite. [1] In fact, this dosing schedule might exceed the ability of most individuals to incorporate creatine into muscle tissue, as evidenced by the renal excretion rate of creatine (40–68% of the supplemented dose) reported in individuals given 30 g/day. [1] A recent study supports the possible use of lower oral doses. One study reported that 3 g/day for 28 days increased muscle creatine and creatine phosphate stores to a level comparable to a loading phase. [17] Most of the gains in size and strength occur within the first month, after which muscles are generally saturated with creatine. Evidence indicates that these gains will remain while supplementation continues, but will gradually disappear over time when the supplement is discontinued. Typically, levels of creatine drop back to pre-supplementation levels about 1 month after discontinuing supplementation. The size and strength increase resulting from improved muscle cell hydration also disappear over this same time interval. However, actual gains in muscle mass due to increased work capacity while on creatine will remain. Anecdotal reports suggest that 20–30% of individuals who take creatine do not respond with increased muscle mass or strength. Presently, this finding is unexplained; however, individuals with lower initial tissue levels are most likely to benefit. [1] Because of the success of creatine monohydrate, several other forms have become available, including creatine phosphate and creatine citrate. These are claimed to produce similar results; however, creatine monohydrate is the only form shown, to date, to increase strength, lean body mass, and tissue creatine phosphate levels. Toxicity
Reported side-effects from creatine supplementation include gastric disturbance, headaches, clenched teeth, and the sound of blood rushing in the ear. Creatine supplementation might cause serum creatinine levels to increase. This is due to the increase in muscle creatine phosphate and its subsequent spontaneous conversion to creatinine. Since most of the studies have only supplemented creatine for short periods of time, and in the single study reporting long-term supplementation only 1 g/day was utilized, [19] it is not currently known whether long-term, high-dose supplementation has adverse side-effects. Some concern exists that caffeine use (0.5 mg/kg per day) can have a negative impact on the effectiveness of creatine. However, in at least one study, participants were instructed to dissolve the creatine monohydrate in tea or coffee before ingestion. Body weight increase was still observed in seven of eight subjects and all subjects had increased muscle total creatine and phosphocreatine resynthesis. [6] Although these results suggest caffeine does not negate the effects of creatine supplementation, until more is known it might be best to minimize caffeinated substances, or drink them several hours away from supplementation, if seeking optimal results.
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Creatine supplementation is widely practiced by athletes in many sports and does not contravene current doping regulations. [3] Since creatine supplementation does not enhance performance in endurance athletes and evidence suggests an actual decline in performance, endurance athletes should avoid creatine supplementation. In athletes concerned with improving strength, body composition, or short-duration repetitive high-intensity exercise, I recommend creatine monohydrate be incorporated into any supplementation protocol. Although quicker results will be seen following a loading dose, the cost-effectiveness of the 3 g/day dose might be a more appealing option for many athletes. HMB HMB (beta-hydroxy beta-methylbutyrate) is a new product which has only been available in limited supply since the end of 1995. The nutritional use of HMB for nitrogen retention has been patented by the Iowa State University Research Foundation and is licensed to Metabolic Technologies. HMB is a leucine metabolite. It has not yet been established how HMB is synthesized from leucine in humans; however, in animals evidence suggests that the majority of circulating HMB is formed following the transamination of leucine to alpha-ketoisocaproate with its subsequent oxidation to HMB. [20] It has not been determined either to what extent HMB is normally produced in vivo or which specific cofactors might influence its production. While the mechanism of action of HMB is still equivocal, it is hypothesized that HMB decreases muscle protein turnover and might work primarily by minimizing protein degradation. Suggestive evidence of HMB’s blocking of catabolism is based on its ability to decrease urinary 3-methylhistidine (a marker of muscle breakdown), and to decrease plasma levels of creatine phosphokinase and lactic dehydrogenase. [21] Anecdotal reports indicate that individuals who work out more often and most intensely get the best results with HMB. This is important since typically the more an individual works out, the more muscle catabolism also occurs; so at a certain point, the anabolic gains achieved by stimulating the muscles through training are offset by the catabolic effects of frequent, high-intensity workouts. HMB’s anti-catabolic effects might move this balance point further in the direction of anabolic growth, allowing an individual to train more often and still receive positive results in strength and mass gains. In a human study conducted over a 3 week period, 3 g/day of oral HMB supplementation was shown to decrease body fat, increase lean mass and strength, and reduce muscle damage in individuals beginning resistance-training exercises. In this trial, participants also consumed either 117 or 175 g/day of protein. While protein intake did not seem to impact strength, participants with higher protein intakes, independent of HMB supplementation, appeared to have greater increases in lean body mass.[21] Because these results came from individuals who had not previously engaged in weight training, doubt existed as to whether they would be reproducible in body-builders or other athletes who had already engaged in long-term resistance training. However, in a subsequent study, not yet published as a full
paper, researchers have indicated that HMB feeding resulted in equal increases in strength, body composition, and decreased fat in both trained and untrained individuals. [22] Dosage
The recommended dosage for HMB is 3 g/day. Since relatively high protein intake was reported in the study demonstrating HMB’s efficacy, and because it is unknown whether the same results will occur while on a low-protein diet, a similar protein intake of between 120 and 175 g/day for athletes supplementing with HMB might produce best results. Toxicity
At this point, the primary concern regarding HMB is anecdotal evidence which indicates that many individuals have not experienced expected results with this supplement. Since HMB is thought to function primarily as an anti-catabolic substance, it is possible these individuals did not train with enough intensity to optimize its effect. The other possibility is that, similar to creatine monohydrate, HMB might be ineffective in some individuals. Since this is such a new supplement, no information is available on its long-term safety. Whey protein Whey protein, often referred to as lactalbumin, is currently the supplemental protein source of choice for many body-builders and strength athletes. Whey proteins represent the major proteins in human breast milk, as opposed to bovine milk which is comprised primarily of casein with lesser amounts of whey. Whey is comprised of alpha-lactoglobulin, beta-lactoglobulin, bovine serum albumin (BSA), and immunoglobulins (IgG1, IgG2, secretory IgA, and IgM). Other components of the lactalbumin fraction include: enzymes, iron binding proteins, calcium, potassium, sodium, phosphorous, and vitamins A, C, B 1 , B2 , B3 , B5 , B12 , folic acid, and biotin. Whey is a balanced source of essential amino acids and peptides with a high protein efficiency ratio. It is considered to be an excellent source of sulfur amino acids (methionine and cysteine), as well as the branched-chain amino acids (leucine,
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isoleucine and valine), and glutamine (see sections on branched-chain amino acids and glutamine for information on their potential benefits). Whey transits the stomach quickly and is rapidly absorbed from the human intestine. The beta-lactoglobulin component remains soluble in the stomach and empties rapidly as an intact protein needing further hydrolysis by pancreatic enzymes. Casein, on the other hand, transits the stomach slowly. [23] No studies exist comparing the impact on nitrogen balance, body composition, or performance of different protein sources in trained athletes. However, whey has been shown to promote growth and enhance nitrogen balance in experimental animals, low-birth-weight infants, and burn victims. [24] [25] [26] Whey protein is rich in substrates for glutathione synthesis, [27] and contains substantially more cysteine, which is considered to be a rate-limiting step in glutathione synthesis, than does casein. Whey also contains high amounts of glutamine and glycine. Glutathione is a powerful antioxidant and is involved in metabolic detoxification pathways. The role free radicals play in the development of exercise-induced tissue damage, or the protective role antioxidants might play, remains to be completely elucidated. Research has indicated that free radical production and subsequent lipid peroxidation are normal sequelae to the rise in oxygen consumption with exercise. [28] However, physical training has been shown to result in an augmented antioxidant system and a reduction in lipid peroxidation. Supplementation with antioxidants appears to further reduce lipid peroxidation but has not been shown to enhance exercise performance. [29] Glutathione levels have been shown to decrease with exercise. [30] Additionally, running a marathon causes a large increase in the tissue content of oxidized glutathione (189%) at the expense of reduced glutathione. [31] While no information is available on the effects of resistance exercise and glutathione levels, it is hypothesized that an increased intake of antioxidants might protect against minor muscle injuries. [32] Whey protein is more efficient at inducing supernormal glutathione levels than a cysteine-enriched casein diet. [33] A whey-rich diet has been shown to increase heart and liver tissue glutathione content in rats. The whey protein diet appeared also to increase longevity when fed at the onset of senescence. [33] Whey-based formula enhances cysteine retention and results in greater taurine excretion, thought to be a reflection of greater taurine stores. [34] Whey protein fed to three HIV-seropositive individuals over a period of 3 months, at doses increasing progressively from 8.4 to 39.2 g/day, resulted in progressive weight gain and increased glutathione levels in all three. [35] Experimental studies suggest that the whey protein component of milk might exert an inhibitory effect on the development of several types of tumor. It is thought that the rich supply of substrates for glutathione synthesis contributes to this inhibitory effect. [36] In experimental animals, a diet consisting of 20 g of whey/100 g diet has been shown to be more protective than similar diets utilizing casein, soybean, or red meat against dimethylhydrazine-induced intestinal cancers. [37] Peptides from whey protein have also been shown to have antithrombotic [38] and immunoenhancing activities. [38] [39] Dosage
The routine use of a post-workout shake might be the most important nutritional supplementation habit for enhancing body composition. It is probably in this manner that whey can be best utilized by athletes concerned with maximizing lean body mass and strength. Amino acid availability following a workout regulates protein synthesis and degradation. Because of the anabolic effects of insulin on protein synthesis and protein degradation, a rapid synergistic response occurs when both amino acids and insulin increase after a protein-containing meal. [40] It is thought that the body is highly insulin-sensitive after exercise and preferentially shuttles carbohydrates and protein into muscle cells rather than fat cells. Experts think this sensitivity gradually declines post-workout for about 2 hours until it again reaches normal sensitivity. A carbohydrate-whey protein supplement has been shown to be more effective in generating a plasma insulin response than either a carbohydrate or a protein supplement alone during recovery from prolonged exhaustive exercise. The rate of muscle glycogen storage was also significantly faster during the carbohydrate-protein treatment. The participants in this study ingested 112.0 g of carbohydrate and 40.7 g of protein immediately after each exercise bout. [41] Whey is an excellent choice as a protein source for the post-workout shake because of its rapid transit into the small intestine and because of its high levels of branched-chain amino acids and glutamine. Glucose polymers or maltodextrins are considered to be the best form of carbohydrates to use because of their ability to stimulate an insulin response. Fat should not be added because it might slow transit and decrease the insulin response. Toxicity
The primary concerns about supplementing whey protein are the possibility of food allergies, its lactose content, and proposed links to insulin-dependent diabetes mellitus (IDDM). While the possibility of food allergies from whey has to be considered, it is probable it is no more, and possibly less, antigenic than soy, casein, or egg-based protein supplements. A significant concern might
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be the method of processing of the whey protein, since high temperatures during heating or drying can generate browning reaction products by covalent interaction of proteins and lactose. Browned proteins have lowered digestibility and are thought to result in greater uptake of intact protein through intestinal mucosa. All whey
protein available contains some degree of lactose, although many have very low amounts. The BSA component of whey has been implicated as a possible trigger for IDDM in children. A similarity exists between the amino acid sequence of the beta-cell protein, found on the insulin-secreting beta cells of the pancreas, and BSA. Because elevated levels of anti-BSA antibodies have been found in sera from children developing IDDM, it has been proposed that absorption of BSA, or partially digested fragments of BSA, stimulate the immune system which then incorrectly destroys beta cells. [42] One study reported the prevalence of anti-BSA antibodies as 52% in children with less than 1 year of IDDM, 47% in children with greater than 1 year of IDDM, and 28% in the control group. The researchers concluded that the prevalence of anti-BSA antibodies is higher in IDDM subjects than in control subjects; however, because of the large overlap of antibody titers observed in patients and control subjects, anti-BSA antibodies were neither sensitive nor specific markers of IDDM.[43] Others have found that IgG antibodies to BSA were not significantly increased at the onset of IDDM. [44] Currently, the exact nature of the relationship between BSA and IDDM remains unclear. Phosphatidylserine Phosphatidylserine is becoming widely used by individuals engaged in resistance training, primarily due to its presumed ability to prevent muscle tissue degradation. Phosphatidylserine has been shown to have an effect on the body’s production of glucocorticoids. While the mechanism of action of phosphatidylserine is still unknown, it has been proposed that it exerts an effect on the hypothalamic–pituitary–adrenal axis. [45] Phosphatidylserine is formed by adding a serine to a phosphatidyl group. This requires pyridoxal 5´-phosphate (active B involved with phosphatidylcholine, choline, betaine, and dimethylglycine metabolism.
6
), and occurs in the same biochemical loop
Physical exercise induces a significant increase in plasma epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), and prolactin (PRL). It is theorized that preventing the increase in cortisol subsequent to intense exercise would prevent the excess muscle tissue breakdown. Pretreatment of eight healthy men with both 50 and 75 mg of intravenous brain cortex-derived phosphatidylserine within 10 minutes of the start of exercise blunted the ACTH and cortisol responses to physical stress. [46] Oral administration of phosphatidylserine derived from brain cortex, 800 mg/ day for 10 days, significantly blunted the ACTH and cortisol responses to physical exercise ( P = 0.003 and P = 0.03, respectively), without affecting the rise in plasma GH and PRL. Although participants also experienced reductions in plasma cortisol concentrations at a dose of 400 mg/day of phosphatidylserine, the area under the curve of plasma cortisol was significantly lower after the higher dose of 800 mg/day. [45] While the results of this preliminary work appear promising, to date no trials have reported an increase in strength or an improvement in body composition after phosphatidylserine supplementation. Until these results are determined, claims of phosphatidylserine’s ability to decrease muscle tissue catabolism should be considered unsubstantiated. Arginine Arginine is an amino acid which is used occasionally by body-builders to stimulate growth hormone secretion. It was very popular in the mid-1980s; however, interest in it has since waned. Several studies have shown its ability to stimulate growth hormone and insulin-like growth factor I secretion and improve nitrogen balance after i.v. administration; however, equivocal results have been obtained following oral supplementation. Oral arginine/lysine (3 g/day of each) is apparently not a practical means of chronically enhancing GH secretion in older men. increasing growth hormone levels in people not already deficient has an anabolic effect.
[47]
Additionally, it is debatable whether
Arginine is required for creatine synthesis and some believe it will enhance synthesis if supplemented. In rats, arginine and glycine supplementation increased muscle creatine.[48] One study reported that individuals receiving arginine and ornithine, 5 days a week for 5 weeks, had higher gains in strength and enhancement of lean body mass when compared with controls. Dosages amounted to 2 or 1 g each of L-arginine and L-ornithine taken orally, and 600 mg of calcium and 1 g of vitamin C as placebos. Subjects taking the arginine and ornithine also had significantly lower urinary hydroxyproline, a marker of tissue breakdown, than subjects receiving placebo. The authors concluded that arginine and ornithine, in conjunction with a high-intensity strength training program, can increase strength and lean body mass, and minimize tissue breakdown. [49] Dosage
The typical dosage is 2 g/day. Based upon the results of Elam et al, [49] it appears that a combination of arginine and ornithine might exert a positive impact on body composition and strength; however, no additional research has substantiated these findings.
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Branched-chain amino acids Leucine, isoleucine, and valine are considered as branched-chain amino acids (BCAAs) because of their similar chemical structures and interlocking methyl groups. Exercise results in marked alterations in amino acid metabolism within the body. The branched-chain amino acids, especially leucine, are particularly important since they contribute as energy substrates and as nitrogen donors in the formation of alanine, glutamine and aspartate. Calculations indicate that the recommended dietary intake of leucine is inadequate, since it is lower than the measured whole-body rates of leucine oxidation. This inadequacy is exacerbated in individuals who are physically active. [50] An increased supply of BCAAs appears to have a sparing effect on muscle glycogen degradation during exercise. [51] Short-term (3–4 hours) infusion of branched-chain amino acids has been shown to suppress muscle protein breakdown. [52] In humans nourished parenterally, provision of balanced amino acid solutions or of only the three BCAAs cause similar improvements in nitrogen balance for several days. [40] Administration of BCAAs can greatly increase their concentration in plasma and subsequently their uptake by muscle during exercise. [51] Long-term exercise following BCAA administration results in significantly greater muscle NH 3 , alanine and glutamine production, as well as lower lactate production, than is observed during exercise without BCAA supplementation.[53] While evidence indicates that BCAAs might be significant in enhancing protein synthesis or minimizing protein degradation, supplementation with these amino acids has not produced significant changes in body composition. If whey or another top-quality protein formula is being used, adequate amounts of BCAAs are provided. Glutamine Glutamine is the most abundant amino acid in the blood and in the free amino acid pool of skeletal muscle. Glutamine stimulates the synthesis and inhibits the degradation of proteins, is an important vehicle for the transport of nitrogen and carbon within the tissues, stimulates the synthesis of hepatic glycogen, and is an energy source for cell division. [54] Because glutamine deficiency can occur during periods of metabolic stress, it has led to the reclassification of glutamine as a conditionally essential amino acid. [55] Glutamine is also a precursor for the synthesis of amino acids, proteins, nucleotides, glutathione, and other biologically important molecules. Glutamine is considered to have an anabolic effect on skeletal muscle. It stimulates the synthesis and inhibits the degradation of proteins. Experiments with various animal models have demonstrated that glutamine supplementation can result in better nitrogen homeostasis, with conservation of skeletal muscle. [55] The mechanism by which glutamine affects skeletal muscle protein turnover, and thus muscle protein balance, is unknown. However, glutamine has an anabolic effect of promoting protein synthesis and also might reduce protein breakdown. [56]
Glutamine was shown to increase cell volume, while insulin and glutamine together seem to work synergistically to enhance cellular hydration. The effects of glutamine in skeletal muscle include the stimulation of protein synthesis, which occurs in the absence or presence of insulin, the response being greater with insulin. [57] During various catabolic states, such as infection, surgery, burns, and trauma, glutamine homeostasis is placed under stress, and glutamine reserves, particularly in the skeletal muscle, are depleted. In these conditions, the body requirements of glutamine appear to exceed the individual’s muscle deposits, resulting in a loss of muscle mass.[58] In critically ill patients, parenteral glutamine reduces nitrogen loss and causes a reduction in mortality. [54] With regard to glutamine metabolism, exercise stress can be viewed in a similar light to other catabolic stresses. Plasma glutamine concentrations increase during prolonged, high-intensity exercise. However, during the post-exercise recovery period, plasma concentrations decrease significantly. Several hours of recovery are required before plasma levels are restored to pre-exercise levels. If recovery between exercise bouts is inadequate, the acute effects of exercise on plasma glutamine concentrations can be cumulative. It has been observed that overtrained athletes appear to maintain low plasma glutamine levels for months or years. [59] Some experts believe that reduced concentration of plasma glutamine can provide a good indication of severe exercise stress. [60] Research suggests that, after exercise, increased availability of glutamine promotes muscle glycogen accumulation by mechanisms possibly including diversion of glutamine carbon to glycogen. [61] Following trauma there is a loss of nitrogen, with a concomitant reduction of skeletal muscle protein synthesis. This is accompanied by a decrease in the stores of muscle free glutamine. Nutritional support with either glutamine or its carbon skeleton, alpha-ketoglutarate, has been shown to counteract the postoperative fall of muscle free glutamine and of muscle protein synthesis. [62] Evidence suggests that oral glutamine supplementation results in an increased release of growth hormone. An oral glutamine load (2 g) was administered to nine healthy subjects to determine the effect on plasma glutamine, bicarbonate, and circulating growth hormone concentrations. Eight of nine subjects responded with an increase in plasma glutamine at 30 and 60 minutes before returning to the control value at 90 minutes. Ninety minutes after the glutamine administration load, both
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plasma bicarbonate concentration and circulating plasma growth hormone concentration were elevated. [63] Dosage
Although some advocates recommend as much as 30 g, it is likely that only marginal benefits are found at supplementary levels higher than 2–3 g/day. Ornithine alpha-ketoglutarate (OKG) Ornithine alpha-ketoglutarate (OKG) is a salt formed of two molecules of ornithine and one molecule of alpha-ketoglutarate. OKG has been successfully used by the enteral and parenteral route in burn, traumatized, and surgical patients, and in chronically malnourished subjects. According to the metabolic situation, OKG treatment decreases muscle protein catabolism and/or increases synthesis. In addition, OKG promotes wound healing. The mechanism of action of OKG is not fully understood, but the secretion of anabolic hormones (insulin, human growth hormone), and the synthesis of metabolites (glutamine, polyamines, arginine, ketoacids) might be involved. [64] This supplement has been available for several years. It has been used successfully in hospitalized burn victims to slow protein loss. Only one study appears to have evaluated its effect on performance. In this study, OKG (10 g/day with 75 g of carbohydrates) was given for 6 weeks. The OKG group experienced a significant increase in bench-press strength and biceps circumference. Body weight and percentage fat were not different between groups. No differences in growth hormone levels were seen between groups. Body composition changes were seen among several individuals in the OKG group, but no significance was found either within or between experimental groups.[64] Anecdotal reports from some individuals supplementing with OKG indicate increased appetite and better disposition to train. Some anecdotal reports claim great results while others experience no results. Dosage
The recommended dosage of OKG is 10 g along with a 75 g carbohydrate drink. Vitamin C There have been several investigations during the past four decades of the potential effect of high-dose vitamin C supplementation on physical performance. However, the results have been equivocal. Most studies could not demonstrate an effect. On the other hand, a suboptimal vitamin C status results in an impaired working capacity which can be normalized by restoring vitamin C body pools. [65] A potent antioxidant required for collagen synthesis, ascorbic acid might help protect muscles from excessive damage due to training or trauma. Data suggests prior vitamin C supplementation might exert a protective effect against exercise-induced muscle damage. [66] Ascorbic acid might decrease cortisol production. [67] It has also been suggested that ascorbic acid might have a role in facilitating an adequate response to stress.
[68]
Dosage
Because of ascorbic acid’s potential for minimizing muscle damage and cortisol-induced muscle catabolism, 1–3 grams should be supplemented daily. Boron Recently, a proliferation of athletic supplements has been marketed touting boron as an ergogenic aid capable of increasing testosterone. While this might to be true in some populations under specific conditions, boron’s impact on testosterone is still equivocal. Boron appears to increase testosterone levels in rats in a time- and dose-dependent manner. [69] In postmenopausal women, increasing dietary intake of boron from 0.25 to 3.25 mg/day has been reported to more than double plasma testosterone. [70] In a subsequent study of healthy men, boron supplementation resulted in an increase in the concentrations of both plasma estrogen and testosterone. [71] However, one study reported that changing boron intake had no impact on testosterone levels in postmenopausal women. [72] The effect of boron supplementation was investigated in 19 male body-builders aged 20–27 years. Ten were given a 2.5 mg boron supplement, while nine were given a placebo every day for 7 weeks. Both groups demonstrated significant increases in total testosterone, lean body mass, and one-repetition maximum squat and bench-press. However, analysis of variance indicated no significant effect of boron supplementation on any of the dependent variables. The authors concluded that the gains were a result of 7 weeks of body-building, not of boron supplementation. [73] Dosage
It is prudent to supplement the diet with 3 mg/day of boron to ensure against deficiency; however, an expectation of increased strength and improved body composition is unrealistic.
Chromium Chromium is highly promoted in body-building circles as a fat-burning supplement and as an aid in increasing
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lean mass. Available research does not support either of these claims. Changes in body weight, a sum of three body circumferences, a sum of three skinfolds, and the one-repetition maximum for the squat and bench-press were examined in 59 college-age students over a 12 week weight-lifting program. Half of the students were given 200 mcg/day elemental chromium as chromium picolinate, while the other half received a placebo. No treatment effects were seen for the strength measurements. The only significant treatment effect found was an increase in body weight observed in the females supplementing with chromium. [74] The effects of 9 weeks of daily chromium supplementation (200 mcg chromium as picolinate) were investigated in a double-blind design in football players during sprint training. Chromium picolinate supplementation was ineffective in bringing about changes in body composition or strength. [75] The same results were shown in another study of 200 mcg of chromium supplemented to untrained males (23 ± 4 years), in conjunction with a progressive, resistive exercise training program. Chromium supplementation was not found to promote a significant increase in strength or lean body mass, or a significant decrease in percentage body fat. [76] Increasing dosage and length of supplementation also did not help. A double-blind, placebo-controlled protocol for 16 weeks provided 400 mcg of chromium as picolinate or a placebo. At the end of 16 weeks, the chromium group failed to show a significantly greater reduction in either percentage body fat or body weight, or a greater increase in lean body mass, than did the placebo group. It was concluded that chromium picolinate was ineffective in enhancing body fat reduction in this group.[77] In yet another study, this one involving 8 weeks of daily chromium supplementation in 36 men in a double-blind design, it was found that strength, mesomorphy, fat-free mass, and muscle mass increased with resistance training independently of chromium supplementation ( P < 0.0001). These findings suggest that routine chromium supplementation has no beneficial effects on body composition or strength gain in men, although it must be noted that the placebo group received a trace level of chromium. [78] Evidence strongly indicates that supplementation of chromium will not enhance strength or body composition. Similar to boron, chromium-rich foods or a supplement containing chromium should be included in the diet to avoid deficiency; however, it is unrealistic to expect gains in strength or improvement in body composition. Selenium Selenium is a trace mineral which is utilized as a cofactor in several enzymes. It is commonly found in antioxidant formulas because of its role as a cofactor in the enzyme glutathione peroxidase. Evidence suggests that the administration of organic selenium partially compensates for and decreases the intensity of oxidative stress in athletes. [79] While optimal antioxidant status is critical to athletes, selenium might have an additional role in the determination of body composition. Selenium deficiency can affect the metabolism of thyroid hormones. Iodothyronine 5´-deiodinase, which is mainly responsible for peripheral T 3 production, has been demonstrated to be a selenium-containing enzyme. [80] In rats fed a selenium-deficient diet, hepatic iodothyronine 5´-deiodinase is decreased by 47%. Lower concentrations of T 3 and T4 have also been demonstrated in selenium-deficient animals. [81] Reduced peripheral conversion of T 4 to T3 secondary to a selenium deficiency might create a functional hypothyroidism which would be expected to adversely impact body composition. Toxicity
There is data suggesting that ingesting more than 750–1,000 ug/day of selenium over an extended period of time may be harmful. Vanadium (vanadyl sulfate) Vanadium as vanadyl sulfate is widely utilized by athletes seeking to improve body composition. It is generally promoted as having an anabolic effect which enhances the transport of amino acids into cells. Several studies have indicated its ability to reduce fasting glucose and improve hepatic and peripheral insulin sensitivity in non-insulin-dependent diabetic humans. [82] [83] [84] However, vanadyl sulfate does not appear to alter insulin sensitivity in non-diabetic subjects. [84] A single study reported the effect of oral vanadyl sulfate (0.5 mg/kg per day) on anthropometry, body composition, and performance in a 12 week, double-blind, placebo-controlled trial involving 31 weight-training volunteers. No significant treatment effects for anthropometric parameters and body composition were observed. Both groups had similar improvements in performance in most exercises; however, a significant improvement in one repetition-maximum leg extension was found in the treatment group. The authors concluded that although vanadyl sulfate was ineffective in changing body composition in weight-training athletes, its performance-enhancing effect required further investigation. [85] Toxicity
Anecdotal reports indicate that body-builders often supplement 15 mg t.i.d.; however, this practice is ill-advised due to both the lack of demonstrated efficacy and the lack of information regarding long-term toxicity of
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high doses of vanadium. Dietary concentrations of 25 mg of vanadium per kg cause mild diarrhea and growth suppression in rats and up to 50 mg/kg severely depressed growth and caused increased diarrhea and mortality. When 12 humans were fed 13.5 mg/day of vanadium for 2 weeks and then 22.5 mg/day for 5 months, five patients developed cramps and diarrhea at the high dosage. [86] Zinc Dietary deficiency of zinc is prevalent. Because of this, zinc supplements have been widely advocated for athletes. While it might not be wise to indiscriminately administer zinc, suggestive evidence indicates that zinc might impact body composition due to its interaction with a variety of hormones. It is thought that intense exercise can result in changes in zinc metabolism. Zinc has been demonstrated to be lowered in trained adolescent gymnasts and even lower in females in the general population. This reduction might play a role in abnormalities of puberty, growth, or muscular performance. [87] Some investigators have concluded zinc might play an important role in modulating serum testosterone levels in normal men. Dietary zinc restriction in normal young men is associated with a significant decrease in serum testosterone concentrations, while zinc supplementation of marginally zinc-deficient normal elderly men resulted in an increase in serum testosterone from 8.3 ± 6.3 to 16.0 ± 4.4 nmol/L ( P = 0.02).[88] However, although zinc deficiency might inhibit testosterone production, zinc supplementation to an individual with adequate levels has not been shown to produce excess testosterone. Zinc deficiency might result in reduced production of growth hormone (GH) and/or insulin-like growth factor I (IGF-I). [89] Oral zinc replacement has normalized growth hormone levels and increased growth rate in teenagers found to be GH-deficient. [90] Zinc supplementation causes a significant increase in liver synthesis of IGF-I (somatomedin C). In chronic zinc deficiency, reduced liver production of IGF-I is responsible for reduced physical growth; moreover, in this situation, receptor resistance to IGF-I (in addition to GH) has been demonstrated. Receptor sensitivity is re-established after supplementation with zinc. Zinc might also play a role in
increasing the number of receptors. [91] Zinc deficiency might affect the metabolism of thyroid hormones. The structure of nuclear thyroid hormone receptors contains zinc ions, crucial for the functional properties of the protein. [80] In experimental animals, zinc deficiency decreases concentrations of triiodothyronine (T 3 ) and free thyroxine (fT 4 ) in serum by approximately 30% when compared with zinc-adequate controls. The concentration of thyroxine (T 4 ) in serum was not affected by zinc deficiency. In these animals, zinc deficiency also decreased the activity of hepatic iodothyronine 5´-deiodinase by 67%. [81] Toxicity
Zinc supplementation is generally safe if maintained at levels within two to eight times the RDA. Symptoms of zinc toxicity include gastrointestinal irritation, vomiting, adverse changes in HDL/LDL cholesterol ratios, and impaired immunity. The latter develops when levels above 180 mg/day are consumed for more than several weeks. Excess intake of zinc may either lower copper levels or aggravate an existing marginal copper deficiency. Because of the multiple interactions of zinc with hormones critical to strength and body composition, it is recommended that athletes get a determination of zinc nutriture and supplement if required. Summary Based upon available information, strength athletes are likely to obtain improved results by following a supplementation routine which includes: • creatine monohydrate (at least 3 g/day) • a post-workout protein shake (40 g of protein) • vitamin C (1–3 g/day) • a multivitamin/mineral formulation containing approximately —3 mg of boron —200 mcg of chromium —200 mcg of selenium —100 mcg of vanadium —15 mg of zinc.
The published results to date on HMB are impressive. For athletes utilizing HMB, the recommended dosage is 3 g/day. While a theoretical argument can be made for the inclusion of phosphatidylserine in a supplement routine, the high cost and the lack of information on bottom-line results of improved strength or body composition make it difficult to justify its use. Although compelling evidence could be used to make an argument for many of the isolated amino acids, a high-quality protein supplement, such as whey, provides adequate levels of all of the amino acids for the majority of athletes. Because of the correlation of low glutamine levels and overtraining, supplementing 2 g/day of glutamine in addition to a protein supplement, in individuals whose training regimen places them at risk for overtraining, seems prudent.
SPORTS NUTRITION FOR ENDURANCE ATHLETES Panax ginseng Panax ginseng, also known as Panax schinseng, is a member
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of the family Araliaceae. In Mandarin Chinese it is called Ren Shen but is commonly referred to as Korean or Chinese ginseng. Several closely related species are also often sold as ginseng. These include Panax quinquefolium (American ginseng); Panax notoginseng, also known as Panax pseudoginseng (Himalayan ginseng), and Panax japonicum (Japanese ginseng). Ginseng was used traditionally as a tonic for a broad range of medical conditions. It was believed to be a revitalizing agent capable of enhancing health and promoting longevity (for a more detailed discussion, see Ch. 100 ). Soviet scholars, beginning in the early 1950s, were the first to establish the fact that many Araliaceae family plants, especially Panax ginseng, are adaptogens. [92] Adaptogens, among their many properties, are thought to promote regeneration of the body after stress or fatigue and to rebuild strength. Because of its reputation as an adaptogen, Panax ginseng is among the most popular botanical supplements used by athletes. Many animal studies with Panax ginseng, or its active components, have demonstrated an enhanced response to physical or chemical stress. [93] [94] [95] [96] [97] In rats, the aqueous suspensions of roots of Panax ginseng were tested for anti-stress activity by the “mice swimming endurance test” and anabolic activity by noting gain in body weights and muscle. A significant increase in mice swimming time was shown by ginseng-fed rats as compared with the control group. [98] In animal models, administration of ginseng has been shown to impact several hormones which might impact performance. High doses of ginseng have been reported to increase blood testosterone level. [99] Experiments indicate that the binding of corticosteroid to certain brain regions is increased in adrenalectomized rats given ginseng saponin. [100] Ginseng saponin has also been reported to act on the hypothalamus and/or hypophysis, stimulating ACTH secretion which results in increased synthesis of corticosterone in the adrenal cortex. [101] While studies with animals have been compelling, ginseng’s value as an ergogenic aid in humans is still equivocal. [102] Extracts of Panax ginseng are reported to increase plasma total and free testosterone, dihydrotestosterone, and FSH and LH levels in infertile males. [103] The addition of ginseng root extract to a multivitamin base is reported to have improved subjective parameters in a population exposed to the stress of high physical and mental activity. [104] In a double-blind, randomized, cross-over study, 50 healthy males received two capsules of a preparation containing ginseng extract, dimethylamino-ethanol bitartrate, vitamins, minerals, and trace elements, or two capsules of placebo every day for 6 weeks. The total workload and maximal oxygen consumption during exercise were significantly greater after the ginseng preparation than after placebo. The authors also noted decreased plasma lactate levels, carbon dioxide production, and heart rate during exercise in participants receiving the ginseng preparation. [105] Others evaluated the impact on performance of a ginseng saponin extract (8 or 16 mg/ kg body weight) ingested daily for 7 days. Although time to exhaustion was significantly less during the pre-supplementation control trial than during the placebo and ginseng trials, no significant difference was found between the placebo and the ginseng trials. [106] It should be noted that the duration of the supplementation period was only 1 week in this trial. Since, historically, ginseng, as a tonic, is used for prolonged time periods and since positive results have been reported following 6 weeks of supplementation, a longer trial might have demonstrated an ergogenic effect. Research in support of the use of Panax ginseng as an ergogenic aid, although equivocal, is promising. Because of the anecdotal reputation and allure this plant holds, it is likely to continue to be utilized by many athletes. Dosage
The quality of available ginseng preparations can vary greatly, so it is imperative to use Panax ginseng with documented potency. A typical dose for general tonic effect would contain at least 25 mg of the saponin ginsenoside. [107] Panax ginseng contains 2–3% ginsenosides, so a dose of 8–12 g of crude herb, assuming it is of high quality, will provide adequate saponin content. Because of the variability in quality of Panax ginseng available, utilizing a preparation standardized for ginsenoside content may be preferable. The dosage for a product standardized to 5% ginsenosides would be 500 mg/day, and to 14% ginsenosides would be about
180 mg.[107] If utilizing ginseng for a prolonged period of time, some authors have recommended discontinuing supplementation periodically for 2 week intervals. Toxicity
The problem of quality control makes toxicology difficult to address. Studies have been performed on standardized extracts of ginseng which demonstrate the absence of side-effects and mutagenic or teratogenic effects. However, toxicity has been reported with products of uncertified constituents. Eleutherococcus senticosus Eleutherococcus senticosus, also known botanically as Acanthopanax senticosus, is a member of the Araliaceae family which also contains Panax ginseng. In China, the plant is called Ci Wu Jia; however, it is most commonly referred to as Siberian ginseng. Because of its wide availability and lower cost, the dried root and rhizome is commonly used as a ginseng substitute; however,
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ginsenosides, characteristic of Panax sp., are not found in the roots of Eleutherococcus senticosus.[107] (For a more detailed discussion, see Ch. 83. )
[ 9]
Eleutherococcus senticosus is classified as an adaptogen and is believed to promote recovery and improve endurance. It has a long history of use in Chinese herbal medicine where it was used to enhance general health, longevity, appetite and memory. Soviet scientists, beginning in the late 1950s, because of the rarity of Panax ginseng, shifted the focus of their research to other members of the Araliaceae family in order to find suitable substitutes. Four adaptogenic plants were identified, studied and finally introduced into therapeutic practice, between 1955 and 1964. Eleutherococcus senticosus was considered to be the most important of these substitutes.[108] Reports indicate that Eleutherococcus was used routinely by both Soviet Olympic athletes and military officers. Extracts of Eleutherococcus prolong the exercise time to exhaustion in swimming rats, [109] and modulate changes of the hypophyseo-adrenal system in rats under extreme conditions.[110] Farnsworth et al [111] reviewed the results of clinical trials of Eleutherococcus in humans. The data they gathered indicated that ingestion of extracts from the plant increased the ability to accommodate to adverse physical conditions, improved mental performance, and enhanced the quality of work under stressful conditions such as during athletic performance. [111] Others, however, have concluded that supplementation of Eleutherococcus senticosus had no ergogenic effect on the measured parameters associated with submaximal and maximal aerobic exercise tasks. The effect on performance during submaximal and maximal aerobic exercise was measured in 20 highly trained distance runners randomly assigned to matched pairs. Participants consumed either 3.4 ml of extract or placebo daily for 6 weeks. During the 8 week double-blind study, subjects completed five trials of 10 minute runs on a treadmill at their 10 km race pace and a maximal treadmill test. No significant differences were observed between Eleutherococcus- and placebo-supplemented groups for heart rate, oxygen consumption, respiratory exchange ratio, and rating of perceived exertion during the 10 km and maximal treadmill tests.[112] Recently, Eleutherococcus senticosus has received attention in the popular press under the name of Ci Wu Jia. Trials of its effect on performance have been sponsored by PacificHealth Laboratories, Inc., which is the manufacturer of a standardized extract and the holder of a patent for the use of Ci Wu Jia to enhance stamina and physical performance during, and enhance recovery following cessation of, exercise. All reports on Ci Wu Jia’s impact on performance have been based on information provided by this manufacturer. Ci Wu Jia reportedly has a carbohydrate-sparing action, shifting metabolism to a higher utilization of fat for energy. The carbohydrate shift is also reported to delay the lactic acid build-up associated with muscle fatigue. Reports indicate that Ci Wu Jia might slightly reduce heart rate during exercise and recovery. Participants have usually consumed 800 mg/day of the standardized extract for 2 weeks. Overall, the evidence for an ergogenic affect from Eleutherococcus senticosus is fair. The reported benefits Russian athletes received from supplementation remain the most compelling evidence to date on the ergogenic potential of this plant. Dosage
Recommended doses vary depending on the form of Eleutherococcus utilized. The dose of a 1:1 fluid extract (33% ethanol) is usually between 2.0 and 4.0 ml one to three times per day; however, doses up to 16.0 ml have been used. A standardized 20:1 solid concentrate, is also available. In this form, a minimum recommended dosage would be 300 mg/day, equivalent to 6 g of powdered root. Better results might be experienced at higher doses. In order to avoid accommodation, Eleutherococcus should be used for no longer than 60 consecutive days, followed by a period of 2–3 weeks of abstinence before again beginning supplementation. [111] Toxicity
Toxicity studies in animals have demonstrated that Eleutherococcus extracts are virtually non-toxic. In human clinical studies it was demonstrated that in the recommended dosage range, they (33% ethanol) are well tolerated and side-effects are infrequent. A few studies found mild side-effects at higher dosages (4.5–6.0 ml three times/day) when used for long periods (60 days). The symptoms included insomnia, irritability, melancholy, and anxiety. Carnitine Carnitine is promoted as a supplement needed to improve the body’s ability to use stored fat as fuel. Supplementation purportedly enhances lipid oxidation, increases VO2max , and decreases plasma lactate accumulation during exercise. Carnitine is a tri-methylated amino acid, roughly similar in structure to choline. The synthesis of carnitine begins with the methylation of lysine by S-adenosylmethionine. Cofactors required for optimal synthesis include: • magnesium • iron • ascorbic acid • folic acid 533
• methylcobalamin • betaine • pyridoxal 5´ phosphate • niacin. Carnitine is located in the mitochondrial membrane and is a cofactor needed for the transformation of free long-chain fatty acids (LCFAs) into acyl-carnitines for subsequent transport into the mitochondrial matrix. Inside the mitochondria, LCFAs are metabolized into energy by the process of beta-oxidation. Several investigators have suggested that L-carnitine supplementation might benefit athletes. One study investigated the effect of giving 2 g/day of L-carnitine for 6 weeks to seven male marathon athletes. Improved running speed of 5.68% and decreased average oxygen consumption and heart rate in the treadmill test followed supplementation. The authors suggest that for carnitine to be effective as an ergogenic aid, several preconditions must be met: having an adequate supply of lipids available as fuel, shifting metabolism towards the utilization of fats as an energy source, and having a relative shortage of available endogenous carnitine. Because the average free and total plasma carnitine levels were below the normal ranges prior to supplementation, the L-carnitine might have helped to overcome a relative
endogenous deficiency for the participants involved in this study. [113] In a double-blind cross-over study of 10 moderately trained male subjects, either 2 g of L-carnitine or placebo are provided orally 1 hour prior to exercise. Supplementation with L-carnitine induced a significant post-exercise decrease of plasma lactate and pyruvate and a concurrent increase of acetylcarnitine. [114] Another study gave 2 g of L-carnitine or a placebo to subjects 1 h before they began exercise. At the maximal exercise intensity, treatment with L-carnitine increased both maximal oxygen uptake and power output. The authors also reported that, at similar exercise intensities, oxygen uptake, carbon dioxide production, pulmonary ventilation and plasma lactate were reduced in participants receiving L-carnitine. [115] While some of the results with L-carnitine supplementation have been promising, not all research is in agreement. One review of carnitine and physical exercise came to the following, among other, conclusions regarding carnitine supplementation: [116] • its impact on performance in athletes is equivocal • it does not enhance fatty acid oxidation, spare glycogen or postpones fatigue during exercise • it does not stimulate pyruvate dehydrogenase activity • it does not reduce body fat or help with weight loss. One research group found chronic carnitine supplementation, 6 g/day, resulted in no differences in VO2 , respiratory exchange ratio, heart rate, or carbohydrate and fat utilization. They also reported that muscle carnitine concentration at rest was unaffected by supplementation. [117] Similar results were reported with carnitine supplementation at 4 g/day for 14 days, which, while effective at increasing plasma total acid-soluble and free carnitine concentrations, had no significant effect on muscle carnitine concentrations. [118] Another group found that loading of athletes with L-carnitine for the 10 days prior to a marathon, while abolishing the exercise-induced fall in plasma-free carnitine and increasing the production of acetylcarnitine, resulted in no detectable improvement in performance. [119] Still another study investigated the effects of L-carnitine supplementation on metabolism and performance of endurance-trained athletes during and after a marathon run. In a double-blind cross-over field study, seven male subjects received 2 g of L-carnitine 2 hours before the start of a marathon run and again after 20 km of running. Although the administration of L-carnitine was associated with a significant increase in the plasma concentration of all analyzed carnitine fractions, significant changes in running time, plasma concentrations of carbohydrate metabolites (glucose, lactate, and pyruvate), of fat metabolites (free fatty acids, glycerol, and beta-hydroxybutyrate), of hormones (insulin, glucagon, and cortisol); and of enzyme activities (creatine kinase and lactate dehydrogenase) were not observed. [120] Although available data on L-carnitine as an ergogenic aid is not compelling, under some experimental conditions pretreatment has favored aerobic processes. It is possible that L-carnitine might only exert a beneficial effect when there are actual deficiencies. Availability of fat as a substrate for fuel might also impact on the ability of carnitine to act as an ergogenic aid. Dosage
Supplementation of 2 g 1 hour prior to intensive exercise might provide some benefits; however, based on the mixed results and the cost of the supplement, chronic administration of L-carnitine is difficult to justify. Toxicity
See above. Choline Choline supplements have been advocated as a means of preventing the decline in choline reported to occur during exercise. Choline in the diet primarily consists of phosphatidylcholine, which after absorption by the intestinal mucosa, is metabolized to choline in the liver. Most choline is re-phosphorylated to phosphatidylcholine; however, a small amount of choline is carried to
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the brain via the bloodstream, where it is converted to acetylcholine, a chemical messenger required for adequate nerve impulses and memory storage and retrieval. Running a 26 km marathon reduced plasma choline by approximately 40% according to one study. [121] The decline has been proposed to reduce acetylcholine levels, resulting in a reduction in the transmission of contraction-generating impulses across skeletal muscle. [122] It has been proposed that this reduction might negatively affect endurance performance. [121] [122] One study investigated the effect of lecithin on the plasma choline concentrations during continuous strain in 10 top level triathletes (four women and six men). The participants received either a placebo or 0.2 g lecithin/kg body mass 1 hour before each exercise. Bicycle exercise without lecithin supply decreased plasma choline concentrations in all the triathletes, on average by 16.9%. When lecithin was given before exercise, average plasma choline concentrations remained at the same level as the initial values. In trial II, with 13 adolescent runners (three girls and 10 boys), mean plasma choline concentrations remained stable when running without supplementation of lecithin. [123] However, another research group found that trained cyclists do not deplete choline during supramaximal brief or prolonged submaximal exercise, nor do they benefit from choline supplementation, as choline bitartrate (2.43 g), to delay fatigue under these conditions. [124] No evidence to date provides compelling justification for the supplementation of choline as an ergogenic aid. Its potential efficacy for improving physical performance remains largely theoretical. Coenzyme Q10 (ubiquinone) Coenzyme Q10 (CoQ10 ), because of its role in mitochondrial energy production, is reputed to enhance performance; however, no studies have demonstrated a significant improvement in any aspect of athletic performance. Biopsy of muscle found that CoQ 10 levels were positively correlated to exercise capacity and marathon performance. [125] Providing 150 mg/day of CoQ10 orally for 2 months to a group of middle-aged men resulted in increased circulating blood levels of CoQ 10 and improved perceived level of vigor; no improvement in aerobic capacity was found. [126] Supplementing cyclists with 100 mg/ day of CoQ10 for 8 weeks produced no measurable effect on performance, VO2 max , submaximal physiological parameters, or lipid peroxidation. [127] Others have found that oral ubiquinone was ineffective as an ergogenic aid in both young and older trained men.
[128]
Based upon available research, CoQ 10 appears to have no value as an ergogenic aid. Pyridoxal-alpha-ketoglutarate (PAK) Pyridoxal-alpha-ketoglutarate (PAK) consists of pyridoxine (about 54%) and alpha-ketoglutarate (about 46%). It is thought to improve the generation of high-energy phosphate bonds, such as ATP or GTP. In addition, an increased level of alpha-ketoglutarate, along with pyridoxal 5´-phosphate, in the mitochondria might enhance the transamination of pyruvate to alanine, which may prevent or reduce lactic acid formation. [129] Administration of PAK has been shown to decrease the plasma concentration of lactate in response to isometric exercise in a group of insulin-independent non-ketotic diabetic patients. [130] The administration of 30 mg/kg of PAK for 30 days has been reported to increase VO2 max (a measurement of maximal aerobic power) and to
decrease lactic acid accumulation during short supramaximal workloads. The administration of alpha-ketoglutarate or pyridoxine separately did not alter VO2 max significantly. [129] Individually and in combination, the use of PAK and sodium bicarbonate on short-term maximal exercise capacity was studied in eight cyclists. Oral tablets of sodium bicarbonate and PAK were given in doses of 200 and 50 mg/kg, respectively. The investigators found no significant differences between treatments in the ability to sustain maximum power during the exercise trial; however, the best results obtained were from individuals utilizing both PAK and bicarbonate. PAK supplemented by itself did not improve participants’ ability to sustain maximum power. [131] Dosage
The typical dose is 1800–3000 mg/day, depending upon body weight. While PAK might be complementary to athletic training, particularly in conjunction with sodium bicarbonate, available information is limited. PAK supplementation appears to positively influence some physiological parameters associated with enhanced aerobic performance; however, to date this supplement has not been shown to produce a “bottom line” result of improving actual performance. Pyruvate Supplementation of pyruvate is becoming popular with athletes due to reports of its endurance and weight loss-enhancing effects. Pyruvate is a stable salt form of pyruvic acid, the naturally occurring end-product of the metabolism of carbohydrates. It is stabilized by the addition of either sodium, potassium, calcium, or magnesium to pyruvic acid. Pyruvic acid occurs naturally in the diet, with fruits and vegetables being good sources. Red apples are possibly the best source with an estimated 450 mg of pyruvic acid per apple.
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Pyruvate is a three-carbon compound containing a carboxylic acid and a ketone group. During the process of glycolysis, glucose is converted to pyruvate. Pyruvate is then either converted to acetylCoA, for entry into the citric acid cycle under aerobic conditions, or to lactate under anaerobic conditions. Pyruvate’s mechanism of action for weight loss and for enhancing endurance is unknown. In published research, pyruvate has usually been given in conjunction with dihydroxyacetone. This combination has been reported to be useful in weight loss routines, where it is partially, isocalorically substituted for glucose in obese women. Participants were placed on severely restrictive hypocaloric diets for 21 days while housed in a metabolic ward. In one study, participants fed dihydroxyacetone and pyruvate (DHAP) showed greater weight loss (6.5 ± 0.3 kg, vs. 5.6 ± 0.2 kg for the placebo) and fat loss (4.3 ± 0.2 kg, vs. 3.5 ± 0.1 kg for placebo). [132] In another trial, pyruvate and dihydroxyacetone, given as approximately 20% of energy intake, reduced the reaccumulation of body weight (1.8 ± 0.2 vs. 2.9 ± 0.1 kg) and fat (0.8 ± 0.2 vs. 1.8 ± 0.2 kg) associated with refeeding after a calorie restricted diet. [133] Pyruvate alone has been reported to be an effective addition to a weight loss program. In one study, participants were obese women housed in a metabolic ward consuming a 4.25 MJ/day liquid diet for 21 days with or without pyruvate partially, isoenergetically substituted for glucose. Participants fed pyruvate showed greater weight loss (5.9 ± 0.7 kg, vs. 4.3 ± 0.3 kg for placebo) and fat loss (4.0 ± 0.5 kg, vs. 2.7 ± 0.2 kg for placebo). [40] The reports indicate that pyruvate had no impact on enhancing nitrogen balance, serum protein concentrations or lean body mass in these subjects. [132] [133] [134] Since the published studies were conducted on obese women consuming restricted calorie diets of either 500 or 1,000 calories/day, these weight losses should not be extrapolated to athletes or other populations on normal or high-calorie diets. Additionally, in the published trials pyruvate has been substituted for glucose, a substance which impacts fat metabolism in overweight individuals because of its role in insulin secretion. It is possible, under similar circumstances, that partially, isocalorically substituting protein or fat for glucose might have produced similar, if not better, results. Pyruvate has been reported to increase the time required to reach exhaustion and to decrease perceived exertion. In the published studies, pyruvate was again given in relatively high amounts in conjunction with dihydroxyacetone. In both studies, untrained males received either 100 g of pyruvate and dihydroxyacetone or 100 g of a glucose polymer derived from the hydrolysis of corn starch as a placebo for 7 days. Arm endurance was 133 ± 20 minutes after placebo and 160 ± 22 minutes after DHAP.[135] Leg endurance was 66 ± 4 minutes after placebo and 79 ± 2 minutes after DHAP. [136] Muscle glycogen, determined by biopsy, at rest and exhaustion did not differ between placebo and DHAP subjects. [136] Plasma free fatty acids, glycerol, and beta-hydroxybutyrate were similar during rest and exercise for placebo and DHAP subjects in both studies.[135] [136] Supplementation of a DHAP mixture has also been reported to decrease the perceived level of exertion. [137] Feeding DHAP for 7 days appears to increase submaximal endurance in untrained athletes; however, it is unresolved whether similar results would be obtained with trained athletes. In the published studies 25 g/day of pyruvate were given along with 75 g/day of dihydroxy-acetone; however, in the lay press Stanko has been quoted as saying: “We see a linear response between 2 and 5 g a day and then the response plateaus. In other words, the response with 10 or 15 g or more is the same as with 5 g.” Supporting documentation for this assertion has apparently not been published in scientific literature to date, nor has any research been published on the endurance effects of the supplementation of pyruvate without dihydroxyacetone. Dosage
Dosage recommendations are 2–5 g/day, taken with food. Better results might be obtained by spreading the 5 g into two or three divided doses. Since the reported results on endurance were obtained in trials comparing DHAP against a glucose polymer, the only justifiable conclusion is that subjects consuming 100 g of DHAP rather than 100 g of hydrolyzed corn starch, a substance with no nutritional value, experienced better endurance. Research evaluating the performance effects of adding 2–5 g of pyruvate to the diet of trained athletes still needs to be published. The available evidence suggesting that pyruvate acts as an ergogenic aid in high dosages in combination with dihydroxyacetone is questionable. No evidence exists in support of claims of ergogenic action for pyruvate supplementation at the recommended dose of between 2 and 5 g. Performance drinks Performance drinks are commonly consumed as an ergogenic aid during endurance sports activities. These drinks are designed to maintain normal hydration, electrolyte balance and blood glucose levels during exercise. Current evidence indicates that ingestion of performance drinks during exercise enhances athletic performance and normalizes markers of thermoregulation. A variety of beverages formulated to provide fluid, carbohydrates, and electrolytes during and following exercise are commercially available. These beverages commonly contain 4–8%
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carbohydrate (as glucose, fructose, sucrose or maltodextrins) and small amounts of electrolytes (most often sodium, potassium, and chloride). Contrary to popular belief, rates of sweating and urine flow are not influenced by fluid ingestion during exercise. [138] Studies have shown that 5–10% solutions of glucose, glucose polymers (maltodextrins) and other simple sugars all have suitable gastric-emptying characteristics for the delivery of fluid and moderate amounts of carbohydrate substrate. The optimal concentration of electrolytes, particularly sodium, remains unknown. Most currently available sports drinks provide a low level of sodium (10–25 mmol/L) in recognition of the fact that sodium intake can promote intestinal absorption of fluid as well as assist in rehydration. [139] Exercise and dehydration result in increases in core temperature, body fluid osmolality, and heart rate; losses of plasma and other body fluid volumes; and depletion of glycogen. All of these homeostatic disturbances can be ameliorated by fluid consumption during exercise. [140] During exercise, water and electrolytes are lost from the body in sweat. Sweat rate is determined primarily by the metabolic rate and the environmental temperature and humidity. Under some conditions, the sweat rate can exceed the maximum rate of gastric emptying of ingested fluids. If this occurs, some degree of dehydration is
observed. Excessive replacement of sweat losses with plain water or fluids with a low sodium content following prolonged exercise has resulted in hyponatraemia, so sodium replacement is considered essential for post-exercise rehydration. [141] For moderate-intensity exercise, water ingestion 30–60 minutes prior to exercise seems to minimize homeostatic disturbances; however, at higher intensities of athletic performance, it probably has little effect. [140] During exercise, ingestion of both water and carbohydrate beverages has been shown to minimize homeostatic disturbances. Subjects allowed to drink a carbohydrate-electrolyte beverage (4.85% polycose, 2.65% fructose) or distilled water ad libitum during 3 hours of continuous exercise in the heat (31.5°C) showed no significant differences between drinks for rectal temperature, heart rate, or sweat rate during exercise. [142] No differences in thermoregulatory responses in individuals consuming either carbohydrate beverages or water have been observed. [143] The efficacy of a given drink is limited by the rate of absorption of fluid from the intestines, which is in turn limited by gastric emptying. Several factors influence gastric emptying, including exercise intensity and the carbohydrate composition of the solution. [144] The gastric-emptying rate might also be influenced by the caloric content, volume, osmolality, temperature, and pH of the ingested fluid; metabolic state and biochemical individuality of the athlete; and the ambient temperature. [145] The caloric content of the ingested fluid might be the most important variable governing gastric-emptying rate. At rest and during running, water has a faster gastric-emptying time than all other drinks. Gastric emptying is progressively slowed as the caloric content of the fluid increases. [144] During moderate exercise, gastric emptying occurs at a rate similar to that during rest; however, more intense exercise appears to inhibit gastric emptying. Evidence indicates that beverages containing below 10% carbohydrate have gastric-emptying rates closest to that of water. [146] Drinks containing less than or equal to 8–10% carbohydrate are absorbed into the body at similar rates and should behave similarly in replenishing body fluids lost in sweat during exercise. [147] Several other factors have been shown to impact gastric emptying. Isotonic drinks appear to empty quickly throughout exercise, whereas the gastric-emptying rate of hypertonic drinks has been shown to decrease over time. [148] Fat is believed to delay gastric emptying; however, medium-chain triglycerides (MCTs) might not inhibit gastric emptying as most fat does. Research indicates that MCT-containing drinks have faster gastric-emptying times than drinks containing 100% maltodextrins. [149] It has been suggested that maltose might be a superior source of carbohydrate for endurance athletes. Some researchers have suggested that ingestion of an 8% solution of maltodextrin or sucrose every 15 minutes during exercise might provide optimal fluid and carbohydrate replacement. [150] The rates of gastric emptying and the peak rates of exogenous carbohydrate oxidation are not significantly different between maltose and glucose. [151] While ingestion of 13 g carbohydrate per hour did not improve performance during prolonged moderate intensity cycling in one study, [152] most studies report that ingestion of carbohydrate beverages has a beneficial effect on performance. Carbohydrate ingested during exercise appears to be readily available as a fuel for the working muscles, at least when the exercise intensity does not exceed 70–75% of maximum oxygen uptake. [153] Rating of perceived exertion is reported to be higher in athletes consuming water than in athletes consuming carbohydrate drinks. [154] For exercise leading to exhaustion in less than 30 minutes, carbohydrate ingestion is not effective in minimizing homeostatic perturbations or improving exercise performance; [140] however, for exercise of longer duration, ingestion of performance beverages appears to enhance performance. Research has shown that 275 ml of a 6% carbohydrate-electrolyte beverage consumed every 20 minutes maintained blood glucose and enhanced performance better than water during endurance cycling. [155] One study compared the effects of orange flavored drinks containing 0, 6.4, and 10% carbohydrate. The solutions, 3 ml/kg body weight, were given double-blind and counter-balanced at time 0 and every 20 minutes during exercise. Blood glucose and lactate, and temperature were similar for all solutions; however,
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performance improved with consumption of a carbohydrate drink during exercise. The best results were obtained with ingestion of a 10% carbohydrate drink.
[ 156]
Eight well-trained men cycled for up to 255 minutes at a power output corresponding to VO2 at lactate threshold (approximately 68% VO2 max ) on three occasions separated by at least 1 week. Subjects drank 5 ml/kg body weight of either a water placebo or a liquid beverage containing a moderate (6% carbohydrate) or high (12% carbohydrate) concentration of carbohydrate, beginning at minute 14 of exercise and every 30 minutes thereafter. Exercise time to fatigue was shorter in subjects receiving placebo (190 minutes) as compared with 6% carbohydrate (235 minutes) and 12% carbohydrate (234 minutes) beverages. [157] In another study, 12 subjects were exercised to exhaustion on a cycle ergometer at a workload corresponding to 70% of maximum oxygen uptake. In one trial, no drinks were given, and in the other trials subjects drank 100 ml every 10 minutes. Median exercise time was greatest (110.3 minutes) for individuals receiving a hypotonic glucose-electrolyte solution (90 mmol/L glucose; 60 mmol/L Na + ; 240 mosmol/kg), followed by individuals receiving an isotonic glucose-electrolyte solution (I: 200 mmol/L glucose; 35 mmol/L Na + ; 310 mosmol/kg) (107.3 min), water (93.1) and no drink (80.7). Significant treatment effects were also observed for heart rate, rectal temperature and serum osmolality. [158] Twelve highly trained male runners ran 15 km at self-selected pace on a treadmill in warm conditions to demonstrate differences in physiological responses, fluid preferences, and performance when ingesting sports drinks or plain water before and during exercise. One hour prior to the start of running, an equal volume (1,000 ml) of either water or a 6 or 8% carbohydrate-electrolyte drink was ingested. Blood glucose was significantly higher 30 minutes following ingestion of the 6 and 8% carbohydrate-electrolyte beverages compared with water, significantly lower at 60 minutes post-ingestion with both sports drinks than with water, but similar after 7.5 km of the run for all beverages. During the first 13.4 km, oxygen uptake and run times were not different between trials; however, the final 1.6 km performance run was faster with both carbohydrate-electrolyte drinks than with water. [159] Research indicates that a sugar drink immediately prior to exercise can impair performance. Carbohydrates will invoke an insulin response which increases the likelihood of hypoglycemia occurring during exercise. A fall in blood glucose will result from the ingestion of glucose solutions fed 15–45 minutes before prolonged exercise; however, the consumption of 18–50% solutions of glucose or glucose polymers 5 minutes before prolonged exercise has potential for improving endurance performance.[140] Many experts recommend consuming a beverage high in carbohydrates within 1 hour after exercise. Exercise-induced depletion of muscle glycogen levels can be rapidly restored by glucose ingestion. Provided adequate carbohydrate is consumed, it appears that the frequency of intake, the form (liquid vs. solid) and the presence of other macronutrients does not affect the rate of glycogen storage. [160] During the post-exercise recovery period, ingesting a carbohydrate-electrolyte beverage is effective in minimizing physiological disturbances. Subjects drink more; plasma volume increases to a higher level; plasma osmolality, glucose, and potassium are greater; and body weight increases more with the ingestion of carbohydrate beverages than with pure water. [161] Dosage
The optimum frequency, volume and composition of drinks will vary widely depending on the intensity and duration of the exercise, the environmental conditions and the physiology of the individual. However, in general, isotonic beverages, with either glucose, glucose polymers, or maltodextrins as the carbohydrate source, produce the best results. Prior to exercise, only water should be consumed. Drinking carbohydrate solutions 15–60 minutes prior to exercise should be avoided since it can impair performance; however, ingestion immediately prior to beginning exercise might be beneficial. This is because once endurance exercise is started, insulin is generally not increased, so the carbohydrates will likely be available as energy substrates. The staggered ingestion of performance drinks will be beneficial when exercise duration exceeds 30 minutes; however, during shorter duration exercise and especially weight-lifting, there appears to be no additional benefit in ingesting anything other than water.
SUMMARY Based upon available information, evidence remains mixed but promising on the supplementation of Panax ginseng and Eleutherococcus senticosus. L-Carnitine’s role as an ergogenic aid remains something of a mystery. The mixed results reported in the literature and the high cost of the supplement make it difficult to justify chronic administration of 2 g/day. No evidence to date supports the supplementation of choline as an ergogenic aid. CoQ 10 ’s failure in several studies to demonstrate any performance-enhancing effect should end any debate or recommendations concerning routine administration of this nutrient as an ergogenic aid. Although PAK supplementation has been shown to enhance certain parameters associated with aerobic exercise, it has not yet demonstrated improved performance. Although
evidence suggests that pyruvate acts as an ergogenic aid in high dosages in combination with dihydroxyacetone, available
538
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PD, Costill DL, Fink WJ et al. Effects of exercise and carbohydrate composition on gastric emptying. Med Sci Sports Exerc 1986; 18: 658–662
147. Davis
JM, Burgess WA, Slentz CA, Bartoli WP. Fluid availability of sports drinks differing in carbohydrate type and concentration. Am J Clin Nutr 1990; 51: 1054–1057
148. Rehrer
NJ, Brouns F, Beckers EJ et al. Gastric emptying with repeated drinking during running and bicycling. Int J Sports Med 1990; 11: 238–243
149. Beckers
EJ, Jeukendrup AE, Brouns F et al. Gastric emptying of carbohydrate – medium chain triglyceride suspensions at rest. Int J Sports Med 1992; 13: 581–584
150. Wagenmakers 151. Hawley
AJ, Brouns F, Saris WH, Halliday D. Oxidation rates of orally ingested carbohydrates during prolonged exercise in men. J Appl Physiol 1993; 75: 2774–2780
JA, Dennis SC, Nowitz A et al. Exogenous carbohydrate oxidation from maltose and glucose ingested during prolonged exercise. Eur J Appl Physiol 1992; 64: 523–527
152. Burgess
WA, Davis JM, Bartoli WP, Woods JA. Failure of low dose carbohydrate feeding to attenuate glucoregulatory hormone responses and improve endurance performance. Int J Sport Nutr 1991; 1: 338–352 153. Maughan 154. Carter
RJ, Noakes TD. Fluid replacement and exercise stress. A brief review of studies on fluid replacement and some guidelines for the athlete. Sports Med 1991; 12: 16–31
155. Davis
JE, Gisolfi CV. Fluid replacement during and after exercise in the heat. Med Sci Sports Exerc 1989; 21: 532–539 JM, Lamb DR, Pate RR et al. Carbohydrate-electrolyte drinks. effects on endurance cycling in the heat. Am J Clin Nutr 1988; 48: 1023–1030
156. Bacharach 157. Davis
DW, von Duvillard SP, Rundell KW et al. Carbohydrate drinks and cycling performance. J Sports Med Phys Fitness 1994; 34: 161–168
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158. Maughan
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161. Carter
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Chapter 60 - Stress management Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION Stress is defined as any disturbance – heat or cold, chemical toxin, microorganisms, physical trauma, strong emotional reaction, etc. – that can trigger the “stress response”. How an individual handles stress plays a major role in determining their level of health. Comprehensive stress management involves a truly wholistic approach designed to counteract the everyday stresses of life. Most often the stress response is so mild it goes entirely unnoticed. However, if stress is extreme, unusual, or long-lasting, the stress response can be overwhelming and quite harmful to virtually any body system. Before discussing methods on how to help patients deal effectively with stress, it is important to understand the stress response. Ultimately, the success of any stress management program is dependent on its ability to improve an individual’s immediate and long-term response to stress.
THE GENERAL ADAPTATION SYNDROME The stress response is actually part of a larger response known as the “general adaptation syndrome”, a term coined by the pioneering stress researcher Hans Selye. To fully understand how to combat stress, it is important to understand the general adaptation syndrome. The general adaptation syndrome is composed of three phases: alarm, resistance, and exhaustion. [1] These phases are largely controlled and regulated by the adrenal glands. The initial response to stress is the alarm reaction which is often referred to as the “fight or flight response”. The fight or flight response is triggered by reactions in the brain which ultimately cause the pituitary gland to release adrenocorticotropic hormone (ACTH), which causes the adrenals to secrete adrenaline and other stress-related hormones. The fight or flight response is designed to counteract danger by mobilizing the body’s resources for immediate
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physical activity. As a result, the heart rate and force of contraction of the heart increases to provide blood to areas necessary for response to the stressful situation. Blood is shunted away from the skin and internal organs, except the heart and lung, while at the same time the amount of blood supplying required oxygen and glucose to the muscles and brain is increased. The rate of breathing increases to supply necessary oxygen to the heart, brain, and exercising muscle. Sweat production increases to eliminate toxic compounds produced by the body and to lower body temperature. Production of digestive secretions is severely reduced since digestive activity is not critical for counteracting stress. Blood sugar levels increase dramatically as the liver converts stored glycogen into glucose for release into the bloodstream. While the alarm phase is usually short-lived, the next phase – the resistance reaction – allows the body to continue fighting a stressor long after the effects of the fight or flight response have worn off. Other hormones, such as cortisol and other corticosteroids secreted by the adrenal cortex, are largely responsible for the resistance reaction. For example, these hormones stimulate the conversion of protein to energy, so that the body has a large supply of energy long after glucose stores are depleted, and promote the retention of sodium to keep blood pressure elevated. As well as providing the necessary energy and circulatory changes required to deal effectively with stress, the resistance reaction provides the changes required for meeting emotional crisis, performing strenuous tasks and fighting infection. However, while the effects of adrenal cortex hormones are quite necessary when the body is faced with danger, prolongation of the resistance reaction or continued stress increases the risk of significant disease (including diabetes, high blood pressure, and cancer) and results in the final stage of the general adaptation syndrome, i.e. exhaustion. Exhaustion may manifest as a partial or total collapse of a body function or specific organ. Two of the major causes of exhaustion are loss of potassium ions and depletion of adrenal glucocorticoid hormones like cortisone. Loss of potassium results in cellular dysfunction and, if severe, cell death. Adrenal glucocorticoid store depletion decreases glucose control, resulting in hypoglycemia. Another cause of exhaustion is weakening of the organs. Prolonged stress places a tremendous load on many organ systems, especially the heart, blood vessels, adrenals, and immune system and is associated with many common diseases, as listed in Table 60.1 .
STRESS: A HEALTHY VIEW The father of modern stress research was Hans Selye MD. Having spent many years studying stress, Dr Selye TABLE 60-1 -- Diseases strongly linked to stress [1] • Angina • Asthma • Autoimmune disease • Cancer • Cardiovascular disease • Common cold • Diabetes (adult onset – type II) • Depression • Headaches • Hypertension • Immune suppression • Irritable bowel syndrome • Menstrual irregularities
• Premenstrual tension syndrome • Rheumatoid arthritis • Ulcers • Ulcerative colitis developed valuable insights into the role of stress in disease. According to Dr Selye, stress in itself should not be viewed in a negative context. It is not the stressor that determines the response; instead it is the individual’s internal reaction which then triggers the response. This internal reaction is highly individualized. What one person may experience as stress, the next person may view entirely differently. Selye perhaps summarized his view best in a passage in his book The Stress of Life:[2] No one can live without experiencing some degree of stress all the time. You may think that only serious disease or intensive physical or mental injury can cause stress. This is false. Crossing a busy intersection, exposure to a draft, or even sheer joy are enough to activate the body’s stress mechanisms to some extent. Stress is not even necessarily bad for you; it is also the spice of life, for any emotion, any activity causes stress. But, of course, your system must be prepared to take it. The same stress which makes one person sick can be an invigorating experience for another. The key statement Selye made may be “your system must be prepared to take it”. A significant body of knowledge has now accumulated delineating methodologies for assisting patients in developing healthful, rather than disease-facilitating, responses to both short-term and long-term stress.
DIAGNOSTIC CONSIDERATIONS Many people who are “stressed out” may not be able to identify exactly what is causing them to feel stressed. Typical presenting symptoms include insomnia, depression, fatigue, headache, upset stomach, digestive disturbances, and irritability. To determine the role that stress may play, the “social readjustment rating scale” developed by Holmes & Rahe [3] may be utilized (see Table 60.2 ). The scale was originally designed to predict the risk of a serious disease due to stress. Various life-changing events are numerically
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TABLE 60-2 -- The social readjustment rating scale Rank Life event
Mean value
1
Death of spouse
100
2
Divorce
73
3
Marital separation
65
4
Jail term
63
5
Death of a close family member
63
6
Person injury of illness
53
7
Marriage
50
8
Fired at work
47
9
Marital reconciliation
45
10
Retirement
45
11
Change in health of family member
44
12
Pregnancy
40
13
Sex difficulties
39
14
Gain of a new family member
39
15
Business adjustment
39
16
Change in financial state
38
17
Death of a close friend
37
18
Change to different line of work
36
19
Change in number of arguments with spouse
35
20
Large mortgage
31
21
Foreclosure of mortgage or loan
30
22
Change in responsibilities at work
29
23
Son or daughter leaving home
29
24
Trouble with in-laws
29
25
Outstanding personal achievement
28
26
Wife begins or stops work
26
27
Beginning or end of school
26
28
Change in living conditions
25
29
Revision of personal habits
24
30
Trouble with boss
23
31
Change in work hours or conditions
20
32
Change in residence
20
33
Change in schools
20
34
Change in recreation
19
35
Change in church activities
19
36
Change in social activities
18
37
Small mortgage
17
38
Change in sleeping habits
16
39
Change in number of family get-togethers
15
40
Change in eating habits
15
41
Vacation
13
42
Christmas
12
43
Minor violations of the law
11
rated according to their potential for causing disease. Notice that even events commonly viewed as positive, such as an outstanding personal achievement, carry with them stress. If a person is under a great deal of immediate stress or has endured a fair amount of stress over a few months time or longer, it is appropriate to more accurately assess adrenal dysfunction by utilizing laboratory methods. Interpretation
The standard interpretation of the social readjustment rating scale is that a total of 200 or more units in 1 year is considered to be predictive of a high likelihood of experiencing a serious disease. However, rather than using the scale solely to predict the likelihood of serious disease, the scale can be used to evaluate a person’s level of stressor exposure, as everyone reacts differently to stressful events.
THERAPEUTIC APPROACH Whether the patient is currently aware of it or not, they have developed a pattern for coping with stress. Unfortunately, most people have found patterns and methods that ultimately do not support good health. Negative coping patterns must be identified and replaced with positive ways of coping. Try to identify any negative or destructive coping patterns listed in Table 60.3 that the patient may have developed and replace the pattern with more positive measures for dealing with stress. Stress management can be substantially improved by assisting the patient in five equally important areas: • techniques to calm the mind and promote a positive mental attitude • lifestyle factors • exercise • a healthful diet designed to nourish the body and support physiological processes • dietary and botanical supplements designed to support the body as a whole, but especially the adrenal glands. Calming the mind and body Learning to calm the mind and body is extremely important in relieving stress. Among the easiest methods for the patient to learn are relaxation exercises. The goal of relaxation techniques is to produce a physiological response known as a “relaxation response” – a response that is exactly opposite to the stress response. Although an individual may relax by simply sleeping, watching television, or reading a book, relaxation techniques are designed specifically to produce the “relaxation response”. The relaxation response was a term coined by Harvard professor and cardiologist Herbert Benson MD in the early 1970s to describe a physiological response that is just the opposite of the stress response. [1] With the stress response (see Table 60.4 ), the sympathetic nervous TABLE 60-3 -- Negative coping patterns • Dependence on chemicals —drugs, legal and illicit —alcohol —smoking • Overeating • Too much television • Emotional outbursts • Feelings of helplessness • Overspending • Excessive behavior
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TABLE 60-4 -- The stress response • The heart rate and force of contraction of the heart increase to provide blood to areas necessary for response to the stressful situation • Blood is shunted away from the skin and internal organs, except the heart and lung, while at the same time the amount of blood supplying required oxygen and glucose to the muscles and brain is increased • The rate of breathing increases to supply necessary oxygen to the heart, brain, and exercising muscle • Sweat production increases to eliminate toxic compounds produced by the body and to lower body temperature • Production of digestive secretions is severely reduced since digestive activity is not critical for counteracting stress • Blood sugar levels are increased dramatically as the liver dumps stored glucose into the bloodstream system dominates. With the relaxation response (see Table 60.5 ), the parasympathetic nervous system dominates. The parasympathetic nervous system controls bodily functions such as digestion, breathing, and heart rate during periods of rest, relaxation, visualization, meditation, and sleep. While the sympathetic nervous system is designed to protect against immediate danger, the parasympathetic system is designed for repair, maintenance, and restoration of the body. The relaxation response can be achieved through a variety of techniques. The methodology should be determined by patient interest, as all produce the same physiological effect – a state of deep relaxation. The most popular techniques are meditation, prayer, progressive relaxation, self-hypnosis, and biofeedback. To produce the desired long-term health benefits, the relaxation technique should be utilized at least 5–10 minutes each day. Breathing
Producing deep relaxation with any technique requires learning how to breathe. One of the most powerful methods of producing less stress and more energy in the body is by breathing with the diaphragm. Diaphragm breathing activates the relaxation centers in the brain. Table 60.6 lists a 10 step technique for teaching diaphragmatic breathing. TABLE 60-5 -- The relaxation response
• The heart rate is reduced and the heart beats more effectively. Blood pressure is reduced • Blood is shunted towards internal organs, especially those organs involved in digestion • The rate of breathing decreases as oxygen demand is reduced during periods of rest • Sweat production decreases, as a person who is calm and relaxed does not experience nervous perspiration • Production of digestive secretions is increased, greatly improving digestion • Blood sugar levels are maintained in the normal physiological range
TABLE 60-6 -- Instructions to assist patients in learning diaphragmatic breathing 1. Find a comfortable and quiet place to lie down or sit 2. Place your feet slightly apart. Place one hand on your abdomen near your navel. Place the other hand on your chest 3. You will be inhaling through your nose and exhaling through your mouth 4. Concentrate on your breathing. Note which hand is rising and falling with each breath 5. Gently exhale most of the air in your lungs 6. Inhale while slowly counting to 4. As you inhale, slightly extend your abdomen, causing it to rise about 1 inch. Make sure that you are not moving your chest or shoulders 7. As you breathe in, imagine the warmed air flowing in. Imagine this warmth flowing to all parts of your body 8. Pause for 1 second, then slowly exhale to a count of 4. As you exhale, your abdomen should move inward 9. As the air flows out, imagine all your tension and stress leaving your body 10. Repeat the process until a sense of deep relaxation is achieved
Progressive relaxation
One of the most popular techniques for producing the relaxation response is progressive relaxation. The technique is based on a very simple procedure of comparing tension with relaxation. Many people are not aware of the sensation of relaxation. In progressive relaxation an individual is taught what it feels like to relax by comparing relaxation with muscle tension. The basic technique is to have the patient contract a muscle forcefully for a period of 1–2 seconds and then give way to a feeling of relaxation. The procedure systematically goes through all the muscles of the body, progressively producing a deep state of relaxation. The procedure begins with contracting the muscles of the face and neck, then the upper arms and chest, followed by the lower arms and hands. The process is repeated progressively down the body, i.e. the abdomen, the buttocks, the thighs, the calves, and the feet. This whole practice is repeated two or three times. This technique is often used in the treatment of anxiety and insomnia. Progressive relaxation, deep breathing exercises, or some other stress reduction technique form an important component of a comprehensive stress management program. Lifestyle factors A patient’s lifestyle is a major determinant in their stress levels. The two primary areas of concern (other than addressing negative coping patterns) are time management and relationship issues. One of the biggest stressors for most people is time. They simply do not feel they have enough of it. Table 60.7 provides tips on time management for patients. Another major cause of stress for many people is interpersonal relationships. Interpersonal relationships
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TABLE 60-7 -- Patient tips for improved time management • Set priorities. Realize that you can only accomplish so much in a day. Decide what is important, and limit your efforts to that goal • Organize your day. There are always interruptions and unplanned demands on your time, but create a definite plan for the day based on your priorities. Avoid the pitfall of always letting the “immediate demands” control your life • Delegate authority. Delegate as much authority and work as you can. You can’t do everything yourself. Learn to train and depend on others • Tackle tough jobs first. Handle the most important tasks first, while your energy levels are high. Leave the busy work or running around for later in the day • Minimize meeting time. Schedule meetings to bump up against the lunch hour or quitting time; that way they can’t last forever • Avoid putting things off. Work done under pressure of an unreasonable deadline often has to be redone. That creates more stress than if it had been done right the first time. Plan ahead • Don’t be a perfectionist. You can never really achieve perfection anyway. Do your best in a reasonable amount of time, then move on to other important tasks. If you find time, you can always come back later and polish the task some more can be divided into three major categories: marital, family, and job-related. The quality of any relationship ultimately comes down to the quality of the communication. Learning to communicate effectively goes a very long way in reducing the stress and occasional (or frequent) conflicts of interpersonal relationships. Table 60.8 lists seven tips for effective communication, regardless of the type of interpersonal relationship. Exercise The immediate effect of exercise is stress on the body. However, with a regular exercise program, the body adapts and exercise becomes an effective stress reduction technique. With regular exercise, the body becomes stronger, functions more efficiently, and has greater endurance. Exercise is a vital component of a comprehensive stress management program and overall good health. People who exercise regularly are much less likely to suffer from fatigue and depression. Tension, depression, feelings of inadequacy, and worries diminish greatly with regular exercise. Exercise alone has been demonstrated to have a tremendous impact on improving mood and the ability to handle stressful life situations. This effect is seen in adolescents, as well as adults. For example, 2,223 boys and 2,838 girls (mean age, 16.3 years) from 10 teams and 25 different individual sports were studied for the relationship between emotional and psychological well-being. The sport and vigorous recreational activity index was positively associated with emotional well-being independently of other variables. [4]
Dietary guidelines Individuals suffering from stress or anxiety need to support the biochemistry of the body by following some important dietary guidelines. Specifically, they must: • eliminate or restrict the intake of caffeine • eliminate or restrict the intake of alcohol • eliminate refined carbohydrates from the diet • eat a diverse range of whole foods • increase the potassium to sodium ratio • eat regular planned meals in a relaxed environment • control food allergies. According to Selye, the difference between stress being harmful or not is based upon the strength of the system. From a purely physiological perspective, it can TABLE 60-8 -- Keys to assist patients in improving communication • The first key to successful communication is the most important. Learn to be a good listener. Allow the person you are communicating with to really share their feelings and thoughts uninterrupted. Empathize with them, put yourself in their shoes. If you first seek to understand, you will find yourself being better understood • Be an active listener. This means that you must be truly interested in what the other person is communicating. Listen to what they are saying instead of thinking about your response. Ask questions to gain more information or clarify what they are telling you. Good questions open lines of communication • Be a reflective listener. Re-state or reflect back to the other person your interpretation of what they are telling you. This simple technique shows the other person that you are both listening and understanding what they are saying. Re-stating what you think is being said may cause some short-term conflict in some situations, but it is certainly worth the risk • Wait to speak until the person or people you want to communicate with are listening. If they are not ready to listen, no matter how well you communicate your message will not be heard • Don’t try to talk over somebody. If you find yourself being interrupted, relax, don’t try and out-talk the other person. If you are courteous and allow them to speak, eventually (unless they are extremely rude) they will respond likewise. If they don’t, point out to them that they are interrupting the communication process. You can only do this if you have been a good listener. Double-standards in relationships seldom work • Help the other person become an active listener. This can be done by asking them if they understood what you were communicating. Ask them to tell you what is was that they heard. If they don’t seem to be understanding what it is you are saying, keep trying until they do • Don’t be afraid of long silences. Human communication involves much more than human words. A great deal can be communicated during silences; unfortunately in many situations silence can make us feel uncomfortable. Relax. Some people need silence to collect their thoughts and feel safe in communicating. The important thing to remember during silences is that you must remain an active listener
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be strongly argued that delivery of high-quality nutrition to the cells of the body is the critical factor in determining the strength of the system. When the eating habits of Americans are examined as a whole, it is little wonder that so many people are suffering from stress, anxiety, and fatigue. Most Americans are not providing their body with the high quality nutrition it deserves. Instead of eating foods rich in vital nutrients, most Americans focus on refined foods high in calories, sugar, fat, and cholesterol. Caffeine
The average American consumes 150–225 mg of caffeine daily, or roughly the amount of caffeine in two cups of coffee. Although most people can handle this amount, some people are more sensitive to the effects of caffeine than other people, due to decreased activity of phase I detoxification (see Ch. 16 ). Even small amounts of caffeine can affect sensitive people, while those with normal sensitivity will respond to large amounts. Excessive caffeine consumption can produce “caffeinism characterized by symptoms of depression, nervousness, irritability, recurrent headache, heart palpitations, and insomnia”. People prone to feeling stress and anxiety tend to be especially sensitive to caffeine. [5] [6] Alcohol
Alcohol produces chemical stress on the body. It also increases adrenal hormone output, interferes with normal brain chemistry, and interferes with normal sleep cycles. While many people believe that alcohol has a calming effect, a study of 90 healthy male volunteers given either a placebo or alcohol demonstrated significant increases in anxiety scores after drinking the alcohol. [6] Refined carbohydrates
Refined carbohydrates (e.g. sugar and white flour) are known to contribute to problems in blood sugar control, especially hypoglycemia. The association between hypoglycemia and impaired mental function is well-known. Unfortunately, most patients experiencing depression, anxiety, or other psychological condition are rarely tested for hypoglycemia, nor are they prescribed a diet which restricts refined carbohydrates. Numerous studies have shown a high percentage of hypoglycemia in depressed patients. [7] [8] As depression is one of the most frequent causes of anxiety, this provides a link between hypoglycemia and feelings of stress. Simply eliminating refined carbohydrate from the diet is occasionally all that is needed for effective therapy in patients that have depression or anxiety due to hypoglycemia. Potassium to sodium ratio
One of the key dietary recommendations to support the adrenal glands is to ensure adequate potassium levels within the body. This can best be done by consuming foods rich in potassium and avoiding foods high in sodium. Most Americans have a dietary potassium-to-sodium (K:Na) ratio of less than 1:2. In contrast, most researchers recommend a dietary potassium-to-sodium ratio of greater than 5:1 for health. However, even this may not be optimal. A natural diet rich in fruits and vegetables can produce a K:Na ratio greater than 50:1, as most fruits and vegetables have a K:Na ratio of over 100:1. Meal planning
Mealtimes should be spent in a relaxed environment. As noted above, digestion is a process largely controlled by the parasympathetic nervous system. Eating in a rushed manner, in a noisy or hurried environment is not conducive to good digestion or good health. Food allergies
People with symptoms of anxiety or chronic fatigue need to be concerned about food allergies. As far back as 1930, pioneering allergist Albert Rowe began noticing that anxiety and fatigue were key features of food allergies. [9] Originally, Rowe described a syndrome known as “allergic toxemia” to describe a syndrome that included the symptoms of anxiety, fatigue, muscle and joint aches, drowsiness, difficulty in concentration, and depression. Around the 1950s, this syndrome began to be referred to as the “allergic tension-fatigue syndrome”. With the popularity of the new chronic fatigue syndrome, many physicians and other people are forgetting
that food allergies can lead to anxiety as well as chronic fatigue. Nutritional and botanical support Nutritional and botanical support for the individual experiencing signs and symptoms of stress largely involves supporting the adrenal glands. Long-term stress and corticosteroids cause the adrenal glands to shrink and become dysfunctional, aggravating the stress symptoms of anxiety, depression, or chronic fatigue. An abnormal adrenal response, either deficient or excessive hormone release, significantly alters an individual’s response to stress. Often the adrenals become “exhausted” as a result of constant demands placed upon it. An individual with adrenal exhaustion will usually suffer from chronic fatigue and may complain of feeling “stressed out” or chronically anxious. They will typically have a reduced resistance to allergies and infection.
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Nutritional supplements
The nutrients especially important for supporting adrenal function include vitamin C, vitamin B 6 , zinc, magnesium, and pantothenic acid. All of these nutrients play a critical role in the health of the adrenal gland as well as the manufacture of adrenal hormones. During stress, the levels of these nutrients in the adrenals decreases substantially. For example, during chemical, emotional, psychological, or physiological stress, the urinary excretion of vitamin C is increased. Examples of chemical stressors include cigarette smoke, pollutants, and allergens. Extra vitamin C in the form of supplementation and an increased intake of vitamin C-rich foods is often recommended to keep the immune system working properly during times of stress. Equally important during high periods of stress or in individuals needing adrenal support is pantothenic acid (B vitamin). Pantothenic acid deficiency results in adrenal atrophy characterized by fatigue, headache, sleep disturbances, nausea, and abdominal discomfort. Pantothenic acid is found in whole-grains, legumes, cauliflower, broccoli, salmon, liver, sweet potatoes, and tomatoes. In patients suffering from chronic stress or a history of corticosteroid (prednisone) use, the typical level of supplementation is 100–500 mg daily. The appropriate daily doses of vitamin B 6 is 50–100 mg; of zinc is 20–30 mg; and of magnesium should be 250–500 mg. Botanical medicines
Several botanical medicines support adrenal function. Most notable are the ginsengs. Both Chinese ginseng ( Panax ginseng) and Siberian ginseng ( Eleutherococcus senticosus) exert beneficial effects on adrenal function and enhance resistance to stress. These ginsengs are often referred to as “general tonics” or “adaptogens”. The term “general tonic” implies that an herb will increase the overall tone of the whole body. The ginsengs are also often referred to as “adrenal tonics” in that they increase the tone and function of the adrenal glands. Chinese and Siberian ginseng can be used to: • restore vitality in debilitated and feeble individuals • increase feelings of energy • increase mental and physical performance • prevent the negative effects of stress and enhance the body’s response to stress • offset some of the negative effects of cortisone • enhance liver function • protect against radiation damage. All of these applications are backed up by good clinical research.
[ 10] [11] [12]
The modern term “adaptogen” is a more descriptive term used to describe the general tonic effects of Siberian and Chinese ginseng. An adaptogen is defined as a substance that: • must be innocuous and cause minimal disorders in the physiological functions of an organism • must have a non–specific action (i.e. it should increase resistance to adverse influences by a wide range of physical, chemical, and biochemical factors • usually has a normalizing action irrespective of the direction of the pathologic state. According to tradition and scientific evidence, both Siberian and Chinese ginsengs possess this kind of equilibrating, tonic, anti-stress action, and so the term adaptogen is quite appropriate in describing its general effects. The ginsengs have been shown to enhance the ability to cope with various stressors, both physical and mental. [10] [11] [12] Presumably this anti-stress action is mediated by mechanisms which control the adrenal glands. Ginseng delays the onset and reduces the severity of the alarm phase response of the general adaptation syndrome. People taking either of the ginsengs typically report an increased sense of well-being. Clinical studies have confirmed that both Siberian and Chinese ginsengs significantly reduce feelings of stress and anxiety. For example, in one double-blind clinical study, nurses who had switched from day to night duty rated themselves for competence, mood, and general well-being, and were given a test for mental and physical performance along with blood cell counts and blood chemistry evaluation. [13] The group administered Panax ginseng demonstrated higher scores in competence, mood parameters, and mental and physical performance when compared with those receiving placebos. The nurses taking the ginseng felt more alert, yet more tranquil, and were able to perform better than the nurses not taking the ginseng. In addition to these human studies, several animal studies have shown the ginsengs to exert significant anti-anxiety effects. In several of these studies, the stress-relieving effects were comparable to diazepam (Valium); however, while diazepam causes behavior changes, sedative effects, and impaired motor activity, ginseng produces none of these negative effects. [14] Based on the clinical and animal studies, it appears that ginseng offers significant benefit to people suffering from stress and anxiety. Panax ginseng is generally regarded as being more potent than Eleutherococcus senticosus. Panax ginseng is probably better for the patient who has experienced a great deal of stress, is recovering from a long-standing illness, or has taken corticosteroids like prednisone for a long period of time. For the patient under mild to moderate stress and experiencing less obvious impaired adrenal function, Eleutherococcus senticosus may be the best choice.
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REFERENCES 1. Benson 2. Selye
H. The relaxation response. New York, NY: William Morrow. 1975
H. The stress of life. New York, NY: McGraw Hill. 1978
3. Holmes
TH, Rahe RH. The social readjustment scale. J Psychosomatic Res 1967; 11: 213–218
4. Steptoe
A, Butler N. Sports participation and emotional wellbeing in adolescents. Lancet 1996; 347: 1789–1792
5. Chou
T. Wake up and smell the coffee. Caffeine, coffee, and the medical consequences. West J Med 1992; 157: 544–553
6. Montiero
MG et al. Subjective feelings of anxiety in young men after ethanol and diazepam infusions. J Clin Psychiatry 1990 51: 12–16
7. Winokur
A et al. Insulin resistance after glucose tolerance testing in patients with major depression. Am J Psychiatry 1988; 145: 325–330
8. Wright 9. Rowe
JH et al. Glucose metabolism in unipolar depression. Br J Psychiatry 1978; 132: 386–393
AH, Rowe A, Jr. Food Allergy. Its manifestations and control and the elimination diets. A compendium. Springfield, IL: CC Thomas. 1972
10.
Farnsworth NR et al. Siberian ginseng (Eleutherococcus senticosus): current status as an adaptogen. Econ Med Plant Res 1985; 1: 156–215
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Hikino H. Traditional remedies and modern assessment: the case of ginseng. In: Wijeskera ROB, ed. The medicinal plant industry. Boca Raton, FL: CRC Press. 1991: p 149–166
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Shibata S et al. Chemistry and pharmacology of Panax. Econ Med Plant Res 1985; 1: 217–284
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Hallstrom C, Fulder S, Carruthers M. Effect of ginseng on the performance of nurses on night duty. Comp Med East & West 1982; 6: 277–282
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Bhattacharya SK, Mitra SK. Anxiolytic activity of Panax ginseng roots: an experimental study. J Ethnopharmacol 1991; 34: 87–92
Section Five - Pharmacology of natural medicines
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Chapter 61 - Alkylglycerols Peter T. Pugliese MD
INTRODUCTION Sharks have existed, virtually unchanged, for some 450 million years. Some scientists attribute this long staying power to the well developed immune system in the shark, an immune system which is quite similar to our own. Sharks have both a humoral and a cellular component to their immune system, and therefore have both B-cells and T-cells. Sharks also have a spleen and a thymus gland just as we do, although they possess large quantities of akylglycerols found mainly in the liver. In this chapter we shall explore the use of alkylglcyerols from the shark both as immune stimulants and as powerful agents in the treatment of neoplastic disorders.
HISTORY Alkylglycerols are ether-linked biological compounds that have a long and fascinating history. Much of the early history is found in the literature of histochemistry and is related to methods of staining specific cellular components. One of the greatest histologists of all time was Robert Feulgen (1884–1955), a German physiological chemist to whom we owe the Feulgen reaction. (The Feulgen reaction, or test, is a method to detect animal nucleic acids. It involves an acid hydrolysis with HCL followed by a 1% solution of decolorized rosaniline, which yields a red color in the presence of nucleic acids.) Robert Feulgen and K. Voit discovered plasmalogens in 1924.[1] At the time they thought they had discovered an aldehyde, which they called plasmal. The origin of plasmal was believed to be an unknown substance, which they called plasmalogen. They were able to demonstrate the presence of this compound in many tissues, from protozoa to humans. Plasmalogens, it was learned later, were ether lipid compounds that are formed in the metabolic pathway of phosphoglycerides. They differ from phosphoglycerides in that they contain an ether linkage on the C-1 of the glycerol molecule. Intensive work on the structure
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and formation of the plasmalogens continued over the next 35 years. It was many years, however, before a formula for plasmalogens was finally agreed upon, yet the biological function of plasmalogens remained unknown until after 1960 when their role in organisms was finally discovered. As in many discoveries there are always unsung heroes: scientists who work quietly in some obscure laboratory, publish a paper and are seen no more. Such was the case with research on the alkylglycerols. The work of Kossel & Edbacher [2] on the starfish Astropecten aurantiacus was unknown until 1943 when Bergmann & Stansbury[3] compared their preparation of batyl alcohol, a natural alkylglcyerol obtained from the starfish, to the original work of Kossel & Edbacher [2] and found similar physical and chemical properties of both compounds. From 1915 the story jumps to the 1920s, after the First World War, and to Japan where Tsujimoto & Toyama[4] were working on unsaponifiable compounds from liver extracts. (Unsaponifiable fractions are those fatty compounds that do not form soaps when shaken with strong bases such as potassium or sodium hydroxide. Steroids are an example of this class of compounds.) It was the work of these two investigators that identified two major alkylglycerols in shark and ray liver oil. They called the first compound selachyl alcohol from the family name for sharks, Selachoidei, and batyl alcohol from the ray family Batoidei. They were uncertain of the exact chemical structure at the time, due to questions about the role of an oxygen atom in the molecules. In 1924, Toyama[5] isolated a third compound from the liver oils of the ratfish, Chimera monstrosa, which he called chimyl alcohol. Four years later Heilbron & Owens [6] described the crucial role of the oxygen atom as an ether linkage. They refluxed batyl alcohol with hydroiodic acid and obtained octodecyl iodide, which was conclusive evidence of a glyceryl ether structure. At about this time, a great deal of work was being conducted on shark liver oil in an attempt to isolate the fat-soluble vitamins A and D. Ether lipids consisting mainly of batyl, chimyl and selachyl alcohols were purified from shark liver oil as a side product of this isolation. This material provided a ready source for further investigation of the ether lipids. This was fortuitous because the first therapeutic use of ether lipids was in 1930 when Giffin & Watkins [7] employed yellow bone marrow to treat a patient with leukopenia. At the time they did not know that the active principle in the marrow was batyl alcohol. Eight years later Marberg & Wiles [8] isolated batyl alcohol from the unsaponifiable fraction of yellow marrow. The biological function of the ether lipids was not fully elucidated until after 1960, although many investigators ascribed certain biological functions to these compounds, e.g. the antileukopenic effect described above, a central depressant action described by Berger [9] in 1948, an erythopoietic effect reported by Sandler [10] in 1949, a tuberculostatic effect reported by Emmerie et al [11] in 1952, a wound healing action reported by Bodman & Maisin [12] in 1958 and a radioprotective effect reported by Brohult [13] in 1960. The alkyl glycerol ethers were found to be widespread in nature, in fact almost universal, although no clear physiological role was defined for them. Current research has opened many investigative channels for these compounds and new information is now available that is beginning to shed light on the molecular action of the ether lipids. A review of the chemistry of the alkyl glyceryl ethers will help to prepare the reader to understand the physiological action and the potential therapeutic applications.
BASIC CHEMISTRY OF THE ALKYL GLYCERYL ETHERS FROM SHARK LIVER OIL Some definitions Lipid chemistry is often viewed as an impenetrable complexity by the student. The terminology is indeed not easy to master at first, but with time and repetition it becomes easier. Part of this problem rests with the lipid chemists who have some difficulty is agreeing on nomenclature. In the case of the ether lipids, we shall limit this discussion to only a few naturally occurring compounds, specifically those occurring in shark liver oil. Lipids may be broadly defined as a class of organic compounds that are water-insoluble. They can then be further divided into simple lipids and complex lipids. For example, simple lipids are esters of fatty acids and an alcohol, such as palmitic acid and glycerol to form a monoglyceride. Another example of a simple lipid is a cholesterol ester. Complex lipids are esters which contain phosphorus and/or nitrogen bases and/or sugars as well as fatty acids and an alcohol. Lecithin, which is phosphotidyl choline, is an important complex lipid. The plasmalogens, which we shall discuss later, are lipid compounds that contain an ether linkage along with both a phosphorus and a nitrogen group, so they are classified as complex lipids.
We also speak of neutral lipids which are not ionically charged, and ionic lipids, or charged lipids. Fats such as common triglycerides found in lard, are neutral lipids, while phospholipids are charged lipids. There are a few other terms that must be defined so that we are all talking the same language. The term alkoxyl refers to an organic group RO, which is part of an ether group ROR. Recently the term has been shortened to alkyl, so we denote ether lipid as alkylglycerides. Note that there is no other oxygen atom associated with the R components. The term acyl refers to a R – C = O. The term carbonyl refers to a C = O group, and the term carboxyl refers to a –COOH
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group, where one oxygen has a double bond to the carbon atom. The ether bond is the key to understanding the unique functioning of the alkylglycerol. This bond, C–O–C, is found throughout nature in many important biological compounds, the most familiar of which is thyroxin from the thyroid gland. In the plant world, guaicol is another familiar ether-linked substance. Glycerol ethers are quite widespread, having been isolated from many life forms and in many different molecular arrangements. The basic structure of these compounds consists of a glycerol molecule with one or more of the hydroxyl groups being replaced by long-chain fatty acids. The bonding of three fatty acid molecules to the glycerol molecule with an ester linkage is known as a triglyceride, or common fat. The ester linkage is characterized by the –COO group where one oxygen is linked in a double bond to a carbon atom. A typical triglyceride and alkylglycerol are shown in Figures 61.1 and 61.2 . While the chemistry of the alkylglycerols in many animals and plants has been studied quite extensively, we shall limit our discussion to the main ether lipids found in shark liver oil. A note, however, on the composition of shark liver oil is in order. Shark liver oil contains high levels of vitamins A and D along with other constituents besides the ether lipids. In commercial preparations of the alkylglycerols extracted from shark liver oil, all of these components are removed in the extraction process.
Figure 61-1 Trigylceride.
Figure 61-2 Alkylglycerol.
In this article, therefore, when we speak of shark liver-derived alkylglycerols we are referring to a highly refined end product containing only the alkylglycerols. One of the major sources of natural alkylglycerols is obtained from the Greenland shark, Somniosus microcephalus, which contains up to 50% of alkylglycerols. Other sources include the elasmobranch fish such as the small shark, Chimaera monstrosa, and the dogfish, Squalus acanthias. Cod liver oil and certain mollusks are additional sources of alkylglycerols. [14] These compounds are found in various organs of the animals studied, including bone marrow fat, spleen liver, plasma and erythrocytes, and in milk. [15] [16] These compounds are found in the unsaponifiable fraction of the oils obtained from the animals. Tsujimoto & Toyama [4] were the first investigators to report the presence of ether lipids in shark liver oil. Three major natural alkylglycerols obtained from the Greenland shark are batyl alcohol, chimyl alcohol and selachyl alcohol. The chemical structure of these compounds is given in Fig. 61.3 . Note that while chimyl and batyl alcohol are saturated chains, selachyl alcohol contains one unsaturated bond. Note also that all the ether bonds are on the number 3 carbon of glycerol. In the natural state these compounds are usually present as ester compounds, with carbons 1 and 2 esterified with C 16 or C18 saturated fatty acids. A fourth natural compound is a
Figure 61-3 Batyl alcohol, chimyl alcohol and selachyl alcohol.
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Figure 61-4 Methoxy-substituted alkylglycerol.
methoxy-substituted alkylglycerol, shown in Fig. 61.4 , which is quite an active compound, but comprises only a small percentage of natural shark liver oil-derived alkylglycerols, about 3%. The biological synthesis of the lipid ethers has been well worked out. Most cells in the human body contain lipid ethers but only in small quantities. The following synthesis scheme has been published and is summarized by Mangold & Paltauf [17] as follows: • Step 1. Coenzyme A derivatives of long-chain fatty acids are reduced to alkyl and alkenyl chains via their alcohols, through an aldehyde. • Step 2. The ether bond is formed by reaction of these alcohols with acyldihydroxyacetone phosphates, resulting in the formation of alkylacyldihydroxyacetone phosphates. • Step 3. Reduction of the alkylacydihydroxyacetone phosphates leads to the formation of alkylglycerophosphates. This may be further summarized as: fatty acid
aldehyde
alcohol
alkyl ether
1-alkenyl ether
It is unlikely that ether lipids exist in nature as free forms; rather, they are esterified. Being ether compounds, they react as aliphatic ethers, i.e. they are stable to most oxidizing and reducing substances, but undergo only one general, non-enzymatic reaction, which is acid hydrolysis. It is not the purpose of this chapter to discuss the isolation and identification of the alkylglycerols. The scheme for this work is well developed and may be found in references by Mangold & Weber. [18] We shall devote our coverage in this chapter instead to the naturally occurring alkylglcyerols from shark liver oil and relate the structure and fate of these compounds to their physiological effects and potential therapeutic use. Absorption, fate and excretion After oral ingestion of ether lipids, absorption occurs from the intestine. About 95% of radioactive (C 14 -labeled) chimyl alcohol is absorbed in the intestine, with 5% being excreted in the feces in one study. [19] In the gastrointestinal tract a large proportion of the ingested ether lipid in the form of 1-O-alkylglycerols are cleaved at the ether bond with the alkyl moieties giving rise to fatty acids. The remainder is incorporated into 1-O-alkyl 2,3-diacyl- sn-glycerols and 1-O-alky-l-2-acyl- sn-glycerol and 1-O-alkyl-2-acyl-sn-glycerol-3-phosphoethanolamines. [20] Ether lipids are only minor components of human diet, so that the major portion of ether lipids in the body is
synthesized in the body. [20] Absorption of the intact ether lipid is the rule since ether lipids are not subject to the action of lipase, which is specific for the ester bond. This means that the “fat” is absorbed rather than the fatty acids. After feeding chimyl alcohol to rats, analysis of the lymph fluid shows that 2–4% of the ether lipids is found as fatty acids combined in phospholipids, about 50% is found in the triglyceride fraction, while another 40% is found as the free chimyl alcohol, or as an esterified alcohol. In the triglyceride fraction, most of the original compound is found as palmitic acid, which indicates that the ether bound in the chimyl alcohol was split during the absorption process. The cetyl alcohol (a C 15 fatty alcohol) moiety of chimyl alcohol is oxidized to palmitic acid (a C 16 fatty acid) during its passage through the intestinal mucosa.
TOXICOLOGY OF THE ALKYLGLYCEROLS Toxicity in animals
Oral toxicity studies with alkylglcyerols have been conducted on rats, mice and dogs. Alexander et al [21] reported that mice given a diet containing 18% alkyldiacylglycerols showed not ill effects after 2 years. Work by Brohult, [22] Peifer et al, [23] Carlson,[24] Berger[9] and Bandi [25] on oral feeding of alkyglycerols to rats has shown that they are relatively non-toxic. Carlson [24] tested dogs with chimyl batyl and selachyl alcohols by feeding levels of 2.4 g/kg of body weight and found no ill effects. Subcutaneous injections of batyl alcohol in mice by Berger [9] found that a dose of 3 g/kg was needed to obtain a subcutaneous LD 50 . Peritoneal injections of batyl alcohol in rats at levels of 5–10 mg/kg of body weight had no effect on the thymus gland or on the production of adenosine triphosphate. Toxicity in humans
Brohult[22] observed that a healthy human being consumes about 10–100 mg/day of alkylglcyerols in an average diet. Sandler [10] gave healthy adult males 45 mg/day of batyl alcohol for 10 days with no ill effects. This was a relatively low dose compared with that consumed by people who eat shark meat and shark by-products. Only the consumption of shark liver has been reported to produce ill effects, mainly diarrhea, due to the high squalene content. Alkylglycerols from the Greenland shark have been used for over 30 years without undesirable side-effects.
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BIOLOGICAL EFFECTS Bacteriostatic effects
As early as 1952 the bacteriostatic effects of alkylglycerols on tubercle bacillus ( Mycobacterium tuberculosis) in vitro were reported. [11] This material was isolated from cod liver oil and consisted of the unsaponifiable fraction. There is very little published data on the antimicrobial effects of the alkylglcyerols from natural sources, but a more recent report using a synthetic product, racemic sn-1(3)-dodecylglycerol, showed some activity against Streptococcus mutans BHT.[26] These investigators found that substantial decreases in the viability of this organism were associated with an accumulation of phosphatidic acid. Current research shows that antibiotic resistance in bacteria is associated with the lipid content of the bacteria in both Gram-positive and Gram-negative organisms. [27] The action of the alkylglycerol was to inhibit the synthesis of lipids in the microbial cell. Hemopoietic effects
Bone marrow was found to be a useful therapy in treating secondary anemia over 60 years ago. Later it was found that the unsaponifiable fraction of the marrow lipids was responsible for this action, i.e. the stimulation of erythrocyte production. Sandler [10] found that batyl alcohol had a beneficial effect on erythrocyte production in rats. Further studies with subcutaneous injections in humans showed an increase in reticulocycte levels in the blood. The erythropoietic, thrombpoietic and granulopoietic stimulatory activities of 1-octadecylglycerol ethers was confirmed by several investigators. [28] [29] [30] It is interesting that chimyl alcohol is able to stimulate hemopoiesis, but selachyl alcohol is not. [31] Protection against radiation damage
The effects of 1-alkylglycerols in the treatment of radiation-induced leukopenia have been studied extensively. Some investigators have confirmed these benficial effects, [32] [33] while others have not. [34] [35] Work by Lorenz et al [36] found that lethal irradiation in mice and guinea pigs was counteracted by post-irradiation injection of bone marrow. It was thought by Sandler[10] that batyl alcohol might be the active factor in bone marrow that prevented irradiation leukopenia. His observations, however, noted an increase mainly in erythropoiesis. Additional studies by Arturson & Linback [37] using intraperitioneal injections of batyl alcohol in mice showed an increase in the production of both erythrocytes and reticulocytes. Other studies have confirmed the positive effect of the alkoxyglycerols on post-irradiation damage. The work of Brohult & Homberg [28] showed that lethal irradiation is counteracted by post-irradiation injections of batyl alcohol. In 1963 Brohult published a thesis on the use of alkylglycerols in radiation treatment. A summary of the major findings in this paper is as follows: • The post-irradiation decrease in thrombocytes and white cell is notably less in patients treated with alkylgycerols than in those not given alkyglycerols. • Patients with low thrombocyte counts due to radiation treatment or chemotherapy had increased counts after treatment with alkylglycerols. • In irradiated rats pretreated with alkylglycerols there was less of a decrease in megacaryocytes and nucleated cells in the bone marrow compared with untreated irradiated controls. • Selachyl alcohol was more effective than batyl alcohol in preventing megacaryocyte decrease. • There was a dose-related response with a maximum response at a certain level and then a decreased response when that level was exceeded. • The alkylglycerols increase the growth rate of rats after treatment and irradiation compared with untreated irradiated rats. • Batyl alcohol has a greater effect than selachyl alcohol on increasing growth rate in rats. • In a series of 350 patients with cervical cancer treated with alkylglycerol and given radiation therapy, therewas a greater survival rate for 1 year and 5 years thanin untreated irradiated controls (we shall discuss this topic in more detail when we discuss the clinical uses of the alkylglycerols).
IMMUNOLOGICAL ASPECTS OF AKYLGLYCEROLS An overview of the immune system Early in the investigation and study of ether lipids it was evident that there was an augmentation of the immune system seen in animals that ingested these compounds. It was also apparent that the macrophage was the key cell in this reaction. A brief introduction to the immune system will acquaint the reader with the relationship of the macrophage to other immune active cells and to the immune system in general. The immune system comprises a set of physiological responses used by the body to destroy or neutralize foreign matter, either living or non-living. Included in this system is a process of maintaining an immune surveillance of the body’s own cells to detect and destroy malignant cells. The essential role of the immune system, therefore, is one of recognition of the components of “the self” and protection from “non-self entities”. Our own cellular constituents make up a vast array of complex molecules to identify and classify. Adding additional complex biochemicals from bacteria, viruses and parasites of all kinds increases the complexity of the system manifold.
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There are two basic responses of the immune system: a non-specific response that protects non-selectively against foreign matter, or cells, without the need for
recognition of specific identities – examples of this response include the barrier provided by the skin, the inflammatory response to injury, and the complement system; and a specific response which depends on recognition of a specific substance prior to an attack by the immune system. The specific response involves highly specialized cells and the formation of specific chemical substances employed in the attack. One of these substances, known collectively as antibodies, are adapter molecules that identify foreign organisms and interact with the other components of the immune system. Each of these components has three main regions, two of which communicate with complement and the phagocytic cells, known as the biological part, and the other serving to recognize and bind to microorganisms, known as the external recognition function. The body makes millions of these antibodies. The most common antibodies are the immunoglobulins known as IgG, IgA, IgM, IgE and IgD. Chemically, the antibody molecule consists of two active regions, known as the Fc, or constant, part, and the Fab, or variable antigen-specific, part. There are two heavy chains and two light chains in each antibody molecule. The Fc part consists only of heavy chains while the Fab part consist of light and heavy chains. Complement A family of proteins known as complement provides a direct means of killing microbes without the need for phagocytosis; however, it plays an important role in phagocytosis as will become apparent in our discussion of alkylglycerols and macrophage activation. A brief review of the major steps in the complement reaction is outlined. Complement is so named because it complements and amplifies the action of the antibodies. Some of the components of the complement system circulate constantly in the bloodstream in an inactive form and are activated in the presence of infection or tissue damage. A cascade reaction results in which some 20 proteins are involved in generating the active moieties. However, we need not discuss all of these, only the major components. Five of the active proteins resulting from the cascade form a complex known as the membrane attack group complex or MAC. This MAC invades the microbial plasma membrane and disrupts it by creating a leaky channel. Other cascade-generated proteins cause vasodilatation and increased vascular permeability. The major action of the complement proteolytic cascade is to cleave a component known as C 3 into two active units C 3a and C3b Complement C3b is an opsonin, a material that helps to attach phagocytes to the microbe. Antibodies are required to activate complement in the classic system, but our concern here is with another complement activation pathway that does not require antibodies, the so-called alternate complement pathway. This system is triggered by certain carbohydrates on the bacterial surface which initiate the cascade at a point about halfway through the classic system to generate C 3b . The interaction of complement with macrophages is a key step in many immune reactions, as complement enhances the ability of macrophages to bind, ingest, and destroy microorganisms. [38] The macrophage The macrophage is an extremely versatile and highly regulated cellular system. Besides their microbicidal activity, macrophages are equipped to recognize and destroy both intracellular and extracellular replicating invaders, whether or not these invaders are prokaryotic or eukaryotic types. They are important scavengers for effector cells and molecules of host origin, as well as for exogenous compounds which they can take up, degrade and detoxify or contain. They are known to regulate a large number of body functions including iron and lipid metabolism. The large number of secretory products generated by the macrophage helps to regulate other cells, including the fibroblasts and cells involved in the formation of myeloid component in the bone marrow. Obviously such powerful cells need to be tightly controlled, and so they are. The resident macrophages in the tissues are usually downregulated to a high degree. The process of activation, which we shall discuss in detail, comes from a variety of extracellular stimuli. We have learned over the years that the macrophage is a multipotential cell with the capacity to develop in many ways, depending on the specific signal it receives. This system is far from being fully understood, but the control of this delicate balance of activities is essential to life, so it has become a prime area of intensive investigation. The macrophages originate from precursor cells in the bone marrow and pass into the circulation as monocytes. They remain in the bloodstream for several hours and then migrate to various tissues where they are transformed into macrophages. The macrophage is an activated monocyte, and is easily distinguished from the smaller neutrophil by its size and characteristic nucleus. While both cells are phagocytic, the macrophage has a far greater potential for killing bacteria. A greater cytoplasmic volume and more cytoplasmic organelles are present in the macrophage, including more lysosomes, microtubles, microfilaments and Golgi membranes. After leaving the bloodstream, the macrophage will enter the peritoneal cavity, other serous cavities, and the red pulp of the spleen and the lymph nodes. Macrophages possess receptors for the Fc pieces of the immunoglobulins and for the C 3b complement fraction
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discussed above. The adherence of a particle to the macrophage is mediated by complement or by complement plus antibody. Either IgM or IgG is required for this reaction to take place along with C 3 . If IgG is bound to the particle it can be ingested without the addition of complement C 3 . The concept of immune activation is quite comprehensive in that it embodies many intercellular and molecular events. [39] The lymphocytes play a key role in activating the macrophage, particularly the T-helper lymphocytes. Macrophages are usually downregulated with respect to their surface active receptors when they are resident in most tissues (resident macrophages are usually not activated). They may be fully activated in several stages, e.g. an inflammatory response in tissues will evoke a reaction that changes the C 3 complement on the surface of the macrophage to fully empower the cell to engulf and destroy bacteria or red cells. They are then further activated to a high killer state by secretions from T-lymphocytes, one of which includes gamma interleukin. Macrophage activation by alkylglycerols
Inflamed cancerous tissue releases alkyl-lysophospholipids and other alkylglycerols which are degradation products of alkyl phospholipids and alkyl neutral lipids. These compounds are found in cancerous tissue in high concentration, but are in a very low concentration in normal tissues. One of these products, dodecylglycerol (DDG), is one of the most potent macrophage activators known. [40] [41] [42] [43] The use of the natural sn-3-octylglycerol, or batyl alcohol, found in shark liver oil produced the same effect as DDG.[44] The mechanism of macrophage activation by the natural akylglycerols is most likely identical to the action of lysophospholipids. Keeping in mind that activated macrophages exhibit increased phagocytosis, one method of assaying substances for activation potency is to measure the ingestion of various particles. Erythrocytes coated with IgG are common target particles used in this assay. Lysophosphotidylcholine has been shown to be effective in increasing macrophage ingestion of IgG-coated erythrocytes. [40] [41] Mice were treated with intraperitoneal injections of batyl alcohol in saline and the macrophages were harvested 4–5 days later. Sheep erythrocyte coated with IgG showed a greatly increased ingestion of erythrocytes. There was no increased ingestion when the cells were coated with IgM or complement, which suggests that batyl alcohol activates the macrophages for Fc-mediated ingestion only. It was interesting that batyl alcohol was more effective at a lower dose than the synthetic compound. [42] There is evidence that oral intake of natural alkylglycerols results in higher levels of plasmalogens in the erythrocytes in human subjects. (Plasmalogens are ether compounds that are formed in the metabolic pathway of phosphoglycerides. They differ from phosphoglycrides in that they contain an ether linkage on the C-1 of the glycerol molecule.) It is know that plasmalogens protect animal cell membranes against oxidative stress. In rat studies, batyl alcohol is incorporated into all tissues except brain tissue and this action is a stereospecific incorporation. [45] It has been shown that alkylglycerols are present in human and cow’s milk, [44] [46] along with other immunological factors. [47] Since the neonate has not developed a mature immune system,[48] the prospect of transmitting immune functional components in the milk is a practical way to provide some protection for the newborn. [49] In one study, lactating rats were fed alkylglcyerols dissolved in corn oil; the composition of the alkylglycerols was similar to that found in shark liver oil, in that batyl alcohol, chimyl alcohol and selachyl alcohol were the major constituents. [49] The findings from this study showed that while peripheral blood granulocytes were elevated there was no elevation of peripheral lymphocytes. Plasma levels of immunoglobulins were elevated in those pups whose dams were fed alkylglycerols, but not in the controls. Both IgG and IgM were elevated to a significant degree.
CLINCIAL USES OF AKYLGLYCEROLS Akylglcyerols have been used primarily to treat various types of cancer, usually as adjunct therapy combined with radiation. We shall present in detail the work of Brohult et al [50] on cervical cancer tumor regression and on the decrease of complications resulting from irradiation therapy. Finally we shall discuss a new akylglycerol, a methoxy-substituted alkylglcyerol that occurs naturally at only 3% in shark liver oil, but may be available as a synthetic compound. Tumor regression with alkylglycerol treatment
Patient selection was determined by stages with the stages being defined as follows: • Stage I – carcinoma strictly confined to the cervix (early stage) • Stage IA – cases of early stromal invasion • Stage IB – all other cases of stage I • Stage IIA – the carcinoma extends beyond the cervix but has not extended onto the pelvic wall; the carcinoma involves the vagina, but not the lower third; no parametrial involvement • Stage IIB – the carcinoma extends beyond the cervix but has not extended onto the pelvic wall; the carcinoma involves the vagina, but not the lower third; parametrial involvement is noted • Stage III – the carcinoma has extended onto the 562
pelvic wall; on rectal examination there is no cancer-free space between the tumour and the pelvic wall; the tumour involves the lower third of the vagina • Stage IV – the carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum. (These definitions are from the International Federation of Gynecology and Obstetrics.) Treatment
Patients were treated with shark liver oil-derived alkylglycerol continuing 100 mg of alkylglycerol, given as two capsules three times a day for a total dose of 600 mg/day. The treated group received 600 mg/day for 7 days prior to irradiation and for 1–3 months after radiation therapy. The study covered three time periods: period 1, from 1 September 1964 to 15 February 1964, comprising 458 patients; period 2, from 1970 to 1973, comprising 137 patients in a double-blind study; period 3, from late 1973 to 1975, comprising 245 patients who were treated with alkylglycerols on as “every second patient”. The control group consisted of all patients who received radiation therapy for cervical cancer but did not receive alkylglycerols. Findings
The control group in this study consisted of 4,404 patients treated during the same periods, while the total treated group was 841 patients. The mortality after 5 years was 31.0% for the group treated with alkyglycerols and 39.6% for the control group. The difference is statistically significant ( P < 0.001).[50] Protection against radiation injuries Studies of patients treated in 1963–1966 and in 1970–1972 by Brohult et al [51] were aimed at evaluating further the protective effects of ether lipids against irradiation injuries in patients with cancer of the cervix of the uterus. Alkylglycerols derived from Greenland shark liver oil were administered to one group of patients at a level of 600 mg/day during the radiation treatment and 300 mg/day for 1–3 months after treatment. Another group of patients was treated the same way during and after radiation, but was also treated prophylactically 8 days before radiation with 600 mg/day of alkylglycerols. The patients receiving alkylglycerols during and after radiation treatment are referred to as the non-prophylactic group, and the patients also given alkylglycerols before the radiation as the prophylactic group. The system proposed by Kottmeier & Gray [52] was used for evaluation of the radiation injuries that had occurred in the bladder, rectum, uterus, and intestine. Radiation injuries of grade I, with minimal objective changes in the mucosa, were excluded. Patients with radiation injuries of grades II–IV were treated as a single group: “patients with radiation injuries”. Grade II was characterized by moderate to severe changes, such as necroses, ulcerations, moderate stenoses, and/or reactions with lengthy bleeding. Radiation complications of grade III included injuries to the bladder, radiation fistulas from the ureters, and rectal and intestinal stenoses of such severity that colostomy or resection was needed. Grade IV was characterized by rectal and intestinal fistulas. Complications included patients with clinical features of radiation injury in whom the symptoms were found to be caused by tumor growth or a combination of tumor growth and radiation injury. These complications were termed “complex injuries” and represented a very serious situation. All patients with complex injuries were dead after 5 years. The incidence of radiation injuries varies with the spread of the cancer and the radiation technique. The incidence is higher in the more advanced tumor stages than in the less advanced ones. It is also higher after 60 Co three-beam treatment of combined high-voltage and X-ray treatment than after conventional X-rays or radium alone. When comparing the groups statistically, standardized proportions have been used in order to cancel out differences with regard to stage distribution and radiation technique. The total incidence of injuries was lower in the groups that had received alkylglycerols (18.1% in the prophylactic group and 24.4% in the non-prophylactic group) than in the controls (37.1%). The prophylactic group had a considerably lower incidence of complex injuries and multiple injuries than both the controls and the non-prophylactic groups. The differences were highly significant ( P < 0.001). Analysis of the patients divided into groups according to tumor stage or radiation technique showed that the incidence of complex injuries was lower in all subgroups of prophylactically treated patients than in the corresponding control groups. A double-blind study in 1970–1972 showed a pronounced protective effect of prophylactic treatment against injuries after radiation therapy. [51] The use of increased doses of radium in intracavitary irradiation was followed by a high incidence of radiation injuries, which was considerably reduced by treatment with alkylglycerols, especially when these compounds were administered prophylactically. [53] The alkylglycerols in other medical conditions While there are few studies to support the use of natural aklylglycerols in disease states other than cancer it seems appropriate to consider this agent in any condition that would benefit from stimulation of an immune component. Currently the alkylglycerols are viewed as
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adjunct therapy rather than primary therapeutic agents, except for the methoxy-substituted alkylglycerols. Newer forms of the alkylglycerols have been synthesized and are being tested successfully with a wide range of tumor types. Conditions that are characterized by a hyperproliferative state may benefit from treatment with alkylglycerol. Considering that one possible effect of the alkylglycerols is competitive inhibition of diacylglycerol, it is plausible that protein kinase C would also be inhibited by this same action since diacylglycerol is a stimulator of protein kinase C. Protein kinase C is essential to the oxidative burst in neutrophils, and agents that inhibit protein kinase C will inhibit this action. [54] The work by Yamamoto et al[42] supports the role of ether analogues as activators of macrophages and as primary cytotoxic agents. This dual role would suggest a wider application of alkyglycerol as adjunct therapy. It has been observed by Oth & Jadhav [55] that alkylglycerols given to lactating mice will increase the peripheral granulocyte count as well as the serum immunoglobulins in the pups. This action suggests the possible use of alkylglycerols in most infectious disorders. Experimental antitumor activity with methoxy-substituted alkyglycerol About 3% of the alkylglycerols in the Greenland shark liver oil consists of methoxy-substituted alkylglycerols. The methoxy-substituted alkylglycerols have been found to inhibit tumor growth in cultured cells. Two cell lines were used, a methylchol-anthrene-induced murine sarcoma (MCGI-SS) and a juvenile osteogenic sarcoma (2T). Marked growth inhibition was noted for the mixture of 2-methoxyalkylglycerols from Greenland shark liver oil, different single components derived from this oil (2-methoxyhexadecylglycerol, 2-methoxyhexadecenylglycerol, and 2-methoxyoctadecenylglycerol), and various synthetic compounds including, for example, 2-ethoxyhexadecylglycerol, 2-methoxyhexadecenylglycerol, and 3-methoxyhexadecylglycerol. [56] In several tumor–host systems, including solid tumors, leukemias, and lymphomas, the methoxy-substituted alkylglycerols were incorporated into the feed in different
concentrations (0.1–2%, w/w). Growth inhibition was noted for melanoma B16, for a methylcholanthrene-induced sarcoma (MCG101) and Lewis lung tumor (LLT) in C57BL/6J mice, for lymphoma LAA in A/Sn mice with synthetic 2-methoxyhexadecylglycerol, and for a spontaneous mammary carcinoma in C3H mice with methoxy-substituted alkylglycerols from Greenland shark liver oil. The survival time of DBA/2J mice transplanted with lymphatic leukemia P1534 was increased by synthetic 2-methoxyhexedecylglycerol. [56] [57] Metastases induced by the injection of MCG1-SS cells into a tail vein or into the portal vein were inhibited in the liver by methoxy-substituted alkylglycerols from Greenland shark liver oil. [57] Spontaneous metastasis formation from a methylcholanthrene-induced sarcoma (MCG1-SS) in lymph nodes and lungs of CBA mice was inhibited by methoxy-substituted alkylglycerols derived from Greenland shark liver oil as well as by synthetic 2-methoxyhexadecylglycerol.[56] Spontaneous metastasis formation from melanoma B16 was inhibited by synthetic 2-methoxyhexadecylglycerol. [57] It is notable that the same substance can both stimulate the immune system and inhibit tumors. This has also be shown to be true for alkyllysophospholipids synthesized with a methoxy group in the 2-position of the glycerol part of the molecule, These substances have been studied at the Max-Planck Institute for Immunobiology at Freiburg and at the Department of Haematology and Oncology of the University of Munich. The German research groups have shown that even alkyllysophospholipids without the 2-methoxy group in the glycerol part can activate macrophages in the bone marrow. This shows that ordinary glycerol ethers, after incorporation into phospholipids, can activate the body’s immune defense system. These investigators think that the macrophage-stimulating effects of alkyllysophospholipids explain the effects of these substances on tumors and tumor spread. Tumor cells have only a low activity of enzymes which can break down ethers. This means that alkyl ethers are incorporated into the cell membrane’s phospholipids which are then recognized and attacked by macrophages which have a high activity of ether catabolic enzymes. In experiments performed at the University of Stockholm, [58] it has been shown that both types of methoxy-substituted alkylglycerols (methoxy group in the 1-position and methoxy group in the 2-position of the glycerol part of the molecule) inhibit growth of two tumour cell lines (neuroblastoma from mice and glioma cells from rats), while alkylglycerols without methoxy groups did not have any growth-inhibiting effects on the tumor cell line studied. Interactions between different types of alkylglycerols and human neutrophil granulocytes have been studied by Palmblad et al. [59] Platelet-activating factor (PAF) was the most potent with regard to the ability to produce an oxidative response, followed by the methoxy-substituted alkylglycerols. The study shows that there is a dissociation between the ability of an alkylglycerol to initiate oxidative and calcium responses, indicating strict structure–activity relationships for the different alkylglycerols studied.
INDICATIONS AND DOSAGE At present, there are no medical conditions for which shark liver oil-derived alkylglycerols are used as specific therapy; however, they may be used as ancillary,
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auxiliary or augmentative agents in many disorders. In cancer chemotherapy or irradiation therapy, they are not only protective but also additive in the overall therapeutic effect. Any disorder that has a proliferative component, and that would include most inflammatory disorders, will respond to alkylglycerols. Immune disorders in particular, can be treated effectively with alkyglycerols. In the prevention of infection or neoplastic diseases, 50 mg of alkylglcyerol three times a day is suggested. For aggressively treated disorders, 300 mg/day or more may be needed. The use of the methoxy-derived alkylglcyerols must await further research and availability of this powerful akylglycerol.
CONCLUSIONS Ether lipids are well known as a new class of tumoricidal compounds, producing strong biological signals. While many new compounds have been synthesized, natural compounds have been known for a long time, beginning with the work of Hanahan on platelet-activating factor, a 1-O-alkyl glycerol. This class of compound, know as plasmalogens, is known to inhibit phosphorylation reactions, particularly those catalyzed by protein kinase C. The dual action of alkylglycerols on both the physical structure of the cell, such as the cell membrane, and the complex biochemical pathways makes them extremely interesting as modulators of cell functions. The biological action of the alkyglycerols suggests they may have both prophylactic and inhibitory properties against tumors. This action is highly selective and appears to be related mainly to the chemical structure of the alkylglycerol. Most clinical trials with alkyglycerols have been with very advanced cases, but these results are encouraging. The mechanisms involved in antitumor activity are many and include macrophage activation, immune cytotoxicity, NK cell activation, enzyme inhibition and activation, and cell membrane disturbances. Other actions include the anti-infective properties as well as the radiation protective properties of these agents. Two areas which hold promise with the use of alkylglycerols are the suppression of autoimmune disorders and the selective destruction of leukemic cells. Much of this work is covered in a report of the First International Symposium on Ether Lipids in Oncology published by The American Oil Chemist Society in 1987. [60] The outlook for the use of alkylglycerols in medical treatment and in the maintenance of health is very optimistic.
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FM. The relationship between chemical structure and central depressant action of a-substituted ethers of glycerol. J Pharmacol Exp Ther 1948; 93: 470
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Sandler OE. Some experimental studies on the erythropoietic effect of yellow bone marrow extracts and batyl alcohol. Acta Med Scand 133: 1949; 225: 72
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Emmerie A, Engel C, Klip W. J Sci Food Agr 1952; 3: 264
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Bodman J, Maisin J H. The a-glyceryl ethers. Clin Chim Acta 1958; 3: 253
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Brohult A. Alkoxyglycerols as growth stimulating substances. Nature (London) 1960; 188: 591
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Tsujimoto M. The liver oils of Elasmobranch fish. J Soc Chem Ind SI 1932; 317
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Holmberg J, Mysen G, Persson G. Component lipids of some food raw materials. Sixth Congress of the International Society for Fat Research (London). 1962
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Hallgren B, Larsson S. The glyceryl ethers in the liver oils of elasmobrach fish. Lipid Res 1962; 3: 31–38
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Bergstrom S, Blomstrand R. The intestinal absorption and metabolism of chimyl alcohol in the rat. Acta Physiol Scand 1956; 38: I66
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Blomstrand R, Ahrens E H, Jr. Absorption of chimyl alcohol in man. Proc Soc Exp Biol Med 1959; 100, 802–805
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Alexander P, Connel T, Brohult A et al. Reduction of radiation induced shortening of life-span by a diet augmented with alkylglycerols and essential fatty acids. Gerontologia 1959; 3: 147
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Brohult A. Alkylglycerols and their use in radiation. Acta Radiol 1963; 223(Suppl): 7
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Carlson WE. MSc thesis. Vancouver, Canada: University of British Columbia. 1966
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Bandi ZT, Mangold HK, Holmer G et al. Substrate specificity of enzymes catalyzing interconversions of long-chain acids and alcohols in the rat. FEPS 1 1971; 12: 217
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Brissette JL, Cabacungan A, Pieringer RA. Studies on the antibacterial activity of dodecylglycerol. J Biol Chem 1986; 261: 6338–6346.
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Hugo WB, Stretton RJ. The role of cellular lipid in the resistance of some Gram-positive bacteria to penicillins. J Gen Microbiol 1966; 42: 133–138
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Brohult A, Holmberg J. Alkylglycerols in the treatment of leucopenia caused by irradiation. Nature (London) 1954; 174, 1102
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Linman JW. Hemopoietic effects of batyl alcohol. J Clin Invest 1958; 37: 913
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Osmond DG, Roylance PJ, Webb AJ et al. Acta Haematol 1963; 29: 180
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Yamamoto N, St Clair DA, Homma S et al. Activation of mouse macrophages by alkylglycerols, inflammation products of cancerous tissues. Cancer Res 1988; 48: 6044–6049
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Chapter 62 - Allium cepa (onion) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Allium cepa (family: Amarylladaceae or Liliaceae) Common name: onion
GENERAL DESCRIPTION There are numerous forms and varieties of onion as this perennial or biennial herb is cultivated worldwide. The part used is the fleshy bulb. Common varieties are white globe, yellow globe and red globe.
CHEMICAL COMPOSITION Onion, like garlic, contains a variety of organic sulfur compounds, including: • S-methylcysteine sulfoxide • trans-S-(1-propenyl)cysteine sulfoxide • S-propylcysteine sulfoxide • dipropyl disulfide. Onion also has the enzyme alliinase, which is released when the onion is cut or crushed, causing conversion of trans-S-(1-propenyl)cysteine sulfoxide to the so-called lacrimatory factor (propanethial S-oxide). Other constituents include: [1] [2] • flavonoids (primarily quercetin) • phenolic acids (e.g. caffeic, sinapic, and p-coumaric) • sterols • saponins • pectin • volatile oils.
HISTORY AND FOLK USE Although not as valued a medicinal agent as garlic, onion has been used almost as widely. Like garlic ( Allium sativum), onion has been used as an antispasmodic, carminative, diuretic, expectorant, stomachic, anthelmintic, and anti-infective agent. Externally it has been used as a rubefacient and poultice, giving relief in skin diseases and insect bites. [1] [2] [3]
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PHARMACOLOGY Onion and garlic, due to their similar constituents, have many of the same pharmacological effects. There are, however, some significant differences that make one more advantageous than the other in certain conditions. Antimicrobial activity Although onion does exhibit some antibacterial, antifungal, and anthelmintic activity, it is not nearly as potent as garlic. Although this suggests that garlic may be better indicated in cases of infection, [2] [3] [4] onion can usually be consumed in larger quantities than garlic, which may increase the concentration of antimicrobial constituents in vivo to approximate those of garlic. Cardiovascular effects Like garlic, onions and onion extracts have been shown to decrease blood lipid levels, increase fibrinolysis, decrease platelet aggregation, and lower blood pressure in several clinical studies. [5] [6] [7] Onion oil, compared with garlic oil, is a stronger inhibitor of the enzymes cyclo-oxygenase and lipoxygenase, which mediate eicosanoid metabolism (prostaglandins, thromboxanes and leukotrienes). [8] This suggests that onions would also have a greater effect on inhibition of platelet aggregation and other events mediated by eicosanoids. Garlic and onion consumption is associated with lower levels of cholesterol and triglycerides, and an increase in fibrinolytic activity [9] (see Ch. 63 for details). As the quantity of onion consumed in the study cited was so much larger than that of garlic (600 g of onion/week compared with 50 g of garlic), an argument could be made that onion consumption was the major determinant. Diabetes Onions have been shown to have significant oral hypoglycemic action, comparable to that of the prescription oral hypoglycemic agents tolbutamide and phenformin. [10] [11] The active hypoglycemic principle in onions is believed to be allyl propyl disulphide (APDS), although other constituents, such as quercetin and anthocyanidins, may play a significant role as well. Experimental and clinical evidence suggests that APDS lowers glucose by competing with insulin (also a disulfide) for degradation sites, thereby increasing the half-life of insulin. Other mechanisms, such as increased hepatic metabolism of glucose or increased insulin secretion, have been proposed. Anti-asthmatic action Onion has historically been used as an anti-asthmatic agent. [2] [3] Its action in asthma, as well as in other conditions associated with increased lipoxygenase derivatives (leukotrienes), such as psoriasis and atopic dermatitis, appears to be greater than that of garlic. (As mentioned previously, onion oil is a much greater inhibitor of cyclo-oxygenase and lipoxygenase.) [8] The net effect is similar to that of cortisol, which inhibits all eicosanoid metabolism via inhibition of phospholipase. Inhibition of leukotriene formation and onion’s quercetin and isothiocyanates content are probably the primary factors responsible for onion’s anti-asthmatic effects.
These effects have been confirmed in experimental studies. [12] [13] Antitumor effects An onion extract was found to be cytotoxic to tumor cells in vitro and to arrest tumor growth when tumor cells were implanted in rats. [14] The onion extract was shown to be unusually non-toxic, since a dose as high as 40 times that of the cytotoxic dose for the tumor cells had no adverse effect on the host. Another species of allium, Allium ascalonicum (shallots), has been shown to exhibit significant antileukemic activity in mice. [15] One human study evaluated onion consumption and stomach cancer in over 120,000 men and women between 55 and 69 years of age. After a 3.3 year follow-up, 139 stomach cancers were diagnosed. The researchers found a strong inverse association between onion consumption and stomach cancer incidence, but no association with the use of leeks or garlic. [16]
DOSAGE Onion can be eaten liberally as part of a nutritious diet. Therapeutic dosages in the various forms are typically 50–150 g/day.
TOXICOLOGY There have been virtually no reports of toxicity. However, those with heartburn may note an aggravation of symptoms. One study evaluated symptoms of acid reflux in 16 normal subjects and 16 heartburn patients. Subjects were studied with an esophageal pH probe for 2 hours after eating a plain hamburger and a glass of ice water, then on another day an identical meal with a slice of raw onion. In the normal patients, ingestion of onions did not increase any of the variables measured (number of reflux episodes, pH < 4, time of pH < 4, heartburn episodes and belches). In contrast, heartburn subjects experienced a significant increase in all. While the authors of the study conclude that onions can be a potent and long-lasting reflexogenic agent in heartburn patients, [17] an alternative explanation may be that onion simply improved digestive acid secretion, making the symptoms of reflux more noticeable.
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SUMMARY The above discussion on the onion highlights its medicinal value, particularly in cardiovascular disease, diabetes mellitus, and inflammatory conditions. As onion is chiefly regarded as a food or seasoning, this chapter, and the other chapters in this section about common foods and seasonings (e.g. Chs 63 , 80 and 124 ) raise questions about the medicinal effects of other common vegetables and/or seasonings. They also may have significant pharmacological effects that have not been investigated. A diet rich in such foods, spices or seasonings may offer protection and possibly treatment for a wide variety of diseases. Once again, the importance of a relatively natural, unprocessed diet to long-term health is supported. The liberal use of the Allium species appears particularly indicated considering the major disease processes of the 20th century.
REFERENCES 1. Leung 2. Raj
A. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York, NY: John Wiley. 1980: p 246–247
KP, Patel NN. Onion – the vegetable drug. Ind Drugs 1977; 14: 156–160
3. Vahora
SB, Rizwan M, Khan JA. Medicinal uses of common Indian vegetables. Planta Med 1973; 23: 381–393
4. Elnima
EI, Ahmed SA, Mekkawi A, Mossa JS. The antimicrobial activity of garlic and onion extracts. Pharmazie 1983; 38: 747–748
5. Louria 6. Mittal
DB, McAnnally JF, Lasser N et al. Onion extract in treatment of hypertension and hyperlipidemia. A preliminary communication. Curr Ther Res 1985; 37: 127–131
MM, Mittal S, Sarin JC, Sharma ML. Effects of feeding onion on fibrinolysis, serum cholesterol, platelet aggregation and adhesion. Ind J Med Sci 1972; 24: 144–148
7. Menon
IS. Fresh onions and blood fibrinolysis. Br Med J 1969; i: 845
8. Norwell
DY, Tarr RS. Garlic, vampires, and CHD. Osteopath Ann 1983; 11: 546–549
9. Sainani
GS, Desai DB, Gohre NH et al. Effect of dietary garlic and onion on serum lipid profile in Jain community. Ind J Med Res 1979; 69: 776–780
10.
Bever BO, Zahnd GR. Plants with oral hypoglycemic action. Quart J Crude Drug Res 1979; 17: 139–196
11.
Sharma KK, Gupta RK, Gupta S, Samuel KC. Antihyperglycemic effect of onion. effect on fasting blood sugar and induced hyperglycemia in man. Ind J Med Res 1977; 65: 422–429
Dorsch W, Adam O, Weber J, Ziegeltrum T. Antiasthmatic effects of onion extracts – detection of benzyl- and other isothiocyanates in mustard oils as antiasthmatic compounds of plant origin. Eur J Pharmacol 1985 107: 17–24 12.
13.
Dorsch W, Weber J. Prevention of allergen-induced bronchial constriction in sensitized guinea pigs by crude alcohol onion extract. Agents Action 1984; 14: 626–630
14.
Nepkar DP, Chander R, Bandekar JR et al. Cytotoxic effect of onion extract on mouse fibrosarcoma 180 A cells. Ind J Exp Biol 1981; 19: 598–600
15.
Caldes G, Prescott B. A potential antileukemic substance present in Allium ascalonicum. Planta Medica 1973; 23: 99–100
16.
Dorant E, van den Brandt PA, Goldbohm RA et al. Consumption of onions and a reduced risk of stomach carcinoma. Gastroenterology 1996; 110: 12–20
17.
Allen ML, Mellow MH, Robinson MG et al. The effect of raw onions on acid reflux and reflux symptoms. Am J Gastroent 1990; 85: 377–380
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Chapter 63 - Allium sativum (garlic) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Allium sativum (family: Amaryllidaceae or Liliaceae) Common names: garlic, allium
GENERAL DESCRIPTION Garlic, a member of the lily family, is a perennial plant that is cultivated worldwide. The garlic bulb is composed of individual cloves enclosed in a white skin. It is the bulb, either fresh or dehydrated, that is used as a spice or medicinal herb.
CHEMICAL COMPOSITION Garlic contains 0.1–0.36% of a volatile oil composed of sulfur-containing compounds: • allicin • diallyl disulfide • diallyl trisulfide • others. The garlic oil is obtained by steamed distillation of the crushed fresh bulbs. [1] These volatile compounds are generally considered to be responsible for most of the pharmacological properties of garlic. Other constituents of garlic include: [1] [2] • alliin (S-allyl- L-cysteine sulfoxide) • S-methyl-L-cysteine sulfoxide • protein (16.8%, dry weight basis) • high concentrations of trace minerals (particularly selenium) • vitamins • glucosinolates • enzymes (alliinase, peroxidase, and myrosinase). Allicin is mainly responsible for garlic’s pungent odor. It is formed by the action of the enzyme alliinase on the compound alliin. The essential oil of garlic yields approximately 60% of its weight in allicin after exposure to alliinase. The enzyme is inactivated by heat, which accounts for the fact that cooked garlic produces neither
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as strong an odor as raw garlic nor nearly as powerful physiological effects.
[1]
HISTORY AND FOLK USE Garlic has been used throughout history for the treatment of a wide variety of conditions. Its usage predates written history. Sanskrit records document the use of garlic remedies approximately 5,000 years ago, while the Chinese have been using it for at least 3,000 years. The Codex Ebers, an Egyptian medical papyrus dating to about 1550 BC, mentions garlic as an effective remedy for a variety of ailments, including hypertension, headache, bites, worms, and tumors. Hippocrates, Aristotle and Pliny cited numerous therapeutic uses for garlic. In general, garlic has been used throughout the world to treat coughs, toothache, earache, dandruff, hypertension, atherosclerosis, hysteria, diarrhea, dysentery, diphtheria, vaginitis, and many other conditions. [1] [2] [3] Stories, verse and folklore (such as its alleged ability to ward off vampires) give historical documentation to garlic’s power. Sir John Harrington in The Englishman’s doctor, written in 1609, summarized garlic’s virtues and faults: [3] Garlic then have power to save from death Bear with it though it maketh unsavory breath, And scorn not garlic like some that think It only maketh men wink and drink and stink. In 1721, during a widespread plague in Marseilles, four condemned criminals were recruited to bury the dead. The gravediggers proved to be immune to the disease. Their secret was a concoction they drank consisting of macerated garlic in wine. This became known as vinaigre des quatre voleurs (four thieves’ vinegar), and it is still available in France today. Garlic’s antibiotic activity was noted by Pasteur in 1858. Garlic was used by Albert Schwietzer in Africa for the treatment of amebic dysentery, and as an antiseptic in the prevention of gangrene during the two World Wars.
PHARMACOLOGY Although garlic has a wide range of well-documented effects, its most important clinical uses are in the areas of infection, cancer prevention, and cardiovascular disease. Antimicrobial activity Garlic has been shown to have broad-spectrum antimicrobial activity against many genera of bacteria, viruses, worms, and fungi, as summarized in several works. [6] These findings support the historical use of garlic in the treatment of a variety of infectious conditions.
[ 4] [5]
Antibacterial activity
As far back as 1944, studies have demonstrated that both garlic juice and allicin inhibited the growth of Staphylococcus, Streptococcus, Bacillus, Brucella, and Vibrio species at low concentrations. [7] [8] In more recent studies using serial dilution and filter paper disk techniques, fresh and vacuum-dried powdered garlic preparations were found to be effective antibiotic agents against many bacteria, as listed in Table 63.1 . In these studies, the antimicrobial effects of garlic were compared with commonly used antibiotics, including penicillin, streptomycin, chloramphenicol, erythromycin, and tetracyclines. Besides confirming garlic’s well-known antibacterial effects, the studies demonstrated its efficacy in inhibiting the growth of some bacteria which had become resistant to one or more of the antibiotics. Garlic administration has also been shown to significantly reduce the number of coliforms and anaerobes in the feces.
[11]
Antifungal activity
Garlic has demonstrated significant antifungal activity in many in vitro and in vivo studies. [4] [12] [13] [14] [15] [16] [17] From a clinical perspective, inhibition of Candida albicans has the most significance, as both animal and in vitro studies have shown garlic to be more potent than nystatin, gentian violet, and six other reputed antifungal agents. [4] [13] [14] [15] Aqueous garlic extracts have been shown in vivo to be very effective, even at a dilution of 1:100, against the very common tinea corporis, capitis and cruris fungal skin infections. [13] In one study at a major Chinese hospital, garlic therapy alone was used effectively in the treatment of cryptococcal meningitis, one of the most serious fungal infections imaginable. [16] TABLE 63-1 -- Microbes inhibited by garlic [4] [5] [6] [9] [10] • Bacteria —alpha- and beta-hemolytic Streptococcus —Citrobacter sp. —Escherichia coli —Klebsiella pneumoniae —Mycobacteria —Proteus vulgaris —Salmonella enteritidis —Staphylococcus aureus • Fungi —Candida albicans —Cryptococcus neoformans • Helminths —Ascaris lumbricoides —hookworms • Viruses —Herpes simplex types 1 and 2 —Human rhinovirus type 2 —Parainfluenza virus type 3 —Vaccinia virus —Vesicular stomatitis virus
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Anthelmintic effects
Garlic extracts have been shown to have anthelmintic activity against common intestinal parasites, including Ascaris lumbricoides (roundworm) and hookworms.[11] [18] Antiviral effects
Garlic’s antiviral effects have been demonstrated by its protection of mice from infection with intranasally inoculated influenza virus, and by its enhancement of neutralizing antibody production when given with influenza vaccine. [19] The in vitro virus-killing effects of fresh garlic, allicin, and other sulfur components of garlic were determined against Herpes simplex types 1 and 2, Parainfluenza virus type 3, Vaccinia virus, Vesicular stomatitis virus, and Human rhinovirus type 2. The order for virucidal activity was:
Ajoene was found in oil-macerates of garlic but not in fresh garlic extracts. No antiviral activity was found for alliin, deoxyalliin, diallyl disulfide, or diallyl trisulfide. Fresh garlic extract was virucidal against all viruses tested. Virucidal activity of commercial products was dependent upon their preparation processes. Those products producing the highest level of allicin and other thiosulfinates had the best virucidal activity. [20] Immune-enhancing effects A large amount of research has shown that garlic has many immune-potentiating properties, most of which are thought to be due to volatile factors composed of sulfur-containing compounds: allicin, diallyl disulfide, diallyl trisulfide and others. Fresh garlic, commercial products containing allicin, and aged garlic preparations have all shown these properties. Garlic has been shown to enhance the pathogen-attacking activity of T-cells, neutrophils and macrophages, to increase the secretion of interleukin, and to increase natural killer cell activity. [21] [22] [23] [24] The increase in killer cell activity was a remarkable 140% in those eating the equivalent of two bulbs a day and 156% in those consuming 1,800 mg of odorless aged garlic. Anti-cancer effects The famous Greek physician Hippocrates prescribed eating garlic as a treatment for cancer. Animal research and some human studies suggest this advice may have
been well-founded. Several garlic components have displayed significant anti-cancer effects.
[ 25] [26] [ 27]
Human studies showing garlic’s anti-cancer effects are largely based on epidemiological studies. [25] [26] [27] [28] These studies show an inverse relationship between cancer rates and garlic consumption. In China, a study comparing populations in different regions found that death from gastric cancers in regions where garlic consumption was high was significantly less than in regions with lower garlic consumption. [28] Garlic extracts and allicin have displayed potent antitumor effects in animal studies. [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] Human studies have shown that garlic inhibits the formation of nitrosamines (powerful cancer-causing compounds formed during digestion). [39] [40] Cardiovascular effects Garlic appears to be an important protective factor against heart disease and strokes via its ability to impact the process of atherosclerosis at many steps. As there is substantial clinical information on garlic’s beneficial effects on the cardiovascular system, the pharmacology is discussed in the section on “clinical applications” below. Other effects Anti-inflammatory effects
Garlic extract has demonstrated significant antiinflammatory activity in experimental models of inflammation. [2] [11] This activity is probably a result of garlic’s inhibition of the formation of inflammatory compounds. Hypoglycemic action
Garlic (and onions) has often been used in the treatment of diabetes. Allicin has been shown to have significant hypoglycemic action. This effect is thought to be due to increased hepatic metabolism, increased release of insulin and/or insulin-sparing effect. [41] The latter mechanism appears to be the major factor, as allicin and other sulfhydryl compounds in garlic and onions compete with insulin (also a disulfide protein) for insulin-inactivating compounds, which results in an increase in free insulin. Miscellaneous effects
Garlic possesses diuretic, diaphoretic, emmenagogue, and expectorant action. [1] [9] It is also a carminative, anti-spasmodic and digestant, making it useful in cases of flatulence, nausea, vomiting, colic, and indigestion. [11] [42]
CLINICAL APPLICATIONS Although garlic has long been used in infectious conditions, a use supported by its antimicrobial and immune-enhancing properties, the primary clinical use of garlic
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has focused on its role in cardiovascular disease. Specifically, garlic is recommended primarily for its ability to lower cholesterol and blood pressure in the attempt to reduce the risk of dying prematurely from a heart attack or stroke. Cardiovascular disease The majority of studies showing a positive effect of garlic and garlic preparations in reducing the risk of cardiovascular mortality are those which use products that deliver a sufficient dosage of allicin. Since allicin is the component in garlic that is responsible for its easily identifiable odor, several manufacturers have developed highly sophisticated methods in an effort to provide the full benefits of garlic without odor. These “odorless” garlic products concentrate for alliin because alliin is relatively “odorless” until it is converted to allicin in the body. Products concentrated for alliin and other sulfur components and stabilized in enteric-coated tablets provide all the benefits of fresh garlic but are more “socially acceptable”. In addition to the use of garlic preparations, garlic consumption as a food should be encouraged, despite its odor, in patients with high cholesterol levels and high blood pressure. Garlic and garlic preparations should also be encouraged in patients with diabetes, candidiasis, asthma, infections (particularly respiratory tract infections), and gastrointestinal complaints. Cholesterol-lowering activity
Foremost in garlic’s ability to offer significant protection against heart disease and strokes is its ability to lower blood cholesterol levels, even in apparently healthy individuals. [43] [44] [45] [46] [47] According to the results from numerous double-blind, placebo-controlled studies in patients with initial cholesterol levels greater than 200, supplementation with commercial preparations providing a daily dose of at least 10 mg alliin or a total allicin potential of 4,000 mcg can lower total serum cholesterol levels by about 10–12%; LDL cholesterol will decrease by about 15%; HDL cholesterol levels will usually increase by about 10%; and triglyceride levels will typically drop by 15%.[47] [48] [49] [50] [51] Although the effects of supplemental garlic preparations on cholesterol levels are modest, the combination of lowering LDL and raising HDL can greatly improve the HDL to LDL ratio, a significant goal in the prevention of heart disease and strokes. Garlic preparations standardized for alliin content exert several other beneficial effects in preventing heart disease and strokes (discussed below). In addition to taking a garlic supplement, individuals TABLE 63-2 -- Effects of garlic and onion consumption on serum lipids under carefully matched diets Garlic/onion
Cholesterol Triglyceride
None
208 mg/dl
109 mg/dl
10–200 g/week
172 mg/dl
75 mg/dl
50–600 g/week
159 mg/dl
52 mg/dl
with high cholesterol levels should eat more garlic and onions, as increased dietary intake of garlic and onion can also lower cholesterol levels. [43] [44] [45] [46] [52] In a 1979 population study, researchers studied three populations of vegetarians in the Jain community in India who consumed differing amounts of garlic and onions. [53] Numerous favorable effects on blood lipids, as shown in Table 63.2 , were observed in the group that consumed the largest amount. Blood fibrinogen (discussed below) levels were highest in the group eating no onions or garlic. The study is quite significant because the subjects had nearly identical diets, except in garlic and onion ingestion. Hypertension
Garlic has demonstrated hypotensive action in both experimental animal models and humans with hypertension. [43] [44] [45] [46] [54] [55] [56] A meta-analysis of published and
unpublished randomized controlled trials of garlic preparations was conducted to determine the effect of garlic on blood pressure relative to placebo. (seven double-blind, one single-blind) were identified as meeting analytical criteria. A total of 415 subjects were included in the analysis.
[54]
Eight trials
All trials used a dried garlic powder standardized to contain 1.3% alliin at a dosage of 600 to 900 mg daily (corresponding to 7.8 and 11.7 mg of alliin or the equivalent of approximately 1.8–2.7 g of fresh garlic daily). The meta-analysis concluded that garlic preparations designed to yield allicin can lower systolic and diastolic blood pressures over a 1–3 month period. The typical drop from pooled data was 11 mmHg in the systolic and 5.0 mmHg in the diastolic. This degree of blood pressure reduction in hypertensives can be quite significant. It is estimated that if the blood pressure-lowering effects of garlic can be maintained, the risk of stroke may be reduced by 30–40% and the risk of heart attack by 20–25%. Platelet aggregation inhibition
Excessive platelet aggregation is strongly linked to atherosclerosis, heart disease, and strokes. Garlic preparations standardized for alliin content as well as garlic oil have demonstrated significant inhibition of platelet aggregation. [43] [44] [45] [46] [57] In one study, 120 patients with increased
575
platelet aggregation were given either 900 mg/day of a dried garlic preparation containing 1.3% alliin or a placebo for 4 weeks. [57] In the garlic group, spontaneous platelet aggregation disappeared, the microcirculation of the skin increased by 47.6%, plasma viscosity decreased by 3.2%, diastolic blood pressure dropped from an average of 74 to 67 mmHg, and fasting blood glucose concentration dropped from an average of 90 to 79 mg/dl. Fibrinolytic activity
Epidemiological studies have suggested that excessive fibrinogen formation is a major primary risk factor for cardiovascular disease. [58] Fibrinogen is an “acute phase” protein involved in the clotting system. However, it plays many other roles, including several which promote atherosclerosis, such as acting as a cofactor for platelet aggregation, determining the viscosity of blood, and stimulating the migration and proliferation of smooth muscle cells in the intima of the artery walls. Early clinical studies stimulated detailed population studies on the possible link between fibrinogen levels and cardiovascular disease. The first such study was the Northwick Park Heart Study in the UK. This large study involved 1,510 men aged 40–64 years who were randomly recruited and tested for a range of clotting factors, including fibrinogen. At 4 years follow-up, a stronger association was found between cardiovascular deaths and fibrinogen levels than for cholesterol. This association has been confirmed in five other prospective epidemiological studies. [58] The clinical significance of these findings can be summarized as follows: 1. Fibrinogen levels should be determined and monitored in patients with, or at high risk for, coronary heart disease or stroke. 2. Garlic and other natural therapies which promote fibrinolysis (e.g. omega-3 oils, bromelain, capsicum, etc.) may offer significant benefit in the prevention of heart attacks, strokes, and other thromboembolic events. Garlic preparations standardized for alliin content as well as garlic oil, and both fried and raw garlic have been shown to significantly increase serum fibrinolytic activity in humans.[59] [60] This increase occurs within the first 6 hours after ingestion and continues for up to 12 hours. Prevention of LDL oxidation
There is growing evidence that lipoprotein (LDL) oxidation plays a significant role in the development of atherosclerosis. Accordingly, substances which prevent oxidation of LDL slow down atherosclerosis. Antioxidants vitamin E, vitamin C, and beta-carotene have all been shown to offer protection against LDL oxidation and heart disease. Garlic is known to exert antioxidant activity, but until recently, there were no studies examining its effects on LDL oxidation. Healthy human volunteers given 600 mg/day of a garlic preparation providing 7.8 mg alliin for 2 weeks had a 34% lower susceptibility to lipoprotein oxidation compared with controls. [61] These results are quite significant given the short amount of time they took to produce coupled with the importance of reducing lipoprotein oxidation. In another study, a placebo-controlled double-blind trial of 23 subjects with coronary artery disease who had one to three major coronary arteries that were 75% blocked or higher, 300 mg of garlic powder, 2 and 4 hours after a single dose, showed the atherogenicity of the patients’ sera to be markedly decreased. There was less cholesterol accumulation and lower levels of oxidized LDL in human aortic smooth muscle cells cultured with patients sera after treatment compared with those cultured with sera obtained prior to the administration of the garlic. After 3 weeks of therapy at 300 mg, three times daily, blood serum atherogenicity was decreased twofold compared with initial levels. [62]
DOSAGE The modern use of garlic features the use of commercial preparations designed to offer the benefits of garlic without the odor. The marketplace is swamped with garlic products with each manufacturer claiming their product is the best. Preparations standardized for alliin content provide the greatest assurance of quality. However, American consumers must be aware of the subtle techniques manufacturers of garlic products use to disguise the quality of their products. Based on a great deal of clinical research, the dosage of a commercial garlic product should provide a daily dose equal to at least 4,000 mg of fresh garlic. This dosage translates to at least 10 mg alliin or a total allicin potential of 4,000 mcg.
Figure 63-1 Conversion of alliin to allicin.
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TOXICITY For the vast majority of individuals, garlic is non-toxic at the dosages commonly used. For some, however, it can cause irritation to the digestive tract, while others are apparently unable to effectively detoxify allicin and other sulfur-containing components. Prolonged feeding of very large amounts of raw garlic to rats results in anemia, weight loss and failure to grow. [63] Although the exact toxicity of garlic has yet to be definitively determined, side-effects are rare at the dosage recommended above.
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Kendler BS. Garlic (Allium sativum) and onion (Allium cepa). A review of their relationship to cardiovascular disease. Prev Med 1987; 16: 670–685
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Kleijnen J, Knipschild P, ter Riet G et al. Garlic, onions and cardiovascular risk factors. A review of the evidence from human experiments with emphasis on commercially available preparations. Br J Clin Pharmacol 1989; 28: 535–544 47.
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Rotzch W, Richter V, Rassoul F, Walper A et al. Postprandial lipaemia under treatment with Allium sativum. Controlled double-blind study in healthy volunteers with reduced HDL 2 - cholesterol
levels. Arzneim Forsch 1992; 42: 1223–1227 51.
Mader FH. Treatment of hyperlipidemia with garlic-powder tablets. Arzneim Forsch 1990; 40: 1111–1116
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Bordia A. Effect of garlic on blood lipids in patients with coronary heart disease. Am J Clin Nutr 1981; 34: 2100–2103
Sainani GS, Desai DB, Gorhe NH, Sainani GS, Desai DB, Gorhe NH et al. Effect of dietary garlic and onion on serum lipid profile in the Jain community. Ind J Med Res 1979; 69: 776–780; Sainani GS et al. Dietary garlic, onion and some coagulation parameters in Jain community. J Assoc Phys Ind 1979; 27: 707–712 53.
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Petkov V. Plants with hypotensive, antiatheromatous and coronary dilating action. Am J Chin Med 1979; 7: 197–236
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Foushee DB, Ruffin J, Banerjee U. Garlic as a natural agent for the treatment of hypertension. A preliminary report. Cytobios 1982; 34: 145–162
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Kiesewetter H, Jung P, Pindur G et al. Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxicol 1991; 29: 151–155
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Chutani SK, Bordia A. The effect of fried versus raw garlic on fibrinolytic activity in man. Atherosclerosis 1981; 38: 417–21
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Phelps S, Harris WS. Garlic supplementation and lipoprotein oxidation susceptibility. Lipids 1993; 28: 475–477
Orekhov AN, Tertov VV, Sobenin IA et al. Garlic powder tablets reduce atherogenicity of low density lipoprotein. A placebo-controlled double-blind study. Nutr Metab Cardiovascular Dis 1996; 6: 21–31 62.
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Nakagawa S, Masamoto K, Sumiyoshi H et al. Effect of raw and extracted-aged garlic juice on growth of young rats and their organs after perioral administration. J Toxicol Sci 1980; 5: 91–112
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Chapter 64 - Aloe vera (Cape aloe) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Aloe vera (family: Lilaceae) Common name: Cape aloe
GENERAL DESCRIPTION There are more than 300 species of aloe plants, but the most popular medicinal variety is currently Aloe vera. The nomenclature of Aloe vera has been somewhat confused as the plant has been known by a variety of names, most notably Aloe barbadensis and Aloe vulgari. The geographical origination of the plant is unclear. Historical records indicate that it may have originated from Egypt or the Middle East. Aloe has been introduced and naturalized throughout most of the tropics and warmer regions of the world, including the Caribbean, the southern US, Mexico, Latin America, the Middle East, India and other parts of Asia. [1] Aloe vera is a perennial plant with yellow flowers and tough fleshy triangular or spear-like leaves arising in a rosette configuration. The leaves are up to 20 inches long and 5 inches across at the base, tapering to a point. There may be as many as 30 leaves per plant. The margins of the leaf are characterized by saw-like teeth. Inside, the meaty leaf is filled with gel that arises from a clear central mucilaginous pulp. Mature aloe measures 1.5–4 feet long and has a base of 3 inches or greater in diameter. The leaf is composed of three distinct layers: an outer layer of tough tissue; a corrugated lining just beneath the outer layer; and the major portion of the leaf, the inner layer consisting of parenchymal cells containing large vacuoles of a semi-solid, gelatinous transparent gel. The bitter latex of the corrugated layer protects the plants from predators. Should an animal bite the leaf, the sap causes irritation. The dried latex (juice) derived from the corrugated layer is the source of the laxative properties of aloe. The parenchymal tissue or gel is the portion of the aloe used in other applications. [2]
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Aloe vera terminology
• • • •
Aloe vera gel – naturally occurring, undiluted parenchymal tissue obtained from the decorticated leaves of Aloe vera Aloe vera concentrate – Aloe vera gel from which the water has been removed Aloe vera juice – an ingestible product containing a minimum of 50% Aloe vera gel Aloe vera latex – the bitter yellow liquid derived from the pericyclic tubules of the rind of Aloe vera, the primary constituent of which is aloin.
CHEMICAL COMPOSITION Aloe vera contains numerous compounds possessing biological activity. While many botanical medicines suffer from substantial geographical variation in content, commercial aloe is quite consistent. One study found that the composition of the major compounds is remarkably invariable, with aloeresin A, aloesin, and aloin (both epimers A and B) contributing between 70 and 97% of total dry weight, in a ratio of approximately 4:3:2, respectively. Minor compounds were less evenly distributed, with aloinoside A and aloinoside B being found in higher concentrations in Western Countries. The aloin content of the exudate did vary but there were no distinct geographical discontinuities. [3] Anthraquinones
In 1851, it was discovered that the cathartic action of aloe was due to aloin, a lemon yellow powder formed from drying of the bitter latex. From this material several anthracenes have been isolated, the major anthraquinone being barbaloin. Barbaloin and aloin are often referred to synonymously. Although aloe contains other anthraquinone derivatives, including the anthracene known as aloe-emodin, barbaloin is considered the most potent cathartic. As a whole, the anthraquinone compounds are water-soluble glycosides easily separated from the water-insoluble resinous material. [1] [2] [3] [4] [5] Saccharides
Recent research on Aloe vera has focused on the glycoprotein, mucopolysaccharide, and polysaccharide constituents. Aloe contains polysaccharides galactose, xylose, arabinose, and acetylated mannose. This latter polysaccharide, which is similar to guar and locust bean, has received considerable clinical research attention as an antiviral and immunopotentiating agent, especially in the treatment of AIDS. Acemannan, a water-soluble, long-chain polydispersed beta-(1,4)-linked mannan polymer interspersed with O-acetyl groups, is discussed below. Prostanoids
Several prostanoid compounds have been discovered in Aloe vera extracts. [6] The conversion of essential fatty acids to prostanoids by the enzyme cyclooxygenase in a plant such as Aloe vera is quite rare. The major unsaturated fatty acid in the plant is gamma-linolenic acid (C18:3) which can be converted to eicosatrienoic acid, the precursor to prostaglandins of the 1 series. The 1 series prostaglandins are known to exert more favorable effects on inflammation, allergy, platelet aggregation, and wound healing. The presence of gamma-linoleic acid and/or prostaglandins in a stable medium, along with inhibitors of thromboxane synthesis, may be another of the important chemical characteristics of aloe responsible for its wound healing effects. Superoxide dismutase
Extracts from the parenchymatous leaf gel and the rind of aloe ( Aloe barbadensis Miller) have been shown to contain seven electrophoretically identifiable superoxide dismutases (SODs). Two of these seven are mangano-SODs, while the other five activities are cupro-zinc SODs. [7] Other constituents
Other biological active compounds found in Aloe vera include: • a serine carboxypeptidase • salicylates • minerals
• vitamins • sterols • amino acids. Table 64.1 provides a partial listing of the remarkably diverse range of compounds isolated from Aloe vera.[2] [3] [4] [5]
HISTORY AND FOLK USE Aloe vera has a storied history of use. Mesopotamian clay tablets dated 1750 BC indicate that Aloe vera was being used for medicinal purposes. Egyptian records from 550 BC also mentioned aloe for infections of the skin. The ancient Greeks were also aware of aloe’s medicinal effects as both Pliny (23–79 AD) and Dioscorides (first century AD) wrote of aloe’s ability to treat wounds and heal infections of the skin. Aloe vera is still widely used in many traditional systems of medicine. In India, for example, in addition to external applications, aloe (whole leaves, the exudate, and the fresh gel) is used as a cathartic, stomachic, and anthelmintic. Aloe vera has been adopted into the materia medicas by many cultures of the world. [1]
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TABLE 64-1 -- Chemical composition of Aloe vera[5] Anthraquinones Aloin, barbaloin, isobarbaloin, anthranol, aloetic acid, anthracene, ester of cinnamic acid, aloe-emodin, emodin, chrysophanoic acid, ethereal oil, resistannol Saccharides
Cellulose, glucose, mannose, L-rhamnose, aldopentose
Prostanoids
Gamma-linolenic acid
Enzymes
Oxidase, amylase, catalase, lipase, alkaline phosphatase
Amino acids
Lysine, threonine, valine, methionine, leucine, isoleucine, phenylalanine
Vitamins
Vitamins B1 , B2 , B6 , C, and E, folic acid, choline, ß-carotene
Minerals
Calcium, sodium, manganese, magnesium, zinc, copper, chromium
Miscellaneous
Cholesterol, triglycerides, steroids, uric acid, lignins, ß-sitosterol, gibberellin, salicylic acid
In the United States, the history of aloe can be traced as far back as the United States Pharmacopoeia of 1820, where a number of aloe preparations were described. Most of these preparations were designed to take advantage of aloe’s laxative effects. By the early 1900s, more than 27 different aloe preparations were in popular use. In 1920, aloe began being cultivated for pharmaceutical use. [4] A major development in the modern use of aloe occurred in 1935 when a group of physicians successfully used the fresh juice to treat a patient suffering from facial burns due to X-rays. [8] The relief offered by aloe in the topical treatment of burns, minor irritations, skin ulcers, and other skin disorders is a major reason why companies supplying dermatologic and cosmetic products have incorporated aloe in many of their formulations. Although more and more of aloe’s medicinal effects are being confirmed, aloe is still predominantly administered without direct medical supervision. Therefore, the history and folk use of aloe are continuing to evolve.
PHARMACOLOGY Gastrointestinal effects The pharmacology of aloe is surprisingly diverse – laxative, immune potentiation, antimicrobial and wound-healing activities help explain its wide ranging folk and clinical applications. Laxative effects
Although physicians have prescribed the whole aloe leaf as a cathartic for more than 2,000 years, it was not until 1851 that the active principle aloin was discovered. [1] In small doses, aloin acts as a tonic to the digestive system, giving tone to the intestinal muscle. At higher dosages, it becomes a strong purgative. Its actions are most obvious on the large intestine where it increases colonic secretions and peristaltic contractions. In combination with strychnine and belladonna, aloin became one of the most popular laxatives for chronic constipation for many years. Since aloin often causes painful contraction, other anthraquinone laxatives like cascara and senna are now much more popular.[9] [10] A substantial amount of research activity continues in an effort to understand the laxative effects of aloe. Research using the rat large intestine shows that the increase in water content of the large intestine induced by barbaloin precedes the stimulation of peristalsis, attended by diarrhea. Therefore, it is suggested that the increase in water content is a more important factor than the stimulation of peristalsis in the diarrhea induced by barbaloin. [11] Further studies by the same researchers suggests that aloe-emodin-9-anthrone (AE-anthrone), produced from barbaloin in the rat large intestine may be the actual chemical mediator of this effect. AE-anthrone not only caused an increase in the intestinal water content, but also stimulated mucus secretion. [12] Bowel detoxification
In 1985, Bland [13] reported the effect of orally consumed Aloe vera juice on urinary indican, gastrointestinal pH, stool culture, and stool specific gravity in a semi-controlled study of 10 (five men and five women) healthy human subjects. [13] Urinary indican (see Ch. 31 ) is used as an indicator of the degree to which either dietary protein is malabsorbed or intestinal bacteria are engaged in putrefactive processes. After one full week of drinking 6 ounces of Aloe vera juice three times daily, urinary indican levels decreased one full unit. This suggests that regular Aloe vera juice consumption can lead to improved protein digestion and assimilation and/or reduced bacterial putrefaction. Inhibition of gastric acid secretion
With Heidelberg gastric analysis, the Aloe vera juice was shown to increase gastric pH by an average of 1.88 units. This supports the findings of other researchers that Aloe vera gel can inhibit the secretion of hydrochloric acid. The Heidelberg test also demonstrated that Aloe vera juice can slow down gastric emptying, possibly leading to improved digestion. Six of the 10 subjects showed marked alterations in stool cultures after the week long study. This implies that Aloe vera juice may exert some bacteriostatic or fungistatic activity. In the four subjects with positive cultures for yeast, there was a reduction in the number of yeast colonies.
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Stool specific gravity was reduced after the week of Aloe vera juice. This implies improved water retention, yet none of the subjects complained of diarrhea or loose stools while taking the Aloe vera juice.
Immune-enhancing and antimicrobial activity Antibacterial and antifungal activity
Aloe has demonstrated activity against many common bacteria and fungi in several studies. In the most detailed of these studies, Robson et al [14] assayed the antimicrobial properties of an Aloe vera extract and reviewed the work of others. [15] [16] [17] Both mean inhibitory and mean lethal concentrations were determined and compared with silver sulfadiazine, a potent antiseptic used in the treatment of extensive burns. As shown in Table 64.2 , the antimicrobial effects of Aloe vera compare quite favorably with those of silver sulfadiazine. A 60% Aloe vera extract was found to be bactericidal against Pseudomonas aeruginosa, Klebsiella pneumoniae, Serratia marcescens, Citrobacter sp., Enterobacter cloacae, Streptococcus pyogenes, and Strep. agalacticae. Seventy per cent concentrations of aloe were bactericidal for Staphylococcus aureus, 80% for E. coli, and 90% for Streptococcus faecalis and Candida albicans. Organisms inhibited in other studies include Mycobacterium tuberculosis, Trichophyton sp., and Bacillus subtilis.[2] [4] [5] The antimicrobial activity against common skin pathogens of Aloe vera gel in a cream base was shown to be slightly better than silver sulfadiazine in agar well diffusion studies. [14] Antiviral effects
Acemannan (acetylated mannose) in injectable form has been approved for veterinary use in fibrosarcomas and feline leukemia. Its action in feline leukemia is quite impressive. Feline leukemia, like AIDS, is caused by a retrovirus (feline leukemia virus or FeLV). The virus is TABLE 64-2 -- Antimicrobial effects of Aloe vera extract in cream base compared with silver sulfadiazine in agar well (6 mm) diffusion [14] Organism Aloe vera
AgSD
Gram-negative E. coli
16
12
Enterobacter cloacae
14
12
K. pneumoniae
14
6
P. aeruginosa
17
12
S. aureus
18
12
S. pyogenes
16
12
S. agalactiae
16
12
S. faecalis
6
11
B. subtilis
19
14
Gram-positive
Inhibition zones measured in mm. so lethal that once cats develop clinical symptoms they are usually euthanized. Typically over 70% of cats will die within 8 weeks of the onset of clinical signs. In a study of 44 cats with clinically confirmed feline leukemia, acemannan was injected (2 mg/kg) weekly for 6 weeks and re-examined 6 weeks after termination of treatment.[18] At the end of the 12 week study, 71% of the cats were alive and in good health. Acemannan has demonstrated significant antiviral activity against several viruses, including the feline AIDS, human immunodeficiency virus type 1 (HIV-1), influenza virus and measles virus.[19] [20] [21] Immune enhancement
Acemannan is a potent immunostimulant.[18] [22] [23] [25] Among the effects noted for acemannan include the enhancement of macrophage release of interleukin-1-alpha, cytokines, tumor necrosis factor, nitric oxide release, as well as phagocytosis and non-specific cytotoxicity. Acemannan also enhances T-cell function and interferon production, although these actions may also be due to enhanced macrophage function. Macrophage production of cytokines IL-6 and TNF-alpha were dependent on the dose of acemannan provided. These effects can be quite substantial. For example, in one study, acemannan has been shown to enhance the macrophage respiratory burst (twofold increase above the media controls), phagocytosis (45% compared with 25% in controls), and killing of Candida albicans (38% killing of Candida albicans compared with 0–5% killing in controls). [26] Hematopoetic effects
Several complex carbohydrates have been found to significantly stimulate hematopoiesis. CARN 750, a polydispersed beta-(1,4)-linked acetylated mannan isolated from the Aloe vera plant, has been shown to have hemato-augmenting properties. Subcutaneous injections of 1 mg/mouse of CARN 750 optimally increased hematopoietic progenitors, measured as interleukin-3-supported colony forming units-culture (CFU-C) and high proliferative potential colony-forming cells (HPP-CFC) assays in the spleen. Providing 2 mg/animal of CARN 750 optimally increased bone marrow cellularity, frequency and absolute number of HPP-CFCs and CFU-Cs. The hematopoietic activity of CARN 750 increased with the frequency of administration. The greatest increase in activity in mice myelosuppressed with radiation. [27] Anti-inflammatory activity Aloe vera has been shown to exert a number of anti-inflammatory actions, including blocking of the generation of inflammatory mediators like thromboxanes
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and bradykinin, reducing neutrophil infiltration during inflammation, and reducing edema. [2] [4] [5] [14] [28] [29] [30] [31] There are several compounds in aloe responsible for these actions. The most important are glycoproteins, which inhibit and actually break down bradykinin, a major mediator of pain and inflammation; various anthraquinones; and salicylates. These anti-inflammatory substances may be of significance in both topical (discussed below) and oral applications. One comprehensive study evaluated the effects of aqueous, chloroform, and ethanol extracts of Aloe vera gel on carrageenan-induced edema in the rat paw, and neutrophil migration into the peritoneal cavity stimulated by carrageenan. Also evaluated was the capacity of the aqueous extract to inhibit cyclooxygenase activity. The aqueous and chloroform extracts decreased the edema induced in the hind paw and the number of neutrophils migrating into the peritoneal cavity, whereas the ethanol extract only decreased the number of neutrophils. The aqueous extract was also found to inhibit prostaglandin E 2 production from arachidonic acid, demonstrating an inhibitory action on cyclooxygenase. The aqueous extract contained anthraglycosides, reductor sugars and cardiotonic glycosides, while the ethanol extract contained saponins, carbohydrates, naftoquinones, sterols, triterpenoids and anthraquinones, and the chloroform extract contained sterols and anthraquinones. [32] Another useful aspect of aloe is its ability to inhibit lipid peroxidation and scavenge free radicals. One study measured the activity of seven anthraquinones and four anthrones against non-enzymatic and enzymatic lipid peroxidation in vitro and their ability to scavenge free radicals. Using rat hepatocytes exposed to strong oxidizing agents, dithranol and anthrone provided the strongest inhibition of non-enzymatic peroxidation. Rhein anthrone and aloe-emodin showed the highest inhibitory activity against peroxidation of linoleic acid catalyzed by lipoxygenase. Anthrone, dithranol and rhein anthrone were the most effective free radical scavengers.[33]
Other effects Wound healing
The topical effects of Aloe vera appear to be due to a combination of enhancement of wound healing along with anti-inflammatory, moisturizing, emollient, and antimicrobial actions. [2] [4] [5] [14] [34] [35] [35A] [36] [37] [38] [39] Aloe vera contains a number of compounds necessary for wound healing, including vitamin C, vitamin E and zinc. Unlike many other anti-inflammatory substances, Aloe vera has been shown to stimulate fibroblast and connective tissue formation, thereby promoting wound repair. Finally, aloe appears to stimulate the epidermal growth and repair process, presumably due to its polysaccharides. Mannose-6-phosphate, the major sugar in the Aloe vera gel, may its most active growth substance.[40] Another interesting effect of aloe in wound healing is its ability to counteract the wound healing suppression effects of cortisone. In one study, Aloe vera at doses of 100 and 300 mg/kg daily for 4 days blocked the wound healing suppression of hydrocortisone acetate up to 100% using the wound tensile strength assay. The authors suggested this response was because of the growth factors present in A. vera masking the wound healing inhibitors. [41] Alcohol detoxification
Oral administration of aloin (300 mg/kg) given 12 hours prior to the administration of alcohol (3.0 g/kg) significantly decreases the blood alcohol area under the curve by a remarkable 40%. This suggests an increase in the rate of blood alcohol elimination from the body of 45–50%. Analysis of hepatic triglyceride (TG) levels revealed that both ethanol and the aloin given alone significantly increased the TG levels in a comparable manner. However, the level obtained by the combined treatment of aloin and ethanol was not statistically different from that produced by either treatment alone. The levels of serum L-aspartate:2-oxoglutarate aminotransferase (AST) and L-alanine:2-oxoglutarate aminotransferase (ALT) activities were not increased by acute alcohol intoxication, aloin alone, or the combined treatment of alcohol and aloin. [42]
CLINICAL APPLICATIONS Burns, frost bite, and other tissue damage
Despite growing consumer awareness of Aloe vera’s soothing effects on burns and wound healing during the past 40 years, few human studies have been carried out. Most of the studies on Aloe vera have utilized different animals in various models of inflammation and wound healing. Virtually all of the studies support the topical use of Aloe vera gel, especially in minor burns or skin inflammation. Some recent research is now supporting its use even for more severe tissue damage. While limited, the human research has been promising. For example, one study found Aloe vera gel quite successful in three patients with chronic leg ulcers of 5, 7, and 15 years’ duration. [43] The gel was applied to the ulcers on gauze bandages. Rapid reduction in ulcer size was noted in all three subjects and complete resolution occurred in two. Encouraging results were also reported for acne and seborrhea. In a study of 27 patients with a partial-thickness burn wound, treatment with Aloe vera gel was compared with vaseline gauze. The average time of healing in the
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aloe gel area was a statistically significant and dramatic 1 week shorter: 11.9 days compared with 18.2 days for the vaseline gauze treated wound. Histological evaluation showed early epithelialization in the Aloe vera gel treated area.[44] Another study compared the therapeutic effects of systemic pentoxifylline with topical Aloe vera cream in the treatment of frostbite. The frostbitten ears of 10 New Zealand white rabbits were assigned to one of four treatment groups: untreated controls, those treated with Aloe vera cream, those treated with pentoxifylline, and those treated with Aloe vera cream and pentoxifylline. The control group had a 6% tissue survival. Tissue survival was notably improved with pentoxifylline (20%), better with Aloe vera cream (24%), and the best with the combination therapy (30%). [45] Aloe appears to be effective even in particularly severe tissue injuries, such as those seen in necrotizing fasciitis. Necrotizing fasciitis usually manifests as a low grade cellulitis that quickly deteriorates to a limb and life-threatening soft tissue infection. Immediate surgical debridement is essential followed by aggressive wound management. An interesting report describes excellent results in two cases. Case #1 was a 72-year-old female who, upon presenting to the ER with a “sore bottom”, was diagnosed with five problems: • anal-rectal abscess • Fournier’s gangrene • ulcerative enterocolitis • chronic blood loss/anemia • protein caloric malnutrition. After debridement, her anal-rectal wound extended from the labia to the left buttock. Care was multidisciplinary and included applying a water-based aloe gel and saline-soaked gauze twice a day. After 45 days, the wound exhibited a pink base with granulation tissue and contraction of the wound edges. Case #2 was a 48-year-old male with seroma of the left leg secondary to a crush injury. Within 3 days he developed deep vein thrombosis in that leg as well as two large seroma cavities on either side of the thigh. Care included packing with aloe gel and saline soaked sponges. Two weeks after admission, the anterior wound was covered with a split thickness skin graft, while partial closure of the lateral cavity was attempted unsuccessfully with retention sutures. After 5 weeks, healing was complete for the anterior wound and 95% complete for the posterior wound. [46] Radiation burns
Research into the topical applications of Aloe vera gel began in the 1930s in the treatment of radiation burns. During the 1930s, X-rays were used therapeutically for cancer, eczema and other skin complaints, and as a depilatory agent. In 1935, Collins & Collins [8] reported the success of Aloe vera gel in one single case, a woman with a patch of severe X-ray dermatitis on her forehead. The woman had tried various medical treatments for 8 months, only to have her condition worsen. The Collins were going to perform a skin graft, but as a temporary measure applied a preparation of fresh whole Aloe vera leaves to reduce the itching. The result was that “Twenty-four hours later she reported that the sensation of itching and burning had entirely subsided”, and by 5 weeks “there was complete regeneration of the skin of the forehead and scalp, new hair growth, complete restoration of sensation, and absence of scar”. Five months after treatment was started there was complete healing. Other case reports followed which, although not as positive as this initial study, clearly indicated that Aloe vera was effective in some cases. Up until the 1940s most of the studies on aloe were reported case histories. [4] In order to substantiate these case studies, animal studies began to appear in the literature. Rowe and colleagues performed several studies in rats with radiation-induced ulcers and determined that fresh aloe pulp was effective while dried aloe powder was not effective. [4] [37] [38] In 1953, Lushbaugh & Hale, [39] working for the US Atomic Energy Commission, produced one of the most convincing studies of the efficacy of Aloe vera gel. Twenty albino rats were exposed to beta-radiation and different treatments were used on quadrants of the affected area of each animal. The treatments used were fresh Aloe vera leaf, a commercial Aloe vera ointment, application of a dry gauze bandage, and an untreated control. Both fresh Aloe vera and the Aloe vera ointment produced clear improvements. At the end of 2 months the Aloe vera-treated areas were completely healed while the other two areas had still not healed at the end of 4 months. However, a recent, large, placebo-controlled, double-blind study has cast doubt on the efficacy of aloe for severe radiation burns. Two phase III randomized trials were reported in this study. The first one was double-blind, utilized a placebo gel, and involved 194 women receiving breast or chest wall irradiation. The second trial randomized 108 such patients to Aloe vera gel vs. no treatment. Skin dermatitis was scored weekly during both trials both by patients and by health care providers.
Skin dermatitis scores were virtually identical on both treatment arms during both of the trials.
[47]
This surprising result might be explained by a another recent study which compared the efficacy of commercially available gels with an acemannan-rich extract from aloe leaves in the treatment of irradiated mice. Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. In most experiments, the gel was applied daily, beginning
585
immediately after irradiation. To determine the timing of application for best effect, gel was applied beginning on days -7, 0, or +7 relative to the day of irradiation (day 0) and continuing for 1, 2, 3, 4, or 5 weeks. The right inner thigh of each mouse was scored on a scale of 0 to 3.5 for severity of radiation reaction from the seventh to the 35th day after irradiation. Dose–response curves were obtained by plotting the percentage of mice that reached or exceeded a given peak skin reaction as a function of dose. The researchers found that while the acemannan-rich extract gel was highly effective, the commercially available gel showed no improvement over the control. They also found that the aloe gel had to applied immediately after irradiation and continued for at least 2 weeks. There was no effect if the aloe gel was applied only before irradiation or beginning 1 week after irradiation. Clearly, the quality and concentration of aloe constituents are crucial if clinical results are to be obtained. [48] Psoriasis
A recent double-blind, placebo-controlled study evaluated the clinical efficacy and tolerability of topical Aloe vera extract 0.5% in a hydrophilic cream and obtained very impressive recults. Sixty patients (36 male/24 female) aged 18–50 years (mean 25.6) with slight to moderate chronic plaque-type psoriasis and PASI (psoriasis area and severity index) scores between 4.8 and 16.7 (mean 9.3) were enrolled and randomized to two groups. The mean duration of the disease prior to enrollment was 8.5 years (range 1–21). Patients self-administered trial medication topically at home three times daily for 5 consecutive days/week (maximum 4 weeks active treatment). Patients were examined on a weekly basis and those showing a progressive reduction of lesions, desquamation followed by decreased erythema, infiltration and lowered PASI score were considered healed. The study was scheduled for 16 weeks with 12 months of follow-up on a monthly basis. The treatment was well tolerated by all the patients, with no adverse drug-related symptoms and no drop-outs. By the end of the study, the Aloe vera extract cream had cured 25/30 patients (83.3%) compared with the placebo cure rate of only 2/30 (6.6%), resulting in significant clearing of the psoriatic plaques (328/396 (82.8%) vs. placebo 28/366 (7.7%), and a decreased PASI score to a mean of 2.2. [49] Gastric ulcers
The use of Aloe vera gel internally to treat peptic ulcers was studied in 1963. [50] Twelve patients with X-ray-confirmed duodenal ulcers were given 1 tablespoon of an emulsion of Aloe vera gel in mineral oil once daily. At the end of 1 year, all patients demonstrated complete recovery and no recurrence. Based on experimental evidence, the following factors were thought to be responsible for the effectiveness: • Aloe vera gel inactivates pepsin in a reversible fashion. When the stomach is devoid of food, pepsin is inhibited by Aloe vera gel; however, in the presence of food, pepsin is released and allowed to digest the food. • The gel inhibits the release of hydrochloric acid via interference with histamine binding to the parietal cells. • Aloe vera gel is an extremely good demulcent which heals and prevents aggravating irritants from reaching the sensitive ulcer. AIDS
Although acemannan has demonstrated some direct antiviral activity against HIV-1 by inhibiting glycosylation of viral glycoproteins, its main promise in treating AIDS and HIV may be to enhance the action of azidothymidine (AZT), the antiviral drug used in AIDS. In vitro studies have shown that acemannan combined with suboptimal non-cytotoxic concentrations of AZT or acyclovir acts synergistically to inhibit the replication of HIV and herpes simplex type 1 (HSV-1). [21] Based on these studies, as well as preliminary human studies, researchers believe that the use of acemannan may reduce the amount of AZT required by as much as 90%. [51] This is quite significant. In addition to AZT being extremely expensive, AZT’s use is often associated with severe side-effects, including anemia and granulocytopenia due to bone marrow suppression. Preliminary clinical studies are suggesting that acemannan and Aloe vera may be beneficial when administered orally in HIV-positive individuals. [52] [53] In one study, 14 HIV patients prescribed oral acemannan (800 mg/day) demonstrated significant increases in circulating monocytes/macrophages. In particular, there were significant increases in the number of large circulating monocytes, indicating improvement in phagocytizing, processing, and presenting cells in the blood. [53] In another study of 15 AIDS patients receiving an oral dose of acemannan (800 mg/day), the average scores of Modified Walter Reed Clinical (MWR) scoring, absolute T-4, absolute T-8, and p24 core antigen levels all improved in those surviving (see Table 64.3 ) at the end of 900 days. Two patients died of AIDS, and another committed suicide. From this study, as well as others, it TABLE 64-3 -- Acemannan in the treatment of AIDS[52] Test
Pretreatment
After 900 days
Modified Walter Reed Clinical (MWR)
65
2.0
Absolute T-4
322/mm3
324/mm3
Absolute T-8
469/mm3
660/mm3
p24 core antigen
5 of 15
4 of 12
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has been suggested that prognostic criteria to determine the most responsive patients arethose with an absolute T-4 count greater than 150/mm 3 and p24 levels less than 300.[52] In another study, Aloe vera juice (0.6 L/day) was used in conjunction with essential fatty acids and a multiple vitamin, mineral and amino acid supplement to treat 30 patients. The 15 AIDS, 12 ARC and two HIV-seropositive patients continued with regular medication, including AZT. After 180 days, all patients showed clinical improvement according to modified Karnofsky Quality Of Life Assessment scores and the Modified Walter Reed Clinical Evaluation; 25% of those positive for the p24 core antigen converted to non-reactive; anemia induced by AZT showed improvement in all patients; and the patients gained an average of 7%. Unfortunately, a more recent study does not reproduce these early promising results. A comprehensive study assessed the safety and efficacy of acemannan as an adjunctive to antiretroviral therapy among 63 male patients (mean age, 39 years) with advanced HIV disease receiving zidovudine (ZDV) or didanosine (ddI). [54] The randomized, double-blind, placebo-controlled trial provided a large dose of acemannan (400 mg orally four times daily). Eligible patients had CD4 counts of 50–300/µl twice within 1 month of study entry and had received 26 months of antiretroviral treatment (ZDV or ddI) at a stable dose for the month before entry. CD4 counts were made every 4 weeks for 48 weeks. p24 antigen was measured at entry and every 12 weeks thereafter. Sequential quantitative lymphocyte cultures for HIV and ZDV pharmacokinetics were performed in a subset of patients. The mean baseline CD4 counts were 165 and 147/µl in the placebo and acemannan groups, respectively; 90% of the patients were receiving ZDV at entry. Six patients in the acemannan group and five in the placebo group developed AIDS-defining illnesses. There was no statistically significant difference between the groups at 48 weeks with regard to the absolute change or rate of decline at CD4 count. Among ZDV-treated patients, the median rates of CD4 change (ACD4) in the initial 16 weeks were -121 and -120 cells/year in the placebo and acemannan groups, respectively; ACD4 decline from week 16 to 48 was 0 and -61 cells/year in the acemannan and placebo groups ( P = 0.11), respectively. There was no statistical difference between groups with regard to adverse events, p24 antigen, quantitative virology, or pharmacokinetics. Twenty-four patients, 11 receiving placebo and 13 receiving acemannan, discontinued study therapy prematurely, none due to serious adverse reactions. The decreased, but not statistically significant, rate of loss of CD4 cells in the acemannan group from weeks 16 to 48, provides a possible ray of
hope that long-term use, such as reported above, may be of value and should be investigated. Asthma
Oral administration of an extract of Aloe vera for 6 months was shown to produce good results in the treatment of asthma in some individuals of various ages. [55] The exception to this was the fact that the Aloe vera extract was not effective at all in patients dependent upon corticosteroids. The mechanism of action is thought to be via restoration of protective mechanisms followed by augmentation of the immune system. The extract used in the study was produced from the supernatant of fresh leaves stored in the dark for 7 days at 4°C. The dosage was 5 ml of a 20% solution of the aloe extract in saline twice daily for 24 weeks. Eleven of 27 patients (40%) without corticosteroid dependence reported significant improvement at the study’s conclusion. Studies indicate that subjecting the leaves to dark and cold results in an increase in the polysaccharide fraction. One gram of the crude extract obtained from leaves stored in the cold and dark produced 400 mg of neutral polysaccharide, as compared with only 30 mg produced from leaves not subjected to cold or dark. Diabetes
Aloe vera also exhibits a hypoglycemic effect in both normal and alloxan-induced diabetic mice. [56] A small human study shows benefit in diabetics. Five patients with non-insulin dependent diabetes ingested half a teaspoonful of aloe 4 times daily for 14 weeks. Fasting blood sugar in every patient fell from a mean of 273 to 151 mg/dl with no change in body weight. The authors concluded that aloe lowers blood glucose levels by an unknown mechanism. [57] A more recent and larger study (49 men and 23 women) now provides more support for the efficacy of aloe in combination with glibenclamide in diabetes. While there was no response to glibenclamide alone, the combination was very effective. [58] The patients were provided with 1 tablespoon of aloe gel and 5 mg of glibenclamide twice a day, with 5 mg twice a day of glibenclamide serving as the control. After 2 weeks, fasting blood sugar decreased significantly in the treated group, and by day 42 had decreased from an average of 289 mg% to a remarkable 148 mg%. While the drop in serum cholesterol was not significant, serum triglycerides decreased from 223 mg% to (again remarkable) 128 mg% by day 42. No adverse effects were noted using standard blood chemistries. Contraception
An interesting new application of aloe is as a spermicide. Twenty samples of fresh ejaculate from healthy human volunteers between 20 and 30 years of age were treated in vitro with a 1% concentration of zinc acetate combined
587
with lyophilized Aloe barbadensis (at concentrations of 7.5–10%). The combination of zinc acetate with lyophilized Aloe barbadensis was shown to possess powerful spermicidal and antiviral effects which were thought to be due to their concentration of minerals (boron, barium, calcium, chromium, copper, iron, potassium, magnesium, manganese, phosphorus, and zinc), which were toxic to the sperm tail, causing instant immobilization. Studies with rabbit vaginal epithelium showed no irritation. This is important because nonoxynol-9, the active spermicidal ingredient used in vaginal contraception for over 30 years, appears to cause cell membrane damage in vaginal and cervical epithelium and may possibly have teratogenic effects. [59] Cancer prevention
The antigenotoxic and chemopreventive effect of Aloe barbadensis on benzo[a]pyrene (B[a]P)–DNA adducts was investigated in vitro and in vivo in an animal model. Aloe showed a time-course and dose-dependent inhibition of [3H]B[ a]P–DNA adduct formation in primary rat hepatocytes, inhibited cellular uptake of [3H]B[ a]P in a dose-dependent manner, and significantly inhibited adduct formation in various organs (liver, kidney, forestomach and lung). When mice were pretreated with aloe for 16 days before B[a]P treatment, inhibition of BPDE-I–DNA adduct formation and persistence was enhanced. Phase II glutathione- S-transferase activity was slightly increased in the liver, but phase I cytochrome P450 activity was not affected. [60] This translates into animal cancer studies as protection from Norman murine sarcoma in mice [61] and efficacy in treatment of spontaneous neoplasms in dogs and cats.[62]
TOXICOLOGY Although rare, hypersensitivity reactions manifesting as generalized nummular eczematous and papular dermatitis as a result of topically applied Aloe vera preparations have been reported. It should be noted that Aloe vera gel has been shown to delay wound healing in cases of surgical wounds such as those produced during laparotomy or cesarean delivery. [63] Topical aloe preparations are not therefore useful for treating deep vertical wounds.
DOSAGE Aloe vera gel can be applied liberally for topical applications. A wide range of products are available on the market; however, simple pure Aloe vera gel is sufficient. Aloe vera juice can be consumed orally as a beverage or tonic. As detailed information is currently lacking as to the optimal dose for these types of products, it is recommended that no more than 1 quart be consumed in any one day. The dose of acemannan being used in HIV/AIDS patients is 800–1,600 mg/day. This would correspond to a dose of approximately 0.5–1 L/day for most Aloe vera juice products. However, it appears that there may be great variation in the amount of acemannan in various products.
Figure 64-1 Aloin and aloe-emodin.
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Heggers JP, Pineless GR, Robson MC. Dermaide Aloe/Aloe vera gel: comparison of the antimicrobial effects. J Am Med Technol 1979; 41: 293–294
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Sheets MA, Unger BA, Giggleman GF, Tizard IR. Studies of the effect of acemannan on retrovirus infections: clinical stabilization of feline leukemia virus-infected cats. Mol Biother 1991; 3: 41–45
Kemp MC, Kahlon JB, Chinnah AD et al. In-vitro evaluation of the antiviral effects of acemannan on the replication and pathogenesis of HIV-1 and other enveloped viruses: modification of the processing of glycoprotein precursors. Antiviral Research 1990; suppl 1: 83 19.
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Kahlon JB, Kemp MC, Carpenter RH et al. Inhibition of AIDS virus replication by acemannan in vitro. Mol Biother 1991; 3: 127–135
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Kahlon JB, Kemp MC, Yawei N et al. In vitro evaluation of the synergistic antiviral effects of acemannan in combination with azidothymidine and acyclovir. Mol Biother 1991; 3: 214–223
Hart LA, Nibbering PH, van den Barselaar MT et al. Effects of low molecular constituents from Aloe vera gel on oxidative metabolism and cytotoxic and bactericidal activities of human neutrophils. Int J Immunol Pharmac 1990; 12: 427–434 22.
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Womble D, Helderman JH. Enhancement of allo-responsiveness of human lymphocytes by acemannan (CarrisynTM). Int J Immunopharmac 1988; 10: 967–974
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Zhang L, Tizard IR. Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fraction from Aloe vera gel. Immunopharmacology 1996; 35: 119–128
Stuart RW, Lefkowitz DL, Lincoln JA et al. Upregulation of phagocytosis and candidicidal activity of macrophages exposed to the immunostimulant acemannan. Int J Immunopharmacol 1997; 19: 75–82 26.
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Egger SF, Brown GS, Kelsey LS et al. Studies on optimal dose and administration schedule of a hematopoietic stimulatory beta-(1,4)-linked mannan. Int J Immunopharmacol 1996; 18: 113–126
28.
Davis RH, Shapiro E, Agnew PS. Topical effect of aloe with ribonucleic acid and vitamin C on adjuvant arthritis. J Am Pod Med Assoc 1985; 75: 229–237
29.
Yagi A, Harada N, Yamada H et al. Antibradykinin active material in Aloe saponaria. J Pharmaceut Sci 1982; 71: 1172–1174
30.
Davis RH, Parker WL, Samson RT, Murdoch DP. Isolation of a stimulatory system in an Aloe extract. J Am Pod Med Assoc 1991; 81: 473–478
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Davis RH, Leitner MG, Russo JM, Byrne ME. Anti-inflammatory activity of Aloe vera against a spectrum of irritants. J Am Pod Med Assoc 1989; 79: 263–266
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Vazquez B, Avila G, Segura D, Escalante B. Anti-inflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol 1996; 55: 69–75
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Malterud KE, Farbrot TL, Huse AE,, Sund RB. Antioxidant and radical scavenging effects of anthraquinones and anthrones. Pharmacology 1993; 47(suppl 1): 77–85
34.
Henry R. An updated review of Aloe vera. Cosmet Toilet 1979; 94: 42–50
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Shida T, Yagi A, Nishimura H, Nishioka I. Effect of Aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Medica 1985; 51: 273–275
35A. Davis
RH, Kabbani JM, Maro NP. Aloe vera and wound healing. J Am Pod Med Assoc 1987; 77: 165–169
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Davis RH, Leitner MG, Russo JM. Aloe vera, a natural approach for treating wounds, edema, and pain in diabetes. J Am Pod Med Assoc 1988; 78: 60–68
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Rowe TD. Effect of fresh Aloe vera gel in the treatment of third-degree Roentgen reactions on white rats. J Am Pharm Assoc 1940; 29: 348–350
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Rowe TD, Lovell BK, Parks LM. Further observations on the use of Aloe vera leaf in the treatment of third-degree X-ray reactions. J Am Pharm Assoc 1941; 30: 266–269
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Lushbaugh CC, Hale DB. Experimental acute radiodermatitis following beta radiation. V. Histopathological study of the mode of action of therapy with Aloe vera. Cancer 1953; 6: 690–698
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Davis RH, Donato JJ, Hartman GM, Haas RC. Anti-inflammatory and wound healing activity of a growth substance in Aloe vera. J Am Podiatr Med Assoc 1994; 84: 77–81
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Davis RH, DiDonato JJ, Johnson RW, Stewart CB. Aloe vera, hydrocortisone, and sterol influence on wound tensile strength and anti-inflammation. J Am Podiatr Med Assoc 1994; 84: 614–621
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Chung JH, Cheong JC, Lee JY et al. Acceleration of the alcohol oxidation rate in rats with aloin, a quinone derivative of Aloe. Biochem Pharmacol 1996; 52: 1461–1468
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El Zawahry M, Hegazy MR, Helal M. Use of aloe in treating leg ulcers and dermatoses. Int J Dermatol 1973; 12: 68–73
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Visuthikosol V, Chowchuen B, Sukwanarat Y et al. Effect of Aloe vera gel to healing of burn wound. A clinical and histologic study. J Med Assoc Thai 1995; 78: 403–409
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Miller MB, Koltai PJ. Treatment of experimental frostbite with pentoxifylline and aloe vera cream. Arch Otolaryngol Head Neck Surg 1995; 121: 678–680
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Ardire L. Necrotizing fasciitis. case study of a nursing dilemma. Ostomy Wound Manage 1997; 43: 30–34
Williams MS, Burk M, Loprinzi CL et al. Phase III double-blind evaluation of an Aloe vera gel as a prophylactic agent for radiation-induced skin toxicity. Int J Radiat Oncol Biol Phys 1996; 36: 345–349 47.
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Anonymous. Aloe vera may boost AZT. Med Tribune 1991; August 22: 4
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McDaniel HR, Combs C, McDaniel R et al. An increase in circulating monocyte/macrophages (MM) is induced by oral acemannan (ACE-M) in HIV-1 patients. Am J Clin Pathol 1990; 94: 516–517
Montaner JS, Gill J, Singer J et al. Double-blind placebo-controlled pilot trial of acemannan in advanced human immunodeficiency virus disease. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12: 153–157 54.
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Ajabnoor MA. Effect of aloes on blood glucose levels in normal and alloxan diabetic mice. J Ethnopharmacol 1990; 28: 215–220
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Gnhannam N, Kingston M, Al-Meshaal IA et al. The antidiabetic activity of Aloes. Hormone Research 1986; 24: 288–294
Bunyapraphatsara N, Yongchaiyudha A, Rungpitarang S, Chokechaijaroenporn O. Antidiabetic activity of Aloe vera juice II. Clinical trial in diabetes meelitus patients in combination with glibenclamide. Phytomed 1996; 3: 245–248 58.
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Peng SY, Norman J, Curtin G et al. Decreased mortality of Norman murine sarcoma in mice treated with the immunomodulator, acemannan. Mol Biother 1991; 3: 79–87
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Schmidt JM, Greenspoon JS. Aloe vera dermal wound gel is associated with a delay in wound healing. Obstet Gynecol 1991; 78: 115–117
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Chapter 65 - Angelica species Michael T. Murray ND Joseph E. Pizzorno Jr ND
Angelica sinensis or polymorpha (family: Umbelliferae or Apiaceae) Common names: Chinese angelica, tang-kuei (dong-quai) Angelica acutiloba (family: Umbelliferae or Apiaceae) Common name: Japanese angelica Angelica archangelica (family: Umbelliferae or Apiaceae) Common name: European angelica Angelica atropurpurea (family: Umbelliferae or Apiaceae) Common name: American angelica Angelica sylvestris (family: Umbelliferae or Apiaceae) Common name: wild angelica
GENERAL DESCRIPTION Angelica spp. are biennial or perennial plants with hollow fluted stems that rise to a height of 3–7 feet. The umbel of greenish-white flowers bloom from May to August. The plants are found in damp mountain ravines and meadows, on river banks, and in coastal areas; angelica is also a widely cultivated species. In Asia, it is grown primarily for its medicinal action, while in the US and Europe, it is cultivated for use as a flavoring agent in most major categories of food products, including alcoholic (e.g. bitters, liqueurs, and vermouths) and non-alcoholic beverages, ice cream, candy, gelatins, and puddings. With all species, the roots and rhizomes are the most extensively used portions of the plant. Angelica sinensis and A. acutiloba
In Asia, the authentic and original medicinal angelica is Angelica sinensis (dong-quai), native to China. While at least nine other angelica species are used in China, dong-quai is by far the most highly regarded. For several thousand years, dong-quai has been cultivated for medicinal use in the treatment of a wide variety of disorders, in particular, “female” disorders. Several hundred years ago, when the supply of Chinese angelica was scarce, the
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Japanese began to cultivate A. acutiloba, an angelica species indigenous to Japan, as a substitute. [1] The two species appear to have very similar therapeutic effects, although it is interesting to note that in China, the Japanese angelica is thought to have no therapeutic value, while in Japan, Chinese angelica is thought of as being without effect. Experimentally, both species exhibit very similar therapeutic effects, so each country’s claim to produce a superior dong-quai appears to be based more on emotion than scientific investigation. Angelica archangelica and A. atropurpurea
Historical usage suggests that European angelica ( A. archangelica) and American angelica (A. atropurpurea) have properties different from the Asian species. This difference has not, however, been evaluated by chemical analysis.
CHEMICAL COMPOSITION Angelica sinensis and A. acutiloba
No comprehensive data could be found listing the concentration of the chemical constituents. It is assumed that Chinese and Japanese angelica are similarly composed of various coumarins and flavonoids which are responsible for their medicinal actions. The essential oil of oriental angelica contains: [2] • n-butylphthalide • cadinene • carvacrol • n-dodecanal • isosafrole • linoleic acid • palmitic acid • safrole • sequiterpene • n-tetradecanol. Angelica archangelica
Also very rich in coumarins, this species of angelica is particularly phototoxic. Coumarins, including osthole, angelicin, osthenol, umbelliferone, archangelicine, bergapten, and ostruthol, are found in significant concentrations, with osthole composing nearly 0.2% of the root. The root is also a good source of flavonoids, including archangelenone and caffeic acids. The root contains 0.3–1.0% volatile oil that is composed mainly of beta-phyllamdrene, alpha-pinene, borneol, limonene, and four macrocylic lactones. [2] [3]
HISTORY AND FOLK USE Angelica sinensis and A. acutiloba
In Asia, angelica’s reputation is perhaps second only to ginseng. Predominantly regarded as a “female” remedy, angelica has been used in such conditions as
dysmenorrhea, amenorrhea, metrorrhagia, menopausal symptoms, and to assure a healthy pregnancy and easy delivery. Angelica is also used in the treatment of abdominal pain, anemia, injuries, arthritis, migraine headache, and many other conditions. [2] [4] Angelica archangelica
One of the most highly praised herbs in old herbal texts, archangelica was used by all north European countries as: … a protection against contagion, for purifying the blood, and for curing every conceivable malady: it was held a sovereign remedy for poisons, agues and all infectious maladies. According to one legend, archangelica was revealed in a dream as a cure for the plague. One explanation for the name is related to its blooming near May 8, the feast day of Michael the Archangel. It was therefore seen as a “protector against evil spirits and witchcraft”. [5] Archangelica has been used for a wide variety of conditions, including flatulent dyspepsia, pleurisy, respiratory catarrh, and bronchitis. The plant was believed to possess carminative, spasmolytic, diaphoretic, expectorant, and diuretic activity. [5] Angelica atropurpurea
American angelica’s therapeutic use mirrors that of European angelica. Its most common use is for heartburn and flatulent colic. [6]
PHARMACOLOGY The pharmacology of Angelica spp. relates to their high coumarin content. However, unlike other scientific investigations of botanical medicines, much of the research done on Angelica spp. has been done on plant extracts, rather than isolated constituents. The overwhelming majority of the studies have been done on the Asian species. Some of the pharmacological activities demonstrated include: • phytoestrogen activity • analgesic activity • cardiovascular effects • smooth muscle-relaxing effects • anti-allergy and immunomodulating activity • antimicrobial activity. Phytoestrogen effects
Plant estrogenic substances or phytoestrogens are components of many medicinal herbs with an historic use
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in conditions which are now treated by synthetic estrogens. Chinese and Japanese angelica contain highly active phytoestrogens, although these compounds are much lower in activity than animal estrogens (1:400 as active). This helps to explain why angelica was used in both excessive and deficient estrogen conditions. Phytoestrogens demonstrate an alterative effect by competing with estrogen for binding sites. When estrogen levels are low they are able to exert some estrogenic activity; when estrogen levels are high they reduce overall estrogenic activity by occupying estrogen receptor sites. This alterative action of angelica’s phytoestrogens is probably the basis of much of the plant’s use in amenorrhea and menopause. Japanese angelica has demonstrated uterine tonic activity, causing an initial increase in uterine contraction followed by relaxation. [7] [8] In addition, administration of Japanese angelica to mice resulted in an increase of uterine weight, increase of the DNA content of the uterus and liver, and increase of glucose utilization by the liver and uterus. [1] [7] Because of these and other effects, angelica has been referred to as a uterine tonic. Cardiovascular effects
Although not used historically for these purposes, angelica does possess significant hypotensive action. [1] [7] This is largely due to its vasodilator activity. Dihydropyranocoumarins and dihydro-furanocoumarins from Umbelliferous plants have been shown to possess significant coronary vasodilatory, spasmolytic, and cyclic-AMP-phosphodiesterase inhibitory properties. [9] The mechanism of action appears to be largely a result of calcium channel antagonism. Agents that interact with calcium channels (calcium channel blockers) are quickly coming into prominence in the treatment of a wide variety of conditions, including hypertension and angina. Umbelliferous plants such as angelica may offer similar effects. Other cardiovascular effects noted for angelica are negative inotropic and anti-arrhythmic action.
[1]
Smooth muscle-relaxing activity
Calcium channel blocking compounds are also capable of relaxing the smooth muscles of visceral organs. Angelica (essential oil) has demonstrated relaxing action on the smooth muscles of the intestines and uterus, while the water extract produces an initial contraction and then prolonged relaxation. [1] [7] [8] This confirms its historical use in the treatment of intestinal spasm and uterine cramps. Its action on other smooth muscles could explain its hypotensive action (vascular smooth muscle) and historical use in asthma (bronchial smooth muscle). Analgesic activity
Both Chinese and Japanese angelica have demonstrated pain-relieving and mild tranquilizing effects in experimental studies in animals. [1] [7] [10] [11] Angelica’s analgesic action was 1.7 times that of aspirin in one study. [11] Its analgesic activity, combined with its smooth muscle-relaxing activity, supports its historical use in such conditions as uterine cramps, trauma, headaches, and arthritis. Anti-allergy and immunomodulating activity
Angelica has a long history of use by Chinese and Japanese herbalists in the prevention and treatment of allergic symptoms in individuals who are sensitive to a variety of substances (pollen, dust, animal dander, food, etc.). [1] [12] Its action is related to its ability to inhibit the production of IgE in a selective manner. Since IgE levels in patients with atopic conditions are typically 3–10 times greater than the upper limit of normal, angelica may offer some benefit by reducing these elevated antibodies. Coumarin compounds have demonstrated immune-enhancing activity in both healthy and cancer patients. [13] [14] Coumarins have been shown to stimulate macrophages and increase phagocytosis. [13] Such activity is thought to offer significant protection against metastasis and growth of tumor cells. Upon coumarin administration, macrophages are said to be “activated” and thus capable of entering the tumor, where a specific destruction of the tumor cells may occur. [13] [14] Coumarin compounds of angelica and the polysaccharides of the water extract of Japanese angelica have immune-modulating activity. They have been shown to possess mitogenic activity to B-lymphocytes, interferon-producing activity, antitumor activity, and complement-activating (both the classical and alternative pathway) activity.[15] [16] [17] [18] Chinese angelica has been shown to increase murine IL-2 production, stimulate the reticuloendothelial system, and increase tumor necrosis factor production. [19] [20] These effects on the immune system by coumarins, polysaccharides, and extracts of Angelica sp. would seem to support their historical anti-cancer effects and their use as adjuncts to current cancer therapy.
Antibacterial activity
Extracts of Chinese angelica have been shown to possess antibacterial activity against both Gram-negative and Gram-positive bacteria, while extracts of Japanese angelica exhibited no antibacterial action. [7] The inconsistency could be due to different essential oil concentrations of the extracts used in the studies. The oil of A. archangelica has also exhibited significant antifungal and anthelmintic properties but virtually no antibacterial
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activity.[3] [21] [22] As other herbs have much greater antimicrobial activity, Angelica sp. would be considered a less than optimum agent if this effect is desired.
CLINICAL APPLICATION Angelica spp. have been used throughout the world in the treatment of a wide variety of conditions. At this time, it appears that A. archangelica and A. atropurpurea are most indicated as expectorants, antispasmodics, and carminatives in the treatment of such conditions as respiratory ailments, gas, and abdominal spasm. Chinese angelica (A. sinensis or polymorpha) and Japanese angelica (A. acutiloba) appear most useful in the treatment of disorders of menstruation, menopause (especially hot flashes), atopic conditions, smooth muscle spasm (e.g. uterine cramps, migraines, abdominal spasm, etc.), and possibly as an immunostimulatory adjunct in cancer therapy. Further human research is needed to document the degree clinical of efficacy of Angelica spp.
DOSAGE • Dried root or rhizome: 1–2 g orally, or by infusion, three times/day • Tincture (1:5): 3–5 ml, three times/day • Fluid extract (1:1): 0.5–2 ml, three times/day.
TOXICOLOGY Angelica is generally considered to be of very low toxicity. However, it does contain many photoreactive substances which may induce photosensitivity. This should be kept in mind when using any Umbelliferous plant. This activity can be used therapeutically in the treatment of vitiligo and psoriasis.
REFERENCES 1. Hikino 2. Duke
JA. Handbook of medicinal herbs. Boca Raton, FL: CRC Press. 1985: p 43–44
3. Leung 4. Duke
AY. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York, NY: John Wiley. 1980: p 28–29
JA and Ayensu ES. Medicinal plants of China. Algonac, MI: Reference Publications. 1985: p 74–77
5. Grieve 6. Lust
H. Recent research on Oriental medicinal plants. Econ Med Plant Res 1985; 1: 53–85
M. A Modern herbal. New York, NY: Dover. 1971: p 35–40
J. The Herb Book. New York, NY: Bantam Books. 1974: p 97–99
7. Yoshiro
K. The physiological actions of tang-kuei and cnidium. Bull Oriental Healing Arts Inst USA 1985; 10: 269–78
8. Harada
M, Suzuki M, Ozaki Y. Effect of Japanese angelica root and peony root on uterine contraction in the rabbit in situ. J Pharm Dyn 1984; 7: 304–311
9. Thastrup
O, Fjalland B, Lemmich J. Coronary vasodilatory, spasmolytic and cAMP-phosphodiesterase inhibitory properties of dihydropyranocoumarins and dihydrofuranocoumarins. Acta Pharmacol et Toxicol 1983; 52: 246–53 10.
Tanaka S, Ikeshiro Y, Tabata M, Konoshima M. Anti-nociceptive substances from the roots of Angelica acutiloba. Arzneim Forsch 1977; 27: 2039–45
Tanaka S, Kano Y, Tabata M, Konoshima M. Effects of “Toki” ( Angelica acutiloba Kitawaga) extracts on writhing and capillary permeability in mice (analgesic and anti-inflammatory effects). Yakugaku Zassh 1071; 91: 1098–1104 11.
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Sung CP, Baker AP, Holden DA et al. Effects of Angelica polymorpha on reaginic antibody production. J Natural Products 1071; 45: 398–406
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Casley-Smith JR. The actions of benzopyrenes on the blood-tissue-lymph system. Folia Angiol 1976; 24: 7–22
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Berkarda B, Bouffard-Eyuboglu H, Derman U. The effect of coumarin derivatives on the immunological system of man. Agents Actions 1983; 13: 50–52
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Ohno N, Matsumoto SI, Suzuki I et al. Biochemical characterization of a mitogen obtained from an oriental crude drug, tohki (Angelica acutiloba Kitawaga). J Pharm Dyn 1983; 6: 903–912
16.
Yamada H, Kiyohara H, Cyong JC et al. Studies on polysaccharides from Angelica acutiloba. Planta Medica 1984; 48: 163–167
Yamada H, Kiyohara H, Cyong JC et al. Studies on polysaccharides from Angelica acutiloba – IV. Characterization of an anti-complementary arabinogalactan from the roots of Angelica acutiloba Kitagawa. Mol Immunol 1985; 22: 295–304 17.
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Kumazawa Y, Mizunoe K, Otsuka Y. Immunostimulating polysaccharide separated from hot water extract of Angelica acutiloba Kitagawa (Yamato Tohki). Immunology 1982; 47: 75–83
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Weng XC, Zhang P, Gong SS, Xiai SW. Effect of immuno-modulating agents on murine IL-2 production. Immunol Invest 1987; 16: 79–86
Haranaka K, Satomi N, Sakurai A, Karanaka R, Okada N, Kobayashi M. Antitumor activities and tumor necrosis factor producibility of traditional Chinese medicines and crude drugs. Cancer Immunol Immunother 1985; 20: 1–5 20.
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Rhee JK, Woo KJ, Baek BK, Ahn BJ. Screening of the wormicidal Chinese raw drugs on Clonorchis sinesis. Am J Chin Med Winter 1981; 9: 277–284
22.
Opdyke DLJ. Angelica root oil. Food Cosmet Toxicol 1975; 13: 713–714
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Chapter 66 - Aspergillus oryzae enzyme therapy Corey Resnick ND
INTRODUCTION Enzymes derived from Aspergillus oryzae and other fungal species are effective in the treatment of a broad range of human diseases. In certain cases, fungal enzymes are significantly more effective than animal-derived enzymes or other available therapies. Some fungal enzyme preparations are particularly well suited for human use because of their ability to hydrolyze physiologically and/or pathologically important substrates over a wide pH range. Although new to many clinicians in the US, fungal enzymes have been used in ethnic food production for many centuries, and in clinical practice and research for about 50 years. In Japan, Aspergillus oryzae has been used in the fermentation of soybeans to produce soy sauce, tamari and miso. (It is interesting to note that the traditional method of adding hot water to miso, rather than boiling the miso, preserves some of the activity of Aspergillus enzymes, which are remarkably heat stable.) Clinically, enzyme preparations have typically been used in oral administration at mealtimes to assist digestion by hydrolyzing dietary substrates such as gluten, casein or lactose. Of possibly greater interest, however, is the use of fungal enzymes administered orally between meals. Based on the theory that some portion of the enzyme is absorbed intact into the bloodstream, enzymes can hydrolyze substrates of therapeutic importance (e.g. fibrin). Indirect evidence in support of this theory is presented later in this chapter. Beginning around the 1950s, published research in Europe and Scandinavia reported on the therapeutic use of purified, concentrated preparations of enzymes from A. oryzae and other fungal species. Bergkvist was among the first to report on the isolation and purification of individual enzymes produced by A. oryzae. Wolf and Ransberger studied the effects of enzymes from Aspergillus and other species (e.g. Lens esculenta and Pisum sativum) along with animal enzymes (e.g. trypsin, chymotrypsin) in the treatment of cancer. Roschlau
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and others studied the effectiveness of intravenously administered proteolytic enzymes from A. oryzae in the treatment of vascular disease in humans and animals. Recent research has studied increasingly diverse types and sources of fungal enzymes, including various protease, lipase, carbohydrase, and cellulase preparations. Controlled in vivo studies using enteral and parenteral routes and in vitro studies have examined the effectiveness of these enzymes in a wide range of conditions including: • maldigestion • malabsorption • pancreatic insufficiency • steatorrhea • celiac disease • lactose intolerance • arterial obstruction • thrombotic disease. Anecdotal reports indicate that plant enzymes are being used in an even broader spectrum of clinical conditions. This chapter reviews published clinical and experimental research in the emerging field of fungal enzyme therapy. Theoretical discussions are presented regarding the oral administration of fungal enzymes for therapeutic purposes, with suggested areas for further research.
PHARMACOLOGY Intact protein absorption Contrary to long held theories that the healthy intestinal mucosa is an essentially impermeable barrier to proteins and large polypeptides, there is now irrefutable evidence that macromolecules can and do pass intact from the human gut into the bloodstream under normal conditions. [1] [2] [3] [4] [5] [6] [7] This may help to explain the apparent effectiveness of enzyme therapy in the nutritional management of a number of conditions, including vascular disease, maldigestion/malabsorption, food allergies, inflammatory bowel disease, immune dysfunction and certain inflammatory disorders. [1] [2] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] Evidence for intestinal absorption of intact proteins
Numerous whole proteins, including plant and animal enzymes, have been shown in human and animal studies to be absorbed intact into the bloodstream following oral administration. These include human albumin and lactalbumin, bovine albumin, ovalbumin, lactoglobulin, ferritin (MW, 500,000), chymotrypsinogen, elastase, and other large molecules, such as botulism toxin (MW, 1,000,000). [1] [2] [3] [18] [19] [20] [21] Even inert particles, such as carbon particles from India ink [1] and whole viruses, [22] can cross the healthy intestine. Immunoglobulins have been detected in peripheral tissues following oral administration. In a study done in rats, 5% of an oral dose of bovine IgG was found substantially intact in peripheral tissues. [6] Studies have demonstrated the intact absorption of plant enzymes, such as bromelain derived from pineapple and peroxidase (MW, 40,000) from horseradish. An in vivo study in fish showed that 0.7% of a dose of horseradish peroxidase was detected intact in examined peripheral tissues following oral administration. [23] Proteins and polypeptides absorbed intact from the gut can exert pharmacological effects in target tissues. Several peptide hormones are known to be biologically active when administered orally, including luteinizing hormone-releasing factor and thytropin-releasing hormone. [24] [25] Even insulin can cross the intestinal mucosa intact and produce significant hypoglycemia under limited circumstances (e.g. in the presence of protease inhibitors or hypertonic solutions in the intestinal lumen).
[26]
[27]
It now appears probable that enzymes such as acid-stable protease from Aspergillus oryzae (molecular weight ~ 35,000) are absorbed intact following oral administration. To the extent that such absorption does occur, Aspergillus-derived proteases may exhibit properties in the bloodstream which they are known to possess in other applications. This may include the ability to hydrolyze dietary proteins and polypeptides which have leaked into the bloodstream as food antigens. Protease from Aspergillus is also known to possess thrombolytic, fibrinolytic and anti-inflammatory properties, [28] [29] [30] [31] [32] [33] [34] and has been shown to be effective
when administered intravenously in re-establishing circulation through chronically obstructed arteries in humans (see below).
[ 35] [36]
Mechanism for intestinal absorption of macromolecules
Two general types of mechanisms have been suggested to account for the intact absorption of macromolecules and particles. [1] [2] In the “transcellular route” macromolecules are believed to penetrate the brush-border membrane of intestinal mucosal cells by: • diffusion through aqueous “pores” or through lipid regions in the membrane • pinocytosis (endocytosis) or phagocytosis • carrier-mediated transport systems • some combination of these routes. A “paracellular” or intercellular route also appears likely, in which molecules pass between mucosal cells. This route includes passage through so-called “extrusion zones” which occur as old cells are displaced by new ones in the rapidly proliferating mucosal tissue. 595
A specialized cell type has recently been identified overlying Peyer’s patches (subepithelial lymphoid tissue) throughout the small intestine. These so-called “M” cells permit subepithelial tissue lymphocytes to come extremely close to the intestinal lumen, apparently facilitating lymphocyte “sampling” of luminal antigens and thereby stimulating an immune response. A number of studies have shown rapid passage through M cells (by pinocytosis) of macromolecules such as horseradish peroxidase and solid particles such as viruses. [1] [2] [37] [38] [39] Pancreatic recycling of enzymes There is strong evidence that the body seeks to conserve its digestive enzymes by absorbing intact endogenous and exogenous enzymes. Several human studies have shown that exogenous pancreatic enzymes, trypsin and chymotrypsin, are absorbed intact into the bloodstream in an enzymatically active form following oral administration. [40] [41] [42] [43] [44] Even more dramatic is the finding that both endogenous and exogenous pancreatic enzymes are not only absorbed intact from the gut, but also transported through the bloodstream, taken up intact by pancreatic secretory cells, and re-secreted into the intestinal lumen by the pancreas, co-mixed with newly synthesized pancreatic enzymes.[45] The existence of this enteropancreatic circulation of proteolytic enzymes is closely analogous to the recycling of bile salts by the liver. Of further interest is the possibility that oral supplementation with enzymes may have a sparing effect on the body’s own digestive enzymes, perhaps aiding organ regeneration, by hydrolyzing substrates (foods) for which endogenous enzyme would otherwise be required. Support for this hypothesis may also be found in the phenomenon of adaptive secretion by which the pancreas, stomach and possibly other organs secrete specific digestive enzymes in direct response to the type and amount of food substrate present. [46] [47]
COMPARISON OF FUNGAL LIPASE AND PANCREATIN pH range
Many of the enzymes derived from A. oryzae and related fungal species possess unusually high stability and activity under a broad range of pH conditions. These properties distinguish them from animal enzymes such as pepsin, pancreatin, trypsin, chymotrypsin, pancrelipase and pancreatic amylase which require pH conditions often lacking in those with impaired health. For example, pepsin is active only below a pH of about 4.5, while pancreatin has digestive activity only in an alkaline medium. In contrast, some preparations of A. oryzae enzymes are stable and active at pH values of 2–12. Enzyme replacement therapy
Human and animal studies have compared the effectiveness of acid-stable lipase from various fungal species with that of pancreatin in the treatment of malabsorption and steatorrhea due to pancreatic insufficiency. Administered orally at mealtime, fungal lipase has been found to be effective in these conditions and to offer certain advantages over both conventional and enteric-coated pancreatic enzyme replacement therapy. Treatment of steatorrhea using pancreatic enzyme replacement therapy is often unsatisfactory due to several factors. Gastric acid destroys up to 90% of the lipase content of exposed pancreatic enzymes (i.e. conventional pancreatin administered in powder, capsule or tablet form). [48] [49] [50] This necessitates large dosages for efficacy and contributes to increased expense, number of tablets or capsules required, and poor patient compliance. [51] [52] Furthermore, pancreatin can cause hyperuricosuria and renal damage in large doses due to its high purine content. [53] Although H 2 receptor antagonists such as cimetidine are often used along with pancreatin to lessen intragastric inactivation, [54] [55] this is unsuccessful at increasing lipid digestion in many patients [56] and carries the risk of possible adverse side-effects. Various forms of enteric-coated pancreatin (i.e. enteric-coated capsules, tablets, granules and microspheres) are formulated to dissolve above pH 5.5–6.0 and are intended to protect exogenous pancreatin against gastric acidity. [54] [57] These are seldom completely effective, however, as, while the capsules or tablets usually remain intact in the stomach, they often fail to dissolve in the duodenum due to hyperacidity; most patients with pancreatic insufficiency also have decreased bicarbonate secretion. Similarly, jejunal acidification can occur, preventing activation of enteric-coated enzyme preparations designed to release in the jejunum. [58] In addition, chemical excipients required for enteric coating can be problematical in sensitive individuals. By contrast, a lipase preparation from Aspergillus oryzae is resistant to inactivation by gastric acidity and is enzymatically active from pH 2 to 10. It digests dietary fat, beginning in the stomach and continuing in the small intestine. [51] [59] It is water-soluble, heat-stable, non-toxic and free from some of the potential drawbacks of pancreatin replacement therapy. [51]
CLINICAL APPLICATIONS Malabsorption and steatorrhea Chronic pancreatitis and cystic fibrosis are the most common causes of pancreatic exocrine insufficiency.
596
Pancreatogenic steatorrhea results from failure of fat digestion, leading to lipid malabsorption, impaired nutrition, weight loss, and considerable social embarrassment.[48] [60] Lipase preparations from Aspergillus oryzae have been shown to be highly effective in treating malabsorption and steatorrhea under a wide variety of conditions. A 1985 cross-over study in Germany compared the effectiveness of 10 teaspoons of a conventional pancreatic enzyme preparation (360,000 lipase units) with that of 10 capsules of enteric-coated pancreatin (100,000 lipase units) and 10 capsules of acid-stable fungal enzymes from Rhizopus arrhizus (75,000 lipase units) in human patients with chronic pancreatitis, severe pancreatic exocrine insufficiency and steatorrhea. [59] Seventeen patients in the study were divided into two treatment groups based on surgical status.
Nine patients had received Whipple’s procedure (bowel resection with partial duodenopancreatectomy) 3–8 months prior to the study (group A). This group had shown a pre-operative reduction in stimulated pancreatic enzyme secretion to less than 10% of normal. In the remaining eight, non-surgical patients (group B), stimulated secretion was reduced to between 4 and 28% of normal. All patients were placed on a diet containing 100 g fat/day and stools were collected for 72 hours, 5 days after discontinuing all medications (pancreatic enzymes, antacids, and H 2 receptor antagonists). Thereafter, each group was placed on identical 2 week periods of treatment using enteric-coated pancreatin first, then conventional pancreatin and, finally, acid-stable fungal enzymes. Stools were collected for the last 3 days of each treatment period and analyzed for stool weight, fat concentration, and total fecal fat excretion. Prior to treatment, all fecal parameters were pathologically elevated in all 17 patients, diarrhea and characteristic abdominal symptoms were present, and the patients had a tendency to lose weight. All three treatment protocols led to a significant reduction in total daily stool weight and total daily fecal fat excretion as compared with controls in both groups. Perhaps more importantly, all patients in both groups became virtually symptom-free on each of the three treatment protocols. Table 66.1 shows fecal fat excretion and stool weight for controls and under each treatment protocol in group A and group B. Individual patient results in each group have been averaged together. A 1988 placebo-controlled, randomized, cross-over study in England compared the effectiveness of 400 mg (4800 lipase units) of acid-stable lipase from A. oryzae with that of 10,000 mg (60,000 lipase units) of pancreatin in the treatment of chronic pancreatic exocrine insufficiency in dogs. [51] Eleven dogs (weighing 15–21 kg) used in the study TABLE 66-1 -- Stool weight and fecal fat in patients with steatorrhea Treatment protocol Fecal fat (g/day)
Stool weight (g/day)
Group A
Group B
Group A
Group B
Placebo
180
82
906
675
Enteric-coated pancreatin
75
39
494
324
Pancreatin
55
48
437
345
Fungal lipase
87
48
519
316
The upper limit of the normal range for fecal fat excretion is 7 g/day and for stool weight is 250 g/day underwent total pancreatectomy to produce pancreatic exocrine insufficiency. All animals received intrasplenic autografts of islet of Langerhans tissue to preserve pancreatic endocrine function. Animals served as their own controls by the use of pre-surgical data. The dogs were maintained on fixed diets containing 46 g/day fat. Each treatment protocol lasted 3 weeks, beginning and ending with weighing of animals and 3 day specimen collections for determination of fecal fat excretion and stool volume. Dogs in the untreated placebo group experienced significant weight loss ( P < 0.01) due to malabsorption averaging 0.9 kg over a 3 week period. Dogs receiving either 400 mg/day of A. oryzae lipase or 10,000 mg/day of pancreatin did not show significant weight loss. Similarly, both fecal fat excretion and stool volume were pathologically elevated in the placebo group. Significant reductions occurred in both fecal fat and stool volume, with no significant difference between fungal lipase and pancreatin treated animals. The most significant finding of the English study was the fact that a small dose of acid-stable lipase from A. oryzae (400 mg) was as effective as a dosage of conventional pancreatin 25 times larger (10,000 mg) in the treatment of malabsorption, malnutrition and steatorrhea due to pancreatic exocrine insufficiency in dogs. In the German study, an acid-stable fungal lipase from R. arrhizus produced largely the same effect as 1.3 times greater lipase activity from enteric-coated pancreatin and 4.8 times greater lipase activity from conventional pancreatin in the treatment of severe pancreatogenic steatorrhea in humans. [59] Unlike pancreatin, A. oryzae lipase delivers enzyme activity in the broad range from pH 2 to 10. It safely digests dietary fat, beginning in the stomach and continuing in the small intestine, and is more effective than pancreatin in the abnormal acidic conditions commonly found in the duodenum and jejunum of pancreatic insufficiency patients. Lactose intolerance Lactose intolerance produces symptoms such as abdominal pain, bloating, cramping, flatulence, belching and
597
diarrhea. [61] Maldigestion of lactose is a common problem in children and adults, occurring in 76% of apparently healthy children in one study, and 56% in another single-blind, controlled trial. [62] Lactose maldigestion can result from genetic non-persistence of intestinal lactase activity at some time after weaning as well as from secondary lactase deficiencies. It may or may not produce symptoms of lactose intolerance. [61] A lactase enzyme derived from Aspergillus oryzae is effective in the treatment of lactose maldigestion and lactose intolerance when taken orally at the time of milk ingestion. [62] [63] [64] [65] [66] [67] Moreover, this enzyme aids in the in vivo digestion of milk sugar even in healthy individuals classified as normal lactose digesters. Furthermore, the A. oryzae-derived lactase is more effective in the digestion of lactose than a similar enzyme derived from the yeast, Kluyveromyces lactis. [62] It is known that milk pre-hydrolyzed in vitro by incubating it under refrigeration with lactase is effective in the prevention of lactose intolerance in susceptible individuals. A 1986 single-blind, controlled study was designed to determine whether ingestion of lactase at mealtime was equally as effective in the treatment of lactose intolerance as pre-hydrolyzed milk, since the latter requires refrigeration which is difficult to obtain in “underdeveloped” parts of the world. The hydrogen breath test was used as an accurate and sensitive measurement of lactose digestion in vivo (see Ch. 23 ). The study included 48 healthy Guatemalan pre-school children. The ability of participants to digest lactose from ingested whole cow’s milk was tested against four treatment protocols as follows (each protocol included 240 ml of whole cow’s milk containing 12 g. of lactose): 1. 2. 3. 4.
whole, intact cow’s milk milk pre-hydrolyzed in vitro with lactase enzyme varying amounts of lactase from K. lactis administered orally with milk varying amounts of lactase from A. oryzae administered orally with milk.
Twenty-seven of the children (56%) proved to be maldigesters of lactose from the ingestion of intact milk. Twenty-five of these lactose maldigesters (93%) were found to show no lactose maldigestion (i.e. successfully treated) after the ingestion of milk pre-hydrolyzed with lactase in vitro for 24 hours. Pre-hydrolyzed milk was used as the standard for successful treatment in comparing the effectiveness of lactase enzymes derived from A. oryzae and K. lactis.[62] All experimental dosages of in vivo lactase from both A. oryzae and K. lactis significantly reduced the volume of post-challenge hydrogen excretion as compared with
intact milk (P < 0.05). However, lactase from A. oryzae was found to be equally as effective as pre-hydrolyzed milk, while K. lactis lactase was only 82% as effective. This research supports the addition of microbial beta-galactosidase (lactase) to milk at mealtimes as effective in the prevention of signs and symptoms of lactose maldigestion. Ingestion of lactase with milk at mealtime avoids the inconvenience of refrigerated 24 hour incubation as well as the sweeter flavor produced when milk is pre-hydrolyzed. In a somewhat surprising result, A. oryzae lactase was also found to increase the degree of lactose digestion in the 21 children classified as normal, complete digesters. This demonstrates that the capacity for lactose digestion is actually a continuum, even in lactase-persistent subjects, rather than an all-or-none phenomenon. The efficacy of these enzymes in lactose-intolerant children and adults has now been replicated in several studies.
[61] [68]
Vascular disease Numerous cross-over, single-blind and placebo-controlled studies have confirmed the effectiveness of a proteolytic enzyme derived from Aspergillus oryzae in treating chronically obstructed arteries in humans. [28] [29] [30] [31] [32] [35] [36] [69] [70] [71] [72] [73] In fact, intravenous therapy with fungal protease from A. oryzae is dramatically more effective than anticoagulant therapy (e.g. heparin, warfarin) at recanalizing obstructed arteries and improving blood flow through stenosed arterial segments. [35] [36] [73] A 1978 controlled, single-blind cross-over study evaluated the effectiveness of protease from A. oryzae versus anticoagulant therapy and placebo in 18 patients (ages 63–75) with stable intermittent claudication of at least 6 months’ duration. [35] Patients were divided into two groups, and a full assessment of each patient was carried out prior to testing. Translumbar aortogram, Doppler ultrasound scanning and peripheral systolic blood pressure were used to assess the patency of eight different arterial segments in each patient (a total of 72 segments in each group). Anticoagulation therapy with warfarin was introduced following assessment and continued throughout an observation period of 3 months and subsequent trial periods. Assessment of peripheral circulation was repeated after the 3 month observation period on anticoagulant therapy. Thereafter, a series of six intravenous infusions of fungal protease and normal saline was given to experimental and control groups, respectively, at regular intervals over the next 2 weeks. Assessment of peripheral circulation was repeated at the end of the protease infusion treatment. No other form of therapy was given, except warfarin for anticoagulation. On admission to the study, the first group of patients receiving fungal protease therapy showed 27 obstructed segments (completely obstructed), 34 stenosed segments (partially obstructed) and only 11 patent arterial segments. The nine patients receiving
598
TABLE 66-2 -- Changes in patency of 72 arterial segments after placebo or fungal enzyme treatment Arterial status
Placebo
Treated
Initial Final Initial Final No. patent
21
21
11
27
No. stenosed
26
23
34
35
No. obstructed
25
28
27
10
saline (placebo) showed 25 obstructed, 26 stenosed and 21 patent arterial segments prior to treatment (see Table 66.2 ). At the end of the 3 month observation period (anticoagulation therapy only), no changes in Doppler ultrasound scanning or ankle/arm blood pressure ratios were found in either group. At the end of the 2 week trial period, the saline group showed that three of the 72 arterial segments had progressed to increased obstruction (i.e. 4% worse). In contrast, treatment with the fungal protease infusion resulted improved patency of 33 of 72 arterial segments (i.e. a 46% improvement). These changes were significant at the 0.1% level ( P < 0.001). The saline group was offered the opportunity to receive a further course of treatment without disclosing a change in regimen from saline to fungal protease infusion. Five placebo patients declined further treatment, while four patients with 32 arterial segments subsequently received the cross-over fungal protease infusion protocol. After treatment, five completely obstructed segments became recanalized. This research demonstrated that 3 months of anticoagulant therapy produced no improvement whatsoever in peripheral circulation; [35] and neither did subsequent infusions of saline (placebo) during a 2 week period. Six intravenous infusions of a fungal protease derived from A. oryzae given within 2 weeks significantly improved peripheral circulation in over half of the chronically obstructed arterial segments in these patients. Furthermore, detailed analysis of study results suggested that an increase in the number and/or dosage of protease infusions might have resulted in even greater improvement in obstructed and stenosed arterial segments. Other studies have shown fungal protease to be effective in the treatment of arterial obstruction in patients with more advanced conditions, such as gangrene and other severe ischemic disease. [36] [70] [72] Celiac disease It has been known since the 1950s that the gluten found in wheat, rye and other grains is the cause of intestinal damage in celiac disease, with the gliadin fraction of gluten being the source of its toxicity. [74] [75] By the 1970s, fractionation studies had succeeded at identifying the components of gliadin involved in the toxic mechanism. The carbohydrate moiety, consisting mainly of glucose, galactose, xylose and arabinose, is the source of gluten’s gastrointestinal toxicity in the celiac patient, rather than the protein fraction as had been previously suspected. [76] [77] [78] Amylytic enzymes from Aspergillus species are effective in vitro in the treatment of celiac disease, as they enzymatically cleave the toxic carbohydrate portion of gliadin. Fungal carbohydrase preparations render grains like wheat and rye virtually harmless to individuals with gluten enteropathy. [76] [77] A 1977 study attempting to identify the source of gliadin toxicity used a preparation of amylytic enzymes from Aspergillus niger to remove the carbohydrate portion of gliadin in vitro. [76] To be certain of the variables being tested, native gliadin was chromatographed showing that carbohydrate was associated with four main protein bands. When the carbohydrase-treated gliadin was chromatographed, no alteration was detected in the protein pattern, but carbohydrate was completely absent. To further establish that the protein make-up remained unchanged as compared with native gliadin, peptide mapping of the treated gliadin was carried out using electrophoresis followed by chromatography. Peptide maps showed no difference between the treated and untreated gliadin, confirming that no alteration had occurred in the primary structure of the protein. Gliadin treated in this manner was baked into loaves of bread made with gluten-free flour. The study compared the effect of bread with treated versus untreated gliadin on four patients with previously diagnosed celiac disease. All four patients had been on gluten-free diets for at least 3 months prior to the study and were virtually symptom-free. Previously, their clinical and physical signs and symptoms had included the diarrhea, malabsorption, decreased body weight and height,
anemia, tetany, impaired D-xylose absorption, decreased intestinal mucosal enzyme secretion, flattened mucosal brush-border and subepithelial tissue lymphocytosis typical of celiac disease. During the test period, patients 1, 2 and 3 received a total of 50 g of treated gliadin baked into loaves of bread (10 g gliadin/450 g loaf). Xylose absorption tests and intestinal biopsies from jejunal villi were performed before and after each test period. The celiac patient receiving untreated gliadin (patient no. 4) experienced a return of signs and symptoms of celiac disease – diarrhea, abdominal pain, low values on xylose absorption studies, decreased mucosal enzyme secretion (alkaline phosphatase, lactase, sucrase) and characteristic histological damage (mucosal lymphocytosis and loss of enterocyte height). The patients who received the treated gliadin remained symptom-free during the test period and showed no abnormalities in
599
histological parameters (i.e. general morphology, epithelial cell height, tissue lymphocytes were normal in these patients). This study demonstrated that carbohydrate-digesting enzymes from Aspergillus sp. can be used in vitro to remove the toxicity of gluten to celiac patients and supports the hypothesis that carbohydrate components of gliadin are responsible for its toxicity, rather than protein components as had been widely suspected. It appears that no controlled studies have been done to evaluate the effectiveness of amylytic fungal enzymes at reducing gluten toxicity to celiac patients in vivo by administering these enzymes with gluten-containing foods at mealtime. It should be noted that although celiac patients show intolerance to the carbohydrate portion of gliadin, this is likely not the only source of gluten-induced pathology. A number of studies suggest that protein components of gluten produce systemic allergic manifestations in some patients. [1] [2] [8] [9] [13] [79] [80] It appears that both gastrointestinal intolerance and immunological hypersensitivity are capable, either individually or in concert, of producing disease symptoms in susceptible individuals. Future studies may also show that both pathological mechanisms are amenable to treatment by hydrolysis of the offending portions of gluten with the appropriate orally administered fungal enzymes. This, however, remains to be proven. Food allergies Antigen sampling by subepithelial immune tissue in the gut helps under normal conditions to program the body’s defenses and protect against exposure to “foreign” dietary proteins and polypeptides. Under pathological conditions, food allergies can be caused by several factors, including the increased supply of dietary antigens which leak into the bloodstream a a result of inadequate protein digestion. [1] [2] [4] [8] [9] [10] [11] [21] By digesting dietary protein, fungal enzymes administered orally at mealtime work to decrease the supply of antigenic macromolecules available to leak into the bloodstream. In addition, orally administered fungal enzymes which have themselves been absorbed intact may help to “digest” antigenic dietary proteins which they encounter in the bloodstream. Further research is needed to evaluate the role of fungal enzymes in the treatment of food allergies.
SUMMARY Although the intact absorption of orally administered protein, including enzymes, can no longer be reasonably denied, the quantitative significance of this process will require additional study. While it appears unlikely that this route of absorption is significant from the standpoint of overall nutritional status, considerable evidence exists supporting the biological and therapeutic importance of intact protein absorption and the role of fungal enzyme therapy. The emerging field of fungal enzyme therapy holds promise as an effective therapy or adjunct in a wide range of conditions, including maldigestion, malabsorption, pancreatic insufficiency, steatorrhea, celiac disease, lactose intolerance, arterial obstruction, and thrombotic disease.
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Chapter 67 - Beta-carotene and other carotenoids Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION The carotenoids represent the most widespread group of naturally occurring pigments in nature. They are a highly colored (red and yellow) group of fat-soluble compounds, composed of hydrocarbons (carotenes) and their oxygenated derivatives (oxycarotenoids or xanthophylls). The basic carotenoid structure consists of eight isoprenoid units with a series of conjugated double bonds. All photosynthetic organisms, whether bacteria or plants, contain carotenoid pigments. These compounds not only function as auxiliary pigments in photosynthesis, but also play a crucial role in protecting the organism or plant against photosensitization by its own chlorophyll. Over 600 carotenoids have been characterized, but only about 30–50 are believed to have vitamin A activity. Biological activity of a carotenoid has historically been considered synonymous with its corresponding vitamin A activity. However, recent research suggests that this function of carotenoids has been overemphasized, as carotenoids have been found to exhibit many other very important physiological activities. For a carotenoid to have vitamin A activity, it must have an unaltered beta-ionone ring with an attached polyene side chain containing 11 carbon atoms. Beta-carotene has been termed the most active of the carotenoids, due to its higher provitamin A activity (see Fig. 67.1 ). Apocarotenoids are compounds that have been shortened by the removal of at least one end of the molecule beyond a designated location (e.g. beta-Apo-8'-carotenal has been cleaved at the 8' carbon). Apocarotenes and xanthophylls have reduced or no vitamin A activity. [1] [2]
Figure 67-1 Beta-carotene.
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DIETARY SOURCES The carotenoids present in green plants are found in the chloroplasts with chlorophyll, usually in complexes with a protein or lipid. Beta-carotene is the predominant form in most green leaves and, in general, the greater the intensity of the green color, the greater the concentration of beta-carotene. Orange-colored fruits and vegetables, e.g. carrots, apricots, mangoes, yams, squash, etc., typically have higher concentrations of provitamin A carotenoids, the provitamin A content again paralleling the intensity of the color. Yellow vegetables have higher concentrations of xanthophylls, and hence a lowered provitamin A activity. In the orange and yellow fruits and vegetables, beta-carotene concentrations are high, but other provitamin A carotenoids typically predominate. The red and purple vegetables and fruits, such as tomatoes, red cabbage, berries, and plums, contain a large portion of non-vitamin A-active pigments, including flavonoids. Legumes, grains, and seeds are also significant sources of carotenoids. Carotenoids are also found in various animal foods, such as salmon and other fish, egg yolks, shellfish, milk, and poultry. Carotenoids are frequently added to foods as colorants. Table 67.1 lists carotenoids with provitamin A activity found in common food sources, while Table 67.2 lists some important carotenoids that have no vitamin A activity. [1] [2] The structures of two of these, lycopene and zeaxanthin, are illustrated in Figures 67.2 and 67.3 .
METABOLISM Absorption
A variety of factors are known to influence the absorption efficacy of vitamin A and carotenoids. Although retinol does not require bile acids to facilitate absorption, carotenoids do. Other factors that affect vitamin A and carotenoid absorption include: • the presence of fat, protein, and antioxidants in the food • the presence of bile and a normal complement of pancreatic enzymes in the intestinal lumen • and the integrity of the mucosal cells. The absorption efficiency of dietary vitamin A is usually quite high (80–90%), with only a slight reduction in efficiency at high doses. In contrast, beta-carotene’s absorption efficiency is much lower (40–60%), and it decreases rapidly with increasing dosage. [1] [3] Carotene supplements are better absorbed than the carotenes from foods.[4] TABLE 67-1 -- Provitamin A carotenoids and food sources Carotenoid Activity (%) Food sources Beta-carotene
100%
Green plants, carrots, sweet potatoes, squash, spinach, apricots, green peppers
Alpha-carotene
50–54
Green plants, carrots, squash, corn, watermelons, green peppers, potatoes, apples, peaches
Gamma-carotene
42–50
Carrots, sweet potatoes, corn, tomatoes, watermelons, apricots
Beta-zeacarotene
20–40
Corn, tomatoes, yeast, cherries
Cryptoxanthin
50–60
Corn, green peppers, persimmons, papayas, lemons, oranges, prunes, apples, apricots, paprika, poultry
Beta-apo-8'-carotenal
72
Citrus fruit, green plants
Beta-apo-12'-carotenal 120
Alfalfa meal
TABLE 67-2 -- Non-provitamin A carotenoids and food sources Food source
Carotenoid Lycopene
Tomatoes, carrots, green peppers, apricots, pink grapefruit
Zeaxanthin
Spinach, paprika, corn, fruits
Lutein
Green plants, corn, potatoes, spinach, carrots, tomatoes, fruits
Canthaxanthin Mushrooms, trout, crustaceans
Crocetin
Saffron
Capsanthin
Red peppers, paprika
Figure 67-2 Lycopene.
Figure 67-3 Zeaxanthin. Transformation in the intestinal mucosa
As stated above, of the more than 600 carotenoids that have been reasonably well characterized, only about 30–50 are believed to have provitamin A activity. Yet carotenoids provide the majority of dietary vitamin A. Provitamin A carotene conversion to vitamin A is dependent on diverse factors: [5] • protein status • thyroid hormones • zinc • vitamin C.
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The conversion diminishes as carotene intake increases and when serum retinol levels are adequate. [6] Beta-carotene and other provitamin A carotenes were originally believed to be cleaved by carotene dioxygenase at the 15,15' double bond, which would yield two molecules of all- trans retinal. It is currently believed, however, that the dioxygenase enzyme non-specifically attacks any one of the double bonds of the beta-carotene, resulting in the formation of a corresponding apo-beta-carotenal or retinal. [7] The apocarotenal formed can either be degraded to retinal or absorbed. The retinal formed is then converted to retinol by retinaldehyde reductase. Uncleaved provitamin A carotenoids, apocarotenoids, and non-provitamin A carotenoids, like retinol, are transported in the chylomicra. Transport, storage, and excretion
No specific carrier protein exists in the plasma for carotenoids. These compounds are typically transported in human plasma in association with the plasma lipoproteins, particularly by LDL. As a consequence, patients with high serum cholesterol or LDL levels tend to have high serum carotene levels. The concentrations found in the plasma usually reflect the dietary concentration, with beta-carotene typically comprising only 20–25% of the total serum carotene level. [8] Carotenes may be stored in adipose tissue, the liver, other organs (the adrenals, testes, and ovaries have the highest concentrations), and the skin (see Table 67.3 ). Deposition in the skin results in carotenodermia. This is a benign (and probably beneficial) state. Carotenodermia not directly attributable to dietary intake or supplementation, however, may be indicative of a deficiency in a necessary conversion factor, i.e. zinc, thyroid hormone, vitamin C, or protein. [1] [2]
PHYSIOLOGICAL ROLES Reproduction
Beta-carotene has also been reported to have a specific effect in fertility distinct from its role as a precursor to vitamin A.
Tissue
TABLE 67-3 -- Distribution of carotenoids in some human tissues (mcg/kg) Carotenoids
Adrenal
20.1 ± 11.9
Liver
8.3 ± 21.3
Testis
5.0 ± 7.7
4.7 ± 2.0
Fat
3.9 ± 6.0
1.3 ± 1.1
Pancreas
2.3 ± 1.2
1.1 ± 1.0
Spleen
1.6 ± 2.2
1.2 ± 0.5
Lung
0.6 ± 1.0
Thyroid
0.6 ± 0.4
[ 9] [ 10] [11]
In bovine nutritional studies, cows fed
Beta-carotene
10.8 ± 5.5
beta-carotene-deficient diets exhibited delayed ovulation and an increase in the number of follicular and luteal cysts. [9] [10] The corpus luteum has the highest concentration of beta-carotene of any organ measured. [11] The carotene cleavage activity changes with the ovulation cycle, with the highest activity occurring during the midovulation stage. It has been speculated that a proper ratio of carotene to retinol must be maintained to ensure proper corpus luteum function. As the corpus luteum produces progesterone, inadequate corpus luteum function could have significant deleterious effects. Inadequate corpus luteum secretory function is one of the characteristic features of infertile and/or irregular menstrual cycles. [12] Furthermore, an increased estrogen to progesterone ratio has been implicated in a variety of clinical conditions, including ovarian cysts, premenstrual tension syndrome, fibrocystic breast disease, and breast cancer. [13] Since supplemental beta-carotene given to cows significantly reduced the incidence of ovarian cysts (42% in control group vs. 3% in the beta-carotene group), it may have a similar effect in humans. [10] [11] Another bovine condition that benefited from increased dietary beta-carotene levels is cystic mastitis. [12] It appears that farmers have a greater appreciation of beta-carotene than do many nutritionists. Of course, there are significant financial reasons as the annual monetary loss from bovine mastitis in the US has been estimated to be at least $1.5–2.0 billion and ovarian cysts represent the major cause of infertility in cattle. Immune system
Some of these effects are probably related to vitamin A’s ability to prevent stress-induced thymic involution as well as promote thymus growth. As carotenes are better antioxidants, they may turn out to be even better at protecting the thymus gland than vitamin A, since the thymus gland is particularly susceptible to free radical and oxidative damage. The clinical use of vitamin A and beta-carotene in infectious diseases is discussed below. Beta-carotene’s primary effects appear to enhance thymus gland function (discussed below) and increase interferon’s stimulatory action on the immune system. [14] Interferon is a powerful immune-enhancing compound that plays a central role in protection against viral infections. Antioxidant activity
In general, carotenes exert significant antioxidant activity, while the antioxidant activity of vitamin A is relatively minor in comparison. [15] The antioxidant activity of carotenes are thought to be the factor responsible for their anti-cancer effects noted in population studies (discussed below). Since aging is associated with free
radical
606
damage, a hypothesis developed that carotenes may also protect against aging as well. There is evidence that seems to support this hypothesis. It appears that tissue carotenoid content is the most significant factor in determining maximal life span potential (MLSP) of mammalian species ( r = 0.835 for 12 mammalian species, and for primates alone, r = 0.939!). [16] For example, human MLSP of approximately 90 years correlates with a serum carotene level of 50–300 mcg/dl, while other primates, such as the rhesus monkey, have a MLSP of approximately 34 years, correlating with a serum carotene level of 6–12 mcg/dl. While beta-carotene has received most of the attention, many carotenes which have either low or no vitamin A activity exert much greater protection compared with beta-carotene. For example, while beta-carotene generates vitamin A much more efficiently than alpha-carotene, alpha-carotene is approximately 38% stronger as an antioxidant and 10 times more effective in suppressing liver, skin, and lung cancer in animals compared with beta-carotene. [17] Even more powerful is lycopene.[18] Studies have shown lycopene to exhibit the highest overall singlet oxygen quenching of the carotenoids thus far studied. Its activity is roughly double that of beta-carotene. Furthermore, lycopene may exert even more impressive anti-cancer effects. To evaluate the role of lycopene as a protective factor in digestive tract cancers, a case–control study was conducted in northern Italy, where tomato intake is high, but also heterogenous, in that some people eat a lot of tomatoes while others eat very few if any. Tomatoes are a perfect food to study as they are quite high in lycopene, but very low in carotene. The data were obtained from a series of hospital-based studies on various cancers of the digestive tract between 1985 and 1991. [19] Frequency of consumption of raw tomatoes was divided into four levels: less than two; three to four; four; five to six; and greater than seven servings per week. Results showed a consistent pattern of protection by high intake of raw tomatoes in all examined cancer sites of the digestive tract. The degree of protection was similar to, but somewhat more marked than, those afforded by green vegetables and fruit studies carried on in the same areas. The results support the findings of other researchers who found, for example, a 40% reduction in the risk of esophageal cancer by simply consuming one serving of raw tomatoes per week and a 50% reduced rate for cancers of all sites among elderly Americans reporting a high tomato intake. These results suggest that increasing dietary lycopene levels may be a significant protector against cancer. According to a detailed analysis of the levels of carotenoids in 120 fruits and vegetables, lycopene is found in very few. contained lycopene.
[20]
Table 67.4 provides a list of the foods which
TABLE 67-4 -- Lycopene content of common foods Food
Lycopene (mg/100 g)
Apricot, canned
0.06
Apricot, dried
0.8
Grapefruit (pink and raw)
3.4
Guava juice
3.3
Tomato, raw
3.1
Tomato juice, canned
8.6
Tomato paste, canned
6.5
Tomato sauce, canned
6.3
Watermelon, raw
4.1
These values indicate that lycopene levels are retained in food processing.
CLINICAL APPLICATIONS There are three primary sources of carotenes on the market: • synthetic all-trans beta-carotene • beta- and alpha-carotene from the algae Dunaliella • mixed carotenes from palm oil. Of these three, palm oil carotenes seem to be the best form (see Table 67.5 ). Palm oil carotenes appear to give much better antioxidant protection. The carotene complex of palm oil closely mirrors the pattern in high carotene foods. In particular, unlike the synthetic version which only provides the trans configuration of beta-carotene, natural carotene sources provide beta-carotene in both a trans and cis configuration: • 60% beta-carotene (both trans and cis isomers) • 34% alpha-carotene • 3% gamma-carotene • 3% lycopene. Palm oil carotenes have been shown to be about 4–10 times better absorbed than synthetic all- trans beta-carotene. been shown to be well absorbed. [24]
[21] [ 22] [23]
Carotenes from Dunaliella have also
The widespread health concerns concerning the use of “tropical oils” like palm and coconut do not apply to carotene products extracted from palm oil as the fat content is minimal. In addition, the real problem with palm oil occurs when it is processed, i.e. partially hydrogenated. Prevention of cancer Epidemiological studies have clearly demonstrated a strong inverse correlation between dietary carotene intake and a variety of cancers involving epithelial tissues (lung, skin, uterine cervix, gastrointestinal tract, etc). [25] [26] The epidemiological association is much stronger for
607
Source
Carotenoid
TABLE 67-5 -- Antioxidant potential of different carotene products (per 25,000 IU of vitamin A activity) Quenching rate % in source mg/25,000 IU Antioxidant potential
Palm oil
Alpha-carotene
1.9
33
7.36
2.60
Beta-carotene
1.4
63
14.04
3.66
Gamma-carotene 2.5
2.5
0.56
0.26
Lycopene
0.1
0.02
0.01
3.1
Total Algal
6.54
Alpha-carotene
1.9
4.0
0.61
0.22
Beta-carotene
1.4
96.0
14.69
3.83
Total Synthetic Beta-carotene
4.05 1.4
100
14.97
Total
3.90 3.90
carotene than for vitamin A. This may reflect carotene‘s superior antioxidant, immune potentiating activity, and anticarcinogenic activity.
[27]
While there is no argument that a diet high in carotenes is protective against cancer, the big question is: “Can beta-carotene supplementation reduce the risk of cancer?” The answer appears to be that synthetic beta-carotene supplementation does not. Three highly publicized reports on cancer prevention trials featuring synthetic all- trans beta-carotene in high-risk groups have produced negative results. It is important to take a close look at each of these studies to help put things into perspective. The Alpha-tocopherol, Beta-carotene Cancer Prevention Study Group
This study’s population was 29,000 men in Finland who smoked and drank alcohol. [28] The men were given beta-carotene (20 mg daily) and/or vitamin E. The results of this study indicated an 18% increase in lung cancer in the beta-carotene group. This result was not totally unexpected as studies in primates demonstrated that when animals were fed alcohol and beta-carotene, they experienced an increase in liver damage as a result of oxidative damage. [29] Other researchers have pointed out that beta-carotene is very susceptible to oxidative damage. [30] The protection against oxidative damage of beta-carotene is the presence of other antioxidant nutrients. [31] Absence of these protective nutrients could result in the formation of cancer-causing compounds, stressing the importance of relying on foods and broader-spectrum nutritional antioxidant support. Adding support to this statement is the fact that the group that received both beta-carotene and vitamin E did not show an increase in cancer, and in the group not receiving beta-carotene supplements there was a strong protective effect of high dietary beta-carotene and blood carotene levels against lung cancer. All together, this data strongly suggests that the protection offered by beta-carotene is only apparent when other important antioxidant nutrients are provided and may not be provided by the synthetic forms. The CARET study
The second trial reporting on the role of beta-carotene in a high-risk group is the Carotene and Retinol Efficacy Trial (CARET). [32] This study was composed of over 18,000 US men and women smokers and asbestos workers. This study was halted 21 months prematurely on 13 January 1996 after 4 years of intervention indicated that beta-carotene supplementation (30 mg daily) increased lung cancer by 28% and overall deaths by 17%. While this appears dramatic, a closer look at the numbers and percentages puts them in their proper perspective. Among active smokers, the risk of lung cancer during the CARET study was 5 out of every 1,000. The 28% increase found with beta-carotene supplementation increased this number to roughly 6 out of 1,000. [32] Interestingly, once again, in the group not taking beta-carotene, the lowest rate of cancer was found among individuals with the highest blood beta-carotene levels; and in former smokers, beta-carotene supplementation actually reduced cancer risk by 20%. The Physician’s Health Study
The Physician’s Health Study is composed of 22,071 US male physicians taking either 50 mg of beta-carotene or a placebo every other day for 12 years. Results demonstrated no significant effect – positive or negative – on cancer or cardiovascular disease, even in the group (11%) who smoked. [33] General comments on the “negative” studies
The results of these three studies indicate that synthetic beta-carotene supplementation may have adverse effects in high-risk groups for cancer and cardiovascular disease. These studies do not invalidate the hundreds of studies showing the preventive effect of a diet rich in carotenes and nutritional antioxidants against cancer and cardiovascular disease. These results seem to indicate the need for a diet high in carotenes and, if carotene supplementation is desired, people should not smoke, natural
608
forms should be used, and the beta-carotene needs to be protected against the formation of toxic derivatives by taking extra vitamin C and E, and selenium. Other prospective studies
In addition to these three highly publicized studies, there have been several prospective and double-blind studies showing promising results. In particular, beta-carotene supplementation has been shown to be especially effective in the treatment of early cancerous lesions of the oral cavity and esophagus. [34] [35] Although beta-carotene has been shown to exert these benefits on its own (in dosages ranging from 15 to 180 mg/day), one of the most positive studies showing a reduction in cancer risk with supplemental beta-carotene to date is one that featured a broader supplement program. The Linxian Cancer Chemoprevention Study is a prospective study of 30,000 rural Chinese adults. In one of the substudies, subjects received one of four supplement programs: • retinol and zinc • riboflavin and niacin • vitamin C and molybdenum • beta-carotene, vitamin E, and selenium (dosages 1–3 times greater than the US RDA). The latter group demonstrated 13% fewer cancer deaths and a reduction of 9% in overall deaths. [36] [37] These results again support the notion that a combination of antioxidants is superior to high levels of any single antioxidant. Prevention of cardiovascular disease As in cancer, a high dietary carotene intake is also associated with lowering the risk of cardiovascular disease. [38] Like other antioxidants, beta-carotene may inhibit damage to cholesterol and the lining of the arteries. [39] However, it appears that beta-carotene is less effective in protecting against cardiovascular disease than vitamin E, probably because vitamin E protects against oxidative damage to cholesterol better than beta-carotene. [40] Immune enhancement Carotenes have demonstrated a number of immune-enhancing effects in recent studies. [14] However, the immune-enhancing effects were demonstrated as far back as 1931 when it was found that a diet rich in carotenes, as determined by blood carotene levels, was inversely related to the number of school days missed by children. [41] Originally it was thought that the immune-enhancing properties of carotenes were due to their conversion to vitamin A. We now know that carotenes exert
many immune system-enhancing effects independent of any vitamin A activity. [14] One of the most impressive studies was conducted on normal human volunteers. [42] Results demonstrated that oral beta-carotene (180 mg/day, approximately 300,000 IU) significantly increased the frequency of OKT4+ (helper/inducer T-cells) by approximately 30% after 7 days, and of OKT3+ (all T-cells) after 14 days. [32] As T4+ lymphocytes play a critical role in determining host immune status, this study indicates that oral beta-carotene may be effective in increasing the immunological competence of the host in conditions that are characterized by a selective diminution of the T4 subset of T-cells, such as the acquired immunodeficiency syndrome (AIDS) and cancer. However, rather than supplementing the diet with synthetic beta-carotene, it may be more advantageous to use natural carotene sources or to increase the intake of carotene-rich foods. In another study, 126 healthy college students were randomly assigned to one of the following groups: • group A, the control group • group B, a group that used a 15 mg (25,000 IU) beta-carotene supplement daily • group C, a group that consumed approximately15 mg beta-carotene per day from carrots. Better results, i.e. increase in white blood cell number and function, were achieved in the group eating the carrots.
[43]
As the absorption studies have shown supplemental beta-carotene to be much better absorbed than the carotenes from carrots and other vegetables, the differences are likely the result of form, i.e. natural is better than synthetic. [4] Vaginal candidiasis It is a well-established fact that women are more susceptible to vaginal candidiasis when the immune system is depressed, a depression which may be due to low carotene levels. Beta-carotene levels were determined in exfoliated vaginal cells in 22 women with vaginal candidiasis and compared to vaginal cells from 20 controls. The beta-carotene level/1 million cells in the women with vaginal candidiasis was 1.46 ng compared with 8.99 ng in the control group, i.e. one-sixth that of normal. [44] These results, coupled with beta-carotene’s known effects on enhancing the immune system, suggest that a low tissue level of beta-carotene is associated with vaginal candidiasis, and a high dietary or supplemental intake of beta-carotene may be protective against vaginal candidiasis. Photosensitivity disorders Beta-carotene has become the treatment of choice for photosensitivity disorders. It is most effective in the treatment
609
of erythropoietic protoporphyria (EPP), while its effectiveness in other photosensitivity disorders, such as polymorphous light eruption, solar urticaria, and discoid lupus erythematosus is significant, but not as great. [45] [46] [47] [48] [49] [50] [51] [52] [53] Beta-carotene also has a small but significant effect in increasing the exposure at which manifestations of sunburn begin, thus allowing some subjects the opportunity to stay in the sun long enough to get a “tan” for the first time. [53] Patients with EPP are characterized by elevated levels of porphyrins in blood, feces, and skin and by sensitivity to visible light. This sensitivity manifests itself after exposure to sunlight by a burning sensation followed by swelling and redness. Topical sunscreens are of no value. The photosensitivity is due to excitation of the porphyrin molecule by ultraviolet radiation, resulting in the production of free radicals that are very deleterious to the skin. Direct cell damage results in the release of chemical mediators which in turn damage other cells, resulting in the manifestations of itching, burning, redness, and swelling. In EPP, it appears that carotene levels must be maintained in the blood at 600–800 mcg/dl for optimum effects and that the protective effect is not usually observed until after 4–6 weeks of therapy. The actions of beta-carotene and other carotenes in human tissue are similar to their action in plant cells, i.e. they function as a cellular screen against sunlight-induced free radical damage.
DOSAGES For carotenes, a daily dosage of 25,000 IU (15 mg of beta-carotene) appears to be reasonable for general health. For the treatment of pre-cancerous lesions and immune enhancement, the dosage range is 25,000–300,000 IU. In the treatment of EPP, the dosage is based on maintaining blood carotene levels between 600 and 800 mcg/dl. For the best clinical impact, it appears the natural mixed forms of carotene should be used in conjunction with a broad range of other natural antioxidants (see Ch. 99 ).
TOXICITY Supplementing the diet with beta-carotene has not been shown to possess any significant toxicity despite its use in very high doses in the treatment of numerous photosensitive disorders (see above). Occasionally patients will complain of loose stools, which usually clears spontaneously and does not necessitate stopping treatment. Elevated carotene levels in the blood do not lead to vitamin A toxicity, nor do they lead to any other significant disturbance besides a yellowing of the skin (carotenodermia). The ingestion of large amounts of carrots or carrot juice (0.45–1.0 kg/day of fresh carrots for several years) has, however, been shown to cause neutropenia as well as menstrual disorders. [54] [55] Although the blood carotene levels of these patients did reach levels (221– 1,007 mcg/dl) similar to those of patients taking high doses of beta-carotene (typically 800 mcg/dl), the disturbances are due to some other factor in carrots, as neither of these effects nor any others have been observed in subjects consuming very high doses of pure beta-carotene, e.g. 300,000–600,000 IU/day (180–360 mg beta-carotene, which is equivalent to 4–8 pounds of raw carrots) over long periods of time. [56] [57] [58] [59] [60] Doses up to 1,000 mg/kg have been given to rats and rabbits for long periods of time with no signs of embryotoxicity, toxicity, tumorigenicity, or interference in reproductive functions. [61]
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Mathews-Roth MM. Photosensitization by porphyrins and prevention of photosensitization by carotenoids. J Natl Cancer Inst 1982; 69: 279–285
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Chapter 68 - Boron Gregory S. Kelly ND*
INTRODUCTION Boron is an ubiquitous constituent of man’s external environment. It typically occurs in nature as borates hydrated with varying amounts of water. Boric acid and borax are important boron-containing compounds. [1] In trace amounts, boron is essential for the growth of many plants, and is found in animal and human tissues at low concentrations. [1] Although it has yet to be recognized as an essential nutrient for humans, recent data from animal and human studies suggest that boron may be important for mineral metabolism, brain function and performance, and prevention of both osteoporosis and osteoarthritis.
SOURCES Because boron in plants is dependent on the availability of boron in the soil, the same food crop can vary greatly in boron content depending on where and how it is grown. In general, soils exposed to high degrees of precipitation have decreased levels of boron. [2] Food processing results in additional loss of boron. [3] Foods of plant origin, such as leafy vegetables, non-citrus fruits, nuts, legumes, and sea vegetables are considered to be the best sources of boron. [1] [4] Wine has also been shown to contribute appreciable amounts of boron to the diet. [5] A diet containing an abundance of these items would provide 2–6 mg/day of boron. [4] [6] Daily intake of boron is dependent upon several variables. Concentration of boron in water varies considerably according to geographic source. In some areas, boron in drinking water and water-based beverages may account for most of the total dietary boron intake. Individual food preference greatly influences daily intake of boron. Fruits, vegetables, tubers, and legumes have higher concentrations of boron than do cereal grains or animal tissues. Boron has also been determined to be a notable contaminant or major ingredient of many * Reprinted with permission from Alternative Medicine Review 1997; 2(1): 48–56
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personal care products and it is occasionally used (boric acid) as a food preservative.
[7]
In a recently published study, 32 subjects from Sydney, Australia, aged 20–53, were assessed over a 7 day period for their dietary intake of boron. The average boron intake in male and female subjects was found to be 2.28 ± 1.3 and 2.16 ± 1.1 mg/day respectively. [5] The boron content of selected Australian foods has been found to correlate with values in Finnish and US Food and Drug Administration tables and is presented in Table 68.1 .[5]
METABOLISM Chemical properties Elemental boron was first isolated in 1808. It is the first member (atomic number 5) of the metalloid or semiconductor family of elements, which include silicon and germanium, and is the only non-metal of the group IIIA elements. Like carbon, boron has a tendency to form double bonds and macromolecules. [8] Boron, as boric acid, acts as a Lewis acid, accepting hydroxyl (OH-) ions and leaving an excess of protons. [9] Because boron complexes with organic compounds containing hydroxyl groups, it interacts with sugars and polysaccharides, adenosine-5-phosphate, pyridoxine, riboflavin, dehydroascorbic acid, and pyridine nucleotides. [10] Borate cross-links with polysaccharides, most likely as borate di-esters, to form
Food
TABLE 68-1 -- Concentration of boron in selected Australian foods Boron (mg/100 g)
Almond
2.82
Apple (red)
0.32
Apricots (dried)
2.11
Avocado
2.06
Banana
0.16
Beans (red kidney)
1.40
Bran (wheat)
0.32
Brazil nuts
1.72
Broccoli
0.31
Carrot
0.30
Cashew nuts (raw)
1.15
Celery
0.50
Chick peas
0.71
Dates
1.08
Grapes (red)
0.50
Hazel nuts
2.77
Honey
0.50
Lentils
0.74
Olive
0.35
Onion
0.20
Orange
0.25
Peach
0.52
Peanut butter
1.92
Pear
0.32
Potato
0.18
Prunes
1.18
Raisins
4.51
Walnut
1.63
Wine (Shiraz Cabernet)
0.86
gels with unique properties. These gels are very plastic in nature and quickly reassemble in response to externally applied stress. ester compounds have been identified as antibiotics. [11]
[9]
Five naturally occurring boron
Biochemistry Boron in food, sodium borate and boric acid are well absorbed from the digestive tract. [12] These compounds are also absorbed through damaged skin and mucous membranes; however, they do not readily penetrate intact skin. [13] No accumulation of boron has been observed in soft tissues of animals fed chronic low doses of boron; however, in acute poisoning incidents, the amount of boric acid in brain and liver tissue has been reported to be as high as 2,000 ppm. Within a few days of consumption of large amounts of boron, levels in blood and most soft tissues quickly reach a plateau. [14] Tissue homeostasis is maintained by the rapid elimination of excess boron primarily in the urine; with bile, sweat, and breath also contributing as routes of elimination. [10] In humans, urinary boron excretion increases over time in all boron-supplemented subjects who have been studied. [15] Evidence suggests that supplemental boron does accumulate in bone; however, cessation of exposure to dietary boron results in a rapid drop in bone boron levels. The half-life of boric acid in animals is estimated to be about 1 day. [14] Biological functions Boron contributes to living systems by acting indirectly as a proton donor and by exerting an influence on cell membrane structure and function. [16] Although the absolute essentiality of boron for plants is well documented, studies to date have not shown it to be unequivocally essential for either animals or humans. However, boron supplementation has been shown to affect certain aspects of animal physiological function. Experimental animals supplemented with boron demonstrate a high degree of variability in their response. In general, supplemental dietary boron has most marked effects when the diet is deficient in known nutrients. [17] Evidence suggests that boron might have a slight effect on decreasing fasting serum glucose concentrations in postmenopausal women. [11] Life span
Boron in an animal model has been shown to have an effect upon life span, although the process is undefined. Extremes in dietary boron, both a deficiency and an excess, decreased the median life span of Drosophilia by 69%, while supplementing the diet with low levels of boron increased life span by 9.5%. [18]
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Brain function
Brain electrophysiology and cognitive performance were assessed in response to dietary manipulation of boron (approximately 0.25 vs. approximately 3.25 mg boron/2,000 kcal per day) in three studies with healthy older men and women. A low boron intake was shown to result in a decrease in the proportion of power in the alpha band and an increase in the proportion of power in the delta band. Other changes in left–right symmetry and brain wave coherence were noted in various sites, indicating an influence on brain function. When contrasted with the high boron intake, low dietary boron resulted in significantly poorer performance ( P < 0.05) on tasks emphasizing manual dexterity, eye–hand coordination, attention, perception, encoding and short- and long-term memory. Collectively, the data from these studies indicate that boron may play a role in human brain function, alertness and cognitive performance. [19] Hematological
Boron supplementation to human subjects, who had previously followed a dietary regimen deficient in boron, increased blood hemoglobin concentrations, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration; and lowered hematocrit, red cell count, and platelet count. [20] Mineral metabolism
Boron also impacts mineral metabolism and has been shown to impact levels of certain hormones in human subjects. In the first nutritional study with humans involving boron, [13] postmenopausal women first were fed a diet that provided 0.25 mg boron/2,000 kcal for 119 days, and then were fed the same diet with a boron supplement of 3 mg boron/day for 48 days. The boron supplementation reduced the total plasma concentration of calcium and the urinary excretions of calcium and magnesium, and elevated the serum concentrations of 17 beta-estradiol and testosterone. [4] In a study designed to determine the effects of boron supplementation on blood and urinary minerals in athletic subjects on Western diets, findings suggested that boron supplementation modestly affected mineral status. [15]
DEFICIENCY SIGNS AND SYMPTOMS Information on boron deficiency is very limited, especially in humans. It is thought that insufficient intake of boron becomes obvious only when the body is stressed in a manner that enhances the need for it. When the diets of animals and humans are manipulated to cause functional deficiencies in nutrients such as calcium, magnesium, vitamin D, and methionine, a large number of responses to dietary boron occur. [21] There is evidence to suggest that more than 21 days on a boron-deficient diet are required to demonstrate detectable effects in humans. [22] The variables that are changed, due to a boron-deficient diet, abruptly improve about 8 days after boron supplementation is introduced. [4] Evidence indicates that hemodialysis results in an excessive decrease in serum boron as compared with controls. [23] While by no means being pathognomonic for a boron deficiency, blood urea nitrogen has been found to be slightly elevated during boron depletion. [24]
NUTRIENT INTERACTIONS Vitamin D
There is considerable evidence that dietary boron alleviates perturbations in mineral metabolism that are characteristic of vitamin D 3 deficiency. [25] After 26 days, chicks fed on a diet inadequate in vitamin D exhibited decreased food consumption and plasma calcium concentrations and increased plasma concentrations of glucose, beta-hydroxybutyrate, triglycerides, triiodothyronine, cholesterol, and alkaline phosphatase activity. Supplemental boron returned plasma glucose and triglycerides to concentrations exhibited by chicks fed on a diet adequate in vitamin D. [26]
In rachitic chicks, boron elevated the numbers of osteoclasts and alleviated distortion of the marrow sprouts of the proximal tibial epiphysial plate, a distortion characteristic of vitamin D 3 deficiency. [25] [27] Higher apparent-balance values of calcium, magnesium, and phosphorus have been observed for rats fed on a vitamin D-deprived diet if the diet is supplemented with boron. [17] After supplementation with 3.25 mg boron daily, plasma levels of D 2 increased in men over 45 and postmenopausal women on low magnesium and copper diets. [28] Calcium
Boron supplementation may have a favorable impact on calcium metabolism. A boron supplement of 3 mg/day affected several indices of mineral metabolism of seven women consuming a low-magnesium diet and five women consuming a diet adequate in magnesium; the women had consumed a conventional diet supplying about 0.25 mg boron/day for 119 days. Boron supplementation modestly reduced the urinary excretion of calcium when dietary magnesium was low. [4] In men over 45 and postmenopausal women, changes caused by boron supplementation include increased concentration of plasma ionized and total calcium as well
614
as reduced serum calcitonin concentration and urinary excretion of calcium. [28] A 1993 study demonstrated that a low boron diet elevated urinary calcium excretion. The high level of calcium excretion was maintained throughout the 6 week study; however, it remained elevated even after boron supplementation began. [29] Copper
Supplemental boron acts to increase serum levels of both copper and copper-dependent enzymes in humans. Boron supplementation (3 mg/day), to five men over the age of 45, four postmenopausal women, and five post-menopausal women on estrogen therapy who had been fed a low boron diet (0.23 mg/2,000 kcal) for 63 days, resulted in higher erythrocyte superoxide dismutase, serum enzymatic ceruloplasmin, and plasma copper. [28] In a subsequent study, these same variables were again found to be higher during boron repletion than while subjects were fed on a diet low in boron. [30] Magnesium
When magnesium deprivation is severe enough to cause typical signs of deficiency, a significant interaction between boron and magnesium is found. [8] A combined deficiency of boron and magnesium causes detrimental changes in the bones of animals. Supplemental boron elevates plasma Mg concentrations and enhances growth.[27] Boron supplementation has resulted in increased serum magnesium concentrations in human female subjects studied. [14] Boron supplementation increases red blood cell magnesium concentrations. [31] It has been shown that serum magnesium concentrations are greater in sedentary females whose diets are supplemented with boron than in exercising female athletes who are supplemented with boron. [32] This finding, while unexplained to date, may indicate an increased loss of boron through urine and perspiration during exercise. Phosphorous
Supplemental boron seems to lower serum phosphorus concentrations in female subjects ages 20–27. [32] However, exercise training diminishes these changes, [14] again possibly indicating increased losses or an increased need for boron as a result of exercise. A low magnesium status along with supplementation of boron may depress the urinary excretion of phosphorus. This does not occur in women with an adequate magnesium intake. [4] Methionine and arginine
In experimental animals, a beneficial impact is consistently observed after boron supplementation when the diet contains marginal methionine and excessive arginine. Among the signs exhibited by rats fed on a diet marginal in methionine and magnesium are depressed growth and bone magnesium concentration, and elevated spleen weight/body weight and kidney weight/body weight ratios. Findings indicate that the severity of these symptoms is alleviated with boron supplementation. [33]
HORMONE INTERACTIONS In rats, supplemental dietary boron substantially depressed plasma insulin, plasma pyruvate concentrations, and creatine kinase activity and increased plasma thyroxine (T4) concentrations. Boron supplementation also decreased plasma aspartate transaminase activity. [34] In animal experiments, boron supplementation offsets the elevation in plasma alkaline phosphatase caused by vitamin D deficiency. [24] One researcher has hypothesized that boron might be required for the synthesis of steroid hormones as well as vitamin D. Since the biosynthesis of steroids such as vitamin D, testosterone, and 17 beta-estradiol involves one or more hydroxylation steps, and because of boron’s ability as a Lewis acid to complex with hydroxyl groups, boron may facilitate the addition of hydroxyl groups to the steroid structures. [4] It has also been suggested that boron may act in an unspecified manner to protect hormones from rapid inactivation. [4] An increase in dietary intake of boron from 0.25 to 3.25 mg/day has been reported to increase plasma 17 beta-estradiol by more than 50% and to more than double plasma testosterone levels in postmenopausal women. The elevation seemed more marked when dietary magnesium was low. [4] In a subsequent study of healthy men, boron supplementation resulted in an increase in the concentrations of both plasma estrogen and testosterone; however, not all published trials support these observations. [5] Ten male bodybuilders, aged 20–26, were given a 2.5 mg boron supplement, while nine male bodybuilders, aged 21–27, were given a placebo for 7 weeks. Because both groups demonstrated significant increases in total testosterone ( P < 0.01), lean body mass (P < 0.01), one repetition maximum squat (P < 0.001) and bench press (P < 0.01), the authors concluded that the gains were a result of 7 weeks of bodybuilding, not of boron supplementation. [35] Table 68.2 lists boron’s impact on selected hormones in either animals or humans. Some of these interactions have only been demonstrated in animal models (*) while others have not been demonstrated unequivocally to date in all age and gender segments of a human population (**).
615
TABLE 68-2 -- Boron’s observed impact on selected hormones Hormone
Increases Decreases
Alkaline phosphatase
+
Aspartate transaminase*
+
Calcitonin
+
Cholecalciferol
+
Creatine kinase*
+
17 beta-estradiol**
+
Insulin*
+
Super oxide dismutase
+
Testosterone**
+
Thyroxine*
+
CLINICAL APPLICATIONS Osteoporosis
A considerable body of evidence has shown that both compositional and functional properties of bone are affected by boron status. [36] In experimental animals, histologic findings suggest that supplemental boron enhances maturation of the growth plate. [24] Boron is also found at the highest concentrations in growing and calcifying areas of long bones. [4] In two human studies, boron deprivation caused changes in indices associated with calcium metabolism in a manner that could be construed as being detrimental to bone formation and maintenance; these changes were enhanced by a diet low in magnesium. [4] [24] The author concluded that boron and magnesium are apparently needed for optimal calcium metabolism and are thus needed to prevent the excessive bone loss which often occurs in postmenopausal women and older men.[24] Osteoarthritis and rheumatoid arthritis
A dietary boron deficiency may be a contributing factor in some cases of arthritis. [37] In areas of the world where boron intake routinely is 1.0 mg/day or less, the estimated incidence of arthritis ranges from 20 to 70%, whereas in areas of the world where boron intake ranges from 3–10 mg/day, the estimated incidence of arthritis ranges from 0 to 10%. [37] Analytical evidence indicates that persons with arthritis have lower boron concentrations in femur heads, bones, and synovial fluid when compared with persons without this disorder. There have also been observations that bones of patients using boron supplements are much harder to cut than those of patients not supplementing with boron. [3] In 1961, the first anecdotal evidence suggesting that boron may be beneficial for osteoarthritis was presented when one patient had reduction of swelling and stiffness and remained symptom free for 1 year following supplementation with 3 mg of elemental boron twice daily for 3 weeks. A human study also offers evidence that boron supplementation may be beneficial in the treatment of this condition. In a double-blind placebo-controlled trial of 20 subjects with osteoarthritis, 50% of subjects receiving a daily supplement containing 6 mg of boron noted a subjective improvement in their condition. Only 10% of those receiving the placebo improved during the same time interval. There was greater improvement in the condition of all joints ( P < 0.01) as well as less pain on movement (P < 0.001) in subjects receiving the boron supplementation. [38] Clinical observations indicate that children with juvenile arthritis (Still’s disease) improve with boron supplementation (6–9 mg/day) in 2–3 weeks, while adults with osteoarthritis may require 2–4 months of supplementation before benefits are detected. Persons with rheumatoid arthritis may experience an aggravation of symptoms (Herxheimer response) for 1–3 weeks, but generally notice improvement within 4 weeks of beginning boron supplementation. [3]
DOSAGE The optimal dose of boron for prevention of osteoporosis and proper physiological function appears to be 3–6 mg/day. While it is best to obtain boron by means of a diet with an abundance of fruits, vegetables, legumes, and nuts, persons whose diet is limited in these items may need a supplement containing 3 mg of elemental boron. In patients with arthritis, a trial period of 2–4 months with a dose of 3 mg of boron t.i.d. seems to be indicated.
TOXICOLOGY Although boron is potentially toxic to all organisms, and, as boric acid and borax, has been used as a pesticide and food preservative, higher animals usually do not accumulate boron because of their ability to rapidly excrete it. [9] Authenticated cases of poisoning in humans have been few and have primarily been the result of accidental ingestion of insecticides and household products containing borates, or use of large amounts of boric acid in the treatment of burns. [39] The improper use of boric acid-containing antiseptics is still one of the most common causes of toxic accidents in newborns and infants. Since boric acid is readily absorbed through damaged skin, it should not be applied topically to extensive wounds. [12] In animals, chronic low-level boron exposure has been shown to cause reduced growth, cutaneous disorders, and suppression of male reproductive system function. [40] Studies indicate that male rodents suffer testicular atrophy with dietary exposure to boric acid above 4,500 ppm and have decreased sperm motility at all exposure levels above 1,000 ppm.[41] Goats orally dosed with toxic but sublethal amounts of
616
boron show significant increases in packed cell volume, hemoglobin, inorganic phosphate, creatine phosphokinase, conjugated bilirubin, sodium, glucose, cholesterol, and aspartate transaminase. Several serum components were significantly decreased after boron dosing, including alkaline phosphatase, magnesium, glutamyltransferase and potassium. There was also an elevation of cerebrospinal fluid monoamine metabolites. [42] Humans given 100 mg of boron intravenously or 270 mg of boric acid orally reported no discomfort and showed no obvious signs of toxicity. [43] [44] Airborne exposures to boron oxide and its hydration product, boric acid, have been reported to cause respiratory and eye irritation. [45] A fatal outcome has been reported following ingestion of 1 g of boric acid by a child; however, adults have survived acute intakes of nearly 300 g. [46] Common signs and symptoms of acute boron toxicity include nausea, as well as vomiting and diarrhea which are blue-green in color. [46] Other symptoms seen with acute exposure are abdominal pain, an erythematous rash involving both the skin and mucous membranes, stimulation or depression of the central nervous system, convulsions, hyperpyrexia, renal tubular damage, abnormal liver function, and jaundice. [12] Increased urinary riboflavin excretion has also been reported subsequent to acute boric acid ingestion. [47] Symptoms of chronic intoxication include anorexia, gastrointestinal disturbances, debility, confusion, dermatitis, menstrual disorders, anemia, convulsions, and alopecia. [12] Because of its ability to increase the excretion of boron, in cases of toxicity, N-acetylcysteine is the preferred intervention.
[48]
SUMMARY Although the skeletal response to boron is modified by other nutritional variables such as calcium, magnesium, vitamin D, methionine, and arginine, there is consider-able evidence that both compositional and functional properties of bone are affected by boron status. Findings suggest that boron is an important nutrient not only for mineral metabolism but also for varied aspects of optimal health in humans. While all published trials
are not in agreement on the impact of boron supplementation on levels of 17 beta-estradiol and testosterone, evidence strongly suggests that boron deficiency results in decreased levels in postmenopausal women, while supplementation tends to normalize levels in these same women. Boron’s impact on sex hormones in other segments of the population is still equivocal. No evidence exists to suggest boron supplementation will act pharmaceutically to increase levels of either 17 beta-estradiol or testosterone above normal physiological levels. Based on available information, boron appears to offer benefits in the prevention of osteoporosis and arthritis. It is also a safe and potentially effective mineral to consider in any treatment regimen for rheumatoid and osteoarthritis.
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Nielsen FH, Mullen LM, Nielsen EJ. Dietary boron affects blood cell counts and hemoglobin concentrations in humans. J Trace Elem Exp Med 1991; 4: 211–223
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Nielsen FH. New essential trace elements for the life sciences. Biol Trace Elem Res 1990; 26–27: 599–611
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Nielsen FH. Facts and fallacies about boron. Nutr Today 1992; May–June: 6–12
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Usuda K, Kono K, Iguchi K et al. Hemodialysis effect on serum boron level in the patients with long term hemodialysis. Sci Total Environ 1996; 191: 283–290
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Nielsen FH. Studies on the relationship between boron and magnesium which possibly affects the formation and maintenance of bones. Mag Trace Elem 1990; 9: 61–69
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Hunt CD. The biochemical effects of physiologic amounts of dietary boron in animal nutrition models. Environ Health Perspect 1994; 102: 35–43
Hunt CD, Herbel JL, Idso JP. Dietary boron modifies the effects of vitamin D3 nutrition on indices of energy substrate utilization and mineral metabolism in the chick. J Bone Miner Res 1994; 9: 171–182 26.
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Hunt CD. Dietary boron modified the effects of magnesium and molybdenum on mineral metabolism in the cholecalciferol-deficient chick. Biol Trace Elem Res 1989; 22: 201–220
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Nielsen FH, Shuler TR, Gallagher SK. Effects of boron depletion and repletion on blood indicators of calcium status in humans fed a magnesium-low diet. J Trace Elem Exp Med 1990; 3: 45–54
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Beattie JH, Peace HS. The influence of a low-boron diet and boron supplementation on bone, major mineral and sex steroid metabolism in postmenopausal women. Br J Nutr 1993; 69: 871–884
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Nielsen FH. Biochemical and physiologic consequences of boron deprivation in humans. Environ Health Perspect 1994; 102: 59–63
Hunt CD, Herbel JL, Nielsen FH. Metabolic responses of postmenopausal women to supplemental dietary boron and aluminum during usual and low magnesium intake: boron, calcium, and magnesium absorption and retention and blood mineral concentrations. Am J Clin Nutr 1997; 65: 803–813 31.
Meacham SL, Taper LJ, Volpe SL. Effects of boron supplementation on bone mineral density and dietary, blood, and urinary calcium, phosphorus, magnesium, and boron in female athletes. Environ Health Perspect 1994; 102: 79–82 32.
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Nielsen FH, Shuler TR, Zimmerman TJ et al. Magnesium and methionine deprivation affect the response of rats to boron deprivation. Biol Trace Elem Res 1988; 17: 91–107
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Hunt CD, Herbel JL. Boron affects energy metabolism in the streptozotocin-injected, vitamin D3-deprived rat. Magnes Trace Elem 1991; 92: 374–386
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Ferrando AA, Green NR. The effect of boron supplementation on lean body mass, plasma testosterone levels, and strength in male bodybuilders. Int J Sport Nutr 1993; 3: 140–149
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McCoy H, Kenney MA, Montgomery C et al. Relation of boron to the composition and mechanical properties of bone. Environ Health Perspect 1994; 102: 49–53
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Newnham RE. Agricultural practices affect arthritis. Nutr Health 1991; 7: 89–100
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Travers RL, Rennie GC, Newnham RE. Boron and arthritis: the result of a double-blind pilot study. J Nutr Med 1990; 1: 127–132
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Minoia C, Gregotti C, Di Nucci A et al. Toxicology and health impact of environmental exposure to boron. A review. G Ital Med Lav 1987; 9: 119–124
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Chapin RE, Ku WW. The reproductive toxicity of boric acid. Environ Health Perspect 1994; 102: 87–91
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Sisk DB, Colvin BM, Merrill A et al. Experimental acute inorganic boron toxicosis in the goat: effects on serum chemistry and CSF biogenic amines. Vet Hum Toxicol 1990; 32: 205–211
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Jansen JA, Anderson J, Schou JS. Boric acid single dose pharmokinetics after intravenous administration to man. Arch Toxicol 1984; 55: 64–67
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Aas Jansen J, Schou JS, Aggerbeck B. Gastro-intestinal absorption and in vitro release of boric acid from water-emulsifying agents. Fd Chen Toxic 1894; 22: 49–53
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Garabrant DH, Bernstein L, Peters JM et al. Respiratory and eye irritation from boron oxide and boric acid dusts. J Occup Med 1984; 26: 584–586
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Von Burg R. Boron, boric acid, and boron oxide. L Appl Toxicol 1992; 12: 149–152
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Banner W Jr, Koch M, Capin DM et al. Experimental chelation therapy in chromium, lead, and boron intoxication with N-acetylcysteine and other compounds. Toxicol Appl Pharmacol 1986; 83: 142–147 48.
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Chapter 69 - Bromelain Michael T. Murray ND Joseph E. Pizzorno Jr ND
Proteolytic enzyme of Ananas comosus (family: Bromeliaceae) Synonyms: bromelin, plant protease concentrate
GENERAL DESCRIPTION Bromelains are sulfhydryl proteolytic enzymes obtained from the pineapple plant. Commercial bromelain is usually derived from the stem, which differs from the bromelain derived from the fruit. Commercial bromelain is a mixture of several proteases (including carboxypeptidase) and small amounts of several non-proteolytic enzymes (acid phosphatase, peroxidase and cellulase), polypeptide protease inhibitors, and organically bound calcium. Japan, Taiwan, and Hawaii are the major suppliers of commercial bromelain. [1]
CHEMICAL COMPOSITION Stem bromelain (in its purified form) is a basic glycoprotein with one oligosaccharide moiety and one reactive sulfhydryl group per molecule. It has a molecular weight of 28,000, and its isoelectric point is pH 9.55. It exhibits activity over the pH range of 3–10, with optimal activity being between 5 and 8, depending on the substrate. [1] Fruit bromelain is an acidic protease (isoelectric point pH 4.6). Its status as a glycoprotein is still in dispute and its molecular weight has been reported as 18,000 by one group of investigators and 31,000 by another. [1]
HISTORY Bromelain was introduced as a therapeutic agent in 1957, and since that time over 200 scientific papers on its therapeutic applications have appeared in the medical literature. [2] [3] Many of the early studies were with Ananase (Rorer), an enteric-coated bromelain tablet. Later studies implied that the failure of bromelain in some of these early studies was due to the enteric coating and inadequate dosages.
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PHARMACOLOGY Commercial bromelain has been reported to exert a wide variety of pharmacological effects: [1] [2] [3] • digestion assistance • anti-inflammatory activity • burn debridement • prevention of induced pulmonary edema • smooth muscle relaxation • inhibition of blood platelet aggregation • enhancement of antibiotic absorption • cancer prevention and remission • ulcer prevention • sinusitis relief • appetite inhibition • shortening of labor • enhanced wound healing. Most of these are discussed below. Activating and deactivating factors
Being sulfhydryl proteases, like papain and ficin, both stem and fruit bromelains are inhibited by oxidizing agents, such as hydrogen peroxide, methyl bromide, and iodoacetate, and by certain metallic ions, such as lead, mercury, cadmium, copper, and iron. Bromelain is also inhibited by human serum both in vivo and in vitro. Magnesium and cysteine are activators of commercial bromelain. [1] Activity
The activity of bromelain is expressed in a variety of enzyme units. The use of milk clotting units (mcu) is the officially recognized method in the Food Chemistry Codex (FCC). Different grades of bromelain are available based on mcu. Absorption
Bromelain has been shown to be absorbed via a number of routes, and has been effectively administered orally, parenterally, and through intravenous infusion. [4] [5] [6] Experiments with dogs have shown oral administration to result in peak levels at 10 hours, while detectable levels are still apparent at 48 hours. Intravenous infusion peaks in 50 minutes and remains detectable for 5 hours. [5] There is definite evidence that, in both animals and humans, up to 40% of the absorbed orally administered bromelain can be absorbed intact. [4] [5] [6] Digestive activity
Bromelain is quite effective as a substitute for trypsin or pepsin in cases of pancreatic insufficiency and post-pancreatectomy. [2] Because of bromelain’s wide pH activity, it can act on substrates in the low pH of the stomach as well as in the high pH of the small intestine. The combination of bromelain with pancreatin and ox bile has been demonstrated via double-blind studies to be highly effective in the treatment of patients with pancreatic insufficiency. [7]
Anti-inflammatory activity
Several mechanisms may account for bromelain’s anti-inflammatory effects: • activation of proteolytic activity at sites of inflammation (although bromelain’s proteolytic actions are inhibited by serum factors) • fibrinolysis activity via the plasminogen-plasmin system • depletion of kininogen • inhibition of biosynthesis of pro-inflammatory prostaglandins and induction of prostaglandin E 1 accumulation (which tends to inhibit the release of PMN lysosomal enzymes).[3] [8] [9] The first hypothesis has not been substantiated, while the latter three may be part of the same mechanism of action. After tissue injury the kinin, complement, fibrinolytic, and clotting systems are activated. These systems are closely interrelated via activation of the Hageman factor (XII) and feedback mechanisms. Fibrin’s role in promotion of the inflammatory response is to form a matrix that walls off the area of inflammation, resulting in blockage of blood vessels and inadequate tissue drainage and edema; while the kinin system cascade causes the production of kinins (e.g. bradykinin and kallidin), which increase vascular permeability, causing edema as well as evoking pain. Bromelain activates fibrinolysis by stimulating plasmin production (see Fig. 69.1 ), resulting in depolymerization of fibrin and thereby preventing fibrin-clogged venous stasis and localized edema. [8] [9] [10] [11] Plasmin has been shown to block the mobilization of endogenous arachidonic acid by phospholipases, thereby reducing platelet aggregation and possibly other prostaglandin-mediated phenomena. [12] Bromelain has also been shown to reduce plasma kininogen, resulting in inhibition in the production of kinins. [13] The depletion of kininogen has been demonstrated to significantly reduce edema. These actions, the activation of plasmin and the reduction of kinin levels, are probably the main pharmacological effects of bromelain. Bromelain’s ability to reduce inflammation has been documented in a variety of experimental models and clinical studies. Inhibition of platelet aggregation
Bromelain has been demonstrated to be a potent inhibitor of platelet aggregation, both in vitro and in vivo.
[ 14]
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Figure 69-1 Bromelain’s effects on the fibrin and kinin pathways.
Again, this is probably due to its plasmin-increasing effects. Plasmin is known to inhibit platelet aggregation by blocking the mobilization of arachidonic acid from membrane-bound phospholipid pools. [12] Platelet aggregation is a major factor in atherogenesis (see Ch.133 ). Bromelain supplementation (in conjunction with potassium and magnesium) has been reported to be quite effective in treating angina (see also Table 69.1 ).[15] Antibiotic, mucolytic, and permeability-modifying activities
Bromelain has been shown in clinical studies to increase serum levels of a variety of antibiotics (e.g. amoxycillin, tetracycline, and penicillin) in many different tissues and body fluids (e.g. cerebral spinal fluid, sputum, TABLE 69-1 -- Diseases and conditions in which bromelain has documented clinical efficacy [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [ 31] [32] [33] [34]
• Angina • Maldigestion • Arthritis • Pancreatic insufficiency • Athletic injury • Phytobezoar • Bronchitis • Pneumonia • Burn debridement • Scleroderma • Cellulitis • Sinusitis • Dysmenorrhea • Staphylococcal infection • Ecchymosis • Surgical trauma • Edema • Thrombophlebitis mucus, blood, urine, uterus, salpinx, ovary, gall bladder, appendix, and epithelial tissue). [16] [17] [18] In these studies the researchers concluded that bromelain itself possesses significant effects. Bromelain was as effective as antibiotics in treating a variety of infectious processes, i.e. pneumonia, perirectal abscess, cutaneous staphylococcus infection, pyelonephritis, and bronchitis. [16]
CLINICAL APPLICATIONS As is evident, bromelain has wide-ranging clinical utility. Bromelain is particularly effective in virtually all inflammatory conditions, regardless of etiology, including those resulting from physical trauma, infectious agents, surgical procedures, immunological reactions, and prostaglandin metabolism. Respiratory tract diseases
It appears that bromelain’s mucolytic activity is responsible for its particular effectiveness in respiratory tract diseases. [19] In the treatment of chronic bronchitis, bromelain was shown to have an antitussive effect and to reduce the viscosity of sputum. Spirometric examination of patients before and after treatment indicated
increased vital capacity and FEV 1 , while the residual volume was reduced. These favorable effects were believed to be the results of enhanced resolution of respiratory congestion, due to bromelain’s ability to fluidify and decrease bronchial secretions. Acute sinusitis has also responded to bromelain therapy. Good-to-excellent results were obtained in 87% of bromelain-treated patients, compared with 68% of the placebo group. [20]
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Thrombophlebitis
Numerous investigators have demonstrated that orally administered bromelain has a potent favorable effect on acute thrombophlebitis, deep vein thrombosis, cellulitis, ecchymosis, and edema. [15] [21] [22] [23] In a double-blind study involving 73 patients with acute thrombophlebitis, bromelain, as an adjunct to analgesics, was shown to reduce all the symptoms of inflammation: pain, edema, redness, tenderness, elevated skin temperature, and disability. [21] In this study and others, the common daily dose of bromelain was 60–160 mg of 1,200 mcu bromelain. According to some researchers, doses of 400–800 mg are needed to achieve consistent results in patients with thrombophlebitis; this probably holds true for most other conditions. [15] Surgical procedures and athletic injuries
The effect of orally administered bromelain on the reduction of edema, bruising, healing time, and pain following various surgical procedures has been demonstrated in several clinical studies. [24] [25] [26] [27] Tassman’s studies of patients undergoing oral surgery concluded that, while post-surgical medication alone is effective, a regimen of pre- and post-surgical medication is recommended. [24] [25] In a double-blind study of patients undergoing oral surgery, bromelain was found to be significantly superior to placebo: swelling decreased in 3.8 days with bromelain, compared with 7 days for the placebo; and the duration of pain was reduced to 5.1 days in the bromelain group, compared with 8.1 in the placebo. [25] Similar observations were made in studies of episiotomy cases. Bromelain reduced edema, inflammation, and pain, and pre-operative administration potentiated the effects. [26] Bromelain has been used in a variety of sports-related injuries. A 1960 study involving boxers highlights its effects. [27] Among the 74 boxers receiving bromelain, in 58 all signs of bruising cleared completely within 4 days. In the remainder, complete clearance took 8–10 days. Among the 72 controls, at the end of 4 days only 10 showed bruises completely cleared, the remainder taking 7–14 days. It is important to recognize that, while bromelain has been shown to effectively reduce pain, this probably is the result of a reduction in tissue inflammation and edema, rather than a direct analgesic effect. In a recent open clinical trial, 59 patients with blunt injuries to the musculoskeletal system (e.g. contusions, muscle strains, ligament tears) were given 500 mg of bromelain three times daily, 30 minutes before meals. Swelling, pain at rest and during motion, signs of inflammation, and tenderness to palpation all rapidly improved.[28] Dysmenorrhea
Bromelain and papain have been used successfully in the treatment of dysmenorrhea. [29] Bromelain is believed to be a smooth muscle relaxant, since it decreases the spasms of the contracted cervix in these patients. Failure of the bromelain protease, when used alone (purified by adsorption), to produce this effect was the first indication that the pharmacologically important factor is not the main protease. The muscle-relaxing effects of bromelain on the uterus are believed to be a result of decreasing prostaglandins of the 2-series, e.g. PGF 2 a and PGE2 , while increasing levels of PGE 1 -like compounds.[3]
DOSAGE Unless bromelain is being used as a digestive aid, administration should be on an empty stomach (between meals). The dosage depends largely on the potency of the bromelain preparation. Most currently available bromelain is in the 1,800–2,000 mcu range, with the typical dosage being 125–450 mg t.i.d. between meals.
TOXICITY Very large doses of bromelain (nearly 2.0 g) have been given with no side-effects. [30] It is virtually non-toxic, as no LD 50 exists up to 10 g/kg. Chronic use appears to be well tolerated. Although no significant side-effects have been noted, as with most therapeutic agents, allergic reactions may occur in sensitive individuals or with prolonged occupational exposure. [31] [32] Bromelain can induce IgE-mediated respiratory and gastrointestinal allergic reactions, as well as cross-react with papain, wheat flour, rye flour, grass pollen, and birch pollen. [31] [32] While side-effects are seldom observed, sensitivity manifested by urticaria or skin rash has occurred. There are no reported cases of anaphylactoid reactions. Other possible, but unconfirmed, reactions include nausea, vomiting, diarrhea, metrorrhagia, and menorrhagia. [33]
REFERENCES 1. Jeung
A. Encyclopedia of common natural ingredients used in foods, drugs, and cosmetics. New York, NY: John Wiley. 1980: p 74–76
2. Taussig 3. Felton
SJ, Batkin S. Bromelain, the enzyme complex of pineapple ( Ananas comosus) and its clinical application. An update. J Ethnopharma 1988; 22: 191–203
G. Does kinin released by pineapple stem bromelain stimulate production of prostaglandin E1-like compounds? Hawaii Med J 1977; 36: 39–47
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4. Miller
J, Opher A. The increased proteolytic activity of human blood serum after oral administration of bromelain. Exp Med Surg 1964; 22: 277–280
5. Izaka
K, Yamada M, Kawano T, Suyama T. Gastrointestinal absorption and anti-inflammatory effect of bromelain. Jap J Pharmacol 1972; 22: 519–534
6. Seifert
J, Ganser R, Brendel W. Absorption of a proteolytic enzyme of plant origin from the gastrointestinal tract into the blood and lymph of adult rats. Z Gastroenterol 1979; 17: 1–18
7. Baakrishnan 8. Lotz-Winter 9. Taussig
V, Hareendran A, Nair C. Double-blind cross-over trial of an enzyme preparation in pancreatic steatorrhoea. J Assoc Phys Ind 1981; 29: 207–209
H. On the pharmacology of bromelain. An update with special regard to animal studies on dose-dependent effects. Plant Med 1990; 56: 249–253
S. The mechanism of the physiological action of bromelain. Med Hypothesis 1980; 6: 99–104
Pirotta F, de Giuli-Morghen C. Bromelain – A deeper pharmacological study. Note I – Anti-inflammatory and serum fibrinolytic activity after oral administration in the rat. Drugs Exp Clin Res 1978; 4: 1–20 10.
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de Giuli-Morghen C, Pirotta F. Bromelain – A deeper pharmacological study. Note II – Interaction with some protease inhibitors and rabbit specific antiserum. Drugs Exp Clin Res 1978; 4: 21–37
12.
Schafer A, Adelman B. Plasmin inhibition of platelet function and of arachidonic acid metabolism. J Clin Invest 1985; 75: 456–461
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Katori M, Ikeda K, Harada Y et al. A possible role of prostaglandins and bradykinin as a trigger of exudation in carrageenin-induced rat pleurisy. Agents Actions 1978; 8: 108–112
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Heinicke R, van der Wal L, Yokoyama M. Effect of bromelain ( Ananase) on human platelet aggregation. Experentia 1972; 28: 844–845
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Taussig S, Nieper H. Bromelain: its use in prevention and treatment of cardiovascular disease present status. J Int Assoc Prev Med 1979; 6: 139–151
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Neubauer R. A plant protease for the potentiation of and possible replacement of antibiotics. Exp Med Surg 1961; 19: 143–160
17.
Luerti M, Vignali M. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Exp Clin Res 1978; 4: 45–48
18.
Tinozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of amoxycillin. Drugs Exp Clin Res 1978; 4: 39–44
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Rimoldi R, Ginesu F, Giura R. The use of bromelain in pneumological therapy. Drugs Exp Clin Res 1978; 4: 55–66
20.
Ryan R. A double-blind clinical evaluation of bromelains in the treatment of acute sinusitis. Headache 1967; 7: 13–17
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Seligman B. Oral bromelains as adjuncts in the treatment of acute thrombophlebitis. Angiology 1969; 20: 22–26
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Seligman B. Bromelain. An anti-inflammatory agent. Angiology 1962; 13: 508–510
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Felton G. Fibrinolytic and antithrombotic action of bromelain may eliminate thrombosis in heart patients. Med Hypothesis 1980; 6: 1123–1133
24.
Tassman G, Zafran J, Zayon G. Evaluation of a plant proteolytic enzyme for the control of inflammation and pain. J Dent Med 1964; 19: 73–77
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Tassman G, Zafran J, Zayon G. A double-blind crossover study of a plant proteolytic enzyme in oral surgery. J Dent Med 1965; 20: 51–54
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Howat R, Lewis G. The effect of bromelain therapy on episiotomy wounds – A double blind controlled clinical trial. J Ob Gyn Brit Commonwealth 1972; 79: 951–953
27.
Blonstein J. Control of swelling in boxing injuries. Practitioner 1960; 203: 206
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Masson M. Bromelain in the treatment of blunt injuries to the musculoskeletal system. A case observation by an orthopedic surgeon in private practice. Fortschr Med 1995; 113: 303–306
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Hunter RG, Henry GW, Henicke RM. The action of papain and bromelain on the uterus. Am J Ob Gyn 1957; 73: 867–880
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Gutfreund A, Taussig S, Morris A. Effect of oral bromelain on blood pressure and heart rate of hypertensive patients. Hawaii Med J 1978; 37: 143–146
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Baur X. Studies on the specificity of human IgE-antibodies to the plant proteases papain and bromelain. Clinical Allergy 1979; 9: 451–457
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Baur X, Fruhman G. Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure. Clinical Allergy 1979; 9: 443–450
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Physicians Desk Reference. Ananase (Rorer). Medical Economics Company. 1982: p 1645
34.
Ballard T. Bromelain. J John Bastyr Col Nat Med 1979; 1: 37–41
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Chapter 70 - Camellia sinensis (green tea) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Camellia sinensis (family: Theaceae) Common names: green tea
GENERAL DESCRIPTION Both green tea and black tea are derived from the same plant, the tea plant ( Camellia sinensis). The tea plant originated in China, but is now grown and consumed worldwide. The tea plant is an evergreen shrub or tree that can grow up to a height of 30 feet, but is usually maintained at a height of 2–3 feet by regular pruning. The shrub is heavily branched with young hairy leaves. Parts used are the leaf bud and the two adjacent young leaves together with the stem, broken between the second and third leaves. Older leaves are considered of inferior quality. Green tea vs. black tea
Green tea is produced by lightly steaming the freshly cut leaf, while black tea is produced by allowing the leaves to oxidize. During oxidation, enzymes present in the tea convert many polyphenolic therapeutic substances to compounds with much less activity. With green tea, oxidation is not allowed to take place because the steaming process inactivates these enzymes. Green tea is very high in polyphenols with potent antioxidant and anti-cancer properties. Oolong tea is a partially oxidized tea. Of the nearly 2.5 million tons of dried tea that are produced each year, only 20% are green tea. India and Sri Lanka are the major producers of black tea. Green tea is produced and consumed primarily in China, Japan, and a few countries in North Africa and the Middle East.
CHEMICAL COMPOSITION The chemical composition of green tea varies with climate, season, horticultural practices, and age of the leaf (position of the leaf on the harvested shoot). The
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major components of interest are the polyphenols. [1] [2] The major polyphenols in green tea are flavonoids, e.g.: • catechin • epicatechin • epicatechin gallate • epigallocatechin gallate • proanthocyanidins. Epigallocatechin gallate is viewed as the most significant active component. The leaf bud and the first leaves are richest in epigallocatechin gallate. The usual concentration of total polyphenols in dried green tea leaf is around 8–12%. Other compounds of interest in dried green tea leaf include: • caffeine (3.5%) • an unusual amino acid known as theanine (one-half of the total amino acid content which is usually 4%) • lignin (6.5%) • organic acids (1.5%) • protein (15%) • chlorophyll (0.5%). One cup of green tea usually contains about 300–400 mg of polyphenols and between 50 and 100 mg of caffeine. Commercial preparations are available that have been decaffeinated and concentrated for polyphenols to between 60 and 80% total polyphenols.
PHARMACOLOGY Most of the epidemiological and experimental studies on tea have focused on the cancer-causing and cancer-protective aspects. Green tea polyphenols are potent antioxidant compounds which have demonstrated greater antioxidant protection than vitamin C and E in experimental studies. [3] In addition to exerting antioxidant activity on its own, green tea may increase the activity of antioxidant enzymes. In mice, oral feeding of a polyphenolic fraction isolated from green tea in drinking water for 30 days resulted in significantly increased activities of antioxidant and detoxifying enzymes (glutathione peroxidase, glutathione reductase, glutathione- S-transferase, catalase, and quinone reductase) in the small intestine, liver, and lungs, and in small bowel and liver. [4] With regard to cancer, a number of in vitro and experimental models of cancer have shown that green tea polyphenols may offer significant protection. [5] [6] [7] [8] Specifically, green tea polyphenols inhibit cancer by blocking the formation of cancer-causing compounds like nitrosamines, suppressing the activation of carcinogens, and increasing detoxification or trapping of cancer-causing agents. Numerous studies have shown that green tea (including green tea polyphenols and extracts) exert significant inhibitory effects on the formation of nitrosamines in various animal and human models. For example, when human volunteers ingest green tea along with 300 mg sodium nitrate and 300 mg proline, nitrosoproline formation is strongly inhibited. [9]
CLINICAL APPLICATION The primary clinical application for green tea is in the prevention of cancer. Epidemiological studies have demonstrated that green tea consumption may be one of the major reasons why the rate of cancer is so low in Japan. In contrast, however, black tea consumption appears associated with a substantial increase in the risk of
several forms of cancer. Green tea also appears to be of value in several chronic diseases, especially those of the heart and liver. Cancer Green tea
The forms of cancer which appear to be best prevented by green tea are those of the gastrointestinal tract, including cancers of the stomach, small intestine, pancreas, and colon; the lung; and estrogen-related cancers, including most breast cancers. [10] A study in Shanghai, China, found a strong inverse association between green tea consumption and various cancers. [11] For men, compared with non-regular green tea drinkers, the group with the highest green tea consumption had an 18% reduced risk for colon cancer; 28% for rectal cancer; and 37% for pancreatic cancer. In women, the highest group of green tea consumers had a reduced risk of 33% for colon, 43% for rectal, and 47% for pancreatic cancer. In preventing breast cancer, in vitro studies have shown that green tea extracts have inhibitory effects on the growth of mammary cancer cell lines. [8] The main anti-cancer action is inhibiting the interaction of estrogen with its receptors. Polyphenol compounds in green tea extracts block the interaction of tumor promoters, hormones and growth factors with their receptors – a kind of sealing-off effect. The sealing-off effect would account for the reversible growth arrest noted in the in vitro studies. In animal studies, green tea has been shown to very effectively inhibit the lung carcinogenesis induced by injections of asbestos and benzo( a)pyrene. Rats consuming water with 2% green tea experienced a cancer rate of only 16% compared with 46% for those consuming water without green tea extract. [12] Black tea
In contrast to green tea’s protective effects, population studies seem to indicate that black tea consumption
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may increase risk for certain cancers (e.g. cancer of the rectum, gall bladder, and endometrium). [12] [13] For example, in one study, the relationship between black tea consumption and cancer risk was analyzed using data from an integrated series of case-control studies conducted in northern Italy between 1983 and 1990. [11] The data set included 119 biopsy-confirmed cancers of the oral cavity and throat, 294 of the esophagus, 564 of the stomach, 673 of the colon, 406 of the rectum, 258 of the liver, 41 of the gall bladder, 303 of the pancreas, 149 of the larynx, 2,860 of the breast, 567 of the endometrium, 742 of the ovary, 107 of the prostate, 365 of the bladder, 147 of the kidney, 120 of the thyroid, and a total of 6,147 controls admitted to hospital for acute non-cancerous conditions. The risk of developing cancer due to tea consumption was derived after allowance for age, sex, area of residence, education, smoking, and coffee consumption. Results indicated an increased risk with tea consumption for cancers of the rectum, gall bladder, and endometrium. There was no association with cancers of the oral cavity, esophagus, stomach, bladder, kidney, prostate, or any other site considered. In another study, men of Japanese ancestry were clinically examined, beginning during the period 1965–1968. [12] For 7,833 of these men, data on black tea consumption habits were recorded. Since 1965, newly diagnosed cancer incidence cases have been identified: 152 colon, 151 lung, 149 prostate, 136 stomach, 76 rectum, 57 bladder, 30 pancreas, 25 liver, 12 kidney and 163 at other (miscellaneous) sites. Compared with “almost-never” drinkers, men who habitually drink black tea more than once a day had a four times greater chance of developing rectal cancer. [14] Cardiovascular and liver disease A prospective epidemiological study begun in 1986 by researchers in Japan evaluated the relationship between diet and chronic disease in Japanese men aged 40 and older. [15] As daily green tea intake increased from less than three, to four to nine, to greater than 10 cups/day, significant increases in serum HDL and decreases in LDL lipoproteins were found. In addition, green tea consumption was found to significantly improve liver profiles, with aspartate aminotransferase and alanine aminotransferase levels decreasing significantly with increasing green tea consumption.
DOSAGE The normal amount of green tea consumed by Japanese and other green tea drinking cultures is about three cups daily or about 3 g of soluble components providing roughly 240–320 mg of polyphenols. For a green tea extract standardized for 80% total polyphenol and 55% epigallocatechin gallate content, this would mean a daily dose of 300–400 mg. Note. When selecting commercial products, it is important to look for the level of epigallocatechin gallate, as well as total polyphenol content.
TOXICITY Green tea is not associated with any significant side-effects or toxicity. As with any caffeine-containing beverage, overconsumption may produce a stimulant effect (nervousness, anxiety, insomnia, irritability, etc.). TABLE 70-1 -- World tea production by type Type
Dry weight (×1000 tons)
Black
1,940
Green
515
Oolong 60 Total
2,515
REFERENCES 1. Graham 2. Min 3. Ho
HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med 1992; 21: 334–350
Z, Peigen X. Quantitative analysis of the active constituents in green tea. Phytother Res 1991; 5: 239–240
C, Chen Q, Shi H et al. Antioxidative effect of polyphenol extract prepared from various Chinese teas. Prev Med 1992; 21: 520–525
4. Khan
SG, Katiyar SK, Agarwal R et al. Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hairless mice. Possible role in cancer chemoprevention. Cancer Res 1992; 52: 4050–4052 5. Katiyar
SK, Agarwal R and Mukhtar H. Green tea in chemoprevention of cancer. Compr Ther 1992; 18: 3–8
6. Mukhtar 7. Wang
H, Wang ZY, Katiyar SK et al. Tea components. Antimutagenic and anticarcinogenic effects. Prevent Med 1992; 21: 351–360
ZY, Khan WA, Bickers DR et al. Protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice by green tea polyphenols. Carcinogenesis 1989; 10: 411–415
8. Komori 9. Stich
A, Yatsumi J, Okabe S et al. Anticarcinogenic activity of green tea polyphenols. Jpn J Clin Oncol 1993; 23: 186–190
HF. Teas and tea components as inhibitors of carcinogen formation in model systems and man. Prevent Med 1992; 21: 377–384
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Yang CS and Wang ZY. Tea and cancer. J Natl Cancer Inst 1993; 85: 1038–1049
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Ji HT, Chow WH, Hsing A et al. Green tea consumption and the risk of pancreatic and colorectal cancer. Int J Can 1997; 7: 255–258
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Luo SQ, Liu XZ, Wang CJ. Inhibitory effect of green tea extract on the carcinogenesis induced by asbestos plus benzo(a)pyrene in rat. Biomed Environ Sci 1995; 8: 54–58
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La Vecchia C, Negri E, Franceschi S et al. Tea consumption and cancer risk. Nutr Cancer 1992; 17: 27–31
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Heilbrun LK, Nomura A, Stemmermann GN. Black tea consumption and cancer risk: a prospective study. Br J Cancer 1986; 54: 677–683
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Imai K, Nakachi K. Cross sectional study of effects of drinking green tea on cardiovascular and liver disease. Br Med J 1995; 310: 693–696
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Chapter 71 - Capsicum frutescens (cayenne pepper) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Capsicum frutescens (family: Solanacea) Common names: cayenne pepper, capsicum, chili pepper, red pepper, American pepper
GENERAL DESCRIPTION Cayenne pepper (also known as chili or red hot pepper) is the fruit of Capsicum annuum, a shrubby, tropical plant which can grow to a height of up to 3 feet. The fruit is technically a berry. Paprika is a milder and sweeter tasting fruit produced from a different variety of Capsicum. Although cayenne pepper is native to tropical America, it is now cultivated in tropical locations throughout the world and has found its way into the cuisine of many parts of the world, particularly south-east Asia, China, southern Italy, and Mexico.
CHEMICAL COMPOSITION The most important constituents of cayenne pepper are the pungent compounds, with capsaicin being the most prominent (see Fig. 71.1 ). Typically, cayenne pepper contains about 1.5% capsaicin and related principles. Other active constituents present include carotenoids, vitamins A and C, and volatile oils.
HISTORY AND FOLK USE The folk use of cayenne pepper is quite extensive. It has been used for: • asthma • fever 630
• sore throats and other respiratory tract infections • digestive disturbances • poultices • cancers.
Figure 71-1 Capsaicin.
It was also used as a counter-irritant in the topical treatment of arthritis and neuralgia.
PHARMACOLOGY The pharmacology of cayenne pepper centers around its capsaicin content. When topically applied to the skin or mucous membranes, capsaicin is known to stimulate and then block small-diameter pain fibers by depleting them of the neurotransmitter substance P. Substance P is thought to be the principal chemomediator of pain impulses from the periphery. In addition, substance P has been shown to activate inflammatory mediators into joint tissues in osteoarthritis and rheumatoid arthritis. [1] When taken internally, cayenne pepper exerts a number of beneficial effects on the cardiovascular system. In addition to possessing several antioxidant compounds, studies have shown that cayenne pepper reduces the likelihood of developing atherosclerosis by reducing blood cholesterol and triglyceride levels, and platelet aggregation as well as increasing fibrinolytic activity [2] [3] [4] (for the significance of these effects see Ch. 133 ). Cultures consuming large amounts of cayenne pepper have a much lower rate of cardiovascular diseases.
CLINICAL APPLICATIONS Cayenne pepper should be recommended as a food for its beneficial antioxidant and cardiovascular effects. Although people with active peptic ulcer may be bothered by “spicy” foods containing cayenne pepper, spicy foods in normal individuals do not cause ulcers. In fact, cayenne pepper exerts several beneficial effects on gastrointestinal function, including acting as a digestant and carminative. [5] Interestingly, capsaicin, although hot to the taste, has actually been shown to lower body temperature by stimulating the cooling center of the hypothalamus. ingestion of cayenne peppers by cultures native to the tropics appears to offer a way for these people to deal with high temperatures.
[6]
The
The modern clinical use of cayenne pepper has focused on the use of topical capsaicin-containing preparations. Commercial ointments containing 0.025 or 0.075% capsaicin are available over the counter. These preparations may offer significant benefit in a number of conditions, including the pain associated with pain disorders, diabetic neuropathy, cluster headache, osteoarthritis, and rheumatoid arthritis. In addition, topically applied capsaicin may be useful in psoriasis. Post-herpetic neuralgia
The first studies and approved use for topically applied capsaicin was in relieving post-herpetic neuralgia. Numerous studies now document this FDA approved application. For example, in one study 39 patients with chronic post-herpetic neuralgia (average duration 24 months) were treated with 0.025% capsaicin cream for 8 weeks. During therapy, the patients rated their pain. Nineteen patients (48.7%) substantially improved after the 8 week trial; five (12.8%) discontinued therapy due to side-effects such as intolerable capsaicin-induced burning sensations (four) or mastitis (one); and 15 (38.5%) reported no benefit. The decrease in pain ratings was significant after 2 weeks of continuous application. Of the responders, 72.2% were still improved 10–12 months after the study; with most continuing to apply the cream regularly. In general, the results of this study are consistent with other studies, i.e. about 50% of people with post-herpetic neuralgia respond to topically applied capsaicin (0.025%).[7] [8] [9] [10] [11] Although this may not be a great response, it is better than the 10% response noted in the placebo group. Higher concentration (0.075 vs.
0.025%) may produce better results (as high as 75% response). [12] Trigeminal neuralgia
Topically applied capsaicin may be effective in reducing the pain of trigeminal neuralgia. [13] In one study, 12 patients were followed up for 1 year after the topical application over the painful area of capsaicin three times a day for several days. Six patients had complete and four patients had partial relief of pain; the remaining two patients had no relief of pain. Of the 10 patients who were responsive to therapy, four had relapses of pain within 95–149 days. There were no relapses following the second therapy for the remainder of the year. These results are quite promising for a condition that usually does not respond to any therapy short of surgery. Post-mastectomy pain
Topically applied capsaicin may help in the relief of pain after breast reconstruction or mastectomy. In one double-blind study, 23 patients with post-mastectomy pain syndrome (PMPS) applied either capsaicin (0.075%) or vehicle-only cream four times daily for 4–6 weeks. [14] There was a significant difference in jabbing pain, in category pain severity scales, and in overall pain relief scales in favor of capsaicin. Five of 13 patients on capsaicin were categorized as good-to-excellent responses, with eight (62%) having 50% or greater improvement. Only one of 10 cases had a good response to vehicle, with three rated as 50% or better.
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In another study, 14 patients with post-mastectomy pain had significant pain relief following application of 0.025% capsaicin cream four times daily for 4–6 weeks. Unpleasant or painful sensations to light touch or pressure in the painful area (hyperaesthesia, allodynia) were also improved.
[15]
Mouth pain due to chemotherapy or radiation
In a study conducted at the Yale Pain Management Center, capsaicin was shown to dramatically reduce the pain from mouth sores as a result of chemotherapy or radiation treatment. [16] The interesting feature in this study was the vehicle used to deliver the capsaicin – taffy. The researchers chose taffy because it could be held in the mouth long enough to desensitize the neurons, its sugar decreased the initial burning sensation, and its soft edges would not aggravate sore mouths like a hard candy. All 11 patients in the Yale study said their pain decreased – in two cases stopping entirely – after eating the capsaicin-laced candy. Diabetic neuropathy
Topically applied capsaicin has been shown to be of considerable benefit in relieving the pain of diabetic neuropathy in numerous double-blind studies. [17] [18] [19] [20] [21] [22] In one large double-blind 8 week study, investigators at 12 sites enrolled 277 men and women with painful diabetic neuropathy of the hands and feet; 69.5% of the group applying the capsaicin cream (0.075%) showed improvement compared with 53.4% in those applying only the vehicle cream. In another study, 40 patients applied either 0.075% capsaicin cream or placebo to their affected extremities daily. After 4 weeks, 76% of treated patients had some pain relief, compared with 50% of placebo patients. In addition, those responding to capsaicin said their pain was cut in half, while those on placebo averaged between 15 and 20% relief. Cluster headaches
Several studies have found that intranasal application of capsaicin ointment by a physician may relieve cluster headaches. In one double-blind study, patients in acute cluster were randomized to receive either capsaicin or placebo in the nostril for 7 days. [23] Patients recorded the severity of each headache for 15 days. Headaches on days 8–15 of the study were significantly less severe in the capsaicin group versus the placebo group. There was also a significant decrease in headache severity in the capsaicin group on days 8–15 compared with days 1–7, but not in the placebo group. Episodic patients appeared to benefit more than chronic patients. Arthritis
Topically applied capsaicin may be effective in relieving the pain of osteoarthritis and rheumatoid arthritis. While one study showed it to be more effective in osteoarthritis, another study showed just the opposite. In the double-blind study showing more effect in osteoarthritis, seven patients with rheumatoid arthritis and 14 patients with osteoarthritis who had painful involvement of the hands applied either capsaicin 0.075% or vehicle-only cream to the hands four times daily. Capsaicin reduced tenderness and pain associated with osteoarthritis, but not rheumatoid arhtritis. [24] In the study showing greater benefit for rheumatoid arthritis, 70 patients with osteoarthritis and 31 with rheumatoid arthritis received capsaicin or placebo for 4 weeks.[25] The patients were instructed to apply 0.025% capsaicin cream or its vehicle (placebo) to painful knees four times daily. Significantly more relief of pain was reported by the capsaicin-treated patients than the placebo patients throughout the study; after 4 weeks of capsaicin treatment, rheumatoid and osteoarthritis patients demonstrated mean reductions in pain of 57 and 33%, respectively. These reductions in pain were statistically significant compared with those reported with placebo. According to overall evaluations, 80% of the capsaicin-treated patients experienced a reduction in pain after 2 weeks of treatment. Psoriasis
Excessive substance P levels in the skin have been linked to psoriasis. This finding prompted researchers to study the effects of topically applied capsaicin. In one double-blind study, 44 patients with symmetrically distributed psoriasis lesions applied topical capsaicin to one side of their body and a placebo to the other side. [26] After 3–6 weeks, significantly greater reductions in scaling and redness were observed on the capsaicin side. Burning, stinging, itching, and skin redness were noted by nearly half of the patients initially, but these diminished or vanished upon continued application. In a more recent study, 197 patients applied capsaicin 0.025% cream or placebo cream four times a day for 6 weeks. [27] Efficacy was based on a physician’s evaluation and a combined psoriasis severity score including scaling, thickness, erythema, and pruritus. Capsaicin-treated patients demonstrated significantly greater improvement in physician’s evaluation and in pruritus relief, as well as a significantly greater reduction in combined psoriasis severity.
DOSAGE Cayenne pepper can be used liberally in the diet. Creams containing 0.025 or 0.075% capsaicin can be applied to affected areas up to four times daily.
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TOXICITY Cayenne pepper is generally recognized as safe (GRAS) in the US. Topically applied capsaicin may produce a local burning sensation; however, this effect will go away with time and rarely is severe enough to mean that use of the cream cannot be continued. This was the only adverse effect noted.
REFERENCES 1. Cordell
GA, Araujo OE. Capsaicin: identification, nomenclature, and pharmacotherapy. Ann Pharmacother 1993; 27: 330–336
2. Kawada 3. Wang
T, Hagihara K, Iwai K. Effects of capsaicin on lipid metabolism fed a high fat diet. J Nutr 1986; 116: 1272–1278
JP, Hsu MF, Teng CM. Antiplatelet effect of capsaicin. Thrombosis Res 1984; 36: 497–507
4. Visudhiphan 5. Horowitz 6. Dib
S, Poolsuppasit S, Piboonnukarintr et al. The relationship between high fibrinolytic activity and daily capsicum ingestion in Thais. Am J Clin Nutr 1982; 35: 1452–1458
M, Wishart J, Maddox A et al. The effect of chilli on gastrointestinal transit. J Gastroenterol Hepatol 1992; 7: 52–56
B. Effects of intrathecal capsaicin on autonomic and behavioral heat loss responses in the rat. Pharmacol Biochem Behavior 1987; 28: 65–70
7. Peikert
A, Hentrich M, Ochs G. Topical 0.025% capsaicin in chronic post-herpetic neuralgia. Efficacy, predictors of response and long-term course. J Neurol 1991; 238: 452–456
8. Bjerring
P, Arendt-Nielsen L, Soderberg U. Argon laser induced cutaneous sensory and pain thresholds in post-herpetic neuralgia. Quantitative modulation by topical capsaicin. Acta Derm Venereol (Stockh) 1990; 70: 121–125 9. Bernstein
JE, Korman NJ, Bickers DR et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989; 21: 265–270
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Watson CP, Evans RJ, Watt VR. Post-herpetic neuralgia and topical capsaicin. Pain 1988; 33: 333–340
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Watson CP, Evans RJ, Watt VR et al. Post-herpetic neuralgia. 208 cases. Pain 1988; 35: 289–297
12.
Bernstein JE, Bickers DR, Dahl MV et al. Treatment of chronic postherpetic neuralgia with topical capsaicin. A preliminary study. J Am Acad Dermatol 1987; 17: 93–96
13.
Fusco BM, Alessandri M. Analgesic effect of capsaicin in idiopathic trigeminal neuralgia. Anesth Analg 1992; 74: 375–377
14.
Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain 1992; 51: 375–379
15.
Watson CP, Evans RJ, Watt VR et al. The post-mastectomy pain syndrome and the effect of topical capsaicin. Pain 1989; 38: 177–186
16.
Nelson C. Heal the burn. Pepper and lasers in cancer pain therapy. J Nat Canc Inst 1994; 86: 1381
17.
The Capsaicin Study Group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care 1992; 15: 159–165
18.
David Chad, associate professor of neurology and pathology, Univ. of Massachusetts at Worcester – reported in Med World News 1989; February 27
19.
Tandan R, Lewis GA, Krusinski PB et al. Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care 1992; 15: 8–14
20.
Tandan R, Lewis GA, Badger GB et al. Topical capsaicin in painful diabetic neuropathy. Effect on sensory function. Diabetes Care 1992; 15: 15–18
21.
Basha KM, Whitehouse FW. Capsaicin: a therapeutic option for painful diabetic neuropathy. Henry Ford Hosp Med J 1991; 39: 138–140
22.
Pfeifer MA, Ross DR, Schrage JP et al. A highly successful and novel model for treatment of chronic painful diabetic peripheral neuropathy. Diabetes Care 1993; 16: 1103–1115
23.
Marks DR, Rapoport A, Padla D et al. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993; 13: 114–116
24.
McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol 1992; 19: 604–607
25.
Deal CL, Schnitzer TJ, Lipstein E et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther 1991; 13: 383–395
26.
Bernstein JE, Parish LC, Rapaport M et al. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986; 15: 504–507
27.
Ellis CN, Berberian B, Sulica VI et al. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol 1993; 29: 438–442
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Chapter 72 - Carnitine Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION Carnitine is an essential nutrient for the transport of long-chain fatty acids into the mitochondrial matrix. Carnitine (beta-hydroxy/gamma-butyrobetaine) was originally isolated from meat extracts in 1905 and its exact chemical structure was determined in 1932 (see Fig. 72.1 ). However, despite extensive physiological and pharmacological studies in the 1930s, no physiological role for carnitine could be determined. [1] [2] [3] Carnitine’s role in human physiology remained a mystery until nearly 50 years after its discovery. The compound was virtually forgotten until Carter et al [4] created new interest in carnitine in 1952 when they established it as a growth factor for the meal worm Tenebrio molitor (hence carnitine’s other name vitamin BT). When other species of organisms were also shown to be dependent on carnitine, researchers began to re-examine its role in humans. Researchers soon found that carnitine was essential in the oxidation of lipids. [1] [2] [3] When the first carnitine-deficient human subjects were described in 1973, it stimulated greater investigation. [5] It had always been assumed that an individual could synthesize adequate amounts of carnitine, ingest adequate amounts of dietary carnitine, or meet needs by a combination of both. The discovery that some individuals required supplemental carnitine to maintain normal energy metabolism has resulted in the need to consider carnitine as a vitamin or essential. [6] Since carnitine can be synthesized (as described below)
Figure 72-1 L-Carnitine.
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from the essential amino acid lysine, many nutritionists and researchers have argued that it should not be considered a vitamin. Others argue that if niacin, which can be synthesized from the essential amino acid tryptophan, can be labelled a vitamin then so should carnitine.
BIOSYNTHESIS Carnitine is synthesized in humans from lysine with the aid of another essential amino acid, methionine. In non-mammalians, carnitine synthesis begins with stepwise methylation of free lysine by S-adenosyl-methionine to produce trimethyllysine. In mammals, however, protein bound trimethyllysine, rather than free lysine, appears to be the major precursor for carnitine synthesis. [1] [2] [3] Trimethyllysine is then converted through a series of enzymatic reactions to butyrobetaine. This can occur in the liver, kidney, brain, heart, and skeletal muscle. However, the conversion of butyrobetaine to carnitine can only occur in the liver, kidney, and brain, as the enzyme required, butyrobetaine hydroxylase, is only present in these tissues. [1] [2] [3] The synthesis of carnitine is largely controlled by the activity of butyrobetaine hydroxylase. This enzyme appears to be age-dependent. In infancy, the activity of butyrobetaine hydroxylase has been shown to be only 12% of the normal adult mean. By 2.5 years, the activity is 30% of the adult mean, and by 15 years the level is within the standard deviation of the adult mean. [1] [2] [3] This data would seem to indicate the importance of preformed-carnitine in breast milk. As is apparent from Figure 72.2 , two essential amino acids (lysine and methionine), three vitamins (ascorbate, niacin, and vitamin B 6 ), and a metal ion (reduced iron) are required for the synthesis of carnitine. Obviously, a deficiency of any one of these nutrients would result in significantly impaired carnitine synthesis. [1] [2] [3]
METABOLISM Transportation into tissues
The heart and skeletal muscles, as well as many other tissues, depend primarily on fatty acid oxidation as a source of energy. Since they cannot synthesize carnitine, its transport into these tissues is of critical importance. Specific carnitine binding transport proteins have been identified for several tissues, e.g. cardiac muscle, skeletal muscle, epididymis, liver, and kidney. [1] [3] The transport proteins facilitate the transfer of carnitine from the serum into the cells via carrier-mediated transport mechanisms. This active transport mechanism allows the tissues to concentrate carnitine at levels 10 times greater than those found in the plasma.
Figure 72-2 Biosynthesis of carnitine. Excretion and degradation
Urinary excretion of unchanged carnitine is the major route of elimination of carnitine. As the tubular reabsorption of carnitine by the kidneys is extremely efficient, the daily turnover of carnitine is estimated to be only 4–6% of the total body pool of the healthy individual. [1] [2] [3] Factors which increase carnitine excretion and degradation are discussed below under causes of carnitine deficiency.
PHYSIOLOGICAL FUNCTIONS Carnitine’s basic function is in the transport of longchain fatty acids into the mitochondrial matrix and the facilitation of beta-oxidation. [1] [2] [3] As acyl-CoA formed in the endoplasmic reticulum or outer mitochondrial membrane cannot penetrate the inner mitochondrial membrane to the site of fatty acid beta-oxidation, the acyl group must be transferred from CoA to carnitine. The acyl-carnitine molecule then transports the fatty acid molecule to the mitochondrial surface of the inner mitochondrial membrane and releases the fatty acid into the matrix where beta-oxidation occurs. This process is summarized in Figure 72.3 . Carnitine has several other physiological functions, including oxidation of the ketoacid analogues of the branched chain amino acids valine, leucine, and isoleucine. [2] [3] This function is extremely important during fasting, starvation, and exercise.
[1]
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Figure 72-3 Role of carnitine in the transport of long-chain fatty acids through the inner mitochondrial membrane.
Carnitine concentrations are extremely high in the epididymis and spermatozoa, suggesting a role for carnitine in male reproductive function. [1] [2] [3] The epididymis derives the majority of its energy requirements from lipids, as do the spermatozoa, during transport through the epididymis. After ejaculation, spermatocytes depend on glycolysis of glucose and fructose and on oxidation of lactate and pyruvate. Carnitine (in the form of acetylcarnitine which is derived from pyruvate) serves as a readily available substrate. The motility of ejaculated sperm correlates positively with acetylcarnitine content. [1] [3]
DEFICIENCY Carnitine deficiency may arise from several causes, as listed in Table 72.1 . Carnitine deficiency states have been classified into two major groups: • systemic carnitine deficiency • myopathic deficiency. Diagnosis of systemic carnitine deficiency can be made using serum or 24 hour urine samples. Total, free, and esterified carnitine levels should be determined. In myopathic carnitine deficiency, diagnosis requires skeletal muscle biopsy. [7] To date, no patients with primary systemic carnitine deficiency have been identified. The systemic deficiency has always been secondary to some other factor rather than a defect in carnitine synthesis. [1] [2] [3] [7] [8] The consequences of systemic carnitine deficiency are impaired lipid metabolism and lipid accumulation in the skeletal muscles, myocardium, and liver. Progressive muscle weakness with lipid storage myopathy is found in all patients. [1] [2] [3] [7] In adults, auxiliary non-mitochondrial oxidation mechanisms are apparently stimulated, resulting in some degree of adaptation. This adaptation occurs in starvation, diabetes, high fat diets, and other causes of secondary carnitine deficiency. Systemic carnitine deficiencies usually respond dramatically to orally administered supplemental L-carnitine. [7] [8] Children are apparently unable to adapt to low carnitine levels as well as adults. [7] Several cases of carnitine deficiency in children, presenting a clinical picture resembling Reye’s syndrome (acute encephalopathy associated with altered liver function due to lipid accumulation), have been reported. [8] [9] [10] The clinical presentation of secondary carnitine deficiency in children includes hypotonia, failure to thrive, recurrent infections, encephalopathy, nonketotic hypoglycemia, and cardiomyopathy. [7] Several fatal cases of systemic carnitine deficiency have been reported. [8] [11] In primary myopathic carnitine deficiency, there is an inborn error of carnitine metabolism that is limited to skeletal muscle. [7] [8] The defect appears to be in the transport of carnitine into the skeletal muscle as serum carnitine, and the carnitine levels in other tissues are normal. Severe lipid-storage myopathy is the result. Supplemental carnitine is generally of no value in myopathic carnitine deficiency. Rather, improvements have been noted using diets high in medium-chain triglycerides and low in long-chain triglycerides. [7]
CARNITINE AS A NUTRIENT Carnitine in the infant diet
It is well known that oxidation of long-chain fatty acids, which requires carnitine, is critical to the survival and TABLE 72-1 -- Causes of carnitine deficiency • Dietary deficiency of the precursor amino acids lysine and methionine • Deficiency of any cofactor (such as iron, ascorbic acid, pyridoxine and niacin) required by the enzymes of the lysine to carnitine pathway • Genetic defect of carnitine biosynthesis • Defective intestinal absorption of carnitine • Liver or kidney dysfunction which impairs carnitine synthesis • Increased metabolic losses of carnitine due to catabolism, impaired tubular resorption, or genetic defect • Defective transport of carnitine from tissues of synthesis to tissues where it is maximally utilized • Increased carnitine requirement due to a high fat diet, drugs (e.g. valproic acid), metabolic stress, or disease
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normal development of the newborn.[3] Carnitine concentrations in fetal and umbilical cord blood are higher than in maternal blood, suggesting the placenta may actively transport carnitine to the fetus since carnitine synthesis is not fully developed. [3] The initial carnitine concentration in the newborn is dependent upon maternal carnitine concentration. Supplementation of carnitine during pregnancy may be needed to ensure adequate tissue concentrations in the fetus as well as the mother. Serum carnitine levels are
typically lower in pregnant women than non-pregnant women, presumably due to increased excretion. [12] [13] The newborn infant is almost entirely dependent on external sources of carnitine. [3] Breast-fed infants have the best chance of achieving optimal carnitine concentrations. The bioavailability of carnitine from breast milk is significantly greater than that in cow’s milk-based formulas, [14] and soy-based infant formulas contain no detectable carnitine. [3] Formula feeding may necessitate supplemental carnitine to achieve normal carnitine concentrations in these infants. Carnitine administration to preterm infants has potentiated weight gain and growth. [15] In preterm infants, serum values of carnitine decrease dramatically due to limited storage capacity coupled with a decreased ability to synthesize carnitine. Administration of L-carnitine to preterm infants is thought to be very important. Dietary carnitine content
Analysis of several hundred foods for carnitine content indicates that meat and dairy products are the major dietary sources of carnitine. [3] In general, the redder the meat, the higher the carnitine content. Cereals, fruits, and vegetables contain little or no carnitine. Preliminary studies indicate that the daily diet contains 5–100 mg of carnitine.[3]
CLINICAL APPLICATIONS Many disease states, in addition to classical as well as secondary carnitine deficiency, may benefit from carnitine administration. There is good evidence to support the assertion that supplemental carnitine may benefit the conditions listed in Table 72.2 and discussed below. Carnitine is available in several different forms. Always be sure that the form being used is L-carnitine alone or bound to either acetic or propionic acid. Never use the D form of carnitine (discussed below under safety issues). As to which form is best, it really depends upon the objective. For Alzheimer’s disease and brain effects, it appears that L-acetylcarnitine (LAC) may provide the greatest benefit. For angina, L-propionylcarnitine (LPC) may be the best choice because the myocardium appears to prefer it to L-acetylcarnitine followed by L-carnitine TABLE 72-2 -- Conditions which may benefit from carnitine supplementation • Cardiovascular diseases • Angina pectoris • Acute myocardial infarction • Myocardial necrosis • Arrhythmias and cardiotoxicity induced by drugs • Familial endocardial fibroelastosis • Cardiac myopathy • Idiopathic mitral valve prolapse • Elevated cholesterol levels • Elevated triglyceride levels • Enhancing physical performance • Alzheimer’s disease, senile depression, and age-related memory defects • Kidney disease and hemodialysis • Diabetes • Liver diseases • Alcohol-induced fatty liver disease • Liver cirrhosis • Muscular dystrophies • Low sperm counts and decreased sperm motility • Chronic obstructive pulmonary disease • AIDS • Inborn errors of amino acid metabolism • Organic acidurias • Glutaric aciduria • Isovaleric acidemia • Propionicacidemia • Methylmalonic aciduria • Toxicity from various drugs (LC). [16] [17] L-Carnitine is, however, the most widely available, least expensive, and best studied form of carnitine. Cardiovascular disease
Normal heart function is critically dependent on adequate concentrations of carnitine. A deficiency of carnitine in the heart would be similar to trying to run an automobile without a fuel pump. There may be plenty of fuel, but there is no way to get it to the engine. While the normal heart stores more carnitine than it needs, if the heart does not have a good supply of oxygen, carnitine levels quickly decrease. This lack of oxygen leads to decreased energy production in the heart and increased risk for angina and heart disease. Carnitine is useful in angina due to its ability to improve oxygen utilization and energy metabolism by the myocardium. As a result of improving fatty acid utilization and energy production, carnitine also prevents the production of toxic fatty acid metabolites. [18] These compounds are extremely damaging as they disrupt cellular membranes. Changes in the properties of cell membranes throughout the heart are thought to contribute to impaired contraction of the heart muscle and increased susceptibility to irregular beats, and eventual death of heart tissue. Supplementing the diet with carnitine increases heart carnitine levels and has been shown to prevent the production of fatty acid metabolites which can damage the heart. In addition to angina, all of these
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effects make carnitine beneficial in recovery from a heart attack, arrhythmias, and congestive heart failure.
[19]
Carnitine also exerts a beneficial effect on blood lipids by lowering triglycerides and total cholesterol levels while raising HDL-cholesterol. After 4 months of therapy with L-carnitine in patients with elevated blood lipids, typical changes observed are a 20% reduction for total cholesterol, a 28% decrease in triglycerides, and a 12%
increase in HDL levels. [20] [21] Due to the higher cost of carnitine compared with other natural agents (e.g. inositol hexaniacinate, garlic, and gugulipid), its use should be reserved for those cases unresponsive to these more cost-effective measures. Carnitine has also been shown to be of benefit in the treatment of intermittent claudication, which is a condition like angina but instead of the pain occurring in the heart it occurs usually in the calf muscle. Like angina, the pain is described as a cramp or tightness. The cause of the pain is reduced oxygen delivery along with an increase in the production of toxic metabolites and cellular free radicals. Its benefits in peripheral vascular disease are the result of improved energy production during ischemia rather than any effect on blood flow. Nonetheless, good results have been obtained in intermittent claudication and other peripheral vascular diseases (discussed below). Angina
Numerous clinical trials have demonstrated that carnitine improves angina and heart disease (note that all three commercial forms have been used). [19] [22] [23] [24] [25] [26] [27] [28] Supplementation with carnitine normalizes heart carnitine levels and allows the heart muscle to utilize its limited oxygen supply more efficiently. This translates to an improvement in cases of angina. Improvements have been noted in exercise tolerance and heart function. The results indicate that carnitine is an effective alternative to drugs in cases of angina. L-Propionylcarnitine
(LPC) may offer the greatest benefit in angina, as well as in other cardiovascular conditions. LPC is taken up by myocardial cells much more rapidly than other forms of carnitine. [16] In one study, LPC (15 mg/kg intravenously) significantly diminished myocardial ischemia as demonstrated by a significant 12 and 50% reduction in ST-segment depression and left ventricular end-diastolic pressure, respectively, during the atrial pacing test. [29] Left ventricular ejection fraction increased by 18%. Recovery of heart function after exercise occurred much quicker in the LPC group compared with the placebo group. L-Carnitine
and LAC have also shown very good results. In one of the larger studies, 200 patients with exercise-induced stable angina received either standard therapy alone (e.g. nitroglycerine, calcium channel blockers, beta-blockers, antihypertensives, diuretics, digitalis, antiarrhythmics, anticoagulants, and hypolipidemics) or in combination with 2,000 mg a day of L-carnitine over a 6 month period. [30] Compared with the control group, the patients on L-carnitine exhibited a significant reduction in premature ventricular contractions at rest, as well as an increased tolerance to exercise as demonstrated by an increased maximal cardiac frequency, increased maximal systolic blood pressure, cardiac output, and reduced ST-segment depression (70% reduction in the L-carnitine group vs. no change in the control group). Reductions in LDL-cholesterol (8%) and triglycerides (12%) were also noted. These results are highly significant and provide a strong rationale for the inclusion of carnitine in patients using standard medical therapy. Recovery from myocardial infarction
In addition to benefiting angina patients, carnitine has also been shown to be useful in helping individuals recover more quickly from a heart attack. [19] In one double-blind study of 160 patients who had been released from a hospital after a heart attack, the group receiving 4 g of L-carnitine daily showed significant improvements in heart rate, blood pressure, angina attacks, rhythm disturbances, and clinical signs of impaired heart function compared to the control group.
[ 31]
In Italy, a larger study involving 472 patients showed additional benefits. [32] The study was performed to evaluate the effects of L-carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. Placebo or L-carnitine was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with L-carnitine compared with those receiving placebo. The percent increase in both end-diastolic and end-systolic volumes from admission to 3, 6 and 12 month evaluation was significantly reduced in the L-carnitine group. Arrhythmias
In double-blind trials, reductions in the use of conventional antiarrhythmic drugs have occurred in patients with angina who have received carnitine.
[19]
Congestive heart failure
Several double-blind clinical studies have shown that carnitine (again, LPC appears to be more effective than LC or LAC) improves cardiac function in patients with
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congestive heart failure. [19] In one double-blind study of LPC versus placebo in a group of 60 patients with mild to moderate (II and III NYHA class) congestive heart failure LPC produced demonstrable benefit. [33] The group was made up of men and women aged between 48 and 73 years in chronic treatment with digitalis and diuretics for at least 3 months and who still displayed symptoms. Thirty of these patients were chosen randomly and for 180 days received 500 mg of LPC three times a day in addition to their usual treatment. At basal conditions and after 30, 90 and 180 days, the maximum exercise time was evaluated using an exercise tolerance test performed on an ergometer bicycle and the left ventricular ejection fraction was tested by means of echocardiography. After 1 month of treatment, the patients treated with LPC, compared with the control group, showed significant increases in the values of both tests, increases which became even more evident after 90 and 180 days. At the stated times, the increases in the maximum exercise time were 16.4, 22.9, and 25.9%, respectively. The ventricular ejection fraction increased by 8.4, 11.6 and 13.6%, respectively. In another double-blind study in similar patients, at the end of 6 months of treatment, maximum exercise time on the treadmill increased 16.4% and the ejection fraction increased by 12.1% after 180 days in the group treated with PLC at a dosage of 1 g twice daily. [34] Peripheral vascular disease
All three forms of carnitine (2–4 g daily) have been shown to improve the walking distance without pain in patients with intermittent claudication. Presumably this improvement is the result of improved energy metabolism within the muscle, as carnitine was not shown to improve blood flow to the calf. LPC appears to offer better effects than either L-carnitine or LAC. [35] [36] However, in one double-blind study, L-carnitine at a dosage of 2 g twice daily demonstrated a 75% increase in walking distance after only 3 weeks of therapy. [37] Enhancing physical performance
The ability to enhance exercise tolerance and physical performance with carnitine may not be limited to patients with cardiovascular disease, as carnitine supplementation has also been shown to be of benefit in healthy subjects and athletes. Efficient utilization of fatty acids by skeletal muscle, like the myocardium, is also dependent upon adequate supply of carnitine. Carnitine supplementation (usually 2 g two to three times daily) has resulted in significant improvements in cardiovascular function in response to exercise in several double-blind studies in both athletes and normal subjects. [38] [39] [40] Compared to control groups, the subjects on carnitine have shown not only improvements in exercise intensity or time, but also evidence of improved energy metabolism within the muscle (lowered blood lactic acid and free fatty acid levels). Obviously, the improved production of energy by the exercising muscle as well as improved heart function could be responsible for carnitine’s ability to enhance physical performance. Although at least three studies showed the benefits of carnitine on exercise performance to be no more of value than a placebo, carnitine supplementation should still be viewed as beneficial, especially in endurance-related events. [41] [42] [43] The reason behind this statement is the fact that studies have demonstrated that carnitine improves energy producing enzymes levels in long distance runners. [44] These athletes received either a placebo or 2 g of L-carnitine twice daily for 4 weeks. Runners receiving the L-carnitine showed a significant increase in enzymes involved in energy production (cytochrome c reductase and cytochrome oxidase). In contrast, there were no changes in the placebo group.
It is interesting to note that normal subjects taking carnitine have improved cardiovascular function and a more rapid return of heart rate to the resting rate after exercise.[45] The significance of these improvements is that it appears that carnitine is able to mimic the benefits in heart and vascular function produced by regular exercise training without working up a sweat. Alzheimer’s disease, senile depression, and age-related memory defect
A great deal of research has been conducted over the last decade with L-acetylcarnitine (LAC) in the treatment of Alzheimer’s disease, senile depression, and age-related memory defects. As described above, LAC is a molecule composed of acetic acid and L-carnitine bound together. This reaction occurs naturally in the human brain, and therefore it is not exactly known how much greater an effect is noted with LAC vs. L-carnitine or PAC. However, LAC is thought to be substantially more active than these other forms of carnitine in conditions involving the brain. [46] [47] LAC is structurally related to acetylcholine, a major neurotransmitter responsible for memory and proper brain function. In Alzheimer’s disease, and to a lesser extent the normal aging human brain, there is a defect in the utilization of acetylcholine. The close structural similarity between LAC and acetylcholine led researchers to begin testing LAC in Alzheimer’s disease. The results have been encouraging. Researchers have now shown that LAC does indeed mimic acetylcholine and is of benefit not only in patients with early-stage Alzheimer’s disease, but also in elderly patients who are depressed or who have impaired memory. [47] It has also been shown to act as a powerful
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antioxidant within the brain cell, to stabilize cell membranes, to improve energy production within the brain cell as well as enhancing or mimicking the function of acetylcholine. [48] The results in delaying the progression of Alzheimer’s disease have been outstanding. The studies have been well controlled and extremely thorough. [46] [49] [50] [51] For example, in one study, LAC (2 g twice daily) or placebo was given to 130 patients with Alzheimer’s disease over the course of 1 year. [51] The patients were evaluated by 14 different outcome measures such as assessment scales, cognitive function tests, memory tests, and physician evaluations. The group receiving the LAC had better outcome scores in all cases. The memory impairment need not be as severe as in Alzheimer’s disease in order for LAC to demonstrate benefit. [52] [53] [54] In one double-blind study of 236 elderly subjects with mild mental deterioration, as evident by detailed clinical assessment, the group receiving 1,500 mg of LAC daily demonstrated significant improvement in mental function, particularly in memory and constructional thinking. [54] Many of the elderly suffer from depression not only as a result of experiencing a great deal of loss in their lives, but also because of the biochemical changes in the brain associated with aging. LAC has been shown to improve depression in elderly subjects in double-blind studies using assessment scales standard to scientific research of antidepressant drugs (e.g. Hamilton Depression Scale, Clinical Global Impression, Sandoz Clinical Assessment, etc.). The usual dosage has been 500 mg three times daily. Those elderly subjects with the highest depression scores are usually the ones who benefit the most from acetyl- L-carnitine. [55] [56] Down syndrome
Given that both Down syndrome and Alzheimer’s disease are characterized by a deficit in cholinergic transmission, a study was conducted to assess the effect of a 90 day treatment with L-acetylcarnitine (LAC) in individuals with Down syndrome. [57] Findings were evaluated statistically and compared to three further groups of subjects: untreated Down syndrome, mental deficiency due to other cases treated and not treated with LAC. Treated Down syndrome patients showed statistically significant improvements of visual memory and attention both in absolute terms and in comparison with the other groups. No improvement was found in mentally deficient non-Down subjects, so that the favorable effect of LAC appears to be specific for Down patients. An effective dosage is 20 mg of LAC for every 2 pounds of body weight. It is suggested that the action of LAC in these pathologies is related to its direct and indirect cholinomimetic effect. Kidney disease and hemodialysis
Carnitine supplementation is very much indicated in kidney diseases because the kidney is a major site of carnitine synthesis. Damage to the kidney or reduced kidney function has a profound effect on carnitine metabolism. It is well established that patients undergoing hemodialysis suffer from carnitine deficiency due to the loss of considerable quantities of carnitine during dialysis as well as decreased synthesis. Serum carnitine levels drop nearly 80% during hemodialysis. [1] [2] [3] Carnitine supplementation has been extensively studied in patients undergoing hemodialysis due to chronic renal failure. These studies indicated that L-carnitine supplementation is effective in reducing triglyceride levels while raising HDL-cholesterol levels and thus helps to decrease the risk of heart disease in dialysis patients. [58] [59] [60] [61] Carnitine-treated dialyzed patients have also shown additional benefits, including: [62] [63] [64] • disappearance of angina pectoris and arrhythmias occurring during dialysis • reduction of muscle symptoms including muscle cramps • increased muscle mass • significant improvement of the chronic anemiaseen in these patients as demonstrated by an increased hematocrit, hemoglobin, and red bloodcell count. In the last decade, a major advancement in the treatment of the anemia associated with hemodialysis is recombinant human erythropoietin (EPO) therapy. However, this therapy is expensive and is not without side-effects. In a recent study, L-carnitine (1 g intravenously after every dialysis session) administered for 6 months led to a significant reduction in dosage as well as improvements in membrane fragility and endogenous EPO secretion. [65] Given the high cost of EPO, if doctors are unwilling to follow this procedure, insurance companies should get involved and force dialysis units to employ L-carnitine. Diabetes
Patients with diabetes have been reported to have reduced serum carnitine concentrations but normal skeletal muscle carnitine levels. Due to the increased risk of atherosclerotic cardiovascular disease and reduced kidney and liver function found in diabetic patients, supplementation with L-carnitine appears warranted. Carnitine (especially LPC) has also been shown to greatly improve peripheral vascular function, as well as nerve function, in patients with diabetes. improvement in nerve conduction is largely due to significantly increased conduction velocity. [67]
[66]
The
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Liver disease
Carnitine plays an extremely important role in the utilization and metabolization of fatty acids in the liver. There is some evidence that carnitine deficiency within the liver promotes fatty infiltration (also known as steatosis or liver congestion). [68] Alcohol ingestion is a common cause of fatty infiltration of the liver. It has been suggested that chronic alcohol consumption results in a functional deficiency of carnitine. A functional deficiency means that there is plenty of carnitine around, but its function is inhibited just as if there was a deficiency. Many commonly used agents for fatty infiltration, such as choline, niacin, and cysteine, appear to have little value in relieving alcohol-induced fatty liver. However, carnitine significantly inhibits, and reverses, alcohol-induced fatty liver disease. [69]
Since carnitine normally facilitates fatty acid transport and oxidation in the mitochondria, a high liver carnitine level may be needed to handle the increased fatty acid load produced by alcohol consumption or other liver injury. [70] Supplemental carnitine has been shown to reduce free fatty acid levels in patients with liver cirrhosis, and to reduce serum triglycerides and liver enzyme levels while elevating HDL-cholesterol in alcohol-induced fatty liver disease. [68] [69] [70] Carnitine’s use in liver disorders associated with fatty infiltration appears warranted, especially when these changes are due to the ingestion of alcohol or exposure to xenobiotics (man-made chemicals toxic to biological processes such as pesticides and herbicides). Muscular dystrophies
Patients with various muscular dystrophies have reduced levels of carnitine in their skeletal muscles. [71] [72] [73] Although levels were not as low as those observed in patients with classical myopathic carnitine deficiency, the low carnitine levels are thought to contribute to the muscular weakness experienced by these patients. Unfortunately, for some reason it has not been determined if supplemental carnitine would be of any value in patients with muscular dystrophy. Low sperm counts and decreased sperm motility
In the human sperm, high carnitine concentrations are critical to sperm energy metabolism. Several studies have shown that the level of free carnitine in the seminal fluid is inversely correlated with sperm count and motility. [74] [75] The lower the carnitine content, the more likely it is that a man is infertile. Given the known physiological role of carnitine in sperm function and its link to male infertility, a recent study was designed to assess the therapeutic effect of carnitine in men with low sperm counts and depressed sperm motility. [76] One hundred men selected from infertility clinics participated in the “Italian Study Group on carnitine and male infertility”. Each subject was given 3,000 mg of L-carnitine daily for 4 months. The results of the study indicated that L-carnitine was able to increase sperm counts and sperm motility, in both a qualitative and a quantitative manner: • the number of ejaculated sperm increased from 142 to 163 billion • the percentage of motile sperm increased from 26.9 to 37.7% • the percentage of sperm with rapid linear progression increased from 10.8 to 18% • the mean sperm velocity increased from 28.4% to 32.5%. The results are even more impressive if only the patients with the poorest sperm motility are studied. This subgroup saw even more significant gains on all parameters. For example, the percentage of motile sperm increased from 19.3 to 40.9% and the percentage of sperm with rapid linear progression increased from 3.1 to 20.3%. Chronic obstructive pulmonary disease
Patients with chronic respiratory insufficiency are often severely affected by even the simplest physical activity. Treatment with resulted in significant improvements in exercise capability. [77]
L-carnitine
(2 g three times/day)
AIDS
Several reports indicate that systemic carnitine deficiency may be a problem in patients with AIDS. Reduced levels of serum carnitine are most often found in AIDS patients. However, more important is the carnitine depletion in peripheral blood mononuclear cells (PBMC). In fact, even AIDS patients with normal serum carnitine levels demonstrate low levels of carnitine in white blood cells. [78] Increasing the carnitine content of the PWBC strongly improved lymphocyte function and highlights the importance of carnitine to immune function. has been shown to prevent the toxicity of the drug AZT on the mitochondria of the muscle cells. [79] AZT poisons the mitochondria of the muscle, leading to abnormal energy production within the muscle which manifests clinically as muscle fatigue and pain. If L-carnitine is able to prevent this negative effect of AZT in human patients with AIDS, it would be a major improvement in the clinical management of AIDS. L-Carnitine
Preliminary studies indicate that L-carnitine supplementation can improve immune function and reduce the level of HIV-induced immune suppression. When AIDS patients being treated with AZT were given 6 g
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of L-carnitine/day, it led to significant increased PBMC proliferation and reduced blood levels of triglycerides and circulating tumor necrosis factor. suspected systemic carnitine deficiency along with the tremendous safety of use, carnitine supplementation appears to be warranted in AIDS.
[80]
Given the
Inborn errors of amino acid metabolism
The use of carnitine in the treatment of inborn errors of metabolism involving the urea acid cycle appears to be well justified. Preliminary studies have shown impressive therapeutic response to L-carnitine supplementation in cases of glutaric aciduria, isovaleric acidemia, propionicacidemia, and methylmalonic aciduria.
[81] [ 82]
[83] [84]
Protection against drug toxicity
Carnitine has been shown to protect against the damaging effects on the heart produced by the chemotherapy drug adriamycin. [85] Carnitine has also been shown to improve the symptoms attributed to anticonvulsant medications such as valproic acid (trade names: Depa, Depakene, Depakote, and Deproic) and carbamazepine (trade names: Epitol and Tegretol). [86] [87] However, the most recent study has challenged the need to administer carnitine prophylactically since no significant differences were noted in well-being scores between the carnitine group and the placebo group. [88]
DOSAGE The daily dosage of L-carnitine in all of its forms has typically been between 1,500 and 4,000 mg in divided doses. Given the safety of carnitine, it appears to be better to err on the side of taking too much rather than too little. The exception is in patients undergoing hemodialysis. A paradoxical effect on triglyceride levels and platelet aggregation in patients on hemodialysis has been reported. [89] Slightly higher doses were used (3 g/day) compared with other studies of supplementation in chronic renal failure (typical dose 20 mg/kg body weight or 2 g/day). In addition, the study size was extremely small, and the results are in conflict with other studies using similar doses. However, it appears wise to reduce the risk of this effect by using lower doses and carefully monitoring patients with impaired renal function.
TOXICOLOGY L-Carnitine
is extremely safe, with no significant side-effects ever being reported in any of the human clinical studies. Again, it is important to mention that only should be used. The D form, the mirror image of the L form, has produced side-effects indicating that it interferes with the natural L form of carnitine. Patients undergoing hemodialysis given a mixture containing D,L-carnitine for 45 days experienced muscle pain and loss of muscle function presumably due to lack of energy.[90] The symptoms disappeared upon cessation of D,L-carnitine supplementation. Subsequent studies showed that D -carnitine produces an L-carnitine deficiency in cardiac and skeletal muscle. [91] While L-carnitine results in significant improvement in exercise tolerance in angina patients, D,L-carnitine actually dangerously reduces exercise tolerance in these patients. [92] L-carnitine
Interactions There are no known adverse interactions between carnitine and any drug or nutrient. Carnitine and coenzyme Q The same is true for pantethine. [94]
10 appear
to work synergistically when combined. [93]
Perhaps the most important interaction is the one with choline. In young adult women, daily choline supplementation (20 mg/kg body weight) resulted in a 75% lower urinary carnitine excretion than in controls, without significantly altering plasma carnitine concentrations. Studies in guinea pigs demonstrated that choline supplementation resulted in a significantly lower urinary excretion and higher skeletal muscle carnitine concentrations. These studies indicate that choline supplementation results in a conservation of carnitine and may increase intracellular carnitine levels. [95]
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Morabito E, Serafini S, Corsico N. Acetyl-L-carnitine effect on nerve conduction velocity in streptotocin-diabetic rats. Arzneim Forsch/Drug Res 1993; 43: 343–346
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Borum PR, Broquist HP, Roelofs RI. Muscle carnitine levels in neuromuscular disease. J Neurol Sci 1977; 34: 279–286
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Carrier HN, Berthiller G. Carnitine levels in normal children and adults and in patients with diseased muscle. Muscle Nerve 1980; 3: 326–334
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Chapter 73 - Catechin [(+)-cyanidanol-3] Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION This naturally occurring flavonoid has been widely used in Europe in the treatment of hepatic disease and other conditions. It is found in high concentrations in Acacia catechu (black catechu, black cutch) and Uncaria gambier (pale catechu, gambier). [1]
PHARMACOKINETIC STUDIES IN HUMANS Studies of radiolabeled catechin demonstrate that 55% of the oral dose administered to human volunteers is excreted in the urine. [2] Of this excreted catechin, 70% was excreted within 12 hours and 90% within 24 hours. Urinary excretion of unchanged catechin was quite low (0.1–1.4% of oral dose). The major urinary metabolites (composing three-quarters of the total urinary excretion) are glucuronides of catechin, and 3'-O-methyl-catechin and its sulphate. The majority of metabolites retained the flavanol ring structure. Ring scission is a minor metabolic pathway and results in the excretion of benzoic, hippuric, and phenylpropionic acids. Unchanged catechin is detected in the plasma between 30 minutes and 12 hours after ingestion, while metabolites persist for at least 120 hours. Researchers have concluded that the rapid rate of absorption, coupled with relatively low plasma levels of the unchanged catechin molecule, suggests that hepatic extraction and localization are extremely efficient, a desirable trait considering catechin’s hepatoprotective properties. [1] [2]
PHARMACOLOGY Antiviral and immunostimulatory effects
Many flavonoids have been shown to possess antiviral activity, with quercetin being perhaps the most effective. Catechin has, however, been shown to inhibit infectivity by human viruses (e.g. polio virus, parainfluenza virus type 3, respiratory synctial virus, and herpes simplex
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type 1).[3] This appears to be due to a direct flavonoid virus interaction. Perhaps more important, however, are its immune stimulation properties. [4] Catechin and 3'-O-methylcatechin, its major derivative, have been shown to significantly increase spontaneous, pokeweed mitogen- and Staphylococcus aureus-induced lymphocyte transformation, and immunoglobulin synthesis. Catechin has also been shown to increase T-cell rosette formation; [5] stimulate cell-mediated immune response (as measured by the leukocyte migration inhibition test); and promote antigen-induced proliferative response in patients with HBsAg-positive chronic active hepatitis. [6] Many of the immunostimulatory effects of flavonoids may be due to their ability to inhibit the catabolism of cGMP in leukocytes, immune responses (see Ch. 53 for further discussion concerning cyclic nucleotides’ effects on immune functions).
[7]
an action known to augment many
Antioxidant
Catechin has been shown, in vitro and in vivo, to be a powerful free radical scavenger and antioxidant, preventing both environmental chemical- and normal metabolism-induced oxidative damage. [8] Catechin has a sparing effect on glutathione metabolism as well. Anti-endotoxin effects
The role of endotoxins (lipopolysaccharide cell wall components of Gram-negative bacteria) in the pathogenesis of liver diseases (particularly all types of hepatitis, and alcohol-induced cirrhosis) and associated systemic disorders has been demonstrated by many investigators (see Ch. 54 for a complete discussion). Under normal conditions, endotoxins, produced by intestinal Gram-negative bacteria, are absorbed into the portal venous circulation and detoxified by Kuppfer cells. Impairment of the reticuloendothelial system (RES), phagocytic function, or the portal-sinusoidal blood flow – i.e. interference of normal endotoxin clearance mechanisms – amplifies the biologic activities of endotoxins (e.g. activation of the alternative complement pathway, lipid peroxidation, and promotion of such calcium-mediated phenomena as smooth muscle contraction and mast cell degranulation). Catechin’s anti-endotoxin effects are both direct – degradation of endotoxin and prevention of free radical-induced damage by the lipid portion of the endotoxin molecule – and indirect – stabilization of biomembranes and interference with the liver adenylate cyclase system (this latter is significant since exotoxins, such as cholera toxin from Vibrio cholerae, cause their symptoms by excessive activation of adenylate cyclase which disturbs the cyclic AMP/ATP balance in the cells). [9] Collagen effects
Catechin affects collagen metabolism in various ways. These include: • an increase in cross-linkage formation in normal [10] and lathyritic [11] collagen (covalent binding of seven catechin residues per collagen alpha-chain) • a reduction in prolyl and lysyl hydroxylase activities [12] • an accelerated conversion of soluble to insoluble collagen in lathyritic, [13] diabetic, [14] and genetically abnormal [15] collagen. Collagen synthesized in the presence of catechin has been shown to be resistant to the action of collagenase [10] and pepsin. [16] Collagen biosynthesis has variously been reported to be decreased, [12] unaffected, [17] and, in the case of adjuvant arthritis, [18] increased in the presence of catechin. The significance of these effects is discussed below. Histidine decarboxylase
This enzyme is responsible for converting histidine to histamine. Catechin and other flavonoids have been shown to be potent inhibitors of histidine decarboxylase in vitro[19] and in vivo.[20] This action has wide clinical application, e.g. allergic conditions, peptic ulcers, inflammatory processes, and other conditions where histamine is
involved.
CLINICAL AND EXPERIMENTAL STUDIES Hepatitis
An international workshop in 1981 on the use of catechin in diseases of the liver concluded that the flavonoid has much promise for the treatment of many types of hepatic disease, particularly both acute and chronic viral hepatitis. [1] Catechin has been shown, in numerous double-blind clinical studies, to decrease serum bilirubin levels in patients with all types of acute viral hepatitis (i.e. types A, B, and non-A, non-B). [1] [21] [22] [23] [24] [25] [26] [27] Furthermore, there is a more rapid relief of clinical symptoms (i.e. anorexia, nausea, asthenia, pruritus, and abdominal discomfort), a more accelerated clearance of HBsAg from the blood, and a greater reduction of SGPT and SGOT levels than in control groups. The hepatoprotective effect of catechin is related to its free radical and antioxidant properties, its anti-endotoxin effects, and its ability to stabilize membranes. The most recent double-blind study utilizing catechin involved 338 patients with chronic hepatitis B as confirmed by the presence of hepatitis B e antigen (HBeAg). Patients were given either catechin at a daily dose of 1.5 g for 2 weeks, followed by 2.25 g for a further 14 weeks, or a placebo. The HBeAg titer decreased by
[27]
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at least 50% in 44 of 144 cases treated with catechin compared with 21 of 140 cases treated with placebo. The HBeAg disappeared in 16 of the catechin cases and four of the placebo, and a seroconversion was observed in six catechin patients and three placebo patients. The mean HBeAg titer in the catechin group was significantly lower than that in the placebo group at the end of the 16 weeks of therapy. The patients whose HBeAg titers were lowered were largely those with chronic active hepatitis, and they had higher initial values of SGPT, SGOT, and gamma-globulin than the patients whose HBeAg titers remained unchanged. The mean values for these liver function tests also fell significantly in the former subgroup. Catechin was well tolerated, the only notable side-effect being a transient febrile reaction in 13 patients. Alcohol-induced liver disease
Elevated hepatic NADH:NAD ratios and decreased ATP concentrations are found during ethanol intoxication. These metabolic disturbances, along with the increased production of acetate (as a result of ethanol detoxification), produce cholestasis and induce hepatic lipid accumulation by decreasing fatty acid oxidation and favoring incorporation of fatty acids into triglycerides. [28] In animal studies, catechin has been shown to correct these aberrations. [28] [29] [30] However, clinical studies in humans have failed to show convincing evidence that catechin is of benefit in alcohol-related liver disease. [31] [32] This could be a result of insufficient dosage. In the animal studies, the dose is usually 200 mg/kg, compared with 20–40 mg/kg in human studies. Furthermore, the high rate of patient drop-out in long-term studies has prevented adequate evaluation. A recent long-term clinical trial (6 months) demonstrated that 2 g of catechin gave some protection against ethanol-induced hepatic damage, as evidenced by lowering of hepatic enzymes (SGOT, SGPT, and gamma GT). [32] Peptic ulcer
Catechin, via its ability to inhibit histidine decarboxylase, offers anti-ulcer activity. Experimental studies in guinea pigs and rats have demonstrated that catechin has significant anti-ulcer activity in various models. [19] [20] [33] In a human clinical study, oral administration (1,000 mg five times a day) resulted in reduced histamine levels in the gastric tissue (determined by biopsy) of normal patients and those with gastric and duodenal ulcers and acute gastritis. [20] It was also demonstrated that the histamine levels, which significantly increase in patients with urticaria and food allergy after the local application of the antigen to the gastric mucosa, could be decreased by the prior administration of catechin. Postoperative complications
The formation of adhesions is a common and severe problem in surgery, particularly in abdominal surgery. Lower abdominal surgery, particularly appendectomies and gynecological procedures, are often followed by adhesions which may result in pain and obstruction. The incidence of postoperative peritoneal adhesions varies from 67 to 92%. [34] It has been assumed that surgery leads to the stimulation of connective tissue formation, resulting in an overproduction of procollagen and collagen and increased deposition around the damaged or ischemic area. In rats, catechin, when administered within the first 5 days following the procedure, substantially inhibits adhesion formation following experimental adhesion induction. [35] Catechin, via its inhibition of procollagen and collagen biosynthesis, should also reduce adhesion formation in humans. Intraperitoneal administration was significantly more effective than the oral administration in the experimental study. However, in humans, oral administration may result in sufficient tissue concentrations. Catechin has also been shown, in a double-blind study, to significantly reduce postoperative edema. [35] Osteogenesis imperfecta (OI)
This heterogenous autosomal dominant bone disease is characterized by defective synthesis of collagen, resulting in impaired connective tissue and bone matrix formation. Prior to the use of catechin for this disorder, treatment was based solely upon orthopedic measures, as no effective medical treatment was available. [36] The main clinical problems in OI are multiple fractures of the long bones in children and progressive collapse of the vertebral bodies in adulthood. Catechin has been shown to reduce fractures. There is also histological, electron microscopic, and biochemical evidence of improvement after treatment. [36] [37] Catechin’s role in improving collagen defects in OI probably centers around its ability to: • reduce, by its reduction of lysyl hydroxylase activity, the increased level of hydroxylysine reported in the collagen of many patients with type I OI • increase the number of cross-links in the collagen matrix (which may be deficient or exhibit delayed maturation in OI) • improve the supramolecular organization and stability of the collagen fibers • possibly increase the reduced collagen production occurring in OI. Rheumatoid arthritis and scleroderma
The effects that catechin has on collagen suggest that the flavonoid would have therapeutic benefit in rheumatoid
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arthritis and scleroderma, as well as in other collagen diseases. Inflammation and collagen are linked in several ways. Pre-existing collagen is destroyed during the initial stages of inflammation, whereas its biosynthesis is increased in the later stages. Catechin appears to be an ideal agent due to its ability to inhibit the breakdown of collagen caused by either free radicals or enzymes (hyaluronidase, collagenase, and pepsin), coupled with its ability to cross-link with collagen fibers and inhibit pro-collagen biosynthesis. [12] Catechin was included in a long-term treatment program of 115 patients with generalized scleroderma that brought about arrest of progression in 89% of the patients, and a subtotal or total recovery in more than 40%. [38] Although a number of combinations of collagen inhibitors were used in the study, the combination of catechin with D-penicillamine and L-glutamine was the most effective. Unfortunately, catechin was not used alone. Cancer
Several epidemiological studies have now shown an inverse correlation between tea consumption and the incidence of several cancers. For example, people in Japan smoke more cigarettes than those in Western countries, yet their incidence of lung cancer is lower. Other studies show a lower incidence of colonic polyps in humans drinking green tea. This protection has been attributed in part to their high tea consumption. This is consistent with laboratory research showing a preventive effect of tea in animal models of lung cancer. In mice models, drinking green tea resulted in lung tumor induction being inhibited by 50%. Green and black tea reduced the incidence of cancer of the lung, forestomach, esophagus, and liver in rats and mice when these were induced by carcinogens. These anti-cancer effects appear to be due to catechin’s potent antioxidant activity of tea, lowering the modification of DNA in the tissues by hydroxyl radicals and similar active oxygen compounds. [39]
DOSAGE Typically, the dosages used have been: • 1 g three times a day for hepatic disease • 1 g five times a day for peptic ulcers • 500 mg three times a day for osteogenesis imperfecta.
TOXICOLOGY Catechin was initially regarded as being remarkably free from side-effects. However, soon after its introduction in France, rare but serious side-effects began to be linked with catechin. Chief among the serious side-effects were autoimmune hemolysis, febrile reactions, and urticaria. Catechin must be used with extreme caution. Two different series of case reports highlight the seriousness of side-effects. In the first, six patients who developed hemolysis while receiving catechin were studied.[40] The disorder was episodic in all patients and resolved after discontinuation. The causative antibodies could be demonstrated in all six cases, even when the hemolytic episode had preceded analysis by more than 1 year. It seems that the stable association of catechin with RBC generates antigenic sites against which a heterogeneous immune response is elicited, giving rise to long-lasting drug-dependent antibodies as well as autoantibodies. In the other series of patients, five patients who received catechin for 4–36 months were presented. [41] Three developed both hemolytic anemia and thrombocytopenia, while two had only thrombocytopenia. After suspending the catechin, the hematological values returned to normal in all of the patients. Catechin-dependent platelet antibodies were detected in four of the five patients, and catechin-dependent red blood cell antibodies were present in three.
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Ryle P, Chakraborty J, Shaw G, Thomson A. The effect of (+)-cyanidanol-3 on alcoholic fatty liver in the rat. In: Conn H, ed. International workshop on (+)-cyanidanol-3 in diseases of the liver. Royal Society of Medicine International Symposia Series, #47. London: Academic Press. 1981: p 185–193 30.
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Rivkind A, Marshood M, Durst A, Becker Y. Cianidanol ([+]-Cyanidanol-3) prevents the development of abdominal adhesions in rats. Arch Surg 1983; 118: 1431–1433
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Baruch J. Effect of Endotelon in postoperative edema. Results of a double-blind study versus placebo in 32 female patients. Ann Chir Plast Esthet 1984; 29: 393–395
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Chapter 74 - Centella asiatica (gotu kola) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Centella asiatica (family: Umbelliferae or Apiaceae) Synonym: Hydrocotyle asiatica L. Common names: gotu kola, Indian pennywort, South African pennywort, mandukaparni
GENERAL DESCRIPTION Centella asiatica is an herbaceous perennial plant native to India, China, Indonesia, Australia, the South Pacific, Madagascar, and southern and middle Africa. This slender, creeping plant flourishes in and around water. Although it grows best in damp, swampy areas, centella is often observed growing along stone walls or other rocky, sunny areas at elevations of approximately 2,000 feet in India and Ceylon. [1] Depending on the environment, the form and shape of centella can change dramatically. In shallow water, centella will form floating leaves, while in dry locations, the leaves are small and thin, and numerous roots are formed. [1] Typically, the constantly growing roots give rise to reddish stolons. The round-to-reniform, smooth-surfaced leaves, found on furrowed petioles, can reach a width of 1 inch and a length of 6 inches. The leaf margin may be smooth, crenate, or slightly lobed. Usually three to six red flowers arise in a sessile manner or on very short pedicels in axillary umbels at the end of 0.08–0.3 inches long peduncles. The fruit, formed throughout the growing season, is approximately 0.2 inches long with seven to nine ribs and a curved, strongly thickened pericarp. [1] Historically, the entire plant is used medicinally, with harvesting occurring at any time during the year.
[1]
CHEMICAL COMPOSITION Although the primary pharmacologically active constituents of Centella asiatica are known to be triterpenoid compounds, [2] the exact chemical profile of centella is difficult to determine due to duplicate names and contradictory findings. In addition, centella samples from
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Figure 74-1 The triterpene compounds of Centella asiatica.
India, Sri Lanka, and Madagascar apparently do not contain the same constituents. asiatica have been found.[5]
[3] [4]
In India, three (and possibly more) chemically different subspecies of Centella
The concentration of triterpenes in centella can vary between 1.1 and 8%, with most samples yielding a concentration between 2.2 and 3.4%.
[ 5]
Figure 74.1 below illustrates the major triterpenoid components of Centella asiatica: • asiatica acid • madecassic acid • asiaticoside • madecassoside. The Madagascar variety is most commonly used to produce standardized extracts and yields triterpene concentrations of asiatic acid (29–30%), madecassic acid (29–30%), asiaticoside (40%), and madecassoside (1–2%). [2] Centella also contains a green, volatile oil which is composed of an unidentified terpene acetate (which accounts for 36% of the total oil), camphor, cineole, and other essential oils. Centella oil also contains glycerides of fatty acids, various plant sterols such as campesterol, stigmasterol, and sitosterol, and various polyacetylene compounds.[1] [2] Other notable compounds isolated from centella include the flavonoids keampferol, quercetin, and their glycosides, myoinositol, sugars, a bitter substance (vellarin), amino acids, and resins. [1] [2]
HISTORY AND FOLK USE Centella has been utilized as a medicine in India since prehistoric times and is thought to be identical to the plant mandukaparni, listed in the Susruta Samhita. Centella was also used extensively as a medicine, both internally and externally, by the people of Java and other islands of Indonesia. The medicinal use of centella in India and Indonesia centered around its ability to heal wounds and relieve leprosy. [1] In the 19th century, centella and its extracts were incorporated into the Indian pharmacopeia, where in addition to being recommended for wound healing, it was recommended in the treatment of skin conditions such as leprosy, lupus, varicose ulcers, eczema, and psoriasis. It was also used to treat diarrhea, fever, amenorrhea, and diseases of the female genitourinary tract. [1] In China, the leaves are prescribed for turbid leukorrhea and toxic fevers, while the shoots are used for boils and fevers. The plant is also used in the treatment of fractures, contusions, strains, and snakebites. [1] Centella was also used in China to delay senescence. One of the reported “miracle elixirs of life”, centella’s reputation as a promoter of longevity stems from the report of Chinese herbalist, LiChing Yun, who reportedly lived 256 years. LiChing Yun’s longevity was supposedly a result
of his regular use of an herbal mixture chiefly composed of centella. [6] [7] Centella asiatica was first accepted as a drug in France in the 1880s. Since then, extracts of centella have been used in the treatment of many of the same conditions listed above along with those described in “Clinical applications” ( p. 653 ). Centella, or gotu kola, has aroused much curiosity in American consumers. Many confuse gotu kola with kolanuts and assume gotu kola’s rejuvenating activity is nothing more than the stimulant effect of caffeine. However, gotu kola is not related to the kolanut ( Cola nitida or Cola acuminata), nor does it contain any caffeine.
PHARMACOLOGY Centella asiatica, specifically the triterpenes, exerts remarkable wound-healing activity. Although the exact mechanism of action has not yet been fully determined, a number of interesting observations have been made. In one of the early pharmacological investigations of centella, Boiteau & Ratsimamanga [8] demonstrated that asiaticoside substantially hastened the healing of experimentally induced wounds. These authors concluded that asiaticoside works selectively in stimulating the rapid and healthy activity of the reticuloendothelial system. Additional studies on the mechanisms of action of centella’s enhancing wound-healing have shown that asiaticoside given orally, by intramuscular injection, or by implantation to rats, mice, guinea pigs, and rabbits produces a wide range of effects, as shown in Table 74.1 . The efficacy of centella in stimulating collagen synthesis has now been demonstrated in human tissue cultures. added benefit when vitamin C was added to the experimental cultures.
[13]
Interestingly, this research also demonstrated an
The outcome of centella’s complex actions is a balanced
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TABLE 74-1 -- Physiological effects of Centella asiatica • Stimulates hair and nail growth
[1] [8] [9] [10]
• Increases vascularization of connective tissue [1] [8] [9] [10] • Increases the formation of mucin and structural glycosaminoglycans like hyaluronic acid and chondroitin sulfate
[1] [8] [9] [10] [12]
• Increases the tensile integrity of the dermis [1] [8] [9] [10] • Increases keratinization of epidermis through stimulation of the stratum germinativum [1] [10] [12] [13] [14] • Possesses a eutrophic or balancing effect on connective tissue [1] [10] multiphasic effect on cells and tissues participating in the process of healing, particularly connective tissues. Enhanced development of normal connective tissue matrix is perhaps the prime therapeutic action of Centella asiatica.
CLINICAL APPLICATIONS Obviously, from the brief description of centella’s pharma-cological activity given above, it is a valuable agent for the healing of wounds. Table 74.2 provides an abridged list of documented clinical applications of Centella asiatica. The more popular uses of this valuable plant are discussed below. Burns
The standardized extract from Centella asiatica has been effectively used in the treatment of patients with second- and third-degree burns caused by boiling water, electrical current, or gas explosion. Daily local application and/or intramuscular injections of the extract resulted in excellent results when the treatment was begun immediately after the accident. The extract prevented or limited the shrinking and swelling of the skin TABLE 74-2 -- Clinical applications of Centella asiatica References
Conditions Anal fissure
15
Bladder ulcers
16 , 17
Burns
18 , 19
Cellulite
20 , 21 , 22 , 23 , 24 , 25
Cirrhosis
26 , 27 , 28
Dermatitis
20 , 29
Fibrocystic breast
30
Hemorrhoids
31
Keloids
32 , 33 , 34
Leprosy
11 , 19 , 35 , 36
Lupus erythematosus
37
Mental retardation
38
Mycosis fungiodes
37
Peptic ulcer
39 , 40
Perineal lesions
41
Periodontal disease
42
Retinal detachment
43
Scleroderma
44 , 45 , 46 , 47
Skin ulcers
48 , 49 , 50 , 51 , 52 , 53 , 54 , 55
Surgical wounds
8 , 43 , 49 , 56 , 57 , 58 , 59 , 60 , 61
Tuberculosis
8 , 62
Venous disorders
63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75
Wound healing
8 , 43 , 49 , 56 , 57 , 58 , 59 , 60 , 61
caused by skin infection, and it inhibited scar formation, increased healing, and decreased fibrosis.
[18] [ 19]
Cellulite
Standardized extracts of Centella asiatica have demonstrated good results in the treatment of cellulite in a number of clinical studies. [10] [20] [21] [22] [23] [24] [25] Bourguignon [20] observed the action of the extract on several types of cellulite in 65 patients who had undergone other therapies without success. Over a period of 3 months, very good results were produced in 58% of the patients and satisfactory results in 20%. Other investigations have shown a similar success rate (~80%). [21] [22] [23] [24] The effect of centella in the treatment of cellulite appears to be related to its ability to enhance connective tissue structure and reduce sclerosis by acting directly on fibroblasts (see Ch. 141 for further discussion.) Cirrhosis of the liver
Darnis et al[26] reported on the therapeutic use of an extract of Centella asiatica in alcohol-induced cirrhosis (six patients), cirrhosis of unknown etiology (two patients), and chronic hepatitis. In the cirrhosis patients, improvement in the histological findings and regression of inflammatory infiltration were observed. No effect was observed in the patients with chronic hepatitis. Other reports have supported the use of centella in fibrotic conditions of the liver. [27] [28] Keloids
The standardized extract of Centella asiatica has demonstrated impressive clinical results in the treatment of keloids and hypertrophic scars. [32] [33] [34] Its mechanism of action appears to be multifaceted, but is basically due to reducing the inflammatory phase of scar formation while simultaneously enhancing the maturation phase of scar formation. Keloids and hypertrophic scars are characterized by a prolonged inflammatory phase which may go on for months or even years without progressing to the maturation phase. The inflammatory phase is characterized histologically by large numbers of immature, swollen collagen bundles intermingled with inflammatory debris, while the maturation phase is characterized by mature fibrocytes, normal collagen fibers, and few inflammatory cell elements. In one study, a total of 227 patients with keloids or hypertrophic scars were treated by oral administration with a standardized centella extract (effective dosage 60–90 mg). The centella extract was used alone in 139 patients (the curative group) and 88 used the extract along with surgical scar revision (preventive group). [32] In the curative group, 116 patients (82%) were found
654
after 2–18 months to have benefited from the extract, either by relief of their symptoms or by disappearance of the inflammatory phase. In a double-blind substudy of 46 of the 139 patients, 22 out of 27 receiving the extract improved, while only nine of 19 given a placebo improved. In the preventive group, the centella extract also demonstrated significant positive effect. The therapeutic course in these patients was started a few weeks prior to surgery. If a positive response was observed, the patient was brought to surgery and kept on the centella extract for 3 months. (This method of preselection allowed the researchers to offer other forms of therapy to unresponsive patients.) Clinical improvement was observed in 72 of the 88 patients (79%). Leprosy
Several investigators have reported impressive clinical results using Centella asiatica and its extracts (oral, intramuscular, and/or topical) in the treatment of leprosy in both uncontrolled and controlled studies. [11] [19] [35] [36] The therapeutic response is comparable to that of dapsone, the standard allopathic drug used in the treatment of leprosy. In addition to its wound-healing activity, it appears that oxyasiaticoside, an oxidized form of asiaticoside, inhibits the growth of the tubercle bacillus in vitro and in vivo by dissolving the waxy coating of Mycobacterium leprae.[8] Improving mental function
Appa Rao et al [38] reported a significant increase in the mental abilities of 30 developmentally disabled children treated with Centella asiatica. After a 12 week period, the children were more attentive and better able to concentrate on assigned tasks. Centella’s triterpenes have demonstrated mild tranquilizing, anti-stress, and anti-anxiety action via enhancement of cholinergic mechanisms. mechanism is responsible for the enhancement of mental function as well.
[ 76]
Presumably this
Scleroderma
The standardized extract of Centella asiatica has been tested in several trials in the treatment of scleroderma (including systemic sclerosis). [44] [45] [46] [47] In addition to decreasing skin induration, patients have noticed a lessening of arthralgia and improved finger motility. Presumably the positive therapeutic response is a result of centella’s eutrophic effect on connective tissue, thereby preventing the excessive collagen synthesis observed in scleroderma. Venous disorders
Numerous studies have demonstrated that standardized extracts of Centella asiatica are effective in the treatment of venous insufficiency. This appears to be due to centella’s ability to enhance the connective tissue structure of the perivascular sheath, reduce sclerosis, and improve blood flow through the affected limbs. [1] [10] [63] [64] [65] [66] [67] [68] [69] [ 70] [71] [ 72] [73] [ 74] [75]
Significant improvement in symptomatology (such as feelings of heaviness in the lower legs, paresthesias, nocturnal cramps, etc.), physical findings (edema, telangiectasias, trophic ulcers, vein distensibility, etc.), and functional capacity (improved venous flow) was observed in approximately 80% of patients in the clinical trials [1] [10] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] (for further discussion, see Ch. 193 ). Wound healing
Standardized extracts of Centella asiatica have been shown, in a large number of clinical studies, to greatly aid wound repair. [1] [8] [10] [43] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] The types of wounds healed include: • surgical wounds such as episiotomies and ENT surgeries • skin ulcers due to arterial or venous insufficiency • traumatic injuries to the skin • gangrene • skin grafts • schistosomiasis lesions • perineal lesions produced during childbirth.
DOSAGE The majority of clinical studies on Centella asiatica utilized proprietary formulas available in Europe (e.g. Madecassol, TECA, and Centelase). These standardized extracts contain asiaticoside (40%), asiatic acid (29–30%), madecassic acid (29–30%), and madecassoside (1–2%). Since the concentration of triterpenes in centella can vary between 1.1 and 8%, it is difficult to calculate an appropriate dosage when simply using the crude plant material. However, since most samples yield a concentration between 2.2 and 3.4%, approximately 2–4 g/day of crude plant material would contain an appropriate quantity of triterpenes, although it is not known if this correlates with the clinical efficacy of the standardized extracts. Daily dosages of the various forms of centella are as follows: • Standardized extract (40% asiaticoside, 29–30% asiatic acid, 29–30% madecassic acid, and 1–2% madecassoside): 60–120 mg/day • Crude dried plant leaves: 2–4 g/day • Tincture (1:5): 10–20 ml/day • Fluid extract (1:1): 2.0–4.0 ml/day.
TOXICOLOGY Centella asiatica and its extracts are very well-tolerated,
655
especially orally. [1] However, the topical application of a salve containing centella has been reported to cause contact dermatitis, although quite infrequently.
[ 1]
While the oral administration of asiaticoside at a dose of 1 g/kg body weight has not proved toxic in toxicology studies, the toxic dose of asiaticoside by intramuscular application to mice and rabbits is reported as 40–50 mg/kg body weight. [1] Asiaticoside has been implicated as a possible skin carcinogen where repeated applications are used in an experimental animal model. the extract in rabbits have proved negative. [32]
[77]
Teratological studies using
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Chapter 75 - Cimicifuga racemosa (black cohosh) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Cimicifuga racemosa (family: Ranunculaceae) Common names: black cohosh, macrotys, rattleweed, black snake root
GENERAL DESCRIPTION Cimicifuga racemosa is a perennial herb native to North America that grows on hillsides and in woods at higher elevations from Maine and Ontario to Wisconsin, Georgia, and Missouri. The large, creeping rhizome produces stems up to 9 feet high. The ovate or oblong leaflets are 1–6 inches long and 4 inches wide, while the smaller leaflets are ternate, then pinnate, and sometimes even further divided. Small, white, fetid flowers grow in long racemes from May to August. The rhizome is the portion of the plant used for medicinal purposes.
CHEMICAL COMPOSITION The components of cimicifuga which have garnered the most attention are the triterpene glycosides: • actein • cimicifugoside (aglycone cimegenol) • 27-deoxyactein. Other compounds of interest include flavonoids (formononetin) and caffeic acid derivatives (isoferulic acid) (see Figs 75.1 and 75.2 ).
HISTORY AND FOLK USE The generic name Cimicifuga comes from the Latin cimex,
Figure 75-1 Cimigenol.
658
Figure 75-2 Formononetin.
a bug, and fugo, to drive away, alluding to its use as a vermifuge. Native Americans used cimicifuga rhizomes for the relief of pain during menses and childbirth as well as snakebite. The rhizome of Cimicifuga racemosa was listed in the National Formulary from 1936 to 1950, and in the United States Pharmacopeia from 1820 to 1936. Eclectic physicians in the early part of the 20th century used cimicifuga in gynecological disorders as well as rheumatoid and myalgic pain. While use in the US declined dramatically from 1950 to 1995, cimicifuga preparations have been used extensively in Europe during this same period primarily as a natural alternative to hormone replacement therapy during menopause. This popularity is based upon substantial empirical and clinical evidence.
PHARMACOLOGY The primary pharmacological effects of cimicifuga appear to revolve around its ability to impact endocrine regulatory mechanisms. [1] [2] [3] [4] Much of this activity may be related to various phytoestrogenic components of cimicifuga, with formononetin perhaps being the most significant. [5] However, the activity of phytoestrogens is substantially less than endogenous estrogens, indicating they exert more of an anti-estrogen than pro-estrogen effect. The estrogenic action of cimicifuga goes well beyond its phytoestrogen content. For example, the isoflavonoid formononetin has been identified as being the chief phytoestrogen of cimicifuga; however, it is much less active than many other phytoestrogens (e.g. genestein), as its relative binding affinity for estrogen receptors is only one-hundredth as strong as 17-beta-estradiol. [5] In addition, cimicifuga’s action appears to be more closely related to estriol than to estradiol. While estradiol is associated with an increased risk for breast, ovarian, and endometrial cancers, estriol is actually associated with offering some protection against these cancers. [6] [7] The reason may be that estriol is much weaker in action and has a shorter dwelling time on receptors on the surface of the cells compared with the more potent estradiol. Estrogen-dependent tumors are not stimulated by the weak-acting estriol, as it is acting as a partial antagonist to estradiol. Physiologically, estriol exerts its effects primarily on the vaginal lining, while estradiol exerts its effects primarily on the uterine lining. This action appears to mirror the effects with extracts of cimicifuga noted in clinical studies in menopausal women concerning its effect on the vaginal epithelium. Cimicifuga’s primary effect on endocrine regulatory mechanisms appears to be the result of complex synergistic actions of its key ingredients – the triterpenes and flavone derivatives. Evidence suggests that these compounds act on both the hypothalamus and vasomotor centers to produce significant clinical benefits in menopause. For example, one study involved in determining the endocrinological actions of cimicifuga extract involved treating 110 women with either cimicifuga extract (supplying a total daily dosage of 8 mg of 27-deoxyactein) or placebo. [4] After 2 months of treatment, LH decreased by 20% in the cimicifuga group compared with the placebo group. Unlike estrogens, cimicifuga does not affect the release of prolactin and follicle-stimulating hormone (FSH). Researchers then divided the extract into three distinct types of active compounds based upon their ability to reduce LH secretion in ovariectomized rats and to compete in vitro with 17-beta-estradiol for estrogen receptor binding sites, as follows: • constituents that did not bind to estrogen receptors, but that did suppress LH secretion • constituents able to bind to estrogen receptor sites and to inhibit LH secretion
• compounds able to bind to estrogen receptors, but which did not inhibit LH secretion. The authors concluded that: “the LH suppressive effect of Cimicifuga racemosa extracts observed in menopausal women and ovariectomized rats is caused by at least three different synergistically acting compounds.” In summary, one of cimicifuga’s key pharmacological effects is inhibition of the secretion of luteinizing hormone (LH) by the pituitary. This effect is accomplished equally by components which do and do not bind to estrogen receptors. If cimicifuga was simply mimicking the effects of estrogen, it would certainly alter the secretion of other pituitary hormones just like estrogen, but it does not.
CLINICAL APPLICATIONS A special extract of Cimicifuga racemosa standardized to contain 1 mg of triterpenes calculated as 27-deoxyacteine per tablet (trade name = Remifemin) is the most widely used and thoroughly studied natural alternative to hormone replacement therapy in menopause. In 1996, nearly 10 million monthly units of this extract were sold in Germany, the US, and Australia. Clinical studies have shown this cimicifuga extract to relieve not only hot flashes, but also depression and vaginal atrophy. [4] [8] [9] [ 10] [11]
While there is also some evidence that cimicifuga may provide benefit in other gynecological complaints such as premenstrual syndrome, amenorrhea (both primary
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TABLE 75-1 -- Cimicifuga in the treatment of menopause Percentage no longer present (%) Percentage improved %
Symptom
Total percentage improved (%)
Hot flashes
43.3
43.3
86.6
Profuse perspiration
49.9
38.6
88.5
Headache
45.7
36.2
81.9
Vertigo
51.6
35.2
86.8
Heart palpitation
54.6
35.2
90.4
Ringing in the ears
54.8
38.1
92.9
Nervousness/irritability 42.4
43.2
85.6
Sleep disturbances
46.1
30.7
76.8
Depressive moods
46.0
36.5
82.5
and secondary), dysmenorrhea, polymenorrhea, uterine fibroids, and fibrocystic breast disease, its primary clinical application is menopause.
[12] [13] [14]
Menopause
In a large open study involving 131 doctors and 629 female patients, cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein) produced clear improvement of menopausal symptoms in over 80% of patients within 6–8 weeks. [8] As shown in Table 75.1 , both physical and psychological symptoms improved. Most patients reported noticeable benefits within 4 weeks after the onset of cimicifuga therapy. After 6–8 weeks, complete resolution of symptoms were achieved in a large percentage of patients. Cimicifuga was very well tolerated as there was no discontinuation of therapy and only 7% of patients reported mild transitory stomach complaints. In a double-blind study, 60 patients were given cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein), conjugated estrogens (0.625 mg daily), or diazepam (2 mg daily) for 12 weeks. [9] Results from standard indexes of menopausal symptoms indicated a clear advantage of cimicifuga extract over both drugs. Cimicifuga’s effect on relieving the depressive mood and anxiety associated with menopause was far superior to either diazepam or conjugated estrogens, as shown in Table 75.2 . One of the most utilized assessments in clinical studies in menopause is the Kupperman Menopausal Index. This quantitative assessment of menopausal symptoms is achieved by grading in severity: severe = 3, moderate = 2, mild = 1, not present = 0. The symptoms assessed are: TABLE 75-2 -- Effect on Kupperman Menopausal Index of cimicifuga compared with conjugated estrogens and diazepam Treatment group Beginning At 12 weeks Cimicifuga
35
14
Conjugated estrogens
35
16
Diazepam
35
20
• hot flashes • depressive moods • profuse perspiration • feelings of vertigo • sleep disturbances • loss of concentration • headache • joint pain • nervousness/irritability • heart palpitation. The results on the Kupperman Menopausal Index from this trial clearly demonstrate cimicifuga extract’s superiority over conjugated estrogens and diazepam, especially when safety and side-effects are taken into consideration. In another double-blind study, 80 patients were given cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein), conjugated estrogens (0.625 mg daily), or placebo for 12 weeks. [10] Cimicifuga produced better results in the Kupperman Menopausal Index, the Hamilton anxiety test, and the vaginal lining than estrogens or placebo. The number of hot flashes experienced each day dropped from an average of five to less than one in the cimicifuga group. In comparison, the estrogen group only dropped from five to 3.5. Even more impressive was the effect of cimicifuga on the vaginal lining. While both conjugated estrogens and the placebo produced little effect, a dramatic increase in the number of superficial cells was noted in cimicifuga group. In a double-blind study of 110 women, cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein) was shown to exert significant improvements in menopausal symptoms.[4] In addition to providing relief of hot flashes, cimicifuga once again demonstrated impressive results on the vaginal lining as
confirmed by vaginal smear. In a study of 60 women under the age of 40 who had hysterectomies leaving at least one intact ovary, the women were given either cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein), estriol (1 mg daily), conjugated estrogens (1.25 mg daily), or estrogen-progestin combination (Trisequens,
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one tablet daily). [11] Although the hormone therapies produced better results as determined by a modified Kupperman’s Menopausal Index, cimicifuga still displayed significant effects in relieving the symptoms of “surgical menopause”. These results indicate that cimicifuga can be a suitable alternative to estrogens in women having partial, and possibly even complete, hysterectomies. Effects on bone resorption
One of the most publicized effects of estrogen is its role in maintaining bone health and preventing osteoporosis. While there is experimental and epidemiological evidence that phytoestrogens prevent osteoporosis and reduce bone resorption, there are currently no long-term studies demonstrating cimicifuga can prevent or improve osteoporosis. However, based on cimicifuga’s mechanism of action and long-term clinical experience, many experts believe it will be shown to positively influence bone resorption. In patients at high risk for osteoporosis or those with confirmed low bone density, physicians should monitor therapy with cimicifuga by using the Osteomark-NTX or other suitable indicator of bone resorption.
DOSAGE The dosage of cimicifuga is based on its content of 27-deoxyactein, which serves as an important biochemical marker to indicate therapeutic effect. The dosage of the cimicifuga extract used in the majority of clinical studies has been 2 mg of 27-deoxyacteine twice daily. Here are the approximate dosage recommendations using other forms (non-standardized) of Cimicifuga racemosa: • 27-deoxyacteine: 2 mg b.i.d. • powdered rhizome: 1–2 g • tincture (1:5): 4–6 ml • fluid extract (1:1): 3–4 ml (1 tsp) • solid (dry powdered) extract (4:1): 250–500 mg. The German Commission E has recommended that treatment with cimicifuga be limited to 6 months (which is also the standard recommendation for hormone replacement therapy); however, this recommendation was made prior to the detailed toxicology studies discussed below. Based on currently available data, cimicifuga is appropriate for long-term continued use.
TOXICOLOGY The standardized extract of Cimicifuga racemosa providing 1 mg of 27-deoxyactein per approximately 40 mg of extract per tablet known as Remifemin has been used in Germany since 1956 and has a remarkable safety record. No serious side-effects have ever been reported. The BGA, the German equivalent to the FDA in the US, includes no contraindications or limitations of use for cimicifuga. Therefore, cimicifuga offers a suitable natural alternative to hormone replacement therapy for menopause, especially where hormone replacement therapy is contraindicated, e.g. in women with a history of cancer, unexplained uterine bleeding, liver and gall bladder disease, pancreatitis, endometriosis, uterine fibroids or fibrocystic breast disease. Since cimicifuga extract shows some, albeit weak, estrogenic activity, researchers have sought to determine Remifemin’s effect on established breast tumor cell line whose growth in vitro depends on the presence of estrogens. The results from these experiments show no stimulatory effects, but rather inhibitory effects. [15] Furthermore, combining Remifemin with tamoxifen was shown to potentiate the inhibitory effects of tamoxifen. Detailed toxicology studies have also been performed on Remifemin. No teratogenic, mutagenic, or carcinogenic side-effects have been noted. The no-effect dosage in studies in a 6 month chronic toxicity study in rats was at 1,800 mg/kg body weight – or roughly 90 times the therapeutic dose. [16] A 6 month toxicological study in rats is comparable to an unlimited treatment time in humans.
REFERENCES 1. Harnischfeger
G, Stolze H. Proven active substances from natural materials. Black snake root. Notabene Medici 1980; 10: 446–450
2. Jarry
H, Harnischfeger G. Studies on the endocrine efficacy of the constituents of Cimicifuga racemosa. I. Influence on the serum concentration of pituitary hormones in ovariectomied rats. Planta Med 1985; 51: 80–83 3. Jarry
H, Harnischfeger G, Duke E. Studies on the endocrine efficacy of the constituents of Cimicifuga racemosa. II. In vitro binding of compounds to estrogen receptors. Planta Med 1985; 51: 291–296 4. Duker
EM et al. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Medica 1991; 57: 420–424
5. Miksicek
RJ. Commonly occurring plant flavonoids have estrogenic activity. Molecular Pharmacology 1993; 44: 37–43
6. Tzingounis 7. Lemon
VA, Aksu MF, Greenblatt RB. Estriol in the management of the menopause. JAMA 1978; 239: 1638–1641
HM. Pathophysiologic considerations in the treatment of menopausal symptoms with oestrogens; the role of oestriol in the prevention of mammary carcinoma. Acta Endocrinol 1980; 233:
17–27 8. Stolze
H. An alternative to treat menopausal complaints. Gynecology 1982; 3: 14–16
9. Warnecke
G. Influencing menopausal symptoms with a phytotherapeutic agent. Med Welt 1985; 36: 871–874
10.
Stoll W. Phytopharmacon influences atrophic vaginal epithelium. Double-blind study – Cimicifuga vs. estrogenic substances. Therapeuticum 1987; 1: 23–31
11.
Lehmann-Willenbrock E et al. Clinical and endocrinologic examinations of climacteric symptoms following hysterectomy with remaining ovaries. Zent Gynakol 1988; 110: 611–618
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12.
Bruker A. Essay on the phytotherapy of hormonal disorders in women. Med Welt 1960; 44: 2331–2333
13.
Schildge E. Essay on the treatment of premenstrual and menopausal moods swings and depressive states. Rigelh Biol Umsch 1964; 19(2): 18–22
14.
Gorlich N. Treatment of ovarian disorders in general practice. Arztl Prax 1962; 14: 1742–1743
Nesselhut T, Borth S, Kuhn W. Influence of Cimicifuga racemosa extracts with estrogen-like activity on the in vitro proliferation of mammary carcinoma cells. Arch Gynecol Obstet 1993; 254: 817–818 15.
16.
Korn WD. Six-month oral toxicity study with Remifemin-granulate in rats followed by an 8-week recovery period. Hannover: International Bioresearch. 1991
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Chapter 76 - Coenzyme Q10 Alan R. Gaby MD
INTRODUCTION Coenzyme Q10 (CoQ10 ) is a compound found naturally in the human body. Because of its ubiquitous presence in nature and its quinone structure (similar to that of vitamin K), CoQ 10 is also known as ubiquinone ( Fig. 76.1 ). The primary biochemical action of CoQ 10 is as a cofactor in the electron-transport chain, the series of redox reactions that are involved in the synthesis of ATP. Since most cellular functions are dependent on an adequate supply of ATP, CoQ 10 is essential for the health of virtually all human tissues and organs. Although CoQ 10 can be synthesized in vivo, situations may arise in which the body’s synthetic capacity is insufficient to meet CoQ 10 requirements. Susceptibility to CoQ10 deficiency appears to be greatest in cells that are the most metabolically active (such as those in the heart, immune system, gingiva, and gastric mucosa), since these cells presumably have the highest requirements for CoQ 10 . Tissue deficiencies or subnormal serum levels of CoQ 10 have been reported to occur in a wide range of medical conditions, including cardiovascular disease, hypertension, periodontal disease, and acquired immuno-deficiency syndrome (AIDS). In addition, CoQ10 levels decline with advancing age, and this decline might contribute in part to some of the manifestations of aging. A need for supplemental CoQ 10 could theoretically result from: • impaired CoQ 10 synthesis due to nutritional deficiencies • a genetic or acquired defect in CoQ 10 synthesis or utilization 664
• increased tissue needs resulting from a particular illness • the requirement to prevent the side-effects of a medical intervention.
Figure 76-1 Coenzyme Q10 .
Since oral administration of CoQ 10 can increase tissue levels of the nutrient, it is possible to correct CoQ supplementation. [1]
10 deficiency
and its associated metabolic consequences by
Detection of CoQ 10 deficiency
CoQ10 participates in the citric acid cycle (Krebs cycle) enzyme known as succinate dehydrogenase-CoQ 10 reductase. An assay of the activity of this enzyme has been used to detect deficiencies of CoQ 10 .[2] If the enzyme is fully saturated with CoQ 10 in vivo, then addition of exogenous CoQ will not increase enzyme activity. On the other hand, exogenous CoQ will increase activity appreciably when tissue levels of CoQ 10 are low. More recently, measurements of serum CoQ10 levels have been used to detect deficiencies.
CLINICAL APPLICATIONS Immune function
Cells and tissues that play a role in immune function are highly energy-dependent and therefore require an adequate supply of CoQ 10 for optimal function. Several studies have demonstrated immune-enhancing effects of CoQ 10 or its analogues. [3] [4] [5] These effects included increased phagocytic activity of macrophages, increased proliferation of granulocytes in response to experimental infections, and prolonged survival in mice infected with Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Candida albicans. Inoculation of animals with Friend leukemia virus reduced CoQ 10 levels in the blood and spleen, [6] whereas treatment of infected animals with CoQ10 increased the survival rate and decreased the severity of hepatomegaly and splenomegaly. [7] Immune function tends to decline with advancing age. In a study of elderly mice, suppression of the immune response was associated with a marked decline of CoQ levels in thymic tissue. [8] This immune suppression was partly reversed by treatment with CoQ 10 . [9] In a study of eight chronically ill patients, administration of 60 mg/day of CoQ 10 was associated with significant increases in serum levels of immunoglobulin G (IgG) after 27–98 days of treatment. [10] These studies suggest that CoQ10 may help to prevent or reverse the immunosuppression that is associated with aging or chronic disease.
10
Acquired immunodeficiency syndrome (AIDS)
AIDS is a complex disease that is associated with a wide range of nutritional deficiencies and immunological disorders. While correction of nutritional deficiencies will not cure AIDS, appropriate nutritional interventions may help to prevent weight loss and enhance overall immune function. In addition, since oxidative stress is believed to be involved in the pathogenesis of AIDS-related diseases, the antioxidant activity of CoQ 10 may be of value for individuals with AIDS. [11] In one study, blood levels of CoQ 10 were significantly lower in patients with AIDS-related complex (ARC) than in a control group and were significantly lower in patients with AIDS than in those with ARC. [12] Six patients with AIDS or ARC were treated with 200 mg/day of CoQ10 . T-cell helper/suppressor ratios increased in three patients, becoming normal in one case. Five patients reported symptomatic improvement, which was dramatic in some cases. Furthermore, none of the patients developed opportunistic infections during a 4–7 month follow-up period. This study demonstrates that CoQ 10 deficiency is common in patients with HIV infection, and that supplementation with CoQ 10 may improve immune function and reduce the incidence of opportunistic infections. Cancer
Because of its role in enhancing immune function, CoQ 10 has been considered as a possible anti-cancer agent. Administration of CoQ 10 reduced tumor size and increased survival in mice exposed to a chemical carcinogen. [13] Preliminary studies in humans, though uncontrolled, are promising. In one study, 32 women with
breast cancer who were classified as “high risk” because of tumor spread to the axillary lymph nodes received 90 mg/day of CoQ 10 , along with vitamin C, vitamin E, beta-carotene, and essential fatty acids. In six of these women, the tumor became smaller. During the 18 month treatment period, none of the patients died (the expected number of deaths was four) and none showed signs of further distant metastases. Six patients had an apparent partial remission. In addition, patients receiving CoQ 10 required fewer pain killers. [14] In another report, two women with metastatic breast cancer received 390 mg/day of CoQ 10 . One was a 44-year-old woman with numerous liver metastases. After treatment with CoQ10 for 11 months, all of the liver metastases had disappeared and the patient was reported to be in excellent health. The other patient was a 49-yearold woman with breast cancer that had metastasized to the pleural cavity. After 6 months of CoQ 10 therapy, the pleural fluid had completely resolved and the patient was reported to be in excellent health. [15] Although these reports are anecdotal, the results are far better than would normally be expected. Considering that CoQ treatment of breast cancer with CoQ10 seems justified.
10
is virtually free of side-effects, empirical
665
Periodontal disease
Periodontal disease affects about 60% of young adults and 90% of individuals over the age of 65. Although proper oral hygiene is helpful, many people suffer from intractable gingivitis, often requiring surgery and resulting in eventual loss of teeth. Because periodontal disease is so common, the costs of periodontal surgery and other treatments contribute a significant amount to the overall cost of health care in the United States. Healing and repair of periodontal tissues require efficient energy production, which depends on an adequate supply of CoQ 10 . However, gingival biopsies revealed subnormal tissue levels of CoQ 10 in 60–96% of patients with periodontal disease and low levels of CoQ 10 in leukocytes in 86% of cases. [16] [17] [18] [19] These findings indicate that periodontal disease is frequently associated with CoQ 10 deficiency. Eighteen patients with periodontal disease received either 50 mg/day of CoQ 10 or a placebo in a 3 week double-blind trial. [20] [21] Results were assessed according to a “periodontal score”, which included gingival-pocket depth, swelling, bleeding, redness, pain, exudate, and looseness of teeth. All eight patients receiving CoQ 10 improved, compared with only three of 10 receiving the placebo ( P < 0.01). The treating dentists, who were unaware that a study was being conducted, consistently remarked about the “very impressive” rate of healing in patients treated with CoQ 10 . One prosthodontist commented that the amount of healing that took place in 3 weeks in patients receiving CoQ 10 would normally require about 6 months. In an open trial, administration of CoQ 10 produced “extraordinary post-surgical healing” (two to three times as fast as usual) in seven patients with advanced periodontal disease. [22] The beneficial effect of CoQ 10 has also been confirmed in dogs, where it reduced the severity of experimentally induced periodontal disease.
[ 23]
Gastric ulcer
Susceptibility to gastric ulceration is related to the balance between ulcer-promoting factors (such as excessive gastric acidity and infection with Helicobacter pylori) and resistance factors (such as tissue integrity, production of protective mucus, and repair mechanisms). Free radical damage is believed to be one of the primary mechanisms by which external factors induce gastric injury and peptic ulceration. [24] [25] Since CoQ10 possesses antioxidant activity, it may be capable of preventing ulceration by reducing the amount of free radical damage. In addition, the production of protective mucus and the rapid cell turnover of gastric mucosa are highly energy-dependent processes, which require the presence of adequate amounts of CoQ 10 . The efficiency of these protective and reparative processes may be compromised in some patients with gastric ulcers. With advancing age, the fundic mucosa and its rich blood supply are gradually replaced by pyloric tissue, which has poor vascularity. This change in cell type may result in hypoxia in certain portions of the stomach. The hypoxic state of gastric tissue could explain why gastric ulcers frequently become intractable in elderly patients or in those with chronic heart or lung disease. The importance of CoQ10 for healing of gastric ulcers has been demonstrated in animals. [26] Gastric ulcers were induced in mice by the application of acetic acid. The mice were then maintained either in room air (20% oxygen) or under mild hypoxic conditions (17% oxygen). Ulcers healed normally in mice exposed to room air, but increased in size under hypoxic conditions. However, in hypoxic mice treated with CoQ 10 (50 mg/kg per day) the ulcers healed normally. This study demonstrates that hypoxia has an adverse effect on the healing of gastric ulcers in animals, and that the effect of hypoxia can be prevented by administration of CoQ 10 . Although human studies have not been done, empirical use of CoQ 10 seems to be a reasonable option for elderly patients with intractable gastric ulcers, particularly those who also have diseases likely to produce hypoxia. Obesity
The tendency to become overweight is associated in some cases with impaired energy production. This abnormality may be in part genetically determined. Individuals with a family history of obesity have a 50% reduction in their thermogenic response to meals, suggesting the presence of an hereditary defect in energy output. Since CoQ10 is an essential cofactor for energy production, it is possible that CoQ 10 deficiency is a contributing factor in some cases of obesity. Serum levels of CoQ10 were found to be low in 14 (52%) of 27 morbidly obese patients. [27] Nine of these 27 individuals (five with low CoQ 10 levels) received 100 mg/day of CoQ 10 along with a 650 kcal/day diet. After 8–9 weeks, the mean weight loss in the CoQ 10 -deficient group was 13.5 kg, compared with 5.8 kg in those with normal levels of CoQ 10 . One possible interpretation of this study is that about 50% of obese individuals are deficient in CoQ 10 and that replacement therapy accelerates weight loss during calorie restriction. However, it is also possible that CoQ 10 treatment had nothing to do with the accelerated weight loss. Obese individuals with low CoQ 10 levels may have other metabolic abnormalities which are more directly related to their obesity. A low CoQ 10 level might therefore have been an effect, rather than a cause, of the abnormalities that caused obesity. Until a controlled study
666
is done to evaluate the effectiveness of this therapy, the potential value of CoQ
10 as
a treatment for obesity remains speculative.
Physical performance
Because CoQ 10 is involved in energy production and its concentration in muscle is correlated with performance, it is possible that supplementation could enhance aerobic capacity and muscle performance. In one study, six healthy sedentary men (mean age, 21.5 years) performed a bicycle ergometer test before and after taking CoQ10 (60 mg/day) for 4–8 weeks.[28] CoQ10 treatment improved certain performance parameters, including work capacity at submaximal heart rate, maximal work load, maximal oxygen consumption, and oxygen transport. These improvements ranged from 3 to 12% and were evident after about 4 weeks of supplementation. This study suggests that administration of CoQ 10 improves physical performance in sedentary individuals. The effect of CoQ 10 on the performance of trained athletes has not shown benefit (see Ch. 59 for a more complete discussion).
Muscular dystrophy
Biochemical evidence of CoQ 10 deficiency was found in cardiac and skeletal muscle of animals with hereditary muscular dystrophy. [29] In addition, treatment with CoQ10 or its analogues increased survival and improved the performance of dystrophic mice, rabbits, and monkeys, as determined by a reduction of creatinuria, regaining of righting reflex, and weight gain. [30] [31] [32] [33] Deficiency of CoQ 10 has been found in muscle mitochondria of humans with muscular dystrophy. [34] This deficiency could conceivably be involved in the pathogenesis of cardiac disease, which occurs in virtually every form of muscular dystrophy and myopathy. In a double-blind study, 100 mg of CoQ 10 was given daily for 3 months to 12 patients with progressive muscular dystrophy. CoQ 10 treatment resulted in significant improvements in cardiac output and stroke volume, as well as increased physical well-being in four of eight patients. [35] Subjective improvements included increased exercise tolerance, reduced leg pain, better control of leg function, and less fatigue. The mechanism of action of CoQ 10 is probably related to improved energy production in muscle cells. Allergy
When passively sensitized guinea pig lung tissue was preincubated with CoQ 10 , release of both histamine and slow-reacting substance of anaphylaxis induced by antigen challenge was markedly inhibited. [36] This study raises the possibility that CoQ 10 may be of value in the treatment of various allergy-related disorders. However, no clinical trials have been performed in this area. Cardiovascular disease – general considerations
Enhancing myocardial function is an important, though frequently overlooked, component of the overall prevention and treatment of cardiovascular disease. CoQ 10 plays a key role in energy production, and is therefore essential for all energy-dependent processes, including heart muscle contraction. CoQ 10 deficiency has been documented in patients with various types of cardiovascular disease. It is not clear whether a decline in CoQ 10 levels is a primary cause or a consequence of heart disease. However, given the fundamental involvement of CoQ 10 in myocardial function, it is not unlikely that CoQ 10 deficiency would exacerbate heart disease and that correction of such a deficiency would have therapeutic value. In addition, CoQ10 has been shown to be a potent antioxidant. In fact, ubiquinol-10, the reduced form of CoQ 10 , protected human low-density lipoproteins (LDL) more efficiently against lipid peroxidation than did vitamin E. [37] Since oxidation of LDL is believed to be an initiating factor in the development of atherosclerosis, CoQ 10 would appear to be a preventive factor. Cardiac disease
Circulating levels of CoQ 10 are significantly lower in patients with ischemic heart disease and in those with dilated cardiomyopathy (mostly New York Heart Association [NYHA] functional class III or IV) than in healthy controls. [38] [39] In another study, CoQ 10 levels in myocardial tissue (estimated by enzymatic methods) were low in approximately 75% of patients undergoing cardiac surgery. Concentrations of CoQ 10 declined progressively in both blood and myocardial tissue with increasing severity of heart disease. [40] Myocardial deficiencies of CoQ 10 were also found in the majority of patients with aortic stenosis or insufficiency, mitral stenosis or insufficiency, diabetic cardiomyopathy, tetralogy of Fallot, atrial septal defects and ventricular septal defects. [41] In patients with cardiomyopathy and myocardial deficiency of CoQ10 , oral administration of 100 mg/day of CoQ 10 for 2–8 months resulted in an increase in myocardial CoQ 10 levels, ranging from 20 to 85%. [42] These findings suggest that CoQ 10 deficiency is common in patients with various types of cardiovascular disease, and that oral administration of CoQ 10 can increase tissue levels of this nutrient. Cardiomyopathy
In one study, 126 patients with dilated cardiomyopathy (98% of whom were in NYHA functional class III or IV)
667
received 100 mg/day of CoQ10 for periods of up to 66 months. After 6 months of treatment, the mean ejection fraction increased from 41% to 59% (P< 0.001), and remained stable thereafter with continued treatment. After 2 years 84% of the patients were still alive, and at 5.5 years 52% were alive. [43] These survival rates are considerably better than the published survival statistics of patients given conventional therapy (i.e. 2-year survival rate of 50% for symptomatic cardiomyopathy, and 1-year survival rate of 50% for decompensated cardiomyopathy). In another study, 88 patients with cardiomyopathy received 100 mg/day of CoQ 10 for periods of 1–24 months. Significant improvements in at least two of three cardiac parameters (ejection fraction, cardiac output, and NYHA class) were seen in 75–85% of the patients. Approximately 80% of the patients improved to a lower (i.e. more favorable) NYHA functional class. [44] In a double-blind, cross-over trial, 19 patients with cardiomyopathy (NYHA classes III and IV) received 100 mg/day of CoQ 10 or a placebo, each for 12 weeks. Compared with placebo, CoQ 10 treatment significantly increased cardiac stroke volume and ejection fraction. Eighteen patients reported improvement in activity while taking CoQ10 .[45] Congestive heart failure
The potential of CoQ 10 as a treatment for congestive heart failure (CHF) was suggested as early as 1967 by Japanese researchers. [46] In 1976, these same investigators administered 30 mg/day of CoQ 10 to 17 patients with CHF. All of the patients improved, and nine (53%) became asymptomatic after 4 weeks of treatment.[47] In an open trial of 34 patients with refractory NYHA class IV CHF, administration of 100 mg/day of CoQ 10 resulted in sustained improvement in cardiac function in 28 cases (82%). The survival rate after 2 years was 62%, compared with an expected 2-year survival rate of less than 25% for similar patients. [48] In another study, 12 patients with advanced CHF who had failed to respond adequately to digitalis and diuretics received 100 mg/day of coenzyme Q 10 for 7 months. Two-thirds of the patients showed definite clinical improvement after a mean treatment period of 30 days. In these patients, dyspnea at rest disappeared and energy level and tolerance for activity increased. Objective improvements included decreased hepatic congestion, reductions in heart rate and heart volume, and a decline in systolic time intervals (suggesting improved myocardial performance). Withdrawal of coenzyme Q 10 was followed by severe clinical relapse, with subsequent improvement upon resumption of treatment. [49] In a large multicenter trial, 1,113 CHF patients received 50–150 mg/day of CoQ 10 for 3 months (78% of the patients received 100 mg/day). The proportion of patients with improvements in clinical signs and symptoms were as follows: [50] • cyanosis, 81% • edema, 76.9% • pulmonary rales, 78.4% • enlargement of the liver area, 49.3% • jugular reflux, 81.5% • dyspnea, 54.2%
• palpitations, 75.7% • sweating, 82.4% • arrhythmia, 62% • insomnia, 60.2% • vertigo, 73% • nocturia, 50.7%. The results of these uncontrolled studies were confirmed more recently in a double-blind trial. Some 641 patients with CHF (NYHA classes III or IV) were randomly assigned to receive placebo or CoQ 10 (2 mg/kg per day) for 1 year. Conventional therapy was continued in both groups. The number of patients requiring hospitalization during the study for worsening heart failure was 38% less in the CoQ 10 group than in the placebo group ( P < 0.001). Episodes of pulmonary edema were reduced by about 60% in the CoQ 10 group, compared with the placebo group (P< 0.001).[51] Angina
Twelve patients with stable angina pectoris were randomly assigned to receive 150 mg/day of CoQ 10 or a placebo in a 4 week double-blind cross-over trial. CoQ 10 treatment significantly increased exercise tolerance on a treadmill (time before onset of chest pain), and significantly increased the time until ST-segment depression occurred. Compared with placebo, there was a 53% reduction in the frequency of anginal episodes and a 54% reduction in the number of nitroglycerin tablets needed during CoQ 10 treatment; however, these differences were not statistically significant. [52] These results suggest that CoQ 10 is a safe and effective treatment for angina pectoris. Although the amelioration of anginal attacks was not statistically significant, the magnitude of the effect was large. It would therefore be worthwhile to perform a similar study with a larger number of patients. Arrhythmias
Twenty-seven patients with ventricular premature beats (VPBs) and no evidence of organic heart disease received a placebo for 3–4 weeks, followed by 60 mg/day of CoQ10 for 4–5 weeks. The reduction in VPBs was significantly greater after CoQ 10 than after placebo. The beneficial
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effect of CoQ10 was seen primarily in diabetics, in whom the mean reduction in VPB frequency was 85.7%. A significant reduction in VPBs also occurred in one (11%) of nine otherwise healthy patients and in four (36%) of 11 patients with hypertension. [53] Prevention of adriamycin toxicity
The clinical value of adriamycin as an anti-cancer agent is limited by its toxicity, which includes cardiomyopathy and irreversible heart failure. Adriamycin-induced cardiotoxicity is believed to be caused, at least in part, by a reduction in CoQ 10 levels and by inhibition of CoQ 10 -dependent enzymes. In rats treated with adriamycin, administration of CoQ 10 restored the levels of this nutrient to normal and prevented adriamycin-induced morphologic changes in the heart. [54] Treatment with CoQ10 also prevented adriamycin-induced cardiotoxicity in rabbits. [55] Cancer patients receiving adriamycin had lower myocardial levels of CoQ 10 than did controls. The magnitude of CoQ 10 depletion was directly related to the severity of cardiac impairment. [56] To determine the effect of CoQ 10 supplementation on adriamycin cardiotoxicity, seven patients receiving adriamycin were also given 100 mg/ day of CoQ10 , beginning 3–5 days before adriamycin was started. Another seven patients (control group) received adriamycin without CoQ 10 . Cardiac function deteriorated significantly in the control group, whereas patients given CoQ 10 had little or no cardiotoxicity, even though the cumulative dose of adriamycin in the CoQ10 group was 50% greater than that in the control group. [57] Despite the small number of patients in this study, the results are highly encouraging. Since administration of CoQ 10 does not appear to affect the antitumor activity of adriamycin, CoQ 10 prophylaxis seems appropriate for all patients receiving adriamycin. [58] Protection during cardiac surgery
Postoperative low cardiac output is a major cause of early death following cardiac surgery. Fifty patients undergoing cardiac surgery for acquired valvular lesions were randomly assigned to receive 30–60 mg/day of CoQ 10 for 6 days prior to surgery or to a control group that did not receive CoQ 10 . Postoperatively, a state of severe low cardiac output developed in 48% of the patients in the control group, compared with only 12% of those in the CoQ 10 group. These results suggest that pre-operative administration of CoQ 10 increases the tolerance of the heart to ischemia during aortic cross-clamping. [59] Mitral valve prolapse
Cardiac performance was evaluated using an isometric hand-grip test in 194 children with symptomatic mitral valve prolapse. Prior to treatment, all patients had an abnormal hand-grip test. Sixteen children received 2 mg/kg per day of CoQ 10 or a placebo for 6 weeks, in a single-blind trial. Hand-grip strength became normal in seven of the patients receiving CoQ 10 and in none of the placebo-treated patients. [60] However, the relevance of this study to the treatment of mitral valve prolapse in adults is doubtful. Aside from the study’s inadequate blinding, isometric hand-grip may not be a reliable test of cardiac function. Furthermore, impaired cardiac function is not typical of mitral valve prolapse in adults, and the symptoms associated with this condition do not appear to be caused by diminished cardiac function. While the symptoms associated with mitral valve prolapse may respond to magnesium supplementation, [61] the role of CoQ10 in the treatment of this disorder is unclear. Hypertension
Enzymatic assays revealed a deficiency of CoQ 10 in 39% of 59 patients with essential hypertension, compared with only 6% of healthy controls. In animal models of hypertension, including spontaneously hypertensive rats, uninephrectomized rats treated with saline and deoxycorticosterone, and experimentally hypertensive dogs, orally administered CoQ 10 significantly lowered blood pressure. [62] [63] [64] [65] Twenty-six patients with essential hypertension received 50 mg of CoQ 10 twice a day. After 10 weeks of treatment, mean systolic blood pressure decreased from 164.5 to 146.7 mmHg and mean diastolic blood pressure decreased from 98.1 to 86.1 mmHg (P < 0.001). The fall in blood pressure was associated with a significant reduction in peripheral resistance, but there were no changes in plasma renin activity, serum and urinary sodium and potassium, and urinary aldosterone. These results suggest that treatment with CoQ10 decreases blood pressure in patients with essential hypertension, possibly because of a reduction in peripheral resistance.[66] In another study, 109 patients with essential hypertension received CoQ 10 (average dose, 225 mg/day) in addition to their usual antihypertensive regimen. The dosage of CoQ10 was adjusted according to clinical response and blood CoQ 10 levels (the aim was to attain blood levels greater than 2.0 mcg/ml). The need for antihypertensive medication declined gradually, and after a mean treatment period of 4.4 months, about half of the patients were able to discontinue between one and three drugs.[67] Similar results have been reported by others. [68] It should be noted that the effect of CoQ 10 on blood pressure was usually not seen until after 4–12 weeks of therapy. That observation is consistent with the delayed
669
increase in enzyme activity that results from administration of CoQ 10 . Thus, CoQ10 is not a typical antihypertensive drug; rather, it seems to correct some metabolic abnormality that is involved in the pathogenesis of hypertension. Diabetes mellitus
Diabetes mellitus is a multifactorial disease that is associated with a number of different metabolic abnormalities. The electron transport chain, of which CoQ component, plays a major role in carbohydrate metabolism. A deficiency of CoQ 10 might therefore have an adverse effect on glucose tolerance.
10
is a
Decreased levels of CoQ 10 (measured as total CoQ) were found in rats with experimentally induced diabetes. Administration of CoQ 7 (an analog of CoQ 10 ) partially corrected abnormal glucose metabolism in alloxan-diabetic rats. (Before CoQ 10 became commercially available, some therapeutic trials were done with CoQ 7 . These two compounds are considered to be nutritionally equivalent.) Thirty-nine diabetics received 120 mg/day of CoQ 7 for 2–18 weeks. Fasting blood sugar levels fell by at least 30% in 31% of the patients and the concentration of ketone bodies declined by at least 30% in 59% of the patients. One patient who was poorly controlled on 60 units/day of insulin showed a marked fall in fasting blood sugar and ketone bodies after receiving CoQ 7 .[69] Infertility
Because sperm production and function are highly energy-dependent processes, CoQ 10 deficiency could presumably be a contributing factor to infertility in men. In one study, administration of 10 mg/day of CoQ 7 resulted in a considerable increase in sperm count and motility in a group of infertile men. [70] Additional research is needed to determine whether CoQ 10 therapy has a role in the treatment of infertility. Drug interactions
Cholesterol-lowering drugs such as lovastatin and pravastatin inhibit the enzyme 3-hydroxy-3-methylglutaryl(HMG)-CoA reductase, which is required for biosynthesis of both cholesterol and CoQ 10 . Thus, administration of these drugs might compromise CoQ 10 status by decreasing its synthesis. Supplementation of the diet of rats with lovastatin (400 mg/kg of diet) for 4 weeks reduced the concentration of CoQ 10 in the heart, liver, and blood. [71] In another study, administration of lovastatin to five patients receiving CoQ 10 for heart failure was followed by a reduction in blood levels of CoQ 10 and a significant deterioration of clinical status. Some of these patients improved after the dosage of CoQ10 was increased or the lovastatin was discontinued. [72] These results suggest that people who have low CoQ 10 levels and suboptimal cardiac function might develop clinically significant CoQ 10 depletion after taking an HMG-CoA reductase inhibitor. Although individuals with high CoQ 10 levels and good cardiac function can probably tolerate these drugs better, a case can be made that all patients being treated with HMG-CoA reductase inhibitors should also receive CoQ 10 prophylactically. The beta-blockers propranolol and metaprolol have been shown to inhibit CoQ 10 -dependent enzymes.[73] The antihypertensive effect of these drugs might therefore be compromised in the long run by the development of CoQ 10 deficiency. In one study, administration of 60 mg/day of CoQ 10 reduced the incidence of drug-induced malaise in patients receiving propranolol. [74] A number of phenothiazines and tricyclic antidepressants have also been shown to inhibit CoQ 10 -dependent enzymes. It is therefore possible that CoQ 10 deficiency may be a contributing factor to the cardiac side-effects that are frequently seen with these drugs. In two clinical studies, supplementation with CoQ 10 improved electrocardiographic changes in patients on psychotropic drugs. [75]
DOSAGE The optimal dose of CoQ 10 is not known and probably varies according to the severity of the condition being treated. For example, 30 mg/day of CoQ 10 was reportedly effective in the treatment of mild congestive heart failure, 90 mg/day resulted in improvements in some cases of cancer, and 390 mg/day was associated with complete regression of liver metastases in a patient with breast cancer. The usual dosage of CoQ 10 is 30 mg/day, with a range of 20–100 mg/day. Although higher doses were used in some studies, it is not clear that these larger amounts are necessary for most clinical situations. The dosage of CoQ 10 should be adjusted according to the response of the patient. Larger doses (up to 100 mg/day) may be needed in cases of severe cardiac disease. Because of the serious nature of the cardiotoxicity induced by adriamycin, CoQ 10 prophylaxis should follow the reportedly effective dosage schedule (100 mg/day, beginning 3–5 days prior to the start of adriamycin therapy). Some cases of muscular dystrophy may require large doses of CoQ10 ; the dosage in these cases should be assessed according to clinical response. Since the synthesis of new CoQ 10 -dependent enzymes is a slow process, a clinical response might not occur until 8 or more weeks after therapy is begun. [76]
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TOXICOLOGY Coenzyme Q10 is generally well tolerated, and no serious adverse effects have been reported with long-term use. Because safety during pregnancy and lactation has not been proven, CoQ 10 should not be used during these times unless the potential clinical benefit outweighs the risks. CoQ 10 is contraindicated in cases of known hypersensitivity. In a series of 5,143 patients treated with 30 mg/day of CoQ 10 , the following incidence of side-effects was reported: [59] • epigastric discomfort, 0.39% • loss of appetite, 0.23% • nausea, 0.16% • diarrhea, 0.12%.
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Chapter 77 - Coleus forskohlii Michael T. Murray ND Joseph E. Pizzorno Jr ND
Coleus forskohlii (family: Labiatae) Synonyms: Coleus barbatus, Plectranthus barbatus, P. forskohlii Common name: coleus
GENERAL DESCRIPTION Coleus forskohlii is a small member of the mint (Labiatae) family. It grows as a perennial on the sun-exposed, dry hill slopes between an altitude of 1,000 to 6,000 feet on the mountains in the subtropical, temperate climactic zone of India, Nepal, Sri Lanka, and Thailand. Its Latin name comes from the word coleos, which means “sheath” and refers to the fused filaments that form a sheath around the stylus of the flower. The epithet, forskohlii, was given to commemorate the Finnish botanist Forskal, who traveled extensively in Egypt and Arabia in the 18th century. The radially spread rootstock is the portion of the plant that has been used for medicinal purposes. The rootstock is also the source of a compound of unique biological importance, forskolin. No other species of Coleus contains forskolin.
CHEMICAL COMPOSITION The primary chemical of clinical interest contained in C. forskohlii is the diterpine forskolin ( Fig. 77.1 ). In 1974, forskolin was discovered during a large-scale screening of medicinal plants by the Indian Central Drug Research Institute. The screening revealed the presence of a hypotensive
Figure 77-1 Forskolin.
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and spasmolytic component which was initially named coleanol. [1] Additional investigation determined the exact chemical structure and the name was changed to forskolin. Between 1981 and 1994, forskolin was investigated in over 5,000 in vitro research studies designed to understand better the cellular processes governed by cAMP (discussed below). While most of these studies have used this isolated constituent, there is evidence that other components within the plant extract enhance the absorption and biological activity of forskolin. However, no detailed analysis of the chemical composition of C. forskohlii could be found.
HISTORY AND FOLK USE Coleus forskohlii has a long history of use in Ayurvedic, Siddha, and Unani systems of medicine. Studies of the pharmacological activity of forskolin substantiate the traditional uses of C. forskohlii in such conditions as: [1] • cardiovascular disease • eczema • abdominal colic • respiratory disorders • painful urination • insomnia • convulsions.
PHARMACOLOGY The basic mechanism of action of forskolin is the activation of adenylate cyclase, which increases cyclic adenosine monophosphate (cAMP) in cells. perhaps the most important cell-regulating compound. Once formed, it activates many other enzymes involved in diverse cellular functions.
[2]
Cyclic AMP is
Under normal situations, cAMP is formed when an activating hormone (e.g. epinephrine) binds to a receptor site on the cell membrane and stimulates the activation of adenylate cyclase. This enzyme is found in all cellular membranes and only the specificity of the receptor site determines which hormone will activate it in a particular cell. In contrast, forskolin appears to directly activate adenylate cyclase, bypassing hormonal transmembrane activation of adenylate cyclase. The physiological and biochemical effects of a raised intracellular cAMP level include: • inhibition of platelet activation and degranulation • inhibition of mast cell degranulation and histamine release • increased force of contraction of heart muscle • relaxation of the arteries and other smooth muscles • increased insulin secretion • increased thyroid function • lipolysis. Recent studies have found forskolin to possess additional mechanisms of action independent of its ability to directly stimulate adenylate cyclase and cAMP-dependent physiological responses. [3] Specifically, forskolin has been shown to inhibit a number of membrane transport proteins and channel proteins through a mechanism that does not involve the production of cAMP. The result is again a transmembrane signaling that results in activation of other cellular enzymes. Research is underway to determine the exact receptors to which forskolin is binding.
Another action of forskolin is the inhibition of platelet-activating factor (PAF) by interfering with PAF binding to receptor sites. [4] PAF plays a central role in many inflammatory and allergic processes, including neutrophil activation, increasing vascular permeability, smooth muscle contraction including bronchoconstriction, and reduction in coronary blood flow. Treatment of platelets with forskolin prior to PAF exposure results in a 30–40% decrease in PAF binding. This decrease in PAF binding caused by forskolin was concomitant with a decrease in the physiological responses of platelets induced by PAF. However, this forskolin-induced decrease in PAF binding was not a consequence of cAMP formation, as the addition of a cAMP antagonist did not inhibit the action of forskolin. In addition, the inactive analog of forskolin, dideoxyforskolin, which does not activate adenyl cyclase, also reduced PAF binding to its receptor. Researchers speculate that the action of forskolin on PAF binding is due to a direct effect of this molecule and its analog on the PAF receptor itself or to components of the post-receptor signaling for PAF.
CLINICAL APPLICATIONS The therapeutic ramifications of C. forskohlii based on the pharmacology of forskolin are immense. There are many conditions where a decreased intracellular cAMP level is thought to be a major factor in the development of the disease process. At present, C. forskohlii appears to be especially well indicated in these types of conditions which include: • atopic dermatitis • asthma • psoriasis • angina • hypertension. Although C. forskohlii can be used alone, it may prove to be most useful when combined with other botanicals and/or other measures in the treatment of these disorders. Inflammatory conditions Allergic conditions such as asthma and eczema are characterized by a relative decrease in cAMP in both
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the bronchial smooth muscle and the skin. As a result, mast cells degranulate and smooth muscle cells contract more readily. In addition, these allergic conditions are also characterized by excessive levels of PAF. Asthma and eczema
Current drug therapy for allergic conditions like asthma and eczema is largely designed to increase cAMP levels by using substances which either bind to receptors to stimulate adenylate cyclase (e.g. corticosteroids) or inhibit the enzyme phosphodiesterase which breaks down cAMP once it is formed (e.g. methylxanthines). These actions are different than forskolin’s ability to increase the production of cAMP via transmembrane activation of adenylate cyclase. The cAMP-elevating action of forskolin supports the use of C. forskohlii extracts alone or in combination with standard drug therapy in the treatment of virtually all allergic conditions. Coleus forskohlii extracts may be particularly useful in asthma, as increasing intracellular levels of cAMP results in relaxation of bronchial muscles and relief of respiratory symptoms. Forskolin has been shown to have remarkable effects in relaxing constricted bronchial muscles in asthmatics. [5] [6] [7] This type of smooth muscle is also found in the gastrointestinal tract, uterus, bladder, and arteries. Forskolin has been shown to have tremendous antispasmodic action on these various smooth muscles. This antispasmodic action of forskolin supports the folk medicine use of C. forskohlii in the treatment of not only asthma, but also intestinal colic, uterine cramps (menstrual cramps), painful urination, angina, and hypertension. In addition to forskolin’s ability to relax smooth muscle, its other anti-allergic activities, such as inhibiting the release of histamine and synthesis of allergic compounds, are also of benefit in the treatment of asthma. [8] One double-blind clinical study sought to compare the anti-asthmatic effects of forskolin with the drug fenoterol. Sixteen patients with asthma were studied using three different preparations: • single inhalation doses of fenoterol • dry powder capsules of fenoterol (0.4 mg) • metered doses of fenoterol (0.4 mg), and forskolin dry powder capsules (10.0 mg). All three caused a significant improvement in respiratory function and bronchodilation. However, while the fenoterol preparations caused tremors and decreased blood potassium levels, no such negative effects were seen with forskolin. In another study, the bronchodilating effect (after 5 minutes) of forskolin was as good as that produced by fenoterol in 12 healthy volunteers (non-smokers), as determined by whole body plethysmography. [9] Both substances were administered by metered dose inhalers. At the beginning (after 3 and 5 minutes), the protective effect of forskolin against inhaled acetylcholine was as good as that produced by fenoterol, while later on (after 15 and 30 minutes), fenoterol provided stronger protection. Whether orally administered forskolin in the form of C. forskohlii extract would produce similar bronchodilatory effects is yet to be determined. However, based on the plant’s historical use and additional mechanisms of action, it appears likely. Psoriasis
Psoriasis is a common skin disorder that seems to be caused by a relative decrease in cAMP as compared with cyclic guanine monophosphate (cGMP). The result is a tremendous increase in cell division. In fact, cells divide in psoriasis at a rate 1,000 times greater than the normal. Preliminary studies have indicated that forskolin may be of great benefit to individuals with psoriasis via its ability to re-establish the normal balance between cAMP and cGMP. [1] Cardiovascular effects Perhaps the most useful clinical applications of C. forskohlii extracts will turn out to be for cardiovascular diseases such as hypertension, congestive heart failure, and angina. The cardiovascular effects of C. forskohlii and its components have been studied in great detail. [1] [10] [11] Its basic cardiovascular actions involve lowering of blood pressure along with improving contractility of the heart. Again, this is related to increasing cAMP levels throughout the cardiovascular system which results in relaxation of the arteries and increased force of contraction. The net effect is significant improvement of cardiovascular function. Hypertension and cardiac failure
Several clinical and animal studies have supported the use of forskolin in hypertension and cardiac failure. [10] [11] [12] [13] In one human study involving seven patients with dilated cardiomyopathy, forskolin was shown to improve left ventricular function primarily via reduction of preload and without raising metabolic costs. [12] This study confirmed earlier animal studies showing forskolin increases the contractile force of heart muscle. [11] In another human study, the hemodynamic effects of intravenous (3 mcg/kg per minute) forskolin given to patients with dilated cardiomyopathy was evaluated. [13] Although systemic vascular resistance and diastolic pressure fell, forskolin had no effect on cardiac index, ejection fraction, or myocardial oxygen consumption at this very
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low dosage. However, when a small dosage of dobutamine was given along with the forskolin, an increase of all four parameters was observed. At a higher dosage (4 mcg/kg per minute), forskolin increased heart function by 19% and produced a 16% rise in heart rate. However, these changes were associated with symptomatic flush syndromes. These results indicate that forskolin may best be used in congestive heart failure in combination with other botanicals such as Crataegus (see Ch. 79 ). Forskolin has also been shown to be a direct cerebral vasodilator, indicating that it may prove to be useful in cerebral vascular insufficiency and post-stroke recovery. [14] An additional mechanism of action particularly beneficial in a wide range of cardiovascular conditions is inhibition of platelet aggregation. In this area, the evidence indicates that the standardized C. forskohlii extract is superior to pure forskolin. [15] In an animal model for evaluating in vivo inhibition of platelet aggregation, rats were divided into four groups: group 1 received C. forskohlii extract (480 mg/kg supplying 20 mg/kg of forskolin); group 2 received forskolin (20 mg/kg); group 3 received dipyridamole; and group 4 served as the control. All treatments were given orally once daily. ADP-induced platelet aggregation was measured on odd days 1 through 15. All three treatments produced significant inhibition of platelet aggregation. On day 15, the inhibitions were approximately 42% for group 1, 37% for group 2, and 52% for group 3. Hence, the extract of C. forskohlii produced greater inhibition than the pure forskolin.
OTHER CLINICAL APPLICATIONS Coleus forskohlii extracts concentrated and standardized for forskolin content may prove to be useful in a number of other clinical applications, including: • weight-loss programs • hypothyroidism • malabsorption and digestive disorders • depression • prevention of cancer metastases • immune system enhancement. Glaucoma
In clinical studies, forskolin has been shown to greatly reduce intraocular pressure (IOP) when it is applied directly to the eyes. [16] [17] [18] [19] This effect indicates that topical forskolin preparations may turn out to be of benefit in the treatment of glaucoma. Unlike current drug therapy, forskolin actually increases intraocular blood flow, has no side-effects, and does not induce miosis. Weight-loss programs
Lipolysis, the breakdown of stored fat, is regulated by cAMP. Forskolin has been shown to stimulate lipolysis as well as inhibit the synthesis of fat in adipocytes. [22] [23] Forskolin has also been shown to counteract the age-related decreased response of fat cells to lipolytic hormones like epinephrine. [ 24]
[20] [21]
Hypothyroidism
Forskolin has been shown to increase thyroid hormone production as well as stimulate thyroid hormone release.
[25]
Malabsorption and digestive disorders
Forskolin stimulates digestive secretions including the release of hydrochloric acid, pepsin, amylase, and pancreatic enzymes. [26] [27] Forskolin has been shown to promote nutrient absorption in the small intestine. [28] C. forskohlii extracts may prove to be quite useful in treating dry mouth, as forskolin increases salivation. [29] Depression
Forskolin has been shown to exert antidepressant activity in animal studies. [30] Cancer metastases
Forskolin has been shown to be a potent inhibitor of cancer metastasis in mice injected with malignant cells. [31] As little as 82 mcg administered to mice inhibited metastasis by over 70%. Immune system enhancement
Forskolin exhibits potent immune system enhancement (primarily through activation of macrophages and lymphocytes) in several models. [32] [33] [34]
DOSAGE The recommended dosage should be based upon the level of forskolin. As the forskolin content of Coleus root is typically only 0.2–0.3%, crude Coleus products may not be sufficient to produce a pharmacological effect and the safety of the whole root at high dosages is not as well studied. It is best to use standardized extracts which have known forskolin content. Daily dosages are as follows: • forskolin: 5–10 mg two to three times daily • standardized extract (18% forskolin): 50 mg two to three times daily • dried root: 2–5 g two to three times daily.
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TOXICOLOGY The animal studies on forskolin indicate low toxicity. The pharmacology of forskolin suggests it would be wise to restrict the use C. forskohlii preparations in patients with low blood pressure and peptic ulcers. C. forskohlii preparations should be used with caution in patients on prescription medications, especially anti-asthmatics and antihypertensives, due to its ability to potentiate these and other drugs’ effects.
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HPT, Muller AB. Forskolin. from Ayurvedic remedy to a modern agent. Planta Medica 1985; 51: 473–477
2. Seamon
KB, Daly JW. Forskolin. A unique diterpene activator of cAMP-generating systems. J Cyclic Nucleotide Research 1981; 7: 201–224
3. Laurenza
A, Sutkowski EM, Seamon KB. Forskolin. A specific stimulator of adenyl cyclase or a diterpene with multiple sites of action? Trends Pharmacol Sci 1989; 10: 442–447
4. Wong
S, Mok W, Phaneuf S. Forskolin inhibits platelet-activating factor binding to platelet receptors independently of adenylyl cyclase activation. Eur J Pharmacol 1993; 245: 55–61
5. Wong
S, Mok W, Phaneuf S. Forskolin inhibits platelet-activating factor binding to platelet receptors independently of adenylyl cyclase activation. Eur J Pharmacol 1993; 245: 55–61
6. Lichey
J, Friedrich T, Priesnitz M et al. Effect of forskolin on methacholine-induced bronchoconstriction in extrinsic asthmatics. Lancet 1984; ii: 167
7. Bauer
K, Dietersdorfer F, Sertl K. Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma. Clin Pharmacol Ther 1993; 53: 76–83
8. Marone 9. Kaik
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G, Columbo M, Triggiani M. Forskolin inhibits the release of histamine from human basophils and mast cells. Agents Actions 1986; 18: 96–99
G, Witte PU. Protective effect of forskolin in acetylcholine provocation in healthy probands. Comparison of 2 doses with fenoterol and placebo. Wien Med Wochenschr 1986; 136: 637–641
Dubey MP, Srimal RC, Nityand S, Dhawan BN. Pharmacological studies on coleonol, a hypotensive diterpene from Coleus forskohlii. J Ethnopharmacology 1981; 3: 1–13
Lindner E, Dohadwalla AN, Bhattacharya BK. Positive inotropic and blood pressure lowering activity of a diterpene derivative isolated from Coleus forskohlii. Forskolin. Arzneim Forsch 1978; 28: 284–289 11.
12.
Kramer W, Thormann J, Kindler M. Effects of forskolin on left ventricular function in dilated cardiomyopathy. Arzneim Forsch 1987; 37: 364–367
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Schlepper M, Thormann J, Mitrovic V. Cardiovascular effects of forskolin and phosphodiesterase-III inhibitors. Basic Res Cardiol 1989; 84: 197–212
14.
Wysham DG, Brotherton AF, Heistad DD. Effects of forskolin on cerebral blood flow. Implications for a role of adenylate cyclase. Stroke 1986; 17: 1299–1303
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Wysham DG, Brotherton AF, Heistad DD. Effects of forskolin on cerebral blood flow. Implications for a role of adenylate cyclase. Stroke 1986; 17: 1299–1303
16.
Potter DE, Burke JA, Temple JR. Forskolin suppresses sympathetic neuron function and causes ocular hypotension. Current Eye Research 1985; 4: 87–96
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Caprioli J, Sears M. Forskolin lowers intraocular pressure in rabbits, monkeys, and man. Lancet 1983; i: 958–960
18.
Meyer BH, Stulting AA, Muller FO. The effects of forskolin eye drops on intraocular pressure. S Afr Med J 1987; 71: 570–571
19.
Seto C, Eguchi S, Araie M. Acute effects of topical forskolin on aqueous humor dynamics in man. Jap J Ophthalmol 1986; 30: 238–244
20.
Allen DO, Quesenberry JT. Quantitative differences in the cyclic AMP-lipolysis relationships for isoproterenol and forskolin. J Pharmacol Exp Ther 1988; 244: 852–858
21.
Allen DO, Ahmed B, Naseer K. Relationships between cyclic AMP levels and lipolysis in fat cells after isoproterenol and forskolin stimulation. J Pharmacol Exp Ther 1986; 238: 659–664
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Okuda H, Morimoto C, Tsujita T. Relationship between cyclic AMP production and lipolysis induced by forskolin in rat fat cells. J Lipid Res 1992; 33: 225–231
Bianco AC, Kieffer JD, Silva JE. Adenosine 3’,5’-monophosphate and thyroid hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes. Endocrinology 1992; 130: 2625–2633 23.
Hoffman BB, Chang H, Reaven GM. Stimulation and inhibition of lipolysis in isolated rat adipocytes. Evidence for age-related changes in responses to forskolin and PGE1. Horm Metab Res 1987; 19: 358–360 24.
Saunier B et al. Cyclic AMP regulation of Gs protein. Thyrotropin and forskolin increase the quantity of stimulatory guanine nucleotide-binding proteins in cultured thyroid follicles. J Biol Chem 1990; 265: 19 942–19 946 25.
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Roger PP, Servais P, Dumont JE. Regulation of dog thyroid epithelial cell cycle by forskolin, an adenylate cyclase activator. Exp Cell Res 1990; 172: 282–292
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Haye B, Aublin JL, Champion S. Chronic and acute effects of forskolin on isolated thyroid cell metabolism. Mol Cell Endocrinol 1990; 43: 41–50
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Reymann A, Braun W, Woermann C. Proabsorptive properties of forskolin. Disposition of glycine, leucine and lysine in rat jejunum. Naunyn Schmiedebergs Arch Pharmacol 1986; 334: 110–115
Larsson O, Detsch T, Fredholm BB. VIP and forskolin enhance carbachol-induced K+ efflux from rat salivary gland fragments by a Ca2(+)-sensitive mechanism. Am J Physiol 1990; 259: C904–910 29.
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Wachtel H, Loschmann PA. Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity. Interactions with rolipram. Psychopharmacol 1986; 90: 430–435
31.
Agarwal KC, Parks RE. Forskolin. A potential antimetastatic agent. Int J Cancer 1983; 32: 801–804
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Schorlemmer HU. Forskolin for immune stimulation. Chem Abstr 1985; 102: 1009
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Krall JF, Fernandey EI, Connolly-Filtingoff M. Human aging. Effect on the activation of lymphocyte cyclic AMP-dependent protein kinase by forskolin. Proc Soc Exp Biol Med 1987; 184: 396–402
34.
Chang J, Cherney ML, Moyer JA. Effect of forskolin on prostaglandin synthesis by mouse resident peritoneal macrophages. European J Pharmacology 1984; 103: 303–312
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Chapter 78 - Commiphora mukul (mukul myrrh tree) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Commiphora mukul (family: Burseraceae) Common name: mukul myrrh tree
GENERAL DESCRIPTION Commiphora mukul is a small thorny tree 4–6 feet tall that is native to Arabia and India. In its natural setting, the tree remains essentially free of foliage for most of the year. Its bark is ash-colored and comes off in rough flakes, exposing the under-bark that also peels off. Upon injury, the tree exudes a yellowish gum resin that has a balsamic odor. This oleoresin is referred to as “gum guggul” or “guggulu”. It is this resin which is used for medicinal purposes. When tapped during the winter, the average tree yields 1.5–2 lb of resin. [1]
CHEMICAL COMPOSITION Guggulu contains a mixture of diverse chemical constituents which can be separated into several fractions. [1] The first step in the fractionation process involves mixing guggulu with ethyl acetate, yielding a soluble and an insoluble fraction (see Fig. 78.1 ). The insoluble fraction, containing the carbohydrate constituents, is regarded as toxic and is the major reason why extracts of the soluble portion are preferred to crude gum guggul for medical use. The insoluble portion has no demonstrable pharmacological activity other than toxicity. [1] In contrast, the soluble portion possesses significant cholesterol-lowering and anti-inflammatory activity. The soluble portion can be further separated into base, acid, and neutral fractions. The neutral portion possesses almost all of the cholesterol lowering activity while the acid portion possesses the anti-inflammatory components. [1] Upon further purification of the neutral portion, it was determined that the ketone fraction contains the most potent cholesterol-lowering components. The ketone fraction is composed of C 21 or C27 steroids, with the major components being Z- and E-guggulsterone (see Fig. 78.2 ).
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Figure 78-1 Chemical segregation of gum guggulu.
Figure 78-2 E-Guggulsterone.
These compounds are considered the major active components of gum guggul and its extracts. [1] For medicinal purposes, a standardized extract known as gugulipid, which is standardized to contain a minimum of 50 mg of guggulsterones/g, is regarded as the most beneficial in terms of safety and effectiveness. [1] [2] In addition to guggulsterones, gugulipid contains various diterpenes, sterols, esters, and fatty alcohols. These accessory components appear to exert a synergistic effect. [1] [2]
HISTORY AND FOLK USE Guggulu is a highly valued botanical medicine in the Indian system of medicine, Ayurveda. It is included in formulas for a variety of health conditions including rheumatoid arthritis and lipid disorders. The classic Ayurvedic medical text, the Sushrutasamhita, describes in detail the usefulness of guggul in the treatment of obesity and other disorders of fat metabolism, including “coating and obstruction of channels”. [1] [2] Inspired by this description, researchers began studying, in well-designed scientific studies, the clinical effectiveness of gum guggul and its extracts in disorders of lipid metabolism – specifically, its ability to lower cholesterol and triglyceride levels and promote weight loss. This research resulted in the development of a natural cholesterol-lowering substance that is safer and more effective than many cholesterol-lowering drugs, including niacin. Gugulipid was granted approval in India for marketing as a lipid-lowering drug in 1986. [1] [2]
PHARMACOLOGY Lipid disorders
Numerous studies in humans and animals have shown that gum guggul (both crude and purified alcohol extract), [3] [4] [5] [6] [7] its petroleum ether extract (referred to as fraction A),[8] [9] [10] [11] and gugulipid (standardized ethyl acetate extract) [12] [13] all exert effective lipid-lowering activity. All lower both elevated cholesterol and triglyceride levels. The effect on cholesterol is particularly beneficial as guggul lowers VLDL and LDL cholesterol while simultaneously elevating HDL-cholesterol, thus offering protection against heart disease due to atherosclerosis. Guggul preparations appear most indicated in type IIb (increased LDL, VLDL, and triglycerides) and type IV (increased VLDL and triglycerides) hyperlipidemias. In the human clinical trials using gugulipid, cholesterol levels typically dropped 14–27% in a 4–12 week period while triglyceride levels dropped from 22 to 30%. [12] [13] [14] As seen in Table 78.1 , the effect of gugulipid on serum TABLE 78- -- Serum lipid effects of gugulipid compared with standard drugs
Agent
Total cholesterol
Gugulipid
HDL cholesterol
-24%
Triglycerides
+16%
-23%
Cholestyramine -14%
+8%
+10%
Clofibrate
-10%
+11%
-22%
Lovastatin
-34%
+8%
-25%
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cholesterol and triglycerides is comparable to that of conventional lipid lowering drugs. Clofibrate, niacin, and cholestyramine lower cholesterol levels 6–12%, 10–17% and 20–27%, respectively, but are associated with some degree of toxicity. In contrast, appropriate extracts of gugulipid are without reported side-effects. In addition to the excellent safety demonstrated in the human studies, safety studies in animals have demonstrated gugulipid to be non-toxic (see “Toxicology” below). The primary mechanism of action for gum guggul and gugulipid’s cholesterol-lowering action is stimulation of liver metabolism of LDL cholesterol, i.e. guggulsterones increase the uptake of LDL cholesterol from the blood by the liver. [14] [15] However, another action of guggulsterone which also affects lipid levels is its ability to stimulate thyroid function. [16] This thyroid-stimulating effect may be responsible for some of gugulipid’s weight loss activity. In addition to lowering lipid levels, gum guggul and its extracts, including gugulipid, have been shown to prevent the formation of atherosclerosis and aid in the regression of pre-existing atherosclerotic plaques in animals. This implies that it may have a similar effect in humans. Gum guggul and gugulipid have also been shown to prevent the heart from being damaged by free radicals and to improve the metabolism of the heart. [9] [14] Gum guggul and its extracts have a mild effect in inhibiting platelet aggregation and promoting fibrinolysis, implying that it may also prevent the development of a stroke or embolism.[2] [14] This research indicates that gugulipid offers considerable benefit for preventing and treating atherosclerotic vascular disease, the leading cause of death in the US. Anti-inflammatory effects
The guggulsterone fraction of gum guggul has been shown to exhibit significant anti-inflammatory action in experimental models of inflammation (e.g. raw paw edema and adjuvant arthritis method). [17] [18] [19] Its activity in models of acute inflammation is comparable to approximately one-fifth that of hydrocortisone, and equal to phenylbutazone and ibuprofen. [17] In models of chronic inflammation, it was shown to be more effective than hydrocortisone, phenylbutazone, and ibuprofen in reducing the severity of secondary lesions. The antiinflammatory action is thought to be due to inhibition of delayed hypersensitivity reactions. [18] [19]
DOSAGE While the crude oleoresin (gum guggul), alcohol extract, and petroleum ether extract all exert lipid-lowering and anti-inflammatory action, they are associated with side-effects (skin rashes, diarrhea, etc.) at the doses required to produce a clinical effect. It is interesting to note that in classic Ayurvedic texts, the purification of crude guggul in Triphala kashaya is recommended to eliminate these side-effects. [2] Gugulipid, the standardized ethyl acetate extract of the gum guggul, has demonstrated not only greater clinical efficacy, but also much greater patient tolerance than crude or purified gum guggul. The dosage of gugulipid is based on its guggulsterone content. Clinical studies have demonstrated that 25 mg of guggulsterone three times per day is an effective treatment for elevated cholesterol levels, elevated triglyceride levels, or both. For a 5% guggulsterone content extract, this translates to an effective dose of 500 mg three times per day. For comparison, the daily dosage of the other forms would be: • crude gum guggul – 10 g • alcoholic extract – 4.5 g • petroleum ether extract – 1.5 g.
TOXICOLOGY The side-effects of crude gum guggul, alcoholic and petroleum ether extracts are discussed above. In clinical studies, gugulipid has not displayed any untoward side-effects, nor has it adversely affected liver function, blood sugar control, kidney function, or hematological parameters. [11] [12] [13] Safety studies in rats, rabbits, and monkeys have demonstrated gugulipid to be non-toxic. [14] It does not possess any embryotoxic, fetotoxic effects and is therefore considered safe to use in pregnancy. In mice, the oral and intraperitoneal LD 50 values are 1,600 mg/kg. [1]
REFERENCES 1. Satyavati
GV. Gugulipid. A promising hypolipidaemic agent from gum guggul ( Commiphora wightii). Econ Med Plant Res 1991; 5: 47–82
2. Satyavati
GV. Gum guggul ( Commiphora mukul) – The success story of an ancient insight leading to a modern discovery. Ind J Med Res 1988; 87: 327–335
3. Satyavati
GV, Dwarakanath C, Tripathi SN. Experimental studies of the hypocholesterolemic effect of Commiphora mukul. Ind J Med Res 1969; 57: 1950–1962
4. Khana
DS, Agarwal OP, Gupta SK, Arora RB. A biochemical approach to anti-atherosclerotic action of Commiphora-mukul. An Indian indigenous drug in Indian domestic pigs. Ind J Med Res 1969; 57: 900–906 5. Nityand
S, Kapoor NK. Hypocholesterolemic effect of Commiphora mukul resin. Ind J Exp Biol 1971; 9: 376–377
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K, Rajagopalan SS, Koteswara RT, Sitaraman R. Effect of guggul on serum lipids in obese hypercholesterolemic and hyperlipidemic cases. J Assoc Phys India 1978; 26: 367–371
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7. Baldwa
VS, Bhasin V, Ranka PC, Mathur KM. Effects of Commiphora mukul (Guggul) in experimentally induced hyperlipidemia and atherosclerosis. JAPI 1981; 29: 13–17
8. Malhotra
SC, Ahuja MMS. Comparative hypolipidaemic effectiveness of gum guggulu ( Commiphora mukul) fraction “A”, ethyl-p-chlorophenoxyisobutyrate and Ciba-13437-Su. Ind J Med Res 1971; 10: 1621–1632 9. Arora
RB, Das D, Kapoor SC, Sharma RC. Effect of some fractions of Commiphora mukul on various serum lipid levels in hypercholesterolemic chicks and their effectiveness in myocardial infarction in rats. Ind J Exp Biol 1973; 11: 166–168
10.
Malhotra SC, Ahuja MMS, Sundaram KR. Long term clinical studies on the hypolipidaemic effect of Commiphora mukul (guggulu) and clofibrate. Ind J Med Res 1977; 65: 390–395
11.
Verna SK, Bordia A. Effect of Commiphora mukul (gum guggulu) in patients of hyperlipidemia with special reference to HDL-cholesterol. Ind J Med Res 1988; 87: 356–360
12.
Agarwal RC, Singh SP, Saran RK et al. Clinical trial of gugulipid: a new hypolipidemic agent of plant origin in primary hyperlipidemia. Ind J Med Res 1986; 84: 626–634
13.
Nityanand S, Srivastava JS, Asthana OP. Clinical trials with gugulipid, a new hypolipidaemic agent. J Assoc Phys India 1989; 37: 321–328
14.
Gugulipid. Drugs of the Future 1988; 13: 618–619
15.
Singh V, Kaul S, Chander R, Kapoor NK. Stimulation of low density lipoprotein receptor activity in liver membrane of guggulsterone treated rats. Pharmacol Res 1990; 22: 37–44
16.
Tripathi YB, Tripathi P, Malhorta P, Tripathi SN. Thyroid stimulatory action of (Z)-guggulsterone. Mechanism of action. Planta Medica 1988; 54: 271–277
17.
Arora RB, Kapoor V, Gupta SK, Sharma RC. Isolation of a crystalline steroidal compound from Commiphora mukul and its anti-inflammatory activity. Ind J Exp Biol 1971; 9: 403–404
18.
Arora RB, Taneja V, Sharma RC, Gupta SK. Anti-inflammatory studies on a crystalline steroid isolated from Commiphora mukul. Ind J Med Res 1972; 60: 929–931
Sharma JN, Sharma JN. Comparison of the anti-inflammatory activity of Commiphora mukul (an indigenous drug) with those of phenylbutazone and ibuprofen in experimental arthritis induced by mycobacterial adjuvant. Arzneim Forsch 1977; 27: 1455–1457 19.
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Chapter 79 - Crataegus oxyacantha (hawthorn) Michael T. Murray ND Joseph E. Pizzorno Jr ND
• Crataegus oxyacantha (family: Rosacea) Common names: hawthorn, may bush, whitethorn, haw
GENERAL DESCRIPTION Crataegus oxyacantha is a spiny tree or shrub that is native to Europe. It may reach a height of 30 feet, but is often grown as a hedge plant. Its common name, hawthorn, is actually a corruption of “hedgethorn”, as it was used in Germany to divide plots of land. Its botanical name, Crataegus oxyacantha, is from the Greek kratos, meaning hardness (of the wood), oxus meaning sharp, and akantha meaning a thorn. The fruit and blossoms are used medicinally. [1] Other species of crataegus, e.g. C. monogyna and C. pentagyna, have similar pharmacological actions to C. oxyacantha and may be suitable alternatives. [2] [3]
CHEMICAL COMPOSITION Hawthorn leaves, berries, and blossoms contain many biologically active flavonoid compounds, particularly anthocyanidins and proanthocyanidins (polymers of anthocyanidins, also known as biflavans or procyanidins) (see Fig. 79.1 ). [4] [5] These flavonoids are responsible for
Figure 79-1 Proanthocyanidin B 2 .
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Figure 79-2 Vitexin-4'-rhamnoside.
the red to blue colors not only of hawthorn berries, but also of blackberries, cherries, blueberries, grapes, and many flowers as well. These compounds are highly concentrated in hawthorn berry and flower extracts. High-performance liquid chromatography and thin layer chromatography (of crataegus extracts) have demonstrated that extracts of the flowers are particularly rich in flavonoids (quercetin, quercetin-3-galactoside, vitexin, vitexin-4'-rhamnoside, etc.) and proanthocyanidins (see Fig. 79.2 ). [5] [6] In addition to flavonoids, crataegus extracts also contain: [7] • cardiotonic amines (e.g. phenylethylamine, o-methoxyphenylethylamine, tyramine, isobutylamine) • choline and acetylcholine • purine derivatives (e.g. adenosine, adenine, guanine, and caffeic acid) • amygdalin • pectins • triterpene acids (ursolic, oleonolic, and crategolic acids).
HISTORY AND FOLK USE Crataegus flowers and berries have been utilized primarily as cardiac tonics and mild diuretics in organic and functional heart disorders. They were also utilized for their astringent qualities for relief of the discomfort of sore throats. [1]
PHARMACOLOGY The pharmacology of crataegus centers on its flavonoid components. The proanthocyanidins in crataegus are largely responsible for its cardiovascular activities. Synergism with vitamin C As stated above, crataegus is particularly rich in anthocyanidins and proanthocyanidins. These flavonoids have very strong “vitamin P” activity. Included in their effects are an ability to increase intracellular vitamin C levels, stabilize vitamin C (by protecting it from oxidation), and decrease capillary permeability and fragility.
[4] [8]
[9]
Collagen-stabilizing action Crataegus’ flavonoid components possess significant collagen-stabilizing action. Collagen is the most abundant protein of the body and is responsible for maintaining the integrity of ground substance, tendons, ligaments, and cartilage. Collagen is destroyed during inflammatory processes that occur in rheumatoid arthritis, periodontal disease, and other inflammatory conditions involving bones, joints, cartilage, and other connective tissue. Anthocyanidins, proanthocyanidins and other flavonoids are remarkable in their ability to prevent collagen destruction. They affect collagen metabolism in many ways, including:
• the unique ability to actually cross-link collagen fibers, resulting in reinforcement of the natural cross-linking of collagen that forms the collagen matrix of connective tissue (ground substance, cartilage, tendon, etc.) [4] [8] [9] • the prevention of free radical damage, due topotent antioxidant and free radical scavenging action [4] [8] [9] [10] • the inhibition of enzymatic cleavage by enzymes secreted by leukocytes during inflammation [4] [8] [9] • the prevention of the release and synthesis of compounds that promote inflammation, such as histamine, serine proteases, prostaglandins, and leukotrienes.
[9] [ 10]
[11] [12]
These effects on collagen and their potent antioxidant activity make hawthorn extracts extremely useful in the treatment of a wide variety of inflammatory conditions. Hawthorn berries, like cherries, [13] are particularly effective in the treatment of gout, as their flavonoid components are able to reduce uric acid levels as well as reduce tissue destruction. Cardiovascular effects Crataegus extracts are effective in reducing blood pressure, angina attacks, and serum cholesterol levels, preventing the deposition of cholesterol in arterial walls and improving cardiac function. [2] [14] [15] Hawthorn extracts are widely used in Europe for their antihypertensive and cardiotonic activity. The beneficial pharmacological effects of crataegus in the treatment of these conditions appear to be a result of the following actions: • improvement of the blood supply to the heart by dilating the coronary vessels [2] [14] [16] [17] [18] [19] • improvement of the metabolic processes in the heart which results in an increase in the force of 685
contraction of the heart muscle and elimination of some types of rhythm disturbances [2] [14] [20] [21] [22] • inhibition of angiotensin-converting enzyme (ACE). [23] Crataegus’ ability to dilate coronary blood vessels has been repeatedly demonstrated in experimental studies. [2] [14] [16] [17] [18] [19] This effect appears to be due to relaxation of vascular smooth muscle. Various flavonoid components in crataegus have been shown to inhibit vasoconstriction by a variety of substances, including hypophysin, histamine, and acetylcholine. [2] [8] [9] In addition, procyanidins have been shown to inhibit angiotensin converting enzyme (discussed below). [23] Improvement in cardiac metabolism has been demonstrated in humans and animals to whom crataegus extracts have been administered. [2] [14] [20] [21] The improvement is not only a result of increased blood and oxygen supply to the myocardium, but also a result of flavonoid–enzyme interactions. In particular, crataegus extracts and various flavonoid components in crataegus have been shown to inhibit cyclic AMP phosphodiesterase (cAMP-PDE). [22] This results in increased levels of cAMP within the myocardium, leading to a positive inotropic effect, i.e. an increase in the force of contraction. This is particularly beneficial in cases of congestive heart failure (discussed below). Recently, several proanthocyanidins have demonstrated a specific inhibition of angiotensin-converting enzyme similar to that of captopril. [23] Captopril (D-2-methyl-3-mercaptopropanoyl- L-proline, SQ 14,225) is a synthetic ACE inhibitor widely used in the treatment of essential and renal hypertension. The proanthocyanidins that appear to have the highest activity are proanthocyanidins B-5 3,3'-di-O-gallate and C-1 3,3',3?-tri-O-gallate. It is not surprising that these proanthocyanidins are found in relatively high concentrations in hawthorn berries, flowers, and their extracts. [4] [5]
CLINICAL APPLICATIONS The clinical use of crataegus revolves around its cardiovascular effects. Its use in atherosclerosis, hypertension, congestive heart failure, and arrhythmias is discussed below: Atherosclerosis
Crataegus preparations, although in a supplement form, should be thought of as a necessary food in the prevention and treatment of atherosclerosis. Increasing the intake of flavonoid compounds by taking crataegus extracts has numerous health-promoting effects, including reducing cholesterol levels and decreasing the size of existing atherosclerotic plaques. [15] This again is probably a result of collagen stabilization. A decrease in the integrity of the collagen matrix of the artery results in cholesterol deposition. Many researchers feel that if the collagen matrix of the artery remains strong, the atherosclerotic plaque will never develop. Crataegus flavonoids, by increasing the integrity of collagen structures, may offer significant protection against atherosclerosis. In addition, feeding proanthocyanidin extracts to animals has resulted in reversal of atherosclerotic lesions, as well as decreases in serum cholesterol levels.[15] Flavonoids contained in hawthorn extracts appear to offer significant prevention, as well as potential reversing effects, in the treatment of atherosclerotic processes, which are still the major causes of death in the US. Hypertension
Crataegus exerts a mild antihypertensive effect, which has been demonstrated in many experimental and clinical studies. Its action in lowering blood pressure is quite unique, in that it does so through a number of diverse pharmacological effects. Specifically, it dilates the coronary vessels, inhibits ACE, acts as an inotropic agent, and possesses mild diuretic activity. Crataegus’ effects generally require prolonged administration, and in many instances it may take up to 2 weeks before adequate tissue concentrations are achieved. It should be kept in mind that as beta-blockers (e.g. Inderal) lower blood pressure by reducing cardiac output, crataegus administration to patients on these drugs may produce a mild hypertensive response. Congestive heart failure
Crataegus has a long history of use in the treatment of congestive heart failure, particularly in combination with digitalis or other herbs containing cardiac glycosides (e.g. Cereus grandifloris, also known as Cactus grandifloris, and Convallaria majalis). It potentiates the action of the cardiac glycosides, presumably via its ability to inhibit cAMP-PDE and to interact with calcium channels. Because of this enhancing effect, lower doses of cardiac glycosides can be used. In addition, magnesium has also been shown to augment digitalis action. For mild to moderate cases of CHF, crataegus extract used alone may be sufficient, but for moderate to severe CHF, it should be used in combination with other cardiac glycosides. In early or mild stages of CHF, the effectiveness of crataegus has been repeatedly demonstrated in double-blind studies. [24] [25] [26] [27] In one of the most recent studies, 30 patients with congestive heart failure (NYHA stage II) were assessed in a randomized double-blind study. [26] Treatment consisted of a crataegus extract standardized to contain 15 mg procyanidin oligomers per 80 mg
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capsule. Treatment duration was 8 weeks, and the substance was administered at a dose of one capsule taken twice a day. The group receiving the crataegus extract
showed a statistically significant advantage over placebo in terms of changes in heart function as determined by standard testing procedures. Systolic and diastolic blood pressures were also mildly reduced. Like all other studies with crataegus extracts, no adverse reactions occurred. In another study, 78 patients with CHF (NYHA stage II) were given either 600 mg of standardized crataegus extract or placebo daily. [27] The parameter used to mea-sure effectiveness was the patient’s working capacity on a bicycle ergometer. After 56 days of treatment, the crataegus group had a mean increase of 25 W compared with the placebo group’s increase of only 5 W. In addition, the crataegus group also experienced a mild, but significant, reduction in systolic blood pressure (from 171 to 164 mmHg) and heart rate (from 115 to 110 beats/minute). There was no change in blood pressure or heart rate in the placebo group.
DOSAGE The dosage depends on the type of preparation and source material. Standardized extracts, similar to those used in Europe and Asia as prescription medications, are available commercially. The doses listed for the various crataegus formulas are for use three times a day: • berries or flowers (dried): 3–5 g or as infusion • tincture (1:5): 4–5 ml (alcohol may elicit pressor response in some individuals) • fluid extract (1:1): 1–2 ml • freeze dried berries: 1–1.5 g • flower extract (standardized to contain 1.8 vitexin-4'-rhamnoside): 100–250 mg.
TOXICOLOGY Crataegus has been shown to have low toxicity. In rats, the typical acute LD 50 of the tincture is about 25 ml/kg for oral administration; toxicity for chronic administration is found at about 5 ml/kg. [14] Similar results, adjusted for concentration, are found with other forms of crataegus. Although some studies have shown that proanthocyanidins may be carcinogenic, more careful evaluation has indicated that the carcinogenicity was probably due to nitrosamines found in the extracts used. [28] Purified proanthocyanidins have been found to be non-mutagenic, according to the Salmonella mutagenicity assay system.[24]
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M. A modern herbal, vol 1. New York, NY: Dover. 1971: p 385–386
2. Petkov
V. Plants with hypotensive, antiatheromatous and coronarodilating action. Am J Chin Med 1979; 7: 197–236
3. Thompson 4. Kuhnau 5. Ficarra
EB, Aynilian GH, Gora P, Farnsworth NR. Preliminary study of potential antiarrhythmic effects of Crataegus monogyna. J Pharm Sci 1974; 63: 1936–1937
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6. Wagner
H, Bladt S, Zgainski EM. Plant drug analysis. New York, NY: Springer-Verlag. 1984: p 166, 178, 179
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M. Pharmacologic effects of flavonoids on blood vessels. Angiologica 1972; 9: 355–374
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Busse WW, Kopp DE, Middleton E. Flavonoid modulation of human neutrophil function. J Allergy Clin Immunol 1984; 73: 801–809
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Blau LW. Cherry diet control for gout and arthritis. Tex Rep Biol Med 1950; 8: 309–311
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Ammon HPT, Handel M. Crataegus, toxicology and pharmacology. Planta Medica 1981; 43: 101–120, 318–322
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Wegrowski J, Robert AM, Moczar M. The effect of procyanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas. Biochem Pharm 1984; 33: 3491–3497
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Mavers VWH, Hensel H. Changes in local myocardial blood flow following oral administration to a crataegus extract to non-anesthetized dogs. Arzniem Forsch 1974; 24: 783–785
Roddewig VC, Hensel H. Reaction of local myocardial blood flow in non-anesthetized dogs and anesthetized cats to oral and parenteral application of a crataegus fraction (oligomere procyanidins). Arzneim Forsch 1977; 27: 1407–1410 17.
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Rewerski VW, Piechocki T, Tyalski M, Lewak S. Some pharmacological properties of oligomeric procyanidin isolated from hawthorn ( Crataegus oxyacantha). Arzniem Forsch 1967; 17: 490–491
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Hammerl H, Kranzl C, Pichler O, Studlar M. Klinixch-experimentelle toffwechseluntersuchungen mit einem crataegus-extrakt. Arzniem Forsch 1971; 21: 261–263
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Vogel VG. Predictability of the activity of drug combinations – yes or no? Arzniem Forsch 1975; 25: 1356–1365
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O’Conolly VM, Jansen W, Bernhoft G, Bartsch G. Treatment of cardiac performance (NYHA stages I to II) in advanced age with standardized crataegus extract. Fortschr Med 1986; 104: 805–808
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Uchida S, Ikari N, Ohta H et al. Inhibitory effects of condensed tannins on angiotensin converting enzyme. Jap J Pharmacol 1987; 43: 242–245
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O’Conolly VM, Jansen W, Bernhoft G, Bartsch G. Treatment of cardiac performance (NYHA stages I to II) in advanced age with standardized crataegus extract. Fortschr Med 1986; 104: 805–808
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O’Conolly VM, Jansen W, Bernhoft G, Bartsch G. Treatment of cardiac performance (NYHA stages I to II) in advanced age with standardized crataegus extract. Fortschr Med 1986; 104: 805–808
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Leuchtgens H. Crataegus special extract WS 1442 in NYHA II heart failure. A placebo controlled randomized double-blind study. Fortschr Med 1993; 111: 352–354
Schmidt U, Kuhn U, Ploch M, Hubner WD. Efficacy of the hawthorn (Crataegus) preparation LI 132 in 78 patients with chronic congestive heart failure defined as NYHA functional class II. Phytomed 1994; 1: 17–24 27.
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Yu CI, Swaminathan B. Mutagenicity of proanthocyanidins. Food Chem Toxicol 1987; 25: 135–139
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Chapter 80 - Curcuma longa (turmeric) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Curcuma longa (family: Zingiberaceae) Common names: turmeric, curcuma, Indian saffron
GENERAL DESCRIPTION Curcuma longa, a perennial herb of the ginger family, is extensively cultivated in India, China, Indonesia, and other tropical countries. It has a thick rhizome from which arise large, oblong, and long-petioled leaves. The rhizome is the part used; it is usually cured (boiled, cleaned, and sun-dried) and polished. [1]
CHEMICAL COMPOSITION Turmeric contains: [1] [2] • 4–14% of an orange-yellow volatile oil that is composed mainly of turmerone, atlantone, and zingiberone • 0.3–5.4% curcumin • sugars (28% glucose, 12% fructose, 1% arabinose) • resins • protein • vitamins • minerals. Its chemical structure is shown in Figure 80.1 .
HISTORY AND FOLK USE Turmeric is the major ingredient of curry powder and is also used in prepared mustard. It is extensively used in foods for both its color and flavor. In addition, turmeric is used in both the Chinese and Indian (Ayurvedic)
Figure 80-1 Curcumin.
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systems of medicine as an anti-inflammatory agent and in the treatment of numerous conditions, including flatulence, jaundice, menstrual difficulties, bloody urine, hemorrhage, toothache, bruises, chest pain, and colic. [1] Turmeric poultices are often applied locally to relieve inflammation and pain.
PHARMACOLOGY Turmeric and its derivatives have a great deal of pharmacological activity. [2] Although a number of components have demonstrated activity, the volatile oil components and curcumin are believed to be the most active components. Turmeric has been found to be: • an effective antioxidant • anticarcinogenic • anti-inflammatory • cardiovascular • hepatic • gastrointestinal • an antimicrobial agent. Antioxidant effects
Turmeric extracts exert significant antioxidant activity. Although both water- and fat-soluble extracts have been shown to be effective antioxidants in various in vitro and in vivo models, curcumin is the most potent component. [3] [4] [5] [6] The antioxidant activity of curcumin is comparable to standard antioxidants like vitamins C and E, and butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). [3] [7] Because of its bright yellow color and antioxidant properties against lipid peroxidation, curcumin is used in butter, margarine, cheese, and other food products. For active oxygen species, curcumin is slightly weaker than vitamin C, but stronger than vitamin E and superoxide dismutase. Against hydroxyl radicals, curcumin offers greater effectiveness than these vitamins. [3] [4] [7] Not all of the antioxidant properties of turmeric are due to curcumin alone, as the aqueous extract of turmeric is more effective against superoxide than curcumin and is much stronger in inhibiting oxidative damage to DNA. [5] [6] Anticarcinogenic effects
The anti-neoplastic effects of turmeric and curcumin have been demonstrated at all steps of carcinogenesis: initiation, promotion, and progression. In addition to inhibiting the development of cancer, several studies suggest that curcumin can also promote cancer regression. Turmeric and curcumin are non-mutagenic and have been shown to suppress the mutagenicity of several common mutagens (cigarette smoke condensates, benzopyrene, DMBA, etc.), as do chili and capsaicin. [8] [9] [10] Turmeric and curcumin have also demonstrated impressive anti-cancer effects against a number of chemical carcinogens on a wide range of cell types in both in vitro and in vivo studies. [11] [12] [13] [14] [15] [16] [17] [18] Curcumin has demonstrated an impressive ability to reduce the levels of urinary mutagens. [19] [20] The protective effects of turmeric and its derivatives are only partially explained by its direct antioxidant and free radical scavenging effects. It also inhibits nitrosamine
formation, enhances the body’s natural antioxidant system, increases the levels of glutathione and other non-protein sulfhydryls, and acts directly on several enzymes and gene loci. Anti-inflammatory effects
The volatile oil fraction of Curcuma longa has been demonstrated to possess anti-inflammatory activity in a variety of experimental models, e.g. Freund’s adjuvant-induced arthritis, formaldehyde- and carrageenan-induced paw edema, and cotton pellet and granuloma pouch tests. [21] [22] Its effects in these studies were comparable to cortisone and phenylbutazone. Even more potent in acute inflammation is curcumin. [23] [24] [25] Curcumin is as effective as cortisone or phenylbutazone in models of acute inflammation, but only half as effective in chronic models. However, while phenylbutazone and cortisone are associated with significant toxicity, curcumin displays virtually no toxicity (see “Toxicology”, p. 692 ). The rank in order of potency of curcumin analogues, cortisone, and phenylbutazone in carrageenan-induced paw edema is:
[ 24] [25]
Sodium curcuminate can be produced by mixing turmeric with slaked lime. This mixture, applied as a poultice, is an ancient household remedy for sprains, muscular pain, and inflamed joints. [25] Curcumin’s counter-irritant effect may also be a major factor in its topical anti-inflammatory action. [24] Capsaicin, a similar pungent principle from Capsicum frutescens (cayenne pepper), has been shown to be quite effective as a topical pain reliever in cases of post-herpetic neuralgia and arthritis. Both capsaicin and curcumin deplete nerve endings of the neurotransmitter of pain, substance P. [26] Used orally, curcumin exhibits many direct anti-inflammatory effects including: [2] [23] [24] [27] [28] [29] • inhibition of leukotriene formation • inhibition of platelet aggregation • promotion of fibrinolysis • inhibition of neutrophil response to various stimuli involved in the inflammatory process • stabilization of lysosomal membranes.
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In addition to its direct anti-inflammatory effects, curcumin also appears to exert some indirect effects. In models of chronic inflammation, curcumin is much less active in adrenalectomized animals. Possible mechanisms of action include: • stimulation of the release of adrenal corticosteroids • “sensitizing” or priming cortisol receptor sites, thereby potentiating cortisol action • increasing the half-life of endogenous cortisol through alteration of hepatic degradation. Cardiovascular effects
The effects of turmeric and curcumin on the cardiovascular system include the lowering of cholesterol levels is of great significance in preventing atherosclerosis and its complications.
[30] [ 31]
and the inhibition of platelet aggregation. [32] [33] This
Adding as little as 0.1% curcumin to a high cholesterol rat diet decreases cholesterol levels to one-half of those found in rats fed cholesterol but no curcumin. indicates that even at small doses, curcumin may be effective.
[30]
This
Curcumin’s cholesterol-lowering actions include interfering with intestinal cholesterol uptake; increasing the conversion of cholesterol into bile acids by increasing the activity of hepatic cholesterol-7-alpha-hydroxylase, the rate-limiting enzyme of bile acid synthesis; and increasing the excretion of bile acids via its choleretic effects. [30] [31] [34] Turmeric and curcumin’s action on inhibiting platelet aggregation appears mediated by inhibiting the formation of thromboxanes (a promoter of aggregation) while simultaneously increasing prostacyclin (an inhibitor of aggregation). [32] [33] Hepatic effects
Curcumin has exhibited hepatoprotection similar to that of glycyrrhizin and silymarin (see Chs 90 and 111 for further discussion) against carbon tetrachloride and galactosamine-induced liver injury. [2] [35] This protection is largely a result of its potent antioxidant activity. Similar results are seen with Javanese turmeric ( Curcuma xanthorriza). Mice given intraperitoneal injections of the hepatoxic drugs carbon tetrachloride (32 mg/kg) and acetaminophen (600 mg/kg) experienced significantly decreased liver damage, as measured by SGOT and SGPT when treated with 100 mg/kg of turmeric. [36] The antioxidant and hepatoprotective effects alone would support turmeric’s historical use in liver disorders; however, turmeric and curcumin also exert anti-inflammatory and choleretic effects. The increases of SGOT and SGPT commonly seen in experimental models of inflammation have been prevented by curcumin.[23] Curcumin is an active choleretic, increasing bile acid output by over 100%. [2] In addition to increasing biliary excretion of bile salts, cholesterol, and bilirubin, curcumin also increases the solubility of the bile. [34] This suggests a benefit in the prevention and treatment of cholelithiasis. Gastrointestinal effects
Turmeric and its components exert a number of beneficial effects on the gastrointestinal system. Turmeric’s long use as a carminative has significant research support. [2] Specifically, curcumin has been shown to inhibit gas formation by Clostridium perfringens and in rats given diets rich in flatulence-producing foods. In addition, sodium curcuminate has been shown to inhibit intestinal spasm, and another compound from turmeric, p-tolymethylcarbinol, has been shown to increase the secretion of secretin, gastrin, bicarbonate, and pancreatic enzymes. [2] As a component of curries and spicy foods, there is some concern that turmeric may be irritating to the stomach. However, several studies have shown turmeric to be beneficial to gastric integrity. Turmeric and curcumin have been shown to increase the mucin content of the stomach and exert gastroprotective effects against ulcer formation induced by stress, alcohol, indomethacin, pyloric ligation, and reserpine. [2] [37] However, at high doses, curcumin or turmeric may be ulcerogenic (see “Toxicology”, p. 692 ). Antimicrobial effects
Alcohol extracts and the essential oil of Curcuma longa have been shown in one study to inhibit the growth of most organisms occurring in cholecystitis, i.e. Sarcina, Gaffkya, Corynebacterium, and Clostridium. [2] Other microorganisms which are inhibited include Staphylococcus, Streptococcus, Bacillus, Entamoeba histolytica, and several pathogenic fungi. [2] [38] The concentrations used in these studies were relatively high: 0.5–5.0 mg/ml of the alcohol extract and essential oil, and 5–100 ug/ml of curcumin.
CLINICAL APPLICATIONS Turmeric and curcumin have several clinical applications. Most notable are: • cancer prevention and treatment adjunct • inflammation • atherosclerosis • liver disorders • cholelithiasis • irritable bowel syndrome.
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Cancer prevention and treatment adjunct
As discussed above, turmeric and curcumin have demonstrated significant protective effect against cancer development in experimental studies in animals. There is also some human research showing similar results. In one human study, 16 chronic smokers were given 1.5 g of turmeric daily while a control group of six non-smokers served as a control group. [19] At the end of the 30 day trial, the smokers receiving the turmeric demonstrated significant reduction in the level of mutagens excreted in the urine. These results are quite significant as the level of urinary mutagens is thought to correlate with the systemic load of carcinogens and the efficacy of detoxification mechanisms. Due to widespread exposure to smoke, aromatic hydrocarbons, and other environmental carcinogens, the frequent use of turmeric as a spice appears warranted. Turmeric extracts and curcumin have demonstrated direct antitumor results in a number of experimental models of skin, epithelial, stomach and liver cancers. [15] [39] [40] This effect has also been substantiated in a human study. [41] Sixty-two patients with either ulcerating oral or cutaneous squamous cell carcinomas who had failed to respond to the standard treatments of surgery, radiation, and chemotherapy were given either an ethanol extract of turmeric (for oral cancers) or an ointment containing 0.5% curcumin in Vaseline. The ointment or extract was applied topically three times daily. At the end of the 18 month study, the treatment was found to have been effective in reducing the smell of the lesion (90%), itching, exudate (70%), pain (50%), and size of the lesion (10%). Although these are not spectacular results, it must be pointed out that this patient population had failed to respond to standard medical treatment. While more human studies are needed on the use of turmeric and curcumin in cancer, there is ample evidence to support their use in cancer prevention and as an adjunct in an overall cancer treatment plan. Inflammation
Curcuma longa has been used in Ayurvedic medicine, both locally and internally, in the treatment of sprains and inflammation. This use seems to be substantiated not only by the experimental studies described above, but also by clinical investigations. [42] [43] In one double-blind crossover clinical trial in patients with rheumatoid arthritis, curcumin (1,200 mg/day) was compared to phenylbutazone (300 mg/day). The improvements in the duration of morning stiffness, walking time, and joint swelling were comparable in both groups. [42] However, while phenylbutazone is associated with significant adverse effects, curcumin has not been shown to produce any side-effects at the recommended dosage level. In another study which used a new human model for evaluating NSAIDs, the postoperative inflammation model, curcumin was again shown to exert comparable anti-inflammatory action to phenylbutazone. [43] While curcumin has an anti-inflammatory effect similar to phenylbutazone and various NSAIDs, it does not possess direct analgesic action. The results of these studies indicate that turmeric or curcumin may provide benefit in the treatment of inflammation. Furthermore, the safety and excellent tolerability of curcumin compared with standard drug treatment is a major advantage.
TOXICOLOGY Toxicity has not been reported at standard dosage levels. The oral LD 50 levels for turmeric, its alcohol extracts, and curcumin have not been determined, as 2.5 g/kg fed to mice, rats, guinea pigs, and monkeys, and 3.0 g/kg sodium curcuminate fed to rats resulted in neither mortality nor chromosomal aberrations in teratology tests.[2] [44] [45] [46] At very high doses, curcumin or turmeric may damage the gastrointestinal system, as curcumin, with doses of 100 mg/kg body weight, is ulcerogenic in rats.[2]
DOSAGE Based on the evidence presented above, turmeric should be consumed liberally in the diet. When specific medicinal effects are desired, higher doses of turmeric can be given or extracts of Curcuma longa or curcumin can be used. The recommended dosage for curcumin as an anti-inflammatory is 200–400 mg three times a day. To achieve a similar amount of curcumin using turmeric would require a dosage of 4,000–40,000 mg. Because the absorption of orally administered curcumin may be limited (pharmacokinetic studies in animals show that 40–85% of an oral dose of curcumin passes through the gastrointestinal tract unchanged [44] [45] ), curcumin is often formulated in conjunction with bromelain to possibly enhance absorption. In addition, bromelain also has anti-inflammatory effects (see Ch. 69 ). A curcumin–bromelain combination is best taken on an empty stomach 20 minutes before meals or between meals. Providing curcumin in a lipid base such as lecithin, fish oils, or essential fatty acids may also increase absorption. This combination is probably best absorbed when taken with meals.
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OP. Antioxidant properties of curcumin and related compounds. Biochem Pharmacol 1976; 25: 1811–1825
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M, Amonkar AJ, Bhide SV. In vitro antimutagenicity of curcumin against environmental mutagens. Fd Chem Toxic 1987; 25: 545–547
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Azuine MA, Kayal JJ, Bhide SV. Protective role of aqueous turmeric extract against mutagenicity of direct-acting carcinogens as well as benzopyrene-induced genotoxicity and carcinogenicity. J Cancer Res Clin Oncol 1992; 118: 447–452 17.
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Polasa K, Sesikaran B, Krishna TP, Krishnaswamy K. Turmeric ( Curcuma longa)-induced reduction in urinary mutagens. Fd Chem Toxic 1991; 29: 699–706
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Chandra D, Gupta S. Anti-inflammatory and anti-arthritic activity of volatile oil of curcuma longa (Haldi). Ind J Med Res 1972; 60: 138–142
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Arora R, Basu N, Kapoor V, Jain A. Anti-inflammatory studies on Curcuma longa (turmeric). Ind J Med Res 1971; 59: 1289–1295
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Chapter 81 - Dehydroepiandrosterone Alan R. Gaby MD*
INTRODUCTION Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal glands and to a lesser extent by the testes and ovaries. First identified in 1934, DHEA was subsequently shown to be produced in greater quantity than any other adrenal steroid. However, although circulating levels of DHEA and its ester DHEA-sulfate (DHEA-S) are 20 times higher than those of any other adrenal steroid, the function of DHEA in the body was, until recently, unknown. Since DHEA can be converted into other hormones, including estrogen and testosterone, scientists assumed that DHEA is merely a “buffer hormone”, a reservoir upon which the body can draw to produce the other hormones. However, the recent identification of DHEA receptors in the liver, kidney and testis of rats strongly suggests that DHEA has specific physiologic actions of its own. [1] During the past several years, there has been a great deal of interest in DHEA as a possible anti-aging hormone and as a potential treatment for a wide array of medical conditions. This interest has been sparked by two different lines of evidence. First, circulating levels of DHEA decline progressively with age – the levels in 70-year-old individuals are only about 20% as high as those in young adults. This age-related decline does not occur with any of the other adrenal steroids. Furthermore, epidemiologic evidence suggests that higher DHEA levels are associated with increased longevity and prevention of heart disease and cancer. It has therefore been suggested that some of the manifestations of aging may be caused by DHEA deficiency. Second, numerous animal studies have shown that administration of DHEA prevents obesity, diabetes, cancer, and heart disease; enhances the functioning of the immune system; and prolongs life.[2] Since most of these studies were carried out on rodents, which have little circulating DHEA, it is not clear whether the results * Reprinted with permission from Alternative Medicine Review 1996; 1(2): 60–69
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have relevance to human health. However, a growing body of human research, combined with the intriguing observations of innovative clinicians, suggests that DHEA may indeed have value in the treatment of various medical conditions. If this hormone can be convincingly shown to retard the aging process and to fight certain diseases, then DHEA therapy will be recognized as a major breakthrough in clinical medicine.
CLINICAL APPLICATIONS Aging
Preliminary results in mice suggest that DHEA may retard the aging process. Animals treated with this hormone look younger and have glossier coats and less gray hair than control animals. [3] In a recent study, 30 individuals between the ages of 40 and 70 years received 50 mg/day of DHEA or a placebo, each for 3 months, in double-blind cross-over fashion. During DHEA treatment, a remarkable increase in physical and psychological well-being was reported by 67% of the men and 84% of the women. There was no change in libido and no side-effects were seen. [4] In this author’s experience, elderly individuals who suffer from weakness, muscle wasting, tremulousness, fatigue, depression, declining memory and other signs of aging frequently have serum DHEA-S levels near or below the lower limit of normal. Treatment with DHEA (usually 5–10 mg/day for women and 10–20 mg/day for men) often results in improved mood, energy, memory, appetite, and skin color, sometimes after as little as 2 weeks. With continued treatment, the benefits may become even more pronounced and muscle wasting may be partially reversed. Cancer prevention
Administration of DHEA inhibited tumor formation in a strain of mice that develops spontaneous breast cancer. [5] DHEA has also been shown to prevent chemically induced colon [6] and liver [7] cancer, as well as skin papillomas in mice. [8] Premenopausal women with breast cancer had significantly lower plasma levels of DHEA than age-matched controls without breast cancer, whereas postmenopausal women had significantly higher DHEA levels than age-matched controls. [9] In another study, women with DHEA levels in the highest tertile were 60% less likely to develop breast cancer than were women in the lowest tertile. [10] In a prospective case–control study, serum DHEA and DHEA-S levels were significantly lower in individuals who subsequently developed bladder cancer than in those who did not. [11] These findings suggest that DHEA has anti-cancer activity and that low DHEA levels may be a risk factor for cancer. However, further research is required before guidelines can be developed regarding DHEA therapy and cancer. The observation that some postmenopausal women with breast cancer have elevated DHEA levels, and the fact that DHEA is converted in part to estrogen and testosterone should be cause for concern. It is not known whether the anti-cancer effects of DHEA are stronger than the prostate cancer-promoting effects of additional testosterone or the breast cancer-promoting effects of additional estrogen. Until those questions can be answered, DHEA therapy should be approached with caution in patients who are at risk for developing hormone-dependent cancers. Effects on immune function
DHEA exerts a number of different effects on the immune system. Some of these effects appear to result from the anti-glucocorticoid actions of DHEA. For example, DHEA antagonized the suppressive effects of dexamethasone on lymphocyte proliferation in mice [12] and prevented glucocorticoid-induced thymic involution. [13] Administration of DHEA has also been shown to preserve immune competence in burned mice, [14] an effect that extends beyond its anti-glucocorticoid action. [15] Administration of DHEA also protected against acute lethal infections with Coxsackie virus B4 and herpes simplex type 2 encephalitis in mice. DHEA appeared to act by preventing the suppression of immune competence caused by the viral infections. [16] DHEA has also been shown to influence immune function in humans. In a double-blind study, administration of 50 mg/day of DHEA to postmenopausal women (mean age, 56.1 years) produced a twofold increase in natural killer cell activity and a 6% decrease in the proportion of helper T-cells. [17] While the increase in natural killer cell activity might be expected to enhance immune surveillance against cancer and viral infections, the decline in helper T-cells could have adverse consequences. On the other hand, since DHEA is known to mediate T-cell responses, [18] the decline in helper T-cells could merely be a reflection of enhanced T-cell function. Although the implications of these changes in immune function are not entirely clear, it should be noted that 50 mg/day of DHEA has been shown to produce supraphysiologic serum levels in postmenopausal women. [19] Lower doses may therefore be more appropriate and might result in more clear-cut improvements in immune function.
Autoimmune diseases
The potential value of DHEA as a treatment for autoimmune disease was suggested by the observation that DHEA reduced the severity of renal damage in the NZB × NZW mouse, an animal model of spontaneous lupus.
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A clinical trial was therefore performed with 10 women suffering from mild or moderate systemic lupus erythematosus (SLE). [20] Each patient received 200 mg/day of DHEA for 3–6 months. Eight of the 10 patients reported improvements in overall well-being, fatigue, energy, and/or other symptoms. For the group as a whole, there was a significant improvement in the physician’s overall assessment of disease activity. After 3 months, the average prednisone requirement had decreased from 14.5 to 9.4 mg/day. Of three patients with significant proteinuria, two showed marked reductions and one a modest reduction in protein excretion. There was no significant correlation between changes in serum DHEA or DHEA-S levels and clinical response. In addition, pre-treatment levels of these hormones did not predict clinical response. Side-effects were limited to mild or moderate acneiform dermatitis and mild hirsutism. Administration of relatively large doses of DHEA has also been reported to increase stamina and improve the sense of well-being in patients with multiple sclerosis.
[ 21]
During the past 5 years, a number of practitioners have been prescribing DHEA for patients with autoimmune disease. Pre-treatment plasma levels of DHEA or DHEA-S are usually below normal in patients receiving prednisone or related drugs, because these medications cause adrenal suppression. However, in my experience, DHEA-S levels are also frequently low in patients with autoimmune disease who are not receiving corticosteroids. I have seen a 76-year-old woman with rheumatoid arthritis who was maintained on 5 mg/day of prednisone. After taking 10 mg/day of DHEA for several weeks, her joint symptoms improved and she was able to wean off the prednisone. Another woman with poorly controlled dermatomyositis had marked clinical improvement and was able to reduce her prednisone by 50% after receiving 10 mg of DHEA twice a day. A woman with a 3 year history of persistent bleeding due to inflammatory bowel disease reported no further bleeding after taking 15 mg/ day of DHEA. Two other women with SLE had clinical improvements with DHEA. However, low doses were not effective in these cases; results became apparent only after the dose was increased to around 100 mg/day or more. Dr Davis Lamson (personal communication) has given DHEA to six patients with ulcerative colitis who had failed to respond to a combination of conventional therapy and nutritional treatments. In all six cases, the bleeding, diarrhea, and overall condition improved. Some patients with chronic fatigue syndrome (CFS) have also improved clinically with DHEA therapy. However, since cortisol deficiency appears to be the primary problem in some patients with CFS, and since DHEA can antagonize the effects of cortisol, DHEA therapy may actually make some patients with CFS worse. It is important, therefore, to measure both DHEA and cortisol levels before treating patients with CFS. Acquired immunodeficiency syndrome
Preliminary evidence suggests that DHEA may play a role in acquired immunodeficiency syndrome (AIDS). In one study, DHEA inhibited the replication of HIV, the virus believed to cause AIDS. [22] In addition, DHEA has been shown to enhance the immune response to viral infections. Furthermore, DHEA levels are low in people infected with HIV and these levels decline even more as the disease progresses to full-blown AIDS. [23] In a study of 108 HIV-infected men with marginally low helper T-cell counts (between 200 and 499), those with serum DHEA levels below normal were 2.34 times more likely to progress to AIDS than were men with normal DHEA levels.[24] These studies suggest that DHEA deficiency may be one of the factors contributing to immune system failure in HIV-infected patients. To date, only one clinical trial has tested the effect of giving DHEA to HIV-infected patients. Although DHEA did not improve CD4 counts or serum p24 antigen levels, the dosage used (750–2,250 mg/day) seems excessively large, possibly beyond the “therapeutic window” in which DHEA exerts its beneficial effects. [25] The concept of a therapeutic window has been clearly demonstrated for cortisol. For example, cortisol is known to enhance immune function at physiologic levels. However, both a deficiency and an excess of cortisol result in impaired immune function. Future trials of DHEA in HIV-infected patients should therefore use lower doses, perhaps 50–200 mg/day. Allergic disorders
Eight patients with severe attacks of hereditary angioedema were treated with 37 or 74 mg/day of DHEA-S (equivalent to 25 or 50 mg, respectively, of DHEA) every 1–3 days, for 3–29 months. DHEA-S treatment resulted in a dramatic clinical improvement in all eight patients. [26] Practitioners who use DHEA have observed that treatment sometimes reduces the severity of food or chemical allergies. I have seen several patients with multiple chemical sensitivities who responded to physiologic doses of DHEA (5–15 mg/day for women, 10–30 mg/ day for men). However, it is difficult to predict which patients will improve. Subnormal serum levels of DHEA-S are common in asthmatics. DHEA deficiency may result in part from corticosteroid-induced adrenal suppression. However, low levels of DHEA-S were also found in 21% of asthmatics who were not taking steroids. [27] DHEA deficiency may also result from long-term administration of inhaled corticosteroids. In a study of 36 postmenopausal asthmatic
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women, those who were receiving at least 1 mg/day of beclomethasone dipropionate had nearly a 50% reduction in serum DHEA levels, compared with women who were not receiving the drug. Apparently, inhaled corticosteroids are absorbed in amounts sufficient to cause some degree of adrenal suppression. [28] I have seen two female patients with long-standing asthma who had clinical improvement after receiving 10 mg/day of DHEA. In one of these patients, chronic nasal polyps also disappeared, much to the surprise of her otolaryngologist. Obesity
Administration of DHEA prevented the development of obesity in genetically obese mice. [29] However, studies in humans have so far failed to demonstrate a role for DHEA in the treatment of obesity. Cardiovascular disease
Administration of DHEA reduced the severity of atherosclerosis in cholesterol-fed rabbits. 62–100% of the total plasma digitalis-like factors in 11 healthy adults. [31]
[30]
DHEA-S has also been shown to have digitalis-like activity, accounting for
Mean plasma DHEA-S levels were significantly lower in men with a history of heart disease than in men without such a history. In men with no history of heart disease at baseline, a low plasma DHEA-S level (less than 140 mcg/dl) was associated with a more than threefold increase in the age-adjusted risk of death from cardiovascular disease. [32] Similar findings were reported by others, [33] although another epidemiologic investigation found only a modest protective effect of DHEA. [34] In women, no inverse association was found between DHEA-S levels and cardiovascular disease. In fact, cardiovascular death rates were highest in women in the highest tertile of DHEA-S levels and lowest in women in the middle tertile (a U-shaped distribution). [35]
Osteoporosis
At the time of menopause, the amount of DHEA manufactured by the ovaries declines. And, even though the ovaries are not the major source of DHEA, serum DHEA levels decline by more than 60% after menopause. [36] The possible relationship between DHEA deficiency and osteoporosis was suggested by a study of women with Addison’s disease. In these patients, the onset of menopause was followed by an unusually rapid rate of bone loss. This accelerated bone loss was associated with marked reductions in plasma concentrations of DHEA and testosterone (94 and 63% lower, respectively, than those of healthy postmenopausal women). [37] These findings suggest that DHEA and/or testosterone is essential for the maintenance of bone mass in postmenopausal women. In another study, bone mineral density was measured at the lumbar spine, hip, and radius in 105 women aged 45–69 years. Fifty women had normal measurements, whereas 55 had low bone density. The average serum DHEA-S level was 60% lower in the women with low bone density than in those with normal bones. Women with low DHEA values were 40 times more likely to have osteoporosis than were women with normal DHEA levels. In contrast, there was no relationship between estrogen levels and bone density. [38] In a group of 29 postmenopausal women, there was a significant positive correlation between bone mineral content of the distal radius and ulna and age-adjusted serum DHEA levels. [39] There are several mechanisms by which DHEA might prevent osteoporosis. First, one of the breakdown products of DHEA, 5-androstene-3ß, 17ß-diol, is known to bind strongly to estrogen receptors. [40] Therefore, DHEA, like estrogen, might exert an inhibitory effect on bone resorption. Second, there is evidence that androgens (a class of hormones that includes DHEA and testosterone) stimulate bone formation and calcium absorption. [41] Third, the partial conversion of DHEA to estrogen and testosterone would be expected to provide additional protection against bone loss. I often recommend low doses of DHEA (usually 5–10 mg/day) for postmenopausal women whose serum DHEA-S levels are near or below the lower limit of normal. In some cases, DHEA relieves symptoms such as hot flashes that are usually attributed to estrogen deficiency. A combination of DHEA and identical-to-natural progesterone (usually given as a topical cream) may be more effective against hot flashes than either treatment alone. Dementia
In one study, intracerebroventricular administration of DHEA or DHEA-S improved the results of certain memory tests in mice. [42] Some investigators have found low levels of DHEA in patients with Alzheimer’s disease. [43] However, others have failed to confirm those observations. [44] In a small, uncontrolled trial, administration of DHEA appeared to produce modest improvements in cognition and behavior in a group of male patients with Alzheimer’s disease. [45] Diabetes
Administration of 0.4% DHEA in the diet reversed hyperglycemia, preserved beta-cell function, and increased insulin sensitivity in genetically diabetic mice. Although DHEA has been reported to ameliorate insulin
[46]
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resistance in one patient with diabetes, [47] very large doses of DHEA (1,600 mg/day for 28 days) caused mild abnormalities of glucose metabolism. [48] The role of DHEA in the overall management of diabetes is therefore still unclear.
TOXICITY For a steroid hormone, DHEA also appears to be relatively safe. Administration of 1,600 mg/day for 28 days to healthy volunteers resulted in some degree of insulin resistance, but no other significant side-effects occurred. In the SLE studies, 200 mg/day given for a number of months was well tolerated, with the exception of mild to moderate acne and occasional mild hirsutism. Addition of 0.6% DHEA to the diet of rats reduced body weight and enhanced the development of chemically induced pre-neoplastic pancreatic lesions. [49] Although that dose of DHEA is extremely large (the equivalent human dose would be approximately 2,000 mg/day), this report indicates that DHEA is by no means innocuous and should therefore be treated with respect.
DOSAGE As this review suggests, DHEA shows promise for preventing age-related decline and as a treatment for certain diseases. Innovative practitioners have therefore begun prescribing DHEA for their patients and the public is becoming increasingly interested in this purported “anti-aging pill”. Although DHEA appears to be safe, its long-term effects are unknown. It is possible that adverse consequences will become evident with chronic use. It is therefore important that we treat this hormone with respect and err on the side of caution. Although some practitioners are routinely prescribing 50 mg/day for healthy women and 100 mg/day for healthy men, those doses may be supraphysiologic and I am concerned about their long-term safety. Unlike hydrocortisone (cortisol), for which the physiologic replacement dose is known, it is not clear what the physiologic dose of DHEA is. However, it may be lower than many doctors believe. I have treated one patient with severe adrenal insufficiency who had a clear response to 15 mg/day of DHEA. She experienced marked clinical improvement at that dose and her serum level of DHEA-S increased from barely detectable to well above the lower limit of normal. Another woman with a history of bilateral adrenalectomy reported marked symptom relief with DHEA doses as low as 5–10 mg/day. In my practice, I usually prescribe 5–15 mg/day for women and 10–30 mg/day for men. Many patients have obvious improvements with these doses. Some patients who did not improve have tried larger doses, but in most cases, the larger doses were not helpful either. The one exception has been patients with lupus or other autoimmune diseases, who sometimes needed as much as 100 mg/day or more to obtain benefit. I have typically prescribed DHEA in capsule form, in a base of hydroxymethylcellulose, which is said to produce sustained release of the hormone and supposedly better results. With large doses, I recommend twice-a-day dosing, usually morning and evening. Although serum measurements of DHEA and DHEA-S are available through most laboratories, it is not clear how closely one should rely on these measurements; nor is it clear whether DHEA or DHEA-S is the more reliable test. The normal range for DHEA-S as listed by my local laboratory is 350–4,300 ng/ml for women and 800–5,600 ng/ml for men. Many older individuals have values near or below the lower limit of normal. However, I prefer not to use an age-adjusted reference range (as published by some laboratories), since it seems that the age-related decline in serum DHEA-S is undesirable. When DHEA therapy appears to be clinically indicated, I will consider treating women whose DHEA-S levels are below 600 ng/ml and men whose levels are below 1,200 ng/ml. There are as yet no data on what constitutes an optimum serum level. Consequently, I continue to err on the side of caution by using low doses of DHEA. There are also no data available concerning long-term administration of DHEA. While lifetime replacement therapy seems appropriate for patients with age-related DHEA deficiency, other patients should be assessed on a case-by-case basis. I have found that about 10% of patients who are taking thyroid hormone develop symptoms of thyrotoxicosis after starting DHEA therapy. That observation is consistent with a report that DHEA potentiates the action of thyroid hormones. [50] Symptoms of thyroid overtreatment responded to a reduction in the thyroid-hormone dosage, and patients reported that they felt better on DHEA plus lower-dose thyroid hormone than they did on thyroid hormone alone.
SUMMARY In conclusion, DHEA appears to be one of the major therapeutic advances of the past 20 years. However, we must treat this powerful hormone with caution and respect, in order to maximize its benefits and minimize its risks.
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Koo E, Feher KG, Geher T, Fust G. Effect of dehydroepiandrosterone on hereditary angioedema. Klin Wochenschr 1983; 61: 715–717
27.
Dunn PJ, Mahood CB, Speed JF, Jury DR. Dehydroepiandrosterone sulphate concentrations in asthmatic patients. Pilot study. NZ Med J 1984; 97: 805–808
28.
Smith BJ, Buxton JR, Dickeson J, Heller RF. Does beclomethasone dipropionate suppress dehydroepiandrosterone sulphate in postmenopausal women? Aust NZ J Med 1994; 24: 396–401
29.
Cleary MP, Shepard A, Kenks B. Effect of dehydroepiandrosterone on growth in lean and obese Zucker rats. J Nutr 1984; 114: 1242–1251
30.
Gordon GB, Bush DE, Weisman HF. Reduction of atherosclerosis by administration of dehydroepiandrosterone. J Clin Invest 1988; 82: 712–720
31.
Vasdev S, Longerich L, Johnson E et al. Dehydroepiandrosterone sulfate as a digitalis like factor in plasma of healthy human adults. Res Commun Chem Pathol Pharmacol 1985; 49: 387–399
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Barrett-Connor E, Khaw KT, Yen SS. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med 1986; 315: 1519–1524
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Mitchell LE, Sprecher DL, Borecki IB et al. Evidence for an association between dehydroepiandrosterone sulfate and nonfatal, premature myocardial infarction in males. Circulation 1994; 89: 89–93
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Newcomer LM, Manosn JE, Barbieri RL et al. Dehydroepiandrosterone sulfate and the risk of myocardial infarction in US male physicians: a prospective study. Am J Epidemiol 1994; 140: 870–875
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Barrett-Connor E, Khaw KT. Absence of an inverse relation of dehydroepiandrosterone sulfate with cardiovascular mortality in postmenopausal women. N Engl J Med 1987; 317: 711
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Monroe SE, Menon KMJ. Changes in reproductive hormone secretion during the climacteric and postmenopausal periods. Clin Obstet Gynecol 1977; 20: 113–122
37.
Devogelaer JP, Crabbe J, Nagant de Deuxchaisnes C. Bone mineral density in Addison’s disease: evidence for an effect of adrenal androgens on bone mass. Br Med J 1987; 294: 798–800
38.
Szathmari M, Szucs J, Feher T, Hollo I. Dehydroepiandrosterone sulphate and bone mineral density. Osteoporosis Int 1994; 4: 84–88
39.
Brody S, Carlstorm K, Lagrelius A et al. Adrenal steroids in post-menopausal women: relation to obesity and to bone mineral content. Maturitas 1987; 9: 25–32
Taelman P, Kaufman JM, Janssns X, Vermeulen A. Persistence of increased bone resorption and possible role of dehydroepiandrosterone as a bone metabolism determinant in osteoporotic women in late post-menopause. Maturitas 1989; 11: 65–73 40.
Taelman P, Kaufman JM, Janssns X, Vermeulen A. Persistence of increased bone resorption and possible role of dehydroepiandrosterone as a bone metabolism determinant in osteoporotic women in late post-menopause. Maturitas 1989; 11: 65–73 41.
42.
Flood JF, Morley JE, Roberts E. Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci 1992; 89: 1567–1571
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43.
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Leblhuber F. Dehydroepiandrosterone sulphate in Alzheimer’s disease. Lancet 1990; 336: 449
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Schneider LS, Hinsey M, Lyness S. Plasma dehydroepiandrosterone sulfate in Alzheimer’s disease. Biol Psychiatry 1992; 31: 205–208
46.
Coleman DL, Leiter EH, Schwizer RW. Therapeutic effects of dehydroepiandrosterone (DHEA) in diabetic mice. Diabetes 1982; 31: 830–833
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Buffington CK, Pourmotabbed G, Kitabchi AE. Case report. Amelioration of insulin resistance in diabetes with dehydroepiandrosterone. Am J Med Sci 1993; 306: 320–324
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Mortola JF, Yen SSC. The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 1990; 71: 696–704
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Tagliaferro AR, Roebuck BD, Ronan AM, Meeker LD. Enhancement of pancreatic carcinogenesis by dehydroepiandrosterone. Adv Exp Med Biol 1992; 322: 119–129
50.
McIntosh MK, Berdanier CD. Influence of dehydroepiandrosterone (DHEA) on the thyroid hormone status of BHE/cdb rats. J Nutr Biochem 1992; 3: 194–199
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Chapter 82 - Echinacea species (narrow-leafed purple coneflower) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Echinacea sp. (family: Asteraceae) Echinacea angustifolia Common names: narrow-leafed purple coneflower, black sampson, snakeroot Echinacea purpurea Common name: purple coneflower Echinacea pallida Common name: pale purple coneflower
GENERAL DESCRIPTION Echinacea sp. are perennial herbs native to midwestern North America, from Saskatchewan to Texas. The genus derives its name from the Greek echinos (meaning sea urchin). This refers to the prickly scales of the dried seed head portion of the flower. There are nine species of Echinacea which have been taxonomically classified by McGregor based on comparative anatomy and morphology (see Table 82.1 ). [1] Of the nine species, E. angustifolia, E. purpurea, and E. pallida are the most commonly used clinically. E. angustifolia, with a typical height of up to 2 feet, is shorter than E. purpurea (1.5–5 feet) and E. pallida (1–3 feet). Another TABLE 82-1 -- Taxonomic formation of the genus Echinacea[3] Species
Synonyms
Echinacea angustifolia
Brauneria angustifolia
Echinacea atrorubens
Rudbeckia atrorubens
Echinacea laevigata
Brauneria laevigata
Echinacea pallida
Rudbeckia pallida
Brauneria pallida Echinacea paradoxa
Brauneria paradoxa
Echinacea purpurea
Rudbeckia purpurea
Rudbeckia hispida Rudbeckia serotina Echinacea speciosa Echinacea intermedia Echinacea simulata
Echinacea speciosa
Echinacea sanguinea Echinacea tennesseensis
Brauneria tennesseensis
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key to species identification is that E. angustifolia and E. purpurea have yellow pollen, while E. pallida is noticeably paler and has white pollen. The portions of the plant used for medicinal purposes includes the aerial portion, the whole plant including the root, and the root itself. The tap root of E. angustifolia can reach a length of 3–4 feet.[2] [3] E. angustifolia has thick, hairy, 1–3 inches long leaves found at the base of a purple seed head shaped like a cone. The only exception to the family of “purple” coneflower is E. paradoxa which has a yellow flower.
CHEMICAL COMPOSITION Analysis of Echinacea sp. has yielded a wide assortment of chemical constituents with pharmacological activities. The broad chemical composition of this medicinal plant suggests possible synergistic effects among its constituents. For example, in some experimental models, while the water-soluble polysaccharides have shown greater stimulatory effects on the cellular immune system, the lipophilic components have demonstrated more potent effects on enhancing macrophage phagocytosis. [3] [4] The important constituents, from a pharmacological perspective, of Echinacea sp. can be divided into seven categories: • polysaccharides • flavonoids • caffeic acid derivatives • essential oils • polyacetylenes • alkylamides • miscellaneous chemicals.
Polysaccharides
A number of immunostimulatory and mild antiinflammatory polysaccharides have been isolated from Echinacea sp.[2] [3] [5] [6] [7] [8] [9] Most notable are inulin, which is found in a high concentration (5.9%) in E. angustifolia root, and the high molecular weight (25,000–50,000) polysaccharides found in the aerial part of E. purpurea, as these components possess significant immune-enhancing properties. Typically the most potent immune-enhancing polysaccharides are the water-soluble, acidic, branched-chain heteroglycans composed of many types of sugars rather than the polyfructose content of inulin. Flavonoids
The leaves and stems of E. angustifolia and E. purpurea have been shown to contain numerous flavonoids, with rutoside being the most abundant. [3] [9] The total flavonoid content (calculated as quercetin) for E. angustifolia and E. purpurea was 0.48 and 0.38% respectively. [2] [3] [9] [10] Caffeic acid derivatives
Caffeic acid serves as the backbone for a number of important medicinal plant compounds in other plants as well as Echinacea sp. (see Fig. 82.1 ). The first compound believed to be unique to Echinacea was echinacoside, a compound eventually shown to be composed of caffeic acid, a caffeic acid derivative (similar to catechol), glucose, and rhamnose, all attached to a central glucose molecule (see Figs 82.2 and 82.3 ). [11] Echinacoside accumulates in the roots, but is also found in smaller concentrations in the flowers. The roots of E. angustifolia contain 0.3–1.3%, while the roots of E. pallida contain a similar concentration of 0.4–1.7%. [12] It is assumed that E. purpurea has similar echinacoside levels as well. Other caffeic acid derivatives important in the pharmacology of Echinacea include cichoric acid, chlorogenic
Figure 82-1 Caffeic acid.
Figure 82-2 Echinacoside and similar compounds.
Figure 82-3 Other caffeic acid derivatives.
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acid, and cynarin. [3] Cichoric acid was originally isolated from E. purpurea and is found in much higher concentrations in this species compared with E. angustifolia and E. pallida.[2] [3] [9] However, E. angustifolia and E. pallida have higher amounts of other types of caffeic acid derivatives. [2] [3] [13] These differences are not thought to have much clinical significance; rather they may prove to be valuable in quick chemical differentiation of species. Essential oils
The essential oil content varies among the three common species: [14] • E. angustifolia root and leaves contain less than 0.1% • E. purpurea root 0.2% and flowers and leaves contain 0.6% • E. pallida root contains up to 2% and the leaves contain less than 1%. Interestingly, in one study the essential oil content of E. pallida root was found to rise to 3.5–4% in April and May, but fall to 1–1.5% for the rest of the year. [15] The major essential oil components are sesquiterpene derivatives, borneol, alpha-pinine, and related aromatic compounds. [2] [3] Polyacetylenes
A number of polyacetylenes have been identified from the roots of all three commercial species. [16] The difference in the type of polyacetylene and susceptibility to breakdown may help to differentiate which species is best for commercial use. Since the polyacetylenes of E. pallida are quite susceptible to auto-oxidation, E. angustifolia may be better for commercial products. [17] Research has shown that long-term storage greatly decreases the content of polyacetylenes to only trace levels at best. However, the polyacetylene derivatives of auto-oxidation of E. pallida are quite characteristic and useful in differentiating E. pallida from E. angustifolia. Alkylamides
Alkylamides typically exert a tingling sensation on the tongue. This is representative of their mild anesthetic effect. These compounds are found in highest concentrations in the roots. The roots of E. angustifolia contain higher concentrations (0.004–0.039%) than E. purpurea (0.009–0.151%) and E. pallida (.001%). [9] [18] Miscellaneous
There are undoubtedly other constituents which contribute to the pharmacology of Echinacea. The occurrence of a “colorless alkaloid” was first reported by the great John Uri Lloyd in 1897 and substantiated recently by the isolation of the alkaloids tussilagine and isotussilagine. [19] Other compounds isolated from Echinacea sp. include: [2] [3] • resins • glycoproteins • sterols • minerals • fatty acids.
HISTORY AND FOLK USE Echinacea was used extensively by the native Americans living in areas where it grew. In fact, Echinacea was used by the American Indians against more illnesses than any other plant. The root was used externally for the healing of wounds, burns, abscesses, and insect bites; internally for infections, toothache and joint pains;
and as an antidote for snake (rattlesnake) bites. [20] A commercial product containing Echinacea was introduced to Americans around 1870 by H. C. F. Meyer, a German lay healer, who recommended it as a wonder cure called “Meyer’s blood purifier”. [2] [3] Meyer recommended it for almost every conceivable malady and there were numerous case reports of successful treatments for snake bites, typhus, diphtheria, and other infections. Echinacea angustifolia became a favorite with Eclectic physicians as it was thought to be greater in activity than other species. Eclectics used it externally as a local antiseptic, stimulant, deodorant, and anesthetic; and internally for “bad blood”, i.e. to correct “fluid depravation with tendency to sepsis and malignancy”. [21] Although many physicians began to investigate and use Echinacea as a serious medicine, in 1909 the Council on Pharmacy and Chemistry of the American Medical Association refused to recognize Echinacea as an active drug stating: “In view of the lack of any scientific scrutiny of the claims made for it, Echinacea is deemed unworthy of further consideration until more reliable evidence is presented in its favor.” Despite this opposition, Echinacea was included in the National Formulary of the US and remained there until 1950. [2] [3] With the demise of the Eclectic movement, the popularity of Echinacea in the US waned except amongst naturopathic physicians until around 1980 when Echinacea was rediscovered due to the increased consumer interest in immune system disorders such as candidiasis, chronic fatigue syndrome, AIDS, and cancer. [22] Although interest in Echinacea decreased in America between the 1930s and 1980s, European physicians continued research. Much of this research was initiated by a 1932 study by Gerhard Madaus. Madaus demonstrated immune-enhancing effects of a preparation from the fresh juice of the aerial portion of E. purpurea. This was followed by development of a commercial product and a great deal of scientific study. Thus, E. purpurea began to be as respected as E. angustifolia among herbal practitioners in Europe. [2] [3]
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PHARMACOLOGY The chemistry, pharmacology and clinical applications of Echinacea have been the subject of over 200 scientific studies. [2] [3] The overwhelming majority of the clinical studies have utilized an injectable form of a commercial product, Echinacin, containing an extract of the juice of the aerial portion E. purpurea along with 22% ethanol (for preservation). Other studies have utilized an oral Echinacin and another commercial product, Esberitox, which contains not only E. purpurea root extract, but also extracts of E. pallida, Thuja occidentalis, and Baptisia tinctoria. A recent review of published studies on the immunomodulating effects of Echinacea identified 26 controlled clinical studies, 16 of which featured Esberitox. [23] This section summarizes some of the pharmacological information on Echinacea with attention to the species used, part of the plant used, solvent used for extraction, and other relevant features. When no species delineation is made, the activity described is similar in all species. Tissue regeneration and anti-inflammatory properties
Echinacin, as well as polysaccharide components of Echinacea, have been shown to promote tissue regeneration and reduce inflammation in experimental studies. [8] [24] [25] [26] [27] This is apparently largely due to inhibition of the enzyme hyaluronidase via formation of a polysaccharide complex with hyaluronic acid, thereby maintaining the structure and integrity of the collagen matrix in connective tissue and ground substance. In addition to increased hyaluronic acid stabilization, Echinacea also stimulates fibroblast growth and manufacture of glycosaminoglycans, a critical goal in wound healing. [27] Echinacea both exerts a mild direct cortisone-like effect and enhances the secretion of adrenal cortex hormones. [2] [3] [25] The polysaccharide portion appears to be responsible for the direct anti-inflammatory effects, although the alkylamide fraction has also demonstrated some activity. [28] Immunostimulatory properties
Echinacea possesses a broad spectrum of effects on the immune system as a result of its content of a diverse range of active components affecting different aspects of immune function.[2] [3] For example, inulin, the major component in the root of E. angustifolia, activates the alternative complement pathway and thus promotes chemotaxis of neutrophils, monocytes, and eosinophils; solubilization of immune complexes; neutralization of viruses; and bacteriolysis. Echinacea also increases the levels of properdin, the normal serum globulin that stimulates the alternative complement pathway. [2] [3] [29] Another non-specific immune enhancement is Echinacea’s enhancement of serum leukocyte and granulocyte counts. [2] [3] [30] [31] [32] [33] The high-molecular-weight heteroglycan polysaccharide components of Echinacea have profound immunostimulatory effects. [2] [3] [5] [6] [7] The majority of these effects appear to be mediated by the binding of active Echinacea polysaccharides to carbohydrate receptors on the cell surface of macrophages and T-lymphocytes. It should be noted, however, that some of the T-cell activation in early studies is now thought to be due to a contaminant protein. Later studies using a purer polysaccharide fraction have not shown significant results. [3] Echinacea promotes non-specific T-cell activation, i.e. transformation, production of interferon, and secretion of lymphokines. The resultant effect is enhanced T-cell mitogenesis, macrophage phagocytosis, antibody binding, natural killer cell activity; and increased numbers of circulating PMNs. [2] [3] [5] Echinacea polysaccharides have also been shown to enhance macrophage phagocytosis and stimulate macrophages to produce increased amounts of tumor necrosis factor (TNF), interferon, interleukin 1, to destroy tumor cells in tissue culture, and to inhibit Candida albicans infection in rats infected intravenously with a lethal dose (3 × 10 5 cells) of C. albicans.[2] [3] [6] [7] [34] The interactions with macrophages are most likely responsible for much of the immune system enhancement of Echinacea polysaccharides. In addition to the polysaccharides, lipophilic alkylamides and caffeic acid derivatives like cichoric acid are thought to contribute to the immunostimulatory aspects of Echinacea, especially alcoholic extracts. [3] [4] [35] While most research has been devoted to the water-soluble components such as polysaccharides, the lipophilic fraction yields the most potent enhancement of macrophage phagocytosis. [3] [4] The carbon clearance test is often used to measure systemic macrophage activation. The method involves measuring the rate of disappearance of carbon granules from the blood at varying intervals following administration of the test substance. Root extracts of Echinacea administered orally tend to yield greater effects on phagocytic activity than the aerial portion with E. purpurea > E. angustifolia > E. pallida.[3] [4] Although many of the studies have utilized injectable preparations, oral preparations are generally thought to yield similar or even better results, although direct comparisons are apparently not available. For example, intramuscular Echinacin administered to healthy males on four successive days was shown to increase granulocytic phagocytosis by nearly 50%, while the oral administration of an E. purpurea root extract at a dose of 30 drops three times daily to healthy males for five consecutive days resulted in an increase of 120%. [29] This difference may, however, be due to the differing constituents of the forms used. The expressed juice of the aerial portion E. pupurea, as found in Echinacin, has lower
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concentrations of several of the phagocytosis-stimulating compounds characteristic to Echinacea, including polysaccharides, alkylamides and caffeic acid derivatives like cichoric acid compared with alcoholic extract. [3] In general, Echinacea appears to offer benefit for all infectious conditions. An exception to this statement may be acquired immunodeficiency syndrome (AIDS). It is unclear at this time if Echinacea should be recommended for AIDS. Although this condition is associated with widespread depression of the immune system, presumably due to the human immunodeficiency virus (HIV), stimulation of T-cell replication may also stimulate replication of the virus as well. In addition, Echinacin
has been shown to lower T-helper cells and decrease T-helper:suppressor cell ratios. [2] [3] While there are some anecdotal reports of Echinacea’s efficacy in HIV-infected individuals, more research is necessary to determine Echinacea’s effects in HIV. Antiviral properties
The juice of the aerial portion of E. purpurea along with alcoholic and aqueous extracts of the roots have been shown to possess antiviral activity. Some of the viruses inhibited in cell cultures include influenza, herpes and vesicular stomatitis viruses. [3] [36] Although certain Echinacea components (e.g. echinacoside, other caffeic acid derivatives, polysaccharides, etc.) may block virus receptors on the cell surface, the antiviral effects may also be due to inhibition of hyaluronidases. The viral-inhibiting action of Echinacea is significantly diminished when hyaluronidase is added to the cell cultures. [3] [24] [37] Many organisms secrete hyaluronidase, which increases connective tissue permeability and allows the organism to become more invasive. [38] Clinically, the inhibition of hyaluronidase coupled with general immunostimulation of Echinacea are probably more important than direct antiviral activity. The non-specific antiviral action of Echinacea enhances cytotoxic killing of virus-infected cells and the release of interferon. Interferons bind to cell surfaces, where they stimulate synthesis of intracellular proteins that block the transcription of viral RNA. Antibacterial properties
The direct antibacterial activity of Echinacea is quite mild. This is somewhat surprising as Echinacea has a long history of effective use in both internal and external bacterial infections. It is possible that it possesses some anti-infective properties which prevent bacterial adherence, though this has yet to be determined. Clearly its clinical efficacy is due to its strong immune-potentiating actions. Echinacea does possess some mild antibacterial action due largely to echinacoside, the complex caffeic acid derivative, found in highest concentrations in the root of E. angustifolia. Echinacoside and caffeic acid have been shown to have antibacteral action against Staphylococcus aureus, Corynebacterium diphtheria, and Proteus vulgaris. Approximately 6.3 mg. of echinacoside is equivalent to 10 Oxford units of penicillin. [2] [3] [11] Anti-neoplastic activity
Obviously, Echinacea possesses indirect anti-neoplastic activity via its general immuno-enhancing effects. Specifically important is its stimulation of macrophages to greater cytotoxic activity against tumor cells. (Z)-1,8-pentadecadiene, a lipid-soluble component found in the root of E. angustifolia and E. pallida, has been shown, in vivo, to possess significant direct anti-neoplastic activity. [39]
CLINICAL APPLICATIONS Echinacea has long been used clinically for conditions where its pharmacological actions have proven efficacy, especially in infections. Clinical studies have demonstrated effectiveness in a number of infectious conditions using all three routes of administration: injectable, oral, and topical. Again, the majority of clinical studies have utilized Echinacin, containing an extract of the juice of the aerial portion E. purpurea along with 22% ethanol (for preservation) and Esberitox. A recent review of published studies on the immunomodulating effects of Echinacea identified 26 controlled clinical studies, 16 of which featured Esberitox. [23] Infections Numerous clinical studies have confirmed Echinacea’s immune-enhancing actions. Various Echinacea extracts or products have shown results in: • general infectious conditions • influenza • colds • upper respiratory tract infections • urogenital infections • other infectious conditions. The common cold
One of the most popular uses of Echinacea is in the treatment of the common cold. Two recent studies offer considerable support for this clinical application. In one study, 180 patients with influenza were given either an extract of E. purpurea root at a daily dose of 450 mg or 900 mg, or a placebo. The 450 mg dose was found to be no more effective than a placebo; however the group taking the 900 mg dose showed significant reduction of cold symptoms. [40]
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In the other study, 108 patients with colds received either an extract of the fresh-pressed juice of E. purpurea (4 ml twice daily) or placebo for 8 weeks. [41] The number of patients remaining healthy was as follows: Echinacea, 35.2%; placebo, 25.9%. The length of time between infections was: Echinacea, 40 days; placebo, 25 days. When infections did occur in patients receiving Echinacea, they were less severe and resolved quicker. Patients showing evidence of a weakened immune system (CD4/CD8 ratio 100 mg/day) may cause sodium and water retention, hypertension, hypokalemia, and suppression of the renin–aldosterone system. Monitoring of blood pressure and electrolytes and increasing dietary potassium intake is suggested. [6] [7] There is a great individual variation in the susceptibility to the symptom-producing effects of glycyrrhizin. Adverse effects are rarely observed at levels below 100 mg/day, while they are quite common at levels above 400 mg/day. [7] Prevention of the side-effects of glycyrrhizin may be possible by following a high-potassium, low-sodium diet. Although no formal trial has been performed, patients who normally consume high-potassium foods and restrict sodium intake, even those with high blood pressure and angina, have been reported to be free from the aldosterone-like side effects of glycyrrhizin. [53]
[52]
Licorice should probably not be used in patients with a history of hypertension or renal failure, or those who are currently using of digitalis preparations.
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van Marle J, Aarsen PN, Lind A et al. Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium. Eur J Pharmacol 1981; 72: 219–225
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Morgan AG, Pacsoo C, McAdam WA. Maintenance therapy. A two year comparison between Caved-S and cimetidine treatment in the prevention of symptomatic gastric ulcer. Gut 1985; 26: 599–602 38.
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Morgan AG et al. Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982; 23: 545–551
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Glick L. Deglycrrhizinated liquorice in peptic ulcer. Lancet 1982; ii: 817
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Turpie AG, Runcie J, Thomson TJ. Clinical trial of deglycyrrhizinate liquorice in gastric ulcer. Gut 1969; 10: 299–303
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Rees WD, Rhodes J, Wright JE et al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroent 1979; 14: 605–607
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Kassir ZA. Endoscopic controlled trial of four drug regimens in the treatment of chronic duodenal ulceration. Irish Med J 1985; 78: 153–156
44.
Tewari SN, Wilson AK. Deglycyrrhizinated liquorice in duodenal ulcer. Practitioner 1972; 210: 820–825
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Das SK, Gulati AK, Singh VP. Deglycyrrhizinated liquorice in aphthous ulcers. J Assoc Physicians India 1989; 37: 647
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Evans FQ. The rational use of glycyrrhetinic acid in dermatology. Br J Clin Pract 1958; 12: 269–279
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Teelucksingh S, Mackie AD, Burt D et al. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990; 335: 1060–1063
48.
Partridge M, Poswillo D. Topical carbonoxolone sodium in the management of herpes simplex infection. Br J Oral Maxillofac Surg 1984; 22: 138–145
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Csonka G, Tyrrell D. Treatment of herpes genitalis with carbonoxolone and cicloxolone creams. A double blind placebo controlled trial. Br J Ven Dis 1984; 60: 178–181
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Bardhan KD, Cumberland DC, Dixon RA et al. Clinical trial of deglycyrrhizinised liquorice in gastric ulcer. Gut 1978; 19: 779–782
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Multicentre Trial. Treatment of duodenal ulcers with glycyrrhinizin acid-reduced liquorice. Br Med J 1973; 3: 501–503
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Feldman H, Gilat T. A trial of deglycyrrhizinated liquorice in the treatment of duodenal ulcer. Gut 1971; 12: 499–451
53.
Baron J, Nabarro J, Slater J et al. Metabolic studies, aldosterone secretion rate and plasma renin after carbonoxolone sodium as biogastrone. Br Med J 1969; 2: 793–795
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Chapter 91 - Hydrastis canadensis (goldenseal) and other berberine-containing botanicals Michael T. Murray ND Joseph E. Pizzorno Jr ND
Hydrastis canadensis (family: Ranunculaceae) Common names: goldenseal, yellow root, Indian turmeric, eye root, jaundice root Berberis vulgaris (family: Berberidaceae) Common name: barberry Berberis aquifolium (family: Berberidaceae) Common names: Oregon grape, trailing mahona Coptis chinensis Common name: goldthread
INTRODUCTION The plants goldenseal (Hydrastis canadensis), barberry (Berberis vulgaris), Oregon grape (Berberis aquifolium), and goldthread (Coptis chinensis) share similar indications and effects due to their high content of berberis alkaloids. The chief berberis alkaloid, berberine, has been extensively studied in both experimental and clinical settings. Its pharmacological effects are reviewed below. The general description, history and folk use, chemical composition, and specific clinical indications for each plant are presented here. The pharmacology of these plants is primarily discussed in terms of the activity of berberine.
GENERAL DESCRIPTION Hydrastis canadensis
Goldenseal is native to eastern North America and is cultivated in Oregon and Washington. It is a perennial herb with a knotty yellow rhizome from which arises a single leaf and an erect hairy stem. In early spring, it bears two five- to nine-lobed rounded leaves near the top, which are terminated by a single greenish-white flower. The parts used are the dried rhizome and roots. [1] [2] Berberis vulgaris
The common barberry is a deciduous spiny shrub that
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may reach 16 feet in height. Native to Europe, it has been naturalized in eastern North America. Parts used are the barks of the stem and root.
[ 1] [2]
Berberis aquifolium
The Oregon grape is an evergreen spineless ornamental shrub, 3–7 feet in height, native to the Rocky Mountains from British Columbia to California. Parts used are the rhizome and roots. [1] [2] Coptis chinensis
Goldthread is a perennial herb native to China. The parts used are the rhizomes and root.
CHEMICAL COMPOSITION Hydrastis canadensis
Alkaloids isolated from hydrastis include: • hydrastine (1.5–4.0%) • berberine (0.5–6.0%) • berberastine (2.0–3.0%) • canadine • candaline • hydrastinine • other related alkaloids. Other constituents include meconin, chlorogenic acid, phytosterins, and resins. Berberis vulgaris
Barberry contains several alkaloids in its roots: • jatrorrhizine • berberine • berberubine • berbamine • bervulcine • palmatine
[1] [2]
[3]
• columbamine • oxyacanthine. It also contains chelidonic, citric, malic, and tartaric acids. [1] [2] Berberis aquifolium
Oregon grape contains the alkaloids berbamine, berberine, canadine, corypalmine, hydrastine, isocorydine, mahonine, and oxyacanthine. Resins and tannins have also been reported. [1] [2] Coptis chinensis
Goldthread root contains berberine (5–8%) and other alkaloids similar to those found in goldenseal.
[ 3]
HISTORY AND FOLK USE Hydrastis canadensis
Native to North America, hydrastis was used extensively by the American Indian as an herbal medication and clothing dye. Its medicinal use centered around its ability to soothe the mucous membranes of the respiratory, digestive, and genitourinary tracts in inflammatory conditions induced by allergy or infection. The Cherokee and other Indian tribes used hydrastis in disorders of the eye and skin. [1] [2] Berberis vulgaris
This plant is native to most of Europe, and very similar species are found in North Africa and Asia. Barberry’s historical use is as an antidiarrheal agent, bitter tonic, antipyretic, and antihemorrhagic. [1] [2] Berberis aquifolium
Oregon grape’s historical and folk use is similar to that of hydrastis. In addition, Oregon grape was used in the treatment of chronic skin conditions such as acne, psoriasis, and eczema.[1] [2] Coptis chinensis
In China, goldthread was used in the traditional medicine system to “drain fire”. It was used primarily in infectious conditions similar to the historical use of goldenseal. Some specific uses included fever, dysentery, gastrointestinal infection, furuncles, boils, and eye infections. [3]
PHARMACOLOGY The medicinal value of hydrastis, barberry, Oregon grape root, and goldthread is thought to be due to their high content of isoquinoline alkaloids, of which berberine has been the most widely studied. Berberine has demonstrated antibiotic, immunostimulatory, anticonvulsant, sedative, hypotensive, uterotonic, cholerectic, and carminative activity. Berberine’s pharmacological activities support the historical use of the berberine-containing herbs. Antibiotic activity
Perhaps the most celebrated of berberine’s effects has been its antibiotic activity. Although not as potent as many prescription antibiotics, berberine exhibits a broad spectrum of antibiotic activity. Berberine has shown antimicrobial activity against bacteria, protozoa, and fungi, including: [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] • Staphylococcus sp. • Streptococcus sp. 777
• • • • • • • • • • • • • • • •
Chlamydia sp. Corynebacterium diphtheria E. coli Salmonella typhi Vibrio cholerae Diplococcus pneumonia Pseudomonas sp. Shigella dysenteriae Entamoeba histolytica Trichomonas vaginalis Neisseria gonorrhoeae N. meningitidiss Treponema pallidum Giardia lamblia Leishmania donovani Candida albicans.
Its action against some of these pathogens is actually stronger than that of prescription antibiotics commonly used for these pathogens. Berberine’s action in inhibiting Candida, as well as other pathogenic bacteria, prevents the overgrowth of yeast that is a common side-effect of antibiotic use. Table 91.1 lists the in vitro sensitivity of various organisms to berberine sulphate. The antimicrobial activity of berberine increases with pH in all organisms studied. [5] At pH of 8.0, its antimicrobial activity in vitro is typically two to four times greater than it is at pH 7.0, which in turn is one to four times greater than at pH 6.0. This suggests that alkalinization will improve its clinical efficacy, particularly in the treatment of urinary tract infections. Anti-infective activity
Researchers investigated berberine’s ability to inhibit the adherence of group A streptococci to host cells based on the fact that the therapeutic effect of berberine appeared to be greater than its direct antibiotic effects. [11] Recent studies have shown that certain antimicrobial agents can block the adherence of microorganisms to host cells at doses much lower than those needed to kill cells or to inhibit cell growth. Berberine’s ability to inhibit the adhesion of streptococci to host cells has several modes of action. First, berberine causes streptococci to lose lipoteichoic acid (LTA). LTA is the major substance responsible for the adhesion of the bacteria to host tissues. Another important action of berberine is preventing the adhesion of fibronectin to the streptococci as well as eluting already bound fibronectin. The significance of the results of this study are quite profound. It raises many questions and forces researchers as well as practitioners to look at the treatment of
bacterial infections in a new light. Is it better to utilize a substance with bactericidal or bacteriostatic actions over
Organism
TABLE 91-1 -- In vitro sensitivity of microorganisms to berberine sulphate [5] [6] [9] Inhibitory concentration (µg/ml)*
Bacteria Bacillus cereus
25.0
B. cereus
50.0
B. subtilis
25.0
Corynebacterium diphtheria
6.2
Enterobacter aerogenes
2500.05
Escherichia coli
600.05
Klebsiella sp.
>100.0
K. pneumoniae
25.0
Proteus sp.
>100.0
Pseudomonas mangiferae
>100.0
P. pyocyanea
>100.0
Salmonella paratyphi
>100.0
S. typhimurium
>100.0
Shigella boydii
12.5
Staphylococcus aureus
6.2–50.0
Streptococcus pyogenes
12.5
Vibrio cholerae
25.0
Fungi Candida utilis
12.5
C. albicans
12.5
Cryptococcus neoformans
150.0 –
Microsporum gypseum
50.0 –
Saccharomyces cerevisiae
100.0 –
Sporothrix schenkii
6.2
Trichophyton mentagrophytes
100.0 –
Other Entamoeba histolytica
200.0
Erwinia carotovora
100.0
Leishmania donovani
5.08
Mycobacterium tuberculosis
200.0 –
Xanthomonas citri
3.1
~Tested in a solid medium, which typically requires a four to 10 times greater concentration for the same level of inhibition. * Minimum concentration that totally inhibits growth in a liquid medium at pH 8.0. Maximum concentration tested was 100 µg/ml, unless otherwise noted.
a substance which prevents the adherence of bacteria to host cells? Is the true value of botanicals with “anti-infective” actions a multifactorial effect on all aspects of infections from immune stimulation to antimicrobial and anti-adherence actions? The results of the study indicate that berberine interferes with infections due to group A streptococci not only by inhibiting streptococcal growth, but also by blocking these organisms to host cells. The study implies berberine-containing plants may be ideal in the treatment of “strep throat”, a condition historically treated with goldenseal by American naturopathic physicians. Berberine’s action in inhibiting Candida albicans prevents the overgrowth of yeast that is a common side-effect of antibiotic use. Immunostimulatory activity
Berberine has been shown to increase the blood supply to the spleen. [12] This improved blood supply may promote optimal activity of the spleen by increasing the
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release of compounds, such as tuftsin, that potentiate immune function. Berberine has also been shown to activate macrophages, via both enhanced priming and triggering. [13] Anti-cancer effects
Berberine exhibits potent anti-cancer activity both directly by killing tumor cells and indirectly by stimulating white blood cells. [13] [14] [15] The most impressive effect was noted in a study demonstrating antitumor activity against human and rat malignant brain tumors. [15] Several experimental approaches were used in the study. In vitro studies were performed on a series of six human malignant brain tumor cell lines and rat 9L brain tumor cells. Berberine used alone at a dose of 150 mcg/ml showed an average cancer cell kill of 91%. This kill rate was over twice that of 1,3- bis(2-chloro-ethyl)-1-nitrosourea (BCNU), the standard chemotherapeutic agent for brain tumors, which had a cell kill rate of 43%. Studies in rats harboring solid 9L brain tumors also showed that berberine has antitumor effects. Rats treated with berberine, 10 mg/kg, had a 81% cell kill. However, the combination treatment, berberine and BCNU, exihibited additive effects on killing cancer cells. These results indicate that berberine may prove to be more effective than BCNU or, at the very least, a valuable therapeutic addition in the treatment of difficult brain cancers. Antipyretic activity
Historically, berberine-containing plants have been used as febrifuges. Berberine produces an antipyretic effect three times as potent as aspirin in a pyretic model in rats.[16] However, while aspirin suppresses fever through its action on prostaglandins, berberine appears to lower fever by increasing the immune system’s handling of
fever-producing compounds from microorganisms.
CLINICAL APPLICATIONS The broad antimicrobial effects of berberine combined with its anti-infective and immune-stimulating actions supports the historical use of berberine-containing plants in infections of the mucous membranes. Berberine-containing plants may also be useful as an adjunct to standard cancer therapy. Infectious diarrhea
Berberine has shown significant success in the treatment of acute diarrhea in several clinical studies. It has been found effective against diarrheas caused by E. coli (traveler’s diarrhea), Shigella dysenteriae (shigellosis), Salmonella paratyphi (food poisoning), Klebsiella sp., Giardia lamblia (giardiasis), and Vibrio cholerae (cholera). [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] Studies in hamsters and rats have shown that berberine also has significant activity against Entamoeba histolytica, the causative organism of amebiasis. [7] [8] It appears that berberine is effective in treating the majority of common gastrointestinal infections. The clinical studies have produced results with berberine comparable to standard antibiotics in most cases. In fact, in several studies results were better. For example, in a study of 65 children below 5 years of age with acute diarrhea caused by E. coli, Shigella, Salmonella, Klebsiella or Faecalis aerogenes, those given berberine tannate (25 mg/every 6 hours) responded better than those treated with standard antibiotic therapy. [22] In another study, 40 children aged 1–10 years infected with the parasite giardia received either berberine (5 mg/kg body weight each day), the drug metronidazole (10 mg/kg body weight each day), or a placebo of vitamin B syrup in three divided doses. [23] After 6 days, 48% of patients treated with berberine were symptom-free and, on stool analysis, 68% were Giardia-free. In the metronidazole (Flagyl) group, 33% of patients were without symptoms and, on stool analysis, all were Giardia-free. In comparison, 15% of patients on placebo were asymptomatic and, on stool analysis, 25% were Giardia-free. These results indicate that berberine was actually more effective than metronidazole in relieving symptoms at half the dose, but was less effective than the drug in clearing the organism from the intestines. And finally, in a study of 200 adult patients with acute diarrhea, the subjects were given standard antibiotic treatment with or without berberine hydrochloride (150 mg/day). The patients receiving berberine recovered more quickly. [24] An additional 30 cases of acute diarrhea were treated with berberine alone. Berberine arrested diarrhea in all of these cases with no mortality or toxicity. Despite these results, due to the serious consequences of an ineffectively treated infectious diarrhea due to highly pathogenic organisms, the best approach may be to use berberine-containing plants as an adjunct to standard antibiotic therapy. Much of berberine’s effectiveness is undoubtedly due to a combination of its direct antimicrobial activity, inhibition of microbial attachment to mucous membranes and blocking of the action of toxins produced by several pathogenic bacteria. [28] [29] [30] The toxin-blocking effect is most evident in diarrheas caused by enterotoxins (e.g., Vibrio cholerae and E. coli), cholera and traveler’s diarrhea respectively. [25] [26] [27] [28] While cholera is a serious disorder that needs standard antibiotic therapy, traveler’s diarrhea is usually self-limiting. Good results with berberine in the treatment of traveler’s diarrhea have been obtained. In one study, patients with traveler’s diarrhea randomly received
779
berberine sulfate 400 mg in a single dose or served as controls. [27] In treated patients, the mean stool volumes were significantly less than those of controls during three consecutive 8 hour periods after treatment. At 24 hours after treatment, significantly more treated patients stopped having diarrhea as compared with controls (42% vs. 20%). For those patients planning to travel to an underdeveloped country or an area of poor water quality or sanitation, the prophylactic use of berberine-containing herbs during, and 1 week prior to and after visiting may be useful. Trachoma
Water extracts of berberine-containing plants have been employed in a variety of eye complaints, including infectious processes, by cultures throughout the world. Recently, berberine has shown remarkable effect in the treatment of trachoma. [31] [32] Trachoma, an infectious eye disease due to the organism Chlamydia trachomatis, is a major cause of blindness and impaired vision in underdeveloped countries. It affects approximately 500 million people worldwide, and results in blindness in 2 million. The drug sulphacetamide is currently the most widely used anti-trachoma drug. In clinical trials comparing berberine (0.2%) and sulphacetamide (20.0% solution), sulphacetamide showed the best improvement (decrease in conjunctival discharge, edema, and papillary reactions), but the conjunctival scrapings of all patients receiving sulphacetamide were still positive for Chlamydia trachomatis. These patients had a high rate of recurrence of the symptoms. In contrast, patients treated with the berberine solution showed very mild ocular symptoms, which disappeared more gradually, but their conjunctival scrapings were always negative for Chlamydia trachomatis. These patients did not suffer relapse even 1 year after treatment, which suggests that berberine is probably curative for trachoma. [31] [32] Berberine’s efficacy is believed to be due to stimulation of some host defense mechanism, rather than simply a direct action on the organism. As the berberine concentration used in these studies was 100 times less than the concentration of sulphacetamide, and berberine is much cheaper, it may be more cost-effective than other treatments for trachoma. Berberine (0.2% solution) is an appropriate therapy for many types of conjunctivitis. Cholecystitis and cirrhosis of the liver
Berberine has been shown in several clinical studies to stimulate the secretion of bile (cholerectic effect) and bilirubin. [33] [34] [35] In one study of 225 patients with chronic cholecystitis, oral berberine doses of 5–20 mg three times a day before meals caused, over a period of 24–48 hours, disappearance of clinical symptoms, decrease in bilirubin level, and an increase in the bile volume of the gall bladder. Berberine has been shown to correct the hypertyraminemia of patients with liver cirrhosis. It prevents the elevation of serum tyramine following oral tyrosine load by inhibiting the enzyme tyrosine decarboxylase found in bacteria in the large intestine. [35] Berberine inhibits tyrosine decarboxylase and tryptophanase activities of Streptococcus faecalis and E. coli, but not those of animal enzymes. Tyramine is believed to be responsible for some of the cardiovascular and neurological complications of liver disease, such as hepatic encephalopathy. The accumulation of tyramine and its derivatives may cause lowering of peripheral resistance, with resultant high cardiac output, reduction in renal function, and cerebral dysfunction. Berberine, by lowering plasma tyramine levels, helps prevent the complications of cirrhosis. This tyramine-lowering effect of berberine may have significance in other conditions as well. Cancer
Berberine and another alkaloid found in berberine-containing plants, berbamine, have been shown to exert beneficial effects as adjuncts in cancer therapy. In fact, berbamine has been used in China since 1972 in the treatment of depressed white blood cell (WBC) counts due to chemotherapy and/or radiation. In one study, 405 patients with WBC counts < 4,000 were given 150 mg of berbamine daily (50 mg orally three times daily) for 1–4 weeks. Berbamine was viewed as “significantly effective” if WBC increased to > 4,000 after 1 week or increased to > 1,000 after 2 weeks; “effective” if WBC increased to > 4,000 after 2 weeks or increased > 1,000 after 4 weeks; and “ineffective” if there was no change in WBC after 4 weeks of treatment. The overall results for the 405 patients are as follows:
• significantly effective in 163 cases (40.2%) • effective in 125 cases (38.8%) • ineffective in 117 cases (29%). The total effective rate was 71%. However, WBC before therapy was related to overall effectiveness. The effective rate was only 54.8% in 31 cases where WBC was < 1,000 and 82.7% in cases where WBC count was between 3,100 and 3,800. [36]
DOSAGES As no detailed clinical studies have differentiated which berberine-containing herb to use for specific conditions, the following is offered only as a guideline based on experimental studies and historical use. However, the plants can be viewed as interchangeable.
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Hydrastis canadensis. This is used in the treatment of: • infective, congestive and inflammatory states of the mucous membranes • digestive disorders • gastritis • peptic ulcers • colitis • anorexia • painful menstruation. Berberis vulgaris. This is used in the treatment of gall bladder disease, including gallstones, and as a less expensive form of berberine in the treatment of the conditions listed above for hydrastis. Berberis aquifolium. This is used in the treatment of chronic skin diseases and in the conditions listed above for hydrastis. Coptis chinensis. This is used in the treatment of infective, congestive and inflammatory states of the mucous membranes, fever, and infectious disorders of the skin. The dosage should be based on berberine content. As there is a wide range of quality in goldenseal preparations, standardized extracts are recommended. Three times a day dosages as follows: • dried root or as infusion (tea): 2–4 g • tincture (1:5): 6–12 ml (1.5–3 tsp) • fluid extract (1:1): 2–4 ml (0.5–1 tsp) • solid (powdered dry) extract (4:1 or 8–12% alkaloid content): 250–500 mg.
TOXICITY Berberine and berberine-containing plants are generally non-toxic at the recommended dosages. However, berberine-containing plants are not recommended for use during pregnancy and higher dosages may interfere with B vitamin metabolism. The oral LD 50 in rats for berberine is greater than 1,000 mg/kg body weight, indicating that the toxicity is extremely low.
[37]
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Chapter 92 - 5-Hydroxytryptophan Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION 5-Hydroxytryptophan (5-HTP) is the intermediate between tryptophan and serotonin. Although 5-HTP may be relatively new to most clinicians, it has been available through pharmacies for several years and has been intensely researched for the past three decades. It has been used clinically since the 1970s.
TRYPTOPHAN AND 5-HTP METABOLISM Once tryptophan is absorbed from the intestines, it is carried by the blood to the liver along with the other amino acids consumed during the meal. Ingested tryptophan can pass into the general circulation, it can be metabolized into blood proteins, or it can be converted to kynurenine (which then goes on to form nicotinic acid, picolinate and other important metabolites) in the liver. After conversion to kynurenine, it cannot be converted to serotonin. The same is likely true if the tryptophan is incorporated into blood proteins. Unchanged tryptophan can be converted to 5-HTP and then to serotonin. However, if this conversion occurs outside the brain, brain chemistry will not be influenced, and even under the best-case scenario only 3% of a dosage of L-tryptophan in supplemental or dietary form is likely to be converted to serotonin in the brain. [1] The manufacture of serotonin from tryptophan within the brain is highly dependent upon the level of tryptophan or 5-HTP which crosses the blood–brain barrier. While 5-HTP easily crosses the blood–brain barrier, the delivery of tryptophan into the brain is dependent upon several factors. The first factor of importance is the level of free tryptophan in the blood. There are a number of situations where the liver’s conversion of tryptophan to kynurenine takes place at an elevated rate, i.e. stress, elevated cortisol levels, low B-vitamin status, and high dosages of L-tryptophan (i.e. greater than 2,000 mg). All of these situations lead to increased activity of the enzymes (tryptophan oxidase and kynurenine formamidase) that
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convert tryptophan to kynurenine. Elevated levels of kynurenine block the entry of tryptophan into the brain and lower brain serotonin levels. Increasing tryptophan intake makes matters worse when tryptophan oxidase activity is increased. Unlike 5-HTP, which easily enters the brain, the transport of tryptophan across the blood–brain barrier involves the binding of tryptophan to a transport molecule. As tryptophan shares this transport vehicle with several other amino acids, when the ratio of tryptophan to these other amino acids is low (i.e. when the level of tryptophan is low and the level of the other amino acids is high), very little tryptophan is transported into the brain. The protein in almost all foods contains relatively small amounts of tryptophan and larger proportions of other amino acids. This low ratio of tryptophan to the other amino acids generally leads to low serotonin levels with a high-protein intake. Just the opposite occurs with a high-carbohydrate meal.
PHARMACOLOGY Several pharmacokinetic studies have shown that about 70% of a dosage of 5-HTP taken orally is delivered to the bloodstream. metabolized by intestinal cells.
[2] [3]
The remaining 30% is
Once absorbed, there is ample evidence from these pharmacokinetic studies as well as the clinical studies that 5-HTP is delivered to the brain, resulting in increased formation of not only serotonin, but also other brain chemicals such as other monoamines like melatonin, endorphins, dopamine, and norepinephrine. By raising brain serotonin levels (as well as by other effects), 5-HTP has shown positive effects in the various conditions associated with low serotonin levels. Besides raising serotonin and melatonin levels, 5-HTP has been shown to raise beta-endorphin levels. Much of the pain-relieving and mood-elevating benefits of 5-HTP may be related more to its ability to enhance endorphin levels than to its ability to increase serotonin levels. This endorphin-increasing action is useful for both migraine and tension headache, fibromyalgia, as well other painful situations. In addition, raising endorphin levels produces significant effects on mood and behavior. By raising serotonin (and melatonin) and beta-endorphin levels, 5-HTP produces a significant impact on helping to regulate and improve brain chemistry. But it goes well beyond affecting these systems, as 5-HTP has been shown also to raise the levels of other important neurotransmitters such as dopamine and norepinephrine. [4] The ability of 5-HTP to increase both serotonin (and other indoleamines) and catecholamines is quite significant and unique to 5-HTP. It is an effect that 5-HTP does not share with L-tryptophan. The effective treatment of depression requires more than simply raising serotonin levels; catecholamine levels must also be increased. 5-HTP provides the brain with both sets of tools. In a head-to-head comparison study of 5-HTP and L-tryptophan in the treatment of depression, 5-HTP proved superior. [5] The proposed reason is the fact that 5-HTP easily crosses the blood–brain barrier and is not affected by competing amino acids and 5-HTP affects brain chemistry in a broader and more positive fashion. L-Tryptophan is often effective in cases of low serotonin, especially insomnia, but 5-HTP is more broadly effective. 5-HTP vs.L-tryptophan Nutrition-oriented physicians have long used precursor therapy for affecting brain chemistry. Unfortunately, inconsistent results are likely due to its inconsistent elevation of brain serotonin level.
L-tryptophan
has produced inconsistent results. These
There are many advantages of 5-HTP over L-tryptophan. Chief among them are that 5-HTP easily crosses the blood–brain barrier and is one step further on the path to serotonin synthesis. The conversion of tryptophan to 5-HTP by tryptophan hydrolase is the most important step in the manufacture of serotonin. This enzyme is inhibited by a number of factors, including: • stress • vitamin B6 insufficiency • low magnesium levels • insensitivity to insulin • various hormones • genetic factors. In addition, as noted above, these same factors and others are known to increase the activity of tryptophan oxygenase, increasing the conversion of
L-tryptophan
to
kynurenine. Perhaps the biggest advantage of 5-HTP over L-tryptophan is that it is safer. Although L-tryptophan is safe if properly prepared and free of the contaminants linked to eosinophilia myalgia syndrome (EMS), 5-HTP is inherently safer. The reasons are that taking L-tryptophan to produce positive effects in the treatment of depression, insomnia, and other low serotonin conditions requires a relatively high dosage (e.g. a minimum of 2,000 mg in insomnia and 6,000 mg in depression). At high dosages such as these, L-tryptophan is potentially problematic, as more L-tryptophan will be shunted towards the kynurenine pathway and L-tryptophan promotes oxidative damage. Excessive levels of dietary tryptophan or high dosages of L-tryptophan result in tryptophan actually acting as a free radical. [6] By contrast, 5-HTP is an antioxidant. [7] This antioxidant difference is due to the additional molecule of oxygen and hydrogen in 5-HTP. This simple change in molecular structure allows the phenolic ring structure to effectively accept or quench the unpaired electron of a free radical.
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CLINICAL APPLICATIONS There is a massive amount of evidence that suggests that low serotonin levels are a common consequence of modern living. The lifestyle and dietary practices of many people living in this stress-filled era result in lowered levels of serotonin within the brain. As a result, many people are overweight, crave sugar and other carbohydrates, experience bouts of depression, get frequent headaches, and have vague muscle aches and pain. All of these maladies are correctable by raising brain serotonin levels. The primary therapeutic applications for 5-HTP are low serotonin states, as listed in Table 92.1 . Depression
Some of the first clinical studies on 5-HTP for the treatment of depression began in the early 1970s in Japan. The first study involved 107 patients with either unipolar depression or manic bipolar depression. [8] These patients received 5-HTP at dosages ranging from 50 to 300 mg/day. The researchers observed a very quick response (within 2 weeks) in more than half of the patients. Seventy-four of TABLE 92-1 -- Conditions associated with low serotonin levels • Depression • Anxiety • Obsessive compulsive disorder • Obesity • Carbohydrate craving • Bulimia • Insomnia • Narcolepsy • Sleep apnea • Migraine headaches • Tension headaches • Chronic daily headaches • Premenstrual syndrome • Fibromyalgia • Epilepsy • Myoclonus • Chronic pain disorders the patients either experienced complete relief or were significantly improved, and none experienced significant side-effects. These promising results were repeated in several other Japanese studies. One of the interesting aspects in two of these studies was the fact that 5-HTP was shown to be effective in some patients (50% in one study, 35% in another) who had not responded positively to any other antidepressant agent. [9] [10] The most detailed of the Japanese studies was conducted in 1978. [11] The study enrolled 59 patients with depression: 30 were male and 29 were female. The groups were mixed, in that both unipolar and bipolar depressions were included along with a number of other subcategories of depression. The severity of the depression in most cases was moderate to severe. Patients received 5-HTP in dosages of 50 or 100 mg three times daily for at least 3 weeks. The antidepressant activity and clinical effectiveness of 5-HTP was determined by using a rating scale developed by the Clinical Psychopharmacology Research Group in Japan. The improvements among the various patients are detailed in Table 92.2 . These results indicate that 5-HTP was helpful in 14 out of 17 patients with unipolar depression and 12 out of 21 patients with bipolar depression. The degree of improvement in most cases ranged from excellent to very good. The results achieved in this open study are quite good, given how rapidly they were achieved. Thirty-two of the 40 patients who responded to 5-HTP did so within the first 2 weeks of therapy. Typically, in most studies with antidepressant drugs the benefits are not apparent until after 2 weeks to 1 month of use. For this reason, the length of study when assessing antidepressant drugs should be at least 6 weeks, because it may take that long to significantly affect brain chemistry in a positive manner. In contrast, many of the studies with 5-HTP were shorter than 6 weeks because statistically significant results were achieved so soon ( Table 92.3 ). However, the longer 5-HTP is used, the better are the results. Some people TABLE 92-2 -- Improvement in various subtypes of depression Subtype Improvementa 1
2
3
4
5, 6, 7
8
1+2+3/total b
First-episode depression
1
1
0
1
0
0
2/3
Unipolar depression
3
8
3
1
2
0
14/17
Bipolar depression
6
4
2
3
3
3
12/21
Mixed depression
0
1
0
1
0
0
1/2
Presenile or senile depression
3
2
0
3
1
0
5/9
Neurotic depression
0
1
2
1
0
0
3/4
Reactive depression
0
1
1
0
0
0
2/2
Schizophrenic depression
0
1
0
0
0
0
1/1
Total
13
19
8
10
6
3
40/59
Percentage of total (%)
22.0 32.2 13.6 16.9 10.2
a
Improvement: 1, marked improvement; 2, moderately improved; 3, slightly improved; 4, unchanged; 5, 6, 7 felt worse; 8, dropped out.
5.1 67.8%
b
The number of subjects that improved (improvement scores 1, 2 or 3) compared with the total number of subjects in that subtype.
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TABLE 92-3 -- Day when improvements were first noticed Day 1 Day 2 Day 3 Days 4–7
Improvement group
Days 8–14
Day 15
Marked
1
3
2
5
2
0
Moderate
0
1
13
1
4
0
Slight
0
2
2
2
1
1
Total
1
6
17
8
7
1
may need to be on 5-HTP for at least 2 months before they experience the benefits. The only major side-effect noted in this study was mild nausea. The occurrence of nausea due to 5-HTP is actually less frequent than that experienced with other antidepressant drugs (roughly 10% of subjects taking 5-HTP at a daily dosage equal to or less than 300 mg experience nausea compared with about 23% taking Prozac) and about the same as that which occurs with a placebo. In double-blind studies, about 10% or so of people taking the placebo typically complain of nausea. Nonetheless, very mild nausea may be a natural consequence of elevated serotonin levels with 5-HTP. About 30% of the 5-HTP taken orally is converted to serotonin in the intestinal tract. This can lead to a mild case of nausea. Fortunately, this effect wears off after a few of weeks of use. A 5-HTP dosage of 300 mg is sufficient in most cases, but in some cases a higher dosage may be necessary. For example, in one study it was shown that 13 out of 18 subjects with depression given 5-HTP at a level of 150 or 300 mg/day experienced good to excellent results. [12] This percentage of responders is quite good, but if we look at the level of serotonin in the blood as a rough indicator of brain serotonin levels, some interesting conclusions can be made (see Table 92.4 ). The measurements in Table 92.4 suggest that serotonin levels in depressed individuals are considerably lower than those found in normal subjects and that individuals who respond to 5-HTP show a rise in serotonin to levels consistent with normal subjects. The level of serotonin in those who do not respond to 5-HTP remained quite low. These results imply that non-responders may require higher dosages to raise serotonin levels or that additional support may be necessary. When prescribing higher dosages, it is important that the 5-HTP be taken in divided dosages not only to reduce the problem with nausea, but also because rate of brain cell uptake of 5-HTP is limited. TABLE 92-4 -- Level of serotonin in blood (ng/ml): controls, responders, and non-responders After 1 week (150 or 300 mg/day 5-HTP)
Before Normal subjects 150 Responders
78
Non-responders 56
148 77
The first studies of 5-HTP in a double-blind format (the Japanese studies) were open trials. [13] The antidepressive effects of 5-HTP were also compared with [ L-tryptophan in the early 1970s. 5] In one study, 45 subjects with depression were given L-tryptophan (5 g/day), 5-HTP (200 mg/day), or a placebo. The patients were matched in clinical features (age, sex, etc.) and severity of depression. The main outcome measure was the Hamilton Rating Scale for Depression (HDS), the most widely used assessment tool in clinical research in depression. The HDS score is determined by having the test subject complete a series of questions where they rate the severity of their symptoms on a numerical basis, as follows: • 0 – not present • 1 – present but mild • 2 – moderate • 3 – severe • 4 – very severe. Symptoms assessed by the HDS include depression, feelings of guilt, insomnia, gastrointestinal symptoms and other bodily symptoms of depression (e.g. headaches, muscle aches, heart palpitations, etc.), and anxiety. The HDS is popular in research because it provides a good assessment of the overall symptoms of depression. Table 92.5 shows the results of the study. A review of head-to-head comparison studies showed that 5-HTP, at a dosage of 200 mg/day, produced therapeutic success on a par with tricyclic antidepressant drugs. [14] Research has also shown that combining 5-HTP with clomipramine and other types of antidepressant drugs produces better results than any of the compound given alone. [15] [16] [17] [18] [19] [20] For example, in one study, 5-HTP combined with a monoamine oxidase (MAO) inhibitor demonstrated significant advantages compared with the MAO inhibitor alone (see Table 92.6 ). [19] This line of research suggests that 5-HTP might also be used in conjunction with St John’s wort extract or Ginkgo biloba extract, two herbal medicines with proven antidepressant activity. TABLE 92-5 -- HDS from a comparative study of HTP, L-tryptophan and placebo 5-HTP
L-Tryptophan
Placebo
Beginning of the study
26
25
23
End of the study (30 days)
9
15
19
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TABLE 92-6 -- Change in Hamilton Rating Scale for depression [19] 5-HTP + MAO Initial measurement
28.67
26.33
After 8 days
16.67
19.23
After 15 days
11.77
6.03
MAO + placebo
Because 5-HTP was very expensive back in 1972, researchers developed a test to determine who was most likely to respond to it, so that it would not be wasted on people who were unlikely to respond. [13] [21] [22] [23] The test involved the patients first having a spinal tap to measure the level of 5-HIAA (the breakdown product of serotonin) in the cerebrospinal fluid (CSF). The drug probenecid, which prevents the transport of 5-HIAA from the CSF to the bloodstream, was given for the next 3 days. As a result of this blocking action the amount of serotonin produced over a 4 day period could be calculated by a repeat spinal tap on day 4. Since the 5-HIAA could not leave the CSF, it accumulated and provided a measure of serotonin manufacture. The researchers discovered that the average level of 5-HIAA after 3 days of probenecid was significantly lower in depressed individuals than in controls matched for age, sex, and weight. This low level of serotonin reflected a decreased rate of manufacture within the brain. 5-HTP was most effective in patients with a low 5-HIAA response to 3 days of probenecid. [21] [22] [23] In other words, 5-HTP is most effective as an antidepressant when the amount of serotonin manufactured in the brain is reduced. As stated above, 5-HTP will often produce very good results in patients who are unresponsive to antidepressant drugs. One of the more impressive studies involved 99 patients described as suffering from “therapy-resistant” depression. [24] These patients had not responded to any previous therapy including all available antidepressant drugs and electroconvulsive therapy. These therapy-resistant patients received 5-HTP at dosages averaging 200 mg/day but ranging from 50 to 600 mg/day. Complete recovery was seen in 43 of the 99 patients and significant improvement was noted in eight more. Such significant improvement in patients suffering from long-standing, unresponsive depression is quite impressive, prompting the author of another study to state: [25] L-5-HTP merits a place in the front of the ranks of the antidepressants instead of being used as a last resort. I have never in 20 years used an agent which: (1) was effective so quickly; (2) restored the patients so completely to the persons they had been and their partners had known; [and] (3) was so entirely without side-effects. A 1987 review article on 5-HTP in depression highlighted the need for well-designed double blind, head-to-head studies of 5-HTP versus standard antidepressant drugs. [26] Although 5-HTP was viewed as an antidepressant agent with few side-effects, the authors of this review felt that the big question to answer was how 5-HTP compared with the new breed of antidepressant drugs, the selective serotonin reuptake inhibitors like Prozac, Paxil, and Zoloft. In 1991, a double-blind study comparing 5-HTP with a selective serotonin reuptake inhibitor (SSRI) was conducted in Switzerland. [27] 5-HTP was compared in the study with the SSRI fluvoxamine (Luvox). Fluvoxamine is used primarily in the United States as a treatment for obsessive compulsive disorder (OCD), an anxiety disorder characterized by obsessions and compulsions affecting an estimated 5 million Americans. Fluvoxamine exerts antidepressant activity comparable to (if not better than) other SSRIs like Prozac, Zoloft, and Paxil. In the study, subjects received either 5-HTP (100 mg) or fluvoxamine (50 mg) three times daily for 6 weeks. The assessment methods used to judge effectiveness included the Hamilton Rating Scale for Depression (HSD), self-assessment depression scale (SADS), and physician’s assessment (Clinical Global Impression). As can be seen in Table 92.7 , the percentage decrease in depression was slightly better in the 5-HTP group (60.7% vs. 56.1%). 5-HTP was quicker acting than the fluvoxamine and a TABLE 92-7 -- 5-HTP vs. fluvoxamine in percentage changes in the HDS Decrease in HDS 5-HTP (n = 34) After 2 weeks
After 4 weeks
After 6 weeks
Fluvoxamine (n= 29)
Mean decrease (%)
23
18.9
Less than 35% decrease
20
19
35–50% decrease
10
8
50–75% decrease
4
2
Mean decrease (%)
46.2
46.1
Less than 35% decrease
2
8
35–50% decrease
7
3
50–75% decrease
12
13
More than 75% decrease
3
5
Mean decrease (%)
60.7
56.1
Less than 35% decrease
4
5
35–50% decrease
8
3
50–75% decrease
12
8
More than 75% decrease
10
13
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higher percentage of patients responded to 5-HTP than to fluvoxamine. The advantages of 5-HTP over fluvoxamine are evident when looking at the subcategories of the HDS: depressed mood, anxiety, physical symptoms, and insomnia. For depressed mood, 5-HTP produced a 65.7% reduction in severity compared with 61.8% for fluvoxamine; for anxiety, 5-HTP produced a 58.2% reduction in severity compared with 48.3% for fluvoxamine; for physical symptoms, 5-HTP produced a 47.6% decrease in severity compared with 37.8% for fluvoxamine; and, for insomnia 5-HTP produced a 61.7% decrease in severity compared with a 55.9% decrease for fluvoxamine. However, perhaps more important than simply relieving insomnia is 5-HTP’s ability to improve the quality of sleep. By contrast, antidepressant drugs greatly disrupt sleep processes. On the self-assessment depression scale (SADS), 5-HTP produced a 53.3% drop in SADS values compared with a drop of 47.6% for the fluvoxamine group. Anything over a 50% drop is an excellent result. In fact, a 50% drop is the best SSRIs generally produce. 5-HTP is equal to or better than standard antidepressant drugs and the side-effects are much less severe (see Table 92.8 ). In the study comparing 5-HTP with fluvoxamine, this is how the physicians described the differences among the two groups: Whereas the two treatment groups did not differ significantly in the number of patients sustaining adverse events, the interaction between the degree of severity and the type of medication was highly significant: fluvoxamine predominantly produced moderate to severe, oxitriptan [5-HTP] primarily mild forms of adverse effects. Fourteen (38.9%) of the patients receiving 5-HTP reported side-effects compared with 18 patients (54.5%) in the fluvoxamine group. The most common side-effects with 5-HTP were nausea, heartburn, and gastrointestinal problems (flatulence, feelings of fullness, and rumbling sensations). These side-effects were rated as being very mild to mild. In contrast, most of the side-effects experienced
Side-effect
TABLE 92-8 -- 5-HTP vs. antidepressant drugs: comparison of side-effects Percentage of patients experiencing side-effects 5-HTP
Tricyclics
SSRIs
Nausea
9
15
23
Headache
5
16
20
Nervousness
2.5
11
16
Insomnia
2.5
7
17
Anxiety
2.5
9
14
Drowsiness
7
23
11
Diarrhea
2.5
4
12
Tremor
0
18
11
Dry mouth
7
64.5
12
Sweating
2.5
15
9
Dizziness
5
25.5
7
Constipation
5
25
5.5
Vision changes
0
14.5
4
in the fluvoxamine group were of moderate to severe intensity. The only subject to drop out of the 5-HTP group did so after 35 days (5 weeks), while four subjects in the fluvoxamine group dropped out after only 2 weeks. Based on the studies in weight loss, the longer that 5-HTP is used (e.g. after 4–6 weeks of use ), the less of a problem there is with any mild nausea. 5-HTP has been shown to have “equipotency” with SSRIs and tricyclic antidepressants in terms of effectiveness, but offers several advantages in that it is better tolerated and is associated with fewer and much milder side-effects; and because many people prefer to use a naturally occurring, natural substance like 5-HTP over synthetic drugs. L-Tyrosine:
an adjunct to 5-HTP
In the early 1970s, researchers discovered that, in about 20% of patients who responded well to 5-HTP, the results tended to decrease after 1 month of treatment. The antidepressant effects of 5-HTP in these subjects began to wear off gradually after the first month despite the fact that the level of 5-HTP in the blood, and presumably the level of serotonin in the brain, remained at the same level as when they were experiencing benefit. [6] The researchers discovered that while serotonin levels appeared to stay at the same levels after 1 month of treatment, the levels of the other important monoamine neurotransmitters, dopamine and norepinephrine, declined. [28] As discussed above, when depressed patients are treated with 5-HTP they experience a rise not only in serotonin, but also in catecholamines like dopamine and norepinephrine. In about 20% of subjects, the catecholamine-enhancing effects of 5-HTP tended to wear off. Providing these patients with L-tyrosine, the amino acid precursor to the catecholamines, helped to re-establish the efficacy of 5-HTP. [6] [28] The dosage was 200 mg/day for 5-HTP and 100 mg/kg body weight for L-tyrosine. This dosage for L-tyrosine is quite high and would require substantial clinical supervision. Weight loss
A considerable body of scientific evidence documents the major role serotonin in the brain plays in influencing eating behavior. One of the key findings is that when animals and humans are fed tryptophan-free diets, appetite is significantly increased, resulting in binge eating – carbohydrates would be preferable, but in fact the animals will binge on whatever is available. [1] [2] A diet low in tryptophan leads to low brain serotonin levels; as a result the brain senses it is starving and so stimulates the appetite control centers in a powerful way. This stimulation results in a preference for carbohydrates. Researchers discovered that when animals or humans are
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fed a carbohydrate meal, more tryptophan is delivered to the brain, resulting in more serotonin being manufactured. This scenario has led to the idea that low serotonin levels leads to “carbohydrate craving” and plays a major role in the development of obesity as well as bulimia. [29] Cravings for carbohydrate can be mild or quite severe. They may range in severity from the desire to nibble one piece of bread or cookie to uncontrollable binging. At the upper end of the spectrum of carbohydrate addiction is bulimia, a potentially serious eating disorder characterized by binge eating and purging of the food through forced vomiting or the use of laxatives. The serotonin theory of bulimia is that low serotonin levels trigger the binge eating which leads to a rush of serotonin being produced and released in the brain. [30] [31] This increased serotonin effect produces a brief reduction in feelings of stress and tension. This serotonin “fix” is short-lived and is followed by feelings of guilt and low self-esteem. The current medical treatment for bulimia is the use of drugs which enhance the effects of serotonin. Although there are no reports in the medical literature of 5-HTP being used in the treatment of bulimia, given its effects on serotonin levels it merits consideration. 5-HTP may help to prevent the decline in serotonin levels associated with a reduced calorie intake. Concentrations of tryptophan in the bloodstream and subsequent brain serotonin levels plummet with dieting. [32] In response to severe drops in serotonin levels, the brain puts out a strong message to eat. This situation sets up the scenario to explain why most diets do not work. As far back as 1975, researchers demonstrated that giving 5-HTP to rats who were genetically bred to overeat and be obese resulted in significant reduction in food intake. [33] It turns out that these rats bred to be fat have decreased activity of the enzyme which converts tryptophan to 5-HTP and subsequently to serotonin. There is circumstantial evidence that many humans are genetically predisposed to obesity. This predisposition may involve the same mechanism as rats genetically predisposed to obesity. By providing preformed 5-HTP, this genetic defect is bypassed and more serotonin is manufactured. The early animal studies with 5-HTP as a weight loss aid have been followed by a series of three human clinical studies. The first study involved 19 significantly overweight female subjects with a body mass index ranging between 30 and 40. [34] Analysis of the pretreatment dietary intake concluded that these women tended to overeat carbohydrates. Food intake and eating behavior were assessed using a 3 day diet diary at the beginning and end of the two treatment periods. All food was carefully weighed before meals and re-weighed if there were any leftovers. Participants also filled out a self-evaluation of appetite and satiety twice weekly, and mood was evaluated using standard psychological tests.
Food intake (calories/day)
TABLE 92-9 -- The effect of 5HTP on food intake Protein intake (g/day)
Carbohydrate intake (g/day)
Pretreatment 2,903
101
274
Placebo
2,327
85
223
5-HTP
1,819
79
176
The daily dosage of 5-HTP used in the study was 8 mg/kg body weight. Patients were given either the 5-HTP or a placebo 20 minutes before meals for 5 weeks, and after a 1 week interval were switched to receive the other treatment. No dietary restrictions were prescribed because the researchers wanted to answer the question, “Does 5-HTP reduce appetite and promote weight loss without any conscious effort?” To make sure that the women actually took the 5-HTP, researchers measured the level of the serotonin breakdown product, 5-hydroxy-3-indole acetic acid (5-HIAA), in the urine. The results of the study are listed in Table 92.9 . These results with 5-HTP were achieved without the women making any conscious effort to reduce food consumption. The average amount of weight loss during the 5 week period of 5-HTP supplementation was a little more than 3 pounds, compared with less than 1 pound of total weight loss during the placebo period.
Interestingly, evaluation of the various self-tests indicated that appetite or degree of initial hunger did not differ between the two groups. What differed was satiety. In other words, the 5-HTP did not reduce the appetite before a meal, but after consuming an adequate amount of food the satiety centers in the brain were stimulated and the women did not feel hungry. As a result their caloric intake was dramatically reduced. The level of 5-HIAA, the breakdown product of serotonin, in the group receiving the 5-HTP increased by over 50-fold over the control group. This increase provided two things: (1) it assured researchers that subjects actually took the 5-HTP, and (2) it clearly indicated that 5-HTP increased serotonin manufacture. The next study sought to determine if 5-HTP helped overweight individuals to adhere to dietary recommendations. [35] Fourteen overweight female subjects with a body mass index ranging between 30 and 40 were enrolled in the double-blind study. [8] Again, analysis of the pretreatment dietary intake concluded that these women tended to overeat. The women were randomly assigned to receive either 5-HTP (300 mg) or placebo 30 minutes before meals. The 12 week study was divided into two 6 week periods. For the first 6 weeks there were no dietary recommendations, and for the second 6 weeks the women were placed on a 1,200 calorie diet. The women were seen every 2 weeks to evaluate body weight, diet diaries, self-evaluations of appetite and
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TABLE 92-10 -- Impact of 5-HTP on weight loss Placebo
5-HTP group
Weight (pounds) Baseline
207.68
229.46
After 6 weeks
206.58
225.94
After 12 weeks
205.4
219.12
After 6 weeks
1.1
3.52
After 12 weeks
2.28
10.34
Total weight loss (pounds)
satiety. The women were also asked if they experienced the presence of meat aversion, taste or smell alterations, early satiety, and nausea and/or vomiting. To verify patient compliance, urinary measurement of 5-HIAA was again determined. As shown in Table 92.10 , the women taking the placebo lost 2.28 pounds while the women taking the 5-HTP lost 10.34 pounds. Like the previous study, 5-HTP appeared to promote weight loss by promoting satiety. While some of the women reported some aversion to meat or altered taste and smell, every women (100%) reported early satiety (see Table 92.11 ). Most of the women receiving 5-HTP also experienced very mild nausea during the first 6 weeks of the trial, but during the last 6 weeks none complained of nausea. The fact that weight loss is accelerated during the second 6 week period makes it highly unlikely that 5-HTP promotes weight loss as a result of producing nausea. The latest study with 5-HTP enrolled overweight women with a body mass index ranging between 30 and 40 and an overactive appetite. [36] The 28 subjects of the study were given either 5-HTP (300 mg three times daily before meals) or a placebo. For the first 6 weeks there were no dietary restrictions, and for the second 6 weeks the women were placed on a diet of 1,200 calories/day. Carbohydrates contributed to 53% of the calories, fats comprised 29%, and proteins provided 18%. No carbohydrate-rich foods were permitted between meals. Subjects were examined every 2 weeks to evaluate food intake and body weight. Routine blood measurements were also performed at the beginning, at 6 weeks, and at the end of the study. To verify patient compliance, urinary measurement of 5-HIAA was determined. The results from this study were even more impressive
5-HTP
TABLE 92-11 -- Impact of 5-HTP on appetite and satiety Placebo Weeks 1–6
Weeks 7–12
Weeks 1–6
Weeks 7–12
Taste alteration
2/7
1/7
0/7
0/7
Smell alteration
2/7
1/7
0/7
0/7
Meat aversion
3/7
1/7
0/7
0/7
Early satiety
7/7
6/7
2/7
2/7
Nausea
5/7
0/7
1/7
2/7
than the previous studies for several reasons. The group receiving the 5-HTP lost an average of 4.39 pounds after the first 6 weeks and an average of 11.63 pounds after 12 weeks. In comparison, the placebo group lost an average of only 0.62 pounds after the first 6 weeks and 1.87 pounds after 12 weeks. The lack of weight loss during the second 6 week period in the placebo group obviously reflects the fact that the women had difficulty adhering to the diet. Early satiety was reported by 100% of the subjects during the first 6 week period. During the second 6 week period, even with severe caloric restriction, 90% of the women taking 5-HTP reported early satiety. Once again, many of the women receiving the 5-HTP reported mild nausea during the first 6 weeks of therapy. However, the symptom was never severe enough for any of the women to drop out of the study. No other side-effects were reported. Based upon the urinary measurements of 5-HIAA, the women took their 300 mg of 5-HTP with meals and as a result were able to achieve weight loss. The amount of weight loss was amplified by a better capability to adhere to a 1,200 calorie diet. The structure of the dietary changes reflected primarily a reduction in pasta, bread, and other carbohydrate-rich foods (the study was conducted in Rome). Insomnia
Several clinical studies have shown 5-HTP to produce good results in promoting and maintaining sleep in normal subjects as well as in those experiencing insomnia.[36] [37] [38] [39] [40] [42] [43] One of the key benefits with 5-HTP in the treatment of insomnia is its ability to increase sleep quality. This effect is evident by its ability to increase REM sleep (typically by about 25%) while simultaneously increasing deep sleep stages 3 and 4 without increasing total sleep time. [36] [38] The sleep stages that are reduced by 5-HTP to compensate for the increases are non-REM stages 1 and 2, the least important stages of sleep. In one of the studies, the subjects receiving 200 mg of 5-HTP increased the amount of REM sleep by 15.5 minutes during the 5 night study. [36] Those subjects taking 600 mg of 5-HTP increased REM sleep time by an average of 20 minutes for the 5 night study. These results indicate that 5-HTP increases the amount of dream time by about 3–4 minutes a night. Although there was a clear dose-related effect, the lower dosage is sufficient in most cases. In addition, taking too much 5-HTP may increase REM sleep to an abnormal level, lead to an increased risk for disturbing dreams (i.e. nightmares), and cause mild nausea. Migraine and tension headache
The relationship of serotonin and headaches is fully described
791
in Chapter 172 . Because migraine sufferers have low levels of serotonin in their tissues, some researchers refer to migraine as a “low serotonin syndrome”. [43] Although the primary benefits of 5-HTP in the prevention of both migraine and tension headache is related to its ability to normalize underlying imbalances in the serotonin system, it also influences the endorphin system in a positive way. There have been several clinical studies with 5-HTP in headaches, both vascular and non-vascular, that have showed excellent results. In particular, the use of 5-HTP in the prevention of migraine headache offers considerable advantages over drug therapy. Although a number of drugs have been shown to be useful in the prevention of migraine headaches, all of them carry significant side-effects. The problem with drug therapy in the prevention of migraine headaches is perhaps best exemplified by one of the most commonly used drugs, methysergide (Sansert). Methysergide therapy for the prevention of migraine attacks is effective in about 60–80% of cases. However, this effectiveness is not without a high price as side-effects are quite common and can be quite severe. Retroperitoneal fibrosis, pleuropulmonary fibrosis and fibrotic thickening of cardiac valves may occur in patients receiving long-term methysergide maleate therapy. Therefore, this preparation must be reserved for prophylaxis in patients whose vascular headaches are frequent and/or severe and uncontrollable and for those who are under close medical supervision. There have been several studies which have compared 5-HTP with methysergide in the prevention of migraine headaches. In one of the largest double-blind studies, 124 patients received either 5-HTP (600 mg daily) or methysergide (3 mg daily) in identically looking pills for 6 months. [44] Treatment was determined to be successful if there was a reduction higher than 50% in the frequency of attacks or in the number of severe attacks. Although 75% (30 of the remaining 40 patients) taking methysergide demonstrated significant improvement compared with 71% (32 of the 45 patients), this difference was not viewed as being statistically significant (see Table 92.12 ). The advantage of 5-HTP over methysergide was demonstrated when researchers looked at side-effects. Side-effects were more frequent in the group receiving methysergide than in the 5-HTP group. In fact, five patients in the methysergide TABLE 92-12 -- 5-HTP vs. methysergide: clinical effects of treatment in 124 patients Methysergide 5-HTP No attacks (100% reduction)
35%
25%
Improvement (>50% reduction)
40%
46%
No improvement
12.5%
29%
Withdrawal due to side-effects
12.5%
0
group had to withdraw during the trial because of side-effects. Two other studies comparing 5-HTP with drugs used in the prevention of migraine headaches (pizotifen and propranolol) demonstrated that 5-HTP compared quite favorably in terms of effectiveness. [45] [46] While these drugs have significant side-effects, 5-HTP is extremely well tolerated even at dosages as high as 600 mg/day. One of the other key differences noted in these studies between 5-HTP and the drugs was 5-HTP’s ability to improve mood and relieve feelings of depression. Juvenile headache
One of the best uses of 5-HTP is in chronic headaches in children. These headaches are a big problem because of the tremendous risk for side-effects of the current drugs used to treat as well as prevent these headaches in children. Fortunately, there have been several studies of 5-HTP in the treatment of chronic headaches in children and adolescents that have shown excellent results. [47] [48] [49] Given the risks of current drugs used in chronic childhood headaches, a trial of 5-HTP for 2 months certainly seems reasonable. If the headaches are also accompanied by sleep disorders, 5-HTP appears to be especially well-suited. In one study, 48 elementary and junior high students suffering from recurrent headaches (at least one headache every 2 weeks) and sleep disorders, including difficulty it getting to sleep, frequent awakenings, sleep walking, nightmares, and bedwetting, were divided into two groups. [47] Group A was given 5-HTP for 2 months followed by a placebo for 2 months, while group B received just the opposite. It was necessary to divide group A into a nine patient subgroup, Group C. These nine patients did so well on the 5-HTP they did not want to switch over to the other medication even though they had no idea whether they were in fact taking 5-HTP or were on a placebo. The dosage of 5-HTP was based on the child’s weight: 4.5 mg/kg per day. The headache index was reduced by about 70% when the kids were taking 5-HTP compared with an 11.5% drop when they were taking the placebo. In the nine patients in group C, there was an 81.8% decrease in the headache index after the second month. Interestingly, these same patients only exhibited an 18.2% reduction after the first month. These results indicate that evaluation of the benefits of 5-HTP in the treatment of headaches requires at least a 2 month trial. The failure to show benefit with 5-HTP in some studies in headaches may be due to the fact that they lasted less than 2 months. The 25 patients experienced a modest reduction in frequent awakenings, nightmares, sleep walking, and talking while asleep and no change in difficulty falling asleep or in bedwetting. Overall this study demonstrated very good effects in
792
these children. Perhaps the most impressive aspect to consider, however, was the fact that these benefits were achieved without side-effect. Not a single child reported a side-effect while taking 5-HTP. Interestingly, for some reason children rarely experience even mild nausea from 5-HTP. The possible benefits of 5-HTP in children with recurrent headache and/or sleep disorders is far-reaching. Evaluation of the 48 children in the trial demonstrated inadequate school progress compared with their classmates. The children were shown to be of normal intellectual capacity, but demonstrated inattentiveness similar to that observed in depression. Many of the children may have been suffering from depression. The unwillingness of the nine subjects in Group C to switch to the other unknown medication (which was in fact the placebo) is a strong indicator that these children and their parents noted some rather dramatic improvements beyond simply a reduction in headaches or improved sleep. The manner in which 5-HTP may be of benefit in migraine headaches may not simply be the overcoming of some defect in serotonin synthesis. As noted previously, part of the clinical benefit of 5-HTP may be via an ability to increase the levels of beta-endorphin. A decrease in beta-endorphin level in migraine as well as tension headache sufferers has been demonstrated by several investigators. [50] [51] A clinical trial measured the effects of 5-HTP on serotonin and beta-endorphin levels in 20 juvenile patients suffering from migraine or tension-type headaches. [52] Patients were monitored and evaluated for frequency and intensity of headache attacks for 3 months prior to 5-HTP treatment and 3 months of therapy. The researchers reported a statistically significant reduction in the headache score with 5-HTP treatment in both migraine and tension-type sufferers. These improvements were likely due to increased beta-endorphin levels as noted in Table 92.13 . However, the level of beta-endorphin achieved with 5-HTP, especially as measured in the white blood cell, was still far less than that observed in control patients not suffering from recurrent headache. These results imply that longer periods of 5-HTP supplementation may be required before there is a normalization of beta-endorphin levels in children prone to headaches. These results may indicate that 5-HTP alone is not able to raise beta-endorphin levels sufficiently to reduce or eliminate headaches, suggesting that other therapies designed to increase beta-endorphin levels should be used along with 5-HTP. Examples of other therapies which have been shown to raise beta-endorphin levels are
exercise, acupuncture, and biofeedback. Fibromyalgia
The history of the development of 5-HTP as an effective treatment for fibromyalgia began with studies on the drug fenclonine. [53] This drug blocks the enzyme which inhibits the conversion of tryptophan to 5-HTP and, as a result, blocks serotonin production. During the late 1960s and early 1970s, it was thought that increased serotonin formation may promote migraine headaches (the opposite of what was later proved, i.e. increasing serotonin levels reduce migraine headache occurrence). The researchers discovered that providing headache sufferers with fenclonine resulted in very severe muscle pain. This effect was the exact opposite of what was expected, but led to some important advances in the understanding of fibromyalgia – a way to induce its severe symptoms of (as well as symptoms nearly identical to) EMS, the condition caused by contaminated L-tryptophan. The researchers also discovered that migraine sufferers had a greater reaction to the drug than non-headache sufferers. In fact, in most normal subjects fenclonine produced no fibromyalgia. These occurrences highlight just how sensitive migraine sufferers are to low serotonin levels. Migraine headaches and fibromyalgia share a common feature: both are low serotonin syndromes. [54] After over 25 years of research, one of the lead researchers has stated: “In our experience, as well as in that of other pain specialists, 5-HTP can largely improve the painful picture of primary fibromyalgia.” [55] A double-blind study in 50 patients with fibromyalgia found that 100 mg of 5-HTP three times per day significantly improved their symptoms. 92.14 ,
[56]
As shown in Table
TABLE 92-13 -- Serotonin and beta-endorphin levels in juvenile patients with headaches before and after administration of 5-HTP Serotonin (serum, mcg/L) Beta-endorphin (plasma, pmol/L) Beta-endorphin (white blood cells, pmol/106 GB/L) Migraine (13 subjects) Before
104.6
16.2
110.5
After
115.7
19.4
120.3
Before
90.7
14.5
142.3
After
97.2
17.6
152.4
Before
100.5
15.7
129.3
After
108.3
18.4
140.4
96
21.3
359.3
Tension-type (7 subjects)
Total (20 subjects)
Controls (17 subjects)
793
TABLE 92-14 -- Patients’ and physicians’ opinion on the effectiveness of 5-HTP vs. placebo in fibromyalgia Response 5-HTP Placebo Good
11
1
Fair
8
5
Poor
4
8
None
0
9
5-HTP was rated substantially better than placebo by subjects and evaluating physicians. Improvements were noted in all symptom categories: number of painful areas, morning stiffness, sleep patterns, anxiety, and fatigue. In another study, 100 mg of 5-HTP taken three times daily demonstrated maximum results by day 30 of the 90 day trial. [57] One of the primary benefits with 5-HTP in fibromyalgia may be its ability to improve sleep quality. A key finding in patients with fibromyalgia is a reduced REM sleep and an increase in non-REM sleep. [58] In addition, the deeper levels (stages III and IV) are not achieved for long enough periods. As a result, people with fibromyalgia wake up feeling fatigued and in pain. The severity of the pain of fibromyalgia correlates with the rating of sleep quality. For example, a study of 50 women with fibromyalgia syndrome recorded their sleep quality, pain intensity, and attention to pain for 30 days, using palm-top computers programmed as electronic interviewers. [59] They described their previous night’s sleep quality within 30 minutes of awakening each day, and at randomly selected times in the morning, afternoon, and evening rated their present pain. The researchers found that a night of poor sleep was followed by a significantly more painful day, and a more painful day was followed by a night of even poorer sleep. 5-HTP may help to break the cycle by addressing the low serotonin level as well as by promoting a restful sleep. Parkinson’s disease
The use of 5-HTP in Parkinson’s disease provides some benefit, but only if used in combination with the drug Sinemet (the combination of L-dopa with the decarboxylase inhibitor, carbidopa). Although brain levels of serotonin are decreased in Parkinson’s disease, the reduction in dopamine receptors is more severe. Increasing serotonin levels with 5-HTP in patients not taking Sinemet are associated with worsening of symptoms, especially rigidity. [60] One of the key benefits of taking 5-HTP in Parkinson’s disease is that it can help to counteract the negative effects that the mood.[61] [62] [63] In addition, 5-HTP has also been shown to improve the physical symptoms of Parkinson’s disease.
L-dopa
in the Sinemet has on sleep and
About nine out of 10 people with Parkinson’s disease
Patient no.
L-dopa
(mg/day)
TABLE 92-15 -- The effect of HTP on depression in Parkinson’s disease Carbidopa (mg/day) 5-HTP (mg/day)
HDS Before After
1
1,000
175
125
22
11
2
300
75
75
14
3
3
400
150
100
21
13
4
1,000
100
100
12
6
5
500
125
500
18
22
6
1,125
112.5
300
18
7
7
500
50
100
17
13
suffer from depression. The degree of depression in Parkinson’s disease is a reflection of their serotonin levels. The lower the level of serotonin, the more severe is their depression. One study examined the effect of 5-HTP in seven Parkinson’s disease patients, all of whom were on Sinemet. [61] The initial dosage of 5-HTP was 75
mg, which was increased by 25 mg every 3 days until the patients reported a relief of their depression, or up to a maximum of 500 mg/day for 4 months. The impressive results obtained in these patients are shown in Table 92.15 . Six out of seven patients responded to 5-HTP. Note that the dosages of 5-HTP in these five out of the six patients who responded ranged from only 75 to 125 mg. The only patient who did not respond took 500 mg of 5-HTP. Seizure disorders
Most of the recent research on 5-HTP has focused on its use in the treatment of several seizure disorders. [64] [65] [66] [67] [68] 5-HTP has shown good results in most (but not all) studies in patients suffering from diseases characterized by myoclonus, with the exception of epilepsy which is not helped by 5-HTP. The best response to 5-HTP for myoclonus occurs in people who have intention myoclonus, which is most often produced as a result of ischemic damage to the brain.[32] Intention myoclonus can be a problem after a stroke or heart attack, overdosage of a drug like heroin, a severe asthma attack, or an adverse reaction to anesthesia or other chemical. Improvements in intention myoclonus with 5-HTP have been demonstrated in patients. 5-HTP has also produced good results in patients with progressive myoclonus epilepsy, essential myoclonus, palatal myoclonus, and Friedreich’s ataxia. [69] In a 1983 article, one researcher of 5-HTP stated: “Some helpless bedridden patients dramatically improved to the extent that they could walk again and resume independent living.” [70] Because of the phenomenal results, 5-HTP was the first compound to be evaluated as an orphan drug by the Pharmaceutical Manufacturing Associations Commission on Drugs for Rare Diseases.
794
TOXICOLOGY The major concern with 5-HTP is a possible link to L-tryptophan and the eosinophilia-myalgia syndrome (EMS). However, an important distinction must be made in the manufacturing process. While L-tryptophan is produced via bacterial fermentation and filtration, 5-HTP is commercially available through an extraction process from the seed of Griffonia simplicifolia, an African plant. 5-HTP extracted from this natural source avoids the contamination problem associated with past manufacturing of L-tryptophan. Detailed analyses of all the evidence by the Centers for Disease Control (CDC) and other experts have led to the conclusion that the cause of the EMS epidemic could be traced to a single Japanese manufacturer, Showa Denko. [71] [72] Of the six Japanese companies which supplied L-tryptophan to the United States, Showa Denko was the largest (50–60% of all the L-tryptophan). The L-tryptophan was used not only as a nutritional supplement, but also in infant formulas and nutrient mixtures for intravenous feeding. There was a single case report linking 5-HTP to a condition similar to EMS in 1980. [73] However, this case involved the use of very high dosages of 5-HTP (1,400 mg) over a 20 month period. Further examination of the patient indicated a defect in tryptophan metabolism that resulted in elevations in kynurenine. Such defects in tryptophan metabolism are common in patients with scleroderma, which shares many common features with EMS. It appeared that either the 5-HTP may have contained a contaminant to which this man was sensitive, or taking such high dosages of 5-HTP over a prolonged period of time aggravated his abnormal handling of L-tryptophan. There has also been a report of a 28-year-old woman, her husband, and her two sons, 33 and 13 months old, developing an EMS-like illness in response to contaminated 5-HTP. [74] The young boys had inherited the inability to convert tryptophan to 5-HTP. As a result, they required daily administration of 5-HTP (5–7 mg/kg). Both boys had been receiving the 5-HTP almost from birth. The mother was not taking 5-HTP, but she was preparing it for the young boys by opening the capsules, mixing the powder in juice or water, and giving it to them orally with a syringe. She never took the 5-HTP, she only touched it with her hands as she emptied the capsules. When the second boy was about 9 months old, the mother began experiencing symptoms of EMS. Upon consulting a physician in July of 1991 it was noted that her eosinophil count was well over 30%. She continued to worsen and was hospitalized in August of 1991 with a tentative diagnosis of EMS. At this time she was referred to the National Institutes of Health (NIH) for further evaluation. Because of the possible link between the mother’s symptoms and the 5-HTP, the boys and the father were also evaluated. The older boy had an eosinophil count of 9% (normal is 1–4%) and the younger boy had a count of 6%. The father had no abnormalities. The 5-HTP that the boys were using was analyzed by HPLC and found to contain an impurity not found in the 5-HTP that the NIH was using in their studies for ataxia and myoclonus. Switching the boys to the contaminant-free 5-HTP brought about normalization of eosinophil counts. The mother’s case is interesting because she was the most severely affected and she was only coming into contact with the contaminated 5-HTP through her skin. Evidence that uncontaminated 5-HTP does not cause EMS is also provided by researchers who have been using 5-HTP for over 25 years. They state that: “EMS has never appeared in the patients of ours who received only uncontaminated L-tryptophan or 5-hydroxtryptophan (5-HTP).” [75] Furthermore, researchers at the NIH studying the effects of uncontaminated 5-HTP on various metabolic conditions have not observed a single case of EMS nor has a case of elevated eosinophils been attributed to 5-HTP in these studies. [74] In short, there has never been a report of uncontaminated 5-HTP causing EMS. Although there has never been a single person developing EMS from 5-HTP products proven to be free from the contaminants, and it is extremely unlikely that anyone would, nonetheless, to be on the safe side we recommend that long-term continual use of 5-HTP be monitored by regular (every 6 months) eosinophil determination. For any person suffering from scleroderma due to the problem with tryptophan metabolism noted in these patients, we recommend an eosinophil determination after the first month of 5-HTP use, especially if dosages are greater than 500 mg/day.
DOSAGE The dosage should be started at 50 mg three times per day. If the response is inadequate after 2 weeks, increase the dosage to 100 mg three times per day. This recommendation will greatly reduce the mild symptoms of nausea often experienced during the first few weeks of 5-HTP therapy. Because 5-HTP does not rely on the same transport vehicle as L-tryptophan, it can also be taken with food. For insomnia, prescribe 100–300 mg 30–45 minutes before retiring. Start with the lower dose for at least 3 days before increasing dosage.
Figure 92-1 5-Hydroxytryptophan.
795
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Chapter 93 - Hypericum perforatum (St John’s wort) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Hypericum perforatum (family: Hypericaceae) Common names: St John’s wort, Klamath weed, hypericum
GENERAL DESCRIPTION St John’s wort (Hypericum perforatum) is a shrubby perennial plant with numerous bright yellow flowers. It is commonly found in dry, gravelly soils, fields, and sunny places. St John’s wort is native to many parts of the world including Europe, Asia, and the United States. It grows especially well in northern California and southern Oregon. [1] The plant is glabrous throughout, green or sometimes glaucescent; the stems are erect, branched at the top and 30–100 cm long; the leaves are oval or elliptic or oblong-ovate, or rather narrow, oblong-linear, subotuse, flat or more or less revolute-marginedated with numerous pellucid and a few black granular dots. The yellow flowers are numerous, forming a broadly paniculate, almost corymbose inflorenscence, 7–11 cm long and 5–11 cm broad. The lanceolate bracts are 0.5 cm long and acute. The calyx is deeply parted, 5 mm long and about two to three times shorter than corolla. The sepals are lanceolate or narrow lanceolate 4–5 mm long, 1 mm broad, as long as ovary, acute or acuminate, sparingly furnished with black oval dots, with a smooth or sparsely toothed margin. The petals are oblong to oblong-elliptic, 1.2–1.5 cm long and 0.5–0.6 cm broad, with or without numerous black granular dots and lines on the margin in the upper part, while the surface is full of yellow glandular dots, thin lines, and stripes. The three-bundled stames are numerous; the ovary is ovoid, 3–5 mm long. The seed is 1 mm long, cylindric, brown, and minutely pitted longitudinally. [1] The whole plant is used medicinally. Harvesting time is generally July through August. The plant must be dried immediately to prevent degradation of active principles. [1]
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Figure 93-1 Hypericin.
CHEMICAL COMPOSITION The major compounds of interest have been hypericin (see Fig. 93.1 ) and pseudohypericin. These compounds are typically found in very low concentrations, ranging from 0.0095 to 0.466% in the leaves and as much as 0.24% in the flowers. [1] More recently, researchers have been interested in the other chemical constituents (especially the various flavonoid and xanthones). The interest in these other components stems largely from pharmacological studies with commercially available extracts demonstrating effects and benefits beyond hypericin and pseudohypericin. The other active components include: [1] [2] • flavonoids (flowers 16%, leaves 12%, and whole herb 9%) • xanthones • phenolic carboxylic acids (caffeic, chlorogenic, ferulic, and gentisic acids) • essential oils (whole herb content 0.13%) • carotenoids • alkanes • phloroglucinol derivatives • phytosterols • medium-chain fatty acid alcohols.
HISTORY AND FOLK USE St John’s wort has a long history of folk use. Dioscorides, the foremost physician of ancient Greece, as well as Pliny and Hippocrates, utilized St John’s wort in the treatment of many illnesses. Its Latin name, Hypericum perforatum, is derived from Greek and means “over an apparition”, a reference to the belief that the herb was so obnoxious to evil spirits that a whiff of it would cause them to depart. The naming of St John’s wort has its origins in folk traditions. One claims that red spots, symbolic of the blood of St John, appeared on the leaves of the plant on the anniversary of the saint’s beheading. Another comes from a common medieval belief that if one slept with a piece of the plant under his pillow on St John’s Eve, “the Saint would appear in a dream, give his blessing, and prevent one from dying during the following year”. Many people from the time of the ancient Greeks through the Middle Ages believed St John’s wort to have magical powers. Recent research on St John’s wort appears to offer some explanation of this “magical” power. Based on a long history of use as a mood-elevating substance and preliminary in vitro experiments and clinical studies, in 1984 the German Commission E permitted the medicinal use of St John’s wort for depression, anxiety, or nervous excitement. The Commission E evaluates efficacy of herbal medicines based on a doctrine of reasonable certainty versus the United States FDA’s doctrine of absolute proof. Herbal products can be marketed with drug claims if they have been proven to be safe and effective. Whether the herbal product is available by prescription or OTC is based upon its application and safety of use. Herbal products sold in German pharmacies are reimbursed by insurance if they are prescribed by a physician. Because the German system allowed companies to market their products according to the guidelines of the Commission E, many companies achieved success with their products allowing them to fund the necessary research to gain greater acceptance within mainstream conventional medicine. The case of St John’s wort extract
in the treatment of depression is a perfect case in point to illustrate how the Commission E monographs have fueled the science of botanical medicine. For example, originally it was thought that hypericin acted as an inhibitor of the enzyme monoamine oxidase (MAO) – thereby resulting in the increase of CNS monoamines such as serotonin and dopamine. However, newer information indicates that St John’s wort possesses no in vivo inhibition of MAO (discussed below). It appears that the antidepressant activities are related more to modulating the relationship between the immune system and mood, as well as by inhibiting serotonin reuptake (discussed below). In addition, it appears that while hypericin is an important marker, there are other compounds such as flavonoids which are thought to play a major role in the pharmacology of St John’s wort. Over 25 double-blind randomized trials involving a total of 1,757 outpatients with mild to moderately severe depression have shown St John’s wort extracts standardized for hypericin to yield excellent results in the treatment in depression with virtually no side-effects. [1] [3] In 1994 a total of 66 million daily doses of St John’s wort preparations were prescribed by German physicians. [4]
PHARMACOLOGY St John’s wort extracts (primarily of the flowering tops) have shown a wide variety of effects in experimental
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and clinical studies. Some of the activities demonstrated include: [1] [2] • antidepressant effects • antiviral effects • antibiotic effects • increased healing of wounds and burns. Antidepressant activity
Among the different biological hypotheses for depression, the biogenic amine hypothesis is the most widely accepted. This hypothesis suggests that depression is the result of a deficiency in function of the biogenic amines, e.g. serotonin, catecholamines, dopamine, etc. These neurotransmitters are stored in granules within neurons. After stimulation of the neurons, these neurotransmitters are released into the synaptic cleft via exocytosis. After binding to postsynaptic receptors, the neurotransmitters are either taken up again and re-stored in the vesicles or they are catabolized by the enzymes monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). Most antidepressant drugs increase the availability of these amines, particularly serotonin, by either inhibiting the re-uptake or blocking MAO. As stated above, initial studies indicated that St John’s wort extract’s antidepressant action was based on the ability of crude hypericin preparations to inhibit both types A and B MAO. [5] [6] As a result of this inhibition, there is an increase in the level of neurotransmitters within the brain that maintain normal mood and emotional stability including serotonin, catecholamines, and dopamine. These preliminary results identified hypericin as the supposed active constituent. However, later chemical analysis of these crude hypericin preparations identified a content of as much as 20% of other St John’s wort constituents, with the flavonoids being the most important.[1] In other words, it is not known to what extent hypericin or the flavonoids individually contribute to any MAO inhibition. To better understand the influence of hypericin, hypericum total extract, and hypericum fractions on the activity of MAO and COMT, a study was conducted. inhibition of MAO could be shown in the following concentrations:
[7]
An
• hypericin to 10 -3 mol/L • hypericum total extract to 10 -4 mol/L • one extract fraction up to 10 -5 mol/L. A COMT inhibition could not be shown for hypericin, with hypericum extract to 10 -4 mol/L and with two extract fractions also up to 10 -4 mol/L. The MAO inhibiting fraction contained hypericins as well as flavonols, the COMT-inhibition fraction being mainly flavonols and xanthones. The key result from this study, as well as in another in vitro/ex vivo study, is the demonstration that the concentrations of inhibition shown, particularly with regard to the inhibition of MAO activity, are likely not sufficient to explain the clinically proven antidepressive effect of St John’s wort extract. [7] [8] Therefore, additional mechanisms are likely responsible for these clinical benefits. At least two other mechanisms have been proposed: modulation of interleukin-6 activity and inhibition of the re-uptake of serotonin. The modulating effect of St John’s wort extract on interleukin-6 (IL-6) is the most interesting as it proposes a mechanism by which St John’s wort interacts with the link between the immune system and mood. The immune system and the nervous system share many common biochemical features and regulatory interactions. In regards to IL-6, this cytokine is heavily involved in the communication between cells within and outside the immune system. With regard to the nervous system, IL-6 is known to modulate hypothalamic-pituitary-end organ axes, especially the hypothalamic-pituitary-adrenal (HPA) axis. The hypothesis is that an elevation in IL-6 results in activation of the HPA axis leading to elevations in CRH and other adrenal regulatory hormones – hallmark features in depression. St John’s wort extract has shown an ability to reduce IL-6 levels, and hence this action may explain the clinical effectiveness of St John’s wort extract. [9] The study demonstrating reduction of IL-6 levels involved taking blood samples from five healthy volunteers and four depressive patients. [9] The release of interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) was measured quantitatively after an incubation time of 24 hours on microtiter plates. A massive suppression of the interleukin-6 release was found for PHA-stimulated St John’s wort extract. If these effects can be duplicated in vivo, it would provide a mechanism by which St John’s wort extract modulates CRH release and, subsequently, mood. St John’s wort extract has also been shown to inhibit the re-uptake of serotonin similar in fashion to drugs like fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). The study demonstrating a 50% serotonin re-uptake inhibition utilized the 0.3% hypericin content standardized extract at a concentration of 6.2 mcg/ml and did not attempt to identify the active inhibitors. [10] The authors of the study concluded that “the antidepressant activity of Hypericum extract is due to inhibition of serotonin uptake by postsynaptic receptors”. However, an important point must be made – until pharmacokinetic studies demonstrate that St John’s wort components pass across the blood–brain barrier, a primary site of action outside the central nervous system cannot be ruled out. Extracts of St John’s wort have been tested in various animal models designed to study its antidepressant
800
effects. In these studies, St John’s wort extract was found to enhance the exploratory activity of mice in a foreign environment, extend the narcotic sleeping time in a dose-dependent fashion, antagonize the effects of reserpine, and decrease aggressive behavior in socially isolated male mice. [1] [11] These activities are consistent with the expected effects of antidepressant compounds and appear to be the result of increased monoamine activity. Anti-viral activity
In vitro studies have shown that hypericin and pseudohypericin exhibit strong antiviral activity against herpes simplex virus I and II as well as influenza types A and B, and vesicular stomatitis virus. [12] These compounds have also demonstrated remarkable antiviral activity against Epstein–Barr virus. [13] A tremendous amount of excitement was generated when researchers from New York University Medical Center and the Weizmann Institute of Science in Israel demonstrated the anti-retroviral activity of hypericin and pseudohypericin. [14] This preliminary study examined the effect of these compounds on two animal retroviruses, Friend leukemia virus and radiation leukemia virus, both in vitro and in vivo (in mice). The researchers found the effective dose of hypericin in mice to be
1.5– 2.0 mcg/ml. The researchers concluded: Hypericin and pseudohypericin display an extremely effective antiviral activity when administered to mice after retroviral infection. … The antiviral activity is remarkable both in its mechanism of action … and in the potency of one administration of a relatively small dose of the compounds. Availability … and the relatively convenient and inexpensive procedure for the extraction and purification of hypericin and pseudohypericin further enhance the potential of these compounds. Later, two possible mechanisms were described to explain the antiviral activity of both hypericin and pseudohypericin. [15] First, inhibition of assembly or processing of intact virions from infected cells – released virions contain no detectable activity of reverse transcriptase. Second, these compounds also directly inactivate mature and properly assembled retroviruses. The antiviral activity of hypericin against HIV appears to require the interaction with light to activate the hypericin. [16] [17] Another requirement is sufficient concentrations, as entry of hypericin into infected cells is dependent upon the concentration of hypericin in the blood. At sufficient concentrations, hypericin incubated with HIV-infected whole blood decreases culturable HIV, indicating significant antiviral activity. [18] Antibacterial activity
St John’s wort extracts have broad-spectrum antimicrobial activity against both Gram-negative and Gram-positive bacteria. Staphylococcus aureus, Streptococcus mutans, Proteus vulgaris, Escherichia coli, and Pseudomonas aeruginosa.
[ 19]
The organisms they studied included
Pharmacokinetic studies
Recent pharmacokinetic studies have been published using the 0.3% hypericin content standardized extract. [1] [20] The major drawbacks of these studies is the focus on hypericin and pseudohypericin. Nonetheless, these studies effectively demonstrated that hypericin and pseudohypericin are absorbed. In one of the studies, it was shown that after 4 days of taking the standard dosage of the extract (300 mg t.i.d.), a steady state is reached with mean maximal plasma levels during the steady-state period of 8.5 ng/ml for hypericin and 5.8 ng/ml for pseudohypericin. [20] Interestingly, even though pseudohypericin is found in higher concentrations in the extract than hypericin, higher blood levels are achieved with hypericin, indicating that hypericin is more bioavailable than pseudohypericin.
CLINICAL APPLICATIONS The primary use of St John’s wort is in the treatment of depression. It may also be of benefit in the treatment of chronic viral infections and, topically, in various skin products. Depression
Extracts of St John’s wort standardized for hypericin content (most studies used the 0.3% hypericin content extract) has significant support in the treatment of mild to moderate antidepressant. [1] [3] [21] The official German Commission E monograph for St John’s wort lists psychovegetative disturbances, depressive states, fear, and nervous disturbances as clinical indications for St John’s wort. The clinical evaluation of St John’s wort extract began with an initial clinical study of six depressed women, aged 55–65, which measured the change in urinary metabolites of noradrenaline and dopamine following administration of a standardized extract of St John’s wort extract (0.14% hypericin content). [22] Researchers found a significant increase in the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol, a marker commonly used to evaluate the efficacy of antidepressant therapy. A follow-up study by the same researchers followed 15 women with depression taking the same standardized extract. [22] The results demonstrated a significant improvement in symptoms of anxiety, apathy, hypersomnia and insomnia, anorexia, psychomotor retardation, depression, and feelings of worthlessness. No side-effects were observed.
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Since this initial study, a total of 1,592 patients have been studied in 25 double-blind controlled studies (15 compared with placebo, 10 compared with antidepressant drugs including five studies comparing St John’s wort to tricyclics: two vs. imipramine; two vs. amitriptyline; and one vs. desipramine). [1] [3] [21] [23] In these studies, St John’s wort extract was shown to produce improvements in many psychological symptoms, including: • depression • anxiety • apathy • sleep disturbances • insomnia • anorexia • feelings of worthlessness. Even more impressive is that St John’s wort extract was able to achieve these benefits without producing significant side-effects. The scientific investigation of St John’s wort is not complete. From a clinical perspective, the major shortcomings of the existing clinical trials is their relatively short term (8 weeks) and the lack of studies in severely depressed patients. [23] Given the growing popularity of hypericum, studies which address these shortcoming are needed. The currently available information clearly supports the short-term use of St John’s wort extract as an alternative to standard antidepressant drugs in cases of mild to moderate depression. Whether it will be shown to be suitable in the treatment of serious depressions (i.e. depressions associated with psychotic symptoms and/or depressions with serious risk of suicide) remains to answered. As stated above, there have been over 25 double-blind studies with St John’s wort extract in the treatment of depression. The methodological quality of this research, particularly the studies since 1989, has been judged as being acceptable by strict criteria. [3] [21] [23] The overall results have also been judged as providing good documentation of antidepressant activity. [3] [21] [23] The double-blind studies with the highest methodological quality rating are listed in Table 93.1 . Several of the better studies are discussed below. In the study with the highest methodological rating, 135 depressed patients were treated in 20 centers. [35] Patients were given either St John’s wort extract (0.3% hypericin content, 300 mg t.i.d.) or imipramine (25 mg t.i.d.) for a period of 6 weeks. Inclusion diagnoses were typical depressions with single episode, several episodes, depressive neurosis, and adjustment disorder with depressed mood in accordance with DSM-III-R. Main assessment criteria were the Hamilton Depression Scale (HAMD), the Depression Scale according to von Zerssen (D-S) and the Clinical Global Impressions (CGI). In both treatment groups, there were significant decreases in the HAMD from 20.2 to 8.8 in the St John’s wort group, and from 19.4 to 10.7 in the imipramine group. The D-S point value also dropped from 39.6 to 27.2 in the St John’s wort group, and 39.0 to 29.2 in the imipramine group (see Table 93.2 ). The analysis of CGI revealed comparable results in both treatment groups. The main advantage, however, was not so much a difference in therapeutic outcome, but rather a significant advantage in terms of lack of side-effects and excellent patient tolerance in the St John’s wort group. Another high quality randomized, double-blind study examining the effectiveness and tolerance of the 0.3% hypericin content standardized St John’s wort extract compared was maprotiline was performed in a group
Trial (ref no.)
TABLE 93-1 -- Summary of clinical trials with St John’s wort extract in depression No. of patients Baseline HDS Dose (mg/day) Duration (weeks) Responder rate (St John’s wort )
Responder rate (placebo)
Trials comparing St John’s wort with placebo Halama[24]
50
18.0
1.08
4
10/25
0/25
Hansgren et al[25]
72
20.4
2.7
4
27/34
9/38
Harrer & Sommer[26]
120
20.9
0.75
6
22/58
9/58
Hubner et al [27]
40
12.4
2.7
4
14/20
9/20
Quandt et al [28]
88
17.3
0.75
4
29/44
3/44
Reh et al[29]
50
20.0
1.0
8
20/25
11/25
Schmidt & Sommer[30]
65
16.4
1.08
6
20/32
6/33
Schmidt et al[31]
40
29.5
0.75
4
15/25
3/24
Sommer & Harrer[32]
105
15.8
2.7
4
28/50
13/55
Totals
630
185/313 (59%)
63/322 (20%)
Trials comparing St John’s wort extract with an antidepressant drug Bergman et al[33]
80
15.4
0.75
6
32/40
28/40 (amitryptiline)
Harrer et al[34]
102
19.4
2.7
4
27/51
28/51 (maprotiline)
Vorbach et al[35]
135
9.4
2.7
4
42/67
37/68 (imipramine)
Totals
317
101/158 (64%)
93/159 (58%)
* Responder rate, a decrease in the HAMD of greater than 50% or achieving a value less than 10.
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TABLE 93-2 -- Hypericum compared with imipramine St John’s wort
Imipramine
Hamilton Depression Scale Initial measurement
20.2
19.4
Week 6
8.8
10.7
Initial measurement
39.6
39
Week 6
27.2
29.2
Depression Scale (von Zerssen)
of 102 patients with depression. [34] Patients were given either St John’s wort extract (300 mg t.i.d.) or maprotiline (25 mg t.i.d.) for a period of 4 weeks. Effectiveness was determined using the HAMD, D-S, and CGI scales. The total score of the HAMD scale dropped during the 4 weeks of therapy in both treatment groups by about 50%. The mean values of the D-S and the CGI scales showed similar results, and after 4 weeks of therapy, no significant differences in either treatment group were noticed. The onset of the effects occurred up to the second week of treatment, but were observed earlier with maprotiline than with the St John’s wort extract. However, maprotiline treatment resulted in the typical side-effects with tricyclics, e.g. tiredness, mouth dryness, and heart complaints, while St John’s wort caused no significant side-effects. In a multicenter double-blind study, 72 depressive patients with a HAMD greater than 16 were given either St John’s wort extract (0.3% hypericin content, 300 mg) or placebo three times daily for 4 weeks. [25] At the end of the trial period, there was a significant advantage for the St John’s wort group as 27 out of 34 (81%) patients in this group responded based on a HAMD score less than 10, compared with nine out of 38 (26%) in the placebo group. Another way of looking at the results in this study is to examine the drop in the average HAMD in both groups. In the treatment group, the HAMD dropped from an average of 20.8 at the beginning of the trial to 9.2 after 4 weeks, while in the placebo group the drop was from 20.4 to 14.7. At the end of the 4 week trial, the placebo group and treatment group were subsequently treated for an additional 2 weeks with St John’s wort extract in both groups, with the average HAMD in the treatment group dropping below 6 and the original placebo group dropping to below the responder rate of 10. In another double-blind study, 105 patients with different types of mild to moderate depressions were given either 300 mg of the St John’s wort extract standardized to contain 0.3% hypericin or an identically looking placebo three times daily for 4 weeks. [32] The effectiveness of treatment was judged after 2 and 4 weeks according to the HAMD scale, the standard measure to assess an antidepressant’s effectiveness. The results are shown in Table 93.3 . Using the criteria of a decrease in the HAMD of greater TABLE 93-3 -- Hypericum compared with palcebo St John’s wort
Placebo
Baseline 15.81
15.83
Week 2
9.64
12.28
Week 4
7.17
11.30
than 50% or achieving a value less than 10 as identification of responders, 28 out of 42 patients (67%) in the St John’s wort group responded, compared with 13 of 47 patients (27.7%) in the placebo group. The results of this study are consistent with other well-designed studies comparing St John’s wort with placebo. Seasonal affective disorder
Seasonal affective disorder (SAD) represents a subgroup of major depression with a regular occurrence of symptoms in autumn/winter and full remission in spring/summer. Light therapy has become the standard treatment of this type of depression. Apart from this, pharmacotherapy with antidepressants also seems to provide an improvement of SAD symptoms. The aim of a controlled, single-blind study was to evaluate if St John’s wort could be beneficial in treating SAD patients and whether the combination with light therapy would be additionally advantageous. [36] Patients who fulfilled DSM-III-R criteria for major depression with seasonal pattern were randomized in a 4 week treatment study with 900 mg of St John’s wort extract/day (0.3% hypericin content) combined with either bright (3000 lux, n = 10) or dim light (100:1. [90] Together with ascorbate, GSH participates in the regeneration of vitamin E, which emphasizes the cooperation of antioxidants. Oxidative stress decreases this ratio, activates transcription factors and increases production of interleukin 1 and tumor necrosis factor. [91] Depletion of intracellular glutathione is associated with immunodeficiency. [92]
AIDS patients appear to have low levels of reduced glutathione, which could activate transcription factor NF-kappaB to increase transcription of the HIV genome. clinical study demonstrated that low GSH levels in CD4 T cells from HIV-infected subjects is associated with a decreased survival of 2–3 years. [93]
A
N-Acetylcysteine is an effective precursor for glutathione and can raise intracellular GSH. [94] Higher blood levels of glutathione correlate with higher degrees of health in elderly subjects.[95] Whether glutathione concentrations predict aging and whether low glutathione is a cause of aging remain to be determined. There is evidence that dietary glutathione is absorbed and can increase plasma glutathione concentrations in animals and humans. [96] [97] Oral supplementation of glutathione for maintenance and antioxidant protection ranges from 5 to 15 mg/kg body weight for antioxidant support. Detoxification protocols call for somewhat higher intakes, 15–25 mg/kg. [98] Coenzyme Q 10 (ubiquinone)
Ubiquinones are a family of fat-soluble antioxidants containing 1–12 isoprene units. The predominant form in humans is ubiquinone 10 or coenzyme Q
10 (CoQ).
Long
recognized as a lipophilic electron carrier in mitochondrial ATP production, CoQ also functions as an important antioxidant, which can recycle tocopherol. [99] CoQ can enhance the immune system,[100] and has been used to improve status in patients with angina, [101] various cardiomyopathies and heart disease. [102] Ubiquinol, the reduced form of CoQ, protects LDL against lipid peroxidation. [103] Folkers noted that cancer patients are often low in CoQ. [104] CoQ deficiencies occur in the myocardium of older persons, especially those with heart disease. [105] CoQ synthesis requires vitamins B 2 , B6 , B12 and folate, and synthesis may not be optimal in people with a low intake of these important vitamins. The normal value for CoQ in plasma is approximately 0.4 µmol/L, mostly in the reduced form. Ubiquinol is readily oxidized, and dietary forms are ubiquinones, which are readily reduced after absorption. A decline in lipid peroxidation in plasma after supplementation with CoQ supports an antioxidative role for CoQ. [106] Because CoQ is not well absorbed, increasing plasma CoQ levels can be difficult. Oral supplementation with 30 mg of emulsified CoQ (CoQ-zyme) was as effective as 100 mg of powdered CoQ.[107] Uric acid (urate)
Uric acid is a waste product of a purine metabolism, which occurs in high levels in plasma. Urate is a broad-spectrum antioxidant, capable of scavenging free radicals and of chelating transition metals. [108] Uric acid is responsible for 21–34% of the total plasma antioxidant activity, where it appears to protect alpha-tocopherol from peroxyl radicals. [109] Polyfunctional organic acids
Citrate, fumarate, succinate, malate and tartrate can bind (chelate) transition metal ions and block ROS produc-tion, thus acting as preventive antioxidants. These acids require the presence of chain-breaking antioxidants for maximum effectiveness. Not all chelates confer antioxidant properties; for example, iron-ascorbate and iron EDTA complexes catalyze oxidation. [68] Melatonin
In addition to helping to set the body biorhythms, this hormone quenches hydroxyl radicals very efficiently. The central nervous system consumes 20% of the oxygen used daily and thus is likely to generate ROS at a high rate. Melatonin production and sleep may play a pivotal part in preventing oxidative damage of nerves. [110] Though melatonin is sometimes sold as a food supplement, in reality it is a potent hormone. Storage and transport proteins: ferritin, transferrin, ceruloplasmin
Free iron and copper ions catalyze the conversion of H 2 O2 to hydroxyl radicals; therefore proteins that bind these ions help to protect tissues against ROS. Under normal circumstances, it is questionable whether unbound iron is normally present in cells. However, with chronic inflammation, iron may be released from ferritin, and potentially this may pose a hazard. Iron storage disease is linked to oxidative damage. Transferrin (which has a high affinity for iron) and ceruloplasmin (which binds copper) can be considered part of the antioxidant defenses. [111] Iron stored in ferritin does not participate in
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free radical generation. Another intracellular sulfur-rich protein, metallothionein, binds many metals, including copper.
NON-NUTRITIVE ANTIOXIDANTS Flavonoids
The typical diet provides a wide range of substances of plant origin that play important roles in maintaining health. Many act as antioxidants. One of the largest classes is the flavonoids, found mainly in fruits, leaves, stems and roots of vegetables, legumes and tea. Flavonoids potentiate the effects of vitamin C and protect other easily oxidizable substances. About 5,000 flavonoids have been reported; undoubtedly more remain to be discovered. Natural phenolics include: flavonoids (anthocyanidins, catechins, flavanones, flavones, flavonols and isoflavones); tannins (ellagic acid, gallic acid); phenyl isopropenoids (such as caffeic acid, coumaric acids, ferulic acid); lignans; and other substances, including catechol, resveratrol (grape skins), rosmarinic acid (rosemary) and others. Substantial amounts of ingested quercetin are absorbed by the GI tract in humans. [112] Quercetin and kaempferol are among the most abundant flavonoids in the diet. Various flavonoids inhibit peroxidation in vitro by scavenging ROS, superoxide, hydroxyl radical and singlet oxygen. For example, rutin, myricetin and quercetin scavenge superoxide,[113] and block LDL oxidation. [114] Flavonoids from bilberries and grapes were able to protect collagen from superoxide-induced damage. [115] Flavonoids can also bind transition metals, limiting their ability to catalyze free radical formation. [116] The increased consumption of flavonoids correlated with the decreased risk of some forms of cancer and cardiovascular disease. [117] Quercetin inhibited melanoma cells, as a specific example. [118] Ascorbic acid enhances the inhibition of cancer cells by fisetin and quercetin in vitro, suggesting that ascorbate potentiates the action of flavonoids as chemoprotective agents. [119] Previous estimates of daily consumption of total flavonoids ranged from 200 mg to 1,000 mg daily. However, accurate food consumption data and refined analytical methods based on high-performance liquid chromatography indicate that for northern European elderly men, the mean daily intake of the anti-cancer flavonoids was only about 23 mg daily, with quercetin being the predominant flavonoid. [120] Though quercetin consumption was low, this flavonoid level represents substantially more antioxidant activity than the typical daily consumption of vitamin E or beta-carotene. Furthermore, this level of flavonoid consumption correlated with a decreased risk of cardiovascular disease, [120] but not cancer [121] (see Ch. 125 for further discussion). Botanical extracts Botanical extracts have been used for centuries by natural health care practitioners. Recent research has now demonstrated that much of their clinical efficacy is due to their flavonoid constituents, which are often organ-specific. Silybum marianum and other hepatoprotective botanicals
Milk thistle extracts containing silymarin, [122] as well as extracts of Indian herbs such as Picrorhiza kurroa, [123] Eclipta alba, [124] and Tinospora cordifolia, [125] or combinations (Livotrit Plus™), concentrate flavonoids in the liver where they exert hepatoprotective effects. Since liver detoxication promotes autoxidation due to ROS produced by cytochrome P450,[126] the antioxidant properties of these botanical flavonoids largely explains the beneficial effects these plant extracts in normalizing liver function [127] (see Ch. 111 for a more in-depth discussion). Proanthocyanidins
A variety of plant sources yield a family of flavonoids called proanthocyanidins. Often they are chained together (oligomers); hence the name oligomeric proanthocyanidins or OPCs. Pine bark and grape seeds are typical commercial sources. Animal experiments indicate that grape seed extracts can limit lipid peroxidation in the brain, suggesting that constituents or their colonic fermentation products, are absorbed and cross the blood brain barrier. [128] Preparations of European pine bark (Pycnogenol™) have been used as supplements for capillary dysfunction associated in patients with diabetes and for other venous abnormalities. [129] OPCs are also present in legume-derived polyphenols (Phytolens™), which inhibit peroxynitrite-induced apoptosis in human colonic cells, a model system for gut inflammation.[130] Frenchmen consume a high fat diet, yet appear to have a lower mortality due to heart disease. Several explanations have been proposed for the so-called “French paradox”. Of particular interest is the correlation of heart protection with wine consumption. The cholesterol-lowering effect of spirits is not unique to wine. However, red wine contains abundant tannins and other polyphenols, and drinking red wine increases the antioxidant capacity of serum. [131] Such experiments suggest the absorption of polyphenols. Red wine has a higher phenol antioxidant index measured against isolated LDL than white wine. [132] In addition, grape skins and red wine contain resveratrol, a phenolic compound, and phytoalexin, a compound produced by plants in response to environmental stressors. Resveratrol apparently inhibits
platelet aggregation and eicosanoid syntheses and blocks cellular events linked to tumor initiation, promotion and
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progression. [133] These effectsseem to be independent of its antioxidant properties (see Ch. 111 for further discussion). Catechins
Tea is a rich source of polyphenols that are highly substituted with hydroxyl groups. Catechin and gallic acid derivatives – including epigallocatechin, epigallocatechin-3 gallate and epicatechin-3 gallate – which function as radical quenchers in vitro. [134] [135] Tea consumption has been linked to a decreased risk of cancer, and antiproliferative effects seem to be a function of polyphenol content. [136] Urokinase, a proteolytic enzyme overexpressed in many cancers, can be inhibited by green tea flavonoids. Thus, green tea polyphenols probably have multiple effects in the body, including quenching radicals. Green tea extracts free of caffeine are now commercially available (see Chs 84 and 89 ). Other botanicals
Extracts of Ginkgo biloba have long been known to support vascular function and cerebral insufficiency. It seems probable that active constituents, ginkgolides and related flavonoids reduce oxidative stress. [137] [138] Turmeric has a long history of use in Eastern traditions. Curcuminoids are the bright yellow pigments isolated from this source. These lipids limit the metabolism of environmental mutagens. Consumption of extracts equivalent to 20 mg of curcuminoids for 45 days decreased serum lipid peroxides. [139] Animal studies suggest that consumption of curcumin can limit lipid peroxide induced cataracts and curcumin may suppress colon cancer. [140] Curcuminoids are diketones, not flavonoids, which emphasizes the point that many other plant ingredients besides polyphenols may function as antioxidants and as anticarcinogens (see Chs 97 and 105 for further discussion).
COMPARING ANTIOXIDANTS There are several points to consider in comparing flavonoids. Studies of the quenching activity of antioxidants frequently employ single time points measured at a single concentration of antioxidant (end-point assay). This practice can lead to erroneous conclusions when comparing the effectiveness of antioxidants. A far more reliable approach evaluates the IC 50 , the concentration of antioxidant yielding 50% inhibition of a given oxidant or radical. The smaller the IC 50 , the more efficient the antioxidant. To illustrate, Table 99.3 compares IC50 values for several standardized botanical extracts and reference compounds using DPPH (diphenyl picrylhydrazyl radical), one of the test systems used for measuring free radical quenching. [141] Pine bark OPCs, grape seed OPCs, and polyphenols from non-soy legumes (Phytolens™) effectively quench organic free radicals. [130] It is important to compare antioxidant activity in several systems, such as superoxide, lipid peroxidation in LDL or microsomes, chemiluminence to detect the formation of reactive oxygen species, and so on. Table 99.3 presents additional data for quenching superoxide. Accordingly, the order of decreasing effectiveness of these superoxide quenchers is: legume-derived polyphenols (Phytolens™) > ascorbic acid > grape seed OPCs > pine bark OPCs > catechin. [127] [130] After demonstrating in vitro effectiveness, the question arises: “Does a given antioxidant improve cellular function?”. Phytochemicals possess multiple effects, ranging from enzyme inhibition to enzyme induction via alteration of signal transduction. Flavonoids, in particular, often possess multiple effects, leading them to be considered as “biological response modifiers”. There is also a growing awareness of the necessity of understanding the impact of flavonoids on the oxidative stress that contri-butes to mutagenesis and programmed cell death (apoptosis). Consumption of green tea and red wine flavonoids, and of oligomeric proanthocyanidins can decrease various indices of oxidative stress, such as plasma malondialdehyde or F 2 -isoprostanes (from fatty acid peroxidation), tissue inflammation or urinary output of oxidized DNA bases. Effectiveness of an antioxidant in vivo relies upon adequate absorption and assimilation. Water solubility of polyphenols would likely favor intestinal uptake; however, quercetin is readily absorbed, despite minimal water solubility. [112] The effects of bioactive ingredient or ingredients in botanical extracts are seldom completely TABLE 99-3 -- Comparison of free radical quenching by plant antioxidants and reference compounds [127] [130] Test substance DPPH* IC50 (ppm) Superoxide# IC50 (ppm) Pine bark oligomeric proanthocyanidins
4.4
17.8
Grape seed oligomeric proanthocyanidins
2.8–12.2
10.1–43.9
Phytolens™ legume polyphenols
4.9
5.6
Catechin
3.7
40.0
Ascorbic acid
14.5
7.0
IC50 is the concentration of antioxidant able to reduce 50% of a given radical; therefore, the smaller the IC
50
, the more effective the antioxidant.
*, 1,1-diphenyl-2-picrylhydrazl radical. #, superoxide generated by phenazine methosulfate and NADH.
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understood. An additional complication is the fact that intestinal bacteria degrade complex polyphenols to simple phenolic acids. These may be more bioactive than the starting material.
THE ADEQUACY OF ANTIOXIDANT DEFENSES Protection by free radical scavenging enzymes is limited and free radical damage is not completely prevented even in healthy people. All cells lack an enzyme defense against hydroxyl radicals, the most damaging species. Therefore, when free radical production exceeds the scavenging systems, hydroxyl radicals can be released, causing severe cellular damage. The body’s ability to respond to oxidative stress is a function of age, inheritance, medical history, degree of exposure to pollutants and other environmental stressors, and diet. Age
Because repair mechanisms decline with age, the body gradually loses functional resiliency, especially to oxidative stress. According to the free radical theory of aging, aging represents progressive oxidative damage. [142] Ames et al[11] have estimated that the average human cell sustains 10,000 DNA “hits” per day. Although most of these are repaired, unrepaired damage accumulates with age. Subtle structural alterations occur first, leading to decreased repair of damaged membranes and DNA, ultimately limiting the function of the nervous system, the endocrine system and the immune system. [11] A direct link between free radical scavenger enzymes and aging was suggested by the demonstration that transgenic fruit flies with extra copies of SOD and catalase genes produced elevated levels of these enzymes; they lived 30% longer than normal flies; and age-dependent oxidative damage also slowed down. [143] Inheritance
Due to heredity, the levels of protective enzymes can vary among individuals. People who possess low levels of these enzymes face greater risks of free radical-induced disease. This distinction is blurred somewhat because these enzymes are often inducible, and increased enzyme synthesis occurs in many organs,
such as liver and lung, as they adapt to increased oxidative burden (upregulation of antioxidant defense enzymes).
[ 144]
Medical history and environmental exposure
Processes such as trauma, inflammation and infection generally increase ROS production. Oxidative stress sometimes accompanies drug treatment. Cigarette smoke, ozone, oxides of nitrogen, solvents and pesticides can cause toxicity when radicals are created during their detoxification. The gut epithelium does not appear to adapt to long-term oxidative stress and, because of low initial levels of defensive enzymes, may be especially susceptible to oxidative damage with even moderate inflammation.[145] Strenuous physical exercise increases ROS production, and supplementing with antioxidant vitamins such as E, C and CoQ decreases associated oxidative damage, especially in older people, [146] and increases LDL antioxidant capacity in endurance athletes. [147] However, the paradox between exercise-induced oxidative stress and the obvious benefits of exercise has not been entirely resolved. Nutritional status
Americans do not consume enough antioxidants, and the trend seems unlikely to change in the foreseeable future. Perhaps only 10–20% eat the minimum of five daily servings of fruits and vegetables recommended by federal agencies. [148] [149] Median intakes of key antioxidants indicate that the consumption of vitamins C and E, beta-carotene, zinc, selenium, copper and manganese are low for specific segments of the population, and far below the RDAs for some. Furthermore, the RDAs do not address contributing factors concerning chronic diseases, lifestyle choices or medical history, nor do they address the issue of mutually supportive roles of antioxidants. The immune system, in particular, requires ample antioxidant nutrients. [150] They protect immune cells against oxidative damage and limit the production of non-inflammatory eicosanoids. As an example, supplementing apparently healthy, elderly people (who were consuming an otherwise typical diet), with 60–800 mg vitamin E improved several aspects of cell-mediated immunity within 4 months. [151] [152] The research also suggested that consumption of 200 mg/day may be more effective than 800 mg/day. Overall studies indicate that the RDAs for this nutrient and other antioxidants are inadequate for optimal immune function (see Ch. 108 for an indepth discussion of optimum nutrient levels).
GUIDELINES FOR USE OF ANTIOXIDANTS Antioxidants represent powerful additions to the healthcare practitioner’s armamentarium. However, their application in treatment protocols requires an understanding of their strengths and limitations. No single supplement, nutrient or food can maintain the body’s antioxidant defenses: there are simply too many oxidants to be neutralized, too many layers of antioxidant defenses to be sustained, and the range of reactivities of water- and lipid-soluble ROS is far too great. Multiple, complementary antioxidants are far more effective than large amounts of a single antioxidant. Often antioxidants work
842
synergistically. An additional consideration: antioxidant requirements should be balanced against oxidant burden. Thus, exposure to pollutants such as cigarette smoke, nitric oxides and ozone as well as chronic inflammation increases oxidative stress. High intake of fish oil and polyunsaturated fatty acids increases the need for vitamin E. The goal is to support the body’s defense system, rather than quenching all free radicals in the body, which would be counterproductive. Superoxide and nitric oxide play essential roles in maintaining the body’s defenses and homoeostatic mechanisms, for example. Precautions in using antioxidant supplementation 1. The uptake, assimilation and disposal or potential toxicity of polyphenols generally are not well studied. [153] 2. Flavonoids are metabolized and detoxified by liver enzymes, and pharmacologic doses may increase toxin burden. Some flavonoids can induce phase I detoxification enzymes, increasing the ability to transform toxins. The trade-off lies in the possible increased sensitivity to mutagens. In this context, quercetin at typical dietary levels appears to be a possible anticarcinogen. [154] 3. Vitamin E can exacerbate hypertension in susceptible people. High levels may antagonize other fat-soluble vitamins, thus decreasing bone mineralization. It may be contraindicated for patients receiving anticoagulants or for those with a vitamin K deficiency. [155] 4. Large amounts of vitamin C rarely increase oxalate production; the effects seems to be counterbalanced by increased vitamin B 6 .[156] 5. Excessive iron and iron overload may cause hydroxyl radical production in vivo. [157] 6. Beta-carotene may increase the risk of lung cancer in high risk populations unless protected by antioxidants like vitamin E. In addition, beta-carotene may exacerbate liver abnormalities in patients with alcoholic liver disease. Fatal coronary heart disease increased in patients receiving 20 mg/day beta-carotene (with or without alpha-tocopherol). [158] Possibly high levels of beta-carotene are contraindicated for those with smokers with myocardial infarctions. 7. An antioxidant in one system is not necessarily an antioxidant in all systems. For example, vitamin C, vitamin E and beta-carotene exhibit pro-oxidant activity in vitro under certain conditions. Pro-oxidant effects of carotenoids are poorly understood and consumption of large amounts themselves could be hazardous in susceptible individuals. Depending on the concentration of supporting antioxidants, even flavonoids can become prooxidants. [159] 8. Vitamin A is a teratogen when the intake is 25,000 IU or more per day for several months. The general advice to women who are or who might become pregnant is to limit their daily intake of vitamin A from supplements to no more than 5,000 IU/day and to limit their consumption of liver and liver products. [160]
HOW TO CHOOSE ANTIOXIDANTS The traditional definition of an essential (e.g. mineral or vitamin) nutrient is too restrictive from the perspective of life-long protection against chronic disease. The presence of vast numbers of non-vitamin antioxidants – in addition to established nutrients in vegetables, legumes, fruits and grains – poses the question of whether those antioxidants are in fact essential in the diet for optimal health and disease prevention. Consequently, antioxidant supplementation cannot substitute for a prudent diet, cessation of smoking and regular exercise. Supplementation may be most effective for those individuals who have the lowest baseline antioxidant levels, whether due to genetic or environmental causes. Foods supply a rich assortment of substances that can function as antioxidants. As an example, the total oxygen radical capacity of certain fruits has been determined. [161] Strawberry, plum, orange, red grapes, kiwi fruit and grape fruit possess high quenching activity. Blackberry, blueberry, raspberry, strawberry, plums, red wine and red grapes contain large amounts of anthocyanidins with strong antioxidant properties. [162] Further research will undoubtedly uncover many more phytochemical interactions. Though the picture is far from complete, antioxidants apparently operate synergistically. [163] Thus, animal studies indicate that an increased diversity of antioxidants provides more antioxidant protection than single supplements. [164] Even members of the B complex, such as pantothenic acid, may indirectly stimulate antioxidant production. [165] It should be emphasized that many ingredients in foods play important physiologic roles in addition to their properties as antioxidants. Furthermore, their effects may be indirect; antioxidants and response elements help the cell to adapt to ROS exposure and to correct ROS-induced damage. [166] Exploration of the role of a major oxidant, peroxynitrite, and nitrogen oxides as NOS (“nitrogen reactive species”) in chronic degenerative diseases is still in its infancy. [167] Consequently, the antioxidants that best defuse these reactive compounds have not yet been established. Table 99.4 provides a summary of a recommended intake of antioxidants for maintenance as compiled by the European Federation of Health Product Manufacturers.[168] The levels often prescribed in treatment protocols may be considerably higher than those listed. Thus, the consumption of a broad spectrum of antioxidants in amounts geared to meet an individual’s oxidant burden and nutritional status appears to be essential in order to promote optimal health and to minimize the effects of genetic predisposition that compromise defenses against aging, degenerative disease and toxic chemical exposure.
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TABLE 99-4 -- Recommended safe upper limits of daily intake of antioxidants for maintenance [168]
Nutrient
Safe upper limit
Comments
Alpha-tocopherol 900 IU
No toxicity for alpha-tocopherol has been reported. Mild, reversible side-effects have been noted at intakes greater than 1000 mg/day
Beta-carotene
25 mg
Generally no adverse side-effects have been noted other than hypercarotenemia at levels of about 30 mg/day. One study noted an apparent slight increased risk of cancer at 20 mg/day with a high alcohol consumption [60]
Vitamin C
2,000 mg
There are generally no adverse effects with long-term consumption of up to several grams of vitamin C daily. High consumption may be contraindicated with renal insufficiency disease and iron overload
Vitamin A
9,000 RE
Toxicity with chronic consumption of 12,000–23,000 retinol equivalents/day can occur rarely
Copper
9 mg
Copper is interrelated with zinc. Contaminated water is often a source of toxic levels
Manganese
20 mg
Supplementation may raise blood pressure and chronic toxicity may cause neurologic disorders
Selenium
450 mcg
Excessive selenium can be toxic, though organic selenium seems safer. Selenite reportedly reacts with glutathione to produce ROS. Selenocysteine can enter amino acid pools directly, while selenomethionine may be funneled into protein with imbalanced dietary protein
Zinc
30 mg
Rigorous homoeostatic mechanisms regulate zinc balance Extremely high levels block copper assimilation and are immunosuppressive
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Chapter 100 - Panax ginseng (Korean ginseng) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Panax ginseng C.A. Meyer (family: Araliaceae) Synonym: Panax schinseng Nees Common names: Korean ginseng, Chinese ginseng, Asiatic ginseng, Oriental ginseng
GENERAL DESCRIPTION Korean or Chinese ginseng is a small perennial plant which originally grew wild in the damp woodlands of northern China, Manchuria, and Korea. Wild ginseng is now extremely rare. However, ginseng is a widely cultivated plant, especially in Korea, but also in Russia, China, and Japan. In addition to Panax ginseng C.A. Meyer, four other closely related species are often used: • • • •
Panax quinquefolium (American ginseng) Panax japonicum C.A. Meyer (Japanese ginseng) Panax pseudoginseng (Himalayan ginseng) Panax trifolium.
Panax ginseng C.A. Meyer is the most widely used and most extensively studied species. Its pharmacology is the major focus of this chapter. [1] [2] Fully mature, Korean ginseng is a herbaceous plant with a tap-root, five-lobed palmate leaves, and greenish-white flowers in an umbel. In the first year, ginseng bears only a single leaf with three leaflets. In the second year, it bears a single leaf with five leaflets, and in its third year it bears two leaves with five leaflets. It usually starts flowering in its fourth year, while bearing three leaves. The roots of the cultivated plant are 3–4 mm in diameter and 10 cm long, while the roots of wild plants may attain 10 cm in diameter and a length of 50–60 cm. Ginseng is often processed in two forms, white and red ginseng. White ginseng is the dried root whose peripheral skin is frequently peeled off. Red ginseng is the steamed root, which shows a caramel-like color. [2] There are many types and grades of ginseng and ginseng extracts depending on the source, age, and parts of the root used, and the methods of preparation. Old, wild, well-formed roots are the most valued, while rootlets
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of cultivated plants are considered the lowest grade. For largely economic purposes, the majority of ginseng in the American marketplace is derived from the lowest grade root, diluted with excipients, blended with adulterants, or totally devoid of active constituents, i.e. ginsenosides. [3] High quality preparations are available, however. These preparations are extracts of the main root of plants between 4 and 6 years of age and have been standardized for ginsenoside content and ratio to ensure optimum pharmacological effect.
CHEMICAL COMPOSITION Ginseng contains at least 13 different triterpenoid saponins, collectively known as ginsenosides, which are believed to be the most important active constituents. The usual concentration of ginsenosides is between 2 and 3%. The ginsenosides have been designated R 0 , R b1 , Rb2 , R b3 , Rc , Rd , R e , R f , 20-gluco-R f , Rg1 , and Rg2 . The ginsenosides originate from three fundamental aglycones: • oleanolic acid (ginsenoside R 0 ) • 20-S-protopanaxadiol (ginsenosides R b1 to Rd ) • 20-S-protopanaxatriol (ginsenosides R e to Rg2 ). As can be seen from Table 100.1 , the ginsenosides differ primarily in their sugar groups. Ginsenosides R b1 , Rb2 , R c , Re , and Rg1 are present in significant concentrations in Korean ginseng. In contrast, American ginseng ( Panax quinquefolius) contains primarily ginsenosides R b1 and Re , and does not contain ginsenosides R b2 , R f , or, in some instances, R g1 . This allows for
Figure 100-1 Ginsenosides of Panax ginseng.
easy detection of species using HPLC (high-pressure liquid chromatography).
[1] [2] [ 4]
Other components include: [1] [2] [4] • panacene, a volatile oil • free and glucoside-bound sterols (e.g. beta-sitosterol and its beta-glucoside) • polyacetylene derivatives B-elemene and panaxinol • 8–32% starch • low molecular weight polysaccharides
• pectin • vitamins (e.g. thiamin, riboflavin, B 12 , nicotinic acid, pantothenic acid, and biotin) • 0.1–0.2% choline • minerals • simple sugars (glucose, fructose, sucrose, maltose, trisaccharides, etc.) • various flavonoids. Although it had been reported that ginseng contains large amounts of germanium (i.e. 300 ppm), a follow-up study using highly sensitive (detection limit of 1 ppb), flameless atomic absorption spectrometry combined with solvent extraction demonstrated that the highest concentration of germanium measured in samples of ginseng purchased in the Osaka market was only 6 ppb. [5] More research is needed to accurately determine the germanium content of botanical medicines, as the reported concentrations vary widely. Such low levels suggest that a connection between the pharmacology of ginseng and its germanium content is unlikely.
HISTORY AND FOLK USE Perhaps the most famous medicinal plant of China, ginseng has been generally used alone or in combination with other herbs to restore the “Yang” quality. It has also been used as a tonic for its revitalizing properties, especially after a long illness. Conditions for which ginseng is utilized in folk medicine are shown in Table 100.1 It has been used as an alterative, anodyne, aperitif, aphrodisiac, cardiotonic, carminative, emetic, estrogenic, expectorant, gonadotrophic, nervine, sedative, sialogogue, stimulant, stomachic, and tranquilizer. [1] [6] As can be seen from this list, ginseng has been used for most conditions, reflecting a broad range of nutritional and medicinal properties.
PHARMACOLOGY AND CLINICAL INDICATIONS Since the 1950s, a great amount of research has been conducted worldwide to determine whether the therapeutic properties attributed to ginseng belong in the realm of legend or fact. Unfortunately, inconsistent results (due mostly to different procedures in the preparation of
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TABLE 100-1 -- Conditions for which ginseng is utilized in folk medicine • Amnesia • Anemia • Anorexia • Asthma • Atherosclerosis • Boils • Bruises • Cachexia • Cancer • Convulsions • Cough • Debility • Diabetes • Diuretic • Divination • Dysentery • Dysmenorrhea • Dyspepsia • Enterorrhagia • Epilepsy • Epistaxis • Fatigue • Fear • Fever • Forgetfulness • Gastritis • Hangover • Headache • Heart • Hematoptysis • Hemorrhage • Hyperglycemia • Hypertension • Hypotension • Impotence • Insomnia • Intestinal complaints • Longevity promotion • Malaria • Menorrhagia
• Nausea • Neurasthenia • Palpitations • Polyuria • Pregnancy • Puerperium • Rectocele • Rhinitis • Rheumatism • Shortness of breath • Sores • Spermatorrhea • Splenitis • Swelling • Vertigo extracts, use of non-official parts of the plant, use of adulterants, and lack of quality control in the ginseng used) have made determination of ginseng’s true properties difficult. Nonetheless, enough good research does exist to indicate that ginseng possesses pharmacological activity consistent with its near-legendary status, especially when high quality extracts, standardized for active constituents, are used. Over the years, ginseng has been reported to have numerous pharmacological effects in humans and laboratory animals, including:
[1] [ 2] [ 4] [7]
• general stimulatory effects during stress • decrease in sensitivity to stress • increase in mental and physical capacity for work • improved endocrine system function • ameliorating radiation sickness, experimental neurosis, and cancer • enhanced protein synthesis and cell reproduction • improved glucose control in humans and alloxan-induced diabetes in rats • modulation of various immune system parameters • lowering of serum cholesterol • protection of the liver from hepatotoxins. Some of these actions are discussed in greater detail below. Adaptogenic activity
Ginseng was originally investigated for its “adaptogen” qualities. An “adaptogen” was defined in 1957 by the Russian pharmacologist I. I. Brekhman as a substance that:[2] • must be innocuous and cause minimal disorders in the physiological functions of an organism • must have a non-specific action (i.e. it should increase resistance to adverse influences by a wide range of physical, chemical, and biochemical factors) • usually has a normalizing action irrespective of the direction of the pathologic state. According to tradition and scientific evidence, ginseng possesses this kind of equilibrating, tonic, anti-stress action, and so the term adaptogen is quite appropriate in describing its general effects. [2] [7] [8] From a clinical perspective, ginseng can be used as a general tonic, especially in debilitated and feeble individuals. Use in this manner is consistent with its historic application. Anti-fatigue (mental and physical) activity
Some of the first studies of ginseng’s adaptogenic activities were performed during the late 1950s and early 1960s by Brekhman and Dardymov in the USSR, and by Petkov in Bulgaria. [7] [8] [9] [10] [11] In one of Brekhman’s experiments, Soviet soldiers given an extract of ginseng ran faster in a 3 km race than those given a placebo. In another, radio operators tested after administration of ginseng extract transmitted text significantly faster and with fewer mistakes than those given placebo. These and similar results found by European researchers, who demonstrated improvement in human physical and mental performance after the administration of ginseng extracts, prompted researchers to confirm the results in experimental models using mice. [2] [7] [8] [9] In perhaps the best known of these experiments, mice were subjected to swimming in cold water or running up an apparently endless rope to determine if ginseng could increase the time to exhaustion. The results indicated that ginseng possessed significant antifatigue activity, as a clear dose-dependent increase in time to exhaustion was noted in mice receiving ginseng. [2] [8] [12] [13] [14] [15] In one study, the time to exhaustion was increased up to 183% in the mice given ginseng 30 minutes prior to exercising, compared with controls. [8] Experimental animal studies indicated that much of the anti-fatigue action of ginseng was due to the stimulant effect of ginseng on the CNS. Stress coupled with ginseng ingestion induced alterations in energy metabolism during prolonged exercise. [10] [11] [12] [13] [14] [15] Ginseng has been shown to increase locomotor activity, [16] modify EEG tracings,[10] improve metabolic activity in the CNS, [17] and affect the hypothalamo-pituitary-adrenal axis (discussed below), all of which could be largely responsible for ginseng’s anti-fatigue activity on mental
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and physical performance. The CNS activity of ginseng is essentially different from that of the usual stimulants. While stimulants are active under most situations, ginseng reveals its stimulatory action only under the challenge of stress. [17] On the physical level, ginseng’s anti-fatigue properties appear to be closely related to its ability to spare glycogen utilization in exercising muscle. [14] Exercise physiologists have clearly established that during prolonged exercise, the development of fatigue is closely related to the depletion of glycogen stores and the build-up of lactic acid, both in skeletal muscle and in the liver. If an adequate supply of oxygen is available to the working muscle, non-esterified fatty acids are the preferential energy substrate, thus sparing utilization of muscle glycogen, blood glucose, and, consequently, liver glycogen. The greater the ability to conserve body carbohydrate stores by mobilizing and oxidizing fatty acids, the greater the amount of time to exhaustion. Ginseng enhances fatty acid oxidation during prolonged
exercise, thereby sparing muscle glycogen stores. [14] Mental and physical anti-fatigue activity effects have been demonstrated in both animal studies and double-blind, clinical trials in humans. In addition to several Russian studies using soldiers and athletes as subjects, other studies have been published. [18] [19] In one double-blind, clinical study, nurses who had switched from day to night duty rated themselves for competence, mood, and general well-being, and were given an objective test of psychophysical performance, blood counts, and blood chemistry. The group administered ginseng demonstrated higher scores in competence, mood parameters, and objective psychophysical performance when compared with those receiving a placebo. [18] In a double-blind, cross-over study on university students in Italy, ginseng extract was compared with placebo in various tests of psychomotor performance. A favourable effect of ginseng relative to baseline performance was observed in attention (cancellation test), mental arithmetic, logical deduction, integrated sensory-motor function (choice reaction time), and auditory reaction time. However, statistically significant superiority over the placebo group was noted only for mental arithmetic. It is interesting to note that in the course of the trial the students taking ginseng reported a greater sensation of well-being. [19] From a clinical standpoint, ginseng’s anti-fatigue properties may be useful whenever fatigue or lack of vigilance is apparent. Athletes, in particular, may derive some benefit from ginseng use. Standardized extracts of Panax ginseng in combination with Ginkgo biloba (a formula called Gincosan) improved the retention of learned behavior in experiments on young (3 months) and old (26 months) rats. Results suggest Panax and Gingko extracts possess properties similar to those of nootropic drugs. [20] Anti-stress activity
Ginseng has been shown to enhance the ability to cope with various stressors, both physical and mental. Presumably, as has been demonstrated in several animal studies, this is a result of delaying the alarm phase response in Selye’s classic model of stress. These studies found that adrenal cholesterol levels are many times higher in animals given ginseng than in their matched controls, indicating increased tolerance to stress and delayed alarm phase response. [4] [14] [21] [22] Italian researchers have studied the effect of a standardized ginseng extract, whose ginsenosides composition was accurately determined, on the adrenal functions of rats exposed to cold.[4] [21] The ginseng extract significantly counteracted body temperature decline without affecting blood glucose or cortisone levels. In a group of adrenalectomized rats, the ginseng extract had no significant effects. Administration of hydrocortisone to the adrenalectomized rats did, however, cause body temperature to be maintained when the rats were exposed to cold. Histologically, it was noted that there was: • evidence of hyperfunctioning in the supraoptic and paraventricular nuclei of the hypothalamus in rats fed the ginseng extract • remarkable increase in corticotropic basophilic cells (ACTH-producing) in the pars distalis of the pituitary • hyperplasia of the adrenal zona fasiculata, indicating that hyperfunctioning of the adrenal was promoted by the administration of the ginseng extract. Other researchers have demonstrated that ginseng saponins significantly increase plasma ACTH and cortico-steroids (in a parallel kinetic pattern). [23] [24] Since this effect could be blocked by dexamethasone (which acts on the hypothalamus and pituitary to prevent ACTH release), it was concluded that ginsenosides act predominantly on the hypothalamus or pituitary to promote secretion of ACTH. This has been further confirmed by indirect studies. ACTH first stimulates an increase in cAMP in the adrenal and then promotes corticosteroid synthesis. Ginseng administration has been shown to increase adrenal cAMP in normal rats, but not in hypophysectomized rats. These investigations make quite clear that ginseng’s anti-stress action is mediated by the hypothalamo-pituitary-adrenal axis, as: • the anti-stress action of ginseng is greatly reduced by adrenalectomy • ginseng continues to exert its anti-stress action after hypophysectomy only if ACTH is administered • histological and chemical evidence demonstrates a strong link between ginseng and the hypothalamo-pituitary-adrenal axis • dexamethasone blocks the effects of ginseng.
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This release of ACTH and associated pituitary substances (e.g. beta-lipoprotein, endorphins, enkephalins, etc.), coupled with their end-organ effects, is probably responsible for many of the anti-fatigue and anti-stress actions of ginseng, as ACTH and corticosteroids have been shown to bind directly to brain tissue to increase mental activities during stress. From a clinical perspective, it is apparent that ginseng has a balancing effect or alterative action on the hypothalamic-pituitary-adrenal axis by adjusting metabolic and functional systems governing hormonal control of homeostasis. This assists the body’s response to the challenge of stress and therefore is indicated when disruption of this axis is apparent. Ginseng may prove especially effective in restoration of normal adrenal function and prevention of adrenal atrophy associated with corticosteroid administration. In rats, ginseng has been found to inhibit cortisone-induced adrenal and thymic atrophy. [25] Ginseng could be combined with other botanicals with adrenal-enhancing activity (e.g. Bupleuri falcatum, Glycyrrhiza glabra, Curcuma longa, and Eleutherococcus senticosus) in the treatment of adrenal atrophy (a.k.a. exhaustion) (also see Chs 80 and 90 ). [26] [27] Diabetes
Ginseng, used either alone or in combination with other botanicals, has a long folk use in the treatment of diabetes. Ginseng has confirmed hypoglycemic activity. The constituents responsible for this effect include five types of substances: [28] [29] [30] [31] [32] • five glycans (polysaccharides designated panaxans A to E) • adenosine • a carboxylic acid • a peptide • a fraction designated DPG-3-2. The ginsenosides are devoid of hypoglycemic action. (This highlights the importance of using crude, standardized, extracts containing all active principles as opposed to using isolated ginsenosides or pure ginsenoside extracts.) It is interesting to note that ginseng will increase serum cortisol levels in non-diabetic individuals, while in patients with diabetes, serum cortisol levels will be reduced.[33] As cortisol antagonizes insulin, this is presumably a beneficial effect. In addition, DPG-3-2 only exhibits hypoglycemic action or provokes insulin secretion in diabetic and glucose-loaded normal mice while having no effect on normal mice fed a standard diet. [28] This again demonstrates ginseng’s non-specific balancing effect, baffling to researchers who are accustomed to investigating compounds with consistent pharmacological effects. Ginseng is indicated as an adjunctive therapy in the treatment of diabetes, both for its hypoglycemic effect and for its ability to decrease the atherogenic index (see below). Reproductive effects
Although it is claimed to be a “sexual rejuvenator”, human studies supporting this belief are scanty. Ginseng has, however, been shown to:
[34]
• promote the growth of the testes and increase spermatogenesis in rabbits • accelerate the growth of the ovary and enhance ovulation in frogs • stimulate egg-laying in hens • facilitate lordotic response in female rats • increase gonadal weight in both male and female rats • increase testicular nucleic acid content in rats • increase sexual activity and mating behavior in male rats. These animal study results seem to support ginseng’s use as a fertility and virility aid. In other experimental animal studies, ginseng has been shown to increase testosterone levels while decreasing prostate weight. have favorable effects in the treatment of benign prostatic hyperplasia; however, no clinical trials have yet been reported.
[ 35]
This suggests that ginseng should
Ginsenosides have also been shown to bind to human myometrial receptor proteins, and they apparently exert estrogen-like action on the vaginal epithelium. These are significant enough to prevent the atrophic vaginal changes associated with postmenopause and other menopausal symptoms. [36] Other clinical indications involving the reproductive system (based on historical use and experimental evidence) include decreased sperm counts, testicular atrophy or hypofunction, and other organic causes of male infertility, and ovarian atrophy or hypofunction, amenorrhea, and other organic causes of female infertility. It should be noted that several reports of mastalgia have been reported in women taking ginseng. [37] [38] Anti-cancer properties
Long-term oral administration of ginseng to newborn mice has been shown to reduce the incidence and also to inhibit the proliferation of tumors induced by various chemical carcinogens, including DMBA, urethane, and aflatoxin B1. [39] Its anti-cancer effects in other experimental models can be summarized as follows: [39] [40] • it is observed only in slow-growing tumors, such as Ehrlich and sarcoma 180 ascites tumor • it is not observed in rapidly growing tumors, such as L1210 and P388, and Walker carcinoma • there is no dose–response relationship or cumulative effect.
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The lack of a dose–response relationship suggests that ginseng’s anti-cancer effects are indirect and subject to a threshold mechanism. Thus, ginseng once again appears to demonstrate non-specific effects. Cell proliferating and anti-aging effects
Ginseng has a dual effect on cell growth: it stimulates cell division in an adequate nutritional environment, but it acts cytostatically under adverse conditions (as described above). [41] Furthermore, ginseng has yielded impressive results in lengthening the life span of cells in culture. [42] This enhancement of cellular proliferation and function has been shown on a variety of cell types (epithelial, hepatic, lymphocyte, fibroblast, thymic, neural, etc.) and may be a result of potentiation of nerve growth factor (NGF) by ginsenosides. [3] [43] Clinically, these results indicate a potential use of ginseng in healing damage to virtually all tissue types. Again this demonstrates ginseng’s non-specific action. Immunostimulating effects
That ginseng possesses immunostimulating activity is evidenced by its ability to enhance:
[ 44] [45]
• antibody plaque forming cell response • circulatory antibody titer against sheep erythrocytes • cell-mediated immunity • natural killer cell activity • the production of interferon • lymphocyte mitogenesis • reticuloendothelial system proliferative and phagocytic functions. Extracts of Panax ginseng were found to stimulate NK-function in normal individuals and patients with either chronic fatigue syndrome or acquired immunodeficiency syndrome.[46] Ginseng has been shown to prevent viral infections in experimental animals, [47] presumably a result of the combination of effects listed above. Perhaps the most important immune system-enhancing effect of ginseng is its ability to produce a marked hyperplasia of the Kupffer cells of the liver and of the folliculi in the spleen and lymph nodes. [4] [21] The hyperplastic folliculi show an increase in the number and volume of light centers, thus demonstrating morphological evidence of increased host defense capacity against a wide variety of external assaults. It should be noted that large dosages of ginseng may be contraindicated in acute infections. This is due to its in vitro inhibition of lymphocyte transformation (similar to cortisone) at high (i.e. greater than 1 mg/ml), but not low, concentrations. [44] [48] [49] In fact, in vitro, ginseng at 1.6 mcg/ml has been shown to inhibit phytohaemagglutinin-induced transformation of peripheral blood lymphocytes to a greater degree than cortisone at 500 mcg/ ml. [48] The greatest degree of inhibition, however, was observed when ginseng was used in combination with cortisone. These results suggest that ginseng at high doses may be effective against T-cell-mediated inflammatory diseases without producing glucocorticoid-like side-effects. It also suggests that a lower dose of cortisone could be used if ginseng is given simultaneously. When using ginseng, it is important to remember that ginseng’s in vitro effect on lymphocyte proliferation is biphasic, i.e. a strong inhibition at high concentrations and a moderate stimulation at low concentrations, and that while ginseng has demonstrated significant inhibition of lymphocyte proliferation in vitro, this has not been the observed effect in vivo, where lymphocyte proliferation has been enhanced. [44] These effects may be related to ginseng-induced elevation of interferon (which inhibits lymphocyte proliferation) which is dose-dependent. From a clinical perspective, the chronic ingestion of ginseng by individuals with mild immunodeficiency may reduce the risk of viral infection. Use in this manner is consistent with the historical use of ginseng by debilitated individuals. Cardiovascular effects
Ginseng has paradoxical effects on blood pressure. It appears that at low doses it possesses a hypertensive effect, but when administered at larger doses a hypotensive effect is noted. [50] Accordingly it has been reported useful in the treatment of essential hypertension in humans, but it has also been shown to have hypertensive effects as well. [51] This pressor effect must be kept in mind when administering ginseng to both normotensive and hypertensive individuals. Ginseng administered to human subjects with hyperlipidemia has been shown to reduce total serum cholesterol, triglyceride, and non-esterified fatty acid levels, while
raising serum HDL cholesterol levels. Platelet adhesiveness was also decreased. [52] These results in humans confirmed earlier studies on rats fed high-cholesterol diets. [53] [54] The mechanism of action appears to be through accelerated degradation, conversion, and excretion of cholesterol and triglyceride, despite increased lipogenesis and cholesterogenesis. Ginseng has also been shown to be effective in inhibiting experimental disseminated intravascular coagulation in rats. It also inhibited platelet aggregation by various aggregating agents and the conversion of fibrinogen to fibrin. Its mechanism of action appears to be via promotion of urokinase’s fibrinolytic activity. [55] From a clinical perspective, it appears that ginseng may offer some protection against atherosclerotic disease, further supporting its use as a general tonic. It may also possess a blood pressure-regulating effect.
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Hepatic effects
Obviously, any adaptogenic substance must impact the liver, due to the liver’s central role in metabolic and detoxification reactions. Ginseng affects the liver in several ways. As was previously mentioned, ginseng promotes hyperplasia of Kupffer cells (hepatic macrophages). [4] [21] As these cells are responsible for filtering out much of the toxins and debris from the portal circulation, increasing their number and activity could have profound effect. Ginseng has also been shown to increase nuclear RNA biosynthesis, indicating increased protein synthesis. [3] [56] In fact, ginseng has been shown to increase not only nuclear RNA synthesis, but also ribosomal and messenger RNA, the amount of rough endoplasmic reticulum, and the activity of RNA polymerase. [3] [56] [57] [58] These results indicate that ginseng activates virtually every step in protein biosynthesis. As protein synthesis is often reduced in the elderly, the significance of the above-described effects on enhancement of hepatic protein synthesis would be extremely high. However, these results have yet to be confirmed by clinical studies. Ginseng has also been shown to reverse diet-induced fatty liver in animals and to possess significant antihepatotoxic action.
[52] [59]
The clinical indications of these hepatic actions of ginseng are quite broad and support its general tonic/ adaptogen properties. Radiation-protecting effects
Ginseng has been shown to offer some protection against harmful radiation, both in vivo and in vitro, and to hasten recovery from radiation sickness. ever-increasing environmental radiation contamination, ginseng may be an appropriate prophylactic against radiation exposure.
[60] [ 61]
In wake of
TOXICOLOGY The problem of quality control makes toxicology difficult to address. This is exemplified by a 1979 JAMA article entitled “Ginseng abuse syndrome”. [62] In this article, a number of side-effects are reported, including: • hypertension • euphoria • nervousness • insomnia • skin eruptions • morning diarrhea. Given the extreme variation in quality of ginseng in the American marketplace and the use of both non-official parts of the plant and adulterants, it is not surprising that side-effects were noted. None of the commercial preparations used in the trial had been subjected to controlled analysis. Furthermore, the species of ginseng used included Panax ginseng, Panax quinquefolius, Eleutherococcus senticosus, and Rumex hymenosepalus in a variety of different forms, i.e. roots, capsules, tablets, teas, extracts, cigarettes, chewing gum, and candies. It is virtually impossible to derive any firm conclusions from the data presented in the JAMA article. The author’s final words do, however, seem sensible and appropriate: An important caveat is that these GAS [ginseng abuse syndrome] effects are neither uniformly negative nor uniformly predictable. Nevertheless, long-term ingestion of large amounts of ginseng should be avoided, as even a panacea can cause problems if abused. Studies have been performed on standardized extracts of ginseng which demonstrate the absence of side-effects and mutagenic or teratogenic effects. These studies differ markedly from the trial reported in JAMA in that high quality extracts were used.
[ 4] [13] [63] [ 64]
DOSAGE The dosage is inversely proportional to the ginsenoside content, i.e. if an extract or ginseng preparation contains high concentrations of ginsenosides (and presumably other active components), a lower dose will suffice. The standard dose for ginseng is in the range of 4.5–6 g daily. Currently, there is almost a total lack of quality control in ginseng products marketed in the United States. Independent research and published studies have clearly documented that there is a tremendous variation in the ginsenoside content of commercial preparations. [3] [4] In fact, many products on the market contain only trace amounts of ginsenosides, and some formulations contain no ginseng at all. This has led to several problems, ranging from toxicity reactions [62] (discussed below) to lack of medicinal effect. The widespread disregard for quality control in the health food industry has done much to tarnish the reputation of ginseng as well as other important botanicals. The authors recommend the use of standardized ginseng preparations to ensure sufficient ginsenoside content, consistent therapeutic results, and reduced risk of toxicity. Products should be standardized in their ginsenoside content. The typical dose (taken one to three times daily) for general tonic effects should contain a saponin content of at least 5 mg of ginsenosides with a ratio of R b1 to Rg1 of 2:1. For example, for a high quality ginseng root powder containing 5% ginsenosides, the dose would be 100 mg. As each individual’s response to ginseng is unique, the patient should be monitored for signs of possible ginseng toxicity (see below). It is best to begin at lower doses and increase gradually. The Russian approach for long-term administration is to use ginseng cyclically for a period of 15–20 days followed by a 2 week interval without any ginseng.
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Chapter 101 - Pancreatic enzymes Anthony J. Cichoke MA DC
HISTORY Pancreatic enzymes have a long history of clinical use. In the early 20th century, John Beard (a Scottish embryologist) successfully treated cancer using a pancreatic extract, which he described in his book, The Enzyme Treatment of Cancer and its Scientific Basis. In 1934, Ernst Freund (a Viennese physician) found a substance which dissolved cancer cells in the blood of people free from cancer. Cancer patients did not have this material, which Freund called “normal substance”. It was Professor Doctor Max Wolf (considered by many to be the father of modern enzyme therapy) who identified “normal substance” as an enzyme which decomposes fatty materials and proteins. Wolf worked with Freund in Vienna in the early 1930s. This association and the work of John Beard sparked his interest in the possibilities of treating malignant diseases with enzymes. Dr Wolf founded the Biological Institute of New York City and, after studying various enzymes and enzyme combinations, developed what he considered an optimal preparation for the treatment of various acute and chronic conditions. His preparation was a combination of a fractionated hydrolysate of beef pancreas, calf thymus, Pisum sativum (common pea), Lens esculenta (edible lentil), mannitol, and papaya. In the 1960s, Irving Innerfield conducted landmark research in the area of pancreatic enzymes, primarily relating to the clinical use of trypsin, chymotrypsin, and pancreatin, as well as streptokinase. In 1971, Professor Heinrich Wrba, head of the Austrian Cancer Research Institute at the University of Vienna stated: Our present knowledge allows us to include this [enzyme] therapy into the small list of highly-effective causal anti-cancer compounds. It [enzyme therapy] will certainly play an important role in cancer treatment over the next few years. However, it was Karl Ransberger who continued Wolf’s research and refined it, bringing it to doctors, hospitals and patients throughout the world. Ransberger encouraged
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and funded research projects in numerous hospitals and universities in Europe, the Americas, and elsewhere. His research, and that of others, has validated enzyme therapy’s effectiveness in treating numerous conditions, including arthritis, cancer, multiple sclerosis, cardiovascular disease, HIV/AIDS, and other diseases.
PANCREATIC ENZYMES Pancreatic enzymes aid in a surprising variety of bodily functions, including: • digestion • detoxification • bolstering the immune system • slowing the aging process • improving blood clot lysing • enhancing tissue repair • facilitating the inflammatory response • fighting viruses. Genetic weakness, illness, injury, exercise, aging and toxins (both endogenous and exogenous) may result in inadequate production or excessive need for pancreatic enzymes. In these and other situations, additional enzymes from an external source may be necessary. Many variables influence the proper choice of pancreatic enzymes, including: • therapeutic goals • patient’s health status • product —type of enzyme(s) —activity levels —quality control (including pH and temperature ranges) —variables which affect therapeutic application (e.g. enteric coating).
Pancreatic enzymes play an integral role in the digestion of proteins, fats, and carbohydrates. Pancreatic juice contains numerous enzymes, including amylase, lipase, ribonuclease, and deoxyribonuclease; [1] and the proenzymes trypsinogen, chymotrypsinogen, and procarboxypeptidase, which are converted in the small intestine to their active forms, trypsin, chymotrypsin, and carboxypeptidase, respectively. Protein leaves the stomach primarily in the form of proteases, peptones and large polypeptides. [2] Upon reaching the small intestine, these are further digested by the proteolytic enzymes, trypsin, chymotrypsin, and carboxypolypeptidase. Protein digestion mainly occurs in the duodenum and jejunum. Carbohydrates are digested by a-amylase in the pancreatic juice, which breaks down starches (converting them into maltose and other small glucose polymers), while pancreatic lipase digests fats. [2] Pancreatic enzyme supplements The pancreatic enzyme supplements most commonly used include chymotrypsin, trypsin, and pancreatin (which contains proteolytic, amylolytic and lipolytic properties), as well as pancrelipase (similar to pancreatin, but with a higher proportion of lipase). Primarily obtained from hog or ox pancreas, some of these enzymes
(such as lipase) can also be obtained from microbial sources (e.g. Aspergillus niger and Aspergillus oryzae). According to the US Pharmacopoeia, chymotrypsin and trypsin are crystallized from ox pancreas gland extract, and pancreatin from both hog and ox sources, while pancrelipase is derived from hog pancreas. [3] Porcine pancreas is especially rich in amylase and lipase and is similar to human pancreas. [1] Bovine pancreas contains considerable amounts of proteolytic enzymes but substantially lower amounts of lipase and amylase. [1] Other countries (such as Germany, Japan, England, and India) utilize their own pharmacopoeia, and foreign companies may use other sources to formulate their enzyme products. Age, sex and species of pork or ox can affect enzyme concentration and activity levels. For example, sow glands (from pork) are high in lipase, while butcher hogs (young male hogs, up to 90 kg and 6 months) are high in protease. Beef cows and bulls have different enzyme levels than steers or heifers. Beef, though providing all three basic enzyme types, does not exhibit the activity levels of pork (which has an activity level ? to ½ higher). Further, hog physiology is more similar to humans than to that of any other animal. Enzyme extraction processes Because enzymes are particularly sensitive to environmental changes, it is especially important during extraction to control pH (usually with buffers), temperature (using pre-cooled solutions and apparatus), substrate, and proteolysis (controlled through the use of inhibitors) in order to render a product that is enzymatically active.[4] Several steps are typically involved in the production of pancreatic enzyme supplements: • cell membrane rupture • fractionation • crystallization • enzyme isolation. Rupturing the cell membrane
Although a wide variety of methods are employed in enzyme extraction, most entail rupturing the cell membrane of the animal tissue. This can be achieved through mincing, homogenizing, shaking with fine glass beads (at high speed), grinding with sand, freezing (and subsequent
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thawing), oscillations (ultrasonic or sonic), autolysis (either alone or with toluene, ethyl acetate or sodium sulfide), treatment with solvents (e.g. acetone), or lysis with added enzymes.[5] Extracting enzymes from animal tissues is easier than extracting from microorganisms, according to Dixon & Webb [5] . They state that, in many cases, simple extraction with water may be sufficient. All extraction processes, however, must control pH and temperature to protect the enzymes from deactivation. Fractionation
Once the enzyme is brought into a solution, it must be separated from the other substances in the solution. Gel filtration or dialysis can be used to remove the small molecules, leaving large molecules (primarily proteins, with some polysaccharides). [5] Various fractionation methods can be employed for purifying the enzymes, including changing the pH, heating, using organic solvents and/or salts, adsorption, column chromatography, and electrophoresis. [5] Inhibitor affinity chromatography and substrate affinity chromatography are also used. [6] Crystallization
After an enzyme has been purified, it may be possible to crystallize it. Dixon & Webb [5] view this as a final stage method of fractionation. Crystallization can be achieved with ammonium sulfate solutions (the typical method), or at a constant salt concentration by gradually changing the temperature or the pH. [5] Enzyme isolation Chymotrypsin
One method (used in Germany) for extracting chymotrypsin (in the form of its inactive precursor chymotrypsinogen) is by fractionated extraction, ultrafiltration and subsequent chromatographic purification of pancreatic juice. The chymotrypsinogen is converted to the active chymotrypsin by treatment with trypsin in an acid environment. Trypsin
Trypsinogen can be isolated from the animal pancreas by fractionated precipitation and then activation to trypsin in a slightly alkaline environment. Pancreatin
Pancreatin can be obtained by an extraction procedure where, after elimination of the insoluble tissue, organic solvents dissolve and precipitate the enzymes. [1] However, because part of the lipase and other enzymes are inactivated during the manufacturing process, pancreatin, isolated in this way, is not very active. [1] According to Ruyssen & Lauwers, [1] more effective pancreatin can be produced through lyophilization, i.e. by drying under reduced pressure or with acetone. At this low temperature, the enzymes are more stable and less likely to be denatured. [1] After proper defatting, the pancreatin is stable, provided it contains not more than a small percentage of moisture. [1] However, it may contain undesirable microorganisms (such as Salmonella) and must, therefore, be decontaminated. [1] Under carefully controlled conditions, pancreatin can be decontaminated by a terminal heat treatment. [1] According to the US Pharmacopeia,[3] each milligram of pancreatin should contain: • not less than 25 USP units of amylase activity • not less than 2.0 USP units of lipase activity • not less than 25 USP units of protease activity. The US Pharmacopoeia states that: “One USP unit [or 1×] of amylase activity is contained in the amount of pancreatin that decomposes starch at an initial rate such that one microequivalent of glucosidic linkage is hydrolyzed per minute” under the conditions listed in the USP to assay for amylase activity. “One USP unit [or 1×] of lipase activity is contained in the amount of pancreatin that liberates 1.0 µEq of acid per minute at a pH of 9.0 and 37°” under the conditions detailed in the USP to assay for lipase activity. “One USP unit [or 1×] of protease activity is contained in the amount of pancreatin that digests 1.0 mg of casein” under the conditions enumerated in the USP to assay for protease activity. [3] Therefore, a product labeled “4×” would be four times stronger than a product labeled “1×”.
Pancrelipase
Pancrelipase is similar to pancreatin and according to the USP should contain: • not less than 100 USP units of amylase activity • not less than 24 USP units of lipase activity • not less than 100 USP units of protease activity. Pharmacology Chymotrypsin and trypsin are proteolytic enzymes which break down proteins into peptides. Chymotrypsin liberates the amino acids, L-tyrosine, L-tryptophan, and [ [ L-phenylalanine, as well as other molecules including several synthetic esters and amides. 1] Trypsin hydrolyzes primarily lysyl and arginyl residues. 1] Pancreatin contains amylase, lipase, and protease.
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Amylase breaks down starch; lipase breaks down fats; and protease breaks down proteins. Absorption In the past, the efficacy of enzyme therapy has been discounted, since the intestinal epithelial mucosa had been thought to be impermeable to large protein molecules.[7] [8] [9] Research over the past two decades has shown that the intestinal epithelium can be crossed by macromolecules, including intact proteins such as proteolytic enzymes. [10] These macromolecules normally penetrate the mucosal surface via the transcellular route as, in the healthy mucosa, the tight junctions (zonula occludens) between the enterocytes prohibit paracellular passage. [11] [12] [13] [14] Binding to the luminal membrane of the interocyte is followed by phagocytosis. [15] Some of the vacuole membrane vesicles formed fuse with lysosomes, and within the resulting phagolysome, the peptides and proteins may be hydrolyzed by lysosomal enzymes. [13] Other macromolecules avoid intracellular digestion and are passed from the enterocytes through the basolateral membrane into the interstitial space. [16] In the interstitial space, the macromolecules become available to macrophages and lymphoid cells. [17] Those molecules not taken up by macrophages or lymphatic cells eventually pass from the interstitial space into the blood or lymph. [18] The transport of macromolecular material from the lumen to the interstitium has been extensively studied in the epithelium covering the lymphatic structures, such as Peyer’s patches or isolated follicles. [15] In these regions, specialized enterocytes, the follicle-associated epithelium cells (FAE cells) [12] or M-cells [19] (called M-cells because of their occurrence in the microfolds of the luminal surface), transport macromolecular material in both directions. [12] The gut-associated immune system is thus supplied with antigenic macromolecules from the intestinal lumen. [20] [21] [22] The immunoglobulins produced by the plasma cells in the lumina propria (mainly IgA) are transported transcellularly to the luminal surface. The exact degree of the intestinal absorption of intact molecules or large breakdown products of dietary proteins is not yet totally clear. [23] [24] Although it is generally assumed that, apart from a very small proportion, all protein is hydrolyzed into amino acids or small molecular weight peptides before absorption by the mucosa, some research supports the hypothesis that a considerable proportion of dietary protein is taken up in the form of macromolecules and is only then hydrolyzed intercellularly in the peripheral tissue into amino acids (“distributed digestion”). [25] [26] [27] Regardless of the nutritional significance, the transepithelial transfer of particulate matter is at least antigenically sufficient to elicit a response of the gut-associated immune system.[12] The production and secretion of the immunoglobulins promote binding and proteolysis of the antigen material on the mucosal brush-border, thereby reducing its absorption (immunological barrier). [28] Absorption of enzymes
The intestinal transport of macromolecules is especially important for understanding the functions of enzymes. [29] Hydrolases such as trypsin or elastase can be transported functionally intact into the blood from the lumen of the gut. These circulating proteinases are bound to anti-proteinases like alpha-2 macroglobulin or alpha-1 anti-proteinase [20] and can be resorbed from the main stream by pancreatic cells (interopancreatic circulation as an enzyme conservation process). [29] Thus, the intestinal absorption of intact enzymes appears to be important for the balance between hydrolases and anti-proteinases in the intracellular space [30] and is an important factor for the establishment and maintenance of the internal stability in the body. It should be kept in mind that, although there are a number of absorption mechanisms, the primary mechanism for enzymes and other macromolecular enteral absorption is pinocytotic transfer by the M-cells of the small intestinal epithelium. After connection to a receptor in the mucosa of the intestinal wall, the enzymes are then absorbed into the wall by pinocytosis, guided through the intestinal cells in vesicles, and finally released into the blood by exocytosis. [31] To clarify rate of absorption, Steffen, et al, [32] investigated the absorption of an enzyme mixture “A” (EMA: pancreatin, 100 mg; papain, 60 mg; lipase, 10 mg; amylase, 10 mg; trypsin, 24 mg; chymotrypsin, 1 mg; bromelain, 45 mg; the bioflavonoid, rutin, 50 mg) in rabbits. Using electrophoresis, they found that entire enzyme molecules were absorbed. Although enzyme particles were also present, the ratio to the entire amount administered was not measured. EMA was found in both lungs and liver after 1–2 hours. After 1–4 hours, approximately twice as much EMA was found in the liver as in the lungs. The absorption maximum in all animals occurred approximately 1 hour after administration. After 24 hours, EMA was no longer found in either the lungs or liver. The absorption rate of individual and combined enzymes can be seen in Table 101.1 . The absorption rate of orally ingested EMA is about 20% within 6 hours. [21] (For additional discussion of the intestinal absorption of intact macromolecules, see Chs 21 and 66 .) Factors affecting enzyme activity Factors affecting enzyme activity include: • pH • temperature • substrate and substrate concentration • cofactors • metal ions • inhibitors and coating.
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TABLE 101-1 -- Absorption rate of individual and combined enzymes (within 6 hours) [33] [34] Enzyme
Absorption rate
Amylase
45%
Chymotrypsin
14–16%
Pancreatin
18–19%
Papain
6%
Trypsin
26–28%
Enzyme combination (bromelain, chymotrypsin, pancreatin, papain, and trypsin, with the bioflavonoid rutin)
22%
Optimal pH range
Each enzyme has an optimal pH range, depending upon such variables as temperature and substrate concentration, at which the enzymatic catalytic reaction occurs most rapidly. Chymotrypsin is stable at a pH of 3 or 4, suffers reversible denaturation at a pH below 3.0, and becomes inactive at a pH of above 10.0. 3.0 (and at low temperature), is irreversibly denatured at a pH of 8.0 or higher. [1]
[1]
Trypsin, stable at a pH of
The effects of temperature
In general, an increase of 10°F (5.5°C) in the enzymatic environment will approximately double the rate of the chemical reaction. [35] However, since enzymes are proteins, excessively high temperatures denature enzymes, thus destroying their activity. Optimal temperature for an enzyme is the temperature at which the catalyzed enzymatic reaction progresses most rapidly without damage to the enzyme. The enzymes in the human body develop high levels of activity at about body temperature, increasing to maximum at about the temperature of a severe fever, i.e. 104°F (40°C). Substrate concentration
The rate of any reaction is accelerated by increasing the substrate concentration until the enzyme is saturated by substrate. At this level, the rate of reaction becomes independent of substrate concentration and is no longer accelerated by the addition of more substrate. Cofactors
Although all enzymes consist of protein, some are complex proteins, i.e. they have a protein component and a “cofactor”. If the cofactor is removed, the protein (no longer active enzymatically) is called the apoenzyme. A cofactor might be a metal (e.g. iron, magnesium, copper, or zinc), a prosthetic group (a moderately-sized organic molecule), or a coenzyme (small organic compounds). Prosthetic groups and metals can aid in the catalytic function of the enzyme, while coenzymes take part in the enzymatic reaction. Many vitamins, trace elements, and minerals essential to human bodily function are part of enzymatic cofactors. Coenzymes are essential for the activity of many enzymes and serve as a type of substrate in certain reactions. In these reactions, the coenzyme is converted to a form no longer active in catalyzing the reaction. The reaction requires a mix which contains one molecule of cofactor for every molecule of substrate to be converted. Metal ions
Specific metal ions are required for the activity of many enzymes. Certain metal ions increase activity while others decrease or inhibit activity. Calcium, cobalt, copper, iron, magnesium, manganese, molybdenum, potassium and zinc are the most frequent enzyme activators in humans. Certain heavy metal ions inhibit enzyme reactions. These heavy metals include barium, lead and mercury, and they combine with the sulfhydryl reactive group (-SH) which is part of the active site of many enzymes. Inhibitors
Ions, atoms, or molecules which terminate or retard enzyme activity are called inhibitors. These inhibitors are classified as non-competitive or competitive. Non-competitive inhibitors combine with the enzyme at a location other than the active site. The non-competitive inhibitor retards the conversion of the substrate by the enzyme, although it does not affect the bonding of the substrate of the enzyme. An inhibitor is classified as competitive when it combines with the active site of the enzyme, preventing the substrate from having access to the active site. Supplement coating
The normal human stomach has a pH of approximately 1.5–3.0.[36] This low pH inhibits bacterial growth and activates certain enzymes. This acidic nature, however, can destroy pH-sensitive supplemental enzymes. For this reason, many enzyme products are enterically coated. This coating allows the product to reach the small intestine before disintegrating. [1] Other products are encapsulated in “microspheres”, which delays their disintegration. In one study, cellulose acetate phthalate (CAP) and
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maize starch were used as the coating materials for encapsulating pancreatic protease. [37] Results indicate that the coating materials were stable for at least 3 hours (time to pass through each part of the GI tract) in simulated gastric conditions (pH 3.97), but disintegrated rapidly under simulated intestinal conditions (pH of 6.82 and temperature of 39.5°C). Measuring enzyme activity When considering enzymes and enzyme applications, it is extremely important to understand the variables affecting their performance. When selecting an enzyme for therapeutic purposes, more than whether a given product contains amylase, protease, lipase, or other enzymes must be considered. The activity levels of the enzymes are of critical importance. Unfortunately, the labels on most enzyme products sold in this country do not indicate the activity levels of the enzymes contained therein. In addition, when the activity is stated, the consumer has no way of knowing which enzyme assay the manufacturer used unless the label also indicates that the product conforms to the guidelines of the USP. This is particularly confusing because activity levels are greatly affected by the conditions under which the assay was performed (including temperature, pH and substrate). Adding to the confusion, enzyme manufacturers utilize diverse assay methodologies. Therefore, directly comparing the enzymatic activity of competing products is difficult, if not impossible. The utilization of a single assay system (such as detailed in the USP) is probably necessary to directly compare competitive products. Several standardized assay systems are available for enzyme suppliers and are found in the US Pharmacopoeia (for a definitive assay), the NFIA Laboratory Methods Compendium, and the Food Chemical Codex. Incomplete labeling and the inconsistent use of standardized assay methodologies make evaluation of competitive products extremely challenging. Price could be the
first indication of inequities in assay procedures. For example, if company A is selling a product at 1,000 units/g for $30.00 a bottle, and company B is selling a product at 5,000 units/g for $10.00 a bottle, the units are most likely not the same. For clinical reliability, utilize only appropriately labeled products or obtain the assay procedures from each of the manufacturers. If possible, compare competitor products by assays performed in an independent laboratory.
CLINICAL APPLICATIONS Historically, enzyme therapy has been used in a wide variety of applications, ranging from the classic substitution of enzymes for intestinal deficiency to the centuries-old external application of enzymes to treat wound-healing disturbances (e.g. leg ulcers). Enzymes have been used individually or in complex enzyme mixtures. Clinical uses of individual enzymes can be seen in Tables 101.2 , 101.3 , 101.4 , 101.5 , 101.6 . TABLE 101-2 -- Clinical applications of chymotrypsin • In debridement, treatment of abscesses and ulcerations, liquefaction of mucous secretions [38] • In ophthalmic cataract surgeries and therapy of eyeball hematomas and ophthalmorrhagias [38] [39] • Before and after tooth extraction as well as in operative dentistry [40] [41] • After episiotomy surgeries [42] • As an anthelmintic against enterozoic worms [43] • In early recognition of tumor cells
[44]
• In histologic gastroenteric diagnostics
[45]
• In inflammatory conditions (local and systemic) to promote the dispersion of blood extravasates and effusions from fractures [39] [46] [47] [48] [49] [50] [51] [52] [53] • Surgical trauma[42] [51] • Sporting injuries [46] [47] [48] [49] [50] • Accidental soft tissue trauma [46] [47] [48] [49] [50] [53] • Intervertebral disc lesions [54] • In uveitis vitreous hemorrhage, diabetic retinopathy and asthmatic symptoms [55]
TABLE 101-3 -- Clinical applications of trypsin • In debridement of necrotizing wounds, ulcerations, abscesses, empyemas, hematomas, fistulas, and decubitus [56] [57] [58] [59] • To accelerate healing in injuries, inflammations, phlogistic edemas and traumatic changes
[46] [47] [48] [49] [ 50] [51] [ 52] [53]
• As an auxiliary agent in meningitis therapy [60] • As an ointment or dressing (wet or dry)
[1]
• As a liquid or an aerosol to liquefy sputum in bronchial disorders and in the preparation of sputum for cytological examination
[ 1]
• As an anti-inflammatory agent, oily suspensions are injected intramuscularly [1] • As an aid in the treatment of intraocular hemorrhage, thrombophlebitis, intestinal obstruction (due to cirrhosis or carcinoma)
[61]
TABLE 101-4 -- Clinical applications of amylase (needs calcium ions for enzymatic activity) • Acts on starch, glycogen and related poly- and oligosaccharides [5] • In combination with other enzymes, as a digestant [38] [62] [63] • As an anti-inflammatory[62] • In treatment of deficiencies of exocrine pancreas, amylaceous dyspepsia and cystic fibrosis [1]
TABLE 101-5 -- Clinical applications of lipase • In pancreatin-containing remedies to increase pancreatic/lipolytic activities (replacement therapy) [64] [65] [66] [67] • When given with pancreatin, it reduces fat level in stools [68] [69] [70] • Synergistically intensifies the activity of lipoproteid-lipase in the blood
[71]
and migration of agranulocytes
[ 72]
• As a digestive aid[70]
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TABLE 101-6 -- Clinical applications of pancreatin • In pancreatic insufficiency, inadequate secretion of exocrine pancreas, disturbed digestion and after gastrectomy
[ 65] [73] [74] [75] [76] [ 77] [78] [ 79] [80] [ 81] [82] [ 83] [84] [ 85]
• In chronic pancreatitis [86] • Post-pancreatectomy[1] [86] • Ductal obstruction from neoplasm (e.g. of the pancreas or common bile duct) [86] • To treat severe cases of steatorrhea (as found in cystic fibrosis patients)
[87] [88] [89] [90] [ 91]
Inflammatory diseases
One of the basic concepts in systemic enzyme therapy is that all kinds of inflammatory processes (from sports injuries to arthritis to sinusitis to fibrocytis) respond to enzymes. The following is the postulated mechanism of action: 1. In the damaged area, various repair mechanisms are activated, resulting, among other effects, in fibrin surroundng the traumatized region. 2. After having been partly or completely sealed off by microthrombi, blood vessels become highly permeable, and the injured area is disconnected from the normal circulatory system. Stasis results, inhibiting the repair processes. 3. Supplemental enzymes, after absorption, are bound in complexes (e.g. alpha-2-macroglobulin-hydrolase) and circulate to the injured area from the bloodstream. 4. Hydrolytic enzymes directly attack the mircroclots breaking open the clogged vessels and re-establishing circulation. By restoring normal blood flow, post-inflammatory pain and edema are reduced more rapidly and, equally important, the important physiological inflammatory repair
process is not blocked or diminished (as with anti-inflammatory agents), but rather accelerated and reinforced. Even inflammatory diseases, such as arthritis or herpes zoster, have been shown to respond to the systemic application of enzymes. [93] [94] [95] Despite the supportive research, the administration of enzymes in traumatology and injuries is not widely used. All types of injuries, e.g. sprains, strains, hematomas, dislocations, and even postoperative conditions can be effectively treated with enzymes. Individual enzymes and enzyme combinations (particularly ones including trypsin, chymotrypsin, pancreatin, amylase, lipase, papain, and bromelain, with rutin) are effective in treating inflammation because they help limit the injury, aid its rectification, and promote new, healthy tissue formation. They are inflammation activators, not inflammation inhibitors. Enzymes can accelerate the inflammatory process which is a necessary component of wound healing. This acceleration means, on the one hand, that the work of damage control, damage repair, and new tissue construction is carried out more actively, and thus completed more swiftly. On the other hand, it also means that there can be a temporary increase in the visual and sensory effects produced by the inflammation (i.e. more redness, swelling, heat, and pain). Since the inflammatory reaction is so universal, it appears that enzymes and enzyme mixtures can be effectively used to treat a wide variety of chronic disorders. Autoimmune and immune complex-mediated diseases
In autoimmune disease, tissue-bound immune complexes activate the complement system. Activation of the enzyme cascade results in an intense protein-destroying inflammatory response, leading to significant local tissue destruction. For instance, when immune complexes collect in the kidneys, complement activation causes inflammation, resulting in glomerulonephritis. Research shows that some enzymes can inhibit immune complex-mediated diseases, such as glomerulonephritis, by interrupting the complement cascade. Other disorders with similar mechanisms also respond to supplemental enzymes. Some are conditions, such as Crohn’s disease, pulmonary fibrosis, chronic rheumatism, and ankylosing spondylitis, which have not responded well to conventional medical treatments. Cardiovascular disorders
Cardiovascular disease, the number one killer in the US, kills nearly one in every two Americans. In 1988, heart and blood vessel diseases killed nearly 1 million Americans, almost as many as cancer, accidents, pneumonia, influenza, and all other causes of death combined. But cardiovascular disease is not limited to the elderly; nearly 175,000 Americans under the age of 65 die from this disease every year. [96] In normal circulation, there is a constant dynamic balance between blood clotting and fibrinolysis. [97] If fibrinolysis is impaired, abnormal clot formation occurs. If fibrinolysis increases, a tendency toward excessive bleeding results. Therefore, maintenance of proper equilibrium is extremely important for the circulatory system. One study examined the effects of various enzyme combinations on fibrinolysis and fibrin formation. The researchers induced fibrin deposition with calcium ions or staphylocoagulase in the plasma of centrifuged, acellular citrated blood from humans or rabbits and treated the clot with various concentrations of enzyme suspensions. The clots were degraded more rapidly the higher the enzyme content of the solution. [98] [99]
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Combination enzyme therapy Because trypsin, chymotrypsin, lipase, and amylase are substrate-specific, combinations of enzymes are frequently employed for a broader spectrum of activity. In addition, when combined, some enzymes act synergistically with others – hence the use of pancreatin (from animal pancreas), as well as products which include both enzymes from different sources and activating substances. For example, one German product contains an enzyme extract consisting of proteinases, triacylglycerol lipase, and a-glycosidase (amylase), minor amounts of elastase, nuclease, and carboxypeptidase, and Ca 2 + ions to increase activity. Enzyme combinations should not be viewed as simply intensified forms of pancreatin. An enzyme combination has a number of therapeutic advantages as opposed to a preparation with only one or two components. Combining enzymes from diverse sources, i.e. animal, plant, and fungi, results in a wider range of optimal pH, synergism of the combined enzymes, increased percentage of absorption, increased level of effectiveness, and broader range of application. Further, Streichhan states that enzyme combinations are better than single enzymes because: [92] • isoenzymatic activity differences of single biocatalysts are more readily balanced bycombining uniformly acting hydrolases of varying origins • giant molecular substrates are more quickly and more intensively fragmented by a multihydrolytic preparation because the differently acting hydrolases are able to simultaneously disintegrate the giant molecular substrates at many different locations • certain enzymatic mixtures have a broader range of action than pancreatin, bromelain, or any other standardized monohydrolytic preparation – this is because certain enzyme mixtures characteristically possess differences in optimal pH and also differences in reactive properties of the proteo-, lipo-, and/or glycolytic acting hydrolases. Enzyme therapy (hydrolytic enzymes from plants, animals, and fungi) combined with rutin is a proven method for treating a number of conditions, as seen in Table 101.7 .
DOSAGE Enzymes may be administered rectally, topically, orally, or by injection, depending on the condition being treated. Rectally, a retention implant or suppository is given. Topically, ointment is spread over the involved area. Orally, lozenges (dissolved in the mouth), oral tablets or enteric-coated tablets are used. TABLE 101-7 -- Clinical applications of enzyme combinations • Soft-tissue injuries
[100] [101]
• Sprained ankle [101] [102] [103] • Reabsorption of hematomas[100] [104] • Sports medicine [105] [106] [107] [108] [109] [110] [111] • Meniscectomy (pre and post operative therapy) [112] [113] • Traumatology[114] • Pancreatitis [115] • Surgery[100] [116] • Lower extremity bypass surgery[117] • Operative dentistry [118] • Proctology [119] • Sinusitis [120] [121] [122] [123] • Acute and chronic bronchitis [98] [124] [125]
• Cystitis and UTI (lower urinary tract infections) [120] [126] [127] • Prostatitis [120] [126] [128] • Pelvic inflammatory disease [129] [130] • Post-thrombotic syndrome [131] [132] [133] [134] [135] • Pathologic venous processes [131] [136] [137] [138] [139] [140] • Occlusive arterial disease [141] • Lymphedema[142] [143] [144] [145] [146] [147] • Soft tissue rheumatism (non-articular rheumatoid syndrome) [148] [149] • Rheumatoid arthritis (chronic polyarthritis)
[95] [99] [ 120] [124] [133] [144] [150] [151] [152] [153] [154] [155] [156] [ 157] [ 158] [ 159] [ 160] [ 161] [162] [163]
• Ankylosing spondylitis (Bekhterev’s disease) [101] [152] [153] [156] • Degenerative rheumatic joint disease
[108] [ 120]
• Monoarticular, activated osteoarthrosis
[108] [125] [164]
• Multiple sclerosis [98] [165] [166] [167] [168] [169] • HIV infections [170] [171] [172] [173] [174] • Fibrocystic breast disease [146] [175] • Ulcerative colitis and Crohn’s disease [120] [124] [176] [177]
A wide range in daily dosage has historically been used because: • there are individual differences in patient health • the level of effective absorption in tablet strength can vary • there are a wide variety of influencing ranges in pH • enzyme activity levels vary between products. For example, pancreatin dosage depends on the condition being treated, as well as the patient’s diet and digestive requirements. Dosage can vary because of pancreatin’s susceptibility to inactivation in the stomach and duodenum. [182] Table 101.8 indicates the composition of three enzyme combinations (“A”, “B”, and “C”), while Table 101.9 lists several conditions effectively treated with these products, the dose required, and the treatment period. TABLE 101-8 -- Composition of enzyme combinations (mg)[179] Enzyme
“A” “B” “C”
Pancreatin
100 100
Papain
60
60 100
Bromelain
45
45
0
Lipase
10
10
0
Amylase
10
10
0
Trypsin
24
24
40
Chymotrypsin
1
1
40
Rutin
50
0
0
Thymus extract
0
0
40
0
865
Condition
TABLE 101-9 -- Dosage programs for specific conditions Frequency × dosage Treatment period
Combination
Post-thrombotic syndrome[180]
3×5
As needed
A
Oncology[181]
2 × 11
6 weeks or as needed
A
Lymphedema[143]
2×5
2 years
A
Fibrocystic breast disease [174]
2 × 10
6 weeks or as needed
A
Experimental hematoma[100]
3 × 10
24 hours
A
Prophylactic treatment of karate injuries [182]
3×5
During the season
A
Trauma and meniscus operation[112]
3 × 10
Average of 17.7 days
A
Soft tissue injuries and distortions of the ankle [101]
3 × 10 initially, then 3 × 1
As needed
A
Athletic soft tissue injuries [104]
2×5
Spring football season
A
Dental surgery[118]
4×5
Day before surgery to 7th postoperative day
A
Sports injuries[107]
3 × 10
As needed
A
Chronic polyarthritis [183]
4×8
6 months
A
Active arthoses[184]
4×7
6 weeks
A
Extra-articular rheumatism[148]
3 × 10
As needed
B
Adnexitis[129]
3×5
10–14 days
A
Prostatitis[120] [126]
3×5
10 days
A
Mastopathy[185]
2 × 10
A
Multiple sclerosis [166] [167] [168] [169] [177] Initially
2 ampoules injection
Daily
C
As symptoms improve
2 ampoules injection
Every 2 to 3 days, then at longer intervals
C
On injection-free days
3 × 10
A
Later
3×5
A
Finally
3×3
A
Herpes zoster[94] Initially
2 ampoules injection
First 2 days
C
First two days
3–4 × 1
As indicated to 14 days
A
HIV[172] [173]
3 × 10*
As indicated
A
HIV
25/day
12 months
A
* Ongoing studies insufficient to give effective dose levels.
TOXICOLOGY Oral enzymes
In general, side-effects of orally administered enzymes are few and due primarily to excessive dosages or hypersensitivity reactions. According to Wolf & Ransberger, high dosages (70 tablets of 17.5 g each) of a proteolytic enzyme mixture have been given without long-term side effects. [187] Studies and literature searches commissioned by regulatory authorities such as the FDA have apparently confirmed that enzyme preparations obtained from suitable sources (e.g. non-toxic, non-pathogenic sources) are safe to consume. 188 With normal use, stools can be pale or have a pungent odor. Transient intestinal upset, such as diarrhea and gas, may result from excessive dosage of pancreatin. Hyperuricosuria (excess uric acid in the urine) and hyperuricemia (excess uric acid in the blood) have been associated with extremely high doses of exogenous pancreatic enzymes. If the pancreatin preparations are held in the mouth before swallowing, stomatitis can result, as well as ulcerations, and irritation of the mucosa, particularly in infants where pancreatin may also cause perianal soreness. [1] [178] It is not known whether pancreatin given to pregnant woman can harm the fetus since animal reproductive studies have not been conducted. Therefore, pancreatin should probably not be used during pregnancy. [178] Also, since it is not known if pancreatin is distributed into mother’s milk, caution should be exercised with nursing women.[178] Sneezing, lacrimation, rash and other hypersensitivity reactions have been reported in sensitive individuals. Pancrelipase (and any other enzyme derived from pork sources) is contraindicated in those who are hypersensitive or allergic to pork products. Enzymes should not be used by hemophiliacs, nor immediately before or after operations with an increased risk of bleeding. Trypsin is especially contraindicated in those with blood-clotting mechanism disorders, in liver disease, and as an aerosol within a week of pulmonary hemorrhage. [1] Enzyme enemas
Enzyme enemas can sometimes cause the rectum or anus to itch or burn. However, these are only minimal side-effects in relation to the positive benefits obtained. Topical application
Enzymatic activity directed toward proteinaceous components of the epithelium can cause irritation. For
866
example, prolonged skin contact with proteolytic enzymes may cause irritation of the skin, mucous membranes of the throat, nose, and eyes. 188 Injectable enzymes
Injectable forms require more care. Chymotrypsin, when injected, can occasionally create anaphylactic reactions. [1] When injected, trypsin’s toxicity is greatly increased, and rapid infusion is far more toxic than slower infusion. [1] In addition, trypsin must not be administered intravenously. [1] Further, intradermal or scratch testing is advised before parenteral administration. [1] Other contraindications to trypsin’s use are pork allergy and pancreatitis. It should be remembered that, at the beginning of therapy, an individual’s symptoms may occasionally increase in severity. This is a sign that a therapeutic reaction is occurring and should be evaluated positively. The medication need not be discontinued, although a temporary reduction in dose might be advisable.
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K. Enzymtherapie bei chronischer polyarthritis. Der Kassenarzt 1989; 46
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K. Rheumabahandlung mit enzymen ist mehr als nur antiphlogistische therapie. Lecture given at 17th Systemische Enzymtherapie Symposium, Vienna, Austria, 1991
162. Klein
G, Schwann H, Kullich W. Enzymtherapie bei chronischer polyarthritis. Natur-und Ganzheitsmedizin 1988; 1: 112
163. Klein
K. Behandlung der rheumatoiden arthritis mit Wobenzym
164. Singer
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im vergleich zur basistherapie mit gold. Lecture given at 17th Systemische Enzymtherapie Symposium, Vienna, Austria, 1991
F. Aktivierte arthrosen knorpelschonend behandeln. Lecture given at 10th Systemische Enzymtherapie Symposium, Frankfurt, Germany, 1990
165. Masuhr
KF. Eurologie. Stuttgart: Hippokrates. 1989
166. Neuhofer
CH, van Schaik W, Stauder G, Pollinger W. Pathogenetic immune complexes in MS: their elimination by hydrolytic enzymes. A therapeutic approach. International Multiple Sclerosis Conference, Rome. Bologna: Monduzzi Editore SPA. 1988 167. Ransberger
K, van Schaik W. Enzymtherapie bei multipler sklerose. Der Kassenarz, 1986; 41: 42
168. Neuhofer
CH. Enzymtherpie bei multipler sklerose. Hufeland J 1986; 47
169. Neuhofer
CH. Systemische enzymtherapie bei encephalomyelitis disseminata. Der Prakt Arzt 1991; 702
170. Dirringer 171. Inderst
H. Unkonventionelle viruserkrankungen. Bundesgesundhbl 1990; 33: 188
R, Ransberger K, Brand G. Fortschritte in der therapie der erworbenen immunschwache durch naturheilkundliche methoden. Naturheilpraxis 1988; 41: 1050
172. Jager
H, Popescu M, Samtleben W, Stauder G. Hydrolytic enzymes as biological response modifiers (BRM) in HIV-infection. In: San Marino Conferences – highlights in medical virology, immunology and oncology, vol. 1. Oxford: Pergamon Press. 1988 173. Jager
H. Hydrolytische enzyme in der therapie der hiv-erkrankung. Zeitschr Allgemeinmedizin 1990; 19: 160
174. Ransberger
K. Naturheilkundliche therapie von AIDS mit enzympraparaten. Forum des Prakt und Allgemeinarztes 1988; Heft 4. 27, Jahrgang, April 1988
175. Scheef
W. Gutartige veranderungen der weiblichen brust. Therapiewoche 1985; 5090
176. Inderst
R. Colitis ulcerosa und morbus crohn systemische enzymtherapie, medizinische woche Baden-Baden, 1990. Natur-und Ganzheitsmedizin 1991; 2: 28
177. Neuhofer
CH. Autoimmunerkrankungen. Multiple sklerose, amyotrophe lateralsklerose, colitis ulcerosa. Erfahrungsheilkunde, 1988; 38: 451
178. McEvoy
GK, ed. AHFS ‘94 Drug Information, American Hospital Formulary Service. Bethesda, MD: American Society of Hospital Pharmacists. 1994: p 20 814
179. Stauder
G, Pollinger W, Fruth C. Systemische Enzymetherapie. Eine Ubersicht uber Neue Klinische Studient. Allgemein Medizin 1990; 19: 188–191
180. Inderst 181. Wrba
R. Enzymtherapie bei Gefasserkrankungen [Enzyme Therapy in Vascular Diseases]. Allgemein Medizin 1990; 19: 154–157
H. Kombinierte tumortherapie. Stuttgart: Hippokrates. 1992
182. Worschhauser
S. Konservative Therapie der Sportverletzungen. Enzympraparate fur Therapie und Prophylaxe [Conservative Therapy for Sports Injuries. Enzyme Preparations for Therapy and Prophylaxis]. Allgemein Medizin 1990; 19: 173–177 183. Klein
G, Pollmann G, Kullich W. Klinische Erfahrungen mit der Enzymtherapie bei Patienten mit Chronischer Polyarthritis im Vergleich Zur Oralen Goldtherapie [Clincal experience with enzyme therapy in patients with rheumatoid arthritis in comparison with oral gold]. Allgemein Medizin 1990; 19: 144–147 184. Gallacchi
G. Der Einsatz Hydrolytischer Enzyme bei der Aktivierten Arthrose [The Use of Hydrolytic Enzymes in Activated Arthrosis]. Allgemein Medizin 1990; 19: 148–150
185. Dittmar 186. Sears 187. Wolf
F-W, Luh W, Phillipp E. Wobenzym
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zur Behandlung der Mastopathie. Working paper. 1993
A, Walsh G. Biotechnology in the feed industry: proceedings of alltech’s ninth annual symposium. Nicholasville, KY: Alltech Technical Publ. 1993
M, Ransberger K. Enzyme therapy. Los Angeles: Regent House. 1972
FURTHER READING Cichoke AJ. Enzymes and enzyme therapy: how to jump start your way to lifelong good health. New Canaan, CT: Keats. 1994 Cichoke AJ. Acute trauma and systemic enzyme therapy. Portland, OR: Seven C’s Publ. 1993 Cichoke AJ. A new look at chronic disorders and enzyme therapy. Portland, OR: Seven C’s Publ. 1993 Cichoke AJ. A new look at enzyme therapy. Portland, OR: Seven C’s Publ. 1993
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Chapter 102 - Phage therapy: bacteriophages as natural, self-limiting antibiotics * Elizabeth Kutter PhD
INTRODUCTION Phage therapy involves the use of specific viruses – viruses that can attack only bacteria – to kill pathogenic microorganisms. The art was first developed early in this century, but since the advent of chemical antibiotics in the 1940s, it has been little used in the West. Today, however, the growing incidence of bacteria which are resistant to most or all available antibiotics is leading to widespread renewed research interest in the possibilities of phage therapy. [1] [2] [3] [4] Most of the recent articles appearing in the West reflect little knowledge of the extensive Eastern European research and clinical utilization of phage therapy. The good clinical results of Eastern European research provide a substantial basis for optimism and complement the limited recent animal work in the West. We need to draw as much as possible on the largely unknown body of knowledge that has accumulated in Poland and the former Soviet Union as we again explore phage therapy, and to give credit where it is due for the many years of hard, careful work in the field. This chapter has been written in order to put phage therapy into historical and ecological context and to explore some of the most interesting and extensive research in Eastern Europe. * Special thanks to Drs Liana Gachechiladze, Zemphira Alavidze, Amiran Meipariani, Taras Gabisonia, Mzia Kutateladze, Rezo Adamia, Teimuraz and Nino Chanishvili and their colleagues at the Bacteriophage Institute, Tbilisi, for their hospitality and efforts to help me understand the extensive therapeutic work carried out there. Others who have been particularly helpful with information and communication include Dr Marina Shubladze, pediatrician in Tbilisi for 10 years, now residing in Seattle; Nino Mzavia, Nino Trapaidze, Timur and Natasha Zurabishvili, who have worked in my laboratory; Bill Summers (Yale), Hans-Wolfgang Ackermann (Laval University), Eduard Kellenberger (Basel) and Bruce Levin (Emory); Kathy d’Acci, clinical laboratory director, St Peter’s Hospital, Olympia; physicians Jess Spielholz MD, and Robin Moore ND; and, especially, the many colleagues and students involved in our laboratory in Olympia, particularly Barbara Anderson, Pia Lippincot, Mark Mueller, Stacy Smith, Elizabeth and Chelsea Thomas and Jim Neitzel.
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HISTORIC CONTEXT Discovery A century ago, Hankin [5] reported that the waters of the Ganges and Jumna rivers in India had a marked antibacterial action which could pass through a porcelain filter, an antibacterial activity destroyed by boiling. He particularly studied the water’s effects on Vibrio cholerae and suggested that the substance responsible was what kept cholera epidemics from being spread by ingestion of the water of these rivers. However, he did not explore the phenomenon further. Edward Twort and Felix d’Herelle independently reported isolating filterable entities capable of lysing bacterial cultures and of producing small cleared areas on bacterial cultures, implying that discrete particles were involved. [6] They are jointly given credit for the discovery of bacteriophages. Early research It was d’Herelle, a Canadian working at the Pasteur Institute in Paris, who gave these newly discovered organisms the name bacteriophages– using the suffix phage “not in its strict sense of to eat, but in that of developing at the expense of”.[7] He carefully characterized them as viruses which multiply in bacteria and worked out the details of infection of different bacterial hosts by various phages under a variety of environmental conditions. The 90th Annual Meeting of the British Medical Association in Glasgow featured a very interesting discussion among d’Herelle, Twort and several other eminent scientists of the day on the nature and properties of bacteriophages. The main question was whether the observed bacteriolytic principle was an enzyme produced by bacterial activity or a form of tiny virus. Gradually, it became clear that it is indeed viral in nature, able to reproduce and direct the synthesis of its own enzymes. D’Herelle summarized the early phage work in a 300 page book, The Bacteriophage. [7] He wrote classic descriptions of plaque formation and composition, infective centers, the lysis process, host specificity of adsorption and multiplication, the dependence of phage production on the precise state of the host, isolation of phages from sources of infectious bacteria, and the factors controlling stability of the free phage. He quickly became fascinated with the apparent role of phages in the natural control of microbial infections. He noted, for example, the frequent specificities of the phages isolated from recuperating patients for disease organisms infecting them and the rather rapid variations over time of the phage populations. Throughout his life, he worked to develop the therapeutic potential of properly selected phages against the most devastating health problems of the day. However, he initially focused on simply understanding phage biology. Thus, the first known report of successful phage therapy came from Bruynoghe & Maisin, [8] who used phage to treat staphylococcal skin infections. After much travel, including the study of epidemics in Latin America and a year at the Pasteur branch in Saigon, d’Herelle left the Pasteur Institute in 1922. He worked in Holland and then became employed as a health officer by the League of Nations, based in Alexandria, Egypt. Phage therapy and sanitation measures were the primary tools in his arsenal to deal with major outbreaks of infectious disease throughout the Middle East and India. In 1928, he was invited to Stanford to give the prestigious Lane lectures; his discussions were published as the monograph, The Bacteriophage and its Clinical Applications. [9] He gave many lectures for medical schools and societies as he crossed the country. He accepted a regular faculty position at Yale, where he was supported by George Smith who had translated his first two books into English. He continued to spend summers in Paris working with the phage company he had established there and returned permanently to France in 1933. George Eliava, director of the Georgian Institute of Microbiology, saw bacteriocidal action of the water of the Koura river in Tbilisi (Tiflis) which he could not explain until d’Herelle’s bacteriophage work was published. Eliava then spent 1920–21 at the Pasteur Institute and was a very early collaborator of d’Herelle’s; several phage papers of his are cited in d’Herelle. [7] The two developed the dream of founding an Institute of Bacteriophage Research in Tbilisi – to be a world center of phage therapy for infectious disease, including scientific and industrial facilities and supplied with its own experimental clinics. The dream quickly became a reality due to the support of Sergo Orjonikidze, the People’s Commissar of Heavy Industry, despite KGB opposition to this “foreign project”. A large campus on the river Mtkvari was allotted for the project in 1926. D’Herelle sent supplies, equipment and library materials. In 1934 and 1935, he visited Tbilisi for a total of 6 months and wrote a book on The Bacteriophage and the Phenomenon of Recovery ,[10] which was translated into Russian by Eliava. D’Herelle intended to move to Georgia; in fact, a cottage built for his use still stands on the institute’s grounds. However, in 1937, Eliava was arrested as a “people’s enemy” by Beria, then head of the KGB in Georgia and soon to direct the Soviet KGB as Stalin’s much-feared henchman. Eliava was soon executed, sharing the tragic fate of many Georgian and Russian progressive intellectuals of the time, and d’Herelle, disillusioned, never returned to Georgia. However, their institute survived and is still functioning at its original site on the Mtkvari (which it now shares with the more modern Institutes of Molecular Biology & Biophysics and of Animal Physiology). In 1938, the Bacteriophage Institute was merged with the Institute of Microbiology & Epidemiology, under the direction of the People’s Commissary of Health of
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Georgia. In 1951, it was formally transferred to the All-Union Ministry of Health set of Institutes of Vaccine and Sera, taking on the leadership role in providing bacteriophages for therapy and bacterial typing throughout the former Soviet Union. Under orders from the Ministry of Health, hundreds of thousands of samples of pathogenic bacteria were sent to the institute from throughout the Soviet Union to isolate more effective phage strains and to better characterize their usefulness. In
1988, an official Scientific Industrial Union “Bacteriophage” was formed, centered in Tbilisi with branches in Ufa, Habarovsk and Ghorki. Initial attempts at commercialization From the beginning, a major commercial use of phages has been for bacterial identification through a process called phage typing – the use of patterns of sensitivity to a specific battery of phages to precisely identify microbial strains. This technique takes advantage of the fine specificity of many phages for their hosts and is still in common use around the world. However, the sophisticated ability of phages to destroy their bacterial hosts can also have a very negative commercial impact; phage contaminants occasionally spread havoc and financial disaster for the various fermentation industries that depend on bacteria, such as cheese production and fermentative synthesis of chemicals.[11] Phage therapy has been evaluated extensively, with many successes being reported for a variety of diseases, including dysentery, typhoid and paratyphoid fevers, pyogenic and urinary-tract infections and cholera. Phages have been given orally, through colon infusion, as aerosols, and poured directly in lesions. They have also been given as injections: intradermal, intravascular, intramuscular, intraduodenal, intraperitoneal, and even into the lung, carotid artery and pericardium. The early strong interest in phage therapy is reflected in some 800 papers published on the topic between 1917 and 1956. These have been reviewed in some detail by Ackermann & Dubow.[12] The reported results were quite variable. Many of the physicians and entrepreneurs who initially became excited by the potential clinical implications jumped into applications with very little understanding of phages, microbiology or basic scientific process. Thus, many of the studies were anecdotal and/or poorly controlled; many of the failures were predictable, and some of the reported successes did not make much scientific sense. Often, uncharacterized phages, at unknown concentrations, were given to patients without specific bacteriological diagnosis, and there is no mention of follow-up, controls or placebos. Much of the understanding gained by d’Herelle was ignored in this early work, and inappropriate methods of preparation, “preservatives” and storage procedures were often used. On one occasion, d’Herelle reported testing 20 preparations from various companies and finding that not one of them contained active phages! On another occasion, a preparation was advertised as containing a number of different phages, but it turned out that the technician responsible had decided it was easier to grow them up in one large batch than in separate batches. Not surprisingly, checking the product showed that one phage had outcompeted all the others, and this was not, in fact, a polyvalent preparation. In general, there was no quality control except in a few research centers. Large clinical studies were rare, and the results of those that were carried out were largely inaccessible outside of Eastern Europe. Specific problems of early phage therapy work In the 1940s, the new “miracle” antibiotics such as penicillin became widely available, and phage therapy was largely abandoned in the Western world. Many believe (erroneously) that it was proven not to work; however, it simply was never adequately researched. It is thus important to carefully consider the reasons for the early problems and the question of efficacy. These included: • paucity of understanding of the heterogeneity and ecology of either the phages or the bacteria involved • failure to select phages of high virulence against the target bacteria before using them in patients • use of single phages in infections which involved mixtures of different bacterial species and strains • emergence of resistant bacterial strains – this can occur by selection of resistant mutants (a frequent occurrence if only one phage strain is used against a particular bacterium) or by lysogenization (if temperate phages are used, as discussed below) • failure to appropriately characterize or titer phage preparations, some of which were totally inactive • failure to neutralize gastric pH prior to oral phage administration • inactivation of phages by both specific and non-specific factors in bodily fluids • liberation of endotoxins as a consequence of widespread lysis of bacteria within the body (the Herxheimer reaction) – this can lead to toxic shock (which can also be caused by antibiotics) • lack of availability or reliability of bacterial laboratories for carefully identifying the pathogens involved (necessitated by the relative specificity of phage therapy).
BACTERIOPHAGE PHYSIOLOGY Viruses are like spaceships that are able to carry genetic material between susceptible cells and then reproduce
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Figure 102-1 Phage diagram (bacteriophage T4).
in those cells, just as HIV specifically infects human T-lymphocytes which carry the CD-4 surface protein. In the case of bacteriophages, the targets are specific kinds of bacterial cells – they cannot infect the cells of more complex organisms. Each virus consists of a piece of genetic information, determining all of the properties of the virus, which is carried around packaged in a protein coat ( Fig. 102.1 ). Most phages have tails, the tips of which have the ability to bind to specific molecules on the surface of their target bacteria ( Fig. 102.2 ). The viral DNA is then ejected through the tail into the host cell, where it directs the production of progeny phages – often over 100 are produced in just half an hour. Each strain of bacteria has characteristic protein, carbohydrate and lipopolysaccharide molecules present in large quantities on its surface. These molecules are involved in forming pores, motility, and binding of the bacteria to particular surfaces. Each such molecule can act as a receptor for particular phages. Development of resistance to a particular
Figure 102-2 Electron micrograph of phage infecting a bacterium.
phage generally reflects mutational loss of its specific receptor; this loss often has negative effects on the bacterium and does not protect it against the many other phages which use different receptors. Each kind of bacterium has its own phages, which can be isolated wherever that bacterium grows: from sewage, feces, soil, even ocean depths and hot springs. The process of isolation is easy. The sample is placed in an appropriate salt solution; the supernate is separated, and then passed through a filter with a pore size small enough to remove the bacteria. The solution is then mixed (at several different dilutions) with a culture of the bacteria in question. A few drops are spread on a block of appropriate nutrient-agar medium. The next day, a dense lawn of bacteria is seen, dotted with round cleared areas called “plaques”. Each plaque contains about a billion phages, all of them progeny of a single initial phage which multiplied at a high rate and destroyed the bacteria there in the process. An individual plaque is then transferred to a fresh culture of the bacteria in a liquid medium, allowing the culturing of a homogeneous stock of that particular phage, whose properties can then be studied. Properties of phages
One major source of confusion in the early phage work was the perception that all phages were fundamentally similar, though subject to adaptive change depending on the recent conditions of growth. One consequence of this was that often new phages were isolated for each series of experiments, so there was little continuity or basis for comparison. Phages specific for virtually every known bacterial species have been isolated, but few have been well classified. A second early source of confusion affecting therapeutic uses was the question of whether the lytic principle termed “bacteriophage” simply reflected an inherent property of the specific bacteria or required regular reinfection by an external agent. During the 1930s and 1940s, it became increasingly clear that in some senses both were true – that there were in fact two quite fundamentally different groups of bacteriophages. Lytic phages always have to infect from outside, reprogram the host cell and release a burst of phage through breaking open, or lysing, the cell after a relatively fixed interval. Lysogenic phages, on the other hand, have another option. They can actually integrate their DNA into the host DNA, much as HIV can integrate the DNA copy of its RNA. Key technical developments that helped to clarify the general nature and properties of bacteriophages included: • the concentration and purification of some large phages by means of very high-speed centrifugation and the demonstration that they contained equal amounts of DNA and protein[13] 875
• visualization of phages by means of the electron microscope (EM). [14] [15] Soon after, Ruska[12] reported the first attempts to use the EM for phage systematics. [16] This has since become a key tool of the field. [12] Each phage was found to have its own specific shape and size, from the “lunar lander”-style complexity of T4 and its relatives to the globular heads with long or short tails of lambda and T7, to the small filamentous phages that looked much like bacterial pili (see Fig. 102.3 ). Lytic phages
A much better understanding of the interactions between lytic phages and bacteria began with one-step growth curve experiments. [17] [18] These demonstrated an eclipse period during which the DNA began replicating, and there were no free phages in the cell; a period of accumulation of intracellular phages; and a lysis process which released the phage to go in search of new hosts. This phage infection cycle is outlined in Figure 102.4 . In 1943, an event happened which was to have a major impact on the orientation of phage research in the United States and much of western Europe, strongly shifting the emphasis from practical applications to basic science. Physicist-turned-phage biologist Max Delbrueck met with Alfred Hershey and Salvador Luria and formed the “Phage Group”, which eventually expanded largely through the influence of the summer “Phage Course” at Cold Spring Harbor, Long Island, in 1945. Their influence
Figure 102-3 Various phages.
on the origins of molecular biology has been well documented. [19] [20] A major element of the successes of phages as model systems for working out fundamental biological principles was that Delbrueck convinced most phage biologists in the United States to focus on one bacterial host ( E. coli B) and seven of its lytic phages. These were arbitrarily chosen and named T(type)1–T7. As it turned out, T2, T4 and T6 were quite similar to each
Figure 102-4 Bacteriophage intracellular growth cycle. Noteworthy features: nucleolytic action on host chromosome furnishes DNA precursors; replicating DNA is much longer than virion DNA; several phage-coded proteins become associated with the host membrane; maturation of phage head occurs at a membrane site.
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other, defining a family now called the “T-even phages”. These phages were key in demonstrating that DNA is the genetic material, that viruses can encode enzymes, that gene expression is mediated through special copies in the form of “messenger RNA”, that the genetic code is triplet in nature, and many other fundamental concepts. The negative side of this strong focus on a few phages growing under rich laboratory conditions, however, was that there was very little study or awareness of the ranges, roles and properties of bacteriophages in the natural environment. Lysogenic phages
The integration of lysogenic phage DNA into the host DNA leads to virtually permanent association as a prophage with a specific bacterium and all its progeny. The prophage directs the synthesis of a repressor, which blocks the reading of the rest of its own genes and also those of any closely related lysogenic phages – a major advantage for the bacterial cell, protecting it from infection by a significant class of phages and giving it a potential weapon against many competing bacteria. Occasionally, a prophage escapes from regulation by the repressor, cuts its DNA back out of the genome by a sort of site-specific recombination and goes ahead to make progeny phage and lyse open the cell. Sometimes the cutting-out process makes mistakes, and a few bacterial genes get carried along with the phage DNA to its new host; this process, called transduction, plays a significant role in bacterial genetic exchange. Such lysogenic phages are bad candidates for phage therapy, due both to their mode of inducing resistance and to the fact that they can potentially lead to transfer of genes involved in bacterial pathogenicity; this is discussed in more detail below. However, their specificity often makes them very useful for phage typing in distinguishing between bacterial strains.
CLINICAL APPLICATION Current research The growing understanding of phage biology has the potential to facilitate more rational thinking about the therapeutic process and the selection of therapeutic phages. However, there was generally little interaction between those who were so effectively using phages as tools to understand molecular biology and those working on phage ecology and therapeutic applications. Many in the latter group were spurred on by a concern about the increasing incidence of nosocomial infections and of bacteria resistant against most or all known antibiotics. This is particularly true in Poland, France and the former Soviet Union where use of therapeutic phages never fully died out and where there has been some ongoing research and clinical experience. In France, Dr Jean-Francois Vieu led the therapeutic phage efforts until his retirement some 10 years ago. He worked in the Service des Entirobactiries of the Pasteur Institute in Paris and, for example, prepared Pseudomonas phages on a case-by-case basis for patients. The experience there is discussed in Vieu [21] and Vieu et al. [22] Phage therapy was used extensively in many parts of eastern Europe as a regular part of clinical practice, and there is now a company in Moscow making phage for this purpose. However, most of the research and much of the phage preparation came under the direction of key centers in Tbilisi, Georgia, and Wroclaw, Poland. These two groups are discussed below.
Institute of Immunology and Experimental Medicine, Polish Academy of Sciences
The most detailed publications documenting phage therapy have come from Stefan Slopek’s group at the Institute of Immunology and Experimental Medicine, Polish Academy of Sciences, Wroclaw. They published a series of extensive papers describing work carried out from 1981 to 1986 with 550 patients. [23] [24] [25] This set of studies involved 10 Polish medical centers, including the Wroclaw Medical Academy Institute of Surgery Cardiosurgery Clinic, Children’s Surgery Clinic and Orthopedic Clinic, the Institute of Internal Diseases Nephrology Clinic, and Clinic of Pulmonary Diseases. The patients ranged in age from 1 week to 86 years. In 518 of the cases, phage use followed unsuccessful treatment with all available other antibiotics. The major categories of infections treated were: • long-persisting suppurative fistulas • septicemia • abscesses • respiratory tract suppurative infections and bronchopneumonia • purulent peritonitis • furunculosis. In a final summary paper, the authors carefully analyzed the results with regard to such factors as nature and severity of the infection and monoinfection versus infection with multiple bacteria. [25] Rates of success ranged from 75 to 100% (92% overall), as measured by marked improvement, wound healing, and disappearance of titratable bacteria; 84% demonstrated full elimination of the suppurative process and healing of local wounds. Infants and children did particularly well. Not surprisingly, the poorest results came with the elderly and those in the final stages of extended serious illnesses, two groups with weakened immune systems and generally poor resistance. The bacteriophages all came from the extensive collection of the Bacteriophage Laboratory of the Institute of
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Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw. In the later studies, some of the specific phages were named. All were virulent, capable of completely lysing the bacteria being treated. In the first study alone, 259 different phages were tested (116 for S taphylococcus, 42 for Klebsiella, 11 for Proteus, 39 for Escherichia, 30 for Shigella, 20 for Pseudomonas, and one for Salmonella); 40% of them were selected to be used directly for therapy. All of the treatment was in a research mode, with the phage prepared at the institute by standard methods and tested for sterility. Treatment generally involved 10 ml of sterile phage lysate orally half an hour before each meal, with gastric juices neutralized by taking (basic) Vichy water, baking soda or gelatum. In addition, phage-soaked compresses were generally applied three times a day where dictated by localized infection. Treatment ran for 1.5–14 weeks, with an average of 5.3. For intestinal problems, short treatment sufficed, while long-term use was necessary for such problems as pneumonia with pleural fistula and pyogenic arthritis. Bacterial levels and phage sensitivity were continually monitored, and the phage(s) were changed if the bacteria lost their sensitivity. Therapy was generally continued for 2 weeks beyond the last positive test for the bacteria. Few side-effects were observed; those that were seen seemed to be directly associated with the therapeutic process. On about days 3–5, pain in the liver area was often reported, lasting several hours. The authors suggested that this might be related to the extensive liberation of endotoxins as the phage is destroying the bacteria most effectively. In severe cases with sepsis, patients often ran a fever for 24 hours on about days 7–8. [23] Various methods of administration were successfully used, including oral, aerosols and infusion rectally or in surgical wounds. Intravenous administration was not recommended for fear of possible toxic shock from bacterial debris in the lysates. [23] However, it was clear that the phages readily entered the body from the digestive tract and multiplied internally wherever appropriate bacteria were present, as measured by their presence in blood and urine as well as by therapeutic effects. [26] This interesting and rather unexpected finding has been replicated in many studies and systems. [27] [28] [29] [30] Detailed notes were kept throughout on each patient. The final evaluating therapist also filled out a special inquiry form that was sent to the Polish Academy of Science research team along with the notes. The Computer Center at Wroclaw Technical University carried out extensive analyses of the data. They used the categories established in the WHO (1977) International Classification of Diseases in assessing results. They also looked at the effects of age, severity of initial condition, type(s) of bacteria involved, length of treatment and other concomitant treatments. The papers included many specific details on individual patients which helped to give some insight into the ways phage therapy was used, as well as an in-depth analysis of difficult cases. Bacteriophage Institute, Tbilisi
The most extensive and least widely known work on phage therapy was carried out under the auspices of the Bacteriophage Institute at Tbilisi, in the former Soviet republic of Georgia. According to various physicians there, phage therapy is part of the general standard of care, used especially extensively in pediatric, burn and surgical hospital settings. Phage preparation was carried out on an industrial scale, employing 700 people just before the break-up of the Soviet Union, and many tons of a variety of products were shipped throughout the former Soviet Union. They were available both over the counter and through physicians. The largest use was in hospitals, to treat both primary and nosocomial infections, alone or in conjunction with other antibiotics and particularly when antibiotic-resistant organisms were found. The military is still one of the strongest supporters of phage therapy research and development because they have proven so useful for wound and burn infections as well as for preventing debilitating gastrointestinal epidemics among the troops. From the institute’s inception, the industrial part was run on a self-supporting basis, while its scientific branch was government-supported. The latter included the electron microscope facility, permanent strain collection, laboratories studying phages of the enterobacteria, staphylococci and pseudomonads and formulating new phage cocktails, and groups involved in immunology, vaccine production, Lactobacillus work and other therapeutic approaches. It also carried out the very extensive studies needed for approval by the Ministry of Health in Moscow of each new strain, therapeutic cocktail and means of delivery. This careful study of the host range, lytic spectrum and cross-resistance properties of the phages being used was a major factor in the reported successes of the phage therapy work carried out through the institute. All of the phages used for therapy are lytic, avoiding the problems engendered by lysogeny. The problems of bacterial resistance were largely solved by the use of well-chosen mixtures of phages with different receptor specificities against each type of bacterium as well as of phages against the various bacteria likely to be causing the problem in multiple infections. The situation was further improved whenever the clinicians typed the pathogenic bacteria and monitored their phage sensitivity. Where necessary, new cocktails were then prepared to which the given bacteria were sensitive. Not infrequently, using a phage in conjunction with other antibiotics was shown to give better results than either the phage or the antibiotic alone. The depth and extent of the work involved are very
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impressive. For example, in 1983–85 alone, the institute’s Laboratory of Morphology and Biology of Bacteriophages carried out studies of growth, biochemical features and phage sensitivity on 2,038 strains of Staphylococcus, 1,128 of Streptococcus, 328 of Proteus, 373 of P. aeruginosa, and 622 of Clostridium received from clinics and hospitals in towns across the former Soviet Union. New broader-acting phage strains were isolated using these and other institute cultures and were included in a reformulation of their extensively used Piophage preparation; it now inhibited 71% of their Staphylococcus strains instead of 58%; 76% of Pseudomonas instead of 55%; 51% of E. coli instead of 11%; 30% of Proteus instead of 3%: 60% of Streptococcus instead of 38%; and 80% of Enterococcus instead of 3%. [31] In the years since, the formulation has continued to be improved based on further studies, and phages against Klebsiella and Acinetobacter have been isolated and developed into therapeutic preparations. One of the latest developments is their IntestiPhage preparation, which includes 23 different phages active against a range of enteric bacteria. A good deal of work has gone into developing and providing the documentation for Ministry of Health approval of specialized new delivery systems, such as a spray for use in respiratory tract infections, in treating the incision area before surgery, and in sanitation of hospital problem areas such as operating rooms. An enteric-coated pill was also developed, using phage strains that could survive the drying process, and accounted for the bulk of the shipments to other parts of the
former Soviet Union. Much of the focus in the last 12 years has been on combating nosocomial infections, where multi-drug-resistant organisms have become a particularly lethal problem and where it is also easier to carry out proper long-term research. Clinical studies of the effectiveness of the phage treatment and appropriate protocols were carried out in collaboration with a number of hospitals, but little has been published in accessible form. Zemphira Alavidze and her colleagues, who are currently doing most of the actual therapeutic development and clinical application, have manuscripts in preparation which describe their work in institutions such as the Leningrad (St Petersburg) Intensive Burn Therapy Center, the Academy of Military Medicine in Leningrad, the Karan Trauma Center, and the Kemerovo Maternity Hospital. Some of the most intensive studies were carried out in Tbilisi at the Pediatric Hospital, the Burn Center, the Center for Sepsis and the Institute for Surgery. Special mixtures were developed for dealing with strains causing nosocomial infections in various hospitals, and they were very effectively used in sanitizing operating rooms and equipment, water taps and other sources of spread of the infections (most of them involving predominantly Staphylococcus). The number of sites testing positive for the problem bacteria decreased by orders of magnitude over the several months of the trial at each site. Recent work in the West
Levin & Bull,[1] and Barrow & Soothill[4] have provided good reviews of much of the animal research carried out in Britain and the United States since interest in the possibilities of phage therapy began to resurface in the early 1980s. The results, in general, are in very good agreement with the clinical work described above in terms of efficacy, safety and importance of appropriate attention to the biology of the host–phage interactions, reinforcing trust in the reported extensive eastern European results. In Britain, Smith & Huggins [27] [28] carried out a series of excellent, well-controlled studies on the use of phages in systemic E. coli infections in mice and then in diarrhetic disease in young calves and pigs. For example, they found that injecting 10 [6] colony-forming units of a particular pathogenic strain intramuscularly killed 10 out of 10 mice, but none died if they simultaneously injected 10 [4] plaque-forming units of a phage selected against the K1 capsule antigen of that bacterial strain. This phage treatment was more effective than using such antibiotics as tetracycline, streptomycin, ampicillin or trimethoprim/ sulfafurazole. Furthermore, the resistant bacteria that emerged had lost their capsule and were far less virulent. In calves, they found very high and specific levels of protection. They had to isolate different phages for each of their pathogenic bacterial strains, since they did not succeed in isolating phages specific for more general pathogenicity-related surface receptors such as the K88 or K99 adhesive fimbriae, which play key roles in attachment to the small intestine. Still, the phage was able to reduce the number of bacteria bound there by many orders of magnitude and to virtually stop the fluid loss. The results were particularly effective if the phage was present before or at the time of bacterial presentation, and if multiple phages with different attachment specificities were used. Furthermore, the phage could be transferred from animal to animal, supporting the possibility of prophylactic use in a herd. If the phage was given only after the development of diarrhea, the severity of the infection was still substantially reduced, and none of the animals died. [30] Levin & Bull [1] carried out a detailed analysis of the population dynamics and tissue phage distribution of the 1982 Smith & Huggins [27] study, which can be helpful in assessing the parameters involved in successful phage therapy and its apparent superiority to antibiotics. They have gone on to do interesting animal studies of their own and conclude that phage therapy is at least well worth further study. [1] Barrow & Soothill[4] carried out a series of studies preparatory to using phages for infections of burns patients.
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Using guinea pigs, they showed that skin graft rejection could be prevented by prior treatment with phages against Pseudomonas aeruginosa. They also saw excellent protection of mice against systemic infections with both Pseudomonas and Acinetobacter when appropriate phages were used. [4] In the latter case, as few as 100 phages protected against infection with 10 [8] bacteria – several times the LD 50 ! Merrill et al [32] have carried out a series of experiments designed to better understand the interactions of phages with the human immune system, and have started a company called Exponential Therapeutics to explore the possibilities of phage therapy. Their published work has been with a lytic derivative of the lysogenic phage lambda – a poor choice for therapeutic use, as discussed above and below – but they have gathered some very interesting data about factors affecting interactions between phages and the immune system. Bacterial pathogenicity Most bacteria are not pathogenic; in fact, they play crucial roles in the ecological balance in the digestive system, mucous membranes and all body surfaces. They often actually help to protect against pathogens. This is one reason why broad-spectrum antibiotics have such a broad range of side-effects and why more narrowly targeted bacteriocidal agents would be highly advantageous. Interestingly, most of the serious pathogens are close relatives of non-pathogenic strains. Studies clarifying the mechanisms of pathogenesis at the molecular level have progressed remarkably in recent years, crowned by the determination of the complete sequence of (non-pathogenic) E. coli K12 and several other bacterial species, and extensive cloning and sequencing of pathogenicity determinants. Generally, a number of genes are involved, and these are clustered in so-called “pathogenicity islands”, or Pais, which may be 50,000– 200,000 base pairs long. They generally have some unique properties indicating that the bacterium itself probably acquired them as a sort of “infectious disease” at some time in the past, and then kept them because they helped the bacterium to infect new ecological niches where there was less competition. Many of these Pais are carried on small extrachromosomal circles of DNA called plasmids, which can also be carriers of drug-resistance genes. Others reside in the chromosome where they are often found embedded in defective lysogenic prophages which have lost some key genes in the process and cannot be induced to form phage particles. However, they can sometimes recombine with related infecting phages. Therefore, it makes sense to avoid using lysogenic phages or their lytic derivatives for phage therapy to avoid any chance of picking up and moving such pathogenicity islands. For bacteria in the human gut, pathogenicity involves two main factors: • the production of toxin molecules, such as shiga toxin (from Shigella and some pathogenic E. coli) or cholera toxin; these toxins modify proteins in the target host cells and thereby cause the problem • the acquisition of cell-surface adhesions which allow the bacterium to bind to specific receptor sites in the small intestine, rather than just moving on through to the colon. They also all contain the components of so-called type III secretion machinery, related to those involved in the assembly of flagella (for motility) and of filamentous phages, and instrumental in many plant pathogens. For all of the pathogenic enteric bacteria, the infection process triggers changes in the neighboring intestinal cells. These include degeneration of the microvilli, formation of individual “pedestals” cupping each bacterium above the cell surface, and, in the case of Salmonella and Shigella, induction of cell-signalling molecules that trigger engulfment of the bacterium and its subsequent growth inside the cell. Recently, E. coli O157 has been the subject of much concern, with contamination of such products as hamburgers and unpasteurized fruit juices leading to serious problems. Particularly in young children and the elderly, deaths have occurred from hemorrhagic colitis (bloody diarrhea) and from hemolytic-uremic syndrome, where the kidneys are affected. Antibiotic therapy has shown no benefit. [33] Our laboratory has found that the Jack-in-the-box version of O157, at least, is susceptible to several of our phages, and we plan to explore their potential use further, both as prophylactics and as therapeutic agents during outbreaks. [34] T-even phages A substantial fraction of the phages in the therapeutic mixes are relatives of bacteriophage T4, which has played such a key role in the development of molecular biology. This family is generally called the T-even phages, an historical accident reflecting the fact that T2, T4 and T6 from the original collection of Delbrueck’s Phage Group all turned out to be related. Large sets of T-even phages have been isolated for study from all over the world: Long Island sewage treatment plants, animals in the Denver zoo, and dysentery patients in eastern Europe (the latter using Shigella as host). Members of the family are found infecting all of the enteric bacteria and their relatives. [35] Most of the T-even phages use 5-hydroxymethylcytosine instead of cytosine in their DNA, which protects them against most of the restriction enzymes that bacteria make to protect themselves against invaders and gives them a much more effective host range. T4’s entire DNA sequence is known,
and we know a great deal about its
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infection process in standard laboratory conditions and about the methods it uses to target bacteria so effectively. [36] [37] We can potentially use this knowledge to develop more targeted approaches to phage therapy, particularly as more is learned about the similarities and differences in its extended family. [38] [39] We know that different members of the T-even family use different outer membrane proteins and oligosaccharides as their receptors, and we understand the tail-fiber structures involved well enough to potentially predict which phages will work on given bacteria and to engineer phages with new specificities. [40] [41] The T-even bacteriophages share a unique ability which contributes significantly to their widespread occurrence in nature and to their competitive advantage. There have still been far too few studies of T4 ecology and its behavior under conditions more closely approaching the natural environment and the circumstances it will encounter in phage therapy – often anaerobic and/or with frequent periods of starvation. The limited available information in that regard was summarized by Kutter et al.[36] [37] A variety of studies are shedding light on the ability of these highly virulent phages to coexist in balance with their hosts in nature. For example, they can reproduce in the absence of oxygen as long as their bacterial host has been growing anaerobically for several generations. They are also able to control the timing of lysis in response to the relative availability of bacterial hosts in their environment. When E. coli are singly infected with T4, they lyse after 25–30 minutes at body temperature in rich media, releasing about 100–200 phages/cell. However, when additional T-even phages attack the cell more than 4 minutes after the initial infection, the cell does not lyse at the normal time. Instead, it continues to make phages for as long as 6 hours. [42] [43] We have found that they can also survive for a period of time in a hibernation-like state inside starved cells, allowing their host to readapt when nutrients are again supplied, and produce a few additional phages. This is particularly interesting and important since bacteria undergo many drastic changes to survive periods of starvation which increase their resistance to a variety of environmental insults. [44] Thus, for many reasons, the T-even phages make excellent candidates for therapeutic use in enteric and other Gram-negative bacteria, and studies of their ecology and distribution are being carried out with these goals in mind both in Tbilisi and at Evergreen State College. Advantages of phages Phages have many potential advantages: • They are self-replicating but also self-limiting because they will multiply only as long as sensitive bacteria are present. • They can be targeted far more specifically than most antibiotics to the problem bacteria, causing much less damage to the normal microbial balance in the gut. The bacterial imbalance or “dysbiosis” caused by many antibiotic treatments can lead to serious secondary infections involving relatively resistant bacteria, often extending hospitalization time, expense and mortality (see Chs 7 and 9 ). Particular resultant problems include Pseudomonads, which are especially difficult to treat, and Clostridium difficile, the cause of serious diarrhea and membranous colitis. [45] • Phages can often be targeted to receptors on the bacterial surface which are involved in pathogenesis, so any resistant mutants are attenuated in virulence. • Few side-effects have been reported for phage therapy. • Phage therapy would be particularly useful for people with allergies to antibiotics. • Appropriately selected phages can easily be used prophylactically to help prevent bacterial disease at times of exposure or to sanitize hospitals and to help protect against hospital-acquired (nosocomial) infections. • Especially for external applications, phages can be prepared fairly inexpensively and locally, facilitating their potential applications to underserved populations. • Phages can be used either independently or in conjunction with other antibiotics to help reduce the development of bacterial resistance.
CONCLUSION Clearly the time has come to look more carefully at the potential of phage therapy, both by strongly supporting new research and by looking carefully at the research already available. [46] As Barrow & Soothill[4] conclude: Phage therapy can be very effective in certain conditions and has some unique advantages over antibiotics. With the increasing incidence of antibiotic-resistant bacteria and a deficit in the development of new classes of antibiotics to counteract them, there is a need to investigate the use of phage in a range of infections. Phages are quite specific as to the bacteria they attack, and the stipulations of Ackermann & DuBow [12] are important here. The specificity of phages means that: Phages have to be tested [against the bacteria] just as antibiotics, and the indications have to be right, but this holds everywhere in medicine. However, phage therapy requires the creation of phage banks and a close collaboration between the clinician and the laboratory. Phages have at least one advantage. … While the concentration of antibiotics decreases from the moment of application, phage numbers should increase. Another advantage is that phages are able to spread and thus prevent disease. Nonetheless, much research remains to be done … on the stability of therapeutic preparations; clearance of phages from blood and tissues; their multiplication in the human body; inactivation by antibodies, serum or pus; and the release of bacterial endotoxins by lysis. … In addition, therapeutic phages should be characterized at least by electron microscopy.
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While it seems premature to broadly introduce injectable phage preparations in the West without further extensive research, their carefully implemented use in gut and external applications and for a variety of agricultural purposes could potentially help to reduce the emergence of antibiotic-resistant strains. Furthermore, compassionate use of appropriate phages seems warranted in cases where bacteria resistant against all available antibiotics are causing life-threatening illness. They are especially useful in dealing with recalcitrant nosocomial infections, where large numbers of particularly vulnerable people are being exposed to the same strains of bacteria in a closed hospital setting. In this case, the environment as well as the patients can be effectively treated.
REFERENCES 1. Levin
B, Bull JJ. Phage therapy revisited: the population biology of a bacterial infection and its treatment with bacteriophage and antibiotics. Am Nat 1996; 147: 881–898
2. Lederberg 3. Radetsky
J. Smaller fleas … ad infinitum: therapeutic bacteriophage. PNAS 1996; 93: 3167–3168
P. Return of the good virus. Discover 1996; 17: 50–58
4. Barrow
PA, Soothill JS. Bacteriophage therapy and prophylaxis: rediscovery and renewed assessment of the potential. Trends Microbiol 1997; 5: 268–271
5. Hankin
EH. L’action bactericide des eaux de la Jumna et du Gange sur le vibrion du cholera. Ann de l’Inst Pasteur 1896; 10: 511
6. D’Herelle
F, Twort FW, Bordet J, Gratia A. Discussion on the bacteriophage (bacteriolysin): from the Ninetieth Annual Meeting of the British Medical Association, Glasgow, July, 1922. Br Med J 1922; 2: 289–297; reproduced in Stent G. Papers on bacterial viruses. 2nd edn. Boston: Little, Brown. 1965 7. D’Herelle
F. (trans. by G.H. Smith) The bacteriophage: its role in immunity. Baltimore: Williams and Wickens/Waverly Press. 1922
8. Bruynoghe 9. D’Herelle
R, Maisin J. Essais de therapeutique au moyen du bacteriophage du staphylocoque. C R Soc Biol 1921; 85: 1120–1121
F. The bacteriophage and its clinical applications. Springfield: CC Thomas. 1930
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Eliava G. Bakteriofagi fenomenvyzdorovieniya. Tbilisi: Tbilis National University Publications. 1935
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Saunders ME. Bacteriophages in industrial fermentationsin. In: Webster R, Granoff A, eds. Encyclopedia of virology. San Diego, CA: Academic Press. 1994: p 116–121
12.
Ackermann HW, DuBow M. Viruses of prokaryotes I: general properties of bacteriophages, Ch. 7 . Practical applications of bacteriophages. Florida: CRC Press, Boca Raton. 1987
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Schlesinger M. Reindarstellung eines bakteriophagen in mit freiem auge sichtbaren mengen. Biochem. Z. 1933; 264: 6
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Ruska H. Die sichtbarmachung der bakteriophagen lyse im ubermikroskop. Naturwissenschaften, 1940; 28: 45
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Pfankuch E, Kausche G. Isolierung U. Uebermikroskopische abbildung eines bakteriophagen. Naturwissenschaften 1940; 28: 46
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Ruska H. Ergeb. Hyg Bakteriol Immunforsch Exp Ther 1943; 25: 437
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Ellis EL, Delbrueck M. The growth of bacteriophage. J Gen Physiol 1939; 22: 365–384
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Doermann AD. The intracellular growth of bacteriophages. I. Liberation of intracellular bacteriophage T4 by premature lysis with another phage or with cyanide. J. Gen. Physiol. 1952; 35: 645–656
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Cairns J, Stent G, Watson J. Phage and the origins of molecular biology. Long Island, NY: Cold Spring Harbor Laboratory Press. 1966
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Fischer E, Lipson C. Thinking about science: Max Delbrueck and the origins of molecular biology. New York, NY: W.W. Norton. 1988
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Vieu JF. Les bacteriophages. In: Fabre J., ed. Traite de therapeutique, Vol. Serums et vaccins. Paris: Flammarion. 1975: p 337–340b
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Vieu JF, Guillermet F, Minck R, Nicolle P. Données actuelles sur les applications therapeutiques des bacteriophages. Bull Acad Natl Med 1979; 163: 61
Slopek S, Durlakova I, Weber-Dabrowska B et al. Results of bacteriophage treatment of suppurative bacterial infections I. General evaluation of the results. Arch Immunol Ther Exp 1983; 31: 267–291 23.
Slopek S, Kucharewica-Krukowska A, Weber-Dabrowska B, Dabrowski M. Results of bacteriophage treatment of suppurative bacterial infections VI. Analysis of treatment of suppurative staphylococcal infections. Arch Immunol Ther Exp 1985; 33: 261–273 24.
Slopek S, Weber-Dabrowska B, Dabrowski M, Kucharewica-Krukowska A. Results of bacteriophage treatment of suppurative bacterial infections in the years 1981–1986. Arch Immunol Ther Exp 1987; 35: 569–583 25.
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Weber-Dabrowska B, Dabrowski M, Slopek S. Studies on bacteriophage penetration in patients subjected to phage therapy. Archium Immunologiae et Therapiae Experimentalis 1987; 35: 363–368
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Smith HW, Huggins RB. Successful treatment of experimental E. coli infections in mice using phage: its general superiority over antibiotics. J. Gen. Microbiology 1982; 128: 307–318
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Smith HW, Huggins RB. Effectiveness of phages in treating experimental E. coli diarrhoea in calves, piglets and lambs. J. Gen. Microbiology 1983; 129: 2659–2675
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Smith HW, Huggins RB. The control of experimental E. coli diarrhea in calves by means of bacteriophage. J Gen Microbiology 1987; 133: 1111–1126
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Smith HW, Huggins RB, Shaw KM. Factors influencing the survival and multiplication of bacteriophages in calves and in their environment. J Gen Microbiology 1987; 133: 1127–1135
31.
Alavidze Z. Personal communication.
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Merrill C, Biswis B, Carlton R et al. Long-circulating bacteriophages as antibacterial agents. PNAS 1996; 93: 3188–3192
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Greenwald D, Brandt L. Recognizing E. coli O157: H7 infection. Hospital Practice 1997; April 15: 123–140
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Mueller M, Smith S, Kutter E. Unpublished data, 1997
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Ackermann H, Krisch H. A catalogue of T4-type bacteriophages. Archiv Virol 1997; 142: 2329–2345
Kutter E, Kellenberger E, Carlson K et al. Effects of bacterial growth conditions and physiology on T4 infection. In: Karam JD, ed. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology. 1994: p 406–420 36.
Kutter E, Stidham T, Guttman B et al. Genomic map of bacteriophage T4. In: Karam JD, ed. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology. 1994: p 491–519 37.
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Jacob F, Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 1961; 3: 318–356
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Kutter E, Gachechiladze K, Poglazov A et al. Evolution of T4-related phages. Virus Genes 1996; 11: 285–297
Henning U, Hashemolhosseini S. Receptor recognition by T-even-type coliphages. In: Karam JD, ed. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology. 1994: p 291–298 40.
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Doermann AH. Lysis and lysis inhibition with E. coli bacteriophage. J Bacteriol 1948; 55: 257–275
Abedon S. Lysis and the interaction between free phages and infected cells. In: Karam JD, ed. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology. 1994: p 397–405 43.
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Kolter R. Life and death in stationary phase. ASM News 1992; 58: 75–79
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Fekety R. Antibiotic-associated diarrhea and colitis. Cur Opin Infect Dis 1995; 8: 391–397
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Alisky J, Iczkonski K, Rapoport A et al. Bacteriophage shows promise as antimicrobial agents. J Infection 1998; 36: 5–13
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Chapter 103 - Phosphatidylserine Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION Phosphatidylserine is the major phospholipid in the brain, where it plays a major role in determining the integrity and fluidity of cell membranes. Normally the brain can manufacture sufficient levels of phosphatidylserine, but if there is a deficiency of methyl donors like S-adenosylmethionine (SAM), folic acid, and vitamin B 12 , or essential fatty acids, the brain may not be able to make sufficient phosphatidylserine. Low levels of phosphatidylserine in the brain are associated with impaired mental function and depression in the elderly.
PHYSIOLOGICAL FUNCTIONS Phosphatidylserine is responsible for many functions essential to the structural matrix and function of cell membranes. With the help of phosphatidylserine and other phospholipid components, the cell membranes control: • the cellular exchange of nutrients and waste products • movement of electrolytes into and out of cells • reception of molecular messages from outside the cell • transformation of messages into enzymatic responses • cell movement and shape • cell-to-cell recognition and communication. Although phosphatidylserine is found in every cell type in the body, it plays an especially vital role in nerve tissue. It is critical in membrane-to-membrane fusion – a key process in neurotransmitter release – as well as activating cell surface receptors and supporting the transmission of chemical signals.
PHARMACOLOGY The pharmacology of phosphatidylserine appears to be a result of restoring proper levels of phosphatidylserine in cell membranes. As a result, cellular function improves.
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This improvement is most notable in brain tissue. Phosphatidylserine supplementation in animal studies has been shown to significantly improve acetylcholine release, memory, and age-related brain changes. [1] [2] [3] Presumably these effects are responsible for the positive effects noted in human clinical trials. Absorption studies in animals indicate that phosphatidylserine is well absorbed orally. Absorption of phosphatidylserine is very similar to the absorption of phosphatidylcholine, the major component of soy lecithin. Like phosphatidylcholine, with absorption into the intestinal cell the lipid component at position 2 is cleaved from the glycerol backbone. This lysoform of phosphatidylserine is then re-esterified by the enterocyte and transported to various tissues where (presumably) it is reacylated with a specific fatty acid depending upon where it is being delivered. For example, in the brain most of the phosphatidylserine incorporates oleic acid (C18:1n9) or docosahexanoic acid (C22:6n3, DHA) while in the testes C:14:0 and arachidonic acid (C20:4n6) are the major forms. Originally, phosphatidylserine was isolated from bovine brain, but with the concern for bovine spongiform encephalopathy (mad cow disease) an alternative preparation derived from soy was developed. Commercially available phosphatidylserine is now a semi-synthetic product manufactured from soy lecithin. In the United States phosphatidylserine is available in a complex containing the following: • phosphatidylserine – 100 mg • phosphatidylcholine – 45 mg • phosphatidyethanolamine – 25 mg • phosphatidylinositol – 5 mg. The effectiveness of the soy-derived phosphatidylserine has yet to be proven as all of the published clinical studies to date have utilized bovine phosphatidylserine. The difference between the two is that the bovine source has predominantly DHA at the 2 position while the soy preparation has primarily linoleic acid (C18:2n6). Given DHA’s critical role in brain metabolism, until soy phosphatidylserine is shown to produce results equal to that achieved with bovine phosphatidylserine, co-supplementation with DHA should be encouraged when using phosphatidylserine from soy sources.
CLINICAL APPLICATIONS The primary use of phosphatidylserine is in the treatment of depression and/or impaired mental function in the elderly including Alzheimer’s disease. To date there have been 11 double-blind studies completed with phosphatidylserine in the treatment of age-related cognitive decline, Alzheimer’s disease or depression. Good results have been obtained with these studies. [4] [5] [6] [7] [8] [9] In the largest study, a total of 494 elderly patients (aged between 65 and 93 years) with moderate to severe senility were given either phosphatidylserine (100 mg three times daily) or a placebo for 6 months. [4] The patients were assessed for mental performance, behavior, and mood at the beginning and the end of the study. Statistically significant ( P < 0.01) improvements in mental function, mood, and behavior were noted in the phosphatidylserine-treated group. Phosphatidylserine appears to positively affect mood in depressed elderly subjects. [10] [11] [12] [13] [14] This effect could also explain some of phosphatidylserine’s positive effects on memory and cognition. The link between depression and impaired mental function is well-established in the geriatric population. In one small double-blind study of 10 depressed elderly patients, phosphatidylserine was shown to improve depressive symptoms, memory and behavior. [15] Unlike typical antidepressant drugs, phosphatidylserine promoted this improvement without influencing the levels of serotonin and other monoamine neurotransmitters, suggesting another mechanism of action. Improved brain cell membrane fluidity may be one explanation. Another is the fact that phosphatidylserine has been shown to reduce cortisol secretion in response to stress. [16] [17] [18] Typically, cortisol levels will be elevated in depressed patients.
DOSAGE
The standard dosage recommendation for phosphatidylserine is 100 mg three times daily.
TOXICOLOGY No side-effects or adverse interactions have been reported. Animal studies have shown that phosphatidylserine from bovine sources given orally is extremely well tolerated. Dogs tolerated up to 70 g/day for 1 year without any apparent side-effect. In over 35 clinical studies involving more than 800 subjects, phosphatidylserine has been shown to be without side-effect at standard dosage (100 mg three times daily). Rarely, stomach upset has been reported and a large dose (e.g. 600 mg) taken prior to retiring may produce sleeplessness.
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MG, Casamenti F, Pepeu G. Decrease of acetylcholine release from cortical slices in aged rats. Investigations into its reversal by phosphatidylserine. J Neurochem 1990; 55: 819–825
L, Kozak W, Zanotti A et al. Activity of phosphatidylserine on memory retrieval and on exploration in mice. Meth Find Exptl Clin Pharmacol 1987; 9: 657–660
3. Nunzi
MG, Milan F, Guidolin D et al. Effects of phosphatidylserine administration on age-related structural changes in the rat hippocampus and septal complex. Pharmacopsychiat 1989; 22: 125–128 4. Cenacchi
T, Betoldin R, Farina C et al. Cognitive decline in the elderly. A double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging 1993; 5: 123–133
5. Engel
RR, Satzer W, Gunterh W et al. Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol 1992; 2: 149–155 6. Crook
T, Petrie W, Ells C et al. Effects of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull 1992; 28: 61–66
7. Crook
TH, Tinklenberg J, Yesavage J et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991; 41: 644–649
8. Funfgeld
EW, Baggen M, Nedwidek P et al. Double-blind study with phosphatidylserine (PS) in parkinsonian patients with senile dementia of Alzheimer’s type (SDAT). Prog Clin Biol Res 1989; 317:
1235–1246 9. Amaducci
L. Phosphatidylserine in the treatment of Alzheimer’s disease. Results of a multicenter study. Psychopharmacol Bull 1988; 24: 1030–1034
10.
Nerozzi D, Aceti F, Meila E et al. Phosphatidylserine in age-related disturbance of memory. Clin Terapeutica 1987; 120: 399–404
11.
Palmieri G. Double-blind controlled trial of phosphatidylserine in patients with senile mental deterioration. Clin Trials J 1987; 24: 73–83
12.
Ransmayr G. Double-blind placebo-controlled trial of phosphatidylserine in elderly patients with arteriosclerotic encephalopathy. Clin Trials J 1987; 24: 67–72
13.
Villardita C. Multicentre clinical trial of brain phosphatidylserine in elderly patients with intellectual deterioration. Clin Trials J 1987; 24: 84–93
Delwaide PJ, Gyselynck-Mambourg AM, Hurlet A et al: Double-blind, randomized controlled study of phosphatidylserine in senile demented patients. Effect of phosphatidylserine in senile demented patients. Acta Neurol Scand 1986; 73: 136–140 14.
15.
Maggioni M, Picotti GM, Bondiolotti GP et al. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand 1990; 81: 265–270
16.
Monteleone P, Beinat L, Tanzillo C et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology 1990; 52: 243–248
Monteleone P, Maj M, Beinat L et al. Blunting chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men. Eur J Clin Pharamacol 1992; 41: 385–388 17.
18.
Nerozzi D, Aceti F, Melia E et al. Early cortisol escape phenomenon reversed by phosphatidylserine in elderly normal subjects. Clinical Trial J 1989; 26: 33–38
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Chapter 104 - Piper mythisticum (kava) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Piper methysticum (family: Piperaceae) Common name: kava
GENERAL DESCRIPTION Kava is a hardy, slow-growing perennial that generally resembles other members of the pepper family. It is an attractive shrub and can attain heights of more than 9 feet. The plant does not have many leaves, but those it does have are thin, single, heart-shaped, alternate, petiolate, 4–10 inches long, and sometimes wider than they are long. Although Piper methysticum does flower, it is incapable of self-reproduction; its propagation is vegetative and now solely due to human effort. [1] [2] For medicinal purposes, it is the rootstock that is used. The rootstock is knotty, thick, and sometimes tuberous with holes or cracks created by partial destruction of the parenchyma. In other words, the rootstock is often somewhat pithy. From the main rootstock, there are extensions of lateral roots up to 9 feet long. [1] [2]
CHEMICAL COMPOSITION Analysis of the composition of the dried kava rootstock indicates that it contains approximately 43% starch, 12% water, 3.2% simple sugars, 3.6% proteins, 3.2% minerals (primarily potassium), and 15% kavalactones (see Table 104.1 ). [1] [2] Based on detailed analysis of the active ingredients of kava, a laborious process over the past 110 years, many experts now believe that the pharmacological activities of kava are due mostly, if not entirely, to the presence of compounds known as kavalactones (also referred to as kava alpha-pyrones). These compounds are found in the fat-soluble resin of the root. Although the kavalactones are the primary active components, other components appear to contribute to the sedative and anxiolytic activities of kava, as one study found the sedative activity of a crude preparation to be more effective than the
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TABLE 104-1 -- Kavalactones Compound
R
R'
R''
R''' C5–6 C7–8
Kavain
–
=
7,8-Dihydrokavain
–
–
5,6-Dihydrokavain
–
=
Yangonin
OMe
=
=
5,6,7,8-Tetrahydroyangonin
OMe
–
–
Methysticin
O-CH2 -O
–
=
Dihydromethysticin
O-CH2 -O
–
–
5,6-Dehydromethysticin
O-CH2 -O
=
=
5,6-Dihydroyangonin
OMe
–
=
7,8-Dihydroyangonin
OMe
–
=
10-Methoxy-yangonin
OMe
=
=
11-Methoxy-yangonin
OMe
OMe
=
=
11-Hydroxy-yangonin
OMe
HO
=
=
OH –
=
=
=
OMe
Hydroxykavain 11-Methoxy-12-hydroxy dehydrokavain
OH
OMe
Figure 104-1 Kavalactones.
isolated kavalactones ( Fig. 104.1 ). [3] The kavalactone content of the root can vary between 3 and 20%.
HISTORY AND FOLK USE Oceania, i.e. the Pacific island communities of Micronesia, Melanesia, and Polynesia, is one of the few geographic areas of the world that did not have alcoholic beverages before European contact in the 18th century. However, these islanders did possess a “magical” drink used in ceremonies and celebrations because of its calming effect and ability to promote sociability. The drink, also called kava, is still used today in this region of the world, where the people are often referred to as the happiest and friendliest in the world. The origins of kava usage are not known as it predates written history in Oceania. [1] [2] It was first described for the Western world by captain James Cook in the
account of his voyage to the South Seas in 1768. Many myths and legends surround the early use of kava. The plant itself probably originated in the New Guinea/Indonesia area and was spread from island to island by early Polynesian explorers in canoes, along with other plants. Each culture has its own story on the origins of kava. For example, in Samoa a story is told about the origins of kava and sugar cane. The story goes that a Samoan girl went to Fiji where she married a great chief. After some time, she returned to Samoa, but before doing so, she noticed two plants growing on a hill. She saw a rat chewing on one of the plants and noticed that the rat seemed to go to sleep. She concluded that the plant was a comforting food. She decided she would take this plant, sugar cane, back to Samoa, but then she noticed that the rat awoke and began to chew the root of another plant – kava. The animal which had been weak and shy became bold, strong, and more energetic. She decided that she would take both plants back with her to plant in Samoa. The plants grew very well in Samoa and soon a chief from a neighboring island exchanged two laying hens for roots of the two plants. Hence, the Samoans take credit for the spread of both the sugar cane and kava. In Tonga, a legend is told about a great chief named Loau who lived on the island of Euaiki. He went to visit his servant Feva’ anga, who wanted to give a feast in honor of the chief, but it was a time of great famine. In desperation, he and his wife killed and cooked their only daughter to be served to the chief. However, Loau recognized the human flesh in the food when it was served and would not eat it. He instructed Feva’ anga to plant the food in the ground and to bring him the plant that would spring forth. On receiving the mature plant, Loau instructed that a drink be prepared from it and consumed with due ceremony. The kava ceremony Regardless of exactly how kava originated, it has been used in ceremonies by the Oceanic people for thousands of years. There are three basic kava ceremonies: the full ceremonial as enacted on every formal occasion; the one performed at the meeting of village elders, chiefs, and nobles and for visiting chiefs and dignitaries; and the less formal kava circle common on social occasions. [1] [2] The first step of any kava ceremony was the preparation
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of the beverage. A description of the classic process was written in 1777 by Georg Forster, a young naturalist on James Cook’s second Pacific voyage: [Kava] is made in the most disgustful manner that can be imagined, from the juice contained in the roots of a species of pepper-tree. This root is cut small, and the pieces chewed by several people, who spit the macerated mass into a bowl, where some water (milk) of coconuts is poured upon it. They then strain it through a quantity of fibres of coconuts, squeezing the chips, till all their juices mix with the coconut-milk; and the whole liquor is decanted into another bowl. They swallow this nauseous stuff as fast as possible; and some old topers value themselves on being able to empty a great number of bowls. As this traditional method of preparation became frowned upon or made illegal by colonial governments and missionaries, more “sanitary” methods of preparation, involving grinding or grating, took its place in many parts of Oceania. The full kava ceremony, reserved for very highly honored guests, involves leading all of the guests to a platform. The ceremony begins with the arrival of a group of young men dressed in ceremonial attire and carrying a bowl of the kava drink and necessary utensils. The bowl is placed between the kava preparers and the visitors. The kava is placed in a cup by a specially selected individual who then turns and faces the visitor and delivers the beverage to the chief guest. The guest is instructed to hold the cup with both hands and drink from it. If the whole cup is drained without stopping, everyone says “a maca” (pronounced “a matha,” meaning “it is empty”) and claps three times with cupped hands. The cup bearer then returns to the kava bowl and proceeds to serve the person next in rank or importance. Important people who visit Fiji and other islands of Oceania still participate in the kava ceremonies. For example, during a 1992 presidential campaign visit to Hawaii, Hillary Clinton participated in a kava ceremony conducted by the Samoan community on O’ahu. The effects of drinking kava Kava drinkers relate a pleasant sense of tranquillity and sociability upon consumption. Subjective reports given by scientists who have sampled kava themselves are relatively abundant. One of the first scientific studies of kava was performed by the noted pharmacologist Louis Lewin in 1886. A later description written in 1927 is as follows:[1] When the mixture is not too strong, the subject attains a state of happy unconcern, well-being and contentment, free of physical or psychological excitement. At the beginning, conversation comes in a gentle, easy flow and hearing and sight are honed, becoming able to perceive subtle shades of sound and vision. Kava soothes temperaments. The drinker never becomes angry, unpleasant, quarrelsome or noisy, as happens with alcohol. Both natives and whites consider kava as a means of easing moral discomfort. The drinker remains master of his consciousness and his reason. When consumption is excessive, however, the limbs become tired, the muscles seem no longer to respond to the orders and control of the mind, walking becomes slow and unsteady and the drinker looks partially inebriated. He feels the need to lie down…. He is overcome by somnolence and finally drifts off to sleep. A more recent description is provided by researcher R. J. Gregory, who writes from his own experience: Kava seizes one’s mind. This is not a literal seizure, but something does change in the processes by which information enters, is retrieved, or leads to actions as a result. Thinking is certainly affected by the kava experience, but not in the same ways as are found from caffeine, nicotine, alcohol, or marijuana. I would personally characterize the changes I experienced as going from lineal processing of information to a greater sense of “being” and contentment with being. Memory seemed to be enhanced, whereas restriction of data inputs was strongly desired, especially with regard to disturbances of light, movements, noise and so on. Peace and quiet were very important to maintain the inner sense of serenity. My senses seemed to be unusually sharpened, so that even whispers seemed to be loud while loud noises were extremely unpleasant. Drinking about half a coconut shell (100–150 mL) of certain varieties of kava is enough to put most people into a deep, dreamless sleep within 30 minutes. Unlike alcohol and other sedatives, kava does not produce any morning hangover. The kava drinker awakens having fully recovered normal physical and mental capacities.
PHARMACOLOGY Many of the first comprehensive studies on the activities of kavalactones were conducted by a team of scientists from the Freiburg University Institute of Pharmacology in Germany, led by Hans J. Meyer, during the 1950s and 1960s. [3] This research determined that kavalactones exhibit sedative, analgesic, anticonvulsant, and muscle-relaxant effects in laboratory animals. These studies seemed to confirm earlier empirical and subjective observations. More recent studies have utilized better-defined kava extracts. Isolated kavalactones compared with crude extracts
Some evidence suggests that the whole complex of kavalactones and other compounds naturally found in kava produce greater pharmacological activity. In addition, studies have shown that kavalactones are more rapidly absorbed when given orally as an extract of the root rather than as the isolated kavalactones. The bioavailability of lactones, as measured by peak plasma concentrations, is up to three to five times higher from the extract than when given as isolated substances. [3] Further evidence that kava root extracts are superior
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to isolated kavalactones is offered by an animal study showing that while isolated kavalactones are well absorbed by brain, crude kava preparations produce brain concentrations of lactones two to 20 times higher. [4] This evidence suggests that crude extracts standardized for kavalactone content may offer the greatest therapeutic benefit. Several clinical trials have featured a kava extract standardized to contain 70% kavalactones. However, this high percentage of kavalactones may be sacrificing some of the other constituents that may contribute to the pharmacology of kava. More important than the actual percentage of kavalactones is the total dosage of the kavalactones and the assurance that the full range of kavalactones and other important constituents are present. Standardized preparations of kava are now gaining greater popularity in Europe and the United States as mild sedatives and anxiolytics. Sedative effects
Recent studies have confirmed and/or elaborated on the sedative effects of kava. Most notable are studies demonstrating that kavalactones exert many of their effects through non-traditional mechanisms. For example, most sedative drugs including the benzodiazepines (e.g. Valium, Halcion, Tranxene, etc.) work by binding to specific receptors (benzodiazepine or GABA receptors) in the brain which then leads to the neurochemical changes (potentiation of GABA effects) which promote sedation. Studies in animals have shown that the kavalactones do not bind to benzodiazepine or GABA receptors. [5] Instead, the kavalactones are thought to somehow modify receptor domains rather than interacting specifically with receptor binding sites. In addition, other studies have indicated that the kavalactones appear to act primarily on the limbic system, the ancient part of the brain which affects all other brain activities and is the principle seat of the emotions. [6] It is thought that kava may also promote sleep by altering the way in which the limbic system modulates emotional processes. It appears that many of the laboratory models of identifying how a substance works to promote a calming effect are simply not sophisticated enough to evaluate the physiological effects of kava. Analgesic effects
In another example of the unusual pharmacological qualities of kava, a study designed to evaluate its pain-relieving effects could not demonstrate any binding to opiate receptors. [7] The significance of this finding is that the study used experimental models where non-opiate analgesics like aspirin and other non-steroidal anti-inflammatory drugs are ineffective. In addition, it was determined that the sedative or muscle-relaxing effects were not responsible for the pain-relieving effects. These findings indicate that kava reduces pain in a manner unlike morphine, aspirin, or any other pain reliever. Anxiolytic effects
An interesting effect of kava compared with other anxiolytics is that unlike the drugs, kava does not lose effectiveness with time. Kavalactones, even when administered in large dosages, demonstrated no loss of effectiveness in animal studies. [8] Again, this is another example of the unusual qualities of kava. Anti-ischemia effects
Another pharmacological activity of kava of importance is its ability to protect against brain damage due to ischemia. [9] This effect has been demonstrated in two animal models of focal cerebral ischemia. The effectiveness of the kavalactones was due to its ability to limit the infarct area as well as provide a mild anticonvulsant effect. Kava extract may prove useful in the recovery from a stroke.
CLINICAL APPLICATIONS Several European countries have approved kava preparations in the treatment of nervous anxiety, insomnia, and restlessness on the basis of detailed pharmacological data and favorable clinical studies. Anxiety
Early clinical trials used D,L-kavain, a purified kavalactone, at a dose of 400 mg/day. For example, in one double-blind placebo-controlled study of 84 patients with anxiety symptoms, kavain was shown to improve vigilance, memory, and reaction time. [10] In another double-blind study, kavain was compared to oxazepam (a drug similar to diazepam or Valium) in 38 patients. [11] Both substances caused progressive improvements in two different anxiety scores (Anxiety Status Inventory and the Self-rating Anxiety Scale) over a 4 week period. However, while oxazepam and similar drugs are addictive and cause side-effects, kavain appeared to be free of these complications. In perhaps the most significant study, a 70% kavalactone extract was shown to exhibit significant therapeutic benefit in patients suffering from anxiety. [12] The study was double-blind; 29 patients were assigned to receive 100 mg of the kava extract three times daily, while another 29 patients received a placebo. Therapeutic effectiveness was assessed using several standard
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psychological assessments including the Hamilton Anxiety Scale. The result of this 4 week study indicated that individuals taking the kava extract had a statistically significant reduction in symptoms of anxiety including feelings of nervousness and somatic complaints such as heart palpitations, chest pains, headache, dizziness, and feelings of gastric irritation. No side-effects were reported with the kava extract. In another double-blind study, two groups of 20 women with menopause-related symptoms were treated for a period of 8 weeks with the 70% kavalactone extract (100 mg three times daily) or placebo. [13] The measured variable was once again the Hamilton Anxiety Scale. The group receiving the kava extract demonstrated significant improvement at the end of the very first week of treatment. Scores continued to improve over the course of the 8 week study. In addition to improvement in symptoms of stress and anxiety, a number of other symptoms also improved. Most notably there was an overall improvement in subjective well-being, mood, and general symptoms of menopause, including hot flashes. Again, no side-effects were noted. Two additional studies have shown that unlike benzodiazepines, alcohol, and other drugs, kava extract is not associated with depressed mental function or impairment in driving or the operation of heavy equipment. [14] [15] In one of these studies, 12 healthy volunteers were tested in a double-blind cross-over manner to assess the effects of oxazepam (placebo on days 1–3, 15 mg on the day before testing, 75 mg on the morning of the experiment), the extract of kava standardized at 70% kavalactones (200 mg three times daily for 5 days), and a placebo on behavior and event-related potentials (ERPs) in electroencephalograph (EEG) readings on a recognition memory task. The subjects’ task was to identify within a list of visually presented words those that were shown for the first time and those that were being repeated. Consistent with other benzodiazepines, oxazepam inhibited the recognition of both new and old words as noted by ERP. In contrast, kava showed a slightly increased recognition rate and a larger ERP difference between old and new words. The results of this study once again demonstrate the unusual effects of kava. In this case, it improves anxiety, but unlike standard anxiolytics, kava actually improves mental function and, at the recommended levels, does not promote sedation.
DOSAGE In clinical studies using pure kavalactones or kava extracts standardized for kavalactones, the dosage is based on the level of kavalactones. As the kavalactone content of the root varies between 3 and 20%, preparations standardized for kavalactone content are preferred to crude preparations. A standard bowl of traditionally prepared kava drink contains approximately 250 mg of kavalactones, and in Oceania, several bowls may be consumed at one sitting. Dosages are as follows: • anxiolytic dosage: 45–70 mg of kavalactones three times/day
• sedative dosage: 180–210 mg of kavalactones 1 hour before retiring.
TOXICOLOGY Although no side-effects have been reported using standardized kava extracts at recommended levels in the clinical studies, several case reports have been presented indicating that kava may interfere with dopamine and worsen Parkinson’s disease. Until this issue is resolved, kava extract should not be used in Parkinson’s patients.[16] Side-effects may also develop at high dosages. High daily dosages of kava consumed over a prolonged period (a few months to a year) are associated with “kava dermopathy” – a condition of the skin characterized by a peculiar generalized scaly eruption known as kani. [16] The skin becomes dry and covered with scales, especially the palms of the hands, soles of the feet, forearms, the back, and shins. It was thought at one time that kava dermopathy may be due to interference with niacin. However, in a double-blind, placebo-controlled study, niacinamide (100 mg/day) demonstrated no therapeutic effect. [17] It appears that the only effective treatment for kava dermopathy is reduction or cessation of kava consumption. No cases of kava dermopathy have been reported in those taking standardized kava extracts at recommended levels. Other reported adverse effects of extremely high doses of kava (e.g. greater than 310 g/week) for prolonged periods include:
[ 18]
• biochemical abnormalities (low levels of serum albumin, protein, urea, and bilirubin) • presence of blood in the urine • increased red blood cell volume • decreased platelet and lymphocyte counts • shortness of breath. However, the validity of this report of adverse effects is questionable because the subjects were also heavy users of alcohol and cigarettes. Nonetheless, high doses of kava are unnecessary and should be avoided.
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V, Merlin M, Lindstrom L. Kava. The Pacific Drug. New Haven, CT: Yale University Press. 1992
2. Singh
Y. Kava. An overview. J Ethnopharmacol 1992; 37: 13–45
3. Meyer
HJ. Pharmacology of kava. In: Holmstedt B, Kline NS, eds. Ethnopharmacological search for psychoactive drugs. New York: Raven Press. 1979, p 133–140
4. Keledjian 5. Davies
J, Duffield PH, Jamieson DD. Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci 1988; 77: 1003–1006
LP, Drew CA, Duffield P. Kava pyrones and resin. Studies on GABAa, GABAb and benzodiazepine binding sites in rodent brain. Pharm Toxicol 1992; 71: 120–126
6. Holm
E, Staedt U, Heep J. Studies on the profile of the neurophysiological effects of D,L-kavain. cerebral sites of action and sleep-wakefulness-rhythm in animals. Arzneim Forsch 1991; 41: 673–683 7. Jamieson 8. Duffield
DD, Duffield PH. The antinociceptive action of kava components in mice. Clin Exp Pharmacol Physiol 1990; 17: 495–508
PH, Jamieson D. Development of tolerance to kava in mice. Clin Exp Pharmacol Physiol 1991; 18: 571–578
9. Backhauss,
Krieglstein J. Extract of kava ( Piper methysticum) and its methysticum constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol 1992; 215: 265–269
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Scholing WE, Clausen HD. On the effect of d,l-kavain. experience with neuronika. Med Klin 1977; 72: 1301–1306
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Lindenberg D, Pitule-Schodel H. D,L-kavain in comparison with oxazepam in anxiety disorders. A double-blind study of clinical effectiveness. Forschr Med 1990; 108: 49–50, 53–54
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Kinzler E, Kromer J, Lehmann E. Clinical efficacy of a kava extract in patients with anxiety syndrome. Double-blind placebo controlled study over 4 weeks. Arzneim Forsch 1991; 41: 584–588
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Warnecke G. Neurovegetative dystonia in the female climacteric. Studies on the clinical efficacy and tolerance of kava extract WS 1490. Forsch Med 1991; 109: 120–122
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Herberg KW. The influence of kava-special extract WS 1490 on safety-relevant performance alone and in combination with ethylalcohol. Blutalkohol 1993; 30: 96–105
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Munte TF, Heinze HJ, Matzke M. Effects of oxazepam and an extract of kava roots (Piper methysticum) on event-related potentials in a word recognition task. Neuropyschobiol 1993; 27: 46–53
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Schelosky L, Raffauf C, Jendroska K. Kava and dopamine antagonism [letter]. J Neurol Neurosurg Psychiatry 1995; 58: 639–640
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Norton SA, Ruze P. Kava dermopathy. J Am Acad Dermatol 1994; 31: 89–97
18.
Ruze P. Kava-induced dermopathy. A niacin deficiency. Lancet 1990; 335: 1442–1445
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Chapter 105 - Probiotics Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION Probiotics, translated “for life”, refer to bacteria in the intestine considered beneficial to health. At least 400 different species of microflora colonize the human gastrointestinal tract. The most important healthful bacteria are Lactobacillus acidophilus and Bifidobacterium bifidum. This chapter focuses on the principal uses of commercial probiotic supplements containing either or both L. acidophilus and B. bifidum as well as the fructo-oligosaccharides which facilitate their growth. Foods fermented with lactobacilli have been, and still are, of great importance to the diets of most of the world’s people. Most cultures use some form of fermented food in their diet such as yogurt, cheese, miso, and tempeh. The symbiotic relationship between humankind and lactobacilli has a long history of important nutritional and therapeutic benefits for humans.
DESCRIPTION At the turn of the century, Metchnikoff [1] asserted that yogurt was the elixir of life. He theorized that putrefactive bacteria in the large intestine produce toxins which invite disease and shorten life. He believed that the eating of yogurt would cause the lactobacilli to become dominant in the colon and displace the putrefactive bacteria. For years, these claims of healthful effects from fermented foods were considered unscientific folklore. However, a substantial, and growing, body of scientific evidence has now demonstrated that lactobacilli and fermented foods play a significant role in human health. Colonization of Gram-positive lactobacilli begins after birth, after which there is a dramatic increase in their concentration. Bifidobacterium bifidum is first introduced through breast-feeding to the sterile gut of the infant, and large numbers are soon observed in the feces. Later, other bacteria (including such beneficial strains as L. casea, L. fermentum, L. salivores, L. brevis, etc.) become
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TABLE 105-1 -- Lactobacilli found in the human intestine • L. acidophilus • L. bifidus (Bifidobacterium bifidum) • L. brevis • L. casei • L. cellobiosus • L. fermentum • L. leichmannii • L. plantarum • L. salivaroes established in the gut through contact with the world ( Table 105.1 ). Unfortunately, other, potentially toxic, bacteria also eventually cultivate the colon.
[ 2]
Commercial forms For clinical efficacy, products containing L. acidophilus and B. bifidum must provide live organisms in such a manner that they survive the commercial process (transportation, storage, etc.) and the hostile environment of the gastrointestinal tract. Several factors, such as species, strain, adherence, growth media, and diet, are involved in successful colonization. [3] [4] Typically, a high-quality commercial preparation will produce greater colonization than simply eating yogurt. One of the key reasons that most currently available yogurts are not clinically very useful is that they are made with L. bulgaricus or Streptococcus thermophilus. While these two bacteria are friendly and possess some health benefits, they do not colonize the colon. Proper manufacturing, packaging and storing of the product are necessary to ensure viability, the right amount of moisture, and freedom from contamination. Lactobacilli do not respond well to freeze-drying (lyophilization), spray drying, or conventional frozen storage. Excessive temperature during packaging or storage can dramatically reduce viability. Typically, unless the product has been shown to be stable, refrigeration is necessary. Some products do not have to be refrigerated until after the bottle has been opened. While there are a number of excellent companies providing high-quality probiotic products, it is difficult to sort through all of manufacturer’s claims of superiority, and some products have been shown to contain no active L. acidophilus. In fact, one study concluded: “Most of the lactobacilli-containing products currently available [1990] either do not contain the Lactobacillus species advertised and/or contain other bacteria of questionable benefit.” [5] Another study evaluated 16 commercial lactobacillus products for actual microbial content. Four contained the L. acidophilus as stated on the label, while 11 were found to be contaminated with pathogens. [6] Clearly, the clinician needs documentation of product quality and content before prescribing for their patients.
CLINICAL APPLICATIONS The intestinal flora plays a major role in the health of the host. [2] [3] [4] The intestinal flora is intimately involved in the host’s nutritional status and affects immune system function, cholesterol metabolism, carcinogenesis, toxin load, and aging. Due to the importance of L. acidophilus and B. bifidum to human health, probiotic supplements can be used to promote overall good health. There are several specific uses for probiotics, however. The primary areas of use discussed here are: • promotion of proper intestinal environment • post-antibiotic therapy • vaginal yeast infections • urinary tract infections • cancer prevention.
Promotion of proper intestinal environment
Lactobacilli have long been known to play an important role in the prevention of, and defense against, diseases, particularly those of the gastrointestinal tract and vagina. As part of the “normal flora”, they inhibit the growth of other organisms through competition for nutrients, alteration of pH and oxygen tension to levels less favorable to pathogens (disease causing organisms), prevention of attachment of pathogens by physically covering attachment sites, and production of limiting factors such as antimicrobial factors. [2] [3] [4] Lactobacilli produce a variety of factors which inhibit or antagonize other bacteria. These include metabolic end-products such as organic acids (lactic and acetic acid), hydrogen peroxide, and compounds known as bacteriocins. [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] Although some researchers have isolated substances from lactobacilli which they labeled antibiotics, these are probably more accurately described as bacteriocins. Bacteriocins are defined as proteins which are produced by bacteria which exert a lethal effect on closely related bacteria ( Table 105.2 ). In general, bacteriocins have a narrower range of activity than antibiotics, but are often more lethal. Some of the antimicrobial activity of L. acidophilus has been shown to be due to their production of hydrogen peroxide. [17] [18] However, this reaction requires folic acid and riboflavin, which if in short supply will reduce H 2 O 2 production. In addition to these direct effects, some researchers believe the antimicrobial activity is also due to immune system stimulation.[19] [20] [21] [22] [23] [24] The earliest reported therapeutic uses of L. acidophilus in the 1920s suggested that their proliferation in the gut was associated with a concomitant decrease in potentially harmful coliform bacteria. This effect has since been confirmed. [25] [26] [27] However, it is believed that many of the earlier commercial products were less reliable than those used in later published clinical trials because of
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TABLE 105-2 -- Bacteria inhibited by L. acidophilus • Bacillus subtillis • B. cerus • B. stearothermophilus • Candida albicans • Clostridium perfringens • E. coli • Klebsiella pneumoniae • L. bulgaricus • L. fermentum • L. helveticus • L. lactis • L. leichmannii • L. plantarium • Proteus vulgaris • Pseudomonas aeruginosa • P. flourescens • Salmonella typhosa • S. schottmuelleri • Shigella dysenteriae • S. paradysenteriae • Sarcina lutea • Serratia marcescens • Staphylococcus aureus • Streptococcus fecalis • S. lactis • Vibrio comma inappropriate strains and problems in production, storage, and distribution to consumers.
[28]
Post-antibiotic therapy
Acidophilus supplementation is particularly important for preventing and treating antibiotic-induced diarrhea, Candida overgrowth, and urinary tract infections. L. acidophilus has been shown to correct the increase of Gram-negative bacteria observed following the administration of broad-spectrum antibiotics as occurs with any acute or chronic diarrhea. [2] [3] [4] [29] [30] [31] Similarly, a mixture of B. bifidum and L. acidophilus inhibited the lowering of fecal flora induced by ampicillin and maintained the equilibrium of the intestinal ecosystem. [29] Although it is commonly believed that acidophilus supplements are not effective if taken during antibiotic therapy, the research actually supports the use of L. acidophilus during antibiotic administration. [29] [30] Reductions of friendly bacteria and/or superinfection with antibiotic-resistant flora may be prevented by administering L. acidophilus products during antibiotic therapy. A dosage of at least 15–20 billion organisms is required. Probiotic supplements should, however, be taken as far away from the antibiotic as possible. Vaginal yeast infections
Lactobacillus acidophilus has been shown to retard the growth of Candida albicans – the major yeast involved in vaginal yeast infections. [32] Clinical studies have suggested that the introduction of yogurt or lactobacilli to the vagina can assist in clearing up and preventing recurrent vaginal yeast infections as well as bacterial vaginosis. [33] Lactobacillus acidophilus is a normal constituent of the vaginal flora, where it contributes to the maintenance of the acid pH by fermenting vaginal glycogen to lactic acid. [34] [35] [36] [37] It has been shown that suppression of L. acidophilus by broad-spectrum antibiotics leads to the overgrowth of yeast and other bacteria. [38] Reestablishment of normal vaginal lactobacilli can be accomplished by having the woman douche twice a day with an acidophilus solution containing 10
8
live
organisms/ml. However, the right strains must be used. The appropriate lactobacilli produce hydrogen peroxide in the vaginal tract. It is present in 96% of normal vaginas but is absent in women suffering from chronic vaginosis. The production of hydrogen peroxide by lactobacilli is toxic to pathogens such as Gardenerella vaginalis. [39] Not all women’s vaginas are colonized by the right strains of lactobacilli. One study evaluated the lactobacilli in 275 women in the second trimester of pregnancy by obtaining vaginal cultures to detect H 2 O2 -production status as well as the presence of pathological organisms. Women colonized by H 2 O 2 -positive lactobacilli were less likely to have bacterial vaginosis, symptomatic candidiasis and vaginal colonization by Gardnerella vaginalis, Bacteroides, Peptostreptococcus, Mycoplasma hominis, Ureaplasma urelurealyticum, and Viridans streptococci. [40] The women who did not have any vaginal lactobacilli were also more likely to have Chlamydia trachomatis. The researchers also reported that most commercially available products contain lactobacilli that do not produce H 2 O 2 or lactobacillus strains derived from dairy foods, which are unable to bind to vaginal epithelial cells. While douching appears to be the preferred therapy for vaginal infections, even simple consumption of appropriate yogurt products appears beneficial. For example, one study of 33 patients with recurrent Candida vaginitis, found a threefold decrease in infections when they consumed 8 ounces/day of yogurt containing H 2 O2 -producing Lactobacillus acidophilus for a period of 6 months. The mean number of infections per 6 months was 2.54 in the control group, and 0.38 in the yogurt-treated group. Candida colonization decreased from a mean of 3.23/6 months in the control group to 0.84/6 months in the yogurt group. [41] As might be expected, the researchers found an association between the presence of Lactobacillus sp. in the rectum and the vagina. Urinary tract infection
One of the problems with antibiotic therapy for urinary tract infections is that the disturbance in the bacterial flora which protects against urinary tract infections leads
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to recurrent infections. The insertion of lactobaccilli suppositories into the vagina of women after they had been treated with antibiotics has been shown to significantly reduce the recurrence rate. [42] In one study, freeze-dried lactobacilli suppositories given intravaginally once weekly for 1 year to eight women with recurrent UTIs resulted in an impressive 78% reduction in the incidence of infection. [6] Cancer
A series of population studies has suggested that the consumption of high levels of cultured milk products may reduce the risk of colon cancer. [43] Lactobacillus bulgaricus, the primary lactobacilli used for traditional yogurt, has demonstrated potent antitumor activity. [44] Feeding milk and colostrum fermented with L. acidophilus DDS1 has been reported to result in a 16–41% reduction in tumor proliferation in animal studies. [45] In human studies, ingestion of L. acidophilus resulted in reduced activity of the bacterial enzymes associated with the formation of cancer-causing compounds in the gut. [46] The beneficial effects of lactobacilli against cancer appear to extend well beyond the colon. In a double-blind trial conducted in 138 patients surgically treated for bladder cancer, patients were stratified into three groups: (A) with primary multiple tumors, (B) with recurrent single tumors, and (C) with recurrent multiple tumors. [47] In each group, patients were randomly allocated to receive the oral Lactobacillus casei preparation (LCP) or placebo. LCP showed a better effect than placebo in preventing cancer recurrences in subgroups A and B. However, no significant effect was noted in group C. Lactobacillus acidophilus preparations are also of value in cancer patients receiving chemotherapy drugs or radiation therapy involving the gastrointestinal tract. In one study, 24 patients scheduled for internal and external irradiation of the pelvic area for gynecological cancers were selected for a controlled study to test the prevention of intestinal side-effects by administration of L. acidophilus.[48] The test group received 150 ml/day of a fermented milk product supplying them with live L. acidophilus bacteria in a 6.5% lactulose substrate, resulting in prevention of radiotherapy-associated diarrhea. Traveler’s diarrhea
Lactobacilli supplements are routinely recommended by nutritionally oriented doctors to their patients who travel to developing countries. However, one published report casts doubt on this practice. A randomized, double-blind, placebo-controlled trial was conducted on 282 British soldiers deployed to Belize. They received two capsules containing L. fermentum, L. acidophilus or a placebo daily for 3 weeks. There were 10 11 colony-forming units of bacteria in each capsule of lactobacilli. No protection from traveler’s diarrhea was provided by either species. [49] Unfortunately, the H 2 O2 -producing status of the supplement was not reported. Lactose intolerance
Lactose in yogurt with live bacteria is better tolerated in people who are lactose-intolerant than lactose in other dairy foods. This is primarily due to the activity of microbial B-galactosidase which breaks down lactose in vivo. Yogurt containing mixed strains of Streptococcus salvarius ssp. thermophilus and L. delbrueckii ssp. bulgaricus, and fermented milks containing S. thermophilous, L. bulgaricus, L. acidophilus or B. bifidus were evaluated. All the yogurt products dramatically improved lactose digestion regardless of their total or specific B-galactosidase activity. The fermented milks had marginal improvement with B. bifidus and almost complete lactose digestion with L. bulgaricus. These results suggest that B-galactosidase is not the only factor in promoting lactose digestion. [50] Comparable results are found in children. One study of 14 lactose-malabsorbing children, with a mean age of 9.5 years, found that consumption of live yogurt containing L. bulgaricus and S. thermophilous resulted in significantly fewer symptoms than after consuming regular milk and pasteurized yogurt. Breath hydrogen correlated with the degree of symptoms. [51] Crohn’s disease
An interesting study found that four of five patients with disease went into remission for 22 months after having their bowel flora completely replaced with healthier bacteria. The researchers hypothesized that antigens or epitopes on host coliforms in Crohn’s patients may cross-react with, or mimic, antigens or epitopes on epithelial cells of the colon or ileum. The five patients were initially treated with broad-spectrum oral and intravenous antibiotics to sterilize the bowel. They were then reinoculated by oral and rectal administration of two strains of non-pathogenic E. coli and lactobacilli. The clinical improvement lasted 3–4 months. [52]
DOSAGE The dosage of a commercial probiotic supplement is based upon the number of live organisms. The ingestion of one to 10 billion viable L. acidophilus or B. bifidum cells daily is a sufficient dosage for most people. Amounts exceeding this may induce mild gastrointestinal disturbances, while smaller amounts may not be able to colonize the gastrointestinal tract.
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PROMOTING GROWTH OF LACTOBACILLI Fructo-oligosaccharides
Food components which may help to promote the growth of friendly bacteria include fructo-oligosaccharides (FOSs). These short-chain polysaccharides have only recently entered the US market. However, in Japan the number of consumer products containing purified FOSs reached 450 in 1991, and in 1990 the Japanese market for FOSs exceeded $46 million. [53] FOS, which is not digested by humans, provides a preferred substrate for healthful bacteria. Human studies have shown FOS to increase bifidobacteria and
lactobacilli while simultaneously reducing the colonies of detrimental bacteria. Other benefits noted with FOS supplementation include:
[ 53] [54]
• increased production of short-chain fatty acids like butyrate • improved liver function • reduction of serum cholesterol and blood pressure • improved elimination of toxic compounds. The dosage recommendation for pure FOS is 2,000– 3,000 mg daily. Natural food sources of FOS include bananas, Jerusalem artichoke, onions, asparagus, and garlic. However, the estimated average daily ingestion of FOS from food sources is estimated to be only 800 mg. Thus, the supplementation of FOS may often be of clinical benefit. [54] Spirulina
Another possible way to improve the conditions in the intestine is by the consumption of spirulina. While no human studies appear to have been published, intriguing veterinary research has shown that providing horses with spirulina stimulates the growth of Lactobacillus in the cecum. The researchers suggest that this may be due to the mucopolysaccharides in spirulina. [55]
TOXICITY Probiotics are safe and are not associated with any side-effects other than a transient increase in gastrointestinal gas. Interactions
Lactobacillus acidophilus and B. bifidum are negatively affected by alcohol and antibiotics. [56] Although there is no evidence that the organism interferes with the activity of most antibiotics, the metabolism of sulfasalazine, chloramphenicol palmitate, and phthalylsulfathiazole is affected by L. acidophilus. [57]
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VL, Hillier SL. Microbiologic characteristics of Lactobacillus products used for colonization of the vagina. Obstet Gynecol 1990; 75: 244–248
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G, Bruce AW, Taylor M. Vaginal flora and urinary tract infections. Current Opinion in Infectious Disease 1991; 4: 37–41
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SF, Klaenhammer TR. Detection and activity of lacticin B, a bacteriocin produced by Lactobacillus acidophilus. Appl Environ Microbiol 1983; 45: 1808–1815
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TR. Microbiological considerations in the selection of preparations of lactobacillus strains for use in dietary adjuncts. J Dairy Sci 1982; 65: 1339–1349
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TR. Bacteriocins of lactic acid bacteria. Biochemie 1988; 70: 337–349
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Upreti GC, Hinsdill RD. Isolation and characterization of a bacteriocin from a homofermentative Lactobacillus. Antimicrob Agents Chemotherapy 1973; 4: 487–494
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Upreti GC, Hinsdill RD. Production and mode of action of lactocin 27. Bacteriocin from a homofermentative Lactobacillus. Antimicrob Agents Chemotherapy 1975; 7: 139–145
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DeKlerk HC. Bacteriocinogency in Lactobacillus fermenti. Nature 1967; 214: 609
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DeKlerk HC, Smit JA. Properties of a Lactobacillus fermenti bacteriocin. J Gen Microbiol 1967; 48: 309–316
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Friend BA, Shahani KM. Nutritional and therapeutic aspects of lactobacilli. J Appl Nutr 1984; 36: 125–152
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Shahani KM, Vakil JR, Kilara A. Natural antibiotic activity of Lactobacillus acidophilus and bulgaricus. II. Isolation of acidophilin from L. acidophilus. Cult Dairy Prod J 1977; 12: 8
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Shahani KM, Vakil JR, Kilara A. Natural antibiotic activity of Lactobacillus acidophilus and Lactobacillus bulgaricus. Cult Dairy Prod J 1976; 11: 14–17
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Dahiya RS, Speck ML. Hydrogen peroxide formation by lactobacilli and its effect on Staphylococcus aureus. J Dairy Sci 1968; 51: 1568
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Price RJ, Lee JS. Inhibition of pseudomonas species by hydrogen peroxide producing lactobacilli. J Milk Food Technol 1970; 33: 13
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Vesely R, Negri R, Bianchi-Salvadori B et al. Influence of a diet addition with yogurt on the mouse immune system. EOS J Immunol Immunopharmacol 1985; 5: 30–35
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Vincent JG, Veonett RC, Riley RG. Antibacterial activities associated with Lactobacillus acidophilus. J Bacteriol 1959; 78: 477
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Perdigon G, N de Macias ME, Alvarez S et al. Enhancement of immune response in mice fed with Streptococcus thermophilus and Lactobacillus acidophilus. J Diary Sci 1987; 70: 919–926
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Weir D, Blackwell C. Interaction of bacteria with the immune system. J Clin Lab Immunol 1983; 10: 1–12
Perdigon G, N de Macias, Alvarez S et al. Systemic augmentation of the immune response in mice by feeding fermented milks with Lactobacillus casei and Lactobacillus acidophilus. Immunology 1988; 63: 17–23 23.
Perdigon G, Alvarey S, Rachid M. Symposium. Probiotic bacteria for humans. Clinical systems for evaluation of effectiveness. Immune system stimulation by probiotics. J Dairy Sci 1995; 78: 1597–1606 24.
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Clements ML, Levine MM, Black RE et al. Lactobacillus prophylaxis for diarrhea due to enterotoxinogenic Escherichia coli. Antimicrob Agents Chemotherap 1981; 20: 104–108
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Dios Pozo-Olano JD, Warram JH, Gomez RG, Cavazos MG. Effect of a lactobacilli preparation on traveler’s diarrhea. A randomized, double blind clinical trial. Gastroenterol 1978; 74: 829–830
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Thompson GE. Control of intestinal flora in animals and humans: implications for toxicology and health. J Environ Path Toxicol 1977; 1: 113–123
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Clements ML, Levine MM, Ristaino PA. Exogenous lactobacilli fed to man. Their fate and ability to prevent diarrheal disease. Prog Food Nutr Sci 1983; 7: 29–37
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Salminen E, Elomaa I, Minkiunen J. Preservation of intestinal integrity during radiotherapy using live Lactobacillus acidophilus cultures. Clin Radiology 1988; 39: 435–437
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Katelaris PH, Salam I, Farthing MJ. Lactobacilli to prevent traveler’s diarrhea? New Engl J Med 1995; 333: 1360–1361
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Martini MC, Lerebours EC, Lin WJ et al. Strains and species of lactic acid bacteria and fermented milk products (yogurts): effect on in vivo lactose digestion. Am J Clin Nutr 1991; 54: 1041–1046
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Shermak MA, Saavedra JM, Jackson TL et al. Effect of yogurt on symptoms and kinetics of hydrogen production in lactose-malabsorbing children. Am J Clin Nutr 1995; 62: 1003–1006
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Pradhan A, Majumdar MK. Metabolism of some drugs by intestinal lactobacilli and their toxicological considerations. Acta Pharmacol Toxicol 1986; 58: 11–15
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Chapter 106 - Procyanidolic oligomers Michael T. Murray ND Joseph E. Pizzorno Jr ND
GENERAL DESCRIPTION The proanthocyanidins (also referred to as procyanidins) are one of the most beneficial groups of plant flavonoids. The most active proanthocyanidins are those bound to other proanthocyanidins. Collectively, mixtures of proanthocyanidin dimers, trimers, tetramers, and larger molecules are referred to procyanidolic oligomers or PCOs for short. [1] [2] Although PCOs exist in many plants, as well as red wine, commercially available sources of PCOs include extracts from grape seed skin ( Vitex vinifera) and the bark of the maritime (Landes) pine. [1] [2] This chapter reviews the benefits of PCOs from grape seeds and pine bark.
CHEMICAL COMPOSITION Grape seed and pine bark PCO extracts are well defined chemically. Grape seed extracts are available which contain 92–95% PCOs while the pine bark extracts vary from 80 to 85%. Proanthocyanidin B 2 is shown in Figure 106.1 .
HISTORY AND FOLK USE In 1534, French explorer Jacques Cartier lead an expedition up the Saint Lawrence River. Trapped by ice,
Figure 106-1 Proanthocyanidin B 2 .
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Cartier and his crew were forced to survive on a ration of salted meat and biscuits. Cartier’s crew began to exhibit signs and symptoms of scurvy, the cause of which was unknown at that time. Fortunately for Cartier and the surviving members of his crew, they met a Native American who advised them to make a tea from the bark and needles of pine trees. As a result, Cartier and his men survived. More than 400 years later, Professor Jacques Masquelier of the University of Bordeaux, France, read the book Cartier wrote detailing his expedition. Intrigued by Cartier’s story, Masquelier and others concluded that pine bark must contain some vitamin C as well as bioflavonoids which can exert vitamin C-like effects. Masquelier termed the active components of the pine bark “pycnogenols”. [1] [3] This term was used to describe an entire complex of proanthocyanidin complexes found in a variety of plants including pine bark, grape seeds, lemon tree bark, peanuts, cranberries, and citrus peels. The term “pycnogenols” has been replaced in the scientific community by the terms proanthocyanidins, oligomeric proanthocyanidin complexes (OPCs), and/or procyanidolic oligomers (PCO). In the United States, Pycnogenol® is a registered trademark of Horphag Ltd of Guernsey, UK, and refers to the procyanidolic oligomer (PCO) extracted from the bark of the French maritime pine. Masquelier patented the method of extracting PCOs from pine bark in France in 1951, and from grape seeds in 1970. The PCO extract from grape seed emerged as the preferred source based on research between 1951 and 1971, as well as intensive research from 1972 to 1978. [1] The 1970s research was conducted with the goal of gaining approval for PCO as a medicinal agent by the French equivalent of the FDA. During this time, detailed analytical, toxicity, pharmacological, and clinical studies were performed on PCOs derived from grape seeds. PCOs from both grape seeds and pine bark have been marketed in France for decades where they have been promoted to improve retinopathies, venous insufficiency, and vascular fragility.
PHARMACOLOGY Extracts of PCOs have demonstrated a wide range of activity as listed in Table 106.1 . Protection of collagen
Collagen, the most abundant protein of the body, is TABLE 106-1 -- Pharmacological activity of proanthocyanidins [1] [2] • Increase intracellular vitamin C levels • Decrease capillary permeability and fragility • Scavenge oxidants and free radicals • Inhibit destruction of collagen responsible for maintaining the integrity of ground substance as well as the integrity of tendons, ligaments, and cartilage. Collagen is also the support structure of the dermis and blood vessels. PCOs are remarkable in their effect in supporting collagen structures and preventing collagen destruction. They affect collagen metabolism in several ways. They have the unique ability to cross-link collagen fibers, resulting in reinforcement of the natural cross-linking of collagen that forms the so-called collagen matrix of connective tissue. [4] [5] They also protect against free radical damage with their potent antioxidant and free radical scavenging action; and inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation and microbes during infection. [6] [7] PCOs also prevent the release and synthesis of compounds that promote inflammation and allergies such as histamine, serine proteases, prostaglandins, and leukotrienes. [1]
Antioxidant and free radical scavenging activity
Perhaps the most celebrated effects of PCOs in the United States are their potent antioxidant and free radical scavenging activity. Free radical damage has been linked to the aging process and virtually every chronic degenerative disease including heart disease, arthritis, and cancer. Fats and cholesterol are particularly susceptible to free radical damage. When damaged, fats and cholesterol form toxic derivatives known as lipid peroxides and cholesterol epoxides, respectively. The antioxidant and free radical scavenging effects of PCOs were discovered by Masquelier in 1986. [1] A recent study evaluated the free radical scavenging activity of PCOs and determined their inhibitory effects on xanthine oxidase (a primary generator of oxygen-derived free radicals) and the lysosomal enzyme system (which governs the release of enzymes which can damage the connective tissue framework that acts as a protective sheath surrounding capillary walls). [7] This research, summarized in Table 106.2 , provides a detailed explanation of the vascular protective action of PCOs and a strong rationale for their use in vascular disease. In experimental models, the antioxidant activity of TABLE 106-2 -- Antioxidant and free radical scavenging activities of PCOs • Trap hydroxyl free radicals • Trap lipid peroxides and free radicals • Markedly delay the onset of lipid peroxidation • Chelate free iron molecules, thereby preventing iron-induced lipid peroxidation • Inhibit production of free radicals by non-competitively inhibiting xanthine oxidase • Inhibit the damaging effects of the enzymes (e.g. hyaluronidase, elastase, collagenase, etc.) which can degrade connective tissue structures
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PCOs is much greater (approximately 50 times) than that of vitamin C and vitamin E. From a cellular perspective, one of the most advantageous features of PCOs’ free radical scavenging activity is that, because of their chemical structure, they are incorporated into cell membranes. This physical characteristic, along with their ability to protect against both water- and fat-soluble free radicals, provides significant cellular protection against free radical damage. The researchers concluded their discussion with the following comment: “These findings, together [with] those of other investigators, provide a strong rationale for using these compounds in the therapeutic management of microvascular disorders.”
CLINICAL APPLICATIONS Venous and capillary disorders
The primary clinical applications of PCOs are in the treatment of: • venous and capillary disorders including venous insufficiency • varicose veins • capillary fragility • disorders of the retina, including diabetic retinopathy and macular degeneration. Good clinical studies have shown positive results in the treatment of these conditions.
[8] [9] [10] [11] [12] [13] [ 14] [15]
Visual function
Increased intake of PCO is likely to benefit almost everyone. This suggestion is perhaps best illustrated by research evaluating the effects of grape seed PCOs extract on visual function in healthy subjects. [14] [15] In the studies, 100 normal volunteers with no retinal disorder received 200 mg/day of PCOs or placebo for 5 or 6 weeks. The group receiving PCOs demonstrated significant improvement in visual performance in dark and after glare tests compared with the placebo group. Atherosclerosis
There are now numerous studies demonstrating that an individual’s level of antioxidants may be a more significant factor in determining the risk of developing heart disease than cholesterol levels. Antioxidants prevent the oxidation of cholesterol and its carrier proteins as well as preventing the initial damage to the artery which ultimately leads to the process of atherosclerosis. Large-scale studies with vitamin E, vitamin C, and beta-carotene have shown that these antioxidants are capable of significantly reducing the risk of dying of a heart attack or a stroke. For example, in one study of 87,245 nurses, it was discovered that nurses who took 100 IU of vitamin E daily for more than 2 years had a 41% lower risk of heart disease compared with non-users of vitamin E supplements. [16] Another study of 39,910 male health care professionals produced similar results: a 37% lower risk of heart disease with the intake of more than 30 IU of supplemental vitamin E daily. [17] Since PCOs have a greater antioxidant effect than vitamins C and E, it is only natural to speculate they could offer greater protective effects. Support exists for this contention. For example, several studies have shown the protective effects of red wine against heart disease and stroke by protecting against LDL oxidation. [18] The active components in the wine are thought to be proanthocyanidins. Also, a recent study of 805 men beginning in 1985 demonstrated an inverse correlation between flavonoid intake and death due to heart attack. [19] In addition to preventing damage to cholesterol and the lining of the artery, PCO extracts have been shown to lower blood cholesterol levels and shrink the size of the cholesterol deposit in the artery in animal studies. [1] [20] Additional mechanisms of PCOs useful in preventing atherosclerosis include inhibition of platelet aggregation and inhibition of angiotensin-I-converting enzyme. [21] [22] Presumably, PCO extracts may exert similar benefits in humans. PCO extracts, although in a supplement form, should be thought of as a necessary food in the prevention and treatment of atherosclerosis.
DOSAGE As antioxidant support, a daily dose of 50 mg of either the grape seed or pine bark extract is suitable. For comparison, it is now estimated that the average daily intake of total flavonoids in the United States is about 25 mg. An intake greater than 30 mg offers significantly reduced risk for cardiovascular mortality. [19] When being used for therapeutic purposes, the daily dosage should be increased to 150–300 mg.
TOXICITY PCO extracts are without known side-effects.
REFERENCES
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B, Masquelier J. OPC in practice: biflavanols and their application. Rome: Alfa Omega. 1993
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J. Procyanidolic oligomers. J Parfums Cosm Arom 1990; 95: 89–97
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J. Pycnogenols. Recent advances in the therapeutical activity of procyanidins. Natural Prod Med Agents 1981; 1: 243–256
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J, Dumon MC, Dumas J. Stabilization of collagen by procyanidolic oligomers. Acta Therap 1981; 7: 101–105
JM, Godeau G, Robert AM. Evidence by in vivo and in vitro studies that binding of pycnogenols to elastin affects its rate of degradation by elastases. Biochem Pharmacol 1984; 33: 3933–3939
6. Meunier
MT, Duroux E, Bastide P. Free-radical scavenger activity of procyanidolic oligomers and anthocyanosides with respect to superoxide anion and lipid peroxidation. Plant Med Phytother 1989; 4: 267–274 7. Facino
RM, Carini M, Aldini G et al. Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis vinifera. A mechanism for their capillary protective action. Arzneim Forsch 1994; 44: 592–601 8. Henriet
JP. Veno-lymphatic insufficiency. 4,729 patients undergoing hormonal and procyanidol oligomer therapy. Phlebologie 1993; 46: 313–325
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J. Effect of Endotelon in postoperative edema. Results of a double-blind study versus placebo in 32 female patients. Ann Chir Plast Esthet 1984; 29: 393–395
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Lagrue G, Oliver-Martin F, Grillot A. A study of the effects of procyanidol oligomers on capillary resistance in hypertension and in certain nephropathies. Sem Hosp Paris 1981; 57: 1399–1401
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Gomez Trillo JT. Varicose veins of the lower extremities. Symptomatic treatment with a new vasculotrophic agent. Prensa Med Mex 1973; 38: 293–296
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Soyeux A, Segiun JP, Le Devehat C. Endotelon. Diabetic retinopathy and hemorheology (preliminary study). Bull Soc Ophtalmol Fr 1987; 87: 1441–1444
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Proto F et al. Electrophysical study of Vitis vinifera procyanoside oligomers effects on retinal function in myopic subjects. Ann Ott Clin Ocul 1988; 114: 85–93
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Corbe C, Boisin JP, Siou A. Light vision and chorioretinal circulation. Study of the effect of procyanidolic oligomers (Endotelon). J Fr Ophtalmol 1988; 11: 453–460
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Boissin JP, Corbe C, Siou A. Chorioretinal circulation and dazzling. use of procyanidol oligomers. Bull Soc Ophtalmol Fr 1988; 88: 173–174, 177–179
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Stampfer MJ, Henneken SCH, Manson JE. Vitamin E consumption and the risk of coronary disease in women. New Engl J Med 1993; 328: 1444–1448
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Rimm EB. Vitamin E consumption and the risk of coronary heart disease in men. New Engl J Med 1993; 328: 1450–1455
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Frankel EN, Kanner J, German JB. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993; 341: 454–457
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Hertog MG, Feskens EJ, Hollman PC. Dietary antioxidant flavonoids and risk of coronary heart disease. The Zutphen Elderly Study. Lancet 1993; 342: 1007–1011
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Wegrowski J, Robert Am, Moczar M. The effect of procyanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas. Biochem Pharmacol 1984; 33: 3491–3497
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Chang WC, Hsu FL. Inhibition of platelet aggregation and arachidonate metabolism in platelets by procyanidins. Prostagland Leukotri Essential Fatty Acids 1989; 38: 181–188
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Meunier MT, Villie F, Jonadet M. Inhibition of angiotensin I converting enzyme by flavanolic compounds. In vitro and in vivo studies. Planta Med 1987; 54: 12–15
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Chapter 107 - Pygeum africanum (bitter almond) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Pygeum africanum (family: Rosaceae) Synonym: Prunus africanum Common names: bitter almond, red stinkwood
GENERAL DESCRIPTION Pygeum africanum is an evergreen tree native to Africa that can grow to a height of 120–150 feet. It has pendulous branches with thick, oblong-shaped, leather-like, mat-colored leaves and creamy white flowers. The fruit (drupe) resembles a cherry when ripe. The dark brown to gray bark of the trunk is the part used for medicinal purposes.
CHEMICAL COMPOSITION The major active components of the bark are: • lipid-soluble pentacyclic triterpenes • sterolic triterpenes • fatty acids • esters of ferulic acid (see Fig. 107.1 ). The pentacyclic triterpenic components include ursolic acid (see Fig. 107.2 ), oleanolic acid, crataegolic acid, and their derivatives. The sterolic fraction is composed mainly of beta-sitosterol and beta-sitosterone (see Fig. 107.3 ). The fatty acids range from C12 to C24 and the important ferulic acid esters are those bound to n-tetracosanol and n-docosanol. [1] [2] [3] [4]
Figure 107-1 Ferulic acid.
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Figure 107-2 Ursolic acid.
Figure 107-3 ß-Sitosterone.
HISTORY AND FOLK USE The powdered bark of Pygeum africanum was used by the natives of tropical Africa as a treatment for urinary disorders. It was often given with palm oil or milk.
PHARMACOLOGY Pharmacological screening of various extracts prepared with solvents of differing degrees of polarity indicated that the highest activity was found in lipophilic extracts. This finding is interesting in light of pygeum’s historical administration in lipophilic media (palm oil or milk). Virtually all of the pharmacological research has featured a pygeum extract standardized to contain 14% triterpenes including beta-sitosterol and 0.5% n-docosanol. This extract has been extensively studied in both experimental animal studies and clinical trials with humans. The primary target organ for pygeum’s effects in males is the prostate. The three major active components of pygeum appear to exert different, yet complementary, effects in benign prostatic hyperplasia (BPH). In addition, pygeum has been shown to enhance the secretions of the prostate and bulbourethral glands, in terms of both quantity and quality. Ferulic acid esters
The esters of ferulic acid act primarily on the endocrine system. Studies in animals have shown docosanol to reduce levels of leutinizing hormone and testosterone while raising adrenal steroid secretion of both adrenal androgens and corticosteroids. [5] [6] Docosanol also significantly reduces serum prolactin levels. This reduction of prolactin is quite significant as prolactin increases the uptake of testosterone and increases the synthesis of dihydrotestosterone within the prostate. The accumulation of testosterone within the prostate and its subsequent conversion to the more potent dihydrotestosterone is thought to be the major contributing factor to the hyperplasia of the prostatic cells observed in BPH. [7] Although traces of docosanol are present in pygeum, the esterification with ferulic acid results in greater
bioavailability and activity. [2] [4] [8] Ferulic acid esters, as well as the sterol fraction of pygeum, exert cholesterol-lowering action systematically, as well as reducing the intraprostatic cholesterol content.[8] Breakdown products of cholesterol have been shown to accumulate in the prostate tissue affected with either BPH or cancer. [7] These metabolites of cholesterol initiate degeneration of prostatic cells which can promote prostatic enlargement. Drugs which lower cholesterol levels have been shown to have a favorable influence on BPH, preventing the accumulation of cholesterol in the prostatic cells and limiting subsequent formation of damaging cholesterol metabolites. The lowering of intraprostatic cholesterol content is an important aspect of the pharmacology of pygeum. The sterolic fraction is also endowed with competitive action against testosterone accumulation within the prostate. In addition, the sterols of pygeum have also been shown to reduce inflammation by preventing the intraprostatic formation of inflammatory prostaglandins. [8] [9] Other components
Other components of pygeum are also important. For example, the pentacyclic triterpenes exhibit anti-inflammatory effects within the prostatic epithelium and may be responsible for stimulation of the secretory cells of the prostate, seminal vesicles, and bulbourethral glands. [8] [9] [10] And finally, the fatty acids components are similar to those of Serenoa repens (see Ch. 110 ) and may exert similar effects as well as improve the oral bioavailability of other components of the lipophilic extract.
CLINICAL APPLICATIONS Prostate disorders
The pharmacological actions of the standardized pygeum extract supports its use in prostate disorders, BPH in particular. Adding further support are the results from numerous clinical trials of over 600 patients. [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] Consistently, these studies have demonstrated pygeum to effectively reduce the symptoms and clinical signs of BPH, especially in early cases. However, it must be
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TABLE 107-1 -- Results of the most significant open and double-blind studies of the last 20 years on outpatients with Pygeum africanum for 1–3 months Author mg/day Days No. of patients Percentage of patients showing reduction (%) Dysuria Nocturia Frequency
Residual urine
Prostate volume
Open trials Guillemin[11]
100
30
25
80
80
80
80
NC
Lange & Muret[12]
100
30
25
72
NC
72
NC
NC
Wemeau et al [13]
100
45
27
60
NC
71
NC
NC
Viollet[14]
75
60
20
64
NC
64
NC
NC
Lhez & Leguevague[15]
75
90
52
69
NC
NC
NC
NC
Thomas & Rouggilange [16]
75
50
33
60
57
57
NC
–
Huet[17]
50
30
55
85
85
85
NC
20
Rometti[18]
100
50
25
72
72
72
NC
25
Gallizia & Gallizia [19]
100
60
19
90
85
70
20
NC
Durval[20]
100
90
23
72
72
72
72
NC
Pansadoro & Benincasa[21]
75
90
35
94
94
94
94
–
Maver[23]
100
60
60
77
70
57
23
–
Bongi[24]
75
60
50
88
88
88
88
88
Doremieuz et al[25]
100
60
77
85
NC
NC
NC
NC
Del Valio[26]
100
60
30
–
–
48
–
–
Colpi & Farina [27]
150
45
47
–
70
–
76
NC
Donkervoort et al [28]
150
90
20
80
80
80
NC
NC
Dufour & Choquenet [29]
100
45
120
–
78
45
65
NC
Legromandi et al [30]
100
45
104
89
89
89
NC
NC
Ranno et al [31]
200
60
39
75
75
75
NC
NC
Frasseto et al[32]
200
60
20
–
–
–
–
–
Bassi et al [33]
200
60
40
70
70
70
70
70
Double-blind trials
–, not measured; NC, no change. pointed out that improvement is largely symptomatic, as the results on reducing the size of the prostate or the residual urine content of the bladder are modest. The results of the clinical trials on pygeum are given in Table 107.1 . Below, there is a discussion of some of the most important aspects of these studies. One of the major findings in evaluating the effectiveness of pygeum in BPH has been the high rate of responders to placebo. This is well-demonstrated in one of the larger double-blind studies. [29] Similar to the results in other double-blind studies, pygeum extract was shown to be statistically superior to a placebo in reducing the major symptoms of BPH (nocturnal frequency, difficulty in starting micturition, and incomplete emptying of the bladder). However, there was a high percentage of responders to the placebo (see Table 107.2 below). It seems that simply taking a capsule provides relief to many sufferers. Another study highlights the importance of double-blind
Symptom
TABLE 107-2 -- Patients responding to placebo and pygeum Placebo group
Pygeum group
Nocturia
26/52 = 50%
44/56 = 78%
Daytime frequency
16/50 = 33%
27/54 = 50%
Incomplete voiding
14/40 = 35%
21/32 = 66%
Dribbling
15/34 = 44%
13/33 = 39%
Urine flow rate
11/43 = 26%
21/38 = 55%
studies which feature both objective and subjective findings. In the study, both patients and physicians rated the placebo and pygeum extract to be effective in improving subjective symptoms of daytime frequency, nocturia, weak stream, after-dribbling, hesitation, and interruption of flow. [28] However, urodynamic variables (flow, frequency, and histogram) clearly demonstrated the superiority of pygeum over placebo. One of the shortcomings of some of the clinical research on pygeum is the lack, in many of the studies, of objective measures such as urine flow rate (ml/s), residual urine content, and prostate size. Studies that have used objective measurements have shown some good results. For example, in one open trial, 30 patients with BPH given 100 mg/day of the pygeum extract for 75 days demonstrated significant improvements in objective parameters: maximum flow rate increased from 5.43 to 8.20 ml/s and the residual urine volume dropped from 76 to 33 ml. [22] Male infertility and impotence
Pygeum may be effective in improving fertility in cases where diminished prostatic secretion plays a significant role. Pygeum has been shown to increase prostatic secretions and improve the composition of the seminal fluid. [34] [35] [36] Specifically, pygeum administration to men with decreased prostatic secretion has led to increased levels of total seminal fluid plus increases in alkaline
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phosphatase and protein. Pygeum appears to be most effective in cases where the level of alkaline phosphatase activity is reduced (i.e. less than 400 IU/cm 3 ) and where there is no evidence of inflammation or infection (i.e. absence of white blood cells or IgA). The lack of IgA in the semen is a good predictor of clinical success. In one study, the patients with no IgA in the semen demonstrated an alkaline phosphatase increase from 265 to 485 IU/cm 3, [34] In contrast, those subjects with IgA showed only a modest increase from 213 to 281 IU/cm3 . Pygeum extract has also shown an ability to improve the capacity to achieve an erection in patients with BPH or prostatitis as determined by nocturnal penile tumescence in a double-blind clinical trial. [37] BPH and prostatitis are often associated with erectile dysfunction and other sexual disturbances. Presumably by improving the underlying condition, pygeum can improve sexual function. Pygeum vs. serenoa The standardized liposterolic extract of Serenoa repens is another popular botanical treatment for BPH (see Ch. 110 ). In a double-blind study which compared the pygeum extract with the extract of serenoa, the serenoa extract produced a greater reduction of symptoms and was better tolerated. [38] In addition, the improvement of objective parameters, especially urine flow rate and residual urine content, is better in the clinical studies with serenoa. However, there may be circumstances where pygeum is more effective than serenoa. For example, serenoa has not been shown to produce the effects that pygeum has produced on prostate secretion. Although the two extracts have somewhat overlapping mechanisms of actions, they can be used in combination.
DOSAGE The dosage of the lipophilic extract of Pygeum africanum standardized to contain 14% triterpenes including beta-sitosterol and 0.5% n-docosanol is 100–200 mg/day in divided doses. The crude herb is not used.
TOXICOLOGY Acute and chronic toxicity tests in the rat and mouse have shown that the standardized extract of Pygeum africanum bark is non-toxic. Increasing doses from 1 to 6 g/kg in the mouse and from 1 to 8 g/kg in the rat caused no deaths within 48 hours. In chronic toxicity studies, dosing the animals with from 60 to 600 mg/kg for 11 months did not produce any negative effects. In the human clinical trials, the pygeum extract also demonstrated no significant toxicity. The most common side-effect is gastrointestinal irritation, resulting in symptoms ranging from nausea to severe stomach pains; however, rarely does the presence of these side-effects result in discontinuation of therapy.
REFERENCES 1. Longo
R, Tira S. Steroidal and other components of Pygeum africanum bark. Il Farmaco 1982; 38: 288–292
2. Martinelli
EM, Seraglia R, Pifferi G. Characterization of Pygeum africanum bark extracts by HRGC with computer assistance. HRC & CC 1986; 9: 106–110
3. Pierini
N. Identification and determination of n-docosanol in Pygeum africanum bark extract and in medicinal specialties containing them. Boll Chim Farm 1982; 121: 27–34
4. Uberti
E. HPLC analysis of n-docosyl ferulate in Pygeum africanum extracts and pharmaceutical formulations. Fitotherapia 1990; 41: 342–347
5. Muntzing
J, Eneroth P, Gustafsson JA, Liljekvist J. Direct and indirect effects of docosanol, the active principle in Tadenan, on the rat prostate. Invest Urol 1979; 17: 176–180
6. Thieblot
L. Preventive and curative action of Pygeum africanum extracts on experimental prostatic adenoma in the rat. Therapie 1975; 26: 575–580
7. Hinman
F. Benign Prostatic Hyperplasia. New York: Springer-Verlag. 1983
8. Bombardelli 9. Marcoli
E. Methods, composition and compounds for the treatment of prostatic adenoma. EP Appl 8330491.3, June 10, 1985
M. Anti-inflammatory and antiedemigenic activity of extract of Pygeum afrcanum in the rat. New Trends Androl Sci 1985; 1: 89
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Latalski M. The ultrastructure of the epithelium of bulbourethral glands after administration of Pygeum africanum extract. Folia Morphol 1979; 1: 193–201
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Guillemin P. Clinical trials of V1326, or Tadenan, in prostatic adenoma. Med Prat 1970; 386: 75–76
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Lange J, Muret P. Clinical trial of V1326 in prostatic disease. Med 1970; 11: 2807–2811
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Wemeau L, Delmay J, Blankaert J. Tadenan in prostatic adenoma. Vie Medicale 1970; Jan: 585–588
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Viollet G. Clinical experimentation of a new drug from prostatic adenoma. Vie Medicale 1970; June: 3457–3458
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Lhez A, Leguevague G. Clinical trials of a new lipid-sterolic complex of vegetal origin in the treatment of prostatic adenoma. Vie Medicale 1970; Dec: 5399–5404
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Thomas JP, Rouffilange F. The action of Tadenan in prostatic adenoma. Rev Int Serv 1970; 43: 43–45
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Huet JA. Prostatic disease in old age. Med Intern 1970; 5: 405–408
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Rometti A. Medical treatment of prostatic adenoma. La Provence Medicale 1970; 38: 49–51
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Gallizia F, Gallizia G. Medical treatment of benign prostatic hypertrophy with a new phytotherapeutic principle. Recent Med 1972; 9: 461–468
20.
Durval A. The use of a new drug in the treatment of prostatic disorders. Minerva Urol 1970; 22: 106–111
21.
Pansadoro V, Benincasa A. Prostatic hypertrophy. Results obtained with Pygeum africanum extract. Minerva Med 1972; 11: 119–144
22.
Zurita IE, Pecorini M, Cuzzoni G. Treatment of prostatic hypertrophy with Pygeum africanum extract. Rev Bras Med 1984; 41: 364–366
23.
Maver A. Medical therapy of the fibrous-adematose hypertrophy of the prostate with a new vegetal substance. Minerva Med 1972; 63: 2126–2136
24.
Bongi G. Tadenan in the treatment of prostatic adenoma. Minerva Urol 1972; 24: 129–139
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Doremieux J, Masson JC, Bollack C. Prostatic hypertrophy, clinical effects and histological changes produced by a lipid complex extracted from Pygeum africanum. J Med Strasbourg 1973; 4: 253–257 25.
26.
Del Valio B. The use of a new drug in the treatment of chronic prostatitis. Minerva Urol 1974; 26: 81–94
Colpi G, Farina U. Study of the activity of chloroformic extract of Pygeum africanum bark in the treatment of urethral obstructive syndrome caused by non-cancerous prostapathy. Urologia 1976; 43: 441–448 27.
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Donkervoort T, Sterling J, van Ness J, Donker PJ. A clinical and urodynamic study of Tadenan in the treatment of benign prostatic hypertrophy. Urol 1977; 8: 218–225
29.
Dufour B, Choquenet C. Trial controlling the effects of Pygeum africanum extract on the functional symptoms of prostatic adenoma. Ann Urol 1984; 18: 193–195
30.
Legramandi C, Ricci-Barbini V, Fonte A. The importance of Pygeum africanum in the treatment of chronic prostatitis void of bacteria. Gazz Medica Ital 1984; 143: 73–76
31.
Ranno S, Minaldi G, Viscusi G et al. Efficacy and tolerability in the treatment of prostatic adenoma with Tadenan 50. Progresso Medico 1986; 42: 165–169
32.
Frasseto G, Bertoglio S, Mancuso S et al. Study of the efficacy and tolerability of Tadenan 50 in patients with prostatic hypertrophy. Progresso Medico 1986; 42: 49–52
33.
Bassi P, Artibani W, De Luca V et al. Standardized extract of Pygeum africanum in the treatment of benign prostatic hypertrophy. Minerva Urol 1987; 39: 45–50
34.
Lucchetta G, Weill A, Becker N et al. Reactivation from the prostatic gland in cases of reduced fertility. Urol Int 1984; 39: 222–224
35.
Menchini-Fabris GF, Giorgi P, Andreini F et al. New perspectives of treatment of prostato-vesicular pathologies with Pygeum africanum. Arch Int Urol 1988; 60: 313–322
36.
Clavert A, Cranz C, Riffaud JP et al. Effects of an extract of the bark of Pygeum africanum on prostatic secretions in the rat and man. Ann Urol 1986; 20: 341–343
37.
Carani C, Salvioli C, Scuteri A et al. Urological and sexual evaluation of treatment of benign prostatic disease using Pygeum africanum at high dose. Arch Ital Urol Nefrol Androl 1991; 63: 341–345
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Duvia R, Radice GP, Galdini R. Advances in the phytotherapy of prostatic hypertrophy. Med Praxis 1983; 4: 143–148
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Chapter 108 - Recommended optimum nutrient intakes (RONIs) Alexander G. Schauss PhD
INTRODUCTION In 1998, the Food and Nutrition Board of the US Institute of Medicine recommended that to reduce the likelihood of neural tube defects in children, “women should eat a varied diet and take an extra 400 micrograms of folic acid to be absolutely sure that they get enough of the nutrient”. That the public should use a dietary supplement, not just food, to reassure themselves that they are getting the necessary levels of a nutrient to prevent a disease or condition is nothing less than a paradigm shift in official public health policy. In recent years a convincing link between the intake of folic acid and neural tube defects has been established. As a result, the National Institutes of Health and US Department of Health and Human Services have given special attention to the need for folic acid in the diet in the prevention of such neural tube defects as spina bifida. Folic acid is but one of the B vitamins that in recent years has been the subject of research into the role that nutrients play in the prevention, mitigation or treatment of cancers, cardiovascular diseases, mental disorders, and other diseases or conditions. For example, researchers are continuing to unravel the association between levels of folate, pyridoxine (vitamin B 6 ) and inositol, and the reduction of excessive levels of blood homocysteine, a marker associated with the risk of cardiovascular disease. This chapter will discuss the recommended optimal daily intake of nutrients necessary to maintain health and reduce the risk of disease. The conclusion reached by the author for each nutrient is based on a review of thousands of epidemiological, clinical, and experimental papers, offering evidence for optimal versus minimal intake levels. The RDAs The weaknesses of the RDAs
Since the mid-1940s, the US recommended daily allowances (RDAs) have served as a nutritional guideline.
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These guidelines were developed from minimalist criteria aimed solely at the prevention of nutritionally related clinical deficiencies. More recently, in the mid-1990s, these guidelines were superseded by Food and Drug Administration (FDA) nutritional guidelines known as the recommended daily intake levels (RDIs). Curiously, the RDIs show no more promise than did the RDAs in providing the public with useful information on the intake of nutrients in the prevention, mitigation and treatment of a wide range of conditions and diseases for which diet does, or may, play a role. Hence, it is worthwhile to understand the limits of the RDAs and RDIs to fully appreciate the need for recommended optimal nutrition intake (RONIs). Since our understanding of the optimal level of each nutrient in the prevention, mitigation, and treatment of disease remains a somewhat primitive science, the discussion will be framed around the concept of recommended optimal nutrition intake (RONI). As our understanding of the role of each nutrient in disease processes becomes more sophisticated, the values for the RONIs are certain to change. Yet they certainly provide us with better guidelines to maintain health than the minimalist basis from which the RDAs were constructed. The history of the RDAs
In May 1941, a committee of the National Academy of Sciences suggested for the first time that a “recommended daily dietary allowance” of essential nutrients be established. These guidelines were developed with the goal of reducing the incidence of nutritional deficiency diseases in the general population, such as scurvy (deficiency of vitamin C), pellagra (deficiency of niacin), and beri-beri (deficiency of vitamin B 1 ). Since then, nutritionists, dietitians, and physicians have relied on the RDAs, including nine revisions, as guidelines for advising public health officials and the public on recommended nutrient intake levels. According to the committee that established the RDAs, they were intended: • as guidelines for the prevention of nutritional deficiencies • to be related to the nutrient status of population groups, not individuals. In essence, the RDAs provide no information on the role of nutrients in the prevention, amelioration, or treatment of conditions or diseases. A common mistake made by many public health practitioners is to use the RDAs to evaluate the adequacy of an individual’s diet. Even worse is the assumption that maintaining a diet that provides an RDA level of nutrients will somehow ensure wellness over one’s lifetime. Only recently has it become apparent that “healthy normal people” are an ideal. Among Americans aged 60 and over, more than 80% suffer from at least one or more chronic diseases, such as cancer, atherosclerosis, osteoporosis, macular degeneration, or diabetes. Since at least 1951, critics of the RDAs have asserted that they lack the ability to recommend levels of nutrients sufficient to maintain health for a person seeking a healthy life span that is associated with a morbidity-free existence. Studies used to determine the level of a nutrient that is sufficient to prevent a nutritional deficiency are typically conducted for only 6–9 months, about 1% of the average person’s life span. This suggests that these minimalist dietary standards are based on data incapable of suggesting levels of nutrients essential to prevent many conditions and diseases associated with morbidity. Even more germane to this issue is the attention focused in recent years on the role of substances not generally recognized as nutrients that appear to be directly involved in the prevention or mitigation of a diverse host of diseases from colon cancer to coronary heart disease, cataracts, birth defects, and stroke. Early editions of the RDAs that where published in the 1940s clearly stated that the RDAs “vary greatly in disease”. Yet in spite of this realization, the RDAs continue to focus only on the prevention of nutritional deficiencies in population groups. However, this began to change in 1989 with the release of the 10th edition of the RDAs by the National Academy of Sciences. The 10th edition acknowledged for the first time that levels of a nutrient, specifically the nutrient vitamin C, may need to be higher than the RDA for groups at risk of
developing chronic diseases, particularly, smokers. This welcome recommendation by the National Academy of Sciences has opened the door to an entirely new paradigm, namely, the determination of optimal nutrient intake levels needed to minimize the risk of developing conditions and diseases affecting various population groups (i.e. women at risk of birth defects). Unfortunately, the RDAs’ noble attempt remains inadequate because of its minimalist foundation. While a higher level of vitamin C intake for smokers is indeed suggested in the 10th edition, studies of the blood levels of vitamins and minerals in smokers have shown that low levels of other nutrients such as beta-carotene, zinc, vitamin B 6 , and vitamin E may also be needed at significantly higher levels than that recommended for vitamin C or prescribed by the RDAs. Mounting evidence suggests that all of these nutrients, not just vitamin C, and probably many other nutrients and non-nutritive substances, may need to be taken by smokers to compensate for the nutrient loss such a habit produces. The RDAs also fail to address excessive use of alcohol – yet another example of a common addiction that increases nutrient requirements. Individuals who chronically
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consume alcohol have been found to have lower levels of folate, vitamin B 1 , vitamin B6 , vitamin A, beta-carotene, zinc, and vitamin C. The lifestyles of individuals are also neglected in the RDAs. Dieters, for example, are a population who have frequently been found to have low nutrient status. Studies have shown that it is extremely difficult, if not impossible, to meet all of the RDAs for nutrients, let alone maintain health, when chronically consuming less than 1,200 calories/day. An analyses of 11 major reducing diets shows that none can provide 100% of the RDA for vitamins alone. What about individuals with eating disorders (i.e. bulimia nervosa)? Or those working under chronic conditions of stress? Individuals who smoke cigarettes? Or heavy alcohol consumers? We have come to realize that individuals may have habits or lifestyles that require nutrient levels that are well in excess of those recommended by the RDAs. It is important to understand the limits of the RDAs and to appreciate the potential benefits of higher nutrient intake levels. Table 108.1 outlines five limitations of the RDAs as dietary intake guidelines in the prevention of conditions and diseases that affect morbidity and mortality. The need for a guideline to optimal intake levels of nutrients A growing body of evidence indicates that intakes of certain vitamins and minerals at levels well above the RDAs may be necessary to protect against the development of certain conditions and diseases that affect our quality of life and/or life span. For example, antioxidants, such as vitamin C, beta-carotene, vitamin E, and selenium, may prevent free radical damage to vascular endothelial cells associated with the most common form of cardiovascular disease, atherosclerosis. These vitamins/minerals TABLE 108-1 -- Limitations of the RDAs • They are meant to serve as a guideline for the prevention of nutritional diseases, not the promotion of health • The recommendations are based on the nutrient status of large population groups numbering in the millions, not as a guideline to determine individual dietary nutrient requirements • The estimates of the RDAs are based only on short-term research that represents less than 1% of the average person’s lifespan, so they cannot provide nutrient recommendations that may be of benefit over a lifetime in the prevention or amelioration of diseases associated with aging or certain lifestyles • They do not make adjustments for variations in nutrient needs associated with conditions or diseases that affect nutrient requirements • They provide no data on compensatory levels of nutrient intake needed to compensate for nutrient-demanding lifestyle factors such as: chronic stress, chronic intense exercise, cigarette smoking, alcoholism, restrictive dieting routines, polluted environments, exposure to chemical carcinogens, etc. may be required in much higher amounts than the RDA to prevent atherosclerosis than those levels suggested by the RDAs to prevent deficiency symptoms, unless, of course, the development of atherosclerosis is a deficiency symptom of these vitamins. The same might be said of many cancers, heart disease, birth defects, eye diseases (e.g. macular degeneration and cataracts), hearing loss, diabetes, and other conditions and diseases. The development of recommended optimum nutrient intakes
As a result of numerous epidemiological, clinical and experimental studies, it is now possible to extrapolate a list of recommended optimum nutrient intakes, or RONIs, for all of the major vitamins and minerals essential to our health. Nearly 20 years ago an attempt was made by Drs Cheraskin and Ringsdorf at the University of Alabama School of Medicine in Birmingham to establish RONIs. Their study of optimal intake levels of vitamins and minerals in humans spanned a period of 15 years. They examined the dietary intake and physiological levels of nutrients in over 13,500 male and female subjects living in six diverse regions of the United States. The results of their multimillion dollar study was compiled into over 49,000 pages found in 153 bound volumes. A small but significant portion of their findings has been published, in a series of over 100 research papers, during a period of 20 years, ending in the early 1990s. Cheraskin & Ringsdorf’s research investigated the health status of its subjects through a relatively time-consuming evaluation of each person’s health status. Each subject in the study completed the following test or procedure: 1. 2. 3. 4. 5. 6. 7. 8.
the 195 item Cornell Medical Index Health Questionnaire (CMI) physical and anthropometric measurements dental examination eye examination cardiac function tests, including an electroencephalo-gram (EKG) a glucose tolerance test (GTT) a panel of 50 blood chemistries a comprehensive study of each subject’s diet, including a study of food intake over a 7-day period.
Their study attempted to find evidence that there may exist an “ideal” diet consisting of micronutrients, carbohydrates, protein, and fat which could contribute to health and longevity. The hypothesis of the study concluded that relatively symptomless and disease-free individuals are healthier than those with clinical symptoms and signs and that this difference was due to the intake of nutrients from the diet and/or dietary supplementation.
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Findings
Cheraskin & Ringsdorf’s 15 year study of 13,500 subjects found that the healthiest individuals, meaning those with the least clinical symptoms and signs, were those who had consumed dietary supplements and eaten a diet nutritionally dense in nutrients relative to their caloric intake. Nutritionally, density of the diet proved to be a key variable among the healthiest subjects. For example, Cheraskin & Ringsdorf discovered that the “healthiest” subjects had a mean vitamin C intake of 410 mg a day, a good portion of which was consumed from food. The finding of a vitamin C intake above 400 mg a day is particularly interesting in light of anthropological evidence of vitamin C intake in pre-agricultural diets. One study found that humans living prior to the dawn of
agriculture (1,000 mg) have been associated with stomach pain, diarrhea, cardiac arrhythmias, itching, and nausea. These side-effects have, however, have not been observed in humans supplementing with the esterified form of vitamin B 3 (inositol hexaniacinate). Vitamin B6 (pyridoxine, pyridoxal, pyridoxal 5' phosphate, pyridoxamine, and corresponding phosphorylated forms)
(see Table 108.13 )
Vitamin B6 is a group of nitrogen-containing compounds TABLE 108-13 -- Pyridoxine (mg) RDA
Category
Age
Males
11–14
1.7
2.0
15–18
2.0
5.0
19–24
2.0
10.0
25–50
2.0
10.0
51+
2.0
25.0
11–14
1.4
2.0
15–18
1.5
5.0
19–24
1.6
10.0
25–50
1.6
10.0
51+
1.6
20.0
Females
Optimal
that occur naturally in three primary forms: pyridoxine, pyridoxal, and pyridoxamine. Vitamin B6 is required for growth and maintenance of almost every bodily function, amino acid metabolism, and production of neurotransmitters derived from amino acids. It also plays a role in glycogen breakdown, fatty acid metabolism, hormone metabolism, heme biosynthesis, and purine biosynthesis. Studies in humans indicate that the bioavailability of vitamin B 6 from natural sources is limited. In food, B vitamin levels vary. Vitamin B 6 levels in whole wheat bread and peanut butter are, respectively, 75 and 63% as available as that in tuna. Supplementation of vitamin B 6 has been used in treating carpal tunnel syndrome, premenstrual syndrome (PMS), cardiovascular disorders, and diabetic neuropathy. Elderly people may have an increased requirement for vitamin B 6 to maintain health, particularly for their immune system. In one study, healthy elderly people were given either 50 mg/day of vitamin B 6 or placebo. Those supplemented had significant improvement in immunocompetence, especially lymphocytic activity. There is preliminary evidence that inadequate vitamin B 6 status may contribute to the development of coronary heart disease by increasing plasma homocysteine. Homocysteine has been found to be highly atherogenic in animals and may contribute to atherosclerosis in humans. Added evidence that vitamin B 6 might be important in preventing cardiovascular diseases comes from experimental studies in animals. When these animals are given vitamin B 6 -deficient diets, they develop atherosclerotic lesions similar to those found in human atherosclerosis. While there is increasing evidence for a role in vitamin B 6 supplementation in preventing some kinds of cardiovascular diseases, and for enhancing immunity, optimal levels in healthy individuals need not exceed 12–15 times the RDA, even in the elderly. Supplementation of vitamin B 6 up to 250 mg/day is safe for most individuals. Very high doses of vitamin B 6 have been associated with sensory and motor impairment. Daily intakes up to 500 mg/day, which is 250 times the RDA, for up to 6 months appear to be safe. Supplements of pyridoxal 5' phosphate may be preferred over pyridoxine hydrochloric
919
acid supplements in individuals wishing to avoid any reversible side-effects from vitamin B 6 supplementation. Riboflavin (vitamin B 2 ) (see Table 108.14 )
Riboflavin is a precursor of two coenzymes (riboflavin-5'-phosphate and flavin mononucleotide) needed for a wide variety of enzymes in intermediary metabolism. Riboflavin is also required as a precursor of several flavoenzymes that are needed by tissue proteins. The need for riboflavin varies with energy requirements, explaining why riboflavin-deficient people tire easily and have a poor appetite. Riboflavin is especially important for tissue repair, vision, and blood. There is growing evidence that riboflavin may be important in preventing the development of cataracts, commonly associated with aging. There is equivocal evidence that riboflavin supplementation may be required in those exercising regularly. This may be more of a consideration if the exerciser is on a calorie-restrictive diet. Significantly higher than RONI or RDA levels of riboflavin have been employed in migraine prophylaxis with promising results. In one open pilot trial involving 25 patients with a history of migraine related to the syndrome of mitochondrial encephalomyopathy, lactic acidosis, or stroke-like episodes (MELAS), 400 mg/day of riboflavin was given as a prophylactic treatment for migraine. 68% of patients reported improvement on an index of severity. A second randomized, placebo-controlled trial involving 55 patients with similar migraines resulted in a reported 50% improvement among those receiving riboflavin versus a 15% response in the placebo group. It is theorized that riboflavin may in some migraine patients correct a mitochondrial dysfunction resulting from impaired oxygen metabolism. Therefore, the use of riboflavin at significantly higher than RONI levels may suggest that in this and other conditions, the RONI for riboflavin may be inadequate to meet metabolic needs essential in overcoming the pathogenic condition. Evidence is building for a role for riboflavin as an antioxidant, due to its role as a precursor for glutathione
TABLE 108-14 -- Riboflavin (mg) RDA
Category
Age
Males
11–14
1.5
2.0
15–18
1.8
2.2
19–24
1.7
2.5
25–50
1.7
2.5
51+
1.4
2.5
11–14
1.3
1.8
15–18
1.3
1.8
19–24
1.3
2.0
25–50
1.3
2.0
51+
1.2
2.0
Females
Optimal
reductase. A number of studies have demonstrated that certain vitamins, particularly riboflavin and retinol and their derivatives, have the ability to modify molecular reactivity and response to carcinogens. Dietary riboflavin has such an important role. The mechanism of action is through controlling the induction of repair enzymes (poly(ADP-ribose) polymerase, DNA polymerase beta and DNA ligase) responsive to carcinogens that cause damage to DNA. Studies have shown that DNA damage increases proportionate to a deficiency of riboflavin and that increased damage to DNA is reversed via riboflavin supplementation. Riboflavin has no known toxicity, although its theoretical photosensitizing properties raise the possibility of potential risk. The basis for this concern is that riboflavin forms an adduct with tryptophan which increases its rate of photo-oxidation. There is insufficient evidence to support riboflavin supplementation in healthy adults above twice the RDA. Thiamin (vitamin B 1 )
(see Table 108.15 )
Thiamin consists of one pyrimidine and one thiazole ring linked by a methylene bridge. This is important to know because many processed foods are rich in sulfites which split the thiamine molecule into the pyrimidine and thiazole moieties, thus destroying its biological activity. In a study of 1,009 dentists and their wives evaluated for daily thiamin intake, those subjects having the least number of signs or symptoms associated with illness or degenerative diseases consumed an average of 9 mg/day of thiamin, approximately eight times the RDA for this nutrient. There is insufficient evidence to suggest intakes of thiamin above eight times the RDA in healthy persons. However, individuals regularly consuming high intakes of refined carbohydrates (i.e. refined sugar-sucrose, wheat flour products made with unfortified 70% extraction flour) may require supplemental intake of thiamin in the range of 5–15 mg/day until such time as the diet improves. Manifestations of thiamin deficiency (beri-beri) can be induced by chronic alcoholism. TABLE 108-15 -- Thiamin (mg) RDA
Category
Age
Males
11–14
1.3
3.3
15–18
1.5
3.5
19–24
1.5
3.5
25–50
1.5
7.5
51+
1.2
9.2
11–14
1.1
3.1
15–18
1.1
3.1
19–24
1.1
3.1
25–50
1.1
7.1
51+
1.0
9.0
Females
Optimal
920
To date, thiamin, when taken orally, has been reported as harmless in humans, although gastric upset can be experienced at high doses exceeding 100–200 times the RDA. Minerals This author has provided an extensive discussion of minerals and trace elements and their role in human health in Minerals, Trace Elements and Human Health. Readers interested in this topic are advised to consider this work as a source of information, especially as it relates to non-essential elements, such as aluminum, cadmium, lead, mercury and other potentially toxic elements. Boron
(see Table 108.16 )
Boron has only recently been established to be of nutritional significance to humans. An insufficiency manifests only when the body is stressed in some way that enhances the need for boron. Boron is particularly important for optimal calcium, and thus bone metabolism. Most persons eating Westernized diets consume between 0.1 and 0.5 mg/day of boron. Human studies indicate that consuming less than 0.25 mg/day of boron, or less than one-half the estimated average minimum requirement for humans, may require supplementation. Thus an intake of between 1 and 4 mg/day may be appropriate to contribute to optimal health. There is no evidence to suggest that intakes above 10 mg are either beneficial or completely safe. Boron supplementation affects serum phosphorous and magnesium concentrations in young women and the effect is modified by exercise. Boron affects bone mineral density, along with calcium, phosphorous, and magnesium. Supplementation of 3 mg/day of boron for postmenopausal women has resulted in improvement in both calcium and magnesium retention and elevation in circulating serum concentrations of testosterone and estrogen (17-beta-estradiol). This improvement is more marked in women who have been on low magnesium diets. Similar improvements might also be found if the women were
Category
Age
TABLE 108-16 -- Boron (mg) RDA
Optimal
Males
Females
11–14
n/a
1.5
15–18
n/a
2.0
19–24
n/a
2.5
25–50
n/a
2.5
51+
n/a
2.5
11–14
n/a
1.5
15–18
n/a
2.0
19–24
n/a
2.5
25–50
n/a
3.0
51+
n/a
3.0
vitamin D-deficient. There is preliminary evidence based on animal studies that boron has an effect in males on steroidogenesis (e.g. production of testosterone) and testicular function and development proportional to the boron concentration in the testes. There is increasing interest in the role of boron on brain function. Results in animals and humans indicate that dietary boron influences brain electrical activity. Individuals in a low state of alertness consume less boron (3.0 mg/day). Preliminary evidence in animals has demonstrated that boron may modulate immune function that might be of significance to humans. Adequate boron suppresses inflammatory processes. There is some evidence that boron (as sodium tetraborate decahydrate) may prevent arthritis in sheep. In a randomized double-blind clinical trial of 20 patients with severe osteoarthritis given either 6 mg of boron or placebo, five improved and five did not, but only one of the 10 patients on the placebo improved. Boron deficiency in chicks results in a syndrome that resembles human arthritis. There is evidence from other human studies that optimal intakes of boron can enhance memory and cognitive function. There is also preliminary evidence of an association between sufficient boron intake and resistance to dental caries (tooth decay). In all human studies to date, patients reported no side-effects when consuming less than 10 mg/day of boron. Calcium
(see Table 108.17 )
Calcium is primarily stored in bones (99%), where the ratio of calcium to phosphorous is nearly constant at slightly greater than 2:1. Calcium is involved in numerous vital functions throughout the body, including: • protein and fat digestion • energy production • nerve transmission • neuromuscular activity • the absorption of other nutrients, such as vitamin B 12 .
TABLE 108-17 -- Calcium (mg) RDA
Category
Age
Males
11–14
1,200
1,000
15–18
1,200
1,000
19–24
1,200
1,000
25–50
800
700
51+
800
700
11–14
1,200
1,200
15–18
1,200
1,200
19–24
1,200
1,200
25–50
800
800
51+
800
800
Females
Optimal
921
Estimates of adult calcium requirements in humans vary from 300 to 400 mg/day to between 1200 and 1500 mg/day. The lowest requirements are usually seen in populations with low protein intakes. In general, persons with very low protein intakes require less calcium per day. High levels of protein, which are usually also high in phosphorous, require higher calcium intakes. An increase in protein intake affects urinary calcium and calcium retention. It is recommended that calcium intake be increased during adolescence, pregnancy and lactation. In recent years, calcium has received considerable attention in the mass media because of age-related osteoporosis, which is occurring in epidemic proportions in many developed countries and has been linked in to calcium intake. Articles and advertisements suggest that high intakes of calcium via supplementation or enrichment of foods/beverages is essential to the development and maintenance of strong, healthy bones. The attention this nutrient has received is most important to women. Women are more prone to osteoporosis that men because of smaller skeletal mass at maturity and because the most rapid period of bone loss occurs after menopause. However, numerous studies do not show a relationship between levels of dietary calcium intake and the incidence of osteoporosis. In the largest prospective scientific study of bone in premenopausal women aged 20–40 years, no relationship could be found between calcium intake and bone mineral density. This is consistent with studies reported since 1985. When developing or maintaining bone mineral density is a goal, optimal intake of all nutrients essential to bone formation and homeostasis is required. Diet, hormones, age, and gender are just some of the factors that influence calcium requirements and metabolism. Because of these variables and the interrelationships among calcium, protein, phosphorous, magnesium, zinc, vitamin D and boron, etc., it remains difficult to select a single calcium requirement for any age group or gender. Some new supplements incorporating the nutrients required for bone, including hydroxyapatite, have appeared in the marketplace, and may be superior to calcium supplementation alone to ensure adequate nutrient needs of bone. New studies show that even moderate consumption of calcium in foods or as supplements can reduce both heme and non-heme iron absorption. These reductions could have important nutritional implications, especially for premenstrual and pregnant women who are already at risk for iron deficiency. Therefore, it is advisable that calcium supplements in excess of 250 mg not be consumed with meals.
Chromium
(see Table 108.18 )
Chromium is a trace element essential to the metabolism of lipids (e.g. cholesterol), glucose, and insulin regulation. TABLE 108-18 -- Chromium (µg) RDA*
Category
Age
Males
11–14
50–200
200
15–18
50–200
200
19–24
50–200
300
25–50
50–200
300
51+
50–200
300
11–14
50–200
200
15–18
50–200
200
19–24
50–200
300
25–50
50–200
300
51+
50–200
300
Females
Optimal
* Estimated safe and adequate daily dietary intake of mineral, National Research Council, 1989.
The long-term effects of a suboptimal intake of chromium has been related to: • a decrease in tissue chromium associated withaging • an increased incidence of diabetes and atherosclerosis, particularly in developed nations. Illness, aging, stress (i.e. trauma, surgery, intense heat or cold), and strenuous exercise seem to increase chromium losses or needs. Studies of humans with heart disease have demonstrated that chromium deficiency is associated with atherosclerosis, suggesting that optimal chromium levels may reduce the risk of heart disease. Tissues of humans who have died of heart disease have been found to have less chromium than tissues of humans who died of accidental causes. In those patients with atherosclerotic plaque who died of heart disease, no detectable chromium was found in these tissues. There is also evidence in humans that a diet sufficient in chromium along with selenium, copper, potassium, magnesium, and calcium reduces the risk of cardiovascular disease, by having a beneficial effect on serum cholesterol and triglyceride levels. Chromium taken with nicotinic acid (niacin) or the chromium supplement, chromium picolinate (200–400 µg/day), has been shown to lower cholesterol levels in individuals with elevated cholesterol. Traces of chromium have been shown to be required for health as part of the glucose tolerance factor (GTF) involved in the regulation of blood glucose. The brain has high requirements for blood glucose as a fuel. The amount of chromium in foods decreases with processing. The widespread tendency toward increased consumption of highly processed foods, particularly refined sugar, which stimulates urinary losses of chromium, may result in a marginal intake of chromium and depletion of tissue chromium stores. The safety of chromium supplementation is well established. Even in pharmacological doses (50–1,000 mg/day for 1–3 months), it has no toxicity in cats, rats or mice.
922
Copper
(see Table 108.19 )
Copper is an essential element in the human body. About 95% of copper is found in serum as part of ceruloplasmin. Copper is needed by all tissues, but is highest in the liver where it contributes to energy and detoxification mechanisms. The element is also required to absorb, utilize and synthesize hemoglobin, maintain the integrity of the outer covering of nerves (myelin), metabolize vitamin C, and oxidize fatty acids. Both excess and deficiency of copper can result in problems such as: • bone/joint and connective tissue disturbances • cardiovascular degeneration • abnormal electrocardiogram • accelerated aging • depigmentation and dermatitis • anemia • neurological impairments. There is no evidence of a decline in copper status with age. Proper balance of copper to zinc (and other trace elements) is necessary for good health. A low ratio of copper to zinc can result from dietary deficiency of copper or excessive zinc intake, and may result in hypercholesterolemia, myocardial and arterial damage, and increased mortality. High levels of serum copper found in humans living in areas with low selenium levels in their soil and high copper content in drinking water have been associated with a significantly elevated incidence of atherosclerosis. The zinc-to-copper ratio, should ideally be between 8:1 and 14:1. Excess fructose consumption in the presence of inadequate copper intake has been shown in several mammalian species to lead to heart arrhythmias and even heart failure. The level of copper and amount of dietary fructose which results in such cardiovascular problems in humans remain unknown. However, it is known that dietary fructose exacerbates the signs associated with copper deficiency. These signs include anemia, hypercholesterolemia, TABLE 108-19 -- Copper (mg) RDA*
Category
Age
Optimal
Males
11–14
1.5–3.0
1.5–4
15–18
1.5–3.0
1.5–4
19–24
1.5–3.0
1.5–4
25–50
1.5–3.0
1.5–4
51+
1.5–3.0
1.5–4
Females
11–14
1.5–3.0
1.5–4
15–18
1.5–3.0
1.5–4
19–24
1.5–3.0
1.5–4
25–50
1.5–3.0
1.5–4
51+
1.5–3.0
1.5–4
* Estimated safe and adequate daily dietary intake of mineral, National Research Council, 1989
impaired glucose tolerance, pancreatic atrophy, cardiomyopathy, and increased mortality. Fructose consumption during lactation also produces a significant reduction in copper concentrations in breast milk. Even the homeostasis of hormones is impaired by the consumption of fructose with a low-copper diet, which in animal studies has been shown to decrease levels of plasma thyroid hormones, insulin, epinephrine, norepinephrine, and an increase in the glucocorticoids. Copper supplementation should be approached with caution since copper is amongst the most powerful producers of free radicals. However, in proper balance with zinc, the two elements act as antioxidants by removing damaging free radicals such as the superoxide radical. Excess copper supplementation suppresses immune function. Iodine
(see Table 108.20 )
Iodine accumulates in thyroid tissue and is incorporated into thyroxine and triiodothyronine, the hormones of the thyroid gland. Iodine deficiency is the most common cause of endemic goiter and cretinism. Milk and dairy products, as well as bread and bakery products, are the main source of iodine in human food. Iodine is concentrated in milk and eggs, which are only second to seafood as the richest sources of iodine. Marine (sea) salt is a poor source of iodine. In conjunction with two enzymes (myeloperoxidase and hydrogen peroxide), iodine is known to be bactericidal. This bactericidal activity is accomplished by an abundant cellular halide, the chloride anion. The RDA for iodine is 2 µg/kg body weight in adults and somewhat more in children. This amount seems optimal to ensure the biosynthesis of the thyroid hormones. An additional 25 and 50 µg may be required during pregnancy and lactation, respectively. The most common supplementation of iodine is via iodized salt, 1 g of which supplies approximately 75 µg of iodine. In the event of a nuclear reactor accident, a single dose of 300 mg of potassium iodide helps to block the uptake of radioactive iodine-131 by the thyroid. Iodine in large amounts disturbs all thyroid functions. TABLE 108-20 -- Iodine (mcg) RDA
Category
Age
Males
11–14
150
150
15–18
150
150
19–24
150
150
25–50
150
150
51+
150
150
11–14
150
150
15–18
150
150
19–24
150
150
25–50
150
150
51+
150
150
Females
Optimal
923
Iron
(see Table 108.21 )
Most iron in the body is found in the hemoglobin of red blood cells. Some iron is also found in the myoglobin present in skeletal muscles and the heart. The remaining iron is found in enzymes essential to energy production. Iron deficiency is one of the most common deficiency diseases in the world. Even in the US, repeated dietary surveys have found inadequate iron intake to meet even the RDA. The most common cause of this is nutritional, including inadequate absorption of iron due to poor iron intake, reduced bioavailability, etc. Iron loss, resulting from pregnancy, internal bleeding, parasitic infections (e.g. hook worm), low stomach acid (e.g. hypochlorhydria, achlorhydria), and malabsorption, is also an important factor contributing to iron deficiency. There are some data that suggest that iron deficiency anemia may be a secondary outcome of vitamin A deficiency which contributes to defective iron transport. The risk of iron deficiency is relatively high in menstruating women eating a diet inadequate in iron. This is one reason the RDA for iron is higher for women than for men. However, many women are on reduced calorie diets which are unable to provide enough iron and require supplementation. Non-heme iron is the main source of iron in the diet, although it is much more poorly absorbed than heme iron, which is only found in animal sources. Meat, fish, and vitamin C enhance the absorption of non-heme iron, improving absorption. However, new studies are showing that even moderate consumption of calcium in foods or as supplements can reduce both heme and non-heme iron absorption. These reductions could have important nutritional implications, especially for those, such as premenstrual women and pregnant women, who may already be at high risk for iron deficiency. Symptoms of iron deficiency anemia include fatigue, irritability, paleness, intolerance to cold, and a general sense of lack of well-being. Brain function can also be impaired due to iron deficiency. Inadequate iron levels tend to affect the right hemisphere of the brain and have been linked to cognitive impairment, poor attention span, restlessness, and the inability of concentrate. Optimal levels of iron are also essential to immune function. TABLE 108-21 -- Iron (mg) RDA
Category
Age
Optimal
Males
11–14
12
15
15–18
12
15
19–24
10
20
25–50
10
20
51+
10
20
Females
11–14
15
20
15–18
15
20
19–24
15
22
25–50
15
22
51+
15
20
TABLE 108-22 -- Magnesium (mg) RDA
Category
Age
Males
11–14
270
300
15–18
400
500
19–24
350
500
25–50
350
500
51+
350
600
11–14
280
300
15–18
300
400
19–24
280
450
25–50
280
450
51+
280
550
Females
Optimal
Iron supplementation is not safe for individuals with any iron storage disorder such as hemosiderosis, idiopathic hemochromatosis, or thalassemias. Magnesium
(see Table 108.22 )
Magnesium, half of which is in the bone, is required for many metabolic functions. One of its most important is in maintaining the function of the nervous system and neuromuscular transmission and activity. Magnesium deficiency is associated with: • tremors • muscle spasms • convulsions • neuropsychiatric disturbances • coronary artery disease • angina pectoris • cardiac arrhythmias • hypertension. Along with calcium, sodium and potassium, magnesium affects the muscle tone of blood vessels. Blood levels of magnesium are low in patients with myocardial ischemia, coronary artery spasm, mitral valve prolapse, and cardiac tachyarrythmias. Low tissue and blood levels have also been observed in patients prior to, during and after myocardial infarction. Recent studies have also implicated lack of sufficient magnesium as a cause of pre-eclampsia and hypertension in pregnant women. Magnesium insufficiency directly and indirectly affects cardiac function through its effect on potassium, sodium and calcium concentrations in cells and surrounding fluids. Given that coronary and heart disease contribute profoundly to morbidity and mortality in developed countries, an intake above the RDA level is advocated by researchers who have studied this essential nutrient. Manganese (see Table 108.23 )
Manganese is involved in protein, fat and energy metabolism, and is required for bone growth and development,
924
TABLE 108-23 -- Manganese (mg) RDA*
Category
Age
Males
11–14
2–5
5
15–18
2–5
5
19–24
2–5
5
25–50
2–5
5
51+
2–5
10
11–14
2–5
5
15–18
2–5
5
19–24
2–5
5
25–50
2–5
5
51+
2–5
10
Females
Optimal
* Estimated safe and adequate daily dietary intake of mineral, National Research Council, 1989.
and reproduction. Diets high in refined carbohydrates may provide inadequate intake of manganese. Addition of supplemental iron to the diet can depress manganese retention if iron nutriture is poor. Concentrations of manganese in tissues and organs remain relatively constant with age. Sources of dietary manganese are mainly plant foods since animal tissue contains very low amounts of this nutrient. One exceptionally rich dietary source for manganese is tea. However, tea can inhibit the uptake of iron. Phosphorous
(see Table 108.24 )
About 85% of the phosphorous found in the body is in bone as calcium phosphate and hydroxyapatite. Deficiencies of this nutrient are extremely rare as foodstuffs seem to provide an ample supply. Both animal and plant food are rich in phosphates. However, a vitamin D deficiency may reduce absorption of phosphorous. Most
adults consume between 1,000 and 1,500 mg of phosphorous each day of which 50–60% is usually absorbed. A phosphorous intake greatly in excess of calcium, especially if the calcium intake is minimal (400 mg/day or less), can reduce calcium availability and contribute to calcium deficiency. In general, the calcium to phosphorous ratio should be about 1:1 and definitely above 1:2. TABLE 108-24 -- Phosphorous (mg) RDA
Category
Age
Males
11–14
1,200
1,200
15–18
1,200
1,200
19–24
1,200
1,200
25–50
800
800
51+
800
800
11–14
1,200
1,200
15–18
1,200
1,200
19–24
1,200
1,200
25–50
800
800
51+
800
800
Females
Potassium
Optimal
(see Table 108.25 )
Potassium is an essential element in maintaining fluid balance in the cells, transmission of nerve impulses, skeletal muscle contractility, and normal blood pressure. However, it must exist in balance with sodium. During nerve transmission and muscle contraction, potassium and sodium exchange places. Together with high sodium intake, decreased potassium intake may be implicated in hypertension and heart disease. Potassium is also a catalyst in protein and carbohydrate metabolism. Diuretic drugs can deplete potassium and so can be dangerous. When sodium is lost with water from the body, the ultimate damage comes when potassium moves out of the cells with cell water. There is no RDA for potassium. However, some believe that the minimum requirement should be between 1,600 and 2,000 mg/day. Since an intake of about 1,600 mg/day is required just to maintain normal body stores and a normal concentration in plasma and fluid, a higher level would ensure optimal levels. According to some researchers, a diet rich in fruits and vegetables and low in sodium should ensure the maintenance of optimal potassium levels. However, it has been calculated that due to the poor absorbability of potassium in fruit without chloride, only 40% of the potassium, e.g. in a banana, is retained. Unfortunately this finding is often not calculated into food value tables which estimate total potassium intake from foods. This is one reason why, when potassium supplementation is suggested by a physician, potassium chloride is recommended. A low-sodium diet enhances potassium conservation, whereas a high-sodium diet promotes potassium excretion. In a study of vegetarians compared with non-vegetarians, significantly lower blood pressure was found in every decade of age and only 2% of the vegetarians had hypertension (higher than 160/95) as compared with 26% hypertensives in the non-vegetarians. This study further confirms the important role that potassium plays in the regulation of blood pressure. In a study of 10,000 subjects in the United States, it was found that those with the highest levels of calcium, potassium, vitamin A and TABLE 108-25 -- Potassium (g) RDA
Category
Age
Males
11–14
2
2
15–18
2
2
19–24
2
3
25–50
2
3
51+
2
3
11–14
2
2
15–18
2
2
19–24
2
3
25–50
2
3
51+
2
3
Females
Optimal
925
vitamin C had the lowest incidence of hypertension, suggesting that potassium is not the only essential nutrient in maintaining normotensive status in humans. Selenium
(see Table 108.26 )
Selenium is a trace element whose most important biologic function in maintaining health is as an antioxidant. Vitamin C intake of 600 mg/day has been shown to increase dietary selenium absorption by nearly 100%. There is growing evidence that selenium may be protective against certain cancers (e.g. breast, colon, lung) and numerous tumors. Studies to date have given considerable credibility to the theory that decreased selenium status is associated with an increased risk of cancer. A landmark prospective study involving 1,312 subjects (75% of whom were male), reported in the December 1996 Journal of the American Medical Association, found that patients who took daily selenium supplementation at triple the RDA had 63% fewer cases of prostate cancer, 58% fewer colon or rectal cancers, and 47% fewer lung cancers than those who took the placebo. Overall in the selenium group there were 50% fewer cancer deaths than in the placebo group. It is believed that selenium may inhibit tumor growth and induce suicide in malignant cells. There is evidence that in elderly people, several hundred micrograms of selenium and 400 mg of vitamin E improve their mental status, motivation, initiation, emotional stability, mental alertness, interest in the environment, and self-care, while decreasing anxiety, depression, poor appetite, and fatigue. This suggests that optimal selenium nutriture is increasingly important in the latter decades of life. Adequate levels of selenium taken with chromium, copper, potassium, magnesium, and calcium have been found to reduce the risk of cardiovascular disease. There are data suggesting that ingesting more than 750–1000 ug/day of selenium over an extended period of time may be harmful. Therefore optimal levels need to be below this level until there are assurances that higher intakes are safe.
Category
Age
TABLE 108-26 -- Selenium (mcg) RDA
Optimal
Males
Females
11–14
40
75
15–18
50
150
19–24
70
200
25–50
70
200
51+
70
250
11–14
45
75
15–18
50
100
19–24
55
150
25–50
55
175
51+
55
200
TABLE 108-27 -- Sodium (mg) RDA*
Category
Age
Males
11–14
500
400
15–18
500
400
19–24
500
400
25–50
500
400
51+
500
400
11–14
500
400
15–18
500
400
19–24
500
400
25–50
500
400
51+
500
400
Females
Optimal
* Estimated minimum requirement, National Research Council, 1989.
Sodium/sodium chloride
(see Table 108.27 )
Sodium chloride is the primary source of sodium (39% sodium by weight). The healthy adult can maintain sodium balance with an intake of approximately that required by an infant. Close regulation of the concentration and content of sodium within the body is crucial for health. Disorders of sodium regulation are a central feature of many human diseases. In general, the regulation of sodium in the body involves two processes: the control of sodium loss and the control of sodium intake. Sodium chloride occurs naturally in most foods. The problem is that sodium chloride is also added to most processed foods, often in amounts well in excess of that required physiologically or to maintain health. This added intake has been the subject of numerous studies. These studies have frequently found that the level of sodium chloride ingested by Americans is 10–20 times the level required to maintain health. Many studies have found an association between excessive intake of salt and hypertension. The highest intakes (28 g/day) have been found in northern Japan where it is estimated that 38% of the population is hypertensive. In contrast, Alaska natives consume only 4 g/day and rarely develop hypertension. However, some studies do not show an association between salt and hypertension. These studies tend to be too small to discover the association and frequently fail to consider dietary potassium intake. Numerous studies have shown that potassium can limit some of the toxic effects of excessive sodium ingestion. For most individuals, the most prudent approach would be to limit salt intake by restricting salted processed foods. This alone should reduce daily salt intake by between 3 and 5 g, or about one-third the daily salt intake in the average American (10–14.5 g/day). Refraining from adding salt to food at the table would further reduce salt intake another one-third. This would leave only one-third remaining, or approximately that amount of salt per day found in populations with a very low incidence of hypertension. Potassium chloride may be an acceptable substitute to sodium chloride, especially
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when other agents, such as citric acid or other acids, have been added to mask its unpleasant bitter taste. However, it is important to recognize that some individuals with hypotension (low blood pressure) may benefit from added salt. Nevertheless, there remains no known benefit from large sodium or sodium chloride intake. Maintaining a low salt intake throughout life may decrease the risk of developing hypertension in the portion of the population at risk. Zinc
(see Table 108.28 )
An adequate supply of zinc is essential for growth and physical development, and for the metabolism of proteins, fats and carbohydrates. Most aspects of reproduction in both males and females require zinc. This mineral is also vitally important to the immune system. Virtually every enzyme reaction in the brain involves zinc, and its essentiality in the development and function of the central nervous system and brain is uncontested. Zinc is antagonistic to such toxic elements as cadmium, mercury and lead. The highest concentrations of zinc are in the ear and eye. Disorders associated with impairment of either organ may benefit from continuous optimal intakes of zinc over a lifetime. The typical intake of zinc in Western diets is around 10 mg, two-thirds of the RDA. The elderly often consume TABLE 108-28 -- Zinc (mg) RDA
Category
Age
Males
11–14
15
15
15–18
15
18
19–24
15
20
25–50
15
20
51+
15
20
11–14
12
12
15–18
12
15
19–24
12
17
25–50
12
17
51+
12
17
Females
Optimal
less than half the RDA for zinc. While some individuals seem to be poor absorbers, most cases of zinc deficiency, whether chronic or marginal, are self-inflicted. This may result from slimming diets, vegetarianism, or other life-style habits (e.g. alcoholism, excessive exercise). However, in some cases relative zinc deficiencies are induced by exposure to toxic metals, such as cadmium from cigarette smoke or excess copper from copper water pipes. There is increasing evidence that zinc levels decline following physical stress or injury. Zinc is one of the few minerals lost rapidly in the urine following acute or chronic psychological stress, which can lead to inadequate zinc status, despite RDA intake. Impairments of taste, vision, smell, and appetite are often early signs of inadequate zinc status. There is a simple test for zinc status (Zinc Status, Ethical Nutrients, San Clemente, CA) which evaluates the ability to taste a pre-mixed solution of zinc. Individuals unable to taste this solution have been found to be zinc-deficient, in some cases despite being asymptomatic. Insufficient zinc has multiple effects on the immune system, particularly T-lymphocytes, decreased number and activity of killer cells, and impaired antibody production. There is insufficient evidence to suggest that zinc intake should be twice the RDA for zinc. However, since repeated studies of Westernized diets indicate that most populations consume less than the RDA of this essential mineral, it seems prudent that some supplementation of zinc, or increase in zinc-rich foods, be considered a part of maintaining an optimal level of this nutrient over a lifetime. Zinc supplementation is generally safe if maintained at levels within two to eight times the RDA. Symptoms of zinc toxicity include gastrointestinal irritation, vomiting, adverse changes in HDL/LDL cholesterol ratios, and impaired immunity. The latter develops when levels above 180 mg/day are consumed for more than several weeks. Excess intake of zinc may either lower copper levels or aggravate an existing marginal copper deficiency. FURTHER READING Introduction 1. National Research Council, Committee on Diet and Health. Diet and Health. Implications for reducing chronic disease risk. Washington, DC: National Academy Press. 1989 2. The Surgeon General’s Report on Nutrition and Health, Department of Health and Human Services. DHHS publication [PHS] 50210. Washington, DC: Government Printing Office. 1988 3. Verschuren WM, Jacobs DR, Bloemberg BP et al. Serum total cholesterol and long-term coronary heart disease mortality in different cultures. Twenty-five year follow-up of the Seven Countries Study. JAMA 1995; 274: 131–136 4. Block G, Petterson B, Subar A et al. Fruit, vegetables, and cancer prevention. A review of the epidemiologic evidence. Nutr Cancer 1992; 18: 1–29 5. Giovannucci E, Rimm EB, Ascherio A et al. Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995; 87: 265–273 6. Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 1992; 2: 1124–1127 7. Rimm EB, Stampfer MJ, Ascherio A et al. Vitamin E consumption and the risk of coronary heart disease in men. New Engl J Med 1993; 328: 1450–1456 8. Food and Nutrition Board, National Research Council, National Academy of Science. Recommended dietary allowances. 10th edn. Washington, DC: National Academy Press. 1989 9. Kumpulainen JT, Salonen JT, eds. Natural antioxidants and food quality in atherosclerosis and cancer prevention. London: The Royal Society of Chemistry. 1996
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Fat-soluble vitamins Vitamin A/beta-carotene 1. Bendich A, Olson JA. Biological action of carotenoids. FASEB J 1989; 3: 1927–1932 2. Paganini-Hill A, Chao A, Ross RK et al. Vitamin A, beta carotene, and the risk of cancer. A prospective study. J Natl Cancer Inst 1987; 79: 443–448 3. Sommer A. New Imperatives for an old vitamin (A). J Nutr 1989; 119: 96–100 4. Bendich A. Symposium conclusions: biological actions of carotenoids. J Nutr 1989; 119: 112–5 5. Oson JA. Provitamin A function of carotenoids. The conversion of B-carotene to Vitamin A. J Nutr 1989; 119: 105–108 6. Pryor WA. The antioxidant nutrients and disease prevention – what do we know and what do we need to find out? Am J Clin Nutr 1991; 53: 391S–393S 7. Ziegler RG. Vegetables, fruits and carotenoids and the risk of cancer. Am J Clin Nutr 1991; 53: 251S–259S 8. DiMascio P, Murphy ME, Sies H. Antioxidant defense systems. the role of carotenoids, tocopherols and thiols. Am J Clin Nutr 1991; 53: 194S–200S 9. Stahelin HB, Gey KB, Eichholzer M et al. Beta-carotene and cancer prevention. The Basel Study. Am J Clin Nutr 1991; 53: 265S–269S 10. Connett JE, Kuller KH, Kjelsberg MO et al. Relationship between carotenoids and cancer. Cancer 1989; 64: 126–134 11. Colditz GA, Branch LJ, Lipnick RJ et al. Increased green and yellow vegetable intake and lowered cancer deaths in an elderly population. Am J Clin Nutr 1985; 41: 32–36 12. Gaby SK, Singh VN. Vitamin intake and health: a scientific review. New York: Marcel Dekker. 1991: p 29–57 13. Mobarhan S, Bowen P, Andersen B et al. Effects of beta-carotene repletion on beta-carotene absorption, lipid peroxidation, and neutrophil superoxide formation in young men. Nutr Cancer 1990; 14: 195–206 14. Burton GW, Ingold KU. Beta-carotene. an unusual type of lipid antioxidant. Science 1984; 224: 569–573 15. Bendich A, Olson, JA. Biological actions of carotenoids. FASEB J 1989; 3: 1927–1932
16. Palgi A. Association between dietary changes and morality rates: Israel 1949 to 1977; a trend-free regression model. Am J Clin Nutr 1981; 34: 1569–1583 17. Robertson J, Donner AP, Trevithick JR. Vitamin E: biochemistry and health implications, vol. 570. New York: Ann NY Acad Sci. 1989: p 372–382 18. Cheraskin E, Ringsdorf WM, Medford FH. The ‘ideal’ daily vitamin A intake. Int J Vit Nutr Res 1976; 46: 11–13 19. Goodman DS. Vitamin A and retinoids in heath and disease. N Eng J Med 1984; 310: 1023–1031 20. White WS, Kim CI, Kalkwarf HJ et al. Ultraviolet light-induced reduction in plasma carotenoid levels. Am J Clin Nutr 1988; 47: 879–883 21. Willette W. Nutritional epidemiology. New York: Oxford University Press. 1990: p 292–310 22. Salonen JT. Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data. Br Med J 1985; 290: 417–420 23. DiMascio P, Murphy M, Sies H. Antioxidant defense systems. The role of carotenoids, tocopherols, and thiols. Am J Clin Nutr 1991; 53: S19–S20 24. Weisburger J. Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids. Am J Clin Nutr 1991; 53: S226–237 25. Olson JA. Vitamin A. In: Present knowledge in nutrition. 7th edn. Washington DC: International Life Sciences Press. 1996: p 109–119 26. Sommer A., West, KP. The duration of the effect of vitamin A supplementation. [Letter] Am J Public Health 1997; 87: 467 27. Werler MA, Lammer EJ, Mitchell AA. Teratogenicity of high vitamin A intake. [Letter] N Eng J Med 1995; 334: 1195 28. Bates CJ. Vitamin A. Lancet 1995; 345: 31–35 29. Underwood BA. Was the ‘anti-infective’ vitamin misnamed? Nutr Rev 1994; 52: 140–143 30. Schauss AG. Beta-carotene and the incidence of lung cancer in Finnish male smokers. A critique. Q Rev Natural Med 1994; 191–195 31. Prince MR, Frisoli JK. Beta-carotene accumulation in serum and skin. Am J Clin Nutr 1993; 57: 175–181 Vitamin D 1. MacLaughlin J, Holick MF. Aging decreases the capacity of human skill to produce vitamin D3. J Clin Invest; 1985; 76: 1536–1538 2. Lips P, van Ginkel FC, Jongen MJ et al. Determinants of Vitamin D status in patients with hip fracture and in elderly control subject. Am J Clin Nutr 1987; 46: 1005–1010 3. Gaby SK, Singh VN. Vitamin intake and health: a scientific review. New York: Marcel Dekker. 1990: p 59–70 4. Chapuy MC, Chapuy P, Mennier PJ. Calcium and vitamin D supplements. effects on calcium metabolism in elderly people. Am J Clin Nutr 1987; 46: 324–328 5. Anonymous. Vitamin D supplementation in the elderly [editorial]. Lancet 1987; 1: 306–307 6. Webb AR, Holick MF. Influence of season and latitude on cutaneous synthesis of vitamin D3. Ann Rev Nutr 1988; 8: 375–399 7. Garland FC, Garland CF, Gorham ED et al. Geographic variation in breast cancer mortality in the United States. A hypothesis involving exposure to solar radiation. Arch Environ Health 1990; 45: 261–267 8. Sowers MR, Wallace RB, Lemke JH. The association of intakes of vitamin D and calcium with blood pressure among women. Am J Clin Nutr 1985; 42: 135–142 9. Garland C, Shekelle RB, Barrett-Connor E et al. Dietary vitamin D and calcium and risk of colorectal cancer. Lancet 1985; 1: 307–309 10. Garland CF, Comstock GW, Garland FC et al. Serum 25-hydroxy vitamin D and colon cancer. Lancet 1989; 2: 1176–1178 11. Sowers MF, Wallace RB, Hollis BW et al. Relationship between 1,25-dihydroxy vitamin D and blood pressure in our geographically defined population. Am J Clin Nutr 1988; 48: 1053–1056 12. Parfitt AM, Gallagher JC, Heaney RP et al. Vitamin D and bone health in the elderly. Am J Clin Nutr 1982; 36: 1014–1031 13. Omdahl JL, Garry PJ, Hunsaker LA et al. Nutritional status in a healthy elderly population: Vitamin D Nutritional status in a healthy elderly population: vitamin D. Am J Clin Nutr 1982; 36: 1225–1233 14. Wiedmann KH, Brattig NW, Diao GD et al. Serum inhibiting factors (SIF) are of prognostic value in acute viral hepatitis. Lancet 1985; i: 307–309 15. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980; 9: 227–231 16. Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prevent Med 1990; 19: 614–622 17. Crombie IK. Distribution of malignant melanoma on the body surface. Br J Cancer 1981; 43: 842–849 18. Vagero R, Ringback G, Kiveranta H. Vagero Melanoma and other tumors of the skin among office, other outdoor/indoor workers in Sweden. Br J Cancer 1986; 53: 507–512 19. Koh HK, Kligler BE, Lew RA. Sunlight and cutaneous malignant melanoma. Evidence for and against causation. Photochem Photobiol. 1990; 19: 614–622 20. Beaty M, Lee E, Glauart H. FASEB J 1991; 5: 926A 21. Norman AW. Vitamin D. In: Present knowledge in nutrition. 7th edn. Washington DC: International Life Sciences Press. 1996: p 120–129 22. Fraser DR. Vitamin D. Lancet 1995; 345: 104–107 23. Chapuy MC, Arlot ME, Duboeuf F et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327: 1637–1642
Vitamin E 1. Burton GW, Ingold KU. Vitamin E as an in vitro and in vivo antioxidant. In: Diplock AT, Machoin LJ, Parker L, Pryor WA, eds. Vitamin E: biochemistry and health implications. Ann NY Acad Sci 1989; 570: 7–22 2. Wald NJ, Boreham J, Hayward JL et al. Plasma retinol beta-carotene and vitamin E levels in relation to future risk of breast cancer. Br J Cancer 1984; 49: 321–324
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3. Salonen JT, Salonen R, Lappetelainen R et al. Risk of cancer in relation to serum concentration of selenium and vitamins A and E. matched case control analysis. Br Med J 1985; 290: 417–420 4. Haenszel W, Correa P, Lopez A et al. Serum micronutrient levels in relation to gastric pathology. Int J Cancer 1985; 36: 43–48 5. Menkes MS, Comstock GW, Vuilleumier JP et al. Serum beta-carotene vitamins A and E, selenium, and the risk of lung cancer. N Eng J Med 1986; 315: 1250–1254 6. Miyamoto H, Araya Y, Ito M et al. Serum selenium and vitamin E. concentrations in families of lung cancer patients. Cancer 1987; 60: 1159–1162 7. Kok FJ, de Bruijn AM, Vermeeren R et al. Serum selenium, vitamin antioxidants, and cardiovascular mortality. N Eng J Med 1987; 316: 1416 8. Knekt P, Aromaa A, Maatela J et al. Serum vitamin E level and risk of cancer among Finnish men during a 10-year follow-up. Am J Epidemiol 1988; 127: 28–41 9. Gaby WK, Machlin LJ. Vitamin intake and health: a scientific review. New York: Marcel Dekker. 1991: p 71–101 10. Pacht ER, Kaseki H, Mohammed JR et al. Deficiency of vitamin E in the alveolar fluid of cigarette smokers. J Clin Invest 1986; 77: 789–798 11. Steiner M. Effect of alpha-tocopherol administration on platelet function in man. Thromb Haemostas 1983; 49: 73–77 12. Fong JSC. Alpha-tocopherol. Its inhibition on human platelet aggregation. Experientia 1976; 32: 639–641 13. Meydanin SN et al. FASEB J 1989; 3: A1057 14. Prasad JS. Effect of vitamin E supplementation on leukocyte function. Am J Clin Nutr 1980; 33: 606–608 15. Jacques PF. Chylack antioxidant status in persons with and without senile cataract. Arch Ophthalmol 1988; 106: 337–340 16. Taylor A. Associations between nutrition and cataract. Nutr Rev 1989; 47: 225–234 17. Robertson JM, Donner AP, Trevithick JR. Vitamin E intake and risk of cataracts in humans. Ann NY Acad Sci 1989; 570: 372–378 18. Pryor WA. Can vitamin E protect humans against the pathological effects of ozone in smog? Am J Clin Nutr 1991; 53: 702–722 19. Chavance M. Nutrition, immunity, and illness in the elderly. New York: Pergamon Press. 1985: p 137–142 20. Knekt P, Aromaa A, Maatela J et al. Vitamin E and cancer prevention. Am J Clin Nutr 1991; 53: 283S–286S 21. Van Den Berg JJ, Roelofsen B, OpdenKamp JAF et al. Vitamin E: biochemistry and health implications, vol. 570. New York: Ann NY Acad Sci. 1989: p 527–529 22. Riemersma RA, Wood DA, MacIntyre CCA et al. Low plasma vitamins E and C increased risk of angina in Scottish men. In: Diplock AT, Machlin LJ, Packer L et al, eds. Vitamin E: biochemistry and health implications, vol. 570. New York: Ann NY Acad Sci. 1989: p 291–295 23. Robertson J, Donner AP, Trevithick JR. Vitamin E: biochemistry and health implications, vol. 570. New York: Ann NY Acad Sci. 1989: p 372–382 24. Diplock AT, Machlin LJ, Packer L et al, eds. Daily vitamin E consumption and reported cardiovascular findings. New York: Ann NY Acad Sci. 1989: p 1–535 25. Cheraskin E, Ringsdorf WM, Jr. Nutr Rep Int 1970; 2: 107–117 26. Horwitt MK. Supplementation with vitamin E. Am J Clin Nutr 1988; 47: 1088–1089 27. Bendich A, Machlin LJ. Safety of oral intake of vitamin E. Am J Clin Nutr 1988; 48: 612–619 28. Dimitrov NV, Meyer C, Gilliland D et al. Plasma tocopherol concentrations in response to supplements vitamin E. Am J Clin Nutr 1991; 53: 723–729 29. Pascoe GA, Fariss MW, Olafsdottir K et al. A role of vitamin E in protection against cell injury. Maintenance of intracellular glutathione precursors and biosynthesis. Eur J Biochem 1987; 166: 241–247 30. Tolonen M, Markku H, Sarna S. Vitamin E and selenium supplementation in geriatric patients. A double-blind preliminary clinical trial. Biol Trace Elem Res 1985; 7: 161–168 31. Salonen JT, Salonen R, Lappetelainen R et al. Risk of cancer in relation to serum concentrations of selenium and vitamins A and E. matched case-control analysis of prospective data. Br Med J 1985; 290: 417–420 32. Giani E, Masi I, Galli C. Heated fat; vitamin E and vascular eicosanoids. Lipids 1985; 20: 439–448 33. Kneckt P. Serum vitamin E level and risk of female cancers. Int J Epidem 1988; 17: 281–286 34. Sword J, Pope A, Hoekstra W. Endotoxin and lipid peroxidation in vitro in selenium and vitamin E deficient and adequate rat tissue. J Nutr 1991; 121: 258–264 35. Sword J, Pope A, Hoekstra W. Endotoxin and lipid peroxidation in vitro in selenium and vitamin E deficient and adequate rat tissue. J Nutr 1991; 121: 251–257 36. Esterbauer H, Dieber-Rotheneder M, Striegl G et al. Role of vitamin E in preventing the oxidation of low-density lipoprotein. Am J Clin Nutr 1991; 53: 314S–321S 37. Niki E, Yamamoto Y, Komuro E et al. Membrane damage due to lipid oxidation. Am J Clin Nutr 1991; 53: S201–205
38. DiMascio P, Murphy M, Sies H. Antioxidant and defense systems. the role of carotenoids, tocopherols and thiols. Am J Clin Nutr 1991; 53: S194–200 39. Weisburger J. Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants and carotenoids. Am J Clin Nutr 1991; 53: S226–237 40. Sokol RJ. Vitamin E. In: Ziegler EE, Filer LJ Jr, eds. Present knowledge in nutrition. 7th edn. Washington DC: International Life Sciences Press. 1996: p 130–136 41. Meydani M et al. Muscle uptake of vitamin E and its association with muscle fiber type. Nutr Biochem 1997; 8: 74–78 42. Losonczy, KG, Harris, TB, Havlik, RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons. The established populations for epidemiologic studies of the elderly. Am J Clin Nutr 1996; 64: 190–196 43. Veris Research Summary. The role of antioxidants in prevention of coronary heart disease. November, 1996: p 1–16 Vitamin K 1. Frick PG, Riedler G, Brogli H. Dose response and minimal daily requirement for vitamin K in man. J Appl Physiol 1967; 23: 387–389 2. Olson RE. The function and metabolism of vitamin K. Ann Rev Nutr 1984; 4: 281–327 3. Price PA. Role of vitamin K-dependent proteins in bone metabolism. Ann Rev Nutri 1988; 8: 565–583 4. Knapen MHJ, Hamuly’ak K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Int Med 1989; 111: 1001–1005 5. Kuksis A. Fat absorption, vol. 2. Boca Raton, FL: CRC Press. 1987: p 65–86 6. Sadowski JA, Hood SJ, Dallal GE, Garry PJ. Phylloquinone in plasma from elderly and young adults. factors influencing its concentration. Am J Clin Nutr 1989; 50: 100–108 7. Jones DY, Koonsvitsky BP, Ebert ML et al. Vitamin K status of free-living subjects consuming olestra. Am J Clin Nutr 1991; 53: 943–946 8. Suttie, JW. Vitamin K. In: Present knowledge in nutrition. 7th edn. Washington DC: International Life Sciences Press. 1996: p 137–45 9. Binkley, NC, Suttie, W. Vitamin K nutrition and osteoporosis. J Nutr 1995; 125: 1812–1821 10. Ferland, G., Sadowski, JA., O’Brien, ME. Dietary induced subclinical vitamin K deficiency in normal human subjects. J Clin Invest 1993; 91: 1761–1768 Water-soluble vitamins Vitamin C 1. Wartamowicz M, Panczenko-Kresowka B, Ziemlaski S et al. The effect of alpha-tocopherol and ascorbic acid on the serum lipid peroxide level in elderly people. Ann Nutr Metabol 1984; 28: 186–191 2. Calabrese EJ. Does exposure to environmental pollutants increase the need for vitamin C? J Environ Pathol Toxicol Oncol 1985; 5: 81–90
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3. Tannenbaum SR, Wishnok JS, Leaf CD. Inhibition of nitrosamine formation by ascorbic acid. Am J Clin Nutr 1991; 53: 247S–250 4. Block G. Vitamin C and cancer prevention. The epidemiologic evidence. Am J Clin Nutr 1991; 53: 270S–282S 5. Gey KF. Scientific evidence for dietary targets in europe bibliotheca nutr deta, vol. 37. Basil: Karger. 1986 6. Ramirez J, Flowers NC. Leukocyte ascorbic acid and its relationship to coronary artery disease in man. Am J Clin Nutr 1980; 33: 2079–2087 7. Greco AM, Gentile M, DiFilippo O et al. Study of blood vitamin C in lung and bladder cancer patients before and after treatment with ascorbic acid. A preliminary report. Acta Vitaminol Enzymol 1982; 4: 155–162 8. Ghosh J, Das S. Evaluation of vitamin A and C status in normal and malignant conditions and their possible role in cancer prevention. Jpn J Cancer Res 1985; 76: 1174–1178 9. Romney SL, Duttagupta C, Basu J et al. Plasma vitamin C and uterine cervical dysplasia. Am J Obstet Gynecol 1985; 151: 976–980 10. Sergeev AV. Korrekksiia biokhimich eskilch i immunologicheskikh pokazatelei pri rake tolstoi kishki optimal nymi dozami retinilatseta i askorbinovoi kisloty. B Exp Biol Med 1984; 96: 90–92 11. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer. Reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci 1978; 75: 4538–4542 12. Bjelke E. Epidemiologic studies of cancer of the stomach, colon and rectum; with special emphasis on diet. Scand J Gastroenterol 1974; 9: 1–235S 13. Wassertheil-Smoller S, Romney SC, Wylie-Rosett J et al. Dietary vitamin C and uterine cervical dysplasia. Am J Epidemiol 1981; 114: 714–724 14. Marshall J, Graham S, Mettlin C et al. Diet in the epidemiology of oral cancer. Nutr Cancer 1982; 3: 145–149 15. Kune S, Kune GA, Watson LF. Case-control study of dietary etiological factors. The Melbourne Colorectal cancer study. Nutr Cancer 1987; 9: 21–42 16. Fontham ET, Pickle LW, Haenszel W et al. Dietary vitamins A and C and lung cancer risk in Louisiana. Cancer 1988; 62: 2267–2273 17. Lu SH, Otishima H, Fu HM, Tian Y, Li FM, Blettner M, Wahrendorf J, Bortsch H. Urinary excretion of N-nitrosamino acids and nitrate by inhabitants of high and low-risk areas of esophageal cancer in Northern China. Endogenous formation of nitrosoproline and its inhibition by vitamin C. Cancer Res 1986; 46: 1485–1491 18. O’Connor HJ, Habibzedah N, Schorah CJ et al. Effect of increased intake of vitamin C on the mutagenic activity of gastric juice and intrgastric concentrations of ascorbic acid. Carcinogenesis. 1985; 6: 1675–1676
19. Gaby SK, Singh VN. Vitamin intake and health: a scientific review. New York: Marcel Dekker. 1991: p 103–161 20. Sutor DJ, Johnston CS. FASEB J 1988; 2: A851 21. Shilotri PG, Bhat KS. Effect of mega doses of vitamin C on bactericidal activity of leukocytes. Am J Clin Nutr 1977; 30: 1007–1081 22. Anderson R, Oosthuizen R, Maritz R et al. Effects of increasing weekly doses of ascorbate on certain cellular and humoral immune functions in normal volunteers. Am J Clin Nutr 1980; 33: 71–76 23. Kennes B, Dumont I, Brohee D et al. Effect of vitamin C supplements in cell-mediated immunity in old people. Gerontology 1983; 29: 310 24. Ringsdorf WM Jr, Cheraskin E. Vitamin C and human wound healing. Oral Surg 1982; 53: 231–236 25. Schwartz PL. Ascorbic acid in wound healing: a review. J Am Diet Assoc 1970; 56: 497–503 26. Erden F, Gulenc S, Torun M et al. Ascorbic acid effect on some lipid fractions in human beings. Acta Vitaminol Enzymol 1985; 7: 131–138 27. Ziemlanski S, Wartanowicz M, Potrzebnicka K et al. Ascorbic acid and tocopherol levels in the organs and serum of guinea pigs with experimentally induced atherosclerosis. Acta Physiol Pol 1989; 40: 552–557 28. Ginter E, Cerna O, Budlovsky J et al. Effect of ascorbic acid on plasma cholesterol in humans in a long-term experiment. Int J Vit Nutri Res 1977; 47: 123–134 29. Lohmann W. Ascorbic acid and cataract. Ann NY Acad Sci 1987; 498: 307–311 30. Chandra DB, Varma R, Ahmad S et al. Vitamin C in the human aqueous humor and cataracts. Int J Vit Nutr Res 1986; 56: 165–168 31. Hallberg L, Rossander L. Absorption of iron from Western-type lunch and dinner meals. Am J Clin Nutr 1982; 35: 502–509 32. Cook JD, Watson SS, Simpson KM et al. The effect of high ascorbic acid supplementation on body iron stores. Blood 1984; 64: 721–726 33. Freudenheim JL, Johnson NE, Smith EL. Relationships between usual nutrient intake and bone-mineral content of women 35–65 years of age. longitudinal and cross-sectional analysis. Am J Clin Nutr 1986; 44: 863–876 34. Sowers MR, Wallace RB and Lemke JH. Correlates of mid-radius bone density among postmenopausal women. A community study. Am J Clin Nutr 1985; 41: 1045–1053 35. Cheraskin E, Ringsdorf WM Jr, Sisley EL. The vitamin C connection. New York: Harper & Row. 1983: p 1–279 36. Eaton SB, Shostak M, Konner M. The paleolithic prescription. New York: Harper & Row. 1988: p 82, 130–131 37. Riemersma RA, Wood DA, Macintyre CAC et al. Vitamin E. Biochemistry and health implications, vol. 570. New York: Ann NY Acad Sci. 1989: p 291–295 38. Robertson J, Donner AP, Trevithick JR. Vitamin E. Biochemistry and health implications, vol. 570. New York: Ann NY Acad Sci. 1989: p 372–82 39. Krumdieck C, Butterworth CE Jr. Ascorbate–cholesterollecithin interactions. Factors of potential importance in pathogenesis of atherosclerosis. Am J Clin Nutr 1974; 27: 866–876 40. Cheraskin E, Ringsdorf WM Jr. Vitamin C and chronologic versus bone age. J Tenn Dent Assoc 1974; 57: 177–178 41. Cheraskin E, Ringsdorf WM Jr, Medford FH. The ‘ideal’ daily vitamin C intake. J Med Assoc State Alabama 1977; 46: 39–40 42. Cheraskin E, Ringsdorf WM Jr. Vitamin C. Nutr Perspect 1978; 1: 34–36 43. Cheraskin E, Ringsdorf WM Jr. Vitamin C. J Can CA 1978; 22: 97–98 44. Cheraskin E. Vitamin C. J Orthomol Med 1986; 1: 241 45. Cheraskin E. Vitamin C. Nutr Report 1988; 6: 1–8 46. Cheraskin E, Ringsdorf WM Jr, Michael DW et al. Daily vitamin C consumption and reported respiratory findings. Int J Vit Nutr Res 1973; 43: 42–55 47. Yoshioka M, Matsushita T, Chuman Y. Inverse association of serum ascorbic acid level and blood pressure or rate of hypertension in male adults aged 30–39 years. Int J Vit Nutr Res 1984; 54: 343–347 48. Stamler J. Nutrition, lipids and coronary heart disease. New York: Raven Press. 1979: p 25 49. Weisburger J. Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids. Am J Clin Nutr 1991; 53: S226–237 50. Emstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidem 1992; 3: 194–202 51. Levine M, Rumsey S, Wang Y, Park J et al. Vitamin C. In: Present knowledge in nutrition. 7th edn. Washington DC: International Life Sciences Press. 1996: p 146–159 52. Bendich A, Langseth L. The health effects of vitamin C supplementation. A review. J Am Col Nutr 1995; 14: 124–136 53. Weisburger JH. Vitamin C and disease prevention. J Am Col Nutr 1995; 14: 109–111 54. Hemilä H., Herman ZS. Vitamin C and the common cold. A retrospective analysis of Chalmers’ review. J Am Col Nutr 1995; 14: 116–123 55. Johnston CS, Luo B. Comparison of the absorption and excretion of three commercially available sources of vitamin C. J Am Dietetic Assoc 1994; 94: 779–781 56. Hemilä H. Vitamin C and plasma cholesterol. Crit Rev Food Sci Nutr 1992; 32: 33–57 57. Moran JP, Cohen L, Greene JM et al. Plasma ascorbic acid concentrations relate inversely to blood pressure in human subjects. Am J Clin Nutr 1993; 57: 213–217
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Zn by normal human subjects. Am J Clin Nutr 1981; 34: 2648–2652
10. Prasad ASP. Clinical biochemical and nutritional spectrum of zinc deficiency in human subjects: an update. Nutr Rev 1983; 41: 197–208 11. Taper LJ, Oliva JT, Ritchey SJ. Zinc and copper retention during pregnancy. The adequacy of prenatal diets with and without dietary supplementation. Am J Clin Nutr 1985; 41: 1184–1192 12. Schauss AG, Bryce-Smith D. Nutrients and brain function. Basil: Karger. 1987: p 151–162 13. Gibson RS, Anderson BM, Scythes CA. Regional differences in hair zinc concentrations. A possible effect of water hardness. Am J Clin Nutr 1983; 37: 37–42
14. Sandstead HH. Trace element interactions. J Lab Clin Med 1981; 98: 457–462 15. Haring BSA, Van Delft W. Changes in the mineral composition of food as a result of cooking in ‘hard’ and ‘soft’ waters. Arch Environ Health 1981; 36: 33–35 16. Moser-Veillon PB, Reynolds RD. A longitudinal study of pyridoxine and zinc supplementation of lactating women. Am J Clin Nutr 1990; 52: 135–141 17. Bales CW, Freeland-Graves JH, Askey S et al. Zinc, magnesium, copper, and protein concentrations in human saliva. Age- and sex-related differences. Am J Clin Nutr 1990; 51: 462–469 18. Fosmire GJ. Zinc toxicity. Am J Clin Nutr 1990; 51: 225–227 19. Shambaugh GE Jr. Zinc. The neglected nutrient. Am J Otol 1989; 10: 156–160 20. Shambaugh GE Jr. Zinc for tinnitus, imbalance, and hearing loss in the elderly. Am J Otol 1986; 7: 476–477 21. Shambaugh GE Jr. Zinc and presbycusis. Am J Otol 1985; 6: 116–117 22. Cunnigham-Rundles S, Cunningham-Rundles WF. Nutrition and immunology. New York: Alan R. Liss. 1988: p 197–214 23. Cousins RJ, Hempe JM. Zinc. In: Present knowledge in nutrition. 6th edn. Washington, DC: Nutrition Foundation. 1990: p 251–260 24. Shambaugh GE. Zinc, an essential nutrient for hearing and balance. Int J Biosocial Med Res 1991; 13: 192–199 25. Cousins RJ. Zinc. In: Present knowledge in nutrition. 7th edn. Washington, DC: Nutrition Foundation. 1996: p 293–306 26. Thomas EA, Bailey LB, Kauwell GA et al. Erythrocyte metallothionein response to dietary zinc in humans. J Nutr 1992; 122: 2408–2414 27. King JC, Hambidge KM, Westcott JL et al. Daily variation in plasma zinc concentrations in women fed meals at six-hour intervals. J Nutr 1994; 124: 508–516 28. Taylor CM, Bacon JR, Aggett PJ et al. Homeostatic regulation of zinc absorption and endogenous losses in zinc-deprived men. Am J Clin Nutr 1991; 53: 755–763 29. Nishi Y. Anemia and zinc deficiency in the athlete. J Am Col Nutr 1996; 15: 323–324 30. Nishi Y. Zinc and growth. J Am Col Nutr 1996; 15: 340–344 31. Reunanen A, Knekt P, Marniemi J et al. Serum calcium, magnesium, copper and zinc and risk of cardiovascular death. Eur J Clin Nutr 50: 431–437 32. Hambidge KM. Zinc deficiency in young children. Am J Clin Nutr 1997; 65: 160–161 33. Mossad SB, Macknin ML, Medendorp SV et al. Zinc gluconate lozenges for treating the common cold. A randomized, placebo-controlled study. Ann Intern Med 1996; 125: 81–88 34. King JC. Does poor zinc nutriture retard skeletal growth and mineralization in adolescents? Am J Clin Nutr 1996; 64: 375–376 35. Mahajan S, Prasad A, Brewer G et al. Effect of changes in dietary zinc intake on taste acuity and dark adaptation in normal human subjects. J Trace Elem Exp Med 1992; 5: 33–45 36. Kondo T, Toda Y, Matsui H. Effects of exercise and sleep deprivation on serum zinc. J Trace Elem Exp Med 1990; 3: 324–354 37. Zlotkin SH, Casselman CW. Urinary zinc excretion in normal subjects. J Trace Elem Exp Med, 1990; 3: 13–21 38. Berg JM, Shi Y. The galvanization of biology. A growing appreciation for the roles of zinc. Science 1996; 271: 1081–1085 39. Tuormaa TE. Adverse effects of zinc deficiency. A review from the literature. J Orthomol Med 1995; 10: 149–164 40. Krebs NF, Reidinger CJ, Hartley S et al. Zinc supplementation during lactation. Effects on maternal status and milk zinc concentrations. Am J Clin Nutr 1995; 61: 1030–1036 41. Sturniolo GC, Montino MC, Rossetto L et al. Inhibition of gastric acid secretion reduces zinc absorption in man. J Am Col Nutr 1991; 4: 372–375 42. Koyama H, Hosokai H, Tamura S et al. Positive association between serum zinc and apolipoprotein A-II concentrations in middle-aged males who regularly consume alcohol. Am J Clin Nutr 1993; 57: 657–661
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Chapter 109 - Sarsaparilla species Michael T. Murray ND Joseph E. Pizzorno Jr ND
Smilax aristolochiifolia (family: Liliaceae) Synonym: Smilax medica Common name: Mexican sarsaparilla Smilax officinalis (family: Liliaceae) Synonym: Smilax regelii Common name: Honduras sarsaparilla
GENERAL DESCRIPTION Sarsaparilla is a tropical American perennial plant. Its long slender root and short thick rhizomes produce a vine which trails on the ground and climbs by means of tendrils growing in pairs from the petioles of the alternate, obicular to ovate, evergreen leaves. The root is the part of the plant utilized for medicinal purposes.
CHEMICAL COMPOSITION Sarsaparilla contains 1.8–2.4% steroid saponins, including: • sarsaponin • smilasaponin • sarsaparilloside and its aglycones sarsapogenin(see Fig. 109.1 ), smilagenin, pollinastanol. Other constituents include starch, resins, and a trace of volatile oil.
[1]
Figure 109-1 Sarsasapogenin.
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HISTORY AND FOLK USE Sarsaparilla’s medicinal use has been as a tonic and blood purifier. Tonics are defined as agents:
[2]
… which permanently exalt the energies of the body at large, without vitally affecting any one organ in particular. … In short, tonics tone the whole system. A blood purifier or depurative refers to an agent which cleanses and purifies the system. [2] Sarsaparilla’s reputation in this regard probably stems from its importation from the Caribbean and South America to Europe in the 16th century for the treatment of syphilis. [3] Historical use in the treatment of syphilis A French physician, Nicholas Monardes, published a comprehensive account of sarsaparilla and several other “new” drugs in the treatment of syphilis in 1574. Many Europeans at the time believed that syphilis had come to Europe from the West Indies with Columbus’ sailors, and since there was a general belief that whatever disease was native to a country might be cured by the medicinal herbs growing in that region, it was only natural for sarsaparilla to become a popular remedy. Furthermore, the standard treatment for syphilis, mercury, often resulted in greater morbidity and mortality than the disease itself. Sarsaparilla was a welcome alternative, but despite initial excitement, Monardes’ sarsaparilla cure sank in favor. This was probably due to other aspects of the cure, which included confinement to a warm room for 30 days, followed by 40 days of abstinence from both wine and sexual intercourse. [3] However, sarsaparilla continued to be used in the treatment of syphilis. During military operations in Portugal in 1812, a British Inspector General of Hospitals noted that the Portuguese soldiers suffering from syphilis who used sarsaparilla recovered much faster and more completely than their British counterparts who were treated with mercury.[3] Sarsaparilla was also used by the Chinese in the treatment of syphilis. Clinical observations in China demonstrated that sarsaparilla is effective, according to blood tests, in about 90% of acute cases and 50% of chronic cases. [1] [4] Although sarsaparilla was clearly more beneficial in the treatment of syphilis, it was mercury that established itself as the standard treatment for over four and a half centuries. It has been stated that “the use of mercury in the treatment of syphilis may have been the most colossal hoax ever perpetrated” in the history of medicine. Mercury represented a new kind of medicine, one formulated and prepared in a laboratory using the new techniques of chemistry. It helped to prepare the way for the future use of drugs rather than herbal medicines. [3] An interesting note is that sarsaparilla species have been used all over the world in many different cultures for the same conditions, namely gout, arthritis, fevers, digestive disorders, skin disease, and cancer. [1]
PHARMACOLOGY The mechanism of action of sarsaparilla is largely unknown, although the plant does contain several saponins and has been shown to be clinically effective in the treatment of psoriasis. [1] [5] [6] This evidence points to a possible effect on binding of cholesterol and bacterial toxins in the intestines.
Endotoxin binding Evidence seems to support sarsaparilla as an endotoxin binder. Endotoxins are cell wall constituents of bacteria that are absorbed from the gut. Normally, the liver plays a vital role by filtering these, and other, gut-derived compounds before they reach the general circulation. If the amount of endotoxin absorbed is excessive or if the liver is not functioning adequately, the liver can become overwhelmed, and endotoxins will spill into the blood. If endotoxins are allowed to circulate, activation of the alternate complement system occurs. This system plays a critical role in aggravating inflammatory processes, and activation of complement is responsible for much of the inflammation and cell damage that occurs in many diseases, including gout, arthritis, and psoriasis. Historically, these conditions have been treated with sarsaparilla. In further support of sarsaparilla’s effect as a binder of endotoxin is its historical use in the treatment of fever, as absorbed endotoxins produce fever. Sarsaparilla also exhibits some antibiotic activity, but this is probably secondary to its endotoxin-binding action. [1]
CLINICAL APPLICATION Sarsaparilla’s medicinal action appears to be a result of its binding of bacterial endotoxins in the gut, which makes them unabsorbable. This greatly reduces the stress on the liver and other organs and is probably responsible for sarsaparilla’s historical use as a tonic and blood purifier. This ability to bind endotoxins is also the probable reason why sarsaparilla is effective in many cases of psoriasis, gout, and arthritis. Psoriasis
Individuals with psoriasis have been shown to have high levels of circulating endotoxins. Binding of endotoxin in the gut is associated with clinical improvement in
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these individuals. In a controlled study of 92 patients, an endotoxin-binding saponin (sarsaponin) from sarsaparilla greatly improved the psoriasis in 62% of the patients and resulted in complete clearance in 18%. [6]
DOSAGE • Dried root: 1–4 g or by decoction three times/day • Liquid extract (1:1): 8–15 ml three times/day • Solid extract (4:1): 250 mg three times/day.
TOXICOLOGY Although no adverse effects have been reported, it is possible that problems could arise if large doses are used over a long period of time.
REFERENCES 1. Leung
AY. Encyclopedia of common natural ingredients used in food, drugs and cosmetics. New York, NY: John Wiley. 1980
2. Felter
HW. The eclectic materia medica, pharmacology and therapeutics. Portland, OR: Eclectic Medical Publications. 1983
3. Griggs
B. Green pharmacy, a history of herbal medicine. London: Jill Norman & Hobhouse. 1981
4. Bensky 5. Duke
D, Gamble A. Chinese herbal medicine materia medica. Seattle, WA: Eastland Press. 1986
JA. Handbook of medicinal herbs. Boca Raton, FL: CRC Press. 1985
6. Thurman
FM. The treatment of psoriasis with sarsaparilla compound. New Engl J Med 1942; 227: 128–133
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Chapter 110 - Serenoa repens (saw palmetto) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Serenoa repens (family: Arecaceae) Common names: saw palmetto, palmetto scrub, sabal serrulata
GENERAL DESCRIPTION Serenoa repens is a small palm tree native to the West Indies and the Atlantic coast of North America from South Carolina to Florida. The plant grows from 6– 10 feet high, with a crown of large, 2–4 feet high spiny-toothed leaves which form a circular, fan-shaped outline. The berries of the plant are the components used for medicinal purposes. The deep red-brown to black berries are wrinkled, oblong, and 0.5–1 inch long with a diameter of 0.5 inch. [1]
CHEMICAL COMPOSITION The saw palmetto berries contain about 1.5% of a fruity-smelling oil containing saturated and unsaturated fatty acids and sterols. [1] About 63% of this oil is composed of free fatty acids including capric, caprylic, caproic, lauric, palmitic, and oleic acids. The remaining portion is composed of ethyl esters of these fatty acids and sterols, including beta-sitosterol and its glucoside. The lipid-soluble compounds are thought to be the major pharmacological components. Other components of the berries include carotenes, lipase, tannins, and sugars. The purified fat-soluble extract is used medicinally and contains between 85 and 95% of fatty acids and sterols. It is made up predominantly of a complex mixture of saturated and unsaturated free fatty acids, their methyl- and ethyl-esters (approximately 7%), long chain alcohols in free and esterified form, and various free and esterified sterol derivatives. The free fatty acids in this extract are identified by gas chromatography and mass spectrometry as: • caproic acid (C6) • capric acid (C8) 944
• caprylic acid (C10) • lauric acid (C12) • myristic acid (C14) • isomyristic acid (C14) • palmitic acid (C16) • oleic acid (C18:1) • stearic acid (C18). Lauric and myristic acid are the major fatty acids, accounting for approximately 30% of the fatty acid content. The identified alcohols include those with n-C22, n-C23, n-C24, n-C26, n-C28, and n-C30 chains, phytol, farnesol, and geranylgeraniol, in addition to high molecular weight unsaturated polyphenols. The sterolic fraction is composed of beta-sitosterol, stigmasterol, cycloartenol, lupeol, lupenone, and 24-methylcycloartenol. Many of these sterols are esterified with the fatty acids of the extract.
HISTORY AND FOLK USE The American Indians, and later Eclectic and Naturopathic physicians, used saw palmetto berries in the treatment of genitourinary tract disturbances and as a tonic to support the body nutritionally. [2] [3] It was used in men to increase the function of the testicles and relieve irritation in mucous membranes, particularly those of the genitourinary tract and prostate. It has been used in women with disorders of the mammary glands; long-term use was reputed to cause the breasts to enlarge slowly.[2] Many herbalists have considered it to be an aphrodisiac. [1]
PHARMACOLOGY A standardized liposterolic (fat-soluble) saw palmetto berry extract has demonstrated numerous pharmacological effects relating to its primary clinical application in the treatment of the common disorder of the prostate gland, benign prostatic hyperplasia (BPH). BPH is thought to be caused by an accumulation of testosterone in the prostate. Once within the prostate, testosterone is converted to the more potent hormone dihydrotestosterone (DHT). This compound stimulates the cells to multiply excessively, eventually causing the prostate to enlarge. The primary therapeutic action of saw palmetto extract in the treatment of BPH has been thought to be a result of inhibition in the intraprostatic conversion of testosterone to dihydrotestosterone (DHT and inhibition of its intracellular binding and transport. [4] [5] However, more recent research has suggested additional mechanisms of action, including anti-estrogenic and receptor site-binding effects. [6] Estrogen contributes to BPH because it inhibits the hydroxylation and subsequent elimination of DHT. Serenoa appears to inhibit the activity of estrogen in the prostate. For example, in a double-blind study of 35 men with BPH, 18 were given the saw palmetto extract at 160 mg twice daily and 17 were given placebo. [4] At the end of the 90 day study, androgen, estrogen, and progesterone receptors from prostate tissue samples were evaluated by two different techniques. The men receiving the saw palmetto extract had significantly lower cytosol and receptor values for estrogen and progesterone compared with the placebo group. Since the progesterone receptor content is linked to estrogenic activity, the results of the evaluation imply that at least part of the efficacy of the saw palmetto extract is through its anti-estrogenic effect. The results from the androgen receptor analysis were quite interesting: there was no change in the number of cytosol androgen receptors, but the number of nuclear androgen receptors was significantly lower in the saw palmetto group (60% of the placebo group were positive for the nuclear receptor compared with 10% in the saw
palmetto group). These results indicate that the saw palmetto extract probably competitively blocks the translocation of the cytosol androgen receptor to the nucleus. The overall results of the study indicate that the standardized extract of saw palmetto exerts both anti-androgenic and anti-estrogenic activities. Preliminary analysis of the extract indicate that separate fractions are responsible for these effects. Researchers in this study concluded: It cannot be excluded, however, that the primary effect is antiestrogenic and that the inactivation of androgen receptors and progesterone receptors and of the 5-alpha-reductase activity is secondary to the estrogen receptor blockade. The standardized extract has also demonstrated anti-edematous effects and the polysaccharide components have demonstrated immunostimulatory effects. [7] [8]
CLINICAL APPLICATION Currently, the primary clinical application of saw palmetto berries (specifically the fat-soluble extract) is in the treatment of benign prostatic hyperplasia (BPH). Based on its pharmacology, this extract may also be of benefit in conditions of androgen excess in women, such as hirsutism and polycystic ovarian disease. Benign prostatic hyperplasia
In the United States, between 50 to 60% of men between the ages of 40 and 59 years have BPH. This disorder is characterized by increased urinary frequency, night-time awakening to empty the bladder, and reduced force and caliber of urination (see Ch. 138 ). These major symptoms have been shown to be significantly improved in over
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TABLE 110-1 -- Clinical studies demonstrating the efficacy of Serenoa repens extract (85–95% fatty acids and sterols at a dosage of 320 mg/day) Authors
Type of study
No. of patients
Length of study
Results
Boccafoschi & Annoscia[9]
Double-blind, placebo
22
60 days
Significant difference for volume voided, maximum flow, mean flow, dysuria, nocturia
Cirillo-Marucco et al[10]
Open
47
4 months
Significant difference for dysuria, nocturia, urine flow
Tripodi et al [11]
Open
40
30–90 days Significant difference for dysuria, nocturia, volume of prostate, voiding rate, residual urine
Emili et al[12]
Double-blind, placebo
30
30 days
Greca & Volpi[13]
Open
14
1–2 months Significant difference for dysuria, perineal heaviness, nocturia, volume of urine per voiding, interval between two diurnal voidings, sensation of incomplete voiding
Duvia et al[14]
Controlled trial vs. Pygeum africanum
30
30 days
Tasca et al[15]
Double-blind, placebo
30
31–90 days Significant difference for frequency, urine flow measurement
Cukier et al[16]
Double-blind, placebo
168
60–90 days Significant difference for dysuria, frequency, residual urine
Champault et al[17]
Double-blind, placebo
168
60–90 days Significant difference for objective and subjective parameters
Crimi & Russo[18]
Open
32
4 weeks
Significant difference for dysuria, nocturia, volume of prostate, voiding rate
Champault et al[19]
Double-blind, placebo
110
28 days
Significant difference for: dysuria, nocturia, flow measurement, residual urine
Mattei et al[20]
Double-blind
40
3 months
Significant difference for dysuria, nocturia, residual urine
Braeckman[21]
Open
305
3 months
Significant difference for maximum urine flow, prostate volume, and international prostate score
Significant difference for number of voided, strangury, maximum and mean urine flow, residual urine
Significant difference for voiding rate
a dozen double-blind, placebo-controlled clinical trials (summarized in Table 110.1 ). [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] In one of the larger studies involving 110 patients with BPH, impressive clinical results were reported: nocturia decreased by over 45%, flow rate (ml/s) increased by over 50%, and post-micturition residue (ml) decreased by 42% in the group receiving the serenoa extract. [18] In contrast, those on placebo showed no significant improvement in nocturia or flow rate, and post-micturition residue actually worsened. Significant improvements were also noted in self-rating by the patients and global rating by the physicians. Of the 50 treated subjects completing the 30 day study, physicians rated 14 greatly improved, 31 improved, and only five unchanged or worsened. In contrast, no subjects in the placebo group had greatly improved, 16 showed some improvement, and 28 remained unchanged or worsened. Although the saw palmetto extract has shown excellent results in numerous double-blind, placebo-controlled clinical trials, results from a recent open, multicenter study are perhaps the most revealing. [21] The results corroborate those from numerous double-blind, controlled studies showing that the liposterolic extract of saw palmetto (Serenoa repens) standardized to contain 85–95% fatty acids and sterols is an effective treatment for benign prostatic hyperplasia (BPH). While drugs like finesteride (Proscar) typically take up to a year to produce significant benefit, the saw palmetto extract produces better results in a much shorter period of time. Most patients achieve some relief of symptoms within the first 30 days of treatment with the saw palmetto extract. In this study, 305 men were given a dosage of 160 mg twice daily. The subjective evaluations of treatment made by patients after 45 and 90 days of treatment were quite favorable. After 45 days, 83% of patients estimated that the drug was effective. After 90 days, the percentage increased to 88%. Similarly, global evaluations made by physicians after 45 and 90 days demonstrated 81 and 88% effectiveness, respectively. The objective evaluations demonstrated remarkable improvements in all measurements. Maximum urinary flow increased from 9.8 to 12.2 ml/s, mean urinary flow rate increased from 5.8 to 7.4 ml/s, prostatic volume decreased from 40,348 to 36,246 mm 3 ; and the international prostate symptom score decreased from 19.0 to 12.4. No serious adverse reactions were reported. While these results are impressive, perhaps the most impressive changes occurred in the quality of life scores as shown in Table 110.2 . These improvements in quality of life scores demonstrate just how powerful an effect improving bothersome symptoms such as nocturia can have on an individual’s mental outlook. Another important finding was that the saw palmetto extract had no demonstrable effect on serum prostatic specific antigen levels. A recently reported study has now evaluated the long-term efficacy of saw palmetto. This 3 year, multicenter,
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TABLE 110-2 -- Quality of life scores Evaluation Day 0 Day 90
Delighted
0.6%
5.4%
Happy
2.3%
24.0%
Satisfied
9.7%
36.8%
Mitigated
22.7%
20.9%
Unsatisfied 43.8%
9.5%
Unhappy
18.5%
2.4%
Hopeless
2.3%
1.0%
open-label study evaluated 160 mg of a standardized extract (Strogen ® ) in 435 men (aged 41–89 years) with stage I or II BPH. By the end of the study, 120 patients had withdrawn – 12 due to lack of efficacy, 41 due to the need for surgery, 41 lost to follow-up and eight due to adverse reactions. In the remaining 315, the following were reported: • nocturia normalized or improved in 73% • daytime frequency improved in 54% • feeling of incomplete emptying improved in 75% • rectal examination revealed improvement in prostate congestion in 55% • average residual volume decreased from 64 to 38 ml • peak urine flow increased by an average of 6.1 ml/s. A total of 14.7% of the men experienced a continued deterioration of their prostate function. The primary adverse events were mild gastrointestinal disturbance.
DOSAGE The dosage for the liposterolic extract of saw palmetto berries (containing 85–95% fatty acids and sterols) is 160 mg twice daily. A similar dose using fluid extracts and tinctures would require extremely large quantities of alcohol and therefore cannot be recommended. Dosages are as follows: • crude berries: 10 g twice daily • liposterolic extract (standardized at 85–95% fatty acids and sterols): 160 mg twice daily.
TOXICOLOGY No significant side-effects have been reported in the clinical trials of the saw palmetto berry extract or with saw palmetto berry ingestion.
REFERENCES 1. Duke
JA. Handbook of medicinal herbs. Boca Raton, FL: CRC Press. 1985: p 118
2. Felter
HW, Lloyd JU. King’s American dispensatory (1898). Portland OR: Eclectic Med Publ (reprint). 1983: p II: 1750–1752
3. Kuts-Cheraux
AW. Naturae medicina and naturopathic dispensatory. Yellow Springs, OH: Antioch Press. 1953: p 249
4. Carilla
E, Briley M, Fauran F et al. Binding of Permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate. J Steroid Biochem 1984; 20: 521–523
5. Sultan
C, Terraza A, Devillier C et al. Inhibition of androgen metabolism and binding by a liposterolic extract of Serenoa repens B in human foreskin fibroblasts. J Steroid Biochem 1984; 20:
515–519 6. Di
Silverio F, D’Eramo G, Lubrano C. Evidence that Serenoa repens extract displays antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy. Eur Urol 1992; 21: 309–314
7. Tarayre
JP, Delhon A, Lauressergues H et al. Anti-edematous action of a hexane extract of the stone fruit of Serenoa repens Bartr. Ann Pharm Franc 1983; 41: 559–570
8. Wagner
H, Proksch A. Immunostimulatory drugs of fungi and higher plants. Econ Med Plant Res 1985; 1: 113–153
9. Boccafoschi,
Annoscia S. Comparison of Serenoa repens extract with placebo by controlled clinical trial in patients with prostatic adenomatosis. Urologia 1983; 50: 1257–1268
10.
Cirillo-Marucco E, Pagliarulo A, Tritto G et al. Extract of Serenoa repens (Permixon R ) in the early treatment of prostatic hypertrophy. Urologia 1983; 5: 1269–1277
11.
Tripodi V, Giancaspro M, Pascarella M et al. Treatment of prostatic hypertrophy with Serenoa repens extract. Med Praxis 1983; 4: 41–46
12.
Emili E, Lo Cigno M, Petrone U. Clinical trial of a new drug for treating hypertrophy of the prostate (Permixon). Urologia 1983; 50: 1042–1048
13.
Greca P, Volpi R. Experience with a new drug in the medical treatment of prostatic adenoma. Urologia 1985; 52: 532–535
14.
Duvia R, Radice GP, Galdini R. Advances in the phytotherapy of prostatic hypertrophy. Med Praxis 1983; 4: 143–148
Tasca A, Barulli M, Cavazzana A et al. Treatment of obstructive symptomatology caused by prostatic adenoma with an extract of Serenoa repens. Double-blind clinical study vs. placebo. Minerva Urol Nefrol 1985; 37: 87–91 15.
16.
Cukier (Paris), Ducassou (Marseille), Le Guillou (Bordeaux) et al. Permixon versus placebo. C R Ther Pharmacol Clin 1985; 4/25: 15–21
17.
Champlault G, Patel JC, Bonnard AM. A double-blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia. Br J Clin Pharmacol 1984; 18: 461–462
18.
Crimi A, Russo A. Extract of Serenoa repens for the treatment of the functional disturbances of prostate hypertrophy. Med Praxis 1983; 4: 47–51
19.
Champault G, Bonnard AM, Cauquil J, Patel JC. Medical treatment of prostatic adenoma. Controlled trial. PA 109 vs placebo in 110 patients. Ann Urol 1984; 18: 407–410
20.
Mattei FM, Capone M, Acconcia A. Serenoa repens extract in the medical treatment of benign prostatic hypertrophy. Urologia 1988; 55: 547–552
21.
Braeckman J. The extract of Serenoa repens in the treatment of benign prostatic hyperplasia. A multicenter open study. Curr Ther Res 1994; 55: 776–785
22.
Bach D, Ebeling L. Long-term drug treatment of benign prostatic hyperplasia – results of a prospective 3-year multicenter study using Sabal extract IDS89. Phytomed 1996; 3: 105–111
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Chapter 111 - Silybum marianum (milk thistle) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Silybum marianum (family: Compositae) Synonym: Carduus marianum Common names: milk thistle, marian thistle, St Mary’s thistle
GENERAL DESCRIPTION Silybum marianum is a stout, annual or biennial plant, found in dry rocky soils in southern and western Europe and some parts of the United States. The branched stem grows 1–3 feet high and bears alternate, dark green, shiny leaves with spiny, scalloped edges that are markedly streaked with white along the veins. The solitary flower heads are reddish-purple with bracts ending in sharp spines. Flowering season is from June to August. The seeds, fruit, and leaves are used for medicinal purposes.
CHEMICAL COMPOSITION Silybum marianum contains silymarin, a mixture of flavanolignans, consisting chiefly of silibin, silydianin, and silychristine. [1] [2] [3] The concentration of silymarin is highest in the fruit, but it is also found in the seeds and leaves. Other flavanolignans are contained in silybum, including silandrin, silyhermin, silymonin, and neosilyhermin. [1] Silibin is the silymarin component which yields the greatest degree of biological activity (see Fig. 111.1 ).
HISTORY AND FOLK USE Perhaps the most widespread folk use of this plant has
Figure 111-1 Silibin.
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been in assisting the nursing mother in the production of milk. It was also used in Germany for curing jaundice and biliary derangements. It is interesting to note that the discovery of the liver-protecting flavanolignans in Silybum marianum was not the result of systemic pharmacological screening, but rather of investigation of silybum’s empirical effects in liver disorders. [1]
PHARMACOLOGY Silybum marianum extracts (usually standardized to contain 70% silymarin) are currently widely used in European pharmaceutical preparations for hepatic disorders. Silymarin is one of the most potent liver-protecting substances known. [1] [2] [3] [4] [5] [6] [7] [9] Hepatoprotection effects Free radical scaveging
Silybum’s ability to prevent liver destruction and enhance liver function is due largely to silymarin’s inhibition of the factors that are responsible for hepatic damage, i.e. free radicals and leukotrienes, coupled with its ability to stimulate liver protein synthesis. Silybum components prevent free radical damage by acting as antioxidants. [1] [2] [3] [4] Silymarin is many times more potent in antioxidant activity than vitamin E. Effects on hepatic glutathione
Silymarin prevents the depletion of glutathione (GSH) induced by alcohol and other liver toxins. Even in normals, it increases the basal GSH level of the liver by 35% over controls. Protection from liver-damaging chemicals and drugs
The protective effect of silybum against liver damage has been demonstrated in a number of experimental and clinical studies. Experimental liver damage in animals can be produced by such diverse toxic chemicals as carbon tetrachloride, galactosamine, ethanol, and praseodymium nitrate. Silymarin has been shown to protect the liver from all of these toxins. [1] [2] [3] [4] [7] Perhaps the most impressive of silymarin’s protective effects is against the severe poisoning of Amanita phalloides (the deathcap or toadstool mushroom), an effect which has long been recognized in folk medicine. [5] [6] [7] Ingestion of Amanita phalloides or its toxins causes severe poisoning and, in approximately 30% of victims, death. Among the experimental models for measuring protection against liver damage, those based on amanitin or phalloidin toxicity are the most important, because these two peptides from Amanita phalloides are the most powerful liver-damaging substances known. Silymarin has demonstrated impressive results in these experimental models. When silymarin was administered before amanita toxin poisoning, it was 100% effective in preventing toxicity. [5] [7] Even if given 10 minutes after the amanita toxin, it completely counteracted the toxic effects. Two cases reported in the literature found that silymarin still prevents death and greatly reduces the amount of liver damage as long as 24 hours after ingestion. [6] This study reported on a husband and wife who ate toxic mushrooms and developed gastrointestinal symptoms 18 hours later. Despite initial conventional treatment with gastric emptying, intravenous fluids, activated charcoal and a duodenal tube, both patient’s laboratory work showed deteriorating liver and renal function. One patient developed mild hepatic encephalopathy. Treatment with intravenous silibinin at a dose of 20 mg/kg of body weight, penicillin and glucose for 3 days resulted in
reversal of both the organ failures and encephalopathy. Silymarin may also be of great value as an adjunct for patients receiving long-term drug therapy. A very interesting study found that providing psychiatric patients receiving phenothiazines or butyrophenones with the unusually high dose of 800 mg/day of silymarin resulted in significant protection of the liver as measured by malondialdehyde serum liver enzyme levels. [10] The silymarin did not interfere with the efficacy of the antidepressants. Stimulation of hepatic protein synthesis
Perhaps the most interesting effect of silybum components on the liver is their ability to stimulate protein synthesis. of new liver cells to replace the damaged old ones. It has been suggested that: [12]
[ 4] [11] [12]
This results in an increase in the production
silibinin imitates in some way a physiological regulator in animal cells, so that the structure fits into a specific binding site on the polymerase and in such a way causes the observed effects on rRNA synthesis making the drug from Silybum marianum indeed interesting for liver therapy. Interestingly enough, silybinin does not have a stimulatory effect on malignant hepatic tissue.
[ 11]
Anti-inflammatory effects
Leukotrienes, key chemical mediators of inflammation, produced by the transfer of oxygen to polyunsaturated fatty acids (a reaction catalyzed by the enzyme lipoxygenase) can also damage the liver. Silymarin has been shown to be a potent inhibitor of this enzyme, thereby inhibiting the formation of damaging leukotrienes. [13] Silymarin has also been shown to inhibit prostaglandin synthesis during inflammation. intoxication results in increased release, by lipolysis, of fatty
[14]
Free radical damage to membrane structures due to organic disease or
949
acids. This leads, among other things, to increased prostaglandin and leukotriene synthesis. Silymarin counteracts this deleterious process by suppressing the pathological decomposition of membrane lipids and inhibiting prostaglandin formation. [14] As leukotrienes and inflammatory prostaglandins are also involved in the damage of the liver by toxins, their neutralization by silybin is another mechanism for its protection of the liver. Other pharmacological actions Silymarin has demonstrated several other physiologic effects. It is a strong inhibitor of cyclic AMP phosphodiesterase: 13–50 times more active than theophylline and one to three times more active than papaverine. [15] Silymarin has also been shown to prevent the toxic effects of a variety of compounds, e.g. hemolysis induced by phenylhydrazine, X-radiation-induced damage, and brain edema induced by triethyltinsulfate (TZS). [16] [17] [18] Presumably, these effects are related to silymarin’s significant membrane-stabilizing and antioxidant actions. Its action in increasing the osmotic resistance of RBCs is also quite significant. [19]
CLINICAL APPLICATIONS Silymarin’s primary use is as an aid to the liver, although additional clinical applications are regularly being discovered. It can be used to support detoxification reactions or in the treatment of more severe liver disease. In numerous clinical studies, silymarin has been shown to have positive effects in treating several types of liver disease, including: [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] • cirrhosis • chronic hepatitis • fatty infiltration of the liver (chemical- and alcohol-induced fatty liver) • subclinical cholestasis of pregnancy • cholangitis and pericholangitis. The therapeutic effect of silymarin in these disorders has been confirmed by histological, clinical, and laboratory data. Silymarin may also be useful in improving the solubility of the bile in the treatment of gallstones and in psoriasis. Chemical-induced liver damage
In one of the first extensive double-blind clinical trials investigating silymarin’s therapeutic effect in liver disorders, silymarin demonstrated impressive results for 129 patients with toxic metabolic liver damage, fatty degeneration of the liver of various origin, or chronic hepatitis, as compared with a control group comprised of 56 patients. The results might have been even more impressive if the study had lasted longer than 35 days. [20] A follow-up study of patients with liver damage due to alcohol, diabetes viruses, or toxic exposure demonstrated even more striking results. Patients were followed for a long period of time (e.g. 7 weeks). Not only were clinical findings markedly improved in the silymarin-treated groups, but laboratory and liver biopsy data improved as well. Highly significant results were obtained in bromsulphalein retention, SGPT, iron, and cholesterol levels. There were remarkable tissue restorative effects as evidenced by biopsy. Upon completion of silymarin therapy, the liver showed restitution of normal cell structure even in severely damaged livers. These effects on the tissue level correlated well with improvements in blood chemistry. [21] Another study highlighted the benefit of silymarin in individuals exposed to toxic chemicals. In this study, abnormal results of liver function tests (elevated levels of AST, ALT activity) and/or abnormal hematological values (low platelet counts, increased white blood cell counts, and a relative increase of lymphocytes compared with other white blood cells) were observed in 49 of 200 workers exposed to toxic toluene and/or xylene vapors for 5–20 years. [33] Thirty of the affected workers were treated with silymarin, and the remaining 19 were left without treatment. Under the influence of silymarin, the liver function tests and the platelet counts significantly improved. The white blood counts also showed a tendency towards improvement. Cirrhosis
As described above, silymarin is quite effective in treating alcohol-related liver disease. There is a tremendous range in severity of alcohol-related liver disease from relatively mild to serious damage, such as cirrhosis. Even in this severe state, silymarin has shown benefit. Perhaps the most significant benefit is extending the life span of these patients. In one study, 87 cirrhotics (46 with alcoholic cirrhosis) received silymarin, while 83 cirrhotics (45 with alcoholic cirrhosis) received a placebo. [34] The mean observation period was 41 months. In the treatment group, there were 24 deaths with 18 related to liver disease while, in the controls, there were 37 deaths with 31 related to liver disease. The 4-year survival rate was 58% in the treatment group compared with 39% in the controls. Silymarin can also improve immune function in patients with cirrhosis. [35] Whether this effect is involved in the hepatoprotective action or a result of improved liver function has yet to be determined. Viral hepatitis
Silymarin is useful in helping reverse viral-induced liver damage. It is effective in both acute and chronic viral
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hepatitis. In one study of acute viral hepatitis, 29 patients treated with silymarin showed a definite therapeutic influence on the characteristic increased serum levels of bilirubin and liver enzymes compared with a placebo group. [36] The laboratory parameters in the silymarin group had regressed more than in the placebo group by the fifth day of treatment. The number of patients attaining normal liver values after 3 weeks of treatment was significantly higher in the silymarin group than in the placebo group. In a study in chronic viral hepatitis, silymarin was shown to result in dramatic improvement. Used at a high dose (420 mg of silymarin) for periods of 3–12 months, silymarin resulted in a reversal of liver cell damage (as noted by biopsy), an increase in protein level in the blood, and a lowering of liver enzymes. Common symptoms of hepatitis (e.g. abdominal discomfort, decreased appetite, and fatigue) were all improved. [37] Gallstones
Silymarin may help to prevent or treat gallstones via its ability to increase the solubility of the bile. In one study, the composition of the bile was assayed in 19 patients with a history of gallstones (four) or removal of the gall bladder due to gallstones (15) before and after silymarin (420 mg/day for 30 days) or placebo. Silymarin treatment led to significant reduction in the biliary cholesterol concentration and bile saturation index. [38] Psoriasis
Correction of abnormal liver function is indicated in the treatment of psoriasis. Silymarin has been reported to be of value in the treatment of psoriasis, and this may be due to its ability to inhibit the synthesis of leukotrienes, and improve liver function. [39] The connection between the liver and psoriasis relates to one of the liver’s basic tasks – filtering the blood. Psoriasis has been shown to be linked to high levels of circulating endotoxins, such as those found in the cell walls of gut bacteria. If the liver is overwhelmed by an increased number of endotoxins or chemical toxins, or if the liver’s functional ability to filter and detoxify is decreased, the psoriasis is aggrevated. Another factor in psoriasis is excessive production of leukotrienes. Silymarin has been shown to reduce leukotriene formation by inhibiting lipoxygenase. silymarin would inhibit one of the causes of the excessive cellular replication.
[ 13]
Therefore,
Silymarin has other effects of value in patients with psoriasis. Most of these effects revolve around correcting the abnormal cAMP to cGMP ratio observed in the skin of patients with psoriasis. The ratio of these two cellular control agents controls cellular replication. In psoriasis, cGMP levels are high relative to cAMP levels. Silymarin works to lower cGMP levels while raising cAMP levels. [15] Protection against chemical-induced renal damage
Recent research has indicated that the anti-toxin, free radical scavenging effects of silymarin may be of value in protecting the kidneys. [40] In a very provocative study, female rats were given the anti-cancer drug cisplatin either with or without silibinin (300 mg/kg). Compared to the drug-only group, the silibinin-treated group lost significantly less weight, experienced no loss in creatinine clearance, no changes in urea level or magnesium excretion, and only slight degenerative changes in the glomerulus and tubules. Considering the significant problem of serious nephrotoxicity from cisplatin and other chemotherapeutic agents, silibinin may be of great value as an adjunct in the treatment of cancer. Silibin bound to phosphatidylcholine In the past decade, a new form of silymarin has emerged that may provide the greatest benefit. The new form binds silybin to phosphatidylcholine. Preliminary research indicates that phosphatidylcholine-bound silybin is better absorbed and produces better clinical results. Absorption studies
Several human and animal studies have shown phosphatidylcholine-bound silybin is better absorbed. In one study, the excretion of silybin, the major component of silymarin, in the bile was evaulated in patients undergoing gall bladder removal (cholecystectomy). A drainage tube, the T-tube, was used to sample the bile. Patients were given either a single oral dose of the silybin–phosphatidylcholine complex or silymarin. The amount of silybin recovered in the bile in free and conjugated form within 48 hours was 11% for the silybin–phosphatidylcholine group compared with 3% for unmodified silybin. [41] One of the significant features of this study is the fact that silymarin has been shown to improve the solubility of the bile. Since more silybin is being delivered to the liver and gall bladder when the phosphatidylcholine-bound silybin is used, this form is the ideal form for individuals with gallstones or fatty infiltration of the liver, two conditions characterized by decreased bile solubility. In another study, plasma silybin levels were determined after administration of single oral doses of silybin–phosphatidylcholine complex and a similar amount of silymarin to nine healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of the silybin–phosphatidylcholine complex was much
951
greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. The authors concluded that complexa-tion with phosphatidylcholine greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal mucosa. [42] Clinical studies
Several clinical studies have shown phosphatidylcholine-bound silybin to be more effective. In one study, eight patients with chronic viral hepatitis (three with hepatitis B, three with both hepatitis B and hepatitis C, and two with hepatitis C) were given one capsule of phosphatidyl-choline-bound silybin (equivalent to 140 mg silymarin) between meals for 2 months.[43] After treatment, serum malondialdehyde levels (an indicator of lipid peroxidation) decreased by 36% and the quantitative liver function evaluation, as measured by galactose elimination capacity, increased by 15%. A statistically significant reduction of liver enzymes was also seen: AST decreased 17% and ALT decreased 16%. In another study designed primarily to evaluate the dose–response relationship of phosphatidylcholine-bound silybin, positive effects were again displayed. [44] In this study, patients with chronic hepatitis due to either a virus or alcohol were given different doses: 20 patients received 80 mg twice daily, 20 patients received 120 mg twice daily, and 20 patients received 120 mg three times daily for 2 weeks. At all tested doses, phosphatidylcholine-bound silybin produced a remarkable and statistically significant decrease of mean serum and total bilirubin levels. When used at the dose of 240 or 360 mg/day, it also resulted in a remarkable and statistically significant decrease in ALT and GGTP liver enzymes. These results indicate that even short-term treatment of viral or alcohol-induced hepatitis with relative low doses of phosphatidylcholine-bound silybin can be effective, but for the best results higher doses are indicated.
DOSAGE The standard dose of milk thistle is based on its silymarin content (70–210 mg three times daily). For this reason, standardized extracts are preferred. The best results are achieved at higher dosages, i.e. 140–210 mg of silymarin three times daily. The dosage for silybin bound to phosphatidylcholine is 120–240 mg twice daily.
Alcohol-based extracts are virtually always contraindicated in liver disease, as a relatively large amount of alcohol is administered in order to obtain an adequate dose of silymarin.
TOXICITY Silymarin preparations are widely used medications in Europe, where a considerable body of evidence points to very low toxicity. [1] When used at high doses for short periods of time, silymarin given by various routes to mice, rats, rabbits, and dogs has shown no toxic effects. Studies in rats receiving silymarin for protracted periods have also demonstrated a complete lack of toxicity. [1] As silymarin possesses choleretic activity, it may produce a looser stool as a result of increased bile flow and secretion. If higher doses are used, it may be appropriate to use bile-sequestering fiber compounds (e.g. guar gum, pectin, psyllium, oat bran, etc.) to prevent mucosal irritation and loose stools. Because of silymarin’s lack of toxicity, long-term use is feasible when necessary.
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H. Antihepatotoxic flavonoids. In: Cody V, Middleton E, Harbourne JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships. New York, NY: Alan R Liss. 1986: p 545–558 2. Adzet
T. Polyphenolic compounds with biological and pharmacological activity. Herbs Spices Medicinal Plants 1986; 1: 167–184
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H, Kiso Y, Wagner H, Fiebig. Antihepatotoxic actions of flavanolignans from Silybum marianum fruits. Planta Medica 1984; 50: 248–250
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H. Plant constituents with antihepatotoxic activity. In: Beal JL, Reinhard E, eds. Natural products as medicinal agents. Stuttgart: Hippokrates-Verlag. 1981
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G, Tuchweber B, Trost W, Mengs U. Protection against Amanita phalloides intoxication in beagles. Toxicol Appl Pharm 1984; 73: 355–362
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EH, Toorians AWF, Gietema JA et al. Amanita phalloides, a potentially lethal mushroom. Its clinical presentation and therapeutic options. Netherlands J Med 1996; 49: 19–23
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Sonnenbichler J, Zetl I. Biochemical effects of the flavanolignane silibinin on RNA, Protein and DNA synthesis in rat livers. In: Cody V, Middleton E, Harbourne JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships. New York, NY: Alan R Liss. 1986: p 319–331 12.
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Fiebrich F, Koch H. Silymarin, an inhibitor of lipoxygenase. Experentia 1979; 35: 148–150
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Flemming K. Effect of silymarin on X-radiated mice. Arzneim-Forsch 1971; 21: 1373–1375
Zoltan OT, Gyori I. Studies on the brain edema of the rat induced by triethyltinsulfate. Part 7: The therapeutic effect of silymarin, theophylline, and mannitol in the conditioned reflex test. Arzneim-Forsch 1970; 20: 1248–1249 18.
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Seeger R. The effect of silymarin on osmotic resistance of erythrocytes. Arzneim-Forsch 1971; 21: 1599–1605
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Schopen RD, Lange OK, Panne C, Kirnberger EJ. Searching for a new therapeutic principle. Experience with hepatic therapeutic agent legalon. Med Welt 1969; 20: 888–893
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Schopen RD, Lange OK. Therapy of hepatoses. Therapeutic use of silymarin. Med Welt 1970; 21: 691–698
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Sarre H. Experience in the treatment of chronic hepatopathies with silymarin. Arzneim-Forsch 1971; 21: 1209–1212
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Canini F, Bartolucci, Cristallini E et al. Use of silymarin in the treatment of alcoholic hepatic steatosis. Clin Ter 1985; 114: 307–314
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Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alteration of the liver. A double-blind controlled study. Scand J Gastroenterol 1982; 17: 417–1421
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Grossi F, Viola F. Protettori di membrana e silimarina nella terapia epatologica. Cl Terap 1981; 96: 11–23
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Maneschi M, Tiberio C, Cittadini E. Impegno metabolico dell’epatocita in gravidanza. profilassi e terapia con un farmaco stabilizzante di membrana. Cl Terap 1981; 97: 625–630
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Ferenci P, Dragosic SB, Dittrich H. Randomized controlled trial of Silymarin treatment in patients with cirrhosis of the liver. J Hepatology 1989; 9: 105–113
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Nassauto G et al. Effect of silibinin on biliary lipid composition. Experimental and clinical study. J Hepatol 1991; 12: 290–295
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Weber G, Galle K. The liver, a therapeutic target in dermatoses. Med Welt 1983; 34: 108–111
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Gaedeke J, Fels LM, Bokemeyer C et al. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996; 11: 56–62
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Schandalik R, Gatti G, Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneim Forsch 1992; 42: 964–968
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Barzaghi N, Crema F, Gitti G. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990; 15: 333–338
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Vailati A, Aristia L, Sozze E et al. Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 1993; 44: 219–228
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Chapter 112 - Soy isoflavones and other constituents* Kathi Head ND
INTRODUCTION In the past several years, soy and its constituents have received considerable attention, from both researchers and health practitioners. Epidemiological data which indicated that people from Asian cultures have lower rates of certain cancers, including cancer of the breast, prostate and colon, sparked an interest in soy as a contributing factor. While soy constituents, including saponins, lignans, phytosterols, protease inhibitors, and phytates, have come under investigation, the constituents which seem to hold the most promise from a therapeutic standpoint are the two isoflavones, genistein and daidzein. Numerous epidemiological, human, animal, and in vitro studies have demonstrated that soy isoflavones are effective chemopreventive agents for certain types of cancer. Mechanisms involved include: • antiangiogenesis • estrogen receptor binding • modulation of sex hormone binding globulin (SHBG) • anti-inflammatory and antioxidant effects • inhibition of the enzymes protein tyrosine kinase (PTK) and 5 alpha-reductase. Interaction with many other enzymes has been suggested. Evidence also points to the beneficial effects of soy, particularly the isoflavones, in prevention of cardiovascular disease. Isoflavones appear to inhibit platelet-activating factor and thrombin formation. They also increase HDL cholesterol and decrease triglycerides, LDL, VLDL, and total cholesterol. Other potential health benefits of soy include prevention of osteoporosis, via the phytoestrogen effects of isoflavones, and prevention of neovascularization in ocular conditions, via inhibition of angiogenesis. * Reprinted with permission from Alternative Medicine Review 1997; 2: 433–450
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Figure 112-1 Structure of genistein and diadzein.
CHEMICAL COMPOSITION Recent interest in the constituents of soybeans, particularly the isoflavones, has catapulted soy to the status of a promising nutraceutical with potentially significant health benefits. The principal isoflavones in soy are genistein (4',5,7-trihydroxyisoflavone), daidzein (4',7-dihydroxyisoflavone) (see Fig. 112.1 ), and their metabolites. In addition, soy products are a source of lignans, coumestans, saponins, plant sterols, phytates (inositol hexaphosphate), and protease inhibitors, all of which are also receiving attention for their health-promoting benefits. [1] Isoflavones Classification
Flavonoids are a subgroup of the larger group of plant constituents, the polypenols. Flavonoids are further differentiated into isoflavonoids, with isoflavones a subcategory of isoflavonoids (see Fig. 112.2 ). Isoflavonoids differ from other classes of flavonoids by their greater structural variability, their frequent presence in plants in their free form, rather than as a glycoside, and by the greater frequency of isoprenoid substitution. They are not as ubiquitous in nature as some of the other flavonoids, such as flavones and flavonols, being found primarily in one subfamily of Leguminosae, the Papilionoideae. [2] Approximately 600 isoflavonoids have been identified. They are divided into subclasses depending on the oxidation level of the central pyran ring. Isoflavones are the most abundant of the subclasses of isoflavonoids. Genistein and daidzein are two important isoflavones in soy. As can be seen in Figure 112.1 , genistein has a hydroxy group in the 5 position, giving it three hydroxy groups, while
Figure 112-2 Polyphenol classification.
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daidzein has just two. Due to the fact that the 5 hydroxy group on the genistein binds to the 4 ketonic oxygen, genistein is a more hydrophobic molecule than daidzein. This affords genistein some of its unique therapeutic effects. Absorption, metabolism and excretion
Isoflavones undergo extensive metabolism in the intestinal tract prior to absorption. Genistein is formed from biochanin A, and daidzein from formononetin. [1] Genistein and daidzein also occur in soy products in the form of their glycosides, genistin and daidzin. In the case of the glycosides, intestinal bacterial glucosidases cleave the sugar moieties, releasing the biologically active isoflavones, genistein and daidzein. In adults, these are further transformed by bacteria to specific metabolites: equol, O-desmethylangolensis, dihydrogenistein, and p-ethylphenol. Due to soy intake by livestock, isoflavone metabolites are also consumed indirectly in a diet high in dairy products and meat. [3] In at least one study, genistein was found to be well-absorbed in the small intestines by human subjects fed a soy beverage. [4] After absorption, the isoflavones are transported to the liver where they are removed from the portal blood. However, a percentage of the isoflavones in the portal blood can escape uptake by the liver and enter the peripheral circulation. The effectiveness of this hepatic first-pass clearance influences the amount which reaches peripheral tissues. [4] The isoflavones are
then eliminated, primarily via the kidneys, similar to endogenous estrogens.
[5]
After examining plasma, fecal and urinary concentrations of isoflavones in healthy volunteers, Xu et al [6] concluded that the bioavailability of soy isoflavones is influenced by an intact, healthy gut, with microflora capable of converting these isoflavones to their active forms. Wheat fiber appears to decrease the bioavailability of genistein. A small cross-over study of seven healthy women found that a more fiber-rich diet resulted in 55% less plasma genistein 24 hours after soy intake and a 20% reduction in total urinary genistein. The researchers postulated that fairly insoluble wheat fiber reduced the absorption of genistein by its bulking effect and hydrophobic binding. [7] Karr et al [8] found urinary excretion of isoflavones to be reflective of the type and amount of soy ingested. A study conducted on healthy male subjects between the ages of 20 and 40 found that urinary excretion of genistein and daidzein was greater after consumption of 112 g of tempeh, a fermented soy product, than after 125 g of unfermented soy pieces. [9] This finding seems to indicate that fermentation of soy products increases bioavailability of the isoflavones. Plasma levels of soy isoflavones are also increased after consumption of soy and certain other leguminous plants, such as clover. [10] Levels in soy products
Fukutake et al [11] analyzed soy products for genistein and genistin (the glycoside of genistein) content. The results are outlined in Table 112.1 . In general, they found that fermented soy products contain more genistein than soybeans, soy milk and tofu. Alcohol extraction, a process used in the production of many soy protein concentrates and isolates (used in soy protein powders), results in the removal of up to 90% of the isoflavones. [12] The isoflavone content of soybeans varies considerably depending on the variety of soybean (there are over 10,000 varieties of soybeans), the year harvested, geographic location, and the plant part in question.[13] Non-soy legumes, such as lentils and other beans, do not contain appreciable amounts of isoflavones. [14] Other soy constituents Protease inhibitors
Researchers have looked with interest at protease inhibitors (PI) and their potential anti-cancer and antiinflammatory effects. Two prominent protease inhibitors from soybeans are Bowman–Birk inhibitor (BBI) and Kunitz–Trypsin inhibitor (KTI). BBI is a 71-residue inhibitor which has two independent inhibitory sites involving binding with the proteases, trypsin and chymotrypsin. [15] BBI has been found to inhibit expression of certain oncogenes in irradiated animal models [16] and to inhibit chemically induced carcinogenesis. [17] [18] Both in vitro and in vivo animal models have demonstrated that BBI appears to exert its effects directly on the target organ rather than by a non-specific effect on metabolism. [19] [20] TABLE 112-1 -- Levels of genistein and its glycoside, genistin, in soy foods [11] Genistein
Genistin
Soybeans, soy nuts, soy powder
4.6–18.2 mcg/g*
200.6–968.1 mcg/g*
Soy milk, tofu
1.9–13.9 mcg/g
94.8–137.7 mcg/g
Fermented soy miso and natto†
38.5–229.1 mcg/g
71.7–492.8 mcg/g
Calculated daily Japanese dietary intake
1.5–4.1 mg/day
6.3–8.3 mg/day
* mcg/g raw food. † Soy sauce contains both genistein and genistin, but at lower levels than other fermented soy products.
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Some researchers have hypothesized that the dietary intake of exogenous PIs indirectly increases endogenous PI formation. [21] Other researchers have questioned the concept that PIs contribute significantly to the anti-cancer effects of soy. This is due, in part, to the fact that both raw and cooked soy products are equally effective in reducing cancer incidence, even though heating virtually destroys all protease activity. [22] Another reason for skepticism is that ingested PIs (such as purified BBI) are very poorly absorbed from the digestive tract. [22] Some researchers have postulated that the formation of these protease:protease inhibitor complexes might interfere with protein absorption, offering some cancer protection (epidemiological studies indicate that high-fat and high-protein diets increase cancer risk). [23] Protease inhibitors in soy products have been implicated in pancreatic hypertrophy and hyperplasia in animal models. [24] Whether it is the protease inhibitors and whether this hyperplasia contributes to increased rates of pancreatic cancer in these animals are still subjects of debate. Lignans
Lignans are capable of exerting a phytoestrogenic effect in humans. In addition, they exhibit antitumor and antiviral activity. [2] The most prevalent lignans in mammals are enterolactone and enterodiol, formed by gut bacteria, from the plant precursor lignans, matairesinol and secoisolariciresinol, respectively. [3] Oil seeds, such as flaxseed, contain about 100 times the lignan content of other plants. Other sources of lignans in descending order of importance are dried seaweed, whole legumes (including soy), cereal bran, legume hulls, whole grain cereals, vegetables, and fruit. [1] Gender differences in urinary lignan excretion have been observed, with men excreting more enterolactone and less enterodiol than women. The researchers felt this implied a difference in colonic bacterial metabolism of lignans between the genders.[25] Administration of antibiotics nearly completely eliminates the formation of these mammalian lignans from their precursors. [3] Phytosterols
Phytosterols, such as ß-sitosterol, are found in high concentrations in soy products. Although poorly absorbed, they bind cholesterol in the gut. [22] Dietary content of phytosterols differs widely among populations. The typical Western diet contains about 80 mg/day, while the traditional Japanese diet contains approximately 400 mg/day.[26] [27] Coumestans
The phytoestrogen, coumesterol, and other coumestan isoflavonoids have been found by some researchers in significant quantities in soy foods of all types, including: [28] • soybeans • soy flour • soy flakes • isolated soy protein • tofu • soy drinks • soy sprouts. On the other hand, Adlercreutz & Mazur [3] reports its presence only in soy sprouts. The most abundant source is mung bean sprouts. It is also found in significant quantities in other members of the Leguminosiae family, including Trifolium and Medicago spp.[2] Saponins
Saponins are distributed widely in the plant kingdom, including in soybeans. They appear to have anti-cancer properties by virtue of their antioxidant and anti-mutagenic properties. [29] They also bind cholesterol and bile acids in the gut. [22] An in vitro study demonstrated that saponins isolated from soybeans exhibited potent antiviral effects on the HIV virus. Saponin B1 completely inhibited HIV-induced cytopathic changes and virus-specific antigen expression within 6 days of
infection. Saponin B2 exhibited similar, although less potent, effects. [30] Phytates
Although phytic acid (inositol hexaphosphate) has been implicated in blocking the absorption of minerals, the phytate content of plants, including soy, seems to be responsible for some of the anti-cancer properties of vegetable-based foods. Phytic acid is a highly charged antioxidant, capable of scavenging hydroxyl radicals and chelating metal ions such as the pro-oxidant, iron. Graf & Eaton [31] reported the iron-chelating ability of phytate to be more important than the fiber in dietary colon cancer prevention. Vucenik et al [32] reported antitumor effects of phytic acid both in vitro and in animal models. Phytates also appear to enhance natural killer cell activity.[33] Rao et al [34] found these potent antioxidant effects to protect against cardiac ischemia and reperfusion injury in animal models. For a summary of soy constituents and their functions, see Table 112.2 .
PHARMACOLOGY Soy constituents have been shown to have estrogenic, anti-estrogenic, antiviral, [35] anticarcinogenic, [36] [37] [38] bacteriocidal, and antifungal [39] effects. Isoflavones also have anti-mutagenic, [37] antioxidant,[40] [41] mild anti-inflammatory,[42] antihypertensive, [42] and antiproliferative effects. [36] [43] This
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TABLE 112-2 -- Soy constituents and their functions Constituent
Function
Protease inhibitors (Bowman–Birk inhibitor, Kunitz–Trypsin inhibitor)
Inhibit oncogene expression Inhibit chemically induced carcinogenesis Implicated in pancreatic hypertrophy (animal studies)
Lignans (enterolactone, enterdiol)
Phytoestrogen effects (agonistic/antagonistic) Antitumor Antiviral
Phytosterols (ß-sitosterol)
Binds cholesterol in the gut
Coumestans (coumesterol)
Phytoestrogen effects (agonistic/antagonistic)
Saponins
Antioxidant Bind cholesterol and bile acids in the gut Antiviral (HIV)
Phytates
Antioxidant Chelate metal ions (e.g. iron) Enhance natural killer cell activity
Isoflavones (genestein, daidzein and their metabolites)
Phytoestrogen effects (agonistic/antagonistic) Anti-mutagenic Antioxidant Anti-inflammatory Antiproliferative Antihypertensive Angiogenesis inhibition
chapter focuses primarily on isoflavones as these are the constituents found in greatest quantity in soy products. Brief reference will be made to other beneficial constituents. Hormonal effects Infants
Recent advances in understanding the phytoestrogen content of soy foods have led researchers to examine the isoflavone content in commonly consumed infant formulas. A recent study examined the isoflavone content of 25 randomly selected samples from five major brands of soy-based infant formulas. There were significant levels of isoflavones, particularly in the form of the glycosides of genistein and daidzein, in all samples tested. The plasma concentrations of genistein and daidzein were compared in 4-month-old infants fed exclusively soy formula, cow’s milk formula, and breast milk. A 4-month-old infant consuming soy milk was estimated to be ingesting between 4.5 and 8.0 mg/kg body weight per day of total isoflavones. This is a proportionately greater concentration per body weight than that found in adults consuming soy foods. Additionally, the researchers estimated the daily exposure of infants to soy isoflavones was 6–11 times higher, with body weight factored into the equation, than the typical dose necessary to exert hormone-like effects in adults. They found negligible concentrations of isoflavones in breast milk and cow’s milk. [5] There was some evidence of the daidzein metabolite, equol, in the infants who were fed cow’s milk, confirming previous observations that cow’s milk also contains some isoflavones. In this study, the plasma concentration of isoflavones in breast-fed babies was 1/200 the level in soy-formula fed babies. Franke & Custer, [44] on the other hand, reported in 1996 that human breast milk from mothers consuming soy foods provided significant levels of isoflavones. Some researchers have concluded that the isoflavone content of human breast milk appears to be a reflection of the mother’s diet. These findings have raised some interesting questions and stimulated lively debate. Adverse effects of phytoestrogens on development and reproductive capacity of livestock, wildlife and experimental animals have been reported. [45] There has been very little clinical experience with human infants and phytoestrogens, however. In animal models, phytoestrogens have had effects similar to other estrogens, included interfering with normal reproductive system development. [46] On the other hand, phytoestrogenic isoflavones have been found to possess some important anti-cancer properties. Genistein, given in only three doses to newborn mice, decreased breast cancer incidence and tumor numbers significantly. [44] Although millions of Asians have consumed large quantities of soy foods for hundreds of years without any apparent health risk and seemingly with health benefits, long-term studies are needed to clarify the safety of using soy-based infant formulas and to assess the potential beneficial or adverse effects of consuming phytoestrogens in the form of soy isoflavones early in life.
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Adults
Plant lignan and isoflavonoid glycosides are converted by gut bacteria in the intestines to compounds with molecular weights and structures similar to steroid hormones (see Fig. 112.3 ). The pattern of isoflavonoid and lignan excretion in the urine is similar to endogenous estrogens. [47] Studies of the effects of
phytoestrogens on hormone levels are conflicting. Lu et al [48] found that the consumption of soy products by premenopausal women resulted in decreased circulating ovarian steroids and adrenal androgens, as well as increased length of the menstrual cycle. Six healthy females, aged 22–29, were given 12 ounces of soy milk three times daily with meals for 1 month. Daily isoflavone intake was approximately 100 mg each of daidzein and genistein (in the form of their glycosides, daidzin and genistin). The estradiol levels decreased by 31% on days 5–7 of the cycle, 81% on days 12–14, and 49% on days 20–22. Luteal phase progesterone levels decreased by 35%, and DHEA sulfate levels decreased progressively during the month by 14–30%. The length of the menstrual cycle increased during the soy feeding month from 28.3 ± 1.9 to 31.8 ± 5.1 days. In another study, also on premenopausal women, Lu et al found that 60 g of soy protein, with 45 mg of isoflavones daily, resulted in the suppression of midcycle surges of FSH and LH. Plasma concentrations of estradiol increased during the follicular phase in the soy group, while cholesterol decreased by 9.6%. The researchers noted that a similar effect occurs in women given tamoxifen. There were no significant differences in estradiol levels between the soy and control groups at midcycle or during the luteal phase. [49] At least one study found soy protein isolate to have a stimulatory effect on breast tissue in premenopausal women, characterized by increased breast secretions, epithelial cell hyperplasia, and elevated levels of serum estradiol. [50] Wang et al [51] found that genistein competed with estradiol binding to estrogen receptors, with 50% inhibition occurring at 5 × 10 -7 M. A study of soy-supplemented postmenopausal women found a small estrogenic effect on vaginal cytology. However, no difference between soy-supplemented subjects and controls, with regard to serum FSH, LH, sex hormone binding globulin, endogenous estradiol or body weight, was observed. [52] Many studies on phytoestrogens focus on the use of coumestrol, as it has more potent phytoestrogenic effects than lignans, genistein and daidzein. In vitro studies have found that both genistein and coumestrol inhibit the conversion of estrone to 17-beta estradiol. Coumestrol exhibited the strongest inhibition. [53] An in vitro study monitoring the expression of the estrogen-responsive protein pS2 in breast cancer cell MCF-7 tissue culture, to assess the estrogenic response of various plant substances, found that the following substances elicited estrogen-like activity: • daidzein • equol • nordihydroguaiaretic acid • enterolactone • kaempferol. The substances tested that did not appear to have estrogen-like activity were quercetin and enterodiol.
[ 54]
The effects of phytoestrogens vary greatly depending on the species of animal, the particular phytoestrogen compound being tested, the age of the animal, the length
Figure 112-3 Structure of soy isoflavones compared with estrogens.
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of time of ingestion, the presence or absence of exogenous estrogen, the target tissue in question, and the dosage used. The phytoestrogen, coumestrol, was found to have an estrogenic effect, as demonstrated by changes in uterine and brain tissue, when given to prepubescent rats; however, when given to adult female rats, ovarian cycling was inhibited. When given for 10 days to neonatal rats, there was no effect on estrous cycling, but when given for 21 days, it interfered with normal cycling once the rats reached adulthood. The females exhibited persistent estrous and lack of an LH surge, while the males demonstrated a decrease in sexual behavior. [55] Historically, the consumption of soy products in Asian cultures, from a very young age, has not resulted in any apparent negative effects related to hormone imbalances. It is unlikely that animal studies are effective at predicting the effects of phytoestrogens in the human model. [56] The mechanisms for the anti-estrogenic effect of phytoestrogens are largely unknown, but some experts believe it is unlikely to be a direct receptor-mediated effect. [3] One mechanism of action of lignans and isoflavonoids is to stimulate sex hormone-binding glubulin (SHBG) (also known as sex steroid-binding protein (SBP)) synthesis in the liver. SHBG binds to cell surface receptors, resulting in regulation of bioavailability and activity of hormones. [3] In vitro, in MCF-7 human breast cancer cells, SHBG has been found to downregulate estradiol. [57] It appears that phytoestrogens exert mild agonistic and antagonistic effects on estrogen, depending on the level of endogenous estrogen present and on the tissue being tested. In vitro studies demonstrate an estrogenic effect in the absence of endogenous estrogen, and an anti-estrogenic effect in the presence of estrogen. [3] Much research in this area remains to be done. Much of the effect of phytoestrogens might be due to enzyme inhibitions. It appears that phytoestrogens have an inhibitory effect on many enzymes involved in the biosynthesis and metabolism of steroid hormones. The effect on enzymes is further discussed below. Mechanism of action of soy isoflavones Soy’s inhibition of cancer cell growth does not seem to be entirely estrogen-dependent. [58] There are many proposed mechanisms for the therapeutic effects of isoflavones. The mechanisms include: • inhibition of protein tyrosine kinase (PTK) • binding of estrogen receptors (although soy’s inhibition of cancer cell growth does not seem to be entirely estrogen-dependent) • inhibition of production of reactive oxygen species [59] • induction of DNA strand breakage resulting in apoptosis or cell death [58] • inhibition of angiogenesis [60] • modulation of sex steroid-binding protein [61] • inhibition of 5-alpha-reductase [62] • inhibition of P-form phenolsulfotransferase (PST)-mediated sulfation [63] • inhibition of thrombin formation and platelet activation [64] • increased LDL receptor activity. [65]
[58]
The therapeutic implications of each of these mechanisms is elaborated below.
CLINICAL APPLICATIONS Cancer The first clues that soy diets might provide protection from cancer came from epidemiological studies, in which people from Asian cultures eating a diet high in soy foods, such as tofu, demonstrated lower rates of several types of cancers, including types not typically considered to be hormone- or diet-related. Messina et al [66] reviewed 21 epidemiological studies which evaluated the effect of soy diets on 26 different cancer sites. An evaluation of the effect of non-fermented soy products in these studies found that 10 showed decreased risks for rectal, stomach, breast, prostate, colon, and lung cancers, while 15 showed no significant effect. Only one, in which fried bean curd was evaluated, showed an increased risk for esophageal cancer. On the other hand, the effects of fermented soy products – miso soup and
soybean paste – were much less consistent. In 21 studies evaluating fermented soy products, involving 25 cancer sites, an increased cancer risk was found in four, mixed results were obtained in four, no significant effects were found in 14, and a decreased risk was found in three. The increased risks of cancer from consumption of fermented soy products appear to involve primarily the gastrointestinal tract – esophageal, stomach, colorectal, and pancreatic cancers. [66] These studies are summarized in Table 112.3 (Table Not Available) . To put the epidemiological studies into some perspective, Adlercruetz et al [67] found high urinary excretion of the soy isoflavones, equol, daidzein, and O-desmethylangolensin, in both men and women living in rural Japan. Most soy foods contain about 1–2 mg/g of genistein. In Asian cultures people tend to consume 20–80 mg/day. The usual dietary intake of genistein in Western cultures is 2–3 mg/day. Messina et al [66] examined 26 animal studies and reported that 17 (65%) of them demonstrated a protective effect of soy from experimental carcinogensis. There are many proposed mechanisms for the anti-cancer benefits of soy-based foods. Inhibition of PTK activity has been proposed as a major mechanism in the prevention of carcinogenesis. While synthetic PTK inhibitors have been proposed for the treatment of cancer, expected toxicity has restricted their development. In
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TABLE 112-3 -- Summary of epidemiological studies of soy and cancer (From Messina et al [66] ) (Not Available) 1987, genistein was discovered to be a natural PTK inhibitor. [58] Tyrosine kinase inhibition results in the inhibition of leukotriene production, (products of inflammation which have been implicated in the stimulation of tumor growth). In vitro studies found that pretreatment of cancer cell lines with genistein completely inhibited leukotriene production. [68] Influence on a number of other enzymes has been suggested as a possible mechanism for the anti-cancer properties of isoflavones. Some of these enzymes include DNA topoisomerases,[69] [70] ribosomal S6 kinase activity, [71] phospholipase C-gamma,[72] phosphatidylinositol kinases, [73] and mitogen-activated protein kinase. [74] In addition, genistein demonstrated in vitro inhibition of phenolsulfotransferase, an enzyme involved in sulfation-induced carcinogensis. [63] In vitro studies have found genistein to be a very potent inhibitor of neovascularization or angiogenesis, one of the proposed mechanisms for cancer growth inhibition. [60] Isoflavone effects on hormone regulation, expression and metabolism have been elaborated above and are discussed further below in the sections on breast and prostate cancer. At issue in the study of soy isoflavones in the treatment of cancer is whether the concentration achieved by dietary consumption of soy products is enough to influence tumor growth. Studies on human volunteers consuming soy beverages, which provided 42 mg genistein and 27 mg daidzein daily, resulted in peripheral blood concentrations of 0.5–1.0 µM, [4] a concentration much lower than that necessary to inhibit growth of cultured cancer cells. [75] However, these same researchers found non-transformed mammary epithelial cell cultures to be much more sensitive to genistein, with inhibition of growth stimulation occurring in the range of 1–2 µM. This suggests a role of isoflavones as chemopreventive rather than chemotherapeutic agents. Breast cancer
Case-controlled, epidemiological, in vitro, and animal studies point to effectiveness of soy isoflavones in the
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prevention of breast cancer. A recent case-controlled study, examined the effect of phytoestrogens on breast cancer risk. One hundred and forty-four women with early diagnosed breast cancer were paired with age- and area-of-residency-matched controls. Prior to treatment, a questionnaire, and 72 hour urine and blood tests were administered. Urine was assayed for the isoflavones daidzein, genistein, and equol, and the lignans enterodiol, enterolactone, and matairesinol. Adjustments were made for age at menarche, parity, and alcohol and total fat intake. Increased excretion of daidzein, equol, and enterolactone was associated with a reduction in the risk for development of breast cancer. The most significant correlation was between the levels of the soy isoflavone, equol, and the risk of breast cancer, with those in the highest quartile of equol excretion exhibiting onlyone-quarter the risk of those in the lowest quartile – a fourfold reduction in risk. The lignan, enterolactone, and the isoflavone, daidzein, were associated with a threefold reduction in risk. The daidzein results were insignificant, after correcting for confounding variables. Similar trends were noted for both pre- and postmenopausal groups. Unfortunately, no reliable data for genistein were available due to instability of the derivative of genistein being tested and interference by an unknown compound. [76] Two case-controlled studies, one in Singapore [77] and one in Japan,[78] found significant protection from soy intake for pre- but not postmenopausal women. Epidemiological studies demonstrate an inverse relationship between soy intake and incidence of breast cancer (see Table 112.3 (Table Not Available) ). Americans have two to three times the breast cancer rate of Asians eating a traditional diet. [79] An epidemiological study of Asian-American women found tofu intake to correlate inversely with breast cancer incidence, after adjustment for other dietary, menstrual and reproductive factors. [80] This effect was observed in both pre- and postmenopausal women. In summary, all four of the human studies examined seemed to indicate a protective effect of soy against breast cancer in premenopausal women. The effect on postmenopausal women was significant in two of the four studies. In vitro experiments with human breast cancer cells confirm genistein to be a potent inhibitor of cell growth, regardless of estrogen receptor status. Other isoflavones, daidzein and biochanin A, demonstrated weaker growth inhibition. [81] [82] [83] Pagliacci et al [84] reported that the in vitro inhibition of MCF-7 human breast cancer cells occurred through blocks at critical points in cell cycle control as well as via induction of apoptosis. Wang et al [51] found that genistein produced a concentration-dependent effect on breast cancer cell cultures. At lower concentrations (10 -8 –10-6 M), genistein stimulated growth, while higher concentrations (>10 -5 ) inhibited growth. They concluded that the effect of genistein at the lower concentrations appeared to be estrogen receptor-mediated, while effects at higher concentrations were independent of estrogen receptors. Genistein, when administered to neonatal [85] or prepubescent rats,[86] suppressed the development of chemically induced mammary tumors without causing toxicity to the development of the endocrine or reproductive systems. Barnes et al [87] found that soy in the form of raw soybeans as well as soy protein isolate inhibited mammary tumors in experimental models. Prostate cancer
Epidemiological evidence points to the benefits of soy constituents in the prevention of prostate cancer. Japanese men who consume a low-fat, high-soy diet have low mortality rates from prostate cancer. Isoflavones in the plasma of Japanese men were between seven and 110 times higher than in Finnish men, with genistein present in the highest concentrations. [88] Mechanisms suggested include genistein-induced prostate cancer cell adhesion, direct growth inhibition, and induction of apoptosis. Growth inhibition appears to be independent of genistein’s estrogenic effects. [89] An in vitro study indicated that the isoflavones genistein, biochanin A, and equol were potent inhibitors of 5-alpha-reductase, [62] the enzyme necessary for the conversion of testosterone to dihydrotestosterone (implicated in prostate cancer). Studies have found that animals fed soy isolates high in the isoflavones, genistein and daidzein, demonstrated a lower incidence of prostate cancer and a 27% longer disease-free period after exposure to chemical carcinogens than animals fed a soy isolate low in isoflavones. [90] This not only points to the potential chemoprotective effects of soy, but seems to point to the importance of the isoflavones over other soy constituents. Peterson & Barnes [91] found that the isoflavones, genistein and biochanin A, but not daidzein, inhibited several human prostate cancer cell lines. NIH recommendations
The committee of the National Institutes of Health (NIH) studying chemoprevention from soy products made the following recommendations: • Future dietary studies involving soybeans should be carried out using soy products rather than isolated compounds, since soybeans appear to contain several potential anticarcinogens. • Standardized and improved analytical methods are needed so that the contents of all soy-based materials employed in soybean research, whether soybean fractions or soy products, can be accurately described. • Basic research in the absorption, metabolism, and physiology of potential anticarcinogens in humans should be conducted.
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Cardiovascular disease Lipid effects
A large meta-analysis of 38 controlled studies of the effects of soy diets, with animal protein diets serving as the controls, found a statistically significant decrease in serum lipids in the soy group. The changes were most significant in hypocholesterolemic subjects [92] (see Table 112.4 ). The intake of energy, fat, saturated fat, and cholesterol was similar between the two groups. Gooderham et al [93] reported no effect on platelet aggregation or serum lipid levels in healthy, normocholesterolemic men fed soy protein compared with casein. One of the proposed mechanisms for the hypolipidemic effect involves an increase in LDL receptor activity in both humans and animals. [65] Other metabolic changes which have been noted in animals and humans on soy diets include increased cholesterol and bile acid synthesis, increased apolipoprotein B and E receptor activity, and decreased hepatic secretion of lipoproteins (associated with increased clearance of cholesterol from the bloodstream). [94] Proposals for the specific constituents involved include the amino acid profile, saponins, phytic acid, fiber, as well as the effects of isoflavones discussed below. [94] In one study, monkeys were fed soy isolates high in isoflavones and compared in a cross-over trial with a soy isolate in which the isoflavones had been removed via alcohol extraction. LDL, VLDL, and total cholesterol:HDL ratios were significantly lowered, while HDL was significantly elevated in the group on the isoflavone-rich diet.[12] No lipid-lowering effect occurred in the group on the casein diet. TABLE 112-4 -- Results of a meta-analysis of the effects on serum lipids of soy diet compared with meat protein diet [92] 23.2 md/dl decrease 9.3% decrease
Total cholesterol LDL cholesterol
21.7 mg/dl decrease
12.9% decrease
Triglycerides
13.3 mg/dl decrease
10.5% decrease
HDL cholesterol
1.2 mg/dl increase (NS)
2.4% increase
Effects on the atherosclerotic process
Arterial thrombus formation is generally initiated by an injury to the endothelial cells lining the blood vessels. One of the first events after an injury is thrombin formation. This leads to a cascade of events including platelet activation, resulting in thrombus formation. Genistein has been found to inhibit thrombin formation and platelet activation. [64] The pathogenesis of atherosclerotic plaque formation also involves, in addition to lipid accumulation, the infiltration of monocytes and T-lymphocytes into the artery wall, contributing to the thickening of the wall and occlusion of the vessel. Monocytes and lymphocytes are able to adhere to the endothelial cell surfaces via the expression of certain “adhesion molecules”. The infiltration and proliferation appear to be controlled by peptide growth factors. Increased levels of isoflavones, genistein in particular, appear to alter the growth factor activity, and inhibit cell adhesion and proliferation, all activities necessary for lesion formation in the intima of the blood vessels (see Fig. 112.4 ). [95] Cardioprotective effects
Animal studies with monkeys have confirmed the cardioprotective effects of soy. Soy protein diets, when compared with casein diets, resulted in significant improvements in lipid profiles, insulin sensitivity, and a decrease in arterial lipid peroxidation. [96] Furthermore, animal studies also indicate the isoflavone content of the soy is an important factor. Other potential therapeutic benefits While research on the health benefits of soy constituents has focused primarily on the chemopreventive effects for cancer and cardiovascular disease, there are a few other conditions which might benefit from the addition of soy isoflavones to the diet.
Figure 112-4 Impact of soy on atherosclerotic plaque formation.
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Osteoporosis
Animal studies indicate that soy isolates enhance bone density. Ovariectomized rats fed a high-soy diet demonstrated enhanced bone density of the vertebral bodies and femoral bone compared with the group fed a casein diet. While there was considerable bone turnover in the soy-fed group, bone densities suggest that formation exceeded resorption. [97] Further studies on the use of soy isoflavones for the prevention and treatment of osteoporosis are warranted. Eye disorders
Neovascularization complicates many eye disorders, such as proliferative diabetic retinopathy, and is responsible for corneal transplant rejection. Substances which exhibit the capacity to inhibit angiogenesis could play an important role in preventing this vascularization. An animal study demonstrated that genistein, when injected subconjunctivally, inhibited corneal neovascularization. [98] While this was not a human study with the use of oral doses, this study has opens the door for future investigation.
CONCLUSION Research indicates that soy and its individual constituents have several potential health benefits. The primary isoflavones, genistein and daidzein, as well as their metabolites, exert a wide array of effects which appear to offer protection against cancer, cardiovascular disease, osteoporosis, and ocular neovascularization. Many of the studies to date have been epidemiological, animal, or in vitro. Further controlled human trials are needed to confirm the preliminary findings reported in these studies. Soy constituents, particularly the isoflavones, have come under scrutiny, due to their phytoestrogen effects. Because in some cases they act as estrogen agonists, and at other times as antagonists, the use of these isoflavones in cancer patients and in infant formulas is controversial. Further study to determine whether
their use in these situations is harmful or beneficial is indicated.
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Chapter 113 - Tabebuia avellanedae (LaPacho, Pau D’Arco, Ipe Roxo) Terry Willard PhD
Tabebuia avellanedae (family: Bignoniaceae) Tabebuia ipe Tabebuia cassinoides Tecoma ochracea Common names: LaPacho, Pau D’Arco, Ipe Roxo
INTRODUCTION The taxanomical division of plants with medicinal uses in the Bignoniaceae family is confused. The literature often interchanges the genera of Tecoma and Tabebuia. At least four species have been called LaPacho: • • • •
Tecoma ochracea Tecoma ipe Tabebuia cassinoides Tabebuia avellanedae.
This chapter considers the Tabebuia genus.
GENERAL DESCRIPTION The tree from which LaPacho is obtained is a member of the Bignoniaceae family known as Tabebuia avellanedae or Tabebuia ipe. This tropical tree, native to Brazil, can grow up to 125 feet tall and has rose to violet-colored flowers which bloom in profusion just before the new leaves appear. There are about 100 species of these evergreen trees or shrubs, native to tropical America. The leaves are opposite, long-petiolate, digitately five- or seven-foliate. The leaflets are entire or toothed; the flowers large in terminal cymes or panicles; the calyx tubular or campanulate, closed in bud, variously cleft or toothed in anthesis; the corolla tubes ampliate, the limb somewhat bilate; the stamens four; the capsule slender-cylindric, suterete; and the seeds broadly winged. The trees of this genus are very showy when in flower as they usually blossom when leafless. Because the taxonomy of these plants is so difficult, it is quite possible that there is confusion among even trained gatherers.
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One specific way to distinguish the species is at the seedling stage. The four-leaf clover-like cotyledons are distinctively deeply cleft.
[ 1]
CHEMICAL COMPOSITION Many of the studies and chemical analyses on Tabebuia spp. have been performed on the heart wood, while the bark is the product available in the market place and the part utilized in folklore. The major components of Tabebuia avellanedae are 16 quinones (mostly with C 15 skeleton) containing both naphthoquinones (seven, C 10 –C5 ) and anthraquinones (nine, C 14 –C1 ). Both of these groups of quinones rarely occur in the same plant. The lapachol content is usually 2–7%. The quinones are listed in Table 113.1 . Other compounds found in the heart wood include lapachenole, quercetin, and o- and p-hydroxybenzoic acids. [2] Lapachol content can be estimated by study of the yellowish flaky powder found on the surface of the fractured wood chips or bark. If the lapachol content is over 1–2%, mixing with dilute (5%) NaOH generates, due to a litmus-type reaction, a red-brown solution. There is no color if the content is below 0.5%. Exact concentration can be determined by titrating the NaOH reaction or by chromatography. [3] A recent analysis of 10 products found in the market place showed that only one contained lapachol (and only in trace amounts) and the other nine had none. This suggests that many of the products now present on the market are not truly Tabebuia spp., that the wrong part of the plant is being marketed, or that processing and transportation have damaged the product. This might explain the variation in results practitioners have experienced. Standardization of LaPacho products for lapachol or naphthoquinone content is needed to solve this problem. TABLE 113-1 -- Quinones in Tabebuia avellanedae Naphthoquinones • Lapachol • Menaquinone-l • Deoxylapachol • Beta-lapachone • Alpha-lapachone • Dehydro-alpha-lapachone Anthraquinones • 2-Methylanthraquinone • 2-Hydroxymethylanthraquinone
• 2-Acetoxymethylanthraquinone • Anthraquinone-2-aldehyde • 1-Hydroxyanthraquinone • 1-Methoxyanthraquinone • 2-Hydroxy-3-methylquinone • Tabebuin (a newly discovered compound)
HISTORY AND FOLK USE The native Indians of Brazil also refer this tree as Pau D’Arco or Ipe Roxo. The inner bark has been used for medicinal purposes for centuries as a folk remedy for a wide variety of afflictions, including: [4] [5] [6] [7] • boils • chlorosis • colitis • diarrhea • dysentery • enuresis • fever • pharyngitis • snakebite • syphilis • wounds • ulcers • respiratory problems • arthritis • cystitis • constipation • prostatitis • poor circulation • constipation • cancer of the esophagus, head, intestine, lung, prostate and tongue. It is reported to be alexiteric, analgesic, anodyne, antidotal, antimicrobial, diuretic, and fungicidal.
[ 4]
PHARMACOLOGY During the past century, LaPacho has been subjected to scientific scrutiny. The first active constituent to be studied, lapachol, was isolated by Paterno in 1882 (see Fig. 113.1 ). Its structure was determined by Hooker in 1896. In 1927, Fieser synthesized lapachol. It has since been studied by numerous researchers. It is interesting to note that many of the scientific studies have found LaPacho and lapachol to be more effective in treating malaria and cancerous tumors through oral ingestion rather than intravenous or intramuscular injection. [8] An herbalist’s interpretation would be that the body’s recuperative powers are more effectively stimulated
Figure 113-1 Lapachol.
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by the more natural route of nutrient plant material absorption through the digestive tract. Although most of the studies are on individual chemicals, some show significantly better results with the whole extract and diminishing effectiveness as the extracts are refined or individual chemicals are tested. [8] Antimicrobial activity Antibacterial activity
In 1956, a research team at the Universidade do Recife in Brazil reported that lapachol isolated from the Tabebuia avellanedae tree exhibited antimicrobial activity against Gram-positive and acid-fast bacteria, and Brucella sp.[9] It is important to note that the research team found that progressive purification reduced the antimicrobial activity of the extract. This led to the conclusion that there was more than one active substance present in the original extract. Later that year the researchers published a paper proclaiming a new antibiotic substance from Tabebuia avellanedae which demonstrated “strong anti-Brucella activity and fungistatic behavior”. [10] They eventually found that, along with lapachol, the extract of the Tabebuia tree contained alpha-lapachone, beta-zlapachone, and a newly discovered quinone which they named xyloidone. In 1967, another group of researchers discovered seven naphthoquinones, nine anthraquinones, lapachenole, quercetin and o- and p-hydroxybenzoic acids in the heartwood of the tree. [11] Several of these exhibit strong microbicidal and fungicidal activities (see Table 113.2 ). Naphthoquinones are highly effective against Candida albicans and Tricophyton mentagrophytes.[12] Lapachol has been shown to have both antimicrobial and antiviral activity. [13] [14] [15] Beta-lapachone shows diversified antiparasitic activity as well as antiviral action. [17] Alpha-lapachone is also active against certain parasites, and xyloidone is active against numerous bacteria and fungi. [18] [ 19] Another LaPacho component, the flavonoid quercetin, is cytotoxic for certain parasites. [20]
[16]
Xyloidone is effective against a wide array of organism, such as Staphylococcus aureus and the Brucella species. The causative agents of tuberculosis, dysentery, and anthrax are also inhibited by xyloidone. In addition to its activity against a variety of bacteria, this quinone inhibits several species of fungus (including Candida albicans, C. kruzei, and C. neoformans). Mechanism of action
Lapachol, like many naphthoquinones, acts as a respiratory poison by interfering with electron transport in microbes.
[21]
Research showed in 1946 that drug
suppression of malarial parasites could usually be correlated with the inhibition of their oxygen uptake. [22] In 1947, lapachol was found, at concentrations of 100 mg/L, to inhibit O 2 uptake by Plasmodium knowles by 74% and succinate oxidase systems by 26%. [23] In the following year, lapachol was found to exhibit antimalarial activity against Plasmodium lophurae,[24] suggesting respiratory poisoning as a likely mechanism. Mitochondrial respiration is inhibited by 50% at a lapachol concentration of less than 110 µmol/L. [25] Increasing doses of lapachol produced progressive respiratory inhibition in tumor cells isolated from animals. Oxygen consumption and oxygen metabolite production
Microorganism
Lapachol
TABLE 113-2 -- Antimicrobial activity of Tabebuia avellanedae* Chorohidro-lapachol Alpha-lapachone
Beta-lapachone
Xiloidona
B. sutilus
60.0–80.0
8.0–10.0
40.0–50.0
1.0–2.0
4.0–6.0
B. mycoides
40.0–60.0
10.0–15.0
40.0–50.0
5.0–8.0
20.0–30.0
B. anthracis
40.0–60.0
20.0–30.0
40.0–50.0
4.0–6.0
20.0–30.0
S. aureus
60.0–80.0
30.0–40.0
30.0–40.0
2.0–4.0
15.0–20.0
Sar. lutea
40.0–60.0
15.0–20.0
30.0–40.0
4.0–6.0
20.0–30.0
S. hemolyticus
>100.0
60.0–80.0
60.0–80.0
10.0–15.0
>50.0
M. tuberculosis
80.0–100.0
40.0–60.0
30.0–50.0
10.0–15.0
10.0–15.0
M. smegmatis
80.0–100.0
60.0–80.0
30.0–50.0
15.0–20.0
15.0–20.0
M. phisi
60.0–80.0
40.0–60.0
20.0–30.0
10.0–15.0
8.0–10.0
N. asteroides
>100
40.0–60.0
60.0–80.0
10.0–15.0
20.0–30.0
N. catarrhalis
40.0–60.0
30.0–50.0
80.0–100.0
10.0–15.0
100.0
>100.0
>100.0
>100.0
>100.0
K. pneumonia
>100.0
>100.0
>100.0
>100.0
>100.0
S. typhosa
>100.0
>100.0
>100.0
>100.0
>100.0
Br. suis
15.0–20.0
2.0–4.0
20.0–30.0
0.6–1.0
0.8–1.0
Br. abortus
15.0–20.0
2.0–4.0
30.0–40.0
1.0–2.0
1.5–2.0
Br. melitensis
10.0–15.0
2.0–4.0
30.0–40.0
1.0–2.0
1.5–2.0
C. albicans
>100.0
40.0–60.0
80.0–100.0
80.0–100.0
30.0–50.0
C. kruzei
>100.0
40.0–60.0
80.0–100.0
80.0–100.0
50.0–60.0
C. neoformans
>100.0
40.0–60.0
50.0–80.0
30.0–50.0
40.0–60.0
* Minimum concentration of inhibition (mcg/ml).
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are inhibited in neutrophils upon administration of lapachol. [26] The exact site at which lapachol acts has been the subject of some controversy. Some researchers have concluded that 2-hydroxy-3-alkyl-1,4 naphthoquinones, such as lapachol, act just after cytochrome c in the respiratory chain, [27] while others suggest that lapachol exhibited an oligomycin-like action in mitochondria, acting just after cytochrome b. [21] It has been hypothesized that naphthoquinones either prevent an interaction between cytochromes b and c, or act directly on an unknown enzyme between the two.[28] The inhibitory action can be reversed by the addition of 2,4-dinitrophenol, suggesting that lapachol may act on energy conservation reactions.[18] Lapachol has now been shown to act as an uncoupler of oxidative phosphorylation. Lapachol prevents ATP synthesis by stimulating respiration in the absence of a phosphate acceptor. This effect is most pronounced at a high pH level where lipid solubility is the lowest. [29] Hadler & Moreau [25] studied lapachol in combination with showdomycin and demonstrated that lapachol exposes a mitochondrial thiol group which occupies a pivotal position between the cycle that meshes with the respiratory chain and the cycle that meshes with ATP. They believe the side chain acts as a swinging arm while the remainder of the lapachol molecule is embedded in a lipid matrix. [30] In addition to inhibiting cellular respiration and uncoupling oxidative phosphorylation, lapachol inhibits certain enzymes. In particular, it is a competitive inhibitor of glycolase I in erythrocytes. The side chain is again thought to be significant in this action. Lapachol also demonstrates non-competitive inhibition of alpha-keto-aldehyde dehydrogenase, leading to the accumulation of toxic alpha-ketoaldehydes. [30] Lapachol demonstrated 64% inhibition of 3-alpha-hydroxysteroid mediated transhydrogenase at a concentration of 10 -5 M (well within dosage range). [31] Antiviral activity Lapachol has proven to be active against certain viral strains, including herpes virus hominis types I and II. [31] Hydroxynaphthoquinone has been shown to effectively inhibit four influenza viruses. Lapachol also significantly inhibits poliovirus and vesicular stomatitis virus. [14] Studies of beta-lapachone’s antiviral activity have offered insights into the mechanism of this powerful quinone. In experiments with viruses, beta-lapachone demonstrated its ability to inhibit certain enzymes, such as DNA and RNA polymerases. [32] Beta-lapachone was tested against avian myeloblastosis virus and Rauscho murine leukemia virus and found to inhibit retrovirus reverse transcriptase. [33] In the presence of dithioreitol, beta-lapachone inhibits eukaryotic DNA polymerase-alpha activity. Although the mechanism of action for enzyme inhibition is complex, it may be related to superoxide production. [32] This in turn may aid in explaining the structural changes in the DNA of the epimastigotes. The site of action appears to be the enzyme protein. This has great significance for possible treatment of both HIV and HLBV (the implicated viruses in AIDS and Epstein–Barr syndrome). Beta-lapachone also inhibits Friend virus and was the only substance among a number tested which prolonged survival time of chickens infected intraperitoneally with Rous sarcoma virus. [34] Antiparasitic activity The trematode Schistosoma mansoni is the causative agent of the common tropical disease schistosomiasis. The cercariae of this blood fluke live in water and enter the host by penetrating the skin. This debilitating disease, a serious problem in many tropical areas, causes weakening of the host and increases susceptibility to a variety of other pathogens, some of which may be fatal. Lapachol has been tested as a topical barrier to the cercariae and has been found to be highly effective at preventing its penetration. [32] [35] Oral lapachol was also tested and found to significantly reduce penetration. After being consumed, the lapachol was secreted onto the skin, apparently by the sebaceous glands, where it again acted as a topical barrier. The cercariae seek to penetrate the host through or near the sebaceous glands, which suggests that dietary administration of
lapachol would be an efficient means of protecting against infection. Although the mechanism for this anti-schistosomal activity is relatively unknown, Pinto thought that the side chain was involved, and noted that effective barriers are liposoluble. Alpha-lapachone and beta-lapachone, also components of LaPacho, both exhibited activity against S. mansoni.[13] The activity of beta-lapachone against viruses and parasites has been studied in an attempt to understand the mechanism by which this quinone works. Beta-lapachone is notably effective against Trypanosoma cruzi, a zoomastigote responsible for trypanosomiasis, or Chaga’s disease. This disease occurs in both acute and chronic forms and has no known cure. Beta-lapachone causes complete inhibition of T. cruzi at concentrations of 0.8–5.0 µg/mL and progressively inhibits motility with increasing concentrations. When T. cruzi epimastigotes were incubated with the quinone, they were subject to nuclear, mitochondrial, endoplasmic reticular, and cytoplasmic membrane damage, and underwent alterations in the chromatin distribution. Respiration rates were lowered, the mitochondria became swollen, and glucose and pyruvate oxidation was inhibited.
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Lipid peroxidation was stimulated, which resulted in decreased cell viability. In addition, in vitro testing resulted in the rapid decay of DNA, RNA, and protein, and DNA breakage in T. cruzi. This was accompanied by inhibition of DNA, RNA, and protein synthesis and instigation of “unscheduled” DNA synthesis. [36] It is thought that this toxic action against parasites is at least partly due to superoxide production. [37] Both O2 - and H2 O 2 are intermediates of oxygen reduction and both are toxic to living organisms. When beta-lapachone is introduced to T. cruzi, it rapidly enters the epimastigote and is reduced to its semiquinone form in the mitochondria and microsomes of the pathogen. [38] Superoxide is produced by the reduction of molecular oxygen, which is facilitated by auto-oxidation of the semiquinone free radical. Superoxide is then converted to hydrogen peroxide via SOD (superoxide dismutase). Stimulation of lipid peroxidation follows and the cell degenerates. Anti-neoplastic effects Due to the folklore information surrounding the tumor-reducing qualities of the herb LaPacho, it underwent extensive study by the National Cancer Institute (NCI). After initial positive results, it was felt that lapachol was the most active anti-neoplastic agent. Lapachol entered phase I clinical trials at NCI in 1968, based on its activity against Walker 256 tumors (with over a 90% confidence rate). During these trials it was difficult to obtain therapeutic blood levels of lapachol without some mild toxic side-effects such as nausea, vomiting, and anti-vitamin K activity. This is quite hard to understand, as latter studies found the toxicity to be very low, with an LD50 of 487 mg, about the same as caffeine.[4] The IND (investigative new drug status) for the drug was closed in 1970. [39] It has been shown, however, that some of the anthraquinones in LaPacho have vitamin K activity, and therefore use of the whole herb would compensate for lapachol’s effect on vitamin K. [40] An analog, dichloroallyl lawsone, which had a better in vivo activity in the Walker 256 system, was selected to replace lapachol with IND approval in 1975. It was found, as was lapachol, to be an inhibitor of oxidative phosphorylation. In Rhesus monkeys it was observed to have some cardiac toxicity. It was decided subsequently that there was little point to any further analog development and the case was closed. [41] The approach described above indicates a flaw in the underlying philosophy of the pharmaceutical sciences and the NCI program. Since the initial studies came from a whole plant, the detailed studies should have been undertaken on the whole plant: some of the other quinones have also been shown to have anti-neoplastic activities. Was it too complex to consider the chemical reactions of the over 20 components found in the LaPacho? Or was the standard economic/political incentive for patenting an analog an impediment to the investigation of a plant species? Lapachol is rapidly absorbed through the gastrointestinal tract after oral administration to rats bearing W-256 tumors. It is taken up by all tissues except the brain and blood cells. A significant amount appears in the tumor after 6 hours, with most of the drug disappearing from the other body tissue. The half-life of i.v. lapachol in mice is 33 minutes (75 minutes in dogs). Lapachol is extensively metabolized and excreted mostly in the feces. [1] Most other analogs had little effect on cancer. [42] The theories on how lapachol works as an anti-neoplastic agent vary considerably. One of the most prominent involves redox cycle capabilities. The redox function of lapachol was known as early as 1936. [43] In 1947, Ball et al [44] studied the respiratory poison mechanism of naphthoquinones in the i.v. killing of malarial parasites. In 1966, lapachol was shown to stimulate mitochondrial ATPase activity (in the general fashion of uncouplers), while being without effect on ATPase stimulation by dinitrophenol. Its maximum activity is at a high pH where lipid solubility might be expected to be lowest. [10] Lapachol was found to be an in vivo inhibitor of respiration at chemotherapeutic doses. [7] Later, lapachol was shown to augment the flow of electrons from reduced NADP to form oxygen-related free radicals. These seem to be site-specific free radicals that bind to the cancerous DNA or RNA producing either superoxides or free hydroxyl radicals. [45] [46] There seems to be a redox potential which is important for the inhibition of electron transfer in coenzyme Q 10 .[47] It is argued by Bennett et al [48] that this respiration poisoning is not the mechanism of antitumor activity. Lapachol was shown to significantly reduce the pool of uridine triphosphate (UTP), the largest pool of the pyrimidine nucleotides (exposure time was very short, 2–4 hours). Lapachol is theorized to be like dichloroallyl lawsone (DCL) in that it blocks pyrimidine biosynthesis through inhibition of dihydroorotate dehydrogenase. [21] It is also believed that the anti-neoplastic activities of lapachol might stem from its interaction with nucleic acids [49] and it is proposed that interaction of the naphthoquinone moiety between base pairs of the DNA helix occurs with subsequent inhibition of DNA replication and/or RNA synthesis. Free amino groups in the sugar moiety are necessary for DNA binding. [49] Beta-lapachone was shown to decrease the viability of sarcoma cells by stimulating lipid peroxidation. This was accomplished through:
[ 37]
• reduction of lapachone at the mitochondrial and microsomal membranes with generation of the semiquinone form 972
• autooxidation to produce O 2 • production of H 2 O2 via SOD. Anti-inflammatory activity Extracts of the bark from Tabebuia avellanedae demonstrate clear anti-inflammatory activity with low toxicity. [50] Tampons soaked in an alcoholic extract of LaPacho have been shown to be very successful against a wide range of inflammations, such as cervicitis and cervicovaginitis. [2] [33] Quercetin
Quercetin is a highly active flavonoid which inhibits a wide range of enzymes and suppresses the synthesis of DNA, RNA, and proteins. [51] Quercetin’s cytotoxicity may be due to the fact that it inhibits mitochondrial electron transport. [52] Hodnick et al have noted that quercetin produced a substrate-independent, KCN-insensitive, respiratory burst in mitochondria. Other flavonoids which demonstrated this activity produced O 2 - and H2 O2 , suggesting that quercetin may also generate these cytotoxic chemicals.
Among the enzymes inhibited by quercetin are: [36] [37] [53] • NADH oxidase • phosphodiesterase • cAMP-independent protein kinases • Ca2+ phospholipid-dependent protein kinase • tyrosine protein kinases. Shapiro et al suggested that the cytotoxicity of quercetin may be due to its chelating abilities. [20] It is trypanocidal to Trypanosoma brucei, a livestock parasite belonging to the same genus as Trypanosoma cruzi. Soon after the parasite enters the host, the host’s unsaturated iron-building proteins remove iron from the hemoflagellate. Since the parasite is unable to synthesize heme, it encounters a shortage of iron. By chelating the host’s iron, quercetin blocks utilization by the parasite, yet does not adversely affect the host. This flavonoid is also cytotoxic against Crithidia fasiculata. The fact that it is small and lithophilic seems to be significant to its activity. Like lapachol, quercetin inhibited O 2 consumption and H2 O2 production in neutrophils. [28] Many flavonoids exhibit antiviral activity. When mice that had been intracerebrally infected with attenuated viruses, including rabies, were given quercetin in their diet, a prophylactic effect was observed. [54] Quercetin inactivates the following viruses: • herpes simplex type 1 • respiratory syncytial virus • pseudorabies/Aujesky’s virus • poliovirus type 1 • parainfluenza type 3 • Sindbis virus • potato virus X. (Inactivation is defined as reducing viral infectivity tenfold.)
CLINICAL APPLICATION The spectrum of clinical applications of Tabebuia avellanedae is quite broad. Current use has focused on LaPacho’s anti-neoplastic and antimicrobial activity. Its use is extremely popular in the treatment of intestinal candidiasis and vaginal candidiasis (topically and internally). There are also many anecdotal reports of remission of different forms of cancer from use of this botanical. [28] Unfortunately, due to lack of quality control and confusion about the portion of the plant to use (any of the studies and chemical analyses have been done on the heart wood, while the bark is the product available in the market place and discussed in the folklore), it is highly likely that most practitioners are not using effective materials. This could explain varying clinical results.
DOSAGE The usual form of administration of LaPacho is as a decoction, with the standard dose being 1 cup of decocted bark two to eight times/day. The decoction is made by boiling 1 tsp of LaPacho for each cup of water for 5–15 minutes. A more precise dosage based on a lapachol content of 2–4% would be 15–20 g of bark boiled in 500 ml or 1 pint of water for 5–15 minutes three to four times daily. Dosages of other forms (aqueous extract, fluid extract, solid extract) should be based on lapachol content, providing a daily lapachol intake of 1.5–2.0 g/day. A tampon which has been soaked in the decoction or fluid extract is used in the treatment of vaginitis and cervicitis. The tampon is inserted vaginally and changed every 24 hours until resolution.
TOXICOLOGY Although anti-vitamin K activity has been reported for lapachol, the presence of several vitamin K-like substances in the whole plant suggests this is not a problem. Lapachol has been reported to have an oral LD 50 of 1.2–2.4 g/kg in albino rats and 487–621 mg/kg in mice. [55] In comparison, the oral LD 50 of caffeine is 192 mg/kg in rats and 620 mg/kg in mice. [5] Chronic administration of lapachol at a dose of 0.0625– 0.25 g/kg per day to monkeys produces moderate to severe anemia. The anemia was most pronounced during the first 2 weeks of treatment. Death occurred in monkeys after six doses of lapachol at 0.5 g/kg per day and after five doses of 1.0 g/kg per day. [8] There have been no reports in the literature of human toxicity when the whole bark as a decoction is used.
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REFERENCES 1. Duke
JA. Interview. Saturday, February 24, 1984
2. Burnett 3. Pfizer
AR, Thomson RH. Naturally occurring quinones. part x. the quinonoid constituents of Tabebuia avellanedae (Bignoniaceae). J Chem Soc (C) 1967: 2100–2104
C. Antitumor composition from lapachol and its salts, CA70: 9075B. 156
4. Canadian 5. Duke
JA. CRC Handbook of medicinal herbs. Boca Raton, FL: CRC Press. 1985: p 470–473
6. Bernarde 7. Hartwell
10.
A. A Pocket book of Brazilian herbs (folklore – history – uses). Rio de Janeiro: Shogun Editora. 1984: p 22–23
JL. Plants used against cancer. A survey. Lawrence, MA: Quarterman Publications. 1982
8. Morrison 9. de
Health Protection Branch. Herbs and botanical preparations. Information Letter 726, Aug 13 1987
RK, Brown DE, Oleson JJ, Cooney DA. Oral toxicology studies with lapachol. Toxicol Appl Pharmacol 1970; 17: 1–11
Lima OG, d’Albuquerque IL, Machado MP et al. Primeiras Observacoes sobre a acao antimicrobiana do lapachol. Anais da Sociedade de biologica de pernambuco 1956; XIV: 129–135
de Lima OG, d’Albuquerque IL, Machado MP et al. Uma Nova substancia Antibiotica isolada do “Pau D’Arco”, Tabebuia sp. Anais da Sociedade de biologica de pernambuco 1956; XIV: 136–140
11.
Burnett AR, Thomson RH. Naturally occurring quinones. Part X. The Quinonoid Constituents of Tabebuia avellanedae (Bignoniaceae). J Chem Soc (C) 1967; 2100–2104
12.
Gershon H, Shanks L. Fungitoxicity of 1,4-naphthoquinones to Candida albicans and Trichophyton mentagrophytes. Can J Microbiol 1975; 21: 1317–1321
13.
de Lima OG, d’Albuquerque IL, Machado MP et al. Primeiras Observacoes sobre a acao antimicrobiana do lapachol. Anais da Sociedade de biologica de pernambuco 1956; XIV: 129–135
14.
Lagrota M et al. Antiviral activity of lapachol, Rev Microbiol 1983; 14: 21–26
15.
Guiraud P, Steinman R, Campos-Takaki GM. Comparison of antibacterial and antifungal activities of lapachol and b-lapachone. Planta Med 1994; 60: 373–374
Lopes JN, Cruz FS, Docampo R et al. In vitro and in vivo evaluation of the toxicity of 1,4-naphthoquinone and 1,2-naphthoquinone derivatives against Trypanosoma cruzi. Ann Trop Med Parasit 1978; 72: 523–531 16.
Schuerch AR, Wehrli W. ß-Lapachone, an inhibitor of oncornavirus reverse transcriptase and eukaryotic DNA polymerase-a. Inhibitory effect, thiol dependency and specificity. Eur J Biochem 1978; 84: 197–205 17.
Pinto AV, Pinto MDR, Gilbert B. Schistosomiasis mansoni. blockage of cercarial skin penetration by chemical agents. I. naphthoquinones and derivatives. Trans Royal Soc Trop Med Hyg 1977; 71: 133–135 18.
de Lima OG, d’Albuquerqul IL, de Lima CG, Dalia Maia MH. Comunicacao XX. Antividade antimicrobiana de alguns derivados do lapachol em comparacao com a xiloidona, Nova ortonaftoquinona natural isolada de extractos do cerne do “Pau d’Arco” roxo, Tabebuia avellanedae Lor. ex. Griseb. Substancias antimicrobianas de plantas superiores. Revista do Instituto de Antibioticos Recife 1962; 4 19.
20.
Shapiro A, Nathan HC, Hunter SH et al. In vivo and in vitro activity by diverse chelators against Trypanosoma brucei. J Protozool 1982; 29: 85–90
21.
Howland JL. Uncoupling and inhibition of oxidative phosphorylation by 2-hydroxy-3-alkyl-1,4-naphthoquinones. Biochim Biophys Acta 1963; 77: 659–662
22.
Wendel WB. The influence of naphthoquinones upon the respiratory and carbohydrate metabolism of malarial parasites. Fed Proc 1946; 5: 406–407
23.
Ball EG, Anfinsen CB, Cooper O. The inhibitory action of naphthoquinones on respiratory processes. J Biol Chem 1947; 168: 257–270
24.
Fieser LF, Richardson AP. Naphthoquinone antimalarials. II. Correlation of structure and activity against Plasmodium lophurae in ducks. J Am Chem Soc 1948; 70: 3156–3165
25.
Gosalvez M, Garcia-Canero R, Blanco M, Guru charri-Lloyd C. Effects and specificity of anticancer agents on the respiration and energy metabolism of tumor cells. Canc Treat Rep 1976; 60: 1–8
26.
Crawford DR, Schneider DL. Identification of ubiquinone-50 in human neutrophils and its role in microbicidal events. J Biol Chem 1982; 257: 6662–6668
27.
Wendel WB. The influence of naphthoquinones upon the respiratory and carbohydrate metabolism of malarial parasites. Fed Proc 1946; 5: 406–407
28.
Weed B. Second Opinion, Lapacho fight against cancer. Vancouver: Rostrum Communication. 1984
29.
Howland JL. Influence of alkylhydroxynaphthoquinones on the mitochondrial oxidation of tetramethyl-p-phenylenediamine. Biochim Biophys Acta 1967; 131: 247–254
30.
Hadler HI, Moreau TL. The induction of ATP energized mitochondrial volume changes by the combination of the two antitumour agents showdomycin and lapachol, J Antibiot 1969; 513–520
31.
Koide SS. Inhibition of 3a-hydroxysteroid-mediated transhydrogenase of rat liver by various quinones and flavonoids. Biochim Biophys Acta 1962; 59: 708–710
32.
Austin FG. Schistosoma mansoni chemoprophylaxis with dietary lapachol. Am J Trop Med Hygiene 1974; 23: 412–419
Wanick MC et al. Acao antiinflamatoria e cicatrizante do extrato hidroalcoolico do liber do pau d’arco roxo ( Tabebuia avellanedae), em pacientes portadoras de cervicites e cervico-vaginites. Separata da Revista do Instituto de Antibioticos 1970; 10: 41–46 33.
34.
Schaffner-Sabba K, Schmidt-Ruppin KH, Wehrli W. ß-Lapachone. Synthesis of derivatives and activities in tumour models. J Medicinal Chem 1984; 27: 990–994
35.
Gilbert B, de Souza JP, Fascio M et al. Schistosomiasis. Protection against infection by terpenoids. An Acad Brasil Cienc 1970; 42: 397–400
36.
Goijman SG, Stoppani AOM. Oxygen radicals and macromolecule turnover in Trypanosoma cruzi. Life Chem Rep 1984; 2: 216–221
Docampo R, Cruz FS, Boveris A et al. ß-Lapachone enhancement of lipid peroxidation and superoxide anion and hydrogen peroxide formation by sarcoma 180 ascites tumor cells. Biochem Pharmacol 1979; 28: 723–728 37.
38.
Boveris A, Stoppani AOM, Docampo R, Cruz FS. Superoxide anion production and trypanocidal action of naphthoquinones on Trypanosoma cruzi. Comp Biochem Phys 1978: 327–329
39.
Block JB, Serpick AA, Miller W, Wiernik PH. Early clinical studies with lapachol (NSC-11905). Cancer Chemo Rep 1974; 4: 27–28
40.
Preusch PC, Suttie J W. Lapachol inhibition of vitamin K epoxide reductase and vitamin K quinone reductase. Arch Biochem Biophys 1984; 234: 405–412
41.
McKelvey EM, Lomedica M, Lu K et al. Dichloroallyl lawsone. Clin Pharmacol Ther 1979; 586–590
42.
Rao KV. Quinone natural products. Streptonigrin (NSC-45383) and lapachol (NSC-11905) structure-activity relationships. Cancer Chemo Rep 1974; 4: 11–17
43.
Ball EG. Studies on oxidation-reduction. XXII. Lapachol, lomatiol, and related compounds. J Biol Chem 1936; 114: 649–655
44.
Ball EG, Anfinsen CB, Cooper O. The inhibitory action of naphthoquinones on respiratory processes. J Biol Chem 1947; 168: 257–270
45.
Bachur NR, Gordon SL, Gee MV, Kon H. NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc Natl Acad Sci USA 1979; 76: 954–957
46.
Bachur NR, Gordon SL, Gee MV. A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 1978; 38: 1745–1750
47.
Iwamoto Y, Hansen IL, Porter TH, Folkers K. Inhibition of coenzyme Q 10 -enzymes, succinoxidase and NADH-oxidase, by adriamycin and other quinones having antitumor activity. Biochem
Biophys Res Comm 1974; 58: 633–638 48.
Bennett LL, Smithers D, Rose LM et al. Inhibition of synthesis of pyrimidine nucleotides by 2-hydroxy-3-(3,3-dichloroallyl)-1,4-naphthoquinone. Cancer Res 1979; 39: 4868–4874
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Lee S-H, Sutherland TO, Deves R, Brodie AF. Restoration of active transport of solutes and oxidative phosphorylation by naphthoquinones in irradiatiated membrane vesicle from Mycobacterium phlei. Proc Natl Acad Sci USA 1980; 77: 102–106 49.
50.
Oga S, Sekino T. Toxicidade e Atividade Anti-inflamatoria de Tabebuia avellanedae Lorentz e Griesbach (“Ipe Roxo”). Rev Fac Farm Bioquim S Paulo 1969; 7: 47–53
Graziani Y, The effect of quercetin of pp60 v-src kinase activities. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure–activity relationships. New York: Alan R Liss. 1986: p 301–313 51.
Hodnick WF, Roettger WJ, Kung FS. Inhibition of mitochondrial respiration and production of superoxide and hydrogen peroxide by flavonoids. A structure activity study. Plant Flavonoids in Biology and Medicine. Biochemical, Pharmacological, and Structure-Activity Relationships. New York: Alan R Liss. 1986: p 249–252 52.
Srivastava AK, Chiasson JL. Effect of quercetin on serine/ threonine and tyrosine protein kinases. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure–activity relationships. New York: Alan R Liss. 1986: p 315–318 53.
Selway JWT. Antiviral activity of flavones and flavins. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure–activity relationships. New York: Alan R Liss. 1986: p 521–536 54.
55.
Ball EG. Studies on oxidation-reduction. XXII. Lapachol, Lomatiol, and related compounds. J Biol Chem 1936; 114: 649–655
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Chapter 114 - Tanacetum parthenium (feverfew) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Tanacetum parthenium (family: Compositae) Synonym: Chrysanthemum parthenium Common names: feverfew, featherfew
GENERAL DESCRIPTION Feverfew (Tanacetum parthenium) is a composite plant that is cultivated in flower gardens throughout Europe and the United States. The round, leafy, branching stems bear alternate, bipinnate leaves with ovate, hoary-green leaflets. The flowers are small and daisy-like, with yellow disks and from 10 to 20 white, toothed rays. The name feverfew is a corruption of the word febrifuge used to signify its tonic and fever-dispelling properties.
CHEMICAL COMPOSITION The major active chemicals in the plant are sesquiterpene lactones, principally parthenolide. The flowering herb also contains 0.02–0.07% essential oils ( L-camphor, [ [ L-borneol, terpenes, and miscellaneous esters). 1] 2]
HISTORY AND FOLK USE Feverfew has been used for centuries as a febrifuge and for the treatment of migraines and arthritis. Other historical uses of feverfew have been in the treatment of anemia, earache, dysmenorrhea, dyspepsia, trauma, and intestinal parasites. [1] It has also been used as an abortifacient, and in gardens to control noxious pests (its pyrethrin component is an effective insecticide and herbicide).
PHARMACOLOGY Feverfew has demonstrated some remarkable pharmacological effects in experimental studies. Its long folk history of use in the treatment of inflammatory conditions such as fever, arthritis, and migraine suggests that
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it acts in a fashion similar to that of the more common non-steroidal anti-inflammatory agents (NSAIDs), such as aspirin. Extracts of feverfew have been shown to inhibit the synthesis of compounds which promote inflammation, including inflammatory prostaglandins, leukotrienes, and thromboxanes. Unlike aspirin and other NSAIDs, inhibition by feverfew at the initial stage of synthesis is more like that of cortisone than NSAIDs. [3] Feverfew also has a favorable effect on the behavior of blood platelets. [3] [4] The favorable effects include inhibition of platelet aggregation and the secretion of inflammatory and allergic mediators like histamine and serotonin. Parthenolide components also exert a tonic effect on vascular smooth muscle. [5] The combined effect on smooth muscle and platelets is probably the factor responsible for feverfew’s effect in preventing and treating migraine headaches.
CLINICAL APPLICATIONS Feverfew has been used for centuries to relieve fever, migraines and arthritis. The only condition with confirmed scientific documentation at the present time is in the prevention and treatment of migraine headache. Migraine headache
Physician John Hill, in his book The family herbal (1772) noted: “In the worst headache this herb exceeds whatever else is known.” Recently, there has been tremendous increase in the interest in feverfew for migraine headache. This renewed interest began in 1970s in Britain. Increased public awareness of the herb led to scientific investigation. A 1983 survey found that 70% of 270 migraine sufferers who had eaten feverfew daily for prolonged periods claimed that the herb decreased the frequency and/or intensity of their attacks. [6] Many of these patients had been unresponsive to orthodox medicines. This prompted two clinical investigations of the therapeutic and preventive effects of feverfew in the treatment of migraine. The first double-blind study was done at the London Migraine Clinic, using patients who reported being helped by feverfew. [6] Those patients who received the placebo (and as a result stopped using feverfew) had a significant increase in the frequency and severity of headache, nausea, and vomiting during the 6 months of the study, while patients taking feverfew showed no change in the frequency or severity of their symptoms. Two patients in the placebo group who had been in complete remission during self-treatment with feverfew leaves developed recurrence of incapacitating migraine and had to withdraw from the study. The resumption of self-treatment led to renewed remission of symptoms in both patients. The second double-blind study was performed at the University of Nottingham. [7] The results of the study clearly demonstrated that feverfew was effective in reducing the number and severity of migraine attacks. In the study, 72 patients were randomly allocated to receive either one capsule of dried feverfew leaves (82 mg) daily or placebo. After 4 months, patients were transferred to the other treatment for another 4 months. Treatment with feverfew was associated with a reduction in the mean number and severity of attacks and in the degree of vomiting; duration of single attacks was unaltered. The efficacy of feverfew in the prevention of migraine headaches has now been demonstrated in several controlled studies. [8] Rheumatoid arthritis
Inflammatory compounds released by white blood cells and platelets contribute greatly to the inflammation and cellular damage found in rheumatoid arthritis. The inhibition of the release of inflammatory particles by feverfew is much greater than that achieved by NSAIDs like aspirin. [4] This, coupled with many of feverfew’s other effects, indicates that feverfew could greatly reduce inflammation in rheumatoid arthritis. Although a double-blind, placebo-controlled study demonstrated no apparent benefit from oral feverfew in rheumatoid arthritis, the dosage used was small (76 mg dried, powdered feverfew leaf corresponding to two medium-sized leaves), the level of parthenolide was not determined in the product, and patients continued to take
NSAIDs, a practice that has been suggested to reduce the efficacy of feverfew. [9] Therefore, the benefit of feverfew in rheumatoid arthritis has not yet been determined.
DOSAGE The effectiveness of feverfew is dependent upon adequate levels of parthenolide, the active principle. Unfortunately, recent analyses of the parthenolide content of over 35 different commercial preparations indicate a wide variation in the amount of parthenolide. [10] The majority of products contained no parthenolide or only traces. The preparations used in successful clinical trials had a parthenolide content of 0.4–0.66%. In order to achieve the benefits noted in the migraine studies, the dosage of parthenolide must be similar. The dosage of feverfew used in the London Migraine Clinic study was one capsule containing 25 mg of the freeze-dried pulverized leaves twice daily. In the Nottingham study it was one
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capsule containing 82 mg of dried powdered leaves once daily. Therefore, the daily dosage of parthenolide which may be effective in the prevention of a migraine headache is roughly 0.25–0.5 mg. While these low dosages may be effective in preventing an attack, a higher dose (1–2 g) is necessary during an acute attack: • dried pulverized leaves: 25–50 mg two times/day.
TOXICITY There were no reports of toxic reactions in patients taking feverfew in the 6 month migraine study. Feverfew has been used by large numbers of people for many years without reports of toxicity. Chewing the leaves, however, may result in aphthous ulcerations, and some sensitive persons will develop an exudative dermatitis from external contact. [11]
REFERENCES 1. Duke
JA. Handbook of medicinal herbs. Boca Raton, Fl: CRC Press. 1985: p 118
2. Bohlmann 3. Makheja
F, Zdero C. Sesquiterpene lactones and other constituents from Tanacetum parthenium. Phytochemistry 1982; 21: 2543–2549
AM, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew ( Tanacetum parthenium). Prostagland Leukotri Med 1982; 8: 653–660
4. Heptinstall
S, White A, Williamson L, Mitchell JRA. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leukocytes. Lancet 1985; i: 1071–1074
5. Barsby
RWJ, Salan U, Knight BW, Hoult JRS. Feverfew and vascular smooth muscle. Extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content. Planta Medica 1993; 59: 20–25 6. Johnson 7. Murphy 8. Gawel
ES et al. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J 1985; 291: 569–573
JJ, Heptinstall S, Mitchell JRA. Randomized double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet 1988; ii: 189–192
MJ. The use of feverfew in the prophylaxis of migraine attacks. Today’s Ther Trends 1995; 13: 79–86
9. Pattrick
M et al. Feverfew in rheumatoid arthritis. A double blind, placebo controlled study. Ann Rheum Dis 1989; 48: 547–549
Heptinstall S et al. Parthenolide content and bioactivity of feverfew ( Tanacetum parthenium (L.) Schultz-Bip.). Estimation of commercial and authenticated feverfew products. J Pharm Pharmacol 1992; 44: 391–395 10.
11.
Awang DVC. Feverfew. Can Pharm J 1989; 122: 266–270
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Chapter 115 - Taraxacum officinale (dandelion) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Taraxacum officinale (family: Compositae) Common names: • English: dandelion, wet-a-bed, Lion’s tooth • French: dent-de-lion, pissenlit • German: lowenzahn, pfaffenrohrlein • Spanish: diente de leon • Italian: tarassaco • Chinese: p’u kung ying, Ching p’o po, chiang-nou-ts’ao, huang-hua-tii-ting
GENERAL DESCRIPTION Dandelion (Taraxacum officinale) is a member of the Compositae family and is closely related to chicory. [1] Several origins have been attributed to the name Taraxacum, among them the most likely being from the Greek taraxo (disorder, disturbance) and akos (remedy), akeomai (I heal) and from tharakhcharkon, possibly a derivative of a Persian-Arabic word for “edible” and the name by which the plant is referred to in a 13th-century Arabian botanical work. Taraxacum is known around the world by a variety of names. In English speaking countries, dandelion (from the French dent-de-lion, referring to the plant’s lion’s tooth leaves) is its most common name. It is also known as wet-a-bed (after its diuretic action), Lion’s tooth, fairy clock, priest’s crown, swine’s snout, blowball, milk gowan, wild endive, white endive, [4] cankerwort,[5] puffball, and Irish daisy. [1] Dandelion is a variable perennial, growing to a height of 12 inches. Its spatula-like leaves are deeply toothed, shiny, and hairless, and are arranged in a ground level rosette. The yellow flowers bloom for most of the year, are sensitive to light and weather – opening at daybreak and closing at night fall, and opening in dry weather and closing in wet (a closed dandelion flower signals rain). When the flower matures, it closes up, the petals wither, and it forms into a puffball containing seeds which are dispersed by the breeze.
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The rosette formation of grooved leaves channels rainwater into its center and down to a taproot which is thick, dark brown and almost black on the outside. The root is cylindrical, tapering, and somewhat branched. It has a slight odor and a sweetish taste. The inside of dried dandelion root is yellowish, very porous and without pith. It is believed that the plant originated in Central Asia and spread throughout most of the world, preferring the cooler climates. [1] Although Taraxacum is very adaptable, it prefers moist nitrogen-rich soils at altitudes less than 6,000 feet. Most species occur in the temperate zones of the northern hemisphere, with the greatest concentration in north-west Europe. The portion of the plant that is most commonly used is the root; however, the leaves and whole plant can also be used. In addition to its medicinal use, dandelion is also used as a nutritious food and beverage. Tender leaves are used raw in salads and sandwiches, or lightly cooked as a vegetable. Tea is made from the leaves, coffee substitute from the roots, and wine and schnapps from the flowers.
CHEMICAL COMPOSITION The primary therapeutic actions of dandelion are believed to be due to the bitter principle taraxacin, various terpenoids, inulin, and its high concentration of nutrients. Other constituents of dandelion which may contribute to its pharmacology include resins, pectin, taraxanthin (a carotenoid pigment in the flowers), fatty acids, and flavonoids. Many studies show that dandelion is a rich source of vitamins and minerals. [1] The leaves have the highest vitamin A content (14,000 IU/100 g raw) of all greens, as well as ample amounts of vitamins D, B complex, C and minerals such as iron silicon, magnesium, sodium, potassium, zinc, manganese, copper and phosphorus. [1] [2] Dandelion also contains relatively high amounts of choline, an important nutrient for the liver. [3] Taraxacum officinale roots contain the triterpenes ß-amyrin, taraxasterol, taraxerol and the sterols sitosterin, stigmasterin and phytosterin ( Figs 115.1 and 115.2 ).[4] More recent research is now eliciting several compounds which are likely to be clinically significant. Three
Figure 115-1 Taraxerol.
Figure 115-2 Taraxasterol.
flavonoid glycosides – luteolin 7-glucoside and two luteolin 7-diglucosides – have been isolated from dandelion flowers and leaves together with free luteolin and chrysoeriol in the flower tissue. Three hydroxycinnamic acids – chicoric acid, monocaffeyltartaric acid and chlorogenic acid – have been found throughout the plant, and the coumarins, cichoriin and aesculin, have been identified in leaf extracts. Chicoric acid and the related monocaffeyltartaric acid were found to be the major phenolic constituents in flowers, roots, leaves and involucral bracts and also in the medicinal preparations tested. [5]
HISTORY AND FOLK USE While many individuals may consider the common dandelion an unwanted weed, herbalists all over the world have revered this valuable herb. Generally regarded as a liver remedy, dandelion has a long history of folk use throughout the word. In Europe, dandelion was used in the treatment of: • fevers • boils • eye problems • diarrhea • fluid retention • liver congestion • heartburn • various skin problems. In China, dandelion has been used to treat: • breast problems (cancer, inflammation, lack of milk flow, etc.) • liver diseases • appendicitis • digestive ailments. Dandelion’s use in India, Russia, and most other parts of the world revolved primarily around its action on the liver.
PHARMACOLOGY The primary pharmacological activities relate to digestion, liver function, and diuresis.
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Digestive effects
Bitter herbs like dandelion are used to aid digestion based on the belief that bitter principles stimulate the initial phase of digestion including the secretion of salivary and gastric juices. Dandelion goes beyond this initial stimulation by stimulating the release of bile by the liver and gall bladder. Liver effects
Studies in humans and laboratory animals have shown that dandelion root enhances the flow of bile, improving such conditions as liver congestion, bile duct inflammation, hepatitis, gallstones, and jaundice. [6] [7] [8] Dandelion’s action on increasing bile flow is twofold: it has a direct effect on the liver, causing an increase in bile production and flow to the gall bladder (choleretic effect), and a direct effect on the gall bladder, causing contraction and release of stored bile (cholagogue effect). The high choline content of the root may be a major factor in dandelion’s ability to act as a “tonic” to the liver. Historically, dandelion’s positive effect on such a wide variety of conditions is probably closely related to its ability to improve the functional ability of the liver. Diuretic and weight-loss effects
The leaves of dandelion have confirmed diuretic activity. In one study in mice, dandelion exerted a diuretic activity comparable to furosemide (Lasix). [9] Because dandelion replaces potassium lost through diuresis, it does not have the potential side-effects of furosemide such as hepatic coma and circulatory collapse. The dose given was 8 ml/ kg body weight of the aqueous fluid extract of the leaves. This dose produced a 30% loss of body weight in mice and rats in a 30 day period. Much of the weight loss was attributed to the significant diuretic effects. Hypoglycemic effects
Dandelion and inulin have demonstrated experimental hypoglycemic activity in animals. glucose levels, thus preventing sudden and severe fluctuations.
[10]
Since inulin is composed of fructose chains, it may act to buffer blood
CLINICAL APPLICATIONS Although dandelion’s specific action is on the liver, as an alterative or tonic it benefits the body as a whole. It is often used as: • a diuretic • a laxative • a cholagogue • a general stimulant for the urinary system • a choleretic • a depurative (purifier) • a hypoglycemic • an antitumor agent. Liver conditions
Two human studies have demonstrated the liver-healing properties of dandelion. In a 1938 study in Italy, 12 patients with severe liver imbalances, many exhibiting classical symptoms of loss of appetite, low energy and jaundice, were treated with dandelion extract (one 5 ml injection per day for 20 days). [1] Eleven of the 12 patients showed a considerable drop in blood cholesterol. In the other study, dandelion extract was shown to successfully treat hepatitis, swelling of the liver, jaundice and dyspepsia with deficient bile secretion. [6] Dandelion’s effects on the liver, particularly its lipotropic effects, may be put to good use in the treatment of premenstrual syndrome. Decreased clearance of estrogen and other hormones by the liver is believed to be responsible for these symptoms in some women. If dandelion can improve the liver’s ability to detoxify these hormones, symptoms may be likewise improved. Cancer
A Japanese study in 1979 found that dandelion alcoholic extract administered to mice for 10 days markedly inhibited the growth of inoculated Ehrlich ascites cancer cells within a week of treatment. [11] A freeze-dried warm-water extract of the root for use as an antitumor agent was patented by the Japanese in 1979, and TOf-CFr, a glucose polymer isolated by Japanese researchers in 1981, was found to have antitumor properties in laboratory mice. [1] These findings lend support to the Chinese use of dandelion for breast cancers. Kidney stones
One study, using female Wistar rats, evaluated seven botanicals historically used to prevent and treat stone kidney formation: • • • • • • •
Verbena officinalis Lithospermum officinale Taraxacum officinale Equisetum arvense Arctostaphylos uva-ursi Arctium lappa Silene saxifraga.
Variations of the main urolithiasis risk factors – citraturia, calciuria, phosphaturia, pH and diuresis – were measured. The researchers concluded that the beneficial effects caused by these herbal infusions on urolithiasis can be attributed to some disinfectant action, and, tentatively, to the presence of saponins. [12] 982
DOSAGE As a general tonic and mild liver remedy, the root can be used at the following dosages three times/day: • dried root: 2–8 g by infusion or decoction • fluid extract (1:1): 4–8 ml (1–2 tsp) • tincture: alcohol-based tinctures of dandelion are not recommended because of the extremely high dosage required • juice of fresh root: 4–8 ml (1–2 tsp) • powdered solid extract (4:1): 250–500 mg. Preparations of the leaves can be used as a mild diuretic and weight-loss agent at the following dosages three times/day: • dried leaf: 4–10 g by infusion • fluid extract (1:1): 4–10 ml.
TOXICITY No toxic or adverse effects have been reported, for either external or internal use. It is considered safe to use, even in large amounts.
[1]
REFERENCES 1. Hobbs
C. Taraxacum officinale: a monograph and literature review. In: Alstadt E, ed. Eclectic dispensatory. Portland, OR: Eclectic Medical. 1989
2. Leung
AY. Encyclopedia of common natural ingredients used in food, drugs and cosmetics. New York, NY: John Wiley. 1980
3. Broda
B, Andrzejewska E. Choline content in some medicinal plants. Farm Polska 1966; 22: 181–184
4. Devys
M. Triterpene alcohols from dandelion (T. dens-leonis) pollen. CR Acad Sci Ser D. 1969; 269: 798–801
5. Williams
6. Faber
Taraxacum officinale. Phytochemistry 1996; 42: 121–127
K. The dandelion Taraxacum officinale. Pharmazie 1958; 13: 423–436
7. Susnik 8. Bohm
CA, Goldstone F, Greenham J. Flavonoids, cinnamic acids and coumarins from the different tissues and medicinal preparations of
F. Present state of knowledge of the medicinal plant Taraxacum officinale Weber. Med Razgledi 1982; 21: 323–328
K. Choleretic action of some medicinal plants. Arzneimittel-Forsch 1959; 9: 376–378
9. Racz-Kotilla
E, Racz G, Solomon A. The action of Taraxacum officinale extracts on the body weight and diuresis of laboratory animals. Planta Medica 1974; 26: 212–217
10.
Yamashita K, Kawai K, Itakura M. Effects of fructo-oligosaccharides on blood glucose and serum lipids in diabetic subjects. Nutr Research 1984; 4: 491–496
11.
Kotobuki Seiyaku KK. Taraxacum extracts as antitumour agents. Chem Abst 1979; 94: 14 530
12.
Grases F, Melero G, Costa-Bauza A et al. Urolithiasis and phytotherapy. Int Urol Nephrol 1994; 26: 507–511
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Chapter 116 - Taxus brevifolia (Pacific yew) Cathy Flanagan ND
Taxus brevifolia (family: Taxaceae) Common names: Pacific yew, taxol, paclitaxel
GENERAL DESCRIPTION Paclitaxel (also known as taxol) and taxotene (docetaxel) are a complex diterpenoid taxanes extracted from Taxus brevifolia, the Pacific yew. They have been cited as some of the most promising plant compounds tested for anti-cancer properties to date. [1] First collected in 1962 by a USDA team in Washington state as part of the large natural products screening program of the US National Cancer Institute, confirmed activity against the KB cell line in tissue culture was reported in 1964. Isolation studies began in 1965 and by 1971 Wall and co-workers at the Research Triangle Institute (Durham, NC) identified taxol as the active constituent. [2] Taxol became big news in 1989, when investigators at the Johns Hopkins Oncology Center in Baltimore reported a 30% response rate in cases of refractory ovarian cancer, a remarkable rate for this type of cancer. [3] Taxanes used in conjunction with chemotherapy and radiation have demonstrated improved results to either therapy alone along with improved tolerance to the therapies. Yews are evergreen trees or shrubs which produce a seed surrounded by an edible red fleshy aril. The yew is difficult to class taxonomically as its appearance is similar to conifers, but because of the absence of cones and resin ducts, it is placed in a separate order. Although the yew appears to be tenacious, it is slow to reproduce. The species is dioecious, with female trees producing relatively scarce fruits. Seedlings are rare. Most often, new yew trees come from offshoots of a “mother tree”, which is why they are usually found in clusters. They grow best on deep, moist, rich rocky or gravelly soils. The largest known living Pacific yew is in Lewis County, Washington, near Mount Rainier. It stands 21.3 m tall, has a girth of 4.5 m, and is estimated to be 1,000 years old. [2] Although taxol is found in species other than the
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Pacific yew, its concentration is too low to warrant the extensive extraction processing required. Initially, it was thought that the most consistently stable and highly active constituent came from bark isolates, followed by root isolates. Currently, taxol and another compound, baccatin III (from the English yew, T. baccata), are being extracted from needles and twigs of 3- to 5-year-old cuttings being grown for this purpose. Taxol, a complex molecule, can be synthesized from baccatin III, but to date eludes efforts at total synthesis. [4] [5] Harvesting of a sufficient natural source is unrealistic for long-term use, as the Pacific yew, an inhabitant of old-growth stands, is in limited supply. The demand for taxol is estimated at 50–200 kg/patient, which would require 500,000–635,000 kg of bark yearly. One 200-year-old tree, with a 25 cm diameter yields only 2.7 kg of bark. [2] The National Cancer Institute had requested 340,200 kg of dried bark in 1991 for 25 kg to be used in clinical trials alone. Environmentalists are concerned about the decimation of the little old-growth habitat which has survived logging efforts. Ironically, the Pacific yew had been previously regarded as a trash tree, left behind or burnt after logging operations. Now it is sought for its bark, and accessible stands are being harvested for maximum yield. The future of taxol as a viable anti-cancer agent depends either on it, or a molecule similar enough to retain the therapeutic properties, being synthetically produced or on improved harvesting and extraction techniques that will maximize yield while perpetuating the natural source. Researchers at Stanford University have overcome many hurdles in the synthesis, but have not yet been totally successful. Extraction from needles looks promising, as it takes only 27.2 kg of foliage (produced from one tree) versus 4.1 kg of bark (consuming three trees) to obtain 2 g of taxol, the necessary dose for one patient. Harvesting trees in a manner that allows for sprouting of new trees is another way to sustain a supply and the survival of the species. A collaborative research and development agreement between the National Cancer Institute and the Bristol-Myers Squibb Company has made it possible for taxol to be the first drug available through the treatment referral center to designated comprehensive cancer centers for eligible patients before being commercially available. [3] The National Cancer Institute announced (newsletter, September 1992) that taxol had been reclassified as a group C drug, making it available with Medicare reimbursement to women with refractory ovarian cancer.
CHEMICAL COMPOSITION Yew is poisonous because of at least 11 alkaloids, known collectively as taxines. The structure of only two of the alkaloid constituents is known: taxine A, which accounts
Figure 116-1 Paclitaxel.
for 30%, and taxine B, which accounts for 2%. Paclitaxel ( Fig. 116.1 ) is a pseudoalkaloid, but not a constituent of taxine since its nitrogen is acylated with benzoic acid and has no basic principle. The concentration of paclitaxel in yew bark is low, only 0.01%. Taxenes have now been found in species other than the Pacific yew, but at lower concentrations. The harvesting of 500,000–635,000 kg/year of the bark is required to provide the estimated placitaxel needed. Therefore, development of analogs synthesized from natural turpenes are important for long-term use. In the search for precursors for paclitaxel synthesis, the much more prevalent yew needles have been analyzed for paclitaxel analogs. Several have been identified (e.g. 10-deacetyltaxol III, cephalmannine, 10-deacetyltaxol, 10-deacetylcephalomannine, and baccatin-III). As all yew species contain these highly oxygenated diterpenoids based on the unique taxane skeleton, most of the over 100 yew varieties are being screened, as are other members of the Taxus species. Other analogs,
like docefaxel, are made by altering compounds extracted from the yew tree needles. Paclitaxel is synthesized from cyclization of the universal diterpenoid precursor, geranylgeranyl diphosphate to taxa-4(5),11(12)-diene. This olefin is hydroxylated via cytochrome P450 catalysts to taxa-4(20),11(12)-dien-5 alpha-ol. Then this alcohol is converted via an acetylCoA-dependent process to the corresponding
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acetate ester. Further genetic identification and isolations are targeted to improve the yield of taxol from the Taxus species. [6]
HISTORY AND FOLK USE Historically, the yew has been highly valued for its dense, resilient, decay-resistant, tight-grained wood, and its medicinal properties. The Greeks named the yew toxus in reference to its use for making strong bows (toxon), and its poisonous nature (toxikon). [2] It was used as an animal and fish poison by primitive cultures, as well as for murder and suicide. In the 1st century AD, Claudius suggested its use as an antidote for viper bites. Europeans used it as an abortifacient, and for heart ailments and hydrophobia. [2] Native Americans used the yew for many ailments such as: • rheumatism • lung ailments • colds • fever • pain • scurvy • numbness • paralysis • stomach ache • bowel ailments • dysmenorrhea • clots • gonorrhea. Women ate yew berries to prevent conception. Youths rubbed smooth sticks of yew on their developing bodies to gain its strength. Both the bark and the leaves have been brewed for tea, and powders made from the bark alone. The fleshy red aril (berry) that surrounds the seed is not poisonous, although the seed itself is. [7] There is a lot of folklore about the yew’s supernatural powers. As it is a slow-growing, long-lived tree, it was associated with immortality. It was used in spells to raise the dead.[8] Because it was regarded as among the most potent of trees for protection against evil, it was considered unlucky to cut down or damage a yew tree. Many were planted in churchyards/graveyards and alongside homes for protection. Specimens survive today in spite of main trunks being hollowed out from decay following hundreds of years of existence.
PHARMACOLOGY Paclitaxel’s anti-cancer action is unique in that it inhibits cell division by promoting the formation of microtubules, the rod-like structures that function as a cell skeleton, making cells more stable and resistant to depolymerization. In contrast, other anti-cancer phytoagents (i.e. colchicine and vinca alkaloids) induce polymerization of microtubules. In addition, under the influence of paclitaxel, the microtubules polymerize independently of the microtubule-organizing center (MTOC), which is in a perinuclear area, and instead localize predominantly in the cell periphery. [9] This interferes with the mitotic spindle and selectively blocks cells in the G 2 and M phases of the cell cycle, the most radiosensitive phases. Additionally, paclitaxel induces the formation of abnormal spindle asters that do not require centrioles for enucleation and are reversible following treatment. [10] [11] Discovery of this unique mechanism of action by Horowitz and co-workers in 1979 kindled interest in paclitaxel, despite the inherent problems in the utilization of a scarce natural product. [12] [13] In addition, paclitaxel has demonstrated, in vivo, an ability to activate a local release of an apoptosis-inducing cytokine. [14] Studies on cancer cell lines induced with gml, a novel gene, demonstrated a marked increase in sensitivity to paclitaxel via apoptosis. An assay for gml expression could serve as a clinically useful predictor of chemotherapeutic sensitivity. [15] Docetaxel (taxotene) manifests its maximum inhibitory effect against cells that are in S phase. [46] Other analogs (particularly IDN5109) are showing anti-proliferative activity 20- to 30-fold higher than paclitaxel in multi-drug-resistance-positive cancer cells. [16]
CLINICAL APPLICATION Paclitaxel has demonstrated a broad spectrum of antitumor activity. Phase I trials, which began in 1983, demonstrated paclitaxel’s anti-neoplastic activity against several tumor types, such as: [17] [18] [19] [20] [21] [22] [23] [24] • melanoma • adenocarcinoma of unknown origin • refractory ovarian carcinoma • small-cell and non-small-cell lung carcinoma • gastric, colon, prostate, breast, head and neck carcinomas • lymphoblastic and myeloblastic leukemias. Trials are also being conducted with impressive results, using paclitaxel in combination with other anti-neoplastic agents, such as cisplatin. [25] The Gynecology Oncology Group (GOG) reports a 33% response rate in patients who were previously resistant to cisplatin, when they are treated with the combination of cisplatin and paclitaxel. [26] Trials are being conducted on small-cell and non-small-cell lung, renal, gastric, breast, advanced ovarian, colon, and cervical carcinomas; head and neck cancers; small cell lung and prostate carcinomas and low-grade non-Hodgkin’s lymphoma. [27] Table 116.1 lists the short-term partial or complete response rates of various types of cancer to paclitaxel alone or in combination with other chemotherapeutic drugs.
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Cancer type
TABLE 116-1 -- Results of clinical trials of paclitaxel or paclitaxel combinations [28] Response range (%)
Ovarian cancer
20–50
Breast cancer
56–62
Lung cancer
21–46
Melanoma
28
Renal carcinoma
0 (small numbers)
Prostate
50 (small numbers)
TOXICITY Human poisoning from the deliberate consumption of yew leaves or seeds is now rare. Recently published cases, from psychiatric patients and prisoners, describe the first symptoms of intoxication as appearing 1 hour after ingestion. The manifestations include mydriasis, nausea, vomiting, abdominal cramping and arrhythmia. Death occurs from cardiac arrest 3–24 hours after ingestion. [28] The lethal dose in humans is approximately four or five handfuls of leaves, corresponding to 150 needles. No specific antidote is known. Paclitaxel binds 95–98% with plasma proteins, yet is readily eliminated through hepatic metabolism, biliary excretion, and/or extensive tissue binding. Total urinary excretion has been insignificant, indicating that renal clearance contributes minimally to systemic clearance. [24] [29] [30] [31] Hepatic metabolism via cytochrome p450 (CYP) is involved for both paclitaxel and docetaxel. However, the former is hydroxylated by CYP2C8 while the latter is hydroxylated by CYP3A4. [32] Toxicity in clinical trials manifests as: • bone marrow suppression • hypersensitivity • cardiovascular abnormalities • neurotoxicity • arthralgias and myalgias • alopecia • gastrointestinal upset. Junctional tachycardia via conduction block rather than direct primary toxicity on myocytes has been suggested. fluid retention syndrome are minimized with a 3–5 day corticosteroid regime prior to paclitaxel infusions. [34]
[33]
Hypersensitivity, skin reactions and accumulated
Leukemia patients treated with high doses of paclitaxel exhibited mucositis, which also appeared in response to lower, cumulative dosing. An accumulation of epidermal cells with paclitaxel-induced asters has been evident in ulcerated mucosa, indicating that the cell cycle was arrested in mitosis. [35] Paclitaxel has been known to inhibit neurite growth and induce prominent morphological effects, such as microtubule bundles in neurons, in satellite cells and in Schwann cells in organotypic dorsal root ganglion cultures. [36] [37] [38] [39] [40] [41] Clinically, the most common symptoms have been glove-and-stocking paresthesia and perioral numbness. Distal sensory loss to large- (proprioception, vibration) and small-fiber (pin-prick, temperature) modalities and lost or decreased distal deep tendon reflexes have been noted, although motor nerves seem to be spared. In general, the clinical incidence and severity of peripheral neurotoxicity have been dose-related. Patients with a history of substantial alcohol use have appeared to be more predisposed to the development of neurosensory toxic effects of cisplain and paclitaxel.[17] [18] [19] [20] [42] [43] [44] The development of a suitable clinical formulation has been hampered by paclitaxel’s poor aqueous solubility. Cremophor is being used as the vehicle for administration and has been implicated in side-effects such as type 1 hypersensitivity reactions. [45] Neutropenia is the principle dose-limiting toxic effect of paclitaxel and resolves rapidly (15–21 days) after treatment is stopped. [42] The major clinical risk factor for neutropenia seems to be the extent of prior myelotoxic chemotherapy and/or irradiation. Bradyarrhythmias, which have been noted as transient and asymptomatic, have been reported during paclitaxel infusions in at least 29% of ovarian cancer patients, as reported by Mcguire et al. [42] This appears to be more related to paclitaxel, as other agents formulated with Cremophor have not been associated with similar arrhythmias. Atypical chest pains during paclitaxel infusion have been observed, but they are believed to be a manifestation of a hypersensitivity reaction. [29] [43] Other paclitaxel or Cremophor-related side-effects include sudden and complete alopecia – often occurring in a single day – local venous toxic effects such as erythema, tenderness and cellulitis in areas of dermal extravasation, fatigue, headaches, taste perversions, significant elevations in serum triglyceride levels, and minor elevations in hepatic and renal functions. [24] Lipid-coated microbubbles may be an effective way of providing selective affinity for tumor cells, thus reducing systemic effects while maintaining antitumor actions. Additional precautions may be necessary with TABLE 116-2 -- Medications which interact with paclitaxel [47] • Amphotericin B by injection (e.g. Fungizone) • Antithyroid agents • Azathioprine (e.g. Imuran) • Chloramphenicol (e.g. Chloromycetin) • Colchicine • Flucytosine (e.g. Ancobon) • Ganciclovir (e.g. Cytovene) • Interferon (e.g. Intron A, Roferon A) • Plicamycin (e.g. Mithracin) • Zidovudine (e.g. AZT, Retrovir)
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the concurrent use of the medications listed in Table 116.2 . Medical problems which may affect the use of paclitaxel are listed in Table 116.3 . Studies in rats and rabbits have shown that taxol causes miscarriages and fetal deaths. Breast-feeding is contraindicated while receiving paclitaxel. [47] TABLE 116-3 -- Medical problems which may affect the use of paclitaxel • Chickenpox • Herpes zoster • Cardiac arrythmias • Infection
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J, Henkart M, Klausner R, Sandoval IV: role of microtubules in the distribution of the Golgi apparatus. taxol and microinjected anti-alpha-tubulin antibodies. Proc Nat Acad Sci USA 1983; 80: 4286–4290 10.
Rowinsky EK, Donehower RC, Jones RJ et al Microtubule changes and cytotoxicity in leukemic cell lines created with taxol. Cancer Res 1988; 48: 4093–4100
Debrabander M, Geuens G, Nuuydens R et al. Taxol induces the assembly of free microtubules in living cells and blocks the organizing capacity of the centrosome and kinetochores. Proc Nat Acad Sci USA 1981; 78: 5608–5612 11.
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Lanni JS, Lowe SW, Licitra EJ et al. p53-independent apoptosis induced by paclitaxel through an indirect mechanism. Proc Natl Acad Sci USA 1997; 94: 9679–9683
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Kimura Y, Furuhata T, Shiratsuchi T et al. GML sensitizes cancer cells to taxol by induction of apoptosis. Oncogene 1997; 15: 1369–1374
Distefano M, Scambia G, Ferlini C et al. Anti-proliferative activity of a new class of taxanes (14-beta-hydroxy-10–deacetylbaccatin III derivatives) on multidrug-resistance-positive human cancer cells. Int J Cancer 1997; 72: 844–850 16.
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Koeller J, Brown T, Havlin K et al. A phase I/pharmacokinetic study of taxol given by prolonged infusion without premedication Proc ASCO 1989; 8: 82
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Donehower RC, Rowinsky EK, Grochow LB et al. Phase I trial of taxol in patients with advanced cancer. Cancer Treat Rep 1987; 71: 1171–1177
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Wiernik PH, Schwartz EL, Strauman JJ et al. Phase I clinical and pharmacokinetic study of taxol. Cancer Res 1987; 47: 2486–2493
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Wiernik PH, Schwartz EL, Einzig A et al. Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma. J Clin Oncol 1987; 5: 1232–1239
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Legha SS, Tenney DM, Krakoff IR. Phase I study of taxol using a 5-day intermittent schedule. J Clin Oncol 1986; 4: 762–766
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Grem JL, Tutsch KD, Simon KJ et al. Phase I study of taxol administered as a short i.v. infusion daily for 5 days. Cancer Treat Rep 1987; 71: 1179–1184
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Ohnuma T, Zimet AS, Coffey VA et al. Phase I study of taxol in a 24-hour infusion schedule. Proc Am Assoc Cancer Res 1985; 26: 662
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Kris MG, O’Connell JP, Gralla RJ et al. Phase I trial of taxol given as a 3-hour infusion every 21 days. Cancer Treat Rep 1986; 70: 605–607
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Thigpen T, Blessing J, Ball H et al. Phase II trial of taxol as second-line therapy for ovarian carcinoma: a gynecologic oncology group study. Proc ASCO 1990; 9: 604
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Riondel J, Jacrot M, Nissou MF et al. Antineoplastic activity of two taxol derivatives on an ovarian tumor xenografted into nude mice. Anticancer Res 1988; 8: 387–390
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Masurovsky EB, Peterson ER, Crain SM et al. Morphological alterations in dorsal root ganglion neurons and supporting cells of organotypic mouse spinal cord-ganglion cultures exposed to taxol. Neuroscience 1983; 10: 491–509 38.
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Letourneau PC, Ressler AH. Inhibition of neurite initiation and growth by taxol. J Cell Biol 1984; 98: 1355–1362
40.
Letourneau PC, Shattuck TA, Ressler AH. Branching of sensory and sympathetic neuritis in vitro is inhibited by treatment with taxol. J Neuroscience 1983; 10: 491–509
41.
Roytta M, Horwitz SB, Raine CS. Taxol-induced neuropathy: short-term effects of local injection. J Neurocytol 1984; 13: 685: 701
42.
Mcguire WP, Rowinsky EK, Rosenshein NB et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989; 111: 373–379
43.
Rowinsky EK, Burke PJ, Karp JE et al. Phase I and pharmacodynamic study of taxol in refractory acute leukemias. Cancer Res 1989; 49: 4640–4647
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44.
Burgoyne RD, Cumming R. Taxol stabilizes synaptosomal microtubules without inhibiting acetylcholine release. Brain Res 1983; 280: 190–193
45.
Laussus M, Scott D, Leyland-Jones B. Allergic reactions (ar) associated cremophor (c) containing antineoplastic (anp). Proc ASCO 1985; 4: 1042
46.
Ho SY, Barbarese E, D’Arrigo JS et al. Evaluation of lipid-coated microbubbles as a delivery vehicle for Taxol in brain tumor therapy. Neurosurgery 1997; 40: 1260–1266
47.
US Pharmacopeia, Rockville, MD. Drug interactions, vol. II. 1997: p 1237–1238
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Chapter 117 - Uva ursi (bearberry) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Arctostaphylos uva ursi (family: Ericaceae) Common names: bearberry, upland cranberry
GENERAL DESCRIPTION Uva ursi is a small evergreen shrub found in the northern US and in Europe. A single long, fibrous main root sends out several prostate or buried stems 4–6 inches high. The bark is dark brown, the leaves are obovate to spatulate 0.5–1 inch long, the flowers are pink or white growing in sparse terminal clusters, and the fruit is a bright red or pink.
CHEMICAL COMPOSITION Uva ursi’s most active ingredient is arbutin, which typically composes 7–9% of the leaves. Other constituents include: • tannins (6–7%) • flavonoids (quercetin) • allantoin • gallic and ellagic acids • volatile oils • a resin (urvone). [1] [2]
HISTORY AND FOLK USE This plant has a long history of use for its diuretic and astringent properties. Conditions for which it was used include chronic cystitis, nephritis, kidney stones, and bronchitis.[1]
PHARMACOLOGY Antimicrobial
Although pharmacological research has primarily focused on arbutin, the pharmacology of the whole plant is different from that of just arbutin alone. The crude plant extracts are much more effective medicinally than the
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isolated constituent arbutin. This appears to be related to the activity of gallic acid, which prevents the splitting of arbutin by such enzymes as beta-glucosidase. [2] Arbutin undergoes hydrolysis to produce its aglycone, hydroquinone, which has urinary antiseptic properties. [3] This hydrolysis of arbutin is responsible for much of the therapeutic effect of uva ursi.[1] [3] By preventing the splitting of arbutin, the flavonoid components allow more arbutin to be hydrolyzed than when arbutin is administered as an isolated component. Arbutin alone has been reported to be an effective urinary antibiotic, but only if taken in large doses and if the urine is alkaline (once again documenting the value of whole plant medicines). [1] It is reported to be active against Candida albicans and S. aureus, and especially active against E. coli.[4] Uva ursi also has diuretic properties. [1] Anti-inflammatory effects
Some early animal research is now showing that arbutin, and possibly other constituents of uva ursi, potentiate the activity of commonly prescribed anti-inflammatory drugs. One study found that an aqueous extract increased the inhibitory activity of dexamthasone in allergic and inflammatory models without increasing any of the side-effects.[5] Similar results have been demonstrated with isolated arbutin when combined with indomethacin. [6] Inhibition of melanin synthesis
Another recently discovered property of uva ursi is the inhibition of tyrosinase by a 50% alcoholic extract. [7] This effect impairs melanin synthesis, which leads the authors to suggest it could be used as a whitening agent for the skin. However, no clinical trials have been reported.
CLINICAL APPLICATIONS Crude extracts are widely used in Europe as components in certain diuretic and laxative products, but the major use of uva ursi is as a urinary disinfectant in cases of urinary tract infection. [1] Uva ursi is reported to be especially active against E. coli.[3] It can be used in both the acute treatment and the prevention of recurrent cystitis. In one double-blind study, the prophylactic effect of a standardized uva ursi extract compared to a placebo on recurrent cystitis was evaluated in 57 women. [8] At the end of one year, 5/27 women in the placebo group had a recurrence while 0/30 women receiving uva ursi extract had a recurrence. No side-effects were reported in either group. These impressive results indicate that regular use of uva ursi is a safe and effective measure to prevent recurrent cystitis.
DOSAGES • Dried leaves or as an infusion: 1.5 to 4.0 g (1 to 2 tsp) • Freeze-dried leaves: 500 to 1,000 mg • Tincture (1:5): 4 to 6 ml (1 to 1.5 tsp) • Fluid extract (1:1): 1 to 2 ml (¼ to ½ tsp)
• Powdered solid extract (10% arbutin): 250 to 500 mg
TOXICOLOGY The toxicology of uva ursi is proportional to the conversion of arbutin to hydroquinone. Hydroquinone has been shown to be toxic at 1 g (equivalent to approximately 0.5 ounce of the fresh leaves), with signs and symptoms of: [2] • tinnitus • nausea • vomiting • sense of suffocation • shortness of breath • cyanosis • convulsions • delirium • collapse.
REFERENCES 1. Leung
A. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York, NY: John Wiley. 1980: p 316–317
2. Merck
Index, 10th edn. Rahway, NJ: Merck. 1983: p 112–113, 699
3. Frohne
V. Untersuchungen zur frage der harndesifizierenden wirkungen von barentraubenblatt-extracten. Planta Medica 1970; 18: 1–25
4. Mitchell
W. Naturopathic applications of the botanical remedies. Seattle, WA. 1983: p 8
5. Matsuda
H, Nakamura S, Tanaka T, Kubo M. Pharmacological studies on leaf of Arctostaphylos uva-ursi (L.) Spreng. V. Effect of water extract from Arctostaphylos uva-ursi (bearberry) on the antiallergic and antiinflammatory activities on dexamethasone ointment. Yakugaku Zasshi 1994; 112: 673–677 6. Matsuda
H, Tanaka T, Kubo M. Pharmacological studies on leaf of Arctostaphylos uva-ursi (L.) Spreng. III. Combined effect of arbutin and indomethacin on immuno-inflammation. Yakugaku Zasshi 1991; 111: 256–258 7. Matsuda 8. Larsson
H, Higashino M, Nakai Y et al. Studies of cutical drugs from natural sources. IV. Inhibitory efffects of Arctostaphylos plants on melanin biosynthesis. Biol Pharm Bull 1996; 19: 153–156 B, Jonasson A, Fianu S. Prophylactic effect of UVA-E in women with recurrent cystitis: A preliminary report. Curr Ther Res 1993; 53: 441–443
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Chapter 118 - Vaccinium myrtillus (bilberry) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Vaccinium myrtillus (family: Ericaceae) Common names: bilberry, huckleberry, European blueberry, whortleberry, blueberry
GENERAL DESCRIPTION The genus Vaccinium in the family Ericaceae comprises nearly 200 species, most of which are found in the Northern Hemisphere. This chapter focuses on Vaccinium myrtillus and the medicinal use of extracts of its fruit. Vaccinium myrtillus, or bilberry, is a shrubby perennial plant that grows in the sandy areas of the northern US and in the woods and forest meadows of Europe. The angular, green, branched stem grows from a creeping rootstock to a height of 1–1.5 feet. The 0.5–1.0 inch long leaves are oval, slightly dentate, and bright green, while the flowers are reddish- or greenish-pink and bell-shaped. The flowering season is April–June. The fruit is a blue-black berry. [1]
CHEMICAL COMPOSITION The pharmacologically active constituents of bilberries are its flavonoid components, specifically its anthocyanosides. Anthocyanosides are composed of an aglycone (e.g. anthocyanidin) bound to one of three glycosides (arabinoside, glucoside, or galactoside). Over 15 different anthocyanosides originate from the five aglycones found in Vaccinium myrtillus (see Fig. 118.1 ).[2] Other members of the genus Vaccinium, as well as Ribes nigrum (black- currant) and Vitis vinifera (grape), contain similar anthocyanosides. [3] Extracts of these fruits are also used for medicinal purposes in Europe. The concentration of anthocyanosides in the fresh fruit is approximately 0.1–0.25%, while concentrated extracts of Vaccinium myrtillus are produced which yield an anthocyanidin content of 25%. [2] An extract with an anthocyanidin content of 25% actually contains about 37% anthocyanosides due to the conjugation of the anthocyanidin with a glycoside. (For analytical purposes, the
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Figure 118-1 Structures of V. myrtillus anthocyanins [2] Glyc. = arabinoside, glucoside or galactoside
anthocyanosides content should always be expressed in terms of anthocyanidin.) Only very small amounts of free anthocyanidins exist in nature and in V. myrtillus extracts.
HISTORY AND FOLK USE Bilberries have, of course, been used as food and for their high nutritive value. Medicinally, they have been utilized in the treatment of scurvy and urinary complaints (including infection and stones). [1] The dried berries have been used primarily for their astringent qualities in the treatment of diarrhea and dysentery. Decoctions of the leaves have been used in the treatment of diabetes. [1]
PHARMACOLOGY The pharmacology of Vaccinium myrtillus is discussed almost entirely in relationship to its anthocyanoside content, as research has focused primarily on the anthocyanosides. Collagen-stabilizing action
Anthocyanosides possess significant collagen-stabilizing action. [4] [5] [6] [7] [8] [9] [10] Collagen, the most abundant protein of the body, is responsible for maintaining the integrity of “ground substance” as well as tendons, ligaments, and cartilage. Collagen is destroyed during the inflammatory processes that occur in rheumatoid arthritis, periodontal disease, and other inflammatory conditions involving bones, joints, cartilage, and other connective tissue. Anthocyanidins, proanthocyanidins and other flavonoids are remarkable in their ability to prevent collagen destruction. The anthocyanidins in Vaccinium myrtillus extracts have been shown to affect collagen metabolism in several ways: • Anthocyanosides cross-link collagen fibers, resulting in strengthening of the natural cross-linking of collagen that forms the collagen matrix of connective tissue (ground substance, cartilage, tendon, etc.). [4] [5] [6] [7] [8] • Anthocyanosides prevent free radical damage with their potent antioxidant and free radical scavenging action. [4] [5] [6] [7] [9] • Anthocyanosides inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation. [4] [5] [6] [8] [9] [10] • Anthocyanosides and other flavonoid components of V. myrtillus prevent the release and synthesis of compounds that promote inflammation, such as histamine, serine proteases, prostaglandins, and leukotrienes. [4] [5] [6] [11] [12] • Anthocyanosides promote mucopolysaccharide and collagen biosynthesis and stimulate reticulation of collagen fibrils. [13] [14] [15] Normalization of capillary permeability
Anthocyanosides have strong “vitamin P” activity. [4] Included in their effects are an ability to increase intracellular vitamin C levels and to decrease capillary permeability and fragility. [4] [5] [6] Their effect in reducing capillary fragility and permeability is roughly twice that of rutin, in both intensity and duration of action.
[16]
Vaccinium myrtillus extracts have been widely used in Europe in the treatment of various arterial, venous, and capillary disorders. Clinical studies have demonstrated
a positive effect in the treatment of: [17] [18] [19] [20] [21] [22] • capillary fragility • blood purpuras • various encephalic circulation disturbances (similar to Ginkgo biloba) • venous insufficiency • varicose veins • microscopic hematuria caused by diffused and kidney capillary fragility. V. myrtillus’s efficacy in the treatment of a variety of venous disorders relates to the ability of anthocyanosides to protect altered veins (postphlebotic veins as well as varicose veins) via two mechanisms:[15] • increasing the endothelium barrier-effect through stabilization of the membrane phospholipids • increasing the biosynthesis of the acid mucopolysaccharides of the connective ground substance, thus restoring the altered mucopolysaccharide pericapillary sheath. This latter effect leads to a marked increase in newly formed capillaries and collagen fibrils. One interesting effect of the normalization of collagen structures and capillaries is the demonstration that anthocyanosides from Vaccinium myrtillus decrease the permeability of the blood–brain barrier. [8] [23] Increased
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blood–brain permeability has been linked to autoimmune diseases of the central nervous system, schizophrenia, “cerebral allergies”, and a variety of other CNS disorders. Presumably, the anthocyanosides inhibit both enzymatic and non-enzymatic degradation of the basement membrane collagen of brain capillaries, thus helping to maintain or restore the brain’s protection from drugs, pollutants, naturally occurring degradation products, and other cerebral toxins. [7] [8] [9] [10] [23] Another recent study further demonstrates the remarkable efficacy of bilberry in protecting and strengthening the capillaries and microcirculation. In this study, the effects of anthocyanidins on hamster cheek microcirculation were investigated after ischemia and reperfusion. The treated group had decreased adherence of leukocytes to the venules after reperfusion, resulting in prevention of the markedly increased capillary permeability seen in the placebo group. [24] Anti-aggregation effect on platelets
Anthocyanosides, like many other flavonoids, have been shown to possess significant anti-aggregation effects on platelets. [25] [26] [27] Their action in vivo appears to be direct anti-aggregation effects on the platelets and an indirect effect via prostacyclin-like action. [25] [26] [27] Prostacyclin (PGI2 ) is a potent stimulator of adenyl cyclase, the enzyme which catalyzes the production of cAMP from ATP. cAMP prevents platelets from aggregating and adhering to the endothelial surface. Smooth muscle relaxing activity
Anthocyanoside extracts have demonstrated significant vascular smooth muscle-relaxing effects in a variety of experimental models. [28] [29] [30] The clinical application of this research may be in the treatment of dysmenorrhea, for which a preliminary study has demonstrated positive effects. [31]
CLINICAL APPLICATIONS The primary clinical application of bilberry extracts has been in the prevention and treatment of a diverse group of disorders of the eye and vision. However, the same mechanisms of action which benefit the eye are of value to other health problems, especially those involving capillary dysfunction or inflammation. Ophthalmological applications Night vision
Perhaps the most significant clinical applications for Vaccinium myrtillus extracts are in the field of ophthalmology. Interest in V. myrtillus anthocyanosides was first aroused when it was observed that the administration of bilberry extracts to healthy subjects resulted in improved night-time visual acuity, quicker adjustment to darkness, and faster restoration of visual acuity after exposure to glare. [32] [33] Further studies confirmed these results. [34] [35] [36] [37] Results were most impressive in individuals with pigmentary retinitis and hemeralopia. (Hemeralopia refers to “day blindness” or an inability to see as distinctly in bright light as in dim light.) It appears that, in addition to their effect on capillaries, V. myrtillus anthocyanosides have an affinity for the pigmented epithelium of the retina, which composes the optical or functional part of the retina. [38] This is consistent with several of the clinical effects observed. Anthocyanoside extracts of V. myrtillus appear to be of great value in both poor night vision and poor day vision. Glaucoma
Vaccinium myrtillus may play a significant role in the prevention and treatment of glaucoma via its effect on collagen structures in the eye. In the eye, collagen provides tensile strength and integrity to the tissues, i.e. cornea, sclera, lamina cribosa, trabecular meshwork, vitreous, etc. Morphological changes in the collagen of the eye precede clinically detectable abnormalities. These changes may result in elevated intraocular pressure (IOP) readings or, perhaps more significantly, the progression of peripheral vision loss. Changes in collagen structure would explain why there is: • similar peripheral vision loss in patients with normal and elevated IOP • cupping of the optic disc even at low IOP levels • no apparent anatomical reason for decreased aqueous outflow (see Ch. 153 for complete discussion and references). Therefore, primary prevention of glaucoma involves maintaining ground substance and collagen framework integrity. It appears the prevention of collagen matrix breakdown is important here, as it is in other conditions involving collagen abnormalities, i.e. atherosclerosis, rheumatoid arthritis, and periodontal disease. Vaccinium myrtillus consumption may offer significant protection against the development of glaucoma, due to its collagen-enhancing actions. In addition, anthocyanosides may be of benefit in the treatment of chronic glaucoma, as rutin has been demonstrated to lower IOP when used as an adjunct in patients unresponsive to miotics alone. [39] V. myrtillus anthocyanosides are, in general, much more biologically active than rutin. [16]
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Cataracts and retinal degeneration
Vaccinium myrtillus anthocyanosides may offer significant protection against the development of retinal (macular) degeneration and cataracts, particularly diabetic retinopathy and cataracts. Both the rate of retinal degeneration and the occurrence of cataracts in rats can be retarded by changing their diet from a commercial laboratory chow to a “well-defined diet”. [40] [41] Preliminary research suggests that flavonoid components in the well-defined diets may be responsible for the protective effects against cataracts and retinal degeneration. [42] Limited research has shown that, when combined with vitamin E, bilberry significantly slowed the progression of senile cataracts in humans. [43] Vaccinium myrtillus anthocyanoside extracts are widely used in Europe in the prevention of diabetic retinopathy. [43] [44] [45] The positive effects noted in clinical trials may be due to improved capillary integrity as well as inhibition of sorbitol production (see Ch. 147 ). Flavonoids have been shown to be potent in vitro and in vivo inhiitors of sorbitol accumulation. In laboratory experiments they have been shown capable of inhibiting the development of diabetic cataracts. [46] [47] [48] Other clinical applications Diabetes mellitus
A decoction of blueberry leaves has a long history of folk use in the treatment of diabetes. This use is supported by research, which has shown that oral administration reduces hyperglycemia in normal and depancreatized dogs, even when glucose is concurrently injected intravenously. [45] [49] The anthocyanoside myrtillin (3-glucoside of delphinidin) is apparently the most active hypoglycemic component of V. myrtillus. Upon injection, it is somewhat weaker than insulin, but it is also less toxic, even at 50 times the 1 g/day therapeutic dose. It is of interest to note that a single dose can produce beneficial effects lasting for several weeks. [45] The most important benefits from use of anthocyanosides in the treatment of diabetes, however, relate to their ability to improve collagen integrity and capillary permeability. Benefit also possibly derives from their ability to inhibit sorbitol accumulation, thus providing protection from the serious vascular and neurological sequelae of diabetes. Vaccinium myrtillus anthocyanosides have also been shown to have a protective effect on capillary fragility in diabetics and to reduce serum cholesterol and triglyceride levels in primary dyslipidemia. [50] Although studies in rabbits have not confirmed a cholesterol-lowering effect, the anthocyanosides significantly decrease the proliferation of the intima, extracellular matrix production, and calcium and lipid deposition found in the aorta of untreated atherosclerotic rabbits. Presumably, this is a result of increasing collagen cross-linking, thus diminishing the permeability in small, as well as in large, blood vessels. [51] Inflammatory joint disease
The effects of anthocyanosides on collagen structures and their potent antioxidant activity make V. myrtillus anthocyanoside extracts very useful in the treatment of a wide variety of inflammatory conditions, most notably rheumatoid arthritis. Bioflavonoids have been found to increase collagen synthesis and inhibit collagen catabolism in rats with adjuvant-induced arthritis (a chronic progressive polyarthritis with some similarities to rheumatoid arthritis). [13] Blueberries, like cherries, are particularly indicated in the treatment of gout, as their flavonoid components are able to reduce both uric acid levels and tissue destruction (see Ch. 154 ). [52] Microscopic hematuria
The effect of V. myrtillus in the reduction of microscopic hematuria may be reflective of its tissue distribution. Pharmacokinetic studies in rats have demonstrated an affinity for the skin and kidneys. [53] Anthocyanosides’ affinity for these tissues reflects the high concentration of collagen and mucopolysaccharides in the skin and kidneys and the fact that they are excreted via the kidneys.
DOSAGE The standard dose for V. myrtillus is based on its anthocyanoside content, as calculated by its anthocyanidin percentage. Widely used pharmaceutical preparations in Europe are typically standardized for a 25% anthocyanidin content. Dosages are as follows: • anthocyanosides (calculated as anthocyanidin):20–40 mg three times/day • Vaccinium myrtillus (25% extract): 80–160 mg three times/day • fresh berries: 55–115 g three times/day.
TOXICOLOGY Extensive toxicological investigation has demonstrated that V. myrtillus anthocyanoside extracts are devoid of toxic effects. Administration to rats of dosages as high as 400 mg/kg produces no apparent side-effects, and excess levels are quickly excreted through the urine and bile. [16] [24]
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SUMMARY Vaccinium myrtillus anthocyanosides exhibit significant pharmacological activity, particularly on collagen structures. Research has demonstrated a positive effect in the treatment of: • capillary fragility • blood purpuras • various encephalic circulation disturbances • venous insufficiency • varicose veins • microscopic hematuria caused by diffused and kidney capillary fragility • poor night vision • hemeralopia • diabetic retinopathy. Experimental studies indicate that anthocyanoside should also be useful in most inflammatory or degenerative conditions involving connective tissues (e.g. osteoarthritis, gout, rheumatoid arthritis, periodontal disease, etc.), glaucoma, diabetes, cataracts, retinal degeneration, and schizophrenia.
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1. Grieve
M. A modern herbal, vol. 1. New York, NY: Dover Publications. 1971: p 385–386
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A, Bombardelli E, Gabetta B, Martinelli EM. Qualitative and quantitative evaluation of chromatography. J Chromatogr 1983; 279: 365–372 3. Andersen 4. Kuhnau 5. Gabor
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OM. Anthocyanins in fruits of Vaccinium uliginosum L. (bog whortleberry). J Food Sci 1987; 52: 665–666, 680
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JC, Braquet P, Randoux A, Borel JP. Non-enzymatic degradation of acid-soluble calf skin collagen by superoxide ion. Protective effect of flavonoids. Biochem Pharmacol 1983; 32:
53–58 8. Detre
A, Jellinek H, Miskulin M, Robert AM. Studies on vascular permeability in hypertension. Action of anthocyanosides. Clin Physiol Biochem 1986; 4: 143–149
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JC, Braquet P, Borel JP. Oxygen-free radicals as mediators of collagen breakage. Agents Actions 1984; 15: 49–50
Jonadet M, Meunier MT, Bastide J, Bastide P. Anthocyanosides extracted from Vitis vinifera, Vaccinium myrtillus and Pinus maritimus. I. Elastase-inhibiting activities in vitro. II. Compared angioprotective activities in vivo. J Pharm Belg 1983; 38: 41–46 10.
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Middleton E. The flavonoids. Trends in Phramaceutical Science 1984; 5: 335–338
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Amella M, Bronner C, Briancon F et al. Inhibition of mast cell histamine release by flavonoids and biflavonoids. Planta Medica 1985; 51: 16–20
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Rao CN, Rao VH, Steinman B. Influence of bioflavonoids on the collagen metabolism in rats with adjuvant induced arthritis. Ital J Biochem 1981; 30: 54–62
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Ronziere MC, Herbage D, Garrone R, Frey J. Influence of some flavonoids on reticulation of collagen fibrils in vitro. Biochem Pharmacol 1981; 30: 1771–1776
Mian E, Curri SB, Lieti A, Bombardelli E. Anthocyanosides and the walls of the microvessels. Further aspects of the mechanism of action of their protective effect in syndromes due to abnormal capillary fragility. Minerva Med 1977; 68: 3565–3581 15.
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Lietti A, Forni G. Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and anti-inflammatory activity. Arzneim Forsch 1976; 26: 829–832
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Ghiringhelli C, Gregoratti F, Marastoni F. Capillarotropic activity of anthocyanosides in high doses in phlebopathic stasis. Min Cardioangiol 1978; 26: 255–276
Treviso A. Therapeutic value of the association of anthocyanin glucosides with glutamine and phosphorylserine in the treatment of learning disturbances at different ages. Gazz Med Ital 1979; 138: 217–232 18.
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Grismond GL. Treatment of pregnancy-induced phlebopathies. Minerva Ginecol 1981; 33: 221–230
Piovella F, Almasio P, Ricetti MM, Trpin L, Cavanna L. Results with anthocyanidins in the treatment of haemorrhagic diathesis due to defective primary haemastasis. Gazz Med Ital 1981; 140: 445–449 20.
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Pennarola R, Roco P, Matarazzo G et al. The therapeutic action of the anthocyanosides in microcirculatory changes due to adhesive-induced polyneuritis. Gazz Med Ital 1980; 139: 485–491
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Amouretti M. Therapeutic value of Vaccinium myrtillus anthocyanosides in an internal medicine department. Therapeutique 1972; 48: 579–581
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Robert AM, Godeau G, Moati F, Miskulin M. Action of the anthocyanosides of Vaccinium myrtillus on the permeability of the blood brain barrier. J Med 1977; 8: 321–332
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Bertuglia S, Malandrino S, Colantuoni A. Effect of Vaccinium myrtillus anthocyanoside on ischemia reperfusion injury in hamster cheek pouch microcirulcation. Pharmacol Res 1995; 31: 183–187
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Zaragoza F, Iglesias I, Benedi J. Comparison of thrombocyte antiaggregant effects of anthocyanosides with those of other agents. Arch Pharmacol Toxicol 1985; 11: 183–188
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Morazzoni P, Magistretti MJ. Effects of Vaccinium myrtillus anthocyanosides on prostacyclin like activity in rat arterial tissue. Fitoterapia 1986; 57: 11–14
Bottecchia D, Bettini V, Martino R, Camerra G. Preliminary report on the inhibitory effect of Vaccinium myrtillus anthocyanosides on platelet aggregation and clot retraction. Fitoterapia 1987; 48: 3–8 27.
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Bettini V, Mavellaro F, Ton P, Zanella P. Effects of Vaccinium myrtillus anthocyanosides on vascular smooth muscle. Fitoterapia 1984; 55: 265–272
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Bettini V, Mavellaro F, Patron E et al. Inhibition by Vaccinium myrtillus anthocyanosides of barium-induced contractions in segments of internal thoracic vein. Fitoterapia 1984; 55: 323–327
30.
Bettini V, Mayellaro F, Pilla I et al. Mechanical responses of isolated coronary arteries to barium in the presence of Vaccinium myrtillus anthocyanosides. Fitoterapia 1985; 56: 3–10
31.
Colombo D, Vescovini R. Controlled clinical trial of anthocyanosides from Vaccinium myrtillus in primary dysmenorrhea. G Ital Obstet Ginecol 1985; 7: 1033–1038
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Jayle GE, Aubert L. Action des glucosides d’anthocyanes sur la vision scotopique et mesopique du sujet normal. Therapie 1964; 19: 171–185
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Terrasse J, Moinade S. Premiers resultats obtenus avec un nouveau facteur vitamininique P ‘les anthocyanosides’ extraits du Vaccinium myrtillus. Presse Med 1964; 72: 397–400
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Sala D, Rolando M, Rossi PL, Pissarello L. Effect of anthocyanosides on visual performances at low illumination. Minerva Oftalmol 1979; 21: 283–285
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Gloria E, Peria A. Effect of anthocyanosides on the absolute visual threshold. Ann Ottalmol Clin Ocul 1066; 92: 595–607
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Junemann G. On the effect of anthocyanosides on hemeralopia following quinine poisoning. Klin Monatsbl Augenheilkd 1967; 151: 891–896
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Caselli L. Clinical and electroretinographic study on activity of anthocyanosides. Arch Med Int 1985; 37: 29–35
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Wegmann R, Maeda K, Tronche P, Bastide P. Effects of anthocyanosides on photoreceptors. Cytoenzymatic aspects. Ann Histochim 1969; 14: 237–256
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Stocker F. New ways of influencing the intraocular pressure. NY St J Med 1949; 49: 58–63
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Pautler EL, Ennis SR. The effect of diet on inherited retinal dystrophy in the rat. Curr Eye Res 1984; 3: 1221–1224
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Hess H, Knapka JJ, Newsome DA et al. Dietary prevention of cataracts in the pink-eyed RCS rat. Lag Anim Sci 1985; 35: 47–53
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Pautler EL, Maga JA, Tengerdy C. A pharmacologically potent natural product in the bovine retina. Exp Eye Res 1986; 42: 285–288
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Bravetti G. Preventive medical treatment of senile cataracts with vitamin E and anthocyanosides. Clinical evaluation. Ann Ottalmol Clin Ocul 1989; 115: 109
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Scharrer A, Ober M. Anthocyanosides in the treatment of retinopathies. Klin Monatsbl Augenheilkd 1981; 178: 386–389
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Bever B, Zahnd G. Plants with oral hypoglycemic action. Quart J Crude Drug Res 1979; 17: 139–196
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Chaundry PS, Cambera J, Juliana HR, Varma SD. Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethacin. Biochem Pharmacol 1983; 32: 1995–1998
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Varma SD, Mizuno A, Kinoshita JH. Diabetic cataracts and flavonoids. Science 1977; 195: 87–89
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Varma SD, El-aguizy HK, Richards RD. Refractive change in alloxan diabetic rabbits control by flavonoids I. Acta Ophthalmol 1980; 58: 748–759
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Allen FM. Blueberry leaf extract. Physiologic and clinical properties in relation to carbohydrate metabolism. JAMA 1927; 89: 1577–1581
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Passariello N, Bisesti V, Sgambato S. Influence of anthocyanosides on the microcirculation and lipid picture in diabetic and dyslipidic subjects. Gazz Med Ital 1979; 138: 563–566
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Kadar A, Robert L, Miskulin M et al. Influence of anthocyanoside treatment on the cholesterol-induced atherosclerosis in the rabbit. Paroi Arterielle 1979; 5: 187–206
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Chapter 119 - Valeriana officinalis (valerian) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Valeriana officinalis (family: Valerianaceae) Common names: valerian, all heal
GENERAL DESCRIPTION Valerian is a perennial plant native to North America and Europe. The yellow-brown tuberous rootstock produces a flowering stem 2–4 feet high. The stem is round, but grooved and hollow, with leaves arranged in pairs. The small rose-colored flowers are in bloom from June to September. The rootstock is the portion used medicinally.
CHEMICAL COMPOSITION The important active compounds of valerian are the valepotriates (iridoid molecules; see Fig. 119.1 ) and valerenic acid. These compounds are found exclusively in valerian. Originally it was thought that just the valepotriates were responsible for valerian’s sedative effects, but recently an aqueous extract of valerian has also been shown to have a sedative effect. Since the valepotriates are not soluble in water, it was concluded that valerenic acid also possesses sedative action and is the chemical factor responsible for the sedative effect noted in human clinical trials with aqueous extracts of valerian root (see below).
Figure 119-1 Valepotriates in Valeriana officinalis.
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Moreover, because the safety of valepotriates was questioned after studies demonstrated mutagenicity, most commercial extracts feature water-soluble extracts standardized for valerenic acids. [1] [2] [3] Other components of valerian include a volatile oil (0.5–2%), choline (3%), flavonoids, sterols, and several alkaloids (actinidine, valerianine, valerine, and chatinine).
[ 1]
HISTORY AND FOLK USE Valerian’s primary traditional use has been as a sedative for the relief of insomnia, anxiety, and conditions associated with pain. Specific conditions for which it was used include migraine, insomnia, hysteria, fatigue, intestinal cramps, and other nervous conditions.
PHARMACOLOGY Valerian has demonstrated a number of pharmacological effects including: [4] [5] [6] [7] • normalizing of the central nervous system (it acts as a sedative in states of agitation and a stimulant in cases of extreme fatigue) • lowering of blood pressure • enhancement of the flow of bile (choleretic effect) • relaxing intestinal muscles • antitumor and antibiotic activity. Its prime pharmacological effect, however, is consistent with its historical use as a sedative. A recent pharmacological study indicated that both valepotriates and valerenic acid are capable of binding to GABA receptors in a similar fashion to benzodiazepines. [8] However, valerian does not appear to act in a similar fashion, in that side-effects such as impaired mental function, morning hangover, and dependency have not been reported with valerian. In addition, valerian compounds which do not bind to GABA receptors have also been shown to produce sedative effects.
CLINICAL APPLICATIONS The primary clinical application for valerian is as a sedative in the treatment of insomnia. It can also be used in the treatment of stress and anxiety. Insomnia
Several recent clinical studies have substantiated valerian’s ability to improve sleep quality and relieve insomnia.
[9] [ 10] [11] [ 12] [13]
The first studies were performed on subjects who did not have insomnia. In the first double-blind study involving 128 subjects, an extract of valerian root improved subjective ratings for sleep quality and sleep latency (the time required to go to sleep) but left no “hangover” the next morning. [9] In another study, the effects of valerian on sleep were studied in two groups of healthy young subjects. [10] One group slept at home, the other in a sleep laboratory. Sleep was evaluated on the basis of questionnaires, self-rating scales and night-time motor activity. Under home conditions, both doses of an aqueous valerian extract (450 and 900 mg) reduced perceived sleep latency and wake time after sleep onset. Night-time motor activity was enhanced in the middle third of the night and reduced in the last third. The data suggest a dose-dependent effect. In the sleep laboratory, where only the higher dose of valerian was tested, no significant differences from placebo were obtained. However, the direction of the changes in the subjective and objective measures of sleep latency and wake time after sleep onset, as well as in night-time motor activity, corresponded to that observed under home conditions. There was no evidence for a change in sleep stages and EEG spectra. The results indicate that the aqueous valerian extract exerts a mild sedative effect.
While these two studies demonstrated that valerian could improve sleep quality in normal subjects, they failed to answer the question whether valerian could improve sleep patterns in people suffering from insomnia. In a follow-up to these two preliminary studies, valerian extract was shown to significantly reduce sleep latency, improve sleep quality, and reduce night-time awakenings in sufferers of insomnia. [11] This study, performed under strict laboratory conditions, demonstrated that valerian is as effective in reducing sleep latency as small doses of barbiturates or benzodiazepines. However, while these latter compounds also increase morning sleepiness, valerian usually reduces morning sleepiness. In another study of insomniacs, subjects received either a valerian preparation placebo. reporting perfect sleep and 89% reporting improved sleep.
[12]
Compared with the placebo, valerian showed a significant effect, with 44%
And finally, in another double-blind study of insomniacs, 20 subjects received a combination of valerian root (160 mg) and Melissa officinalis (80 mg), a benzodiazepine (triazolam 0.125), or placebo. [13] In the insomniac group, the valerian preparation showed an effect comparable to that of the benzodiazopine, as well as an increase in deep sleep stages 3 and 4. The valerian preparation did not, however, cause daytime sedation and there was no evidence of diminished concentration based on the Concentration Performance Test or impairment of physical performance.
DOSAGE As a mild sedative, valerian may be taken at the following dosages 30–45 minutes before retiring: • dried root (or as tea): 1–2 g • tincture (1:5): 4–6 ml (1–1.5 tsp) 999
• fluid extract (1:1): 1–2 ml (0.5–1 tsp) • solid (dry powdered) extract (4:1): 250–500 mg • valerian extract (1.0–1.5% valtrate or 0.5% valerenic acid): 150–300 mg. For the rare patient with increased morning sleepiness, reducing the dosage will eliminate the problem. For best results, eliminate dietary factors such as caffeine and alcohol which disrupt sleep (see Ch. 164 ).
TOXICITY Valerian is generally regarded as safe and is approved for food use by the United States Food and Drug Administration. [14] A major concern for any sedative or anti-anxiety medication is its potential to affect a person’s ability to drive or operate potentially dangerous machinery. A randomized, placebo-controlled, double-blind study evaluated the impact of a valerian/lemon balm preparation on psychomotor and mental performance tests. [15] No impact was found on reaction time, concentration or attentiveness. One case of valerian overdose has been reported in the literature. [16] The patient presented with mild symptoms, all of which disappeared within 24 hours after taking an overdose of approximately 20 times the recommended therapeutic dose. Since the safety of the valepotriates have been questioned, until there is better information, the best choice is to use water-soluble extracts standardized for valerenic acid content.
REFERENCES 1. Houghton
PJ. The biological activity of Valerian and related plants. J Ethnopharmacol 1988; 22: 121–142
2. von
der Hude W, Scheutwinkel-Reich M, Braun R. Bacterial mutagenicity of the tranquilizing constituents of Valerianaceae roots. Mut Research 1986; 169: 23–27
3. von
der Hude W, Scheutwinkel-Reich M, Braun R. In vitro mutagenicity of valepotriates. Arch Toxicol 1985; 56: 267–271
4. Takeda
S, Endo T, Aburada M. Pharmacological studies on iridoid compounds. III. The choleretic mechanism of iridoid compounds. J Pharm Dyn 1981; 4: 612–623
5. Hendriks
H, Bos R, Allersma DP et al. Pharmacological screening of valerenal and some other components of essential oil of Valeriana officinalis. Planta Medica 1981; 42: 62–68
6. Hazelhoff
B, Malingre TM, Meijer DK. Antispasmodic effects of valeriana compounds. An in vivo and in vitro study on the guinea pig ileum. Arch Int Pharmacodyn 1982; 257: 274–287
7. Bounthanh
C, Bergmann C, Beck JP et al. Valepotriates, a new class of cytotoxic and antitumor agents. Planta Medica 1981; 41: 21–28
8. Mennini
T, Bernasconi P, Bombardelli E et al. In vitro study on the interaction of extracts and pure compounds from Valeriana officinalis roots with GABA, benzodiazepine and barbiturate receptors in rat brain. Fitoterapia 1993; 54: 291–300 9. Leathwood
P, Chauffard F, Heck E et al. Aqueous extract of valerian root ( Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behavior 1982; 17: 65–71
10.
Balderer G, Borbely AA. Effect of valerian on human sleep. Psychopharmacol 1985; 87: 406–409
11.
Leathwood PD, Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Medica 1985; 54: 144–148
12.
Lindahl O, Lindwall L. Double blind study of a valerian preparation. Pharmacol Biochem Behav 1989; 32: 1065–1066
13.
Dressing H, Riemann D, Low H. Insomnia. Are Valerian/Melissa combinations of equal value to benzodiazepine? Therapiewoche 1992; 42: 726–736
14.
Leung A. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York, NY: John Wiley. 1980
15.
Albrecht M, Berger W et al. Psychopharmaceuticals and safety in traffic. Zeits Allegmeinmed 1995; 71: 1215–1221
16.
Wiley LB, Mady SP, Cobaugh DJ, Wax PM. Valerian overdose. A case report. Vet Hum Toxicol 1995; 37: 364–365
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Chapter 120 - Viscum album (European mistletoe) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Viscum album L. (family: Loranthaceae) Common names: European mistletoe, all-heal, birdlime, devil’s fuge
GENERAL DESCRIPTION Viscum album or European mistletoe is an evergreen, semi-parasitic plant found on the branches of deciduous trees in Europe and northern Asia. The roots of the plant penetrate through the bark into the wood of the host tree. The green branches are 1–2 feet long and form pendent bushes with leaves that are opposite, leathery, yellow-green and narrowly obovate. Inconspicuous pale yellow or green flowers appear from March to May, the female developing into sticky white berries which ripen from September to November.[1] [2] Viscum is most commonly seen on old apple, ash, and hawthorn trees. Traditionally, mistletoe from oak has been the most widely used, although it does not grow as well on oak as the previously mentioned trees. [1] [2]
CHEMICAL COMPOSITION Viscum album contains a variety of pharmacologically active substances including alkaloids, polysaccharides, phenylpropanes, lignins, lectins, and viscotoxins. [6] [7] [8] [9] [10] Specific compounds found in viscum include: [ 2] [ 5] [ 6] [10]
[3] [ 4] [ 5]
• a wide range of carbohydrates, including simple sugars as well as polysaccharides • phenolic compounds such as flavonoids, caffeic acid, syringin, and eleutherosides • sterols, including beta-sitosterol, stigmasterol, and triterpenes • various amino acids as well as vasoactive amines, including tyramine, phenylethylamine, and histamine • fatty acids such as linoleic, palmitic, and oleic acids. The alkaloids isolated from viscum appear to be related to those found in the host plant. [3] [4] For example,
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mistletoes growing on solanaceae shrubs contain nicotine alkaloids like hyoscine, anabasine, and isopelletierine; cardiac glycosides have been found in mistletoe growing on Nerium oleander; strychnine has been found in mistletoe growing on Strychnos sp.; and caffeine in mistletoe growing on coffee plants. Since pharmacologically active compounds appear to be concentrated within the mistletoe, different host trees, providing diverse chemical constituents, could be used for different therapeutic action. Also of importance is the fact that the proteins/lectins are present only in aqueous extracts, indicating that therapeutic activity would differ from the alcoholic/ aqueous extracts. The alcoholic/aqueous extracts also demonstrate considerably less toxicity.
HISTORY AND FOLK USE Mistletoe was held in great reverence by the Druids who, dressed in white robes, would search for the sacred plant. When some was discovered, a great ceremony would ensue, culminating in the mistletoe’s separation from the oak with a golden knife. The Druids believed that mistletoe protected them from all evil, and that the oaks on which it was seen growing were to be respected because of the wonderful cures which the priests were able to produce with it. [1] Mistletoe’s use has been recorded in the Middle East, Africa, India, and Japan, and it was mentioned as an anti-cancer drug by Pliny, Dioscorides, and Galen.
[3]
In 1720, an English physician, Sir John Colbatch, extolled the virtues of viscum in a pamphlet entitled The treatment of epilepsy by mistletoe. For many years, mistletoe was used in the treatment of a variety of nervous system disorders, including convulsions, delirium, hysteria, neuralgia, and nervous debility. [1] [3] It has been used in naturopathic medicine in the treatment of hypertension and vascular disorders of the uterus, bladder, and intestines. Probably due to its potential toxicity, viscum use appeared to fall into some disrepute shortly after Colbatch’s work. For many years it was used only in external preparations for the treatment of dermatitis. Then in 1906 a study demonstrating viscum’s hypotensive effect in animals and humans was published. This appears to have restored viscum’s medical prestige, initially in France and eventually throughout Europe. [3]
PHARMACOLOGY Viscum album exhibits diverse pharmacological actions. The herb and various extracts have demonstrated the following activities: • hypotensive • vasodilating • cardiac depressant • sedative • antispasmodic • immunostimulatory • anti-neoplastic. It is interesting to note that purified mistletoe lectins are, in general, not as active in experimental studies as crude preparations. [21] [22] Presumably, there are a number of compounds in viscum which act synergistically. It has also been proposed that alkaloidal components are responsible for the maintenance of lectin structure and activity.[5] During isolation and purification procedures, alkaloidal linkages are cleaved from the lectins, resulting in a loss of specificity for target molecules. Unfermented viscum preparations typically demonstrate a greater direct cytotoxicity to tumor cells due to higher concentrations of the viscotoxin ML I. [14] [23] [24]
Cardiovascular effects
Viscum has exhibited a variety of effects on components of the cardiovascular system. [3] [11] In particular, viscum has repeatedly demonstrated hypotensive action in animal studies. The mechanism of action for its hypotensive effect is still not entirely clear, and no recent investigations have been published. Viscum has been shown to inhibit the excitability of the vasomotor center in the medulla oblongata and to possess cholinomimetic activity. [11] The hypotensive activity may be dependent on the form in which the mistletoe is administered and the host tree from which it was collected. Studies indicate that aqueous extracts are more effective; the highest hypotensive activity was demonstrated by a macerate of leaves of mistletoe parasitizing on willow and gathered in January.[11] Viscum’s non-protein components, e.g. flavonoids, phenol carboxylic acids, phenylpropanes, and lignins, have been shown to possess hypotensive action. Alcoholic solutions (tinctures and fluid extracts) contain these compounds, but not viscotoxins or lectins. However, as stated above, aqueous extracts appear to be more effective. Currently, in Europe, several viscum preparations for hypertension exist. In fact, in Britain alone over 150 different mistletoe preparations can be found in the marketplace. [3] These preparations typically have small amounts of viscum in combination with other botanicals with hypotensive action, e.g. garlic, Crataegus oxyacantha, and Tilia platyphyllos. Anti-neoplastic and immunostimulatory effects
Viscum preparations have been used clinically in Europe for the treatment of cancer since 1926 when Iscador, a
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fermented product made from the crude pressed juice, was introduced as an immunotherapeutic agent for cancer. This work was carried out under the direction of Rudolph Steiner. Since that time, numerous studies have shown that Iscador, and other viscum preparations and components, are effective anti-neoplastic and immunostimulatory agents.[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] Iscador and other fermented viscum preparations differ from non-fermented extracts in their greater effectiveness and their decreased toxicity. [12] Specifically, the major viscotoxin, ML I, is not found in Iscador. [13] It is thought, that fermentation transforms ML I to its A and B chains, which have important immunological properties. [14] The A chain has mitogenic effects and the B chain stimulates macrophages and the release of lymphokines. In addition, there is a rapid decrease of lectin concentration during fermentation. The pharmacological activity of Iscador has been shown to be due to its viscum components, rather than to other constituents such as lactobacilli, which possess adjuvant activity. The lectins have been clearly demonstrated to be the viscum components largely responsible for Iscador’s adjuvant activity. Although in vitro unfermented plant juice has demonstrated a 10-fold greater cytotoxicity to tumor cells than Iscador, fermented Iscador contains a great number of substances which may act synergistically. In vivo studies in mice have demonstrated Iscador to be of greater adjuvant activity than purified mistletoe lectin, and without secondary toxic effects. [15] [16] Viscum’s adjuvant activity is demonstrable in both delayed-type hypersensitivity and antibody responses of mice to sheep red blood cells. [15] [16] Similar to other adjuvants (BCG, levamisole, muramyl dipeptide, bacterial and yeast components, etc.), Iscador is most effective when administered near the tumor, although systemic administration has also yielded positive results. Upon local administration, an inflammatory process ensues which promotes WBC infiltration and an encapsulation of the tumor. The non-specific host defense factors stimulated by Viscum album include: • enhanced macrophage phagocytic and cytotoxic activity [12] [16] • increased neutrophil production [12] • increased thymic weight and enhanced cortical thymocyte activity and proliferation [17] [19] • enhanced natural killer cell activity [12] [18] [20] • increased antibody-dependent, cell-mediated cytotoxicity. [12] [18] Iscador’s effects on these immunological parameters have been confirmed in patients with cancer. [12] [18] Iscador’s effect on stimulating the thymus gland has been demonstrated in several studies. [17] [19] Its ability to induce hyperplasia of the thymic cortex and to accelerate the regeneration of hematopoietic cells following X-irradiation is much greater than any other agent re-ported to date. [17] In addition, thymic lymphocytes became 29 times more responsive to concanavalin A as a result of Iscador administration. In summary, Viscum album exhibits numerous cytotoxic, adjuvant, and immunostimulatory effects which indicate a therapeutic effect in human cancer. These effects have been confirmed in vivo against murine tumors, Lewis lung carcinoma, colon adenocarcinoma 38, and C3H mammary adenocarcinoma 16/C. [4]
CLINICAL APPLICATIONS Cancer
The only clinical application with any significant scientific documentation is the use of viscum preparations as adjuncts in cancer therapy. It must be pointed out that the route of the administration of viscum preparations used in published studies as adjuncts in cancer treatments is subcutaneous or intravenous. It is not known to what degree (if any) the effects noted for Iscador, as well as other preparations and viscum compounds, can be achieved with oral administration. Early clinical investigations of viscum preparations, i.e. Iscador, were not very well documented. Due to the shortage of acceptable controlled clinical trials, the use of Iscador and other viscum preparations as a cancer treatment in Europe has remained controversial, even though positive effects with Iscador in the postoperative treatment of lung, breast, colon, and cervical carcinomas has been shown in several controlled studies. [25] The problem is that the methodological criteria in these studies are quite poor. Until their benefits are better documented, at this time, mistletoe preparations appear most useful as adjuncts to standard therapy. A new generation of mistletoe preparations standardized on mistletoe lectin I (e.g. Eurixor) is emerging. This greater standardization offers significant advantages. Mistletoe lectin I is a potent inducer of cytokines like interleukin 1, interleukin 6, and tumor necrosis factor. Its cytotoxic effects are also related to its ability to induce apoptosis (programmed cell death). [26] In one study, the effect of Eurixor was examined in 40 patients with advanced carcinoma of the breast. Along with standard chemotherapy (VEC regimen), 21 patients were assigned to receive mistletoe (treatment group) while 19 patients were given a placebo (control group). [27] After the fourth cycle of chemotherapy, the treatment group had statistically significantly higher leukocyte levels ( P < 0.001) compared with the control group. The treatment group had an average white blood cell count of 3,000, whilethe control group had an average count
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of 1,000. Furthermore, the parameters of the quality of life and anxiety strain revealed significantly better values in the treatment group than in the control group.
These results show that the adjuvant treatment with mistletoe extracts, in this case Eurixor, is a valuable addition to standard chemotherapy for advanced breast cancer patients. These results are quite important as advanced breast cancer carries with it a very poor prognosis. Similar results have been shown in advanced pancreatic cancer. [28] These results in better designed studies are quite encouraging. Clearly, additional investigations into the pharmacology of Viscum album are needed. Specifically, it must be determined whether the effects noted both in vitro and in vivo in animals, as well as in patients receiving injectable viscum preparations, can be attained by oral administration. In addition, greater clarification is needed to determine optimal viscum preparations. What host tree should be selected for which condition? What is the optimal harvesting time? In what form should the viscum be administered – crude herb, aqueous or alcoholic extract, fermented or non-fermented? Viscum is undoubtedly one of the most complex botanicals, yet, after examining currently available data, it can be said with much confidence that the future medicinal use of Viscum album is quite promising.
DOSAGE The standard dose of Viscum album, based on the British herbal pharmacopoeia, is as follows:[32] • dried leaves: 2–6 g (or by infusion) three times/day • tincture 1:5 (45% alcohol): 1–3 ml three times/day • fluid extract 1:1 (25% alcohol): 0.5 ml three times/day • dried aqueous extract 4:1: 100–250 mg three times/day.
TOXICITY Viscum album possesses significant toxicity. Historically, the berries have been regarded as being considerably more toxic than the leaves and stems despite the fact they both contain similar toxic compounds. The reason the toxicity of the berries is considered to be greater probably stems from fatal poisonings of children resulting from ingestion of the berries. Lethal doses of viscum lectins administered by various routes to mice produce two types of toxicity: • a typical type characterized by death after 3–4 days with marasmus-like symptoms • an atypical type characterized by immediate death from respiratory paralysis. [19] In mice, the LD 50 of the plant juice administered intraperitoneally is 32 mg (dry weight)/kg body weight. [29] The LD 50 values of orally administered Viscum album or extracts of Viscum album have not yet been determined. As stated earlier, alcohol-based extracts contain virtually no viscum proteins. This would imply significantly less toxicity with these preparations. However, this would also imply loss of activity, as much of the pharmacology of viscum relates to its protein content, especially immuno-enhancing activity. It is interesting to note that the toxicity of Korean mistletoe, Viscum album coloratum, appears to be lower than that of European mistletoe. [30] [31] This species has also demonstrated anti-cancer effects, but the effects appear to be due to highly cytotoxic alkaloids rather than to lectins. [5] [30] Studies comparing Korean viscum extracts with European extracts, as well as their alkaloid components, have demonstrated that the Korean mistletoe has greater activity in inhibiting cancer cells. In addition, fresh Korean mistletoe extracts exhibited greater activity compared with fermented extracts. [5] [30] In the future Korean mistletoe may prove to be superior to European mistletoe.
REFERENCES 1. Grieve
M. A modern herbal. New York, NY: Dover Publications. 1971: p 547–548
2. Becker
H. Botany of European mistletoe ( Viscum album L.). Oncology 1986; 43: 2–7
3. Anderson
LA, Phillippson JD. Mistletoe – the magic herb. From the Department of Pharmacognocy, School of Pharmacy, University of London, 1982
4. Khwaja
TA, Dias CB, Pentecost S. Recent studies on the anticancer activities of mistletoe ( Viscum album) and its alkaloids. Oncology 1986; 43: 42–50
5. Jordan
E, Wagner H. Structure and properties of polysaccharides from Viscum album (L.). Oncology 1986; 43: 8–15
6. Wagner 7. Franz
H, Jordan E, Feil B. Studies on the standardization of mistletoe preparations. Oncology 1986; 43: 16–22
H, Ziska P, Kindt A. Isolation and properties of three lectins from mistletoe ( Viscum album L.). Biochem J 1981; 195: 481–484
8. Olsnes
S, Stirpe F, Sandvig K, Phil A. Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe). J Biol Chem 1982; 257: 13,263–13,270
9. Petricic
J, Kalogjera Z. Isolation of glucosides from mistletoe leaves ( Viscum album L.). Acta Pharm Jugosl 1980; 30: 163
10.
Wagner H, Feil B, Kalogjera Z, Petricic J. Phenylpropanes and lignins of Viscum album. Planta Medica 1986; 2: 102
11.
Petkov V. Plants with hypotensive, antiatheromatous and coronarodilatating action. Am J Chin Med 1979; 7: 197–236
12.
Hajto T. Immunomodulating effects of Iscador. A Viscum album preparation. Oncology 1986; 43: 51–65
13.
Jordan E, Wagner H. Detection and quantitative determination of lectins and viscotoxins in mistletoe preparations. Arzneim Forsch 1986; 36: 428–433
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14.
Ribereau-Gayon G, Jung ML, Di Scala D, Beck JP. Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology 1986; 43: 35–41
15.
Bloksma N, Dijk HV, Korst P, Willers JM. Cellular and humoral adjuvant activity of a mistletoe extract. Immunobiol 1979; 156: 309–319
16.
Bloksma N, Schmiermann P, Reuver MD, Dijk HD, Willers J. Stimulation of humoral and cellular immunity by viscum preparations. Planta Medica 1982; 46: 221–227
17.
Rentea R, Lyon E, Hunter R. Biological properties of Iscador. A Viscum album preparation. Lab Invest 1981; 44: 43–48
Hajto T, Lanzrein. Natural killer and antibody-dependent cell-mediated cytotoxicity activities and large granular lymphocyte frequencies in Viscum album-treated breast cancer patients. Oncology 1986; 43: 93–97 18.
19.
Nienhaus J, Stoll M, Vester F. Thymus stimulation and cancer prophylaxis by Viscum proteins. Experentia 1970; 26: 523–525
20.
Hamprecht K, Handretinger R, Voetsch W, Anderer FA. Mediation of human NK-activity by components in extracts of Viscum album. Int J Immunopharm 1987; 9: 199–209
21.
Evans MR, Preece AW. Viscum album – a possible treatment for cancer? Bristol Med Chir J 1973; 88: 17–20
22.
Klamerth O, Vester F, Kellner G. Inhibitory effects of a protein complex from Viscum album on fibroblasts and HeLa cells. Z Physiol Chem 1968; 349: 863–864
23.
Hulsen H, Doser C, Mechelke F. Differences in the in vitro effectiveness of preparations produced from mistletoes of various host trees. Arzneim Forsch 1986; 36: 433–436
24.
Hulsen H, Mechelke F. The influence of a mistletoe preparation on suspension cell cultures of human leukemia and human myeloma cells. Arzneim Forsch 1982; 32: 1126–1127
25.
Kleijnen J, Knipschild P. Mistletoe treatment for cancer. Review of controlled trials in humans. Phytomedicine 1994; 1: 255–260
26.
Janssen O, Scheffler A, Kabelitz D. In vitro effects of mistletoe extracts and mistletoe lectins. Arzneim Forsch 1993; 43: 1221–1225
Heiny BM. Adjuvant treatment with standardized mistletoe extract reduces leukopenia and improves the quality of life of patients with advanced carcinoma of the breast gettin palliative chemotherapy (VEC regimen). Krebsmedizin 1991; 12: 3–14 27.
28.
Friess H et al. Treatment of advanced pancreatic cancer with mistletoe. Results of a pilot trial. Anticancer Res 1996; 16: 915–920
29.
Duke JA. Handbook of medicinal herbs. Boca Raton, FL: CRC Press. 1986: p 512–513
30.
Khwaja TA, Varven JC, Pentecost S, Pande H. Isolation of biologically active alkaloids from Korean mistletoe Viscum album, coloratum. Experentia 1980; 36: 599–600
31.
Manjikian S, Pentecost S, Khwaja TA. Isolation of cytotoxic proteins form Viscum album, coloratum. Proc Am Ass Cancer Res 1986; 27: 266
32.
British Herbal Medicine Association, Scientific Committee. British Herbal Pharmacopoeia. Cowling: British Herbal Medicine Association. 1983: p 235–236
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Chapter 121 - Vitamin A Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION Vitamin A was the first fat-soluble vitamin to be recognized. Although identified as a necessary growth factor in 1913, it was not chemically characterized until 1930. The initial discovery of vitamin A was made almost simultaneously by two groups of research workers, McCollum & Davis at the University of Wisconsin, and Osborne & Mendel at Yale University. They found that young animals fed a diet deficient in natural fats became very unhealthy, as evidenced by their inability to grow and poor immune function. These researchers also noted that the animals’ eyes would become severely inflamed and infected on the restricted diet and that this could be quickly relieved by the addition to the diet of either butterfat or cod liver oil. Once known as the “anti-infective vitamin”, vitamin A has recently regained recognition as a major determinant of immune status.
NOMENCLATURE When isolated in its pure form, vitamin A is a pure, lipid-soluble, yellow crystal with a condensed formula of C 20 H29 OH. Vitamin A is termed retinol, signifying that it is an alcohol that is intricately involved in the function of the retina of the eye. All- trans retinol is found in nature primarily as long-chain retinyl esters. The aldehyde form of all-trans retinol is commonly designated retinaldehyde or retinal, while the acidic form is termed retinoic acid. It has been suggested that retinol serves only as a precursor to these two active forms of vitamin A – retinal being primarily involved with vision and reproduction, while retinoic acid is important in other somatic functions, such as growth and differentiation. Synthetic derivatives of retinoic acid have been developed to treat many dermatological conditions and, more recently, certain forms of cancer. Isotretinoin (13- cis retinoic acid) is used in treating severe cystic acne and disorders of keratinization, such as Darier’s disease and lamellar ichthyosis. Etretinate, an aromatic derivative
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of retinoic acid, has no appreciable activity against acne, but is claimed to be more potent than isotretinoin in the treatment of psoriasiform diseases. These compounds, however, are not without side-effects. [1] [2]
RECOMMENDED DIETARY ALLOWANCE (RDA) Vitamin A was originally measured in international units, with 1 IU being defined as 0.3 mcg of crystalline all- trans retinol or 0.6 mcg beta-carotene. In 1967, an FAO/WHO Expert Committee recommended that vitamin A activity be referred to in terms of retinol equivalents rather than in IU, with 1 mcg of retinol being equivalent to 1 retinol equivalent (RE). The amount of beta-carotene required for 1 RE is 6 mcg, while the amount required for other provitamin A carotenoids is 12 mcg. In 1980, The Food and Nutrition Board of the NRC/NAS adopted this recommendation, and the 1980 RDA for vitamin A is stated in mcg and RE. For the adult male the RDA is set at 1000 RE (750 as retinol and 250 as beta-carotene, 5000 IU), while the RDA for women is lower at 800 RE (4000 IU). Children need 400–1000 RE (2000–5000 IU), increasing from infancy to 14 years. [1] [2] [3] The RDAs for different age groups are shown in Table 121.1 .
DIETARY SOURCES The most concentrated sources of preformed vitamin A are liver, kidney, butter, whole milk, and fortified skim milk, while the leading sources of provitamin A are dark green leafy vegetables (collards and spinach), and yellow-orange vegetables (carrots, sweet potatoes, yams, and squash) (see Table 121.2 ). Ingestion of excessive amounts of liver, i.e. 2.7–11 kg/week, has been reported to cause hypervitaminosis A. [4]
DEFICIENCY Vitamin A deficiency may be due to inadequate dietary intake (primary deficiency) or some secondary factor that interferes with the absorption, storage, or transportation
Group
TABLE 121-1 -- Recommended dietary allowances Retinol equivalents
International Units
Infants 0–1 year
375
1,875
1–3 years
400
2,000
4–6 years
500
2,500
7–10 years
700
3,500
Males 11+ years
1,000
5,000
Females 11+ years
800
4,000
Pregnancy
800
4,000
Children
Young adults and adults
Food
TABLE 121-2 -- Food sources of Vitamin A [4] Portion size
IU/portion
Meats Beef liver, fried
100 g
50,375
Calf liver, cooked
100 g
26,872
Chicken liver, cooked
2 livers
25,760
Sweet potatoes, baked
1 medium
14,600
Carrots, raw
1 large
11,000
Spinach, raw
100 g
8,100
Carrots, cooked
½ cup
8,000
Pumpkin, cooked
½ cup
8,000
Spinach, cooked
½ cup
7,300
Collard greens
½ cup
5,400
Broccoli, cooked
½ cup
1,900
Watermelon
1/16 melon
5,310
Cantaloupe
¼ melon
3,400
Apricots, dried
4 halves
2,275
Apricots, raw
2–3 medium
2,700
Nectarines, raw
1 medium
1,650
Vegetables
Fruits
of vitamin A. Some factors known to induce a vitamin A deficiency include: • malabsorption due to bile acid or pancreatic insufficiency • protein-energy malnutrition • liver disease • zinc deficiency • abetalipoproteinemia. Immune system effects
Immune system abnormalities associated with a vitamin A deficiency include impaired ability to mount an effective antibody response, decreased levels of helper T-cells, and alterations in the mucosal linings of the respiratory and gastrointestinal tract. Vitamin A-deficient individuals are more susceptible to infectious diseases and have higher mortality rates. It appears that while a vitamin A deficiency may predispose an individual to an infection, during the course of an infection vitamin A stores are severely depleted. Thus, a vicious cycle ensues. Infectious conditions associated with vitamin A deficiency include the measles, chicken pox, respiratory synctial virus (RSV), AIDS, and pneumonia. Other effects
Prolonged vitamin A deficiency results in the characteristic signs of follicular hyperkeratosis (build-up of cellular debris in the hair follicles giving the skin a goose bump appearance, which occurs most often at the back of the upper arm), night blindness, and increased rate of infection. As the condition worsens, the mucous
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membranes of the respiratory tract, gastrointestinal tract, and genitourinary tract also become affected, and the classic eye disease known as xerophthalmia due to vitamin A deficiency ensues. Even a mild vitamin A deficiency is associated with a significant increase in mortality. This is extremely significant, as vitamin A deficiency is particularly widespread in developing countries, especially in Asia where as many as 10 million children develop xerophthalmia every year. [1] [2] [5] Xerophthalmia
The term xerophthalmia is generally used to cover all the ocular manifestations of vitamin A deficiency. Blindness is one of the most serious consequences of vitamin A deficiency. Although it rarely occurs in the United States, it is the major preventable cause of blindness in Asia. The xerophthalmia of vitamin A deficiency is staged, as shown in Table 121.3 . In an effort to prevent vitamin A deficiency in underdeveloped countries, large prophylactic doses (200,000 IU) are given by the World Health Organization to children every 6 months. Determination of deficiency
The rapid dark adaptation test (see Ch. 26 ) is perhaps the most sensitive of the currently available tests designed to determine vitamin A deficiency. Measurement of serum retinol levels is usually not useful, since they may not become lowered until marked deficiency occurs. Deficiency in the United States and other developed countries is usually secondary to malabsorption, liver disease, or proteinuria. [1] [2]
METABOLISM Absorption
A variety of factors are known to influence the absorption efficacy of vitamin A and carotenoids. Although TABLE 121-3 -- The staging of the xerophthalmia Signs and symptoms
Stage Diagnosis XO
Night blindness
Poor dark adaptation
X1A
Xerosis of conjuctiva
Dryness with “lackluster” appearance, thickening, wrinkling, and diffuse pigmentation of conjunctiva
X1B
Bitot’s spots
Usually triangular-shaped collections of desquamated keratinized epithelial cells and mucus
X2
Xerosis of cornea
Dryness of cornea leading to keratinization and a hazy milky appearance
X3
Keratomalacia
Ulceration, distortion, and softening of the cornea with eventual perforation and iris prolapse and infection
retinol does not require bile acids to facilitate absorption, carotenoids do. Other factors that affect vitamin A and carotenoid absorption include: • the presence of fat, protein, and antioxidants in the food • the presence of bile and a normal complement of pancreatic enzymes in the intestinal lumen
• the integrity of the mucosal cells. The absorption efficiency of dietary vitamin A is usually quite high (80–90%), with only a slight reduction in efficiency at high doses. In contrast, beta-carotene’s absorption efficiency is much lower (40–60%), and it decreases rapidly with increasing dosage. [1] [2] Carotene supplements are better absorbed than the carotenes from foods.[6] Transformation in the intestinal mucosa
The majority of absorbed retinol is esterified with palmitic acid or another free fatty acid within the intestinal mucosal cells. It is then incorporated, along with triglycerides, phospholipids, and cholesterol esters, into chylomicra. The chylomicron is transported through the lymphatic channels into the general circulation and eventually is removed from the circulation by the liver. Transport, storage and excretion
Upon reaching the liver, vitamin A is stored primarily in special perisinusoidal lipocytes (Ito cells), while the hepatocytes contain only a minor fraction of the total vitamin A stored in the liver. Although small amounts of vitamin A are found in most tissues (see Table 121.4 ), more than 90% of the total body vitamin A content is stored in the liver. It is stored as a lipoglycoprotein complex consisting of 96% retinyl esters and 4% unesterified retinol. The retinyl esters are hydrolyzed by a tightly bound retinyl ester hydrolase which transfers the released all- trans retinol to intracellular retinol binding protein (RBP). The bound retinol is then processed through the Golgi apparatus and secreted into the plasma where it forms a reversible 1:1 molar complex with prealbumin. [1] [2]
Tissue
TABLE 121-4 -- Distribution of vitamin A in some human tissues (mcg/kg) Vitamin A
Adrenal
10.4 ± 7.1
Liver
149 ± 132
Testis
1.14 ± 1.23
Fat
1.46 ± 1.55
Pancreas
0.52 ± 0.28
Spleen
0.89 ± 0.88
Lung
0.91 ± 1.89
Thyroid
0.43 ± 0.33
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Adequate dietary protein and zinc are necessary for proper retinal mobilization. The half-lives of RBP and prealbumin are less than 12 hours, making them particularly likely to be deficient during protein-calorie malnutrition or other situations in which protein metabolism is abnormal. A zinc or vitamin E deficiency will also severely impair vitamin A metabolism, as these two nutrients function synergistically in many physiological processes of vitamin A metabolism (absorption, transport, and mobilization in particular). [2] Retinol is transferred into the cell after RBP binds to a cell surface receptor. The retinol is then quickly bound by cellular retinol binding protein (CRBP) in the cell cytosol. Retinoic acid is metabolized differently from retinol. It is absorbed through the portal system and transported in the plasma bound to albumin. It does not accumulate in the liver or other tissues in any appreciable amounts. It is metabolized quite rapidly to more polar oxygenated compounds. Intracellularly, it is bound to the cellular retinoic acid binding protein (CRABP). [7] Vitamin A metabolites are excreted mainly through the feces (via the bile) and the urine. During periods of deficiency there appears to be an adaptation in utilization, as evidenced by a reduction in the rate of vitamin A catabolism. [1] [2]
PHYSIOLOGICAL ROLES OF VITAMIN A Vision
The best understood physiological role of vitamin A is its effects on the visual system. The human retina has four kinds of vitamin A-containing photopigments: • rhodopsin, present in the rods (maximum absorption at 498 nm) • three iodopsins, present in the cones —blue cones (maximum absorption 420 nm) —green cones (maximum absorption 534 nm) —red cones (maximum absorption 563 nm).
The vitamin A form found in these pigments is the 11-cis isomer of vitamin A aldehyde (retinal). When a photon of light strikes the dark-adapted retina, the 11- cis configuration is converted to the all- trans form of the retinaldehyde and split from the rhodopsin molecule to yield opsin and all- trans retinol. This leads to a change in membrane potential and subsequent visual excitation. During light adaptation, as the visual processes are largely dependent on the cone cells, the released all- trans retinal or retinol from the rod cells is transported to pigment epithelial cells and stored as retinyl palmitate. During dark adaptation these processes are reversed, and, in addition, the retinal is isomerized to the 11- cis form. As the rod cells are particularly sensitive to vitamin A deficiency, night blindness or poor dark adaptation is an early consequence of vitamin A deficiency (see Ch. 26 ). [1] [2] Growth and development
Vitamin A is believed to affect growth and development by its necessary role in the synthesis of many glycoproteins (e.g. mucus), some of which may control cellular differentiation, and by its function as CRBP in controlling gene expression. [1] [2] The adhesion between cells is apparently related to glycoprotein synthesis, which is markedly depressed in vitamin A deficiency. Consequently, during deficiency there is a loss of normal stimuli for cellular growth and differentiation. CRBP is transferred directly into the nucleus and may function in a fashion similar to some of the steroid hormones. The effects of a vitamin A deficiency most readily seen at the cellular level are in those differentiating tissues that have a rapid turnover rate, i.e. epithelial cells of the oral cavity, respiratory tract, urinary tract, and ducts of secretory glands. [1] [2] Epithelial tissue development and maintenance
The role of vitamin A and carotenoids in the development and maintenance of epithelial tissue cannot be overstated. Vitamin A status determines whether mucin or keratin is synthesized in epidermal cells – the presence of adequate vitamin A results in mucin production, while a lack results in hyperkeratinization of the skin,
cornea, upper respiratory tract, and genitourinary tract. Mucopolysaccharide synthesis also appears to be dependent on adequate vitamin A status.
[1] [2] [ 8]
Reproduction
The requirement of vitamin A for reproductive functions in higher animals has been known since 1922. [2] Beta-carotene has also been reported to have a specific effect in fertility distinct from its role as a precursor to vitamin A. [9] [10] [11] In bovine nutritional studies, cows fed beta-carotene-deficient diets exhibited delayed ovulation and an increase in the number of follicular and luteal cysts. [9] [10] The corpus luteum has the highest concentration of beta-carotene of any organ measured. [11] The carotene cleavage activity changes with the ovulation cycle, with the highest activity occurring during the midovulation stage. It has been speculated that a proper ratio of carotene to retinol must be maintained to ensure proper corpus luteum function. As the corpus luteum produces progesterone, inadequate corpus luteum function could have significant deleterious effects. Inadequate corpus luteum secretory function is one of the characteristic features of infertile
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and/or irregular menstrual cycles. [12] Furthermore, an increased estrogen to progesterone ratio has been implicated in a variety of clinical conditions, including ovarian cysts, premenstrual tension syndrome, fibrocystic breast disease, and breast cancer. [13] Since supplemental beta-carotene given to cows significantly reduced the incidence of ovarian cysts (42% in control group vs. 3% in the beta-carotene group), it may have a similar effect in humans. [10] [11] Another bovine condition that benefited from increased dietary beta-carotene levels is cystic mastitis. [12] It appears that farmers have a greater appreciation of beta-carotene than do many nutritionists. Of course, there are significant financial reasons, as the annual monetary loss from bovine mastitis in the United States has been estimated to be at least $1.5–2.0 billion and ovarian cysts represent the major cause of infertility in cattle. Immune system
Vitamin A is absolutely essential to proper immune function. The first way in which vitamin A affects the immune system is that it plays an essential role in maintaining the epithelial and mucosal surfaces and their secretions. These systems constitute a primary non-specific host defense mechanism. Furthermore, vitamin A has been shown to stimulate and/or enhance numerous immune processes, including induction of antitumor activity, enhancement of white blood cell function, and increased antibody response. [14] These effects are not due simply to a reversal of vitamin A deficiency, since many of these effects are further enhanced by (supposedly) excessive amounts of vitamin A. Retinol has also demonstrated significant antiviral activity and has prevented the immunosuppression induced by glucocorticoids, severe burns, and surgery. Some of these effects are probably related to vitamin A’s ability to prevent stress-induced thymic involution and to promote thymus growth. As carotenes are better antioxidants, they may turn out to be even better in protecting the thymus gland than vitamin A, since the thymus gland is particularly susceptible to free radical and oxidative damage. The clinical uses of vitamin A and beta-carotene in infectious diseases are discussed below.
CLINICAL APPLICATIONS Adequate tissue vitamin A levels are vital for optimum health. In addition, this nutrient can be used beyond its “physiological” role in the treatment of various conditions. Supplemental vitamin A is used primarily to enhance the immune system in viral illnesses and in the treatment of numerous skin disorders. Natural vitamin A is available either as retinol or retinyl-palmitate. Absorption may be improved via either micellization or emulsification. Micellization is the process of making the fat-soluble vitamin A into very small droplets (micelles) so that the material is dispersed in water. Emulsification is the process of emulsifying the vitamin A with another chemical (such as lecithin) so that it can mix with water. Despite manufacturers’ claims, it is important to remember that regular vitamin A is absorbed at a rate of 80–90%. Viral illnesses
As discussed above, vitamin A is absolutely critical to a healthy functioning immune system. Vitamin A-deficient individuals are more susceptible to infectious diseases in general, but especially viral infections. While vitamin A deficiency may predispose an individual to an infection, during the course of an infection vitamin A stores are severely depleted. Measles
Vitamin A deficiency is a major problem in many developing countries as 5–10 million children in these countries exhibit severe vitamin A deficiency. Recently, a number of well-designed studies have confirmed an effect first noted in 1932 – vitamin A supplementation can significantly reduce infant mortality among measles patients by at least 50%. Typically the dosage of vitamin A in double-blind studies has been 200,000–400,000 IU administered only once or twice to replenish body stores.[15] [16] The benefits of vitamin A supplementation in the treatment of measles is not limited to developing countries. A study of “well nourished” children in Long Beach, California, suffering from measles indicated that 50% were deficient in vitamin A. [17] This finding supports the use of vitamin A supplementation even in the US. Infants with RSV infections
Wide-scale immunization programs have reduced the risk of measles in children. However, vitamin A therapy appears appropriate for other childhood viral illnesses. One of the more common viruses is the respiratory syncytial virus (RSV), a common cause of severe respiratory disease in young children. Studies have shown that children with RSV have low serum vitamin A levels. Furthermore, the lower the vitamin A level, the greater the severity of the disease, similar to the relationship shown in measles. Because vitamin A supplementation diminishes the morbidity and death caused by measles, a group of researchers decided to determine vitamin A’s safety and absorption pattern in RSV as a first step in determining the therapeutic effectiveness. [18] Twenty-one children with a mean age of 2.3 months
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(range, 1–6 months) with mild RSV infection were treated with 12,500–25,000 IU of oral micellized vitamin A. Baseline vitamin A levels were shown to be low, but within 6 hours of receiving 25,000 IU, but not 12,500 IU, of vitamin A normal levels were re-established. Despite the young age, none of the children experienced any obvious signs or symptoms of vitamin A toxicity. Although the study was not designed as a therapeutic trial, the subjects receiving vitamin A had hospital stays that were shorter than those of children with a similar severity of illness who were not enrolled in the study. Although vitamin A supplementation is an attractive treatment of RSV infections, due to its low cost, wide availability, and ease of administration, recent placebo-controlled trials are suggesting it may be of value only in the most severe cases. A placebo-controlled study of 180 children in Chile with RSV provided 50–200,000 IU of retinyl palmitate (according to age) within 2 days of admission. [19] Supplementation resulted in no significant benefit, except for those children suffering from hypoxemia. These children experienced substantial benefit – a more rapid resolution of tachypnea and shortening of their hospital stay from 9.3 to 5.5 days. AIDS
Another viral illness that may benefit from vitamin A supplementation is AIDS. It was recently shown that a vitamin A deficiency is quite common during HIV infection and that vitamin A deficiency is clearly associated with a decreased level of circulating helper T-cells, one of the hallmark features of AIDS. [20]
Analysis of vitamin A levels, helper T-cells, and other blood parameters in HIV individuals indicated that more than 15% had low serum vitamin A levels. When vitamin A levels were low, helper T-cell levels were much lower than the levels in HIV-infected individuals who had normal levels of vitamin A. Vitamin A deficiency was also shown to be associated with a higher rate of mortality due to HIV. Increasing beta-carotene may be the preferred form of vitamin A for supplementation in HIV patients as there is concern that retinoic acid, the active form of vitamin A, may actually increase HIV replication in humans. Low beta-carotene levels are common in AIDS, presumably as a result of fat malabsorption. Low beta-carotene levels are associated with greater impairment of immune function. [21] Skin disorders
The use of high-dose vitamin A therapy for acne and other skin disorders was introduced in dermatology in the late 1930s. It is still used by a few dermatologists, although, since the advent of the synthetic retinoids, this type of therapy is not as popular as it once was. Vitamin A therapy has been shown to be quite effective in treating skin conditions associated with excessive formation of keratin (hyperkeratosis), a skin protein which can clog the pores of the skin to produce a “goose bump” effect. Examples of some skin conditions associated with hyperkeratosis include acne, psoriasis, ichthyosis, lichen planus, Darier’s disease, palmoplantar keratoderma, and pityriasis rubra pilaris. The dosages of vitamin A used to treat these conditions have typically been quite high (300,000–500,000 IU/day for 5–6 months in the treatment of acne, and 1–3.5 million IU/day for 1–2 weeks for the other conditions). [22] [23] [24] [25] The use of these high dosages usually results in the development of significant toxicity (see below). Although there is some evidence that carotenes may be more useful, and less toxic, in some of these conditions, the pharmacological activity responsible for the effects of vitamin A in hyperkeratosis are believed to result when serum retinol levels exceed serum retinol binding protein capacity, causing destabilization of membranes and destruction of the keratin-producing cells. [21] In monitoring for vitamin A toxicity, laboratory tests appear unreliable until obvious toxicity symptoms are apparent. The first significant toxic symptom is usually headache followed by fatigue, emotional instability, and muscle and joint pain. Chapped lips (cheilitis) and dry skin (xerosis) will generally occur in the majority of patients, particularly in dry weather. Because high doses of vitamin A during pregnancy can cause birth defects, women of child-bearing age should use effective birth control during vitamin A treatment and for at least 1 month after discontinuation. High doses of vitamin A may not be necessary if other nutritional factors like zinc and vitamin E are included. These nutrients work with vitamin A in promoting healthy skin. A safe and effective recommendation for vitamin A in the treatment of acne is less than 25,000 IU/day. Dry eyes
Dry-eye disorders are a complex group of diseases characterized by a localized water deficiency in the tear ducts; a mucin deficiency; or a combination of the two. Despite the diversity of underlying causes, the changes in the conjunctiva of the eye are similar in all cases, i.e. loss of goblet cells (mucin-producing cells), abnormal enlargement of non-goblet epithelial cells, and an increase of cellular layers and keratin deposition, stratification and keratinization. Apart from topical vitamin A therapy, all other non-surgical therapies of dry eye, i.e. the frequent application of artificial tears, lubricants, or slow-releasing polymers, and the therapeutic use of soft contact lenses, are not
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directed toward reversing the underlying process, but rather toward alleviating the symptoms. The hypothesis that a localized vitamin A deficiency in the lining of the outer eye may be responsible for dry eye, considering vitamin A’s vital role in epithelial tissue, seems obvious. Clinical studies featuring commercial vitamin A eye drops (Viva-Drops from Vision Pharmaceuticals) have yielded impressive clinical results in the treatment of dry eyes.[26] [27]
DOSAGE Dosage ranges for vitamin A reflect the intent of use. For general health purposes, a dosage of 5,000 IU for men and 2,500 IU for women appears reasonable. During an acute viral infection, a single oral dosage of 50,000 IU for 1 or 2 days appears to be safe even in infants (note, however, that women who might be pregnant must not use vitamin A supplements; beta-carotene is fine). For the treatment of acne and hyperkeratotic skin disorders, high-dose therapy may be useful but should be monitored closely by a physician.
TOXICITY Vitamin A supplementation must be avoided during pregnancy. Vitamin A in large doses has been shown to be teratogenic. Unfortunately, the safe dosages for pregnant women have not yet been determined. According to recent studies, dosages greater than 10,000 IU during pregnancy (specifically during the first 7 weeks after conception) have probably been responsible for one out of every 57 cases of birth defects in the United States. Women who are at risk of becoming pregnant should keep their supplemental vitamin A levels below 5,000 IU or, better yet, look to carotenes. [28] Acute toxicity with vitamin A is most often seen in children as a result of the accidental ingestion of a single large dose of vitamin A (100,000–300,000 IU) and manifests as:[1] • raised intracranial pressure with vomiting • headache • joint pain • stupor • occasionally papilledema. Symptoms rapidly subside upon withdrawal of the vitamin, and complete recovery always results. [1] Vitamin A toxicity may occur in adults when taking an excess of 50,000 IU/day for several years. Smaller daily doses may produce toxicity symptoms if there are defects in storage and transport of vitamin A such as occurs in cirrhosis of the liver, hepatitis, or protein calorie malnutrition, and in children and adolescents. [29] [30] Signs of vitamin A toxicity generally include: • dry, fissured skin • brittle nails • alopecia • gingivitis • cheilosis • anorexia • irritability • fatigue • nausea. Serum levels of vitamin A of 250–6,600 IU/dl are typical of toxicity. Prolonged, severe hypervitaminosis A will result in bone fragility and thickening of the long bone. Toxicity is typically encountered during high-dose vitamin A therapy for various skin conditions. Although dosages below 300,000 IU/day for a few months rarely cause toxicity symptoms, early recognition is still very important. Cheilitis (chapped lips) and xerosis (dry skin) will generally appear in the majority of patients,
particularly in dry weather. The first significant toxicity symptom is usually headache, followed by fatigue, emotional lability, and muscle and joint pain. Laboratory tests are of little value in monitoring toxicity, as serum vitamin A levels correlate poorly with toxicity, and SGOT and SGPT are elevated only in symptomatic patients. [21] Interactions
Vitamin E and zinc are particularly important to the proper function of vitamin A. A deficiency of zinc, vitamin C, protein, or thyroid hormone will impair the conversion of provitamin A carotenes to vitamin A. Studies have demonstrated a link between exposure to toxic chemicals and vitamin A nutrition. Administration of compounds such as polybrominated biphenyls, dioxin, and other toxic chemicals to rats results in a decrease in the hepatic content of vitamin A. Administration of vitamin A concurrently with the xenobiotics partially prevents the symptoms of toxicity. Exposure to these compounds results in an increased vitamin A requirement due to the enhanced degradation of vitamin A in the liver. [31] [32]
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R, ed. Nutrition reviews. Present knowledge in nutrition. 6th edn. Washington, DC: Nutrition Foundation. 1989: p 96–107
2. Underwood
B. Vitamin A in animal and human nutrition. In: Sporn M, Roberts A, Goodman S, eds. The retinoids, vol 1. Orlando, Fl: Academic Press. 1984: p 282–392
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MV, Mahan LK. Food, nutrition and diet therapy. 5th edn. Philadelphia, PA: WB Saunders. 1984: p 103–107, 224
4. Selhorst
JB, Waybright EA, Jennings S et al. Liver lover’s headache. Pseudotumor cerebri and vitamin A intoxication. JAMA 1984; 252: 3365
5. Sommer
A, Tarwato I, Hussaini G et al. Increased mortality in children with mild vitamin A deficiency. Lancet 1983; ii: 584–588
6. Brown
ED, Micozzi MS, Craft NE. Plasma carotenoids in normal men after a single ingestion of vegetables or purified beta-carotene. Am J Clin Nutr 1989; 49: 1258–1265
7. Goodman 8. Zile
DS. Overview of current knowledge of metabolism of vitamin A and carotenoids. JNCI 1984; 73: 1375–1379
MH, Cullum ME. The function of vitamin A. Current concepts. Proc Soc Exp Biol Med 1983; 172: 139–152
9. Folman
Y, Rosenberg M, Ascarelli M et al. The effect of dietary and climatic factors on fertility, and on plasma progesterone and oestradiol-17B levels in dairy cows. J Steroid Biochem 1983; 19:
863–868 10.
Editor. Metabolism of beta-carotene by the bovine corpus luteum. Nutr Rev 1983; 41: 357–358
11.
Lotthammer KH. Importance of beta-carotene for the fertility of dairy cattle. Feedstuffs 1979; 51: 16–19
12.
O’Fallon JV, Chew BP. The subcellular distribution of B-carotene in bovine corpus luteum. Proc Soc Exp Biol Med 1984; 177: 406–411
13.
Sherman BM, Korenman SG. Inadequate corpus luteum function: a pathophysiological interpretation of human breast cancer epidemiology. Cancer 1974; 33: 1306–1312
14.
Semba RD. Vitamin A, immunity, and infection. Clin Inf Dis 1994; 19: 489–499
15.
Fawzi WW et al. Vitamin A supplementation and child mortality. JAMA 1993; 269: 898–903
16.
Hussey GD, Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990; 323: 160–164
17.
Arrieta AC, Zaleska M, Stutman HR. Vitamin A levels in children with measles in Long Beach, California. J Pediatr 1992; 121: 75–78
18.
Neuzil KM, Gruber SC, Chytil F. Safety and pharmacokinetics of vitamin A therapy for infants with respiratory syncytial infections. Antimicrob Agents Chemother 1995; 39: 1191–1193
19.
Dowell SF, Papic Z, Bressee JS et al. Treatment of respiratory syncytial virus infection with vitamin A. A randomized, placebo-controlled trial in Santiago, Chile. Ped Inf Dis J 1996; 15: 782–786
20.
Semba RD et al. Increased mortality associated with vitamin A deficiency during human immunodeficiency virus type 1 infection. Arch Intern Med 1993; 153: 2149–2154
21.
Ullrich R et al. Serum carotene deficiency in HIV-infected patients. AIDS 1994; 8: 661–665
22.
Kligman AM, Mills OH, Leyden JJ et al. Oral vitamin A in acne vulgaris. Int J Derm 1981; 20: 278–285
23.
Thomas JR, Cooke J, Winkelmann RK. High-dose vitamin A in Darier’s disease. Arch Dermatol 1982; 118: 891–894
24.
Randle HW, Diaz-Perez J and Winkelmann RK. Toxic doses of vitamin A for pityriasis rubra pilaris. Arch Dermatol 1980; 116: 888–892
25.
Winkelmann RK, Thomas JR, Randle HW. Further experience with toxic vitamin A therapy in pityriasis rubra pilaris. Cutis 1983; 31: 621–629
26.
Rengstorff RH. Topical treatment of external eye disorders with preparations containing vitamin A. Practical Optometry 1993; 4: 163–165
27.
Westerhout D. Treatment of dry eyes with aqueous antioxidant eye drops. Contact Lens J 1989; 19: 165–173
28.
Rothman KJ, Moore LL, Singer MR. Teratogenecity of high vitamin A intake. N Engl J Med 1995; 333: 1369–1373
29.
Hatoff DE, Gertler SL, Miyai K et al. Hypervitaminosis A unmasked by acute viral hepatitis. Gastroenterol 1982; 82: 124–128
30.
Harris WA, Erdman JW. Protracted hypervitaminosis. A following long-term, low level intake. JAMA 1982; 247: 1317–1318
31.
Cullum ME, Zile MH. Acute polybrominated biphenyl toxicosis alters vitamin A homeostasis and enhances degradation of vitamin A. Toxicol Appl Pharmacol 1985; 81: 177–181
Thunberg T, Ahlborg Ug, Wahlstrom B. Comparison of the effects of 2,3,7,8–tetrachlorodibenzo-p-dioxin and six other compounds on vitamin A storage, the UDP–gluconosyltransferase and aryl hydrocarbon hydroxylase activity in the rat liver. Arch Toxicol 1984; 55: 16–19 32.
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Chapter 122 - Vitamin toxicities and therapeutic monitoring Michael T. Murray ND Joseph E. Pizzorno Jr ND
INTRODUCTION When nutrients such as vitamins are being used at high doses for pharmacological effects, the physician must be vigilant for possible toxicity or side-effects. In general, vitamin therapy is virtually “non-toxic” and the small risk of developing any toxicity can be further reduced by careful monitoring of the patient. The physician should also be aware of toxicity resulting from self-administered vitamins. The primary signs and symptoms of vitamin toxicity are listed in Tables 122.1 and 122.2 , which are complemented by a more detailed discussion of toxicity and guidelines for monitoring selected vitamins.
VITAMIN TOXICITY Lipid-soluble vitamins Vitamin A
The majority of the cases of hypervitaminosis A involve acute ingestion by young children. [1] [2] Adverse reactions to acute ingestion are usually transient. Chronic ingestion in children, usually a result of administration by a parent, may result in long-lasting changes in bone formation. When large doses of vitamin A are being given, careful monitoring is necessary. Rather than using sudden large doses, a gradual stepwise increase in dosage is indicated, with a symptom evaluation made before increasing the dose. Usually, the first recognized symptom of hypervitaminosis is frontal headache. If signs or symptoms appear, supplementation should be discontinued until they disappear. Therapy may be carefully resumed at a lesser dose. Periodic liver enzyme levels should be determined to check for hepatic damage. Typically, SGOT levels are the first to be affected. [1] [2] [3] [4] As vitamin A has been shown to have teratogenic effects in animals (e.g. resorption of fetus, cleft palate, spina bifida, anencephaly, etc.), supplementation above the RDA is not warranted in pregnant, or potentially pregnant, women. According to recent studies (see Ch. 121 ),
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Vitamin
Toxic dose
Carotene Chronic: none
TABLE 122-1 -- Toxic doses and side-effects of lipid-soluble vitamins Toxic signs and symptoms No apparent toxicity, even at large doses (250 mg/day); synthetic form may be a problem for heavy smokers not taking other antioxidants
Vitamin A Acute —infants: 75–300,000 IU
Anorexia, bulging fontanelles, hyperirritability, vomiting
—adults: 2–5 million IU
Headache, drowsiness, nausea, vomiting
Chronic —infants: 18–60,000 IU/day
Premature epiphyseal bone closing, long bone growth retardation
—adults: 100,000 IU/day
Anorexia, headache, blurred vision, loss of hair, bleeding lips, cracking and peeling skin, muscular stiffness and pain, severe hepatic damage and enlargement, anemia, teratogenesis
Vitamin D Acute: 1–3,000 IU/kg Chronic: 10–50,000 IU/day
Anorexia, nausea, vomiting, diarrhea, headache, polyuria, polydipsia Weight loss, pallor, constipation, fever, hypercalcemia, calcium deposits in soft tissues
Vitamin E Chronic: >800 IU/day
Severe weakness, fatigue, exacerbation of hypertension, potentiation of anticoagulants
Vitamin K Chronic: none
Phylloquinone (K1 ), unlike menadione (K 3 ), is not associated with side-effects when given orally
Toxic dose Ascorbic acid
TABLE 122-2 -- Toxic doses and side-effects of water-soluble vitamins Toxic signs and symptoms
Acute: usually >10 g Nausea, diarrhea, flatulence Chronic: >3 g/day
Increased urinary oxalate and uric acid levels in extremely rare cases, impaired carotene utilization, chelation and resultant loss of minerals may occur
Biotin
Chronic: >10 mg/day No side-effects from oral administration at therapeutic doses have been reported
Folic acid
Chronic: 15 mg/day
Abdominal distension, anorexia, nausea, sleep disturbances (see discussion)
Niacin
Acute: >100 mg
Transient flushing, headache, cramps, nausea, vomiting
Chronic: 3–7 g/day
Anorexia, abnormal glucose tolerance, increased plasma uric acid levels, gastric ulceration, elevated liver enzymes
Niacinamide
Chronic: >1,000 mg/day
Same as for niacin
Pantothenic acid
Chronic
Occasional diarrhea
Pyridoxine
Acute
No acute effects are noted at therapeutic doses
Chronic: 300 mg/day Sensory and motor neuropathy Riboflavin
Chronic
No toxic effects have been noted
Thiamin
Chronic
No toxic effects noted for humans after oral administration
Vitamin B12
Chronic
No side-effects from oral administration have been reported
dosages greater than 10,000 IU during pregnancy (specifically during the first 7 weeks after conception) have probably been responsible for one out of every 57 cases of birth defects in the United States. Carotenoids
Carotenoids appear to be without toxic effects at the therapeutic doses usually used and are therefore more appropriate than vitamin A for most conditions. The only effect of large dosages is an apparently benign yellowing of the skin. Three large, recent, widely publicized therapeutic trials with synthetic beta-carotene have found that it appears to increase the risk of cancer for heavy smokers. However, several factors complicate the interpretation of these results. The significance of the these trials is fully discussed in Ch. 121 . Vitamin D
Large doses of vitamin D are rarely used clinically; self-administration is the usual cause of toxicity. Vitamin D has great potential to cause toxicity. Dosages greater than 1,000 IU/day are certainly not recommended. Toxicity is characterized by hypercalcemia, deposition of calcium into internal organs, and kidney stones. It has also been suggested that long-term overconsumption of vitamin D 2 in fortified foods contributes to atherosclerosis and heart disease, possibly as a result of decreasing magnesium absorption.[5] Vitamin E
Although vitamin E is a fat-soluble vitamin it has an excellent safety record. Recent clinical trials of vitamin E supplementation at doses as high as 3,200 IU/day in a wide variety of subjects for periods of up to 2 years have not shown any unfavorable side-effects. Detailed safety assessments have been carried out in several studies. For example, in one double-blind trial in 32 elderly (>60 years old) people, the effect of daily supplementation of 800 IU of D,L-alpha-tocopheryl acetate for 30 days was assessed by measuring general health, nutrient status, liver and kidney function, metabolism, blood cell status, blood nutrient and antioxidant status, thyroid hormones, and urinary function. [6] The only significant effect noted was an increase in serum vitamin
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E levels. Vitamin E at this dose was extremely well-tolerated and no side-effects were reported. The results of this study are not surprising and are consistent with a large body of knowledge demonstrating that vitamin E supplementation is extremely safe. Vitamin K
Large doses of the synthetic, water-soluble vitamin K 3 (menadione), when administered to infants, may cause hemolytic anemia, hyperbilirubinemia, hepatomegaly, and possibly death. Adults with G6PD deficiency may show hemolytic reactions. [7] The natural vitamin K1 (phytadione or phylloquinone) does not appear to have any toxicity when given orally, until huge doses (200 mg) are given. [8] Water-soluble vitamins Ascorbic acid
Vitamin C has been reported to have perhaps the lowest toxicity of all vitamins. Diarrhea and intestinal distension or gas are the most common complaints at higher dosages. High doses have been shown to: • increase the urinary excretion of calcium, iron and manganese • increase the absorption of iron • increase urinary oxalate or uric acid levels, but only in an extremely small subgroup of the population • alter many routine laboratory tests, i.e. serum B 12 , aminotransferases, bilirubin, glucose, stool occult blood. It is necessary to take these effects into consideration when supplementing with mega-doses of vitamin C. The primary concern with high dosages of vitamin C often cited in the medical literature is the development of calcium oxalate kidney stones. However, numerous studies have now demonstrated that in persons not on hemodialysis or suffering from recurrent kidney stones, severe kidney disease, or gout, high dosage vitamin C therapy will not cause kidney stones. Vitamin C administration of up to 10 g/day has not shown any effect on urinary oxalate levels. [9] [10] There have been reports that abrupt cessation of high dosage vitamin C intake leads to “rebound scurvy”, or in pregnant women to the presence of rebound scurvy after birth in their babies. However, other studies do not support the existence of rebound scurvy with sudden cessation or after pregnancy with high doses of vitamin C. While the existence of rebound scurvy is controversial (some experts question its existence), it is better to err on the side of caution. At this time a safe recommendation to pregnant women would be a daily dosage of 500 mg. Folic acid
It has been reported that eight out of 14 healthy human subjects who consumed 15 mg/day of folic acid for 1 month developed abdominal distension, flatulence, nausea, anorexia, sleep disturbances with vivid dreams, malaise, and irritability. [11] This, however, has not been confirmed in a double-blind clinical study [12] and other investigations. [13] [14] [15] Folic acid supplementation appears to be without side-effects, even at high doses (e.g. 15 mg/ day). Niacin
The acute side-effects of niacin are well known. The most common and bothersome is the skin flushing that typically occurs 20–30 minutes after the niacin is taken. Long-term consequences of niacin therapy include gastric irritation, nausea, and liver damage. In an attempt to combat the acute reaction of skin flushing, several manufacturers began marketing “sustained-release”, “timed-release” or “slow-release” niacin products. These formulations allow the niacin to be absorbed gradually, thereby reducing the flushing reaction. However, while these forms of niacin reduce skin flushing, they have actually proven to be more toxic to the liver. In a recent study, it was strongly recommended that the use of sustained-release niacin be restricted because of the high percentage (78%) of patient withdrawal due to side-effects – 52% of the patients taking the sustained-release niacin developed liver damage, compared with none of the patients taking immediate-release niacin. [16] Because niacin can impair glucose tolerance, it should probably not be used in diabetics unless they are under close observation. Niacin should also not be used in patients with pre-existing liver disease or elevation in liver enzymes, gout, or peptic ulcers. Side-effects can occur with any form of niacin, including niacinamide. Although niacinamide does not cause the acute flushing of the skin, it can cause liver damage. Inositol hexaniacin is the safest form of niacin currently available. Both short- and long-term studies have shown it to be virtually free of side-effects other than an
occasional mild gastric upset or mild flushing of the skin. Regardless of the form of niacin being used, periodic checking (at least every 3 months) of liver function tests are indicated when high-dose (i.e. 2–6 g/day) niacin, inostitol hexaniacinate, or niacinamide therapy is being used. Pyridoxine
Vitamin B6 is one of the few water-soluble vitamins that is associated with some toxicity when taken in large doses or moderate dosages for long periods of time.
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Large doses of vitamin B 6 are currently being used for a wide variety of conditions. Doses greater than 2,000 mg/day can produce symptoms of nerve toxicity (tingling sensations in the feet, loss of muscle coordination, and degeneration of nerve tissue) in some individuals. Chronic intake of dosages greater than 500 mg/day can be toxic if taken daily for several months. [17] There are also a few rare reports of toxicity occurring at chronic long-term dosages as low as 150 mg/day. [18] [19] [20] The toxicity is thought to be a result of supplemental pyridoxine overwhelming the liver’s ability to add a phosphate group to produce the active form of vitamin B 6 (pyridoxal-5-phosphate). As a result, it is speculated either that pyridoxine is toxic to the nerve cells or that it actually acts as an anti-metabolite by binding to pyridoxal-5-phosphate receptors thereby creating a relative deficiency of vitamin B 6 . It appears to make sense to limit dosages to 50 mg. If more than 50 mg are desired, then the dosages should be spread throughout the day.
LABORATORY TESTS FOR VITAMIN TOXICITY Only a limited number of routine laboratory tests are available for detecting vitamin toxicity. These are presented in Table 122.3 . TABLE 122-3 -- Laboratory tests for vitamin toxicity Vitamin
Laboratory test
Vitamin A
SGOT, serum vitamin A
Vitamin D
Serum calcium
Niacin
SGOT, SGPT
Vitamin C
Urinary oxalate and uric acid
REFERENCES 1. Miloslav 2. Omaye
R. CRC handbook series in nutrition and food, section E: nutritional disorders, vol. 1. Cleveland, OH: CRC Press. 1978
S. Safety of megavitamin therapy. Adv Exp Med Biol 1984; 177: 169–203
3. DiPalma 4. Buist
J and Ritchie D. Vitamin toxicity. Ann Rev Pharmacol Toxicol 1977; 17: 133–148
R. Vitamin toxicities, side effects and contraindications. Int Clin Nutr Rev 1984; 4: 159–171
5. Seelig
MS. Magnesium deficiency with phosphate and vitamin D excess: role in pediatric cardiovascular nutrition. Cardio Med 1978; 3: 637–650
6. Meydani 7. Krupp
MA, Chatton MJ. Current medical diagnosis and treatment. Los Altos, CA: Lange Medical. 1984: p 803–808
8. Bicknell 9. Rivers
SN et al. Assessment of the safety of high-dose, short-term supplementation with vitamin E in healthy older adults. Am J Clin Nutr 1994; 60: 704–709
F, Prescott F. The vitamins in medicine. 3rd edn. Milwaukee, WI: Lee Foundation. 1953: p 694
JM. Safety of high level vitamin C ingestion. Int J Vitamin Nutr Res 1989; 30: 95–102
10.
Wanzilak TR et al. Effect of high dose vitamin C on urinary oxalate levels. J Urol 1994; 151: 834–837
11.
Hunter R, Barnes J. Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1970 i: 61–63
12.
Hellstrom L. Lack of toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1971; i: 59–61
13.
Sheehy T. Folic acid. Lack of toxicity. Lancet 1973; i: 37
14.
Richens A. Toxicity of folic acid. Lancet 1971; i: 912
15.
Boss G, Ragsdale R, Zettner A and Seegmiller J. Failure of folic acid (pteroglutamic acid) to affect hyperuricemia. J Lab Clin Med 1980; 96: 783–789
16.
McKenney JM et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994; 271: 672–677
17.
Cohen M, Bendich A. Safety of pyridoxine – A review of human and animal studies. Toxicol Lett 1986; 34: 129–139
18.
Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurol 1985; 35: 1466–1468
19.
Waterston JA, Gilligan BS. Pyridoxine neuropathy. Med J Aust 1987; 146: 640–642
20.
Dalton K, Dalton MJT. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand 1987; 76: 8
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Chapter 123 - Vitex agnus castus (chaste tree) Donald J. Brown ND
Vitex agnus castus (family: Verbenaceae) Common name: chaste tree
GENERAL DESCRIPTION Vitex agnus castus, also known as chaste tree, is a shrub with finger-shaped leaves and slender violet flowers. Vitex agnus castus grows in creek beds and on river banks in valleys and lower foothills in the Mediterranean and central Asia. The plant blooms in high summer and, after pollination, develops dark-brown to black fruit the size of a peppercorn. The fruit possess a pepper-like aroma and flavor. The ripe, dried fruit of Vitex agnus castus is the part of the plant used in medicinal preparations today. [1]
CHEMICAL COMPOSITION The fruit of Vitex contains essential oils, iridoid glycosides, and flavonoids. [2] The essential oils include limonene, 1,8 cineole, and sabinene. [3] The primary flavonoids include castican, orientin, and isoVitexin. The two isolated iridoidglycosides are agnuside and aucubin (see Figs 123.1 and 123.2 ). [4] Agnuside serves as a reference material for quality control in the manufacture of Vitex extracts. One study found delta-3-ketosteriods in the flowers and leaves of Vitex. The authors reported (albeit in a somewhat vague manner) that this fraction of the leaves and flowers “probably” contained progesterone and 17-hydroxyprogesterone. Testosterone and epitestosterone were also presumed to be present. [5] Additional research is needed.
Figure 123-1 Aucubin.
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Figure 123-2 Agnuside.
HISTORY AND FOLK USE The genus name Vitex is derived from the “vitilium” which means plaiting. The flexible, but tough and hard, branches were used for construction of wattle fences. Plinius, 1st century AD, has the earliest reference to the plant as Vitex. The species name agnus castus originates from the Latin “castitas” (chastity) and the equating of the Greek “agnos” with the Latin “agnus” (lamb). Vitex agnus castus belonged to the official medicinal plants of antiquity and is mentioned in the works of Hippocrates, Dioscorides, and Theophrast. The first specific medicinal indications can be found in the writings of Hippocrates, 4th century BC. He recommends the plant for injuries, inflammation, and swelling of the spleen, and the leaves in wine for hemorrhages and the “passing of afterbirth”. In the Corpus Hippocratum he states: If blood flows from the womb, let the woman drink dark red wine in which the leaves of the chaste tree have been steeped. A draft of chaste leaves in wine also serves to expel a chorion held fast in the womb. Dioscorides attributed to the fruit a hot and astringent activity and recommended it for wild animal bites, swelling of the spleen, and dropsy. Decoctions of the fruit and plant were used as sitz baths for diseases of the uterus. The English name for Vitex agnus castus, “chaste tree”, is derived form the belief that the plant would suppress libido in women taking it. In Greek cities, festivals in the honor of Demeter included a vow of chastity by the local women. The Catholic church in Europe developed a variation on this theme by placing the blossoms of the plant in the clothing of novice monks to supposedly suppress libido. It is interesting to note that another common name for Vitex agnus castus, “monk’s pepper”, derived from the fact that monks in southern Europe commonly used the fruit as a spice in their cooking.
PHARMACOLOGY According to Dr Rudolf Fritz Weiss, Vitex acts on the diencephalohypophyseal system. Vitex increases LH production (see Fig. 123.3 ). The result is a shift in the ratio of estrogen to progesterone, in favor of progesterone. This
Figure 123-3 Impact of Vitex on pituitary hormone secretion.
is, in fact, a corpus luteum-like hormone effect. [6] The ability of Vitex to increase or modulate progesterone levels in the body is therefore an indirect effect and not a direct hormonal action. [7] This is in contrast to other phytomedicines, like Black cohosh, frequently used in gynecology, which directly bind to estrogen receptors
through their content of phytoestrogens. [8] Vitex also modulates the secretion of prolactin from the pituitary gland. Early animal studies indicated an increase in lactation and enlargement of the mammary gland following administration of Vitex. [7] Current research with Vitex indicates usefulness in hyperprolactinemia. In studies with rats, Vitex was shown to inhibit prolactin release by the pituitary gland – particularly under stress. The mechanism of action appears to involve the ability of Vitex to directly bind dopamine receptors and subsequently inhibit prolactin release in the pituitary. [9] [10] Slight hyperprolactinemia is commonly associated with corpus luteum insufficiency. [11]
CLINICAL APPLICATIONS The causes of menstrual disorders are multifaceted and can vary greatly in their manifestation. Frequently, therapeutic interventions must be used on a trial and error basis over the duration of a number of menstrual cycles to determine their efficacy. Nutritional interventions like vitamin B 6 , magnesium, and vitamin E, as well as phytomedicines such as dong quai and evening primrose oil, have all shown greater efficacy when used over time periods of several months. This reflects the gradual balancing effect that many of these interventions have on the female hormonal system. Vitex certainly fits this mould. The majority of clinical studies completed with Vitex have been non-controlled studies with large populations
1021
of female patients in European gynecology practices. Vitex, which has a Commission E Monograph in Germany, is frequently used in these practices as an initial intervention in a number of menstrual disorders, including: • premenstrual syndrome • hypermenorrhea • polymenorrhea • anovulatory cycles • secondary amenorrhea • infertility • hyperprolactinemia. Many of these cases can be linked to corpus luteum insufficiency. Vitex is also used in cases of poor lactation, uterine fibroids, and climacteric. Corpus luteum insufficiency
Corpus luteum insufficiency (also referred to as luteal phase defect) is a manifestation of suboptimal ovarian function. In laboratory terms, corpus luteum insufficiency is usually defined as an abnormally low progesterone level 3 weeks after the onset of menstruation (serum progesterone below 10–12 ng/ml). This state is normal during puberty and at menopause. However, it is usually considered abnormal when occurring in women between the ages of 20 and 40 years. [12] Corpus luteum insufficiency points to abnormal formation of ovarian follicles, an abnormality that may be so pronounced that no secondary or tertiary follicles are produced, with a resulting lack of ovulation (anovulation). Corpus luteum insufficiency also leads to a relative deficiency of progesterone. Insufficient levels of progesterone may also result in the formation of ovarian cysts. Corpus luteum insufficiency may result in a myriad different menstrual abnormalities. Table 123.1 lists the most common clinical conditions in 1,592 women diagnosed with corpus luteum insufficiency. Foremost are hypermenorrhea (heavy periods), polymenorrhea (abnormally frequent periods), and persistent anovulatory bleeding. It is interesting to note that secondary amenorrhea (lack of a period) may sometimes be observed in women with corpus luteum insufficiency. Disturbances of other hormones may also be associated with corpus luteum insufficiency. One study found hyperprolactinemia in 70% of cases. exaggerated response to the thyroid-releasing hormone (TRH) test which is associated with manifest or latent hypothyroidism.
[ 13]
Also noted is an
Premenstrual syndrome
Premenstrual syndrome (PMS) is one of the most frequent complaints found in gynecology practices. According to TABLE 123-1 -- The most common clinical conditions in 1,592 women diagnosed with corpus luteum insufficiency Diagnosis No. of patients Percentage of total Hypermenorrhea
418
26.3
Polymenorrhea
369
23.2
Persistent anovulatory bleeding
216
13.6
Secondary amenorrhea
202
12.7
Dysmenorrhea
186
11.7
Anovulatory cycles
175
11.0
Involuntary sterility
145
9.1
Oligomenorrhea
69
4.3
Menorrhagia/metrorrhagia
66
4.1
Irregular menstrual cycles
32
2.0
Primary amenorrhea
1
0.1
some estimates, 30–40% of menstruating women are affected by PMS.[14] Table 123.2 lists the different categories for PMS and the symptoms associated with them. Two monitoring surveys of gynecology practices in Germany examined the effect of Vitex on 1,542 women with a diagnosis of PMS. [15] The mean age of the patients was 34.7 with a range of 13–62 years. Additional diagnoses noted with these patients included corpus luteum insufficiency ( n = 1016) and uterine fibroids ( n = 170). Patients were placed on a proprietary Vitex liquid extract known as “Agnolyt ® ” and were instructed to take 40 drops daily. The average duration of treatment was 166 days. The efficacy of treatment was assessed by both patients and their physicians. These assessments are listed in Table 123.3 . In over 90% of the cases, symptoms were completely relieved, with a report of side-effects in only 2% of the patients (listed in Table 123.3 ). Only 17 of the 1,542 women studied had to stop treatment due to side-effects. Improvement in symptoms began after an average treatment duration of 25.3 days. After completion on the monitoring period, 562 patients continued taking Agnolyt. Another study with 36 patients with a diagnosis of
Subgroup
TABLE 123-2 -- PMS subgroups Symptoms
Prevalence
PMS-A
Anxiety
75–80%
Nervous tension PMS-H
Irritability
60–70%
Fluid retention Weight gain Swollen extremities Abdominal bloating Breast tenderness PMS-C
Increased appetite
35–40%
Sweet craving Headache Fatigue Fainting spells PMS-D
Depression
30–35%
Insomnia Forgetfulness
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TABLE 123-3 -- Efficacy of Vitex Percentage of patients
Outcome Patient assessment Improved
57%
Relieved
33%
No change
4%
No data
5%
Physician assessment Very good/good
71%
Satisfactory
21%
Unsatisfactory
4%
No data
3%
PMS used 40 drops of Vitex liquid extract (Agnolyt ® ) daily over 3 cycles. A reduction was noted in physical symptoms (headaches, pressure and tenderness in the breasts, bloating and fatigue) and psychological changes (increased appetite, craving for sweets, nervousness/restlessness, anxiety, irritability, lack of concentration, depression, mood swings, and aggressiveness). Additionally, the interval of the luteal phase was normalized from an average of 5.4 days to one of 11.4 days and a diphasic cycle was established. [16] A recent study compared the efficacy of Vitex (3.5– 4.2 mg/day of dried fruit extract – Agnolyt ® ) with vitamin B 6 (200 mg/day) in 175 women with premenstrual tension symdrome.[17] While both were effective (symptom scale decreased from 15.2 to 5.1 in the Vitex group and from 11.9 to 5.1 in the B 6 group), 24.5% reported excellent results, compared with only 12.1% with B6 . However, over twice as many women (12) reported side-effects from Vitex than from B6 (5). Abnormal menstrual cycles
The first major clinical study on Vitex was published in 1954. Fifty-seven women suffering from a variety of menstrual disorders were given Vitex on a daily basis. Fifty patients developed a cycle in phase with menses while seven women did not respond. Of the 50 women, six with secondary amenorrhea demonstrated one or more cyclic menstruations. Of nine with oligomenorrhea (scant or infrequent menstrual flow), six experienced a shortening of the menstrual interval and an increase in bleeding. Most striking was a dramatic improvement in menstrual regularity among 40 patients with cystic hyperplasia of the endometrium. This condition is associated with a relative deficiency of progesterone and is characterized by dysfunctional uterine bleeding. No side-effects were observed with Vitex treatment. [18] An observational study of 126 women with menstrual disorders utilized 15 drops of Vitex liquid extract three times daily over several cycles. In 33 women suffering from polymenorrhea, the duration between periods lengthened, on average, from 20.1 days to 26.3 days. In 58 patients with menorrhagia, a statistically significant shortening of menses was achieved. Fourteen patients became pregnant during the study; among them were three women with primary infertility over 2, 3, and 8 years, as well as two patients with secondary infertility over 4 and 15 years. [19] Twenty patients with secondary amenorrhea were admitted to a 6 month study using Vitex liquid extract at 40 drops daily. Laboratory monitoring of progesterone, FSH, LH, and pap smears were performed at pre-study, 3 months, and 6 months. At the end of the 6 month study, data were available in 15 patients. The onset of cycles with menstruation was observed with Vitex treatment in 10 out of 15 patients. The hormone values showed increased values for progesterone and LH, while FSH values either did not change or decreased slightly. [20] Two non-blind uncontrolled trials studied the effect of Vitex on corpus luteum function in 48 infertile women between 23 and 39 years of age. The inclusion criteria were normal prolactin levels (below 20 ng/ml), normal results in the prolactin and thyroid-stimulating hormone (TSH) stimulation tests and an abnormally low serum progesterone (below 12.0 ng/ml on the 20th day of the cycle). Treatment consisted of Vitex liquid extract, 40 drops daily, without any other medication for 3 months. Forty-five women completed the studies (three were excluded because of concurrent hormone use). The outcome of therapy was assessed by the normalization of the midluteal progesterone level and by correction (lengthening) of any pre-existing shortening of the phases of the cycle. Treatment was deemed successful in 39 of the 45 patients. Seven women became pregnant, serum progesterone was restored to normal (>12 ng/ml) in 25 patients and there was a trend toward normalization of progesterone levels in seven cases. [21] Hyperprolactinemia
A mentioned previously, Vitex has shown a modulating effect on prolactin. A double-blind, placebo-controlled study examined the effect of a proprietary Vitex preparation (“Strotan ® ”) on 52 women with luteal phase defects due to latent hyperprolactinemia. The daily dose of the Vitex extract was 20 mg and the study lasted for 3 months. Hormonal analysis was performed at days 5–8 and day 20 of the menstrual cycle before and after 3 months of therapy. After 3 months of therapy, 37 cases were available for analysis (20 placebo and 17 Vitex). Prolactin release was significantly reduced in the Vitex group. Shortened luteal phases were normalized
and deficits in progesterone production were normalized. No side-effects were noted and two women in the Vitex group became pregnant. [22]
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Potential indications
Anecdotal clinical reports have indicated a potential use for Vitex in the management of climacteric (hot flashes) in the early stages of menopause. [24] Uterine fibroids which are embedded into the muscle or are subserous may have their growth arrested by use of Vitex. Submucosal fibroids, however, are not likely to respond. Mild cases of endometriosis for which progesterone therapy are indicated also may respond to Vitex.
DOSAGE The majority of clinical studies with Vitex agnus castus (Vitex) have been performed with a tincture of the fruit. Most medicinal texts, as well as monographs in Europe, list the entire preparation as “medicinally active”. [1] This is an indication that the medical activity of the fruit is examined as a whole and that specific “active constituents” have not been individually isolated. Since the early 1950s, the standard Vitex extract used for clinical research and treatment in Europe has been an alcohol-based tincture of the fruits of the plant known as Agnolyt® . A 100 ml amount of the solution is standardized to contain 9 g of the fruit. The recommended dosage is 40 drops with some liquid in the morning over several months without interruption. It is recommended that treatment with this extract be continued over several weeks after relief of symptoms is determined. The recent development of a solid extract equivalent of the tincture has allowed used by alcohol-sensitive women. The capsules, which contain 4.2 mg of the dried extract, have a one-a-day recommendation also. It is important to note that Vitex is not a fast-acting medication. In cases of anovulatory cycles and infertility, treatment duration may be as long as 5–7 months before inception occurs. For secondary amenorrhea of more than 2 years’ duration, Vitex should be administered for at least 1.5 years. In other conditions mentioned, however, first indications of efficacy with Vitex are usually seen within one or two cycles. Extensive or complete freedom of symptoms usually occurs after 4–6 months of treatment.
TOXICOLOGY Human and animal studies have determined Vitex to be safe for most women of menstruating age. Vitex should not be used during pregnancy, but it is safe for use during lactation. Safety has not been determined in children. Vitex is not recommended in women taking hormone replacement therapy. Side-effects noted in one large population study are listed in Table 123.4 . Side-effects noted in other clinical observations have included itching and an occasional rash. Again, these side-effects are rare and have been noted in only 1–2% of the patients monitored on Vitex. Some women also report that menstrual flow increases during Vitex treatment. This is often an indication of therapeutic efficacy.
Side effect
TABLE 123-4 -- Side-effects from Vitex in 1,542 women No. of patients reporting
No information
7
Nausea
5
Gastric complaints
3
Acne
3
Changes in menses rhythm
2
Diarrhea
2
Erythema
2
Allergy
1
Weight gain
1
Giddiness
1
Heartburn
1
Hypermenorrhea
1
Pruritis
1
Alopecia
1
Cardiac palpitations
1
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2.
Agni casti fructus (Chaste tree fruits). Bundesanzeiger No. 90, May 15, 1985
Agni cast fructus (chaste tree fruits). Commission E Monograph, December 2, 1992
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KJ, Balzevic N. The composition of the essential oil of Vitex agnus castus. Planta Medica 1992; 58: A 681
4. Gomaa
CS. Flavonoids and iridoids from Vitex agnus castus. Planta Medica 1978; 33: 277
5. Saden-Krehula 6. Weiss
RF. Herbal medicine. Sweden: Ab Arcanum. 1988
7. Amann
W. Removing an ostipation using Agnolyt. Ther Gegenew 1965; 104: 1263–1265
8. Reichert 9. Sliutz
M, Kustrak D, Blazevic N. Delta-3-ketosteroids in flowers and leaves of Vitex agnus castus. Planta Medica 1990; 56: 547
RG. Phyto-estrogens. Quart Rev Nat Med Spring 1994, pp. 27–33
G, Speiser P et al. Agnus castus extracts inhibit prolactin secretion of rat pituitary cells. Horm Metab Res 1993; 25: 253–255
10.
Jarry H, Leonhardt S, Wuttke W. Agnus castus as dopaminergous effective principle in mastodynon N. Zeitschrift Phytother 1991; 12: 77–82
11.
Schneider HPG, Goeser R, Cirkel U. Prolactin and the inadequate corpus luteum. In: Lisuride and other dopamine agonists. New York: Raven Press. 1983: p 113–120
12.
Propping D, Katzorke T, Beliken L. Diagnosis and therapy of corpus luteum deficiency in general practice. Therapiewoche 1988; 38: 2992–3001
13.
Muhlenstedt D, Wutke W, Schneider HPG. Short luteal phase and prolactin. Fertil Steril 1977; 373–374
14.
Lurie SR. The premenstrual syndrome. Obstet Gynecol 1990; 45: 220–228
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Dittmar FW, Bohnert KJ et al. Premenstrual syndrome: treatment with a phytopharmaceutical. TW Gynakol 1992; 5: 60–68
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Coeugniet E, Elek E, Kuhnast R. Premenstrual syndrome (PMS) and its treatment. Arztezeitchr Naturheilverf 1986; 27: 619–622
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Lauritzen CH, Reuter HD, Repges R et al. Treatment of premenstrual tension syndrome with Vitex agnus castus: controlled, double-blind study versus pyridoxine. Phytomed 1997; 4: 183–189
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Probst V, Roth OA. On a plant extract with a hormone-like effect. Dtsch Med Wschr 1954; 79: 1271–1274
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Bleier W. Phytotherapy in irregular menstrual cycles or bleeding periods and other gynecological disorders of endocrine origin. Zentralblatt Gynakol 1959; 81: 701–709
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Losh EG, Kayser E. Diagnosis and treatment of dyshormonal menstrual periods in the general practice. Gynakol Praxis 1990; 14: 489–495
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Propping D, Katzorke T. Treatment of corpus luteum insufficiency. Zeits Allgemeinmedizin 1987; 63: 932–933
Milewicz A, Gejdel E et al. Vitex agnus castus extract in the treatment of luteal phase defects due to hyperprolactinemia: results of a randomized placebo-controlled double-blind study. Arzneim-Forsch Drug Res 1993; 43: 752–756 22.
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Mohr H. Clinical investigations of means to increase lactation. Dtsch Med Wschr 1954; 79: 1513–1516
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Du Mee C. Vitex agnus castus. Aust J Med Herbalism 1993; 5: 63–65
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Chapter 124 - Zingiber officinale (ginger) Michael T. Murray ND Joseph E. Pizzorno Jr ND
Zingiber officinale (family: Zingiberaceae) Common name: ginger
GENERAL DESCRIPTION Ginger is an erect perennial herb with thick tuberous rhizomes (underground stems) from which the aerial stem grows to a height of 2–4 feet. Grass-like alternate leaves, 6–12 inches long and 0.75 inch wide, shoot off from the aerial stem. Wild ginger will produce a beautiful flower, but cultivated ginger rarely flowers. Although ginger is native to southern Asia, it is now extensively cultivated throughout the tropics (e.g. India, China, Jamaica, Haiti, and Nigeria). Jamaica is the major producer, with exports to all parts of the world amounting to more than 2,000,000 lb annually. The knotted and branched rhizome, commonly called the “root”, is the portion of ginger used for culinary and medicinal purposes. Extracts and the oleoresin are produced from dried unpeeled ginger, as peeled ginger loses much of its essential oil content. [1] [2] Ginger oil is produced from the fresh ginger via steam distillation.
CHEMICAL COMPOSITION The following compounds have been isolated from ginger: [1] [2] • starch (up to 50%) • protein (~ 9%) • lipids (6–8%) composed of triglycerides, phosphatidic acid, lecithins, and free fatty acids • a protease (2%) • volatile oils (1–3%), the principal components of which are sesquiterpenes (bisabolene, zingiberene and zingiberol) and various “pungent” principles, aromatic ketones, known collectively as gingerols vitamins (especially niacin and vitamin A) • resins. The pungent principles are thought to be the most
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Figure 124-1 Gingerol.
Figure 124-2 Zingerone.
Figure 124-3 Shogaol.
pharmacologically active components of ginger. Gingerol and its derivatives can be found in concentrations as high as 33% in ginger oleoresin (see Fig. 124.1 ). The fresh oleoresin will have a higher percentage of the more pungent gingerol, as gingerol can be dehydrated during storage to form shogaol or have its fatty acid moiety cleaved to form zingerone (see Figs 124.2 and 124.3 ). The oleoresin is made by extracting the oily and resinous materials with the aid of a solvent (alcohol, hexane, or acetone).
HISTORY AND FOLK USE Ginger has been used for thousands of years in China for medicinal purposes. Chinese records dating from the 4th century BC indicate that it was used to treat numerous conditions: [1] • stomach ache • diarrhea • nausea • cholera • hemorrhage • rheumatism • toothache. It was used by Eclectic physicians in the US in the late 1800s as a carminative, diaphoretic, appetite stimulant, and local counter-irritant.
[3]
Ginger is widely used as a spice, especially in Asian and Indian dishes. It is also used in many baked goods, beverages (ginger ale), candy, liqueurs, and cosmetic products (perfumes, soaps, creams, etc.).
PHARMACOLOGY Ginger possesses numerous pharmacological properties, the most relevant are: • its antioxidant effects • inhibition of prostaglandin, thromboxane, and leukotriene synthesis • inhibition of platelet aggregation • cholesterol-lowering actions • choleretic effects • cardiotonic effects • gastrointestinal actions • thermogenic properties • antibiotic activities. Antioxidant effects
Ginger’s strong antioxidant properties have led to its being investigated for preventing the development of rancidity in meat products. [4] Ginger has been shown to prolong the shelf life of fresh, frozen, and pre-cooked pork patties. Since the use of many synthetic antioxidants is prohibited by law, ginger may one day be used commercially to extend the shelf life of meats and other foods. Presumably the antioxidant components of ginger are absorbed in vivo where they undoubtedly contribute greatly to the pharmacology of ginger. In comparison, curcumin is about 30 times more potent in preventing lipid peroxidation than zingerone. [5] Effects on prostaglandin and leukotriene metabolism
Numerous constituents in ginger have been shown to be potent inhibitors of prostaglandin and leukotriene synthesis. [6] [7] [8] The most potent components appear to be the pungent principles, although the aqueous extract has also demonstrated inhibition. Inhibition of prostaglandin and leukotriene formation could explain some of ginger’s historical use as an anti-inflammatory agent. However, ginger and its extracts also have strong antioxidant activities, and fresh ginger contains a protease that may have similar action to other plant proteases (e.g. bromelain, ficin, papain, etc.) on inflammation. [1] Effects on platelets
Ginger, like garlic and onions, is an inhibitor of platelet aggregation. However, ginger’s effects may be far more
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powerful. In a comparison, an aqueous extract of ginger was shown to exert greater inhibitory effects on platelet aggregation than aqueous garlic and onion extracts. Ginger was shown to produce a greater inhibition on thromboxane formation and pro-aggregatory prostaglandins. Ginger, but not onion or garlic, also significantly reduced platelet lipid peroxide formation.
[ 9]
The superiority of ginger over onions was also demonstrated in a controlled study. [10] Female volunteers given either 70 g raw onions or 5 g raw ginger demonstrated that ginger has a pronounced effect in lowering platelet thromboxane production while onion actually produced a mild elevation (pooled results). Cholesterol-lowering and hepatic effects
Ginger has been shown to significantly reduce serum and hepatic cholesterol levels in cholesterol-fed rats by impairing cholesterol absorption as well as stimulating cholesterol-7-alpha-hydroxylase, the rate-limiting enzyme of bile acid synthesis. [11] [12] [13] In addition, ginger has also been shown to increase bile secretion. [14] Therefore, ginger works to lower cholesterol by promoting excretion and impairing absorption. Cardiotonic and hypotensive properties
Gingerol has shown potent cardiotonic activity (positive ionotropic and chronotropic effects) on isolated guinea pig left atria. [15] [16] These effects are a result of acceleration of calcium uptake by the sarcoplasmic reticulum. Gingerol was the first substance shown to produce these effects. Individuals with heart problems or high blood pressure are probably better off using fresh ginger rather than the dried preparation. This recommendation is based not only on the fact that gingerol is the more potent cardiotonic, but also because shogaol has been shown to produce a blood pressure-elevating effect in animals. [17] Gingerol is found predominantly in fresh ginger while shogaol is rarely found in fresh ginger. Analgesic effects
Ginger has demonstrated analgesic effects in experimental studies in animals. [18] This effect is thought to be a result of shogaol inhibiting the release of substance P in a similar fashion to capsaicin, the pungent principle of red pepper ( Capsicum frutescens). Gastrointestinal smooth muscle effects
One interesting aspect of ginger is its ability to simultaneously improve gastric motility while exerting antispasmodic effects. This is consistent with its use as a gastrointestinal tonic. A lipophilic ginger extract was shown in one study to enhance gastric motility, as evidenced by increased intestinal transport of a charcoal meal fed to rats, [19] and various fat-soluble components of ginger, such as galanolactone, demonstrated antagonism of serotonin receptor sites. [20] This latter mechanism may be responsible for ginger’s antispasmodic effects on visceral and vascular smooth muscle. Ginger has been shown to inhibit serotonin-induced diarrhea. [21] Anti-ulcer effects
Ginger has demonstrated significant anti-ulcer effects in a variety of animal models. [22] [23] [24] Ginger prevents ulcer formation due to ethanol, indomethacin, aspirin, and other common ulcerogenic compounds. The pungent principles appear to be responsible for this effect. Interestingly, in one study, roasted ginger demonstrated inhibition of ulcer formation in three gastric ulcer models while dry ginger had no such effect. [25] Thermogenic properties
Ginger is noted for its apparent ability to subjectively warm the body and has historically been used as a diaphoretic. In animal studies, ginger has been shown to help maintain body temperature and to inhibit serotonin-induced hypothermia. [21] [26] Crude extracts and the pungent components of ginger have been shown to increase oxygen consumption, perfusion pressure, and lactate production in the perfused rat hind limb. [27] These effects signify increased thermogenesis. Gingerol is the most potent thermogenic component of ginger. A human study demonstrated that consuming a ginger sauce (containing unspecified amounts of ginger principles) with a meal produced no significant effect on metabolic rate. [28] However, there were
two problems with this study: (1) the concentration of gingerol in the preparation used was probably low or zero; and (2) the effective concentration range of gingerol for its thermogenic effects is quite narrow. Given ginger’s historical use as a “warming” substance, these scientific investigations appear to support its use as a diaphoretic and thermogenic aid, although confirmation in humans is still lacking. Antibiotic activity
Ginger, shogaol, and zingerone have been shown to be strongly inhibitory against Salmonella typhi, Vibrio cholerae, and Tricophyton violaceum, while aqueous extracts at 2.5, 5, and 25% concentration have been shown to be effective against Trichomonas vaginalis. [29]
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CLINICAL APPLICATIONS Ginger is widely used as a condiment for its unique flavors, but from the above-described pharmacology it obviously has important medicinal effects as well. In general, like many other culinary herbs and spices such as garlic and onions, ginger provides many health-promoting effects. Specifically, ginger provides benefit to many body systems including the digestive, hepatobiliary, and cardiovascular systems. Historically, the majority of complaints for which ginger was used concerned the gastrointestinal system. A clue to ginger’s efficacy in alleviating gastrointestinal distress is offered in several recent double-blind studies in motion sickness, hyperemesis gravidum, and postoperative nausea and vomiting. Human studies have also shown a positive effect in arthritis and migraine headaches. Motion sickness
Ginger was first shown to be effective in treating motion sickness by Mowrey & Clayson in 1982. [30] In their study, ginger (940 mg) was shown to be far superior to Dramamine (100 mg) in relieving symptoms of nausea and vomiting. Since this initial study, several better designed follow-up studies have evaluated the effectiveness of ginger as a motion sickness medication. The appearance of motion sickness trials using ginger prompted an interest in ginger by NASA, which subsequently funded a study at Louisiana State University. This study compared ginger, both fresh and dried powdered, with scopolamine by measuring the number of head movements experimental subjects could make in a rotating chair until they reached an end-point of motion sickness short of vomiting. Ginger was not shown to produce any protection against motion sickness in this model or in two additional protocols (vestibular stimulation only and combined vestibular-visual stimulation). [31] However, in perhaps a more “real life” test, ginger (1 g) given to naval cadets, unaccustomed to sailing in heavy seas, was shown to reduce the tendency to vomiting and cold sweating compared with a placebo in a double-blind trial. [32] Mowrey & Clayson proposed that the anti-motion sickness effects of ginger were due to local gastrointestinal tract effects rather than to central nervous system effects. Although ginger’s mechanism of action in alleviating gastrointestinal distress has yet to be fully elucidated, there is evidence to support this hypothesis. Ginger has been shown to partially inhibit the excessive gastric motility characteristic of motion sickness. [31] To further support a gastric versus a CNS mechanism of action, one study clearly demonstrated that neither the vestibular nor the oculomotor system, both of which are of critical importance in the occurrence of motion sickness, was influenced by ginger (1 g). [33] However, in a double-blind cross-over placebo-controlled study, ginger (1 g) was shown to produce significant reductions in induced vertigo, but not nystagmus. [34] These results suggest that ginger may dampen the vestibular impulses to the autonomic centers of the brain. The overall effectiveness of ginger in motion sickness has yet to be determined. Issues that the studies have raised include the variability in the quality of commercial ginger preparations and the time required for ginger to produce its effects. Commercial preparations vary widely in chemical composition and often contain adulterants, and in the ginger study conducted at sea, ginger only reduced symptoms of cold sweating and vomiting at the end of 4 hours. In other words, it appears that ginger may prove to be more effective when well-defined preparations are given at least 4 hours prior to experiencing motion. Nausea and vomiting
Ginger’s anti-emetic actions has been studied in hyperemesis gravidum, the most severe form of pregnancy-related nausea and vomiting. This condition usually requires hospitalization. In a double-blind randomized cross-over trial, ginger root powder at a dose of 250 mg four times a day brought about a significant reduction in both the severity of the nausea and the number of attacks of vomiting in 19 of 27 cases of early pregnancy (less than 20 weeks). [35] These clinical results, along with the safety and the relatively small dose of ginger required and the problems (e.g. teratogenicity) with anti-emetic drugs in pregnancy, support the use of ginger in nausea and vomiting in pregnancy. This is becoming a well-accepted prescription even in orthodox obstetrical practices – ginger (as well as vitamin B 6 ) was recommended as an effective treatment of early nausea and vomiting of pregnancy in a 1992 review of current drug therapy during pregnancy published in the medical journal Current Opinion in Obstetrics and Gynecology. The anti-emetic action of ginger was also observed in women who had undergone major gynecological surgery. In a double-blind study, 500 mg of dry powdered ginger root was shown to significantly reduce the incidence of nausea compared with placebo in a manner similar to the drug metoclopramide. [36] Inflammatory conditions
Ginger’s ability to inhibit the formation of inflammatory prostaglandins, thromboxanes, and leukotrienes, along with its strong antioxidant activities and protease component, suggests a possible benefit in inflammatory conditions. To test this hypothesis, a preliminary clinical
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study was conducted on seven patients with rheumatoid arthritis, in whom conventional drugs had provided only temporary or partial relief. [37] One patient took 50 g/day of lightly cooked ginger while the remaining six took either 5 g of fresh or 0.1–1 g of powdered ginger daily. All patients reported substantial improvement, including pain relief, increased joint mobility, and decreased swelling and morning stiffness. In the follow-up to this study, 28 patients with rheumatoid arthritis, 18 with osteoarthritis, and 10 with muscular discomfort who had been taking powdered ginger for periods ranging from 3 months to 2.5 years were evaluated. [38] Based on clinical observations, Srivastava & Mustafa reported that 75% of the arthritis patients and 100% of the patients with muscular discomfort experienced relief in pain or swelling. The recommended dosage was 500–1,000 mg/day, but many patients took three to four times this amount. Patients taking the higher dosages also reported quicker and better relief. Srivastava & Mustafa [39] have also reported ginger to be beneficial in migraine headache. Given ginger’s effects on platelets, eicosanoids, and serotonin inhibition, this recommendation makes sense.
DOSAGE There remain many questions concerning the best form of ginger and the proper dosage. Most research studies have utilized 1 g of dry powdered ginger root. Practically speaking, this is a small dose of ginger. For example, ginger is commonly consumed in India at a daily dose of 8–10 g. Furthermore, although most studies have used powdered ginger root, fresh (or possibly freeze-dried) ginger root or extracts concentrated for gingerol at an equivalent dosage may yield even better results because they may deliver higher levels of gingerol as well as the active protease.
In the treatment of nausea and vomiting due to motion sickness, pregnancy, or postoperatively, a dosage of 1–2 g of dry powdered ginger may be effective. This would be equivalent to approximately 10 g or one-third of an ounce of fresh ginger root, roughly a quarterinch slice. For inflammatory conditions like rheumatoid arthritis, the dosage should be double this amount. For ginger extracts standardized to contain 20% gingerol and shogaol, an equivalent dosage in treating motion sickness or nausea and vomiting would be 100–200 mg. For inflammatory conditions like rheumatoid arthritis, the dosage is 100–200 mg three times daily.
TOXICOLOGY Ginger does not appear to produce any toxicity problems when used at normal dosages. Although ginger extracts and several components in ginger have been shown to possess potent mutagenic activity, ginger also contains several equally potent anti-mutagenic substances. [40] [41] The significance of this mutagenicity (the study was conducted in E. coli not the Ames test) has not been entirely determined, but the long historic use and lack of carcinogenic or toxic effect in animals suggest that it is not a problem. In acute toxicity tests in mice, ginger extract administered as a lavage was tolerated up to 2.5 g/kg with no mortality or side-effects during a 7 day trial period. [42] Increasing the dosage to 3.0–3.5 g/kg resulted in a 10–30% mortality. In comparison, 0.6 g/kg of aspirin produced mortality in 25%, stomach ulcers in 40%, and hypothermia in 60% of subjects. Some individuals consuming high doses, i.e. greater than the equivalent of 6 g of dried powdered ginger alone on an empty stomach, may experience some gastrointestinal discomfort. Administration of 6 g of dried powdered ginger has been shown to increase the exfoliation of gastric surface epithelial cells in human subjects.[43] This may cause some gastric distress and ultimately could lead to ulcer formation. Therefore, it is recommended that dosages on an empty stomach be less than 6 g.
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YB, Kim YS, Ashmore CR. Antioxidant property in ginger rhizome and its application to meat products. J Food Sci 1986; 51: 20–23
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F, Iwakami S, Shibuya et al. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull 1992; 40: 387–391
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KC. Isolation and effects of some ginger components on platelet aggregation and eicosanoid biosynthesis. Prostaglandins Leurotri Med 1986; 25: 187–198
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Srivastawa KC. Effect of onion and ginger consumption on platelet thromboxane production in humans. Prost Leukotri Ess Fatty Acids 1989; 35: 183–185
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Giri J, Sakthi Devi TK, Meerarani S. Effect of ginger on serum cholesterol levels. Ind J Nutr Diet 1984; 21: 433–436
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Srinivasan K, Sambaiah K. The effect of spices on cholesterol 7 alpha-hydroxylase activity and the serum and hepatic cholesterol levels in the rat. Int J Vitam Nutr Res 1991; 61: 364–369
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Yamahara J, Miki K, Chisaka T et al. Cholagogic effect of ginger and its active constituents. J Ethnopharmacol 1985; 13: 217–225
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Shoji N, Iwasa A, Takemoto T et al. Cardiotonic principles of ginger ( Zingiber officinale Roscoe). J Pharm Sci 1982; 10: 1174–1175
Kobayashi M, Ishida Y, Shoji N, Ohizumi Y. Cardiotonic action of [8]-gingerol, an activator of the Ca Pharmacol Exp Ther 1988; 246: 667–673 16.
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Suekawa M, Aburada M, Hosoya E. Pharmacological studies on ginger. II. Pressor action of (6)-shogoal in anesthetized rats, or hindquarters, tail and mesenteric vascular beds of rats. III. Effect of spinal destruction on (6)-shagoal-induced pressor response in rats. J Pharmacobio Dyn 1986; 9: 842–860 17.
Onogi T, Minami M, Kuraishi Y, Staoh M. Capsaicin-like effect of (6)-shagoal on substance P-containing primary afferents of rats. A possible mechanism of its analgesic action. Neuropharmacol 1992; 31: 1165–1169 18.
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Yamahara J, Huang QR, Li YH et al. Gastrointestinal motility enhancing effect of ginger and its active constituents. Chem Pharm Bull 1990; 38: 430–431
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Huang QR, Iwamoto M, Aoki S et al. Anti-5-hydroxytryptamine effect of galanolactone, diterpinod isolated from ginger. Chem Pharm Bull 1991; 39: 397–399
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Huang Q, Matsuda H, Sakai K et al. The effect of ginger on serotonin induced hypothermia and diarrhea. Yakugaku Zasshi 1990; 110: 936–942
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Al Yahya MA, Rafatullah S, Mossa JS et al. Gastroprotective actitivity of ginger, Zingiber officinale Rosc., in albino rats. Am J Chin Med 1989; 17: 51–56
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Yamahara J, Mochizuki M, Rong HQ et al. The anti-ulcer effect in rats of ginger constituents. J Ethnopharmacol 1988; 23: 299–304
Yamahara J, Hatakeyama S, Taniguschi K et al. Stomachic principles in ginger. II. Pungent and anti-ulcer effects of low polar constituents isolated from ginger, the dried rhizome of Zingiber officinale Roscoe cultivated in Taiwan. The absolute stereostructure of a new diarylheptanoid. J Pharm Soc Japan 1992; 112: 645–655 24.
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Kano Y, Zong QN, Komatsu K. Pharmacological properties of galenical preparation. XIV. Body temperature retaining effect of the Chinese traditional medicine, “goshuyu-to” and component crude drugs. Chem Pharm Bull 1991; 39: 690–692 26.
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Elderhsaw TPD, Colquhoun EQ, Dora KA et al. Pungent principles of ginger ( Zingiber officinale) are thermogenic in the perfused rat hind limb. Int J Obesity 1992; 16: 755–763
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Henry CJK, Piggott SM. Effect of ginger on metabolic rate. Human Nutr Clin Nutr 1987; 41C: 89–92
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Chang HM, But PPH. Pharmacology and applications of Chinese materia medica, vol. 1. Philadelphia, PA: World Scientific. 1986: p 366–369
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Mowrey D, Clayson D. Motion sickness, ginger, and psychophysics. Lancet 1982; i: 655–657
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Stewart JJ, Wood MJ, Wood CD, Mims ME. Effects of ginger on motion sickness susceptibility and gastric function. Pharmacology 1991; 42: 111–120
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Grontved A, Brask T, Kamskard J, Hentzer E. Ginger root against seasickness – a controlled trial on the open sea. Acta Otolaryngol 1988; 105: 45–49
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Holtman S, Clarke AH, Scherer H, Hohn M. The anti-motion sickness mechanism of ginger. Acta Otolaryngol 1989; 108: 168–174
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Grontved A, Hentzer E. Vertigo-reducing effect of ginger root. ORL 1986; 48: 282–286
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Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 1990; 38: 19–24
Bone ME, Wilkinson DJ, Young JR et al. Ginger root – a new antiemetic. The effect of ginger root on postoperative nausea and vomiting after major gynecological surgery. Anaesthesia 1990; 45: 669–671 36.
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Srivastava KC, Mustafa T. Ginger ( Zingiber officinale) and rheumatic disorders. Med Hypothesis 1989; 29: 25–28
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Srivastava KC, Mustafa T. Ginger ( Zingiber officinale) in rheumatism and musculoskeletal disorders. Med Hypothesis 1992; 39: 342–348
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Mustafa T, Srivastava KC. Ginger ( Zingiber officinale) in migraine headaches. J Ethnopharmacol 1990; 29: 267–273
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Nakamura H, Yamamoto T. Mutagen and antimutagen in ginger, Zingiber officinale. Mutation Res 1982; 103: 119–126
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Nagabhushan M, Amonkar AJ, Bhide SV. Mutagenicity of gingerol and shogaol and antimutagenicity of zingerone in salmonella/microsome assay. Cancer Lett 1987; 36: 221–233
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Desai HG, Kalro RH, Choksi AP. Effect of ginger and garlic on DNA content of gastric aspirate. Ind J Med Res 1990; 92: 139–141
Section Six - Specific health problems
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Chapter 125 - Acne vulgaris and acne conglobata Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Open comedones – dilated follicles with central dark, horny plugs (blackheads) • Closed comedones – small follicular papules with (red papules) or without (whiteheads) inflammatory changes • Superficial pustules – collections of pus at follicular opening • Nodules – tender collections of pus deep in dermis • Cysts – from nodules that fail to discharge contents to the surface • Large deep pustules – from nodules that break down adjacent tissue leading to scars.
GENERAL CONSIDERATIONS Acne is the most common of all skin problems. Acne vulgaris is characterized as a pilosebaceous disease with comedones, papules, and pustules, while acne conglobata is a more severe form, with cyst formation and subsequent scarring. The lesions occur predominantly on the face and, to a lesser extent, on the back, chest, and shoulders. It is more common in males and onset is typically at puberty (somewhat later for conglobata form). In acne vulgaris the onset reflects an increase in pilosebaceous gland size and sebum secretion due to androgenic stimulation. The severity and progression are determined by a complex interaction between hormones, keratinization, sebum, and bacteria. The lesions begin in the upper portion of the follicular canal, with hyperkeratinization being the first microscopic change. This leads to blockage of the canal, resulting in dilation and thinning. Eventually a comedo is formed. The formation of open or closed comedones appears to be related to the degree of keratinization and the level of blockage of the duct. Despite a large amount of purulent exudate in pustular and cystic lesions, the only bacteria commonly cultured
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are normal skin species: Propionibacterium acnes (Corynebacterium acnes) and Staphylococcus albus. P. acnes is believed to release lipases that hydrolyze sebum triglycerides into free fatty acid lipoperoxides, thus promoting an inflammatory cascade. Acne-like lesions can occur in response to a variety of compounds: corticosteroids, halogens, isonicotinic acid, diphenylhydantoin, and lithium carbonate. Exposure to various industrial pollutants also causes acne: machine oils, coal tar derivatives, and chlorinated hydrocarbons. Cosmetics, pomades, over-washing, and repetitive rubbing can produce acne. Endocrinological aspects
Acne is considered to be an androgen-dependent condition, and androgen excess, either systemic or local, is associated with more severe forms of the disease. Androgens control sebaceous gland secretion and exacerbate the development of abnormal keratinizing follicular epithelium. Endocrine disorders producing excess andro-gens are important etiological factors: idiopathic adrenal androgen excess, partial defect in 21-hydroxylase, and polycystic ovarian syndrome. Free testosterone, dihydroepiandrosterone, dehydroepiandrosterone sulfate, and low sex-hormone-binding globulin levels have all been implicated. [1] [2] [3] The skin of acne patients shows greater activity of 5-alpha-reductase, the enzyme converting testosterone to the more potent androgen, dihydrotestosterone. [4] [5] This increased activity is independent of systemic levels of androgens and may explain the poor correlation between systemic levels of androgens and the severity of the acne lesions.
THERAPEUTIC CONSIDERATIONS Effective treatment of acne is a significant clinical challenge. Success can only be obtained by a rigorous, comprehensive application of dietary, nutritional, and botanical interventions. Nutrition Diet
Subjects fed a high-protein diet (44% protein, 35% carbohydrate, and 21% fat) show substantially less 5-alpha-reduction of testosterone and enhanced cytochrome P450 hydroxylation of estridiol, both therapeutic goals. [6] A high carbohydrate diet (10% protein, 70% carbohydrate, and 20% fat) had the opposite effect. Foods high in iodine should be eliminated, and milk consumption (due to high hormone content) should be limited. be eliminated.
[7]
Trans-fatty acids and high-fat foods should also
Sugar, insulin, and chromium
Many dermatologists have reported that insulin is effective in the treatment of acne, suggesting impaired cutaneous glucose tolerance and/or insulin insensitivity. The insulin was either given systemically (5–10 units two to three times a week) or injected directly into the lesion.
[8] [9]
One study comparing the results of oral glucose tolerance tests in acne patients showed no differences from controls. However, repetitive skin biopsies revealed that the acne patients’ skin glucose tolerance was significantly impaired. [10] One researcher of the role of glucose tolerance in acne coined the term “skin diabetes” to
describe the disorder of acne. [11] Considering the known immunosuppressive effects of sugar (see Ch. 53 ), all concentrated carbohydrates should be strictly eliminated. High-chromium yeast is known to improve glucose tolerance and enhance insulin sensitivity [12] and has been reported in an uncontrolled study to induce rapid improvement in patients with acne. [13] Vitamin A
Retinols, including oral vitamin A, have been shown in many studies to reduce sebum production and the hyperkeratosis of sebaceous follicles. Retinol has been shown to be effective in treating acne when used at high, and potentially toxic, dosages, i.e. 300,000–400,000 IU per day for 5–6 months. [14] Vitamin A toxicity. Although dosages of vitamin A below 300,000 IU/day for a few months rarely cause toxicity symptoms, [14] early recognition is important. Cheilitis (chapped lips) and xerosis (dry skin) will generally occur in the majority of patients, particularly in dry weather. The first significant toxic symptom is usually headache followed by fatigue, emotional lability, and muscle and joint pain. Laboratory tests appear unreliable for monitoring toxicity, since serum vitamin A levels correlate poorly with toxicity, and SGOT and SGPT are elevated only in symptomatic patients. Of far greater concern is the teratogenicity of massive dosages of vitamin A. Women of child-bearing age should use effective birth control during treatment and for at least 1 month after discontinuation. It is the authors’ opinion that massive doses should be reserved for intractable cases and retinol therapy should not be used alone. The major problem with many of the clinical studies using retinol and retinol analogues has been their simplistic use as isolated agents. As noted below, many other factors are of critical importance. Zinc
Zinc is vitally important in the treatment of acne. It is involved in local hormone activation, retinol-binding
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protein formation, wound healing, immune system activity, and tissue regeneration. Zinc supplementation in the treatment of acne has been the subject of much controversy and many double-blind studies. The inconsistency of the results may be due to the differing absorbability of the various zinc salts used. For example, studies using effervescent zinc sulphate show efficacies similar to tetracycline, with fewer side-effects from chronic use, [15] while those using plain zinc sulfate have shown less beneficial results. [16] The majority of patients required 12 weeks of supplementation before good results were demonstrated, although some showed dramatic improvement immediately. In the most recent study, 66 patients with inflammatory acne were given zinc gluconate (30 mg elemental zinc) or placebo for 2 months. [17] Based upon the number and severity of lesions, an “inflammatory score” was attributed to each patient. In the placebo group the inflammatory score dropped from 58 to 47 in the 2 month period, while in the treatment group the score dropped from 49 to 27. Physicians rated 24 of 32 patients in the zinc group as responders compared with only eight of 34 in the placebo group. This latest study utilized a common form of zinc, but unfortunately there have been no studies to date using zinc picolinate or zinc monomethionine, two better absorbed forms of zinc. The importance of zinc to normal skin function is well recognized, especially in light of the zinc-deficient syndrome acrodermatitis enteropathica. Zinc is essential for retinol-binding protein and thus for serum retinol levels. [18] Although low levels of zinc increase 5-alpha-reduction of testosterone, high concentrations significantly inhibit this reaction. [19] Serum zinc levels are lower in 13- and 14-year-old males than in any other age group. [20] Vitamin E and selenium
Serum vitamin A levels in rats on a vitamin E-deficient diet remain low regardless of the amount of oral or intravenous vitamin A supplementation. Serum levels return to normal after vitamin E is restored to the diet. Vitamin E has been shown to regulate retinol levels in humans. Male acne patients have significantly decreased levels of erythrocyte glutathione peroxidase, which normalizes with vitamin E and selenium treatment. The acne of both men and women improves with this treatment.[21] This improvement is probably due to inhibition of lipid peroxide formation, and suggests the use of other free-radical quenchers. Pyridoxine
Women with premenstrual aggravation of acne are often responsive to vitamin B 6 supplementation, reflecting its role in the normal metabolism of steroid hormones. [24] In rats, a vitamin B 6 deficiency appears to cause an increased uptake and sensitivity to testosterone. [25] In some patients, thyroid therapy has resulted in marked improvement. [26] Pantothenic acid
Pantothenic acid, which is physiologically active in the synthesis of cholesterol and steroid hormones, may be of value at high dosages in the treatment of acne. This was evaluated in a study of 100 Chinese (45 males and 55 females) between 10 and 30 years of age (80% were between the ages of 13 and 23) with varying ranges of acne lesions. They were provided 10 g/day of pantothenic acid in four divided doses and a cream consisting of 20% by weight pantothenic acid was applied four to six times a day. Within 1 or 2 days of starting, there was a noticeable decrease in sebum secretion. Within 1–2 weeks, the frequency of new acne eruptions began to decline and existing lesions started to regress. No side-effects were noted. [27] Miscellaneous factors
One study showed that 50% of patients with severe acne had a positive microclot test, indicating circulating endotoxins. [22] This is important since circulating endotoxins have been shown to cause an increased copper:zinc ratio, [23] and to enhance tissue destruction via activation of the alternate complement pathway and formation of fibrin. Topical treatments A variety of topical gels, ointments, and creams containing natural products are available which can be used in the treatment of acne. The goal of these preparations is the same as benzoyl peroxide, i.e. to reduce the bacteria level and reduce inflammation. Although there are many possibilities to choose from, the most popular formulas are those which feature either tea tree oil or azeleic acid. Tea tree oil
Melaleuca alternifolia or “tea tree” is a small tree native to only one area of the world: the north-east coastal region of New South Wales, Australia. The leaves, the portion of the plant that is used medicinally, are the source of a valuable therapeutic oil.
Tea tree oil possesses significant antiseptic properties and is regarded by many as the ideal skin disinfectant. This claim is supported by its efficacy against a wide range of organisms (including 27 of 32 strains of P. acnes),[28] and its good penetration and lack of irritation to the skin. The therapeutic uses of tea tree oil are based largely on its antiseptic and antifungal properties.
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In a study conducted at the the Royal Prince Hospital in New South Wales, Australia, a 5% tea tree oil solution was shown to demonstrate similar beneficial effects as 5% benzoyl peroxide in acne, but with substantially fewer side-effects. [29] However, this 5% tea tree oil solution is probably not strong enough for moderate to severe acne. Stronger solutions (up to 15%) should provide even better results. Numerous studies have shown that tea tree oil is extremely safe for use as a topical antiseptic, but it can occasionally produce contact dermatitis. Azelaic acid
This naturally occurring nine-carbon dicarboxylic acid has exerted numerous pharmacological activity, including antibiotic activity against P. acnes. Clinical studies with 20% azelaic acid creams have shown it to produce results equal to those achieved with benzoyl peroxide, retinion, and oral tetracycline. [30] It has been shown to be effective in all of the different forms of acne. In order to achieve benefits, azelaic acid must be applied to affected areas twice daily continuously for a period of at least 4 weeks. Treatment usually has to be continued for at least 6 months to maintain the benefits produced after the first month. A recent review article found topical cream containing 20% azelaic acid to be as effective as 5% benzoyl peroxide, 4% hydroquinone cream, 0.05% tretinoin, 2% erythromycin and 0.5–1 g/day oral tetracycline in ameliorating comedonal, papulopustular and nodulocystic acne, but less effective than oral isotretinoin at a dose of 0.5–1 mg/kg per day in reducing conglobate acne. The authors suggested that the few side-effects of topical azelaic acid and lack of overt systemic toxicity made it a better choice for chronic use than other agents. The lower incidence of allergic sensitization, exogenous ochronosis, and residual hypopigmentation offer a clear advantage over conventional drugs. [31]
THERAPEUTIC APPROACH Acne is a multifactorial disease requiring an integrated therapeutic approach in order to avoid supplement toxicity while attaining the desired clinical results. Patients should be checked for treatable causes and underlying hormonal abnormalities before specific therapies are initiated. Also, considering the widespread use of long-term broad-spectrum antibiotics, systemic candidiasis must be ruled out (see Ch. 48 ). Diet
Eliminate all refined and/or concentrated carbohydrates, and limit high-fat and high-carbohydrate foods. Avoid foods containing trans-fatty acids and iodine. Supplements
• Vitamin A: 100,000 IU/day for 3 months • Vitamin E: 400 IU/day • Vitamin C: 1000 mg/day • Zinc: 50 mg/day (picolinate is best [23] ) • Selenium: 200 µg/day • Yeast (brewer’s) – 1 tbls two times/day (if patient is susceptible to gout, use chromium supplement instead). Physical medicine
Sun or UV lamp. Topical treatment
• Tea tree oil (5–15%) preparations • Azelaic acid (20%) preparations • Thorough daily cleansing with calendula soap • Drain comedones with comedo extractor.
REFERENCES 1. Pochi
P. Acne: endocrinological aspects. Cutis 1982; 30: 212–222
2. Schiavone 3. Darley
F, Rietschel R, Squotas D, Harris R. Elevated free testosterone levels in women with acne. Arch Dermatol @ 119: 799–802, 1983
C, Moore J, Besser G et al. Androgen status in women with late onset or persistent acne vulgaris. Clin Exp Dermatol 1984; 9: 28–35
4. Takayasu 5. Sansone
S, Wakimoto H, Itami S, Sano S. Activity of testosterone 5-alpha-reductase in various tissues of human skin. J Invest Dermatol 1980; 74: 187–191
G, Reisner R. Differential rates of conversion of testosterone to dihydrotestosterone in acne and normal human skin – a possible pathogenic factor in acne. J Invest Dermatol 1971; 56:
366–372 6. Kappas
A, Anderson K, Conney A et al. Nutrition-endocrine interactions. Induction of reciprocal changes in the delta-5-alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man. Proc Natl Acad Sci USA 1983; 80: 7646–7649 7. Ayres
S, Mihan R. Acne vulgaris: therapy directed at pathophysiological defects. Cutis 1981; 28: 41–42
8. Semon
H, Herrmann F. Some observations on the sugar metabolism in acne vulgaris, and its treatment by insulin. Br J Derm 1940; 52: 123–128
9. Grover
R, Arikan N. The effect of intralesional insulin and glucagon in acne vulgaris. L Invest Derm 1963; 40: 259–261
10.
Abdel KM, El Mofty A, Ismail A, Bassili F. Glucose tolerance in blood and skin of patients with acne vulgaris. Ind J Derm 1977; 22: 139–149
11.
Cohen J, Cohen A. Pustular acne staphyloderma and its treatment with tolbutamide. Can Med Assoc J 1959; 80: 629–632
12.
Offenbach E, Pistunyer F. Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids in elderly patients. Diabetes 1980; 29: 919–925
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13.
McCarthy M. High chromium yeast for acne? Med Hypoth 1984; 14: 307–310
14.
Kugman A, Mills O, Leyden J et al. Oral vitamin A in acne vulgaris. Int J Dermatol 1981; 20: 278–285
15.
Michaelson G, Juhlin L, Ljunghall K. A double blind study of the effect of zinc and oxytetracycline in acne vulgaris. Br J Dermatol 1977; 97: 561–565
16.
Weimar V, Puhl S, Smith W, Broeke J. Zinc sulphate in acne vulgaris. Arch Dermatol 1978; 114: 1776–1778
17.
Dreno B, Amblard P, Agache P. Low doses of zinc gluconate for inflammatory acne. Acta Derm Venereol 1989; 69: 541–543
18.
Michaelson G, Juhlin L, Vahlquist A. Effects of oral zinc and vitamin A on acne. Arch Dermatol 1977; 113: 31–36
19.
Leake A, Chisholm G, Habib F. The effect of zinc on the 5-alpha-reduction of testosterone by the hyperplastic human prostate gland. J Steroid Biochem 1984; 20: 651–655
20.
Michaelsson G, Vahlquist A, Juhlin L. Serum zinc and retinol-binding protein in acne. Br J Dermatol 1977; 96: 283–286
21.
Michaelsson G, Edqvist L. Erythrocyte glutathione peroxidase activity in acne vulgaris and the effect of selenium and vitamin E treatment. Acta Derm Venerol (StockH) 1984; 64: 9–14
22.
Juhlin L, Michaelsson G. Fibrin microclot formation in patients with acne. Acta Derm Venerol (StockH) 1983; 63: 538–540
23.
Etzel K, Swerdel M, Swerdel J, Cousins R. Endotoxin-induced changes in copper and zinc metabolism in the syrian hamster. J Nutr 1982; 112: 2363–2373
24.
Snider B, Dieteman D. Pyridoxine therapy for premenstrual acne flare. Arch Dermatol 1974; 110: 130–131
25.
Symes E, Bender D, Bowen J, Coulson W. Increased target tissue uptake of, and sensitivity to, testosterone in the vitamin B6 deficient rat. J Steroid Biochem 1984; 20: 1089–1093
26.
Barnes B. Thyroid therapy in dermatology. Cutis 1971; 8: 581–583
27.
Leung LH. Pantothenic acid deficiency as the pathogenesis of acne vulgaris. Med Hypoth 1995; 44: 490–2
28.
Carson CF, Riley TV. The antimicrobial activity of tea tree oil. Med J Australia 1994; 160: 236
29.
Bassett IB, Pannowitz DL, Barnetson RSC. A comparative study of tea-tree oil versus benzoyl peroxide in the treatment of acne. Med J Australia 1990; 153: 455–458
30.
Nazzaro-Porro M. Azelaic acid. J Am Acad Dermatol 1987; 17: 1033–1041
31.
Nguyen Q, Bui TP. Azelaic acid. Pharmacokinetic and pharmacodynamic properties and its therapeutic role in hyperpigmentary disorders and acne. Int J Derm 1995; 34: 75–84
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Chapter 126 - Affective disorders Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY Depression
The official definition of clinical depression, according to the American Psychiatric Association in its Diagnostic and statistical manual of mental disorders (DSM-IV), is based upon the following eight primary criteria: • Poor appetite with weight loss, or increased appetite with weight gain • Insomnia or hypersomnia • Physical hyperactivity or inactivity • Loss of interest or pleasure in usual activities, or decrease in sexual drive • Loss of energy and feelings of fatigue • Feelings of worthlessness, self-reproach or inappropriate guilt • Diminished ability to think or concentrate • Recurrent thoughts of death or suicide. The presence of five of these eight symptoms definitely indicates clinical depression; the individual with four is probably depressed. According to the DSM-IV, the symptoms must be present for at least 1 month to be called depression. Clinical depression is also referred to as major depression or unipolar depression. Dysthymia
Like clinical depression, dysthymia is diagnosed according to DSM-IV criteria. In order to be officially diagnosed as dysthymic, a patient must be depressed most of the time for at least 2 years (1 year for children or adolescents) and have at least three of the following symptoms: • Low self-esteem or lack of self-confidence • Pessimism, hopelessness, or despair • Lack of interest in ordinary pleasures and activities • Withdrawal from social activities • Fatigue or lethargy • Guilt or ruminating about the past 1040
• Irritability or excessive anger • Lessened productivity • Difficulty in concentrating or making decisions. Manic phase
• The mood is typically elation, but irritability and frank hostility are not uncommon • Inflated self-esteem, grandiose delusions, boasting, racing thoughts, decreased need for sleep, psychomotor acceleration, weight loss due to increased activity and lack of attention to dietary habits. Seasonal affective disorder
• Regularly occurring winter depression frequently associated with summer hypomania.
INTRODUCTION Affective disorders are disturbances in mood. Used in this context, mood is a prolonged emotional tone dominating an individual’s outlook. Normal, typically transient, moods (sadness, grief, elation, etc.) are a part of every-day life, making the demarcation between “normal” and “pathological” often difficult to determine. Depression and mania, either alone or in alternation, are the most common affective disorders, with depression alone being much more common. In order to separate states of depression which alternate with mania from the more common types of depression, i.e. those uncomplicated by mania, the terms “unipolar” and “bipolar” are commonly used. A unipolar depressive suffers from depression alone, while the bipolar depressive suffers from either mania alone or mania alternating with depression. Many nutritional, environmental, and lifestyle factors are discussed in this chapter, and it is important to recognize that they have a much broader scope of clinical application than simply to depression and mania. This chapter is really a compilation of many chapters that address factors associated with mood disturbance. As the biochemistry of mood and behavior have become better understood, many conditions once thought of as having a psychological or sociological etiology are now being shown to have a physiological or biochemical basis as well. There appear to be at least eight factors that modify the functional state of the brain, thus affecting mood and behavior: • the individual genetic make-up • the particular age of neuronal development, which results in age-specific variability • the functional plasticity of the brain during development, which contributes to the functional and structural shaping of the system • the motivational state, affected by various biological drives, which channels behavior toward specific goals by setting priorities or prejudicing the context of particular types of incoming information • the availability of memory-stored information and related processing strategies • the environment, which can adjust the incoming information depending on its momentary significance • disease or lesion of the brain, which could cause aberrant functional states • conditions of the metabolic/hormonal system or the internal biochemical environment of the CNS.
This chapter focuses on the nutritional, environmental, and lifestyle factors which contribute to affective disorders as well as specific therapies to alter brain neurotransmitter levels.
DEPRESSION Obviously, there is a spectrum of clinical depression that ranges from mild feelings of depression to serious considerations of suicide. Mild depression is also known as dysthymia. Dysthymia is a term coined in the 1980s that replaced the term depressive neurosis which was used in the 1950s and the term depressive personality which was used in the 1970s.
GENERAL CONSIDERATIONS Depression is a major problem in the United States. Approximately 17 million Americans suffer true clinical depression each year and over 28 million Americans take antidepressant drugs or anxiolytics. The obvious question is: “Why are so many Americans depressed?”. Five basic theoretical models of depression attempt to answer this question: • The “aggression-turned-inward” construct, which although apparent in many clinical cases, has no substantial proof • The “loss model,” which postulates that depression is a reaction to the loss of a person, thing, status, self-esteem, or even a habit pattern • The “interpersonal relationship” approach, which utilizes behavioral concepts, i.e. the person who is depressed uses depression as a way of controlling other people (including doctors). It can be an extension and outgrowth of such simple behavior as pouting, silence, or ignoring something or someone. It fails to serve the need and the problem worsens • The “learned helplessness” model, which theorizes 1041
that depression is the result of habitual feelings of pessimism and hopelessness • The “biogenic amine” hypothesis, which stresses biochemical derangement characterized by imbalances of biogenic amines. Although the biogenic amine model of depression is the dominant medical model of depression, there is much value to counseling, especially in clear cases of psychological etiology. Of the various psychological theories of depression, the one that we feel has the most merit is the learned helplessness model developed by Martin Seligman PhD. During the 1960s, Dr Seligman discovered that animals could be trained to be helpless. His animal model provided a valuable clue to human depression as well as serving as a model to test antidepressant drugs. [1] The learned helplessness model
Seligman’s early experiments were performed on three groups of dogs. The first group of dogs was given an escapable electrical shock. The dogs could turn off the shock by simply pressing a panel with its nose. This group of dogs would thus have control. The second group of dogs was “yoked” to the first group. They would get exactly the same shocks as the first group, but would be unable to turn off the shock. The shock would cease only when the “yoked” dog in the first group would press its nose to the panel. Thus, the second group had no control over the degree of shock they received. The third group of dogs received no shocks at all. Once the dogs went through this first part of the experiment, they would be placed in what is known as a shuttle box – a box separated in the middle by a small barrier that the dogs could jump over. The dogs would be electrically shocked, but they would be able to escape the shock by simply jumping over the barrier to the other side. Seligman hypothesized that the first and third groups would quickly figure this out, but that the second group of dogs would have learned to be helpless in that they would believe that nothing they would do mattered. Seligman thought that the dogs in the second group would simply lie down and accept the shock. As predicted, the first and third groups of dogs learned within seconds that they could avoid the shock by jumping over the barrier, while the dogs in the second group would simply lie down and not even make an effort to jump over the barrier though they could see the shock-less side of the shuttle box. Seligman and his colleagues went on to show that many humans react in an identical fashion to animals in these experiments. The adoption of Seligman’s model was revolutionary in psychopharmacology as it became an effective experiment to test antidepressive drugs. Basically, when animals that had learned to be helpless were given antidepressant drugs, they would unlearn helplessness and start exerting control over their environment. Researchers discovered that when animals learned to be helpless it resulted in alteration of brain monoamine content. The drugs would restore proper monoamine balance and alter the animal’s behavior. Researchers also discovered that when animals with learned helplessness were taught how to gain control over their environment their brain chemistry also normalized. The alteration in brain monoamine content in the animals with learned helplessness mirrors the altered monoamine content in human depression. While most physicians quickly look to drugs to alter brain chemistry, helping the patient to gain greater control over their life will actually produce even greater biochemical changes. One of the most powerful techniques to produce the necessary biochemical changes in the brains of depressed individuals is to teach them to be more optimistic. Outside the laboratory setting, Seligman discovered that the determining factor on how a person would react to uncontrollable events, either “bad” or “good”, was their explanatory style – the way in which they explained events. Optimistic people were immune to becoming helpless and depressed. However, individuals that were pessimistic were extremely likely to become depressed when something went wrong in their lives. Seligman and other researchers also found a direct correlation between an individual’s level of optimism and the likeliness of developing not only clinical depression but other illnesses as well. [2] [3] In one of the longer studies, patients were followed for a total of 35 years. While optimists rarely got depressed, pessimists were extremely likely to battle depression and other psychological disturbances.
THERAPEUTIC CONSIDERATIONS Modern psychiatry focuses on manipulating neurotransmitter levels in the brain rather than identifying and eliminating the psychological factors which are responsible for producing the imbalances in serotonin, dopamine, GABA, and other neurotransmitters. Depression can often be due to an underlying organic or physiological cause (see Table 126.1 ). Identification and elimination of the underlying cause should be the primary therapy. The depressed individual needs a comprehensive clinical evaluation. The basic clinical approach to a person suffering from depression is to ascertain what nutritional, environmental, social and psychological factors are involved in the disease process. After the diagnosis of depression has been made, it is important to rule out the simple organic factors which are known to contribute to the depression, i.e.: • nutrient deficiency or excess • drugs (prescription, illicit, alcohol, caffeine, nicotine, etc.) 1042
• hypoglycemia • consumption • hormonal derangement • allergy • environmental factors
• microbial factors.
TABLE 126-1 -- Organic and physiological causes of depression • Pre-existing physical condition —diabetes —heart disease —lung disease —rheumatoid arthritis —chronic inflammation —chronic pain —cancer —liver disease —multiple sclerosis • Prescription drugs —antihypertensives —anti-inflammatory agents —birth control pills —antihistamines —corticosteroids —tranquilizers and sedatives • Premenstrual syndrome • Stress/low adrenal function • Heavy metals • Food allergies • Hypothyroidism • Hypoglycemia • Nutritional deficiencies • Sleep disturbances Each of these is discussed below. Regardless of whether there is an underlying organic cause, counseling is always recommended for the depressed individual. Counseling There are a number of counseling techniques that can be quite useful. The therapy that has the most merit and support in the medical literature is cognitive therapy. In fact, cognitive therapy has been shown to as effective as antidepressant drugs in treating moderate depression. [4] [5] However, while there is a high rate of relapse of depression when drugs are used, the relapse rate for cognitive therapy is much lower. People taking drugs for depression tend to have to stay on them for the rest of their lives. That is not the case with cognitive therapy because the patient is taught new skills to deal with depression. [6] Psychologists and other mental health specialists trained in cognitive therapy seek to change the way the depressed person consciously thinks about failure, defeat, loss, and helplessness. Cognitive therapists employ five basic tactics. First they help patients recognize the negative automatic thoughts that flit through the consciousness at the times when the patient feels the worst. The second tactic is disputing the negative thoughts by focusing on contrary evidence. The third tactic is teaching the patient a different explanation to dispute the negative automatic thoughts. The fourth tactic involves learning how to avoid rumination (the constant churning of a thought in one’s mind) by helping the patient better control their thoughts. The final tactic is questioning depression-causing negative thoughts and beliefs, and replacing them with empowering positive thoughts and beliefs. Cognitive therapy does not involve the long, drawn-out process of psychoanalysis. It is a solution-oriented psychotherapy designed to help the patient learn skills to improve the quality of his or her life. Hormonal factors Many hormones are known to influence mood; however, it is beyond the current scope of this text to address all of them. Instead, the focus will be on the effects of the thyroid and adrenal hormones. Thyroid function
Depressive illness is often a first or early manifestation of thyroid disease, as even subtle decreases in available thyroid hormone are suspected of producing symptoms.[7] [8] The link between hypothyroidism and depression is well known, but whether the thyroid hypofunction is a result of depression-induced hypothalamic-pituitary-thyroid (HPT) dysfunction, or of thyroid hypofunction, remains to be definitively determined. It is probably a combination. Depressed patients should be screened for hypothyroidism, particularly if they complain of fatigue or have any other symptoms suggestive of hypothyroidism. Stress and adrenal function
Like the thyroid gland, dysfunction of the adrenal gland is closely associated with depression. Often this dysfunction is the result of stress – a major factor to consider in the depressed individual. The patient’s level of, and response to, stress can be measured with the adrenal stress index. This test measures the level of the cortisol and dehydroepiandrosterone (DHEA) in the saliva. The typical pattern found in depression is an elevated morning cortisol level and a decreased DHEA level. That elevations in cortisol reflect a disturbance in the hypothalamic-pituitary-adrenal (HPA) axis is the basis of the dexamethasone suppression test (discussed below). Defects in HPA regulation seen in affective disorders include excessive cortisol secretion which is independent of stress responses, abnormal nocturnal release of cortisol, and inadequate suppression by dexamethasone. [9] The CNS effects of increased endogenous release of
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cortisol mirror the effects of exogenous cortisol: depression, mania, nervousness, insomnia, and, at high levels, schizophrenia. The effects of glucocorticoids on mood
are related to their induction of tryptophan oxygenase (see Fig. 126.2 below). This results in shunting of tryptophan to the kynurenine pathway at the expense of serotonin and melatonin synthesis. [10] Tests of hypothalamic-pituitary function
The two tests widely used as aids in classifying psychiatric conditions are the dexamethasone suppression test (DST) and the thyroid stimulation test. [11] [12] The basic function of these tests is to determine if the condition is a result of hypothalamic dysfunction and to categorize the psychiatric illness, e.g. severe major affective disorders versus severe psychotic disorders. It is generally held that the DST is of little clinical value as a screening test and it is debatable whether it offers more information than urinary free cortisol. Since thyroid hormone assays are not able to detect all cases of thyroid hypofunction, they are not an effective screening procedure. The thyroid stimulation test (TRH) is significantly more sensitive in diagnosing “subclinical hypothyroidism”. [12] A grading system for hypothyroidism as determined by the TRH test has been proposed as follows: • Grade 3 (subclinical hypothyroidism – 4%). Patientsare usually without classic signs of thyroid failure, have normal T 3 RU, T4 , and TSH levels, but definitely abnormal TSH response to the TRH test. • Grade 2 (mild hypothyroidism – 3.6%). Patients may have mild isolated clinical signs or symptoms of hypothyroidism, but demonstrate normal T 3 RU and T 4 levels. Baseline TSH levels are elevated, and there is an abnormal TRH test. • Grade 1 (overt hypothyroidism – 1%). Patients demonstrate signs and symptoms of classical hypothyroidism along with abnormal laboratory values, i.e. reduced T3 RU and T4 levels, increased TSH levels, and abnormal TRH response. The TRH test may have wide clinical utility as dysfunction of the thyroid gland is implicated in many conditions. Environmental toxins Heavy metals (lead, mercury, cadmium, arsenic, nickel, and aluminum) as well as solvents (cleaning materials, formaldehyde, toluene, benzene, etc.), pesticides, and herbicides have an affinity to nervous tissue. As a result, a variety of psychological and neurological symptoms can occur, including: [13] [14] [15] • depression • headaches • mental confusion • mental illness • tingling in extremities • abnormal nerve reflexes • other signs of impaired nervous system function. (See Chs 18 and 37 for further discussion.) Detailed medical history and hair mineral analysis are good screening mechanisms for environmental toxicity. If the hair mineral analysis is inconclusive, a more sensitive indicator is the 8 hour lead mobilization test. This test employs the chelating agent EDTA (edetate calcium disodium) and measures the level of lead excreted in the urine for a period of 8 hours after the injection of EDTA. Lifestyle factors A health-promoting lifestyle and diet are very important in the treatment of depression. Particularly important is the cessation of smoking, excessive alcohol consumption, and the intake of caffeine. These lifestyle changes coupled with regular exercise and a healthful diet are more than likely to produce better clinical results than Prozac, with no side-effects and no cost. Smoking
Cigarette smoking is one of the major factors contributing to premature death in the United States. Cigarette smoking is also a significant factor in depression. Central to the effect of nicotine is the stimulation of adrenal hormone, including cortisol, secretion. Elevated cortisol levels are a well-recognized feature of depression. [3] One of the key effects of cortisol (and stress) on mood is activation of tryptophan oxygenase, resulting in less tryptophan being delivered to the brain. Since the level of serotonin in the brain is dependent upon the amount of tryptophan delivered to the brain, cortisol dramatically reduces the level of serotonin and melatonin. [10] In addition, cortisol also “down-regulates” serotonin receptors in the brain, making them less sensitive to the serotonin that is available. Cigarette smoking also leads to a relative vitamin C deficiency as the vitamin C is utilized to detoxify the cigarette smoke. Low levels of vitamin C in the brain can result in depression and hysteria. [16] Alcohol
Alcohol, a brain depressant, increases adrenal hormone output, interferes with many brain cell processes, and disrupts normal sleep cycles. Alcohol ingestion also leads to hypoglycemia. The resultant drop in blood sugar produces a craving for sugar because it can quickly
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elevate blood sugar. Unfortunately, increased sugar consumption ultimately aggravates the hypoglycemia. Hypoglycemia aggravates the mental and emotional problems of the alcoholic. Caffeine
Although caffeine is a well-known stimulant, the intensity of response to caffeine varies greatly, with people prone to feeling depressed or anxious tending to be especially sensitive to caffeine. The term “caffeinism” is used to describe a clinical syndrome similar to generalized anxiety and panic disorders which includes such symptoms as depression, nervousness, palpitations, irritability, and recurrent headache. [17] Several studies have looked at caffeine intake and depression. For example, one study found that, among healthy college students, moderate and high coffee drinkers scored higher on a depression scale than did low users. Interestingly, the moderate and high coffee drinkers also tended to have significantly lower academic performance.[18] Several other studies have shown that depressed patients tend to consume fairly high amounts of caffeine (e.g. greater than 700 mg/day). [19] [20] In addition, the intake of caffeine intake has been positively correlated with the degree of mental illness in psychiatric patients. [21] [22] The combination of caffeine and refined sugar seems to be even worse than either substance consumed alone. Several studies have found an association between this combination and depression. In one of the most interesting studies, 21 women and two men responded to an advertisement requesting volunteers “who feel depressed and don’t know why, often feel tired even though they sleep a lot, are very moody, and generally seem to feel bad most of the time”. [23] After baseline psychological testing, the subjects were placed on a caffeine- and sucrose-free diet for 1 week. The subjects who reported substantial improvement were then challenged in a double-blind fashion. The subjects took either a capsule containing caffeine and a Kool-Aid drink sweetened with sugar or a capsule containing cellulose and a Kool-Aid drink sweetened with Nutrasweet. Each challenge lasted up to 6 days. About 50% of test subjects became depressed during the test period
with caffeine and sucrose. Another study using a similar format as the Kool-Aid study described above found that seven of 16 depressed patients were found to be depressed with the caffeine and sucrose challenge, but became symptom-free during the caffeine- and sucrose-free diet and cellulose and Nutrasweet test period. [24] The average American consumes 150–225 mg of caffeine daily, or roughly the amount of caffeine in one to two cups of coffee. Although most people appear to tolerate this amount, some people are more sensitive to the effects of caffeine than others. Even small amounts of caffeine, as found in decaffeinated coffee, are enough to affect some people adversely. Patients with depression or any psychological disorder should be advised to avoid caffeine completely. Exercise
Regular exercise may be the most powerful natural antidepressant available. In fact, many of the beneficial effects of exercise noted in the prevention of heart disease may be related just as much to its ability to improve mood as to its improvement of cardiovascular function. [25] Various community and clinical studies have clearly indicated that exercise has profound antidepressive effects. [26] These studies have shown that increased participation in exercise, sports, and physical activities is strongly associated with decreased symptoms of anxiety, depression, and malaise. Furthermore, people who participate in regular exercise have higher self-esteem, feel better, and are much happier than people who do not exercise. Much of the mood-elevating effects of exercise may be attributed to the fact that regular exercise has been shown to increase the level of endorphins, which are directly correlated with mood. [27] One of the most interesting studies that examined the role of exercise and endorphins in depression compared the beta-endorphin levels and depression profiles of 10 joggers with those of 10 sedentary men of the same age. The 10 sedentary men tested were more depressed, perceived greater stress in their lives, and had a higher level of cortisol and lower levels of beta-endorphins. As the researchers stated, this “reaffirms that depression is very sensitive to exercise and helps firm up a biochemical link between physical activity and depression”. [28] At least 100 clinical studies have now evaluated the efficacy of an exercise program in the treatment of depression. In an analysis of the 64 studies prior to 1980, physical fitness training was shown to relieve depression and improve self-esteem and work behavior. [29] Unfortunately, the quality of many of the studies was less than ideal. However, because of the good results noted in the analysis of these studies, there was a flurry of well-designed studies conducted in the 1980s to better determine how effective exercise could be as a therapy. These studies utilized stricter scientific criteria than the earlier ones, yet they produced similar results. It was concluded that exercise can be as effective as other antidepressants, including drugs and psychotherapy. [30] More recently, even stricter studies have further demonstrated that regular exercise is a powerful antidepressant. [31] [32] [33] The best exercises are either strength training (weight lifting) or aerobic activities such as walking briskly, jogging, bicycling, cross-country skiing, swimming, aerobic dance, and racquet sports.
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Nutrition A deficiency of any single nutrient can alter brain function and lead to depression, anxiety and other mental disorders (see Table 126.2 ). However, the role of nutrient deficiency is just the tip of the iceberg with regard to the role of nutrient effects on the brain and mood. According to Melvin Werbach MD: [34] It is clear that nutrition can powerfully influence cognition, emotion, and behavior. It is also clear that the effects of classical nutritional deficiency diseases upon mental function constitute only a small part of a rapidly expanding list of interfaces between nutrition and the mind. … Even in the absence of laboratory validation of nutritional deficiencies, numerous studies utilizing rigorous scientific designs have demonstrated impressive benefits from nutritional supplementation. A high potency multiple provides a good nutritional foundation upon which to build. When selecting a multiple vitamin and mineral formula it is important to make sure that it provides the full range of vitamins and minerals at high potency levels. Deficiencies of a number of nutrients are quite common in depressed individuals. The most common deficiencies are folic acid, vitamin B 12 and vitamin B6 . The significance of these deficiencies is discussed below. Dietary guidelines
Since the brain requires a constant supply of blood sugar, hypoglycemia must be avoided. Symptoms of hypoglycemia can range from mild to severe and include: • depression, anxiety, irritability, and other psychological disturbances • fatigue • headache • blurred vision • excessive sweating • mental confusion • incoherent speech • bizarre behavior • convulsions.
TABLE 126-2 -- Behavioral effects of some vitamin deficiencies Behavioral effects
Deficient vitamin Thiamin
Korsakoff’s psychosis, mental depression, apathy, anxiety, irritability
Riboflavin
Depression, irritability
Niacin
Apathy, anxiety, depression, hyperirritability, mania, memory deficits, delirium, organic dementia, emotional lability
Biotin
Depression, extreme lassitude, somnolence
Pantothenic acid
Restlessness, irritability, depression, fatigue
B6
Depression, irritability, sensitivity to sound
Folic acid
Forgetfulness, insomnia, apathy, irritability, depression, psychosis, delirium, dementia
B12
Psychotic states, depression, irritability, confusion, memory loss, hallucinations, delusions, paranoia
Vitamin C
Lassitude, hypochondriasis, depression, hysteria
Several studies have shown hypoglycemia to be very common in depressed individuals. [35] [36] [37] [38] Simply eliminating refined carbohydrate from the diet is occasionally all that is needed for effective therapy in patients who have depression due to reactive hypoglycemia. The dietary guidelines for depression are identical to the dietary guidelines for optimal health. It is now a well-established fact that certain dietary practices cause, while others prevent, a wide range of diseases. Quite simply, a health-promoting diet provides optimal levels of all known nutrients and low levels of food components which are detrimental to health, such as sugar, saturated fats, cholesterol, salt, and food additives. A health-promoting diet is rich in whole “natural” and unprocessed foods. It is especially high in plant foods, such as fruits, vegetables, grains, beans, seeds and nuts, as these foods contain not only valuable nutrients but also
additional compounds which have remarkable health-promoting properties. Folic acid and vitamin B 12
Folic acid and vitamin B 12 function together in many biochemical processes. Folic acid deficiency is the most common nutrient deficiency in the world. In studies of depressed patients, 31–35% have been shown to be deficient in folic acid. [39] [40] [41] [42] In elderly patients this percentage may be even higher. Studies have found that among elderly patients admitted to a psychiatric ward, the number with folic acid deficiency ranges from 35 to 92.6%. [43] [44] Depression is the most common symptom of a folic acid deficiency. Vitamin B 12 deficiency is less common than that of folic acid deficiency, but it can also cause depression, especially in the elderly. [45] [46] Correcting the folic acid and/or vitamin B 12 deficiency results in a dramatic improvement in mood. Folic acid, vitamin B 12 , and a form of the amino acid methionine known as SAM (S-adenosyl-methionine) function as “methyl donors” ( Fig. 126.1 ). They carry and donate methyl molecules to important brain compounds including neurotransmitters. SAM is the major methyl donor in the body. The antidepressant effects of folic acid appear to be a result of raising brain SAM content. One of the key brain compounds dependent on methylation is tetrahydrobiopterin (BH 4 ). This compound functions as an essential coenzyme in the activation of enzymes which manufacture monoamine neurotransmitters like serotonin and dopamine from their corresponding amino acids. Patients with recurrent depression have been shown to have reduced BH 4 synthesis, probably as a result of low SAM levels. BH 4 supplementation
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Figure 126-1 Relationship between folate cycle, SAM and transmethylation.
has been shown to produce dramatic results in these patients. [47] [48] Unfortunately, BH4 is not currently available commercially. However, since BH 4 synthesis is stimulated by folic acid, vitamin B 12 , and vitamin C, it is possible that increasing these vitamin levels in the brain may stimulate BH 4 formation and the synthesis of monoamines like serotonin. [49] There is evidence to support the contention that supplementing the diet with folic acid, vitamin C, and vitamin B 12 can increase BH 4 levels. In addition, the folic acid supplementation and the promotion of methylation reactions have been shown to increase the serotonin content. [50] [51] [52] The serotonin-elevating effects are undoubtedly responsible for much of the antidepressive effects of folic acid and vitamin B 12 . Typically the dosages of folic acid in the antidepressant clinical studies have been very high: 15–50 mg. High-dose folic acid therapy is safe (except in patients with epilepsy) and has been shown to be as effective as antidepressant drugs. [53] A dosage of 800 mcg of folic acid and 800 mcg of vitamin B 12 should be sufficient in most circumstances to prevent deficiencies. Folic acid supplementation should always be accompanied by vitamin B 12 supplementation to prevent folic acid from masking a vitamin B 12 deficiency. Vitamin B6
B6 levels are typically quite low in depressed patients, especially women taking birth control pills or Premarin. [54] [55] [56] [57] [58] Considering the many functions of vitamin B6 in the brain, including the fact that vitamin B 6 is absolutely essential in the manufacture of all monoamines, it is likely that many of the millions of people who are taking Prozac may be suffering depression simply as a result of low vitamin B 6 . Patients with low B6 status usually respond very well to supplementation. The typical effective dosage is 50–100 mg. Omega-3 fatty acids
An insufficiency of omega-3 oils has been linked to depression. [59] This may be related to the impact of dietary fatty acids on the phospholipid composition of neurological cell membranes. While it is thought that the cell is programmed to selectively incorporate the different fatty acids it needs to maintain optimal function, the lack of essential fatty acids (particularly the omega-3 oils) and excess of saturated fats and animal fatty acids lead to the formation of cell membranes which are much less fluid than normal. A relative deficiency of essential fatty acids in cellular membranes substantially impairs cell membrane function. Since the basic function of the cell membrane is to serve as a selective barrier that regulates the passage of molecules into and out of the cell, a disturbance of structure or function disrupts homeostasis. Because the brain is the richest source of phospholipids in the human body and proper nerve cell function is critically dependent on proper membrane fluidity, alterations in membrane fluidity impact behavior, mood, and mental function. Studies have shown that the biophysical properties, including fluidity, of brain cell membranes directly influence neurotransmitter synthesis, signal transmission, uptake of serotonin and other neurotransmitters, neurotransmitter binding, and the activity of monoamine oxidase. All of these factors have been implicated in depression and other psychological disturbances. Researchers have concluded that omega-3 fatty acids may reduce the development of depression just as they reduce the development of coronary artery disease. This conclusion was based on several factors:
[ 59]
• Recent studies have suggested that lowering plasma cholesterol by diet and medications increases suicide, homicide, and depression. • The quantity and type of dietary fats consumed influence serum lipids and alter the biophysical and biochemical properties of cell membranes. • Dietary advice to lower cholesterol levels tends to increase the ratio of omega-6 to omega-3 fatty acids and decreases the level of the esssential omega-3 fatty acid, docosahexanoic acid. • Epidemiological studies in various countries and the United States have indicated that decreased consumption of omega-3 fatty acids correlates with increasing rates of depression. • There is also a consistent association between depression and coronary artery disease. Food allergies
Depression and fatigue have been linked to food allergies for over 65 years. In 1930, Rowe coined the term “allergic toxemia” to describe a syndrome that included the
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symptoms of depression, fatigue, muscle and joint aches, drowsiness, difficulty in concentration, and nervousness. [60] Although the term allergic toxemia is not used anymore, food allergies still play a major role in many people with depression. [61] Monoamine metabolism and precursor therapy The use of monoamine (MA) precursors, particularly tryptophan, 5-hydroxytryptophan (5-HTP), and tyrosine, has offered a more “natural way” of influencing MA
metabolism than monoamine oxidase inhibitors or tricyclic antidepressants. The tryptophan catastrophe
For more than 30 years, L-tryptophan was used by millions of people in the US and around the world safely and effectively for insomnia and depression. But in October 1989, some people taking tryptophan started reporting strange symptoms to physicians – severe muscle and joint pain, high fever, weakness, swelling of the arms and legs, and shortness of breath. [62] The syndrome was dubbed EMS (eosinophilia-myalgia syndrome). Laboratory studies showed that the blood of subjects with EMS contained a very high level of eosinophils. In patients with EMS, eosinophil levels rose to greater than 1,000/mm3 , roughly double the normal level, and the percentage of eosinophils often increased to levels above 30%. The problem with such severe elevations in eosinophils is that these white blood cells contain packets that have high levels of histamine and other allergic and inflammatory compounds. When these compounds are released by eosinophils, this leads to intense symptoms of an allergic and inflammatory nature, e.g. severe muscle and joint pain, high fever, weakness, swelling of the arms and legs, skin rashes, and shortness of breath – the same symptoms as those experienced by people with EMS. What was suspected was that one or more newly introduced contaminants which activated eosinophils and other white blood cells had to be the reason behind EMS because L-tryptophan had been used successfully by over 30 million people worldwide without side-effect. Detailed analysis of all the evidence by the Centers for Disease Control (CDC) led to the conclusion that the cause of the EMS epidemic could be traced to one Japanese manufacturer, Showa Denko.[63] [64] Of the six Japanese companies which supplied L-tryptophan to the United States, Showa Denko was the largest, supplying 50–60%. The L-tryptophan was used not only as a nutritional supplement, but also in infant formulas and nutrient mixtures used for intravenous feeding. The L-tryptophan produced from October 1988 to June 1989 by Showa Denko became contaminated with substances now linked to EMS due to changes in the bacteria being used to produce the L-tryptophan and in the filtration process. The change in the filtration process resulted in the L-tryptophan being contaminated with impurities linked to EMS. Examination of the pre-filtered material indicated that it had no detectable levels of the impurities linked to EMS. Somehow the filtration process produced the contaminants. While the epidemic of EMS during the last half of 1989 was clearly related to the contaminated L-tryptophan produced by Showa Denko, there have been a handful of other reported cases of EMS in people who never took L-tryptophan and in people who took L-tryptophan prior to the contaminated batch manufactured by Showa Denko hitting the shelves. It is likely that in these earlier reports of EMS-like illnesses among L-tryptophan users, the subjects were also using contaminated [ [ L-tryptophan and they also had a predisposition to EMS (discussed below). 65] 66] This conclusion is based upon the fact that uncontaminated tryptophan 5-HTP has never produced EMS. Clearly it is absolutely essential that non-contaminated L-tryptophan be used to avoid the possibility of EMS. The total number of reported cases of EMS in the United States eventually reached 1,511. Included in this number were 36 deaths attributed to L-tryptophan. In Europe the total number of cases was 171 and there were no deaths. [63] [64] [65] [66] The difference between the US and the European experiences is that the dominant ® L-tryptophan supplement in Europe was Optimax , a product marketed by Merck, the largest pharmaceutical company in the world. The supplier of the tryptophan used in the Merck product was Ajimomato. One of the interesting aspects of the entire L-tryptophan catastrophe is that it did not affect more people. Based on very detailed studies, it was concluded that EMS affected 144 out of every 100,000 men and 268 out of every 100,000 women taking L-tryptophan. [67] If 50% of these L-tryptophan users were taking Showa Denko supplied L-tryptophan, we can assume that EMS affected 144 out of every 50,000 men, and 268 out of every 50,000 women, taking contaminated L-tryptophan. In other words, roughly one out of every 250 people who took the contaminated L-tryptophan developed EMS. The obvious question is: “Why didn’t everyone taking the contaminated L-tryptophan experience EMS?”. The answer appears to be that only those with an abnormal activation of the kynurenine pathway reacted to the contaminant. [68] Kynurenine and its metabolites (especially quinolic acid) are also linked to other EMS-related illnesses including the toxic oil syndrome, one of the largest food-related epidemics that has occurred to date. This syndrome occurred in Spain during the month of May in 1991. It affected more than 20,000 people and caused over 12,000 hospitalizations. It was caused by the ingestion of canola oil contaminated with a compound very similar
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to one of the contaminants in the contaminated Showa Denko L-tryptophan.[69] One of the interesting findings from studies conducted by researchers from the CDC was that people who took a multiple vitamin preparation were extended some protection against EMS. [70] When regular vitamin users did develop EMS, it was less severe than the EMS experienced in non-vitamin users. A likely explanation for this occurrence is that either the vitamins (particularly vitamin B 6 and niacin) shunted tryptophan metabolism away from the kynurenine pathway or the contaminants are somehow metabolized by vitamin-dependent enzymes. L-Tryptophan
The basic theory of tryptophan supplementation in depression (and insomnia) is that it will increase the level of serotonin and melatonin in the brain. This theory is supported by the considerable evidence that many depressed individuals have low tryptophan and serotonin levels. Unfortunately, supplementation with L-tryptophan in depressed patients has produced mixed results in the published clinical trials. In only two out of eight studies comparing L-tryptophan with a placebo was L-tryptophan shown to be more effective than the placebo. But interestingly, nine out of 11 studies comparing L-tryptophan with conventional antidepressant drugs showed no difference. [71] [72] [73] [74] [75] [76] There are many factors to consider when looking at these studies, such as study size, severity of depression, duration, and dosage. In addition, a number of factors, such as hormones like estrogen and cortisol, as well as tryptophan itself, stimulate the activity of tryptophan oxygenase which results in tryptophan being converted to kynurenine and less tryptophan being delivered to the brain ( Fig. 126.2 shows the metabolism of tryptophan). In summary, L-tryptophan is only modestly effective in the treatment of depression when used alone. In order to gain any real benefit from L-tryptophan, it must be used along with vitamin B6 and the niacinamide form of vitamin B 3 to help block the kynurenine pathway to provide better results. Better yet is the use of 5-HTP.
Figure 126-2 Tryptophan metabolism.
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5-Hydroxytryptophan (5-HTP)
As the pharmacology of 5-hydroxytryptophan is fully described in Chapter 92 , only a concise summary is presented here. Unlike tryptophan, 5-HTP cannot be converted to kynurenine and easily crosses the blood–brain barrier. As a result, while only 3% of an oral dose of L-tryptophan is converted to serotonin, over 70% of
an oral dose of 5-HTP is converted to serotonin. In addition to increasing serotonin levels, 5-HTP causes an increase in endorphin and catecholoamine levels. Numerous double-blind studies have shown 5-HTP to have “equipotency” with SRIs and tricyclic antidepressants in terms of effectiveness and to offer several advantages in that it is less expensive, better tolerated and associated with fewer and much milder side-effects. [77] [78] [79] [80] [81] Phenylalanine and tyrosine
Although the number of clinical studies utilizing phenylalanine or tyrosine for depression does not approach the number using tryptophan and 5-HTP, there is evidence that these monoamine precursors may be effective in some individuals. [82] [83] General catecholamine metabolism is briefly illustrated in Figure 126.3 . Phenylalanine, besides being hydroxylated to tyrosine and degraded to phenylketonic acids, can be decarboxylated to phenylethylamine (PEA). [82] This compound has amphetamine-like stimulant properties and is suggested to be an endogenous stimulatory or antidepressive substance in humans. (Note that this biogenic amine is found in high concentrations in chocolate, which might explain the latter’s addictiveness.) Low urinary PEA levels are found in depressed patients, while high levels are found in schizophrenia. [82] [83] Phenylalanine, both D- and L- forms, has been demonstrated to increase urinary PEA output and CNS PEA concentrations. As phenylalanine is a tyrosine hydroxylase inhibitor, it is expected that more shunting of phenylalanine to PEA synthesis will occur with supplementation. The pharmacological activity of supplemental tyrosine in depressives may be related to its increasing of “trace amine” levels (octopamine, tyramine and PEA), rather than just its enhancement of catecholamine synthesis or possibly its stimulation of thyroid hormone synthesis. The largely negative results using L-dopa alone in affective disorders tend to substantiate this assumption. [81] Central norepinephrine turnover, however, is decreased in depressed patients. This may be a result of the low serum tyrosine levels seen in some depressed individuals. [83] Like tryptophan, the brain tyrosine content is best determined by the ratio of serum tyrosine concentration to the sum of its brain-uptake competitors, i.e. leucine, isoleucine, valine, tryptophan, and phenylalanine. Tyrosine ratios are increased by high-protein meals. Tyrosine
Figure 126-3 Catecholamine metabolism.
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supplementation results in increased levels of 3-methoxy-4-hydroxyphenethylene glycol (MHPG) in the urine. This compound is believed to be the principal breakdown product of norepinephrine in the CNS and may provide a biochemical marker for determining which amino acid to supplement. Table 126.3 summarizes clinical studies using phenylalanine and/or tyrosine for depression. These results indicate that phenylalanine and tyrosine supplementation offer encouraging alternatives to tricyclics and MAO inhibitors. In the early 1970s, van Praag et al discovered that about one out of five patients who responded well to 5-HTP tended to relapse after 1 month of treatment. The antidepressant effects of 5-HTP in these subjects began to wear off gradually after the first month despite the fact that the level of 5-HTP in the blood, and presumably the level of serotonin in the brain, remained at the same level as when they were experiencing benefit. [81] These researchers discovered that while serotonin levels appeared to stay at the same levels after 1 month of treatment, the levels of other the other important monoamine neurotransmitters, dopamine and norepinephrine, declined. [84] These patients responded to supplemental tyrosine. S-Adenosyl-methionine (SAM)
SAM was discussed briefly above with vitamin B 12 and folic acid in its methylation role ( pp. 1045 ). SAM is involved in the methylation of monoamines, neurotransmitters, and phospholipids like phosphatidylcholine and phosphatidylserine. Normally, the brain manufactures all the SAM it needs from the amino acid methionine. However, SAM synthesis is impaired in depressed patients. Supplementing the diet with SAM in depressed patients results in increased levels of serotonin, dopamine, and phosphatides, and improved binding of neurotransmitters to receptor sites, resulting in increased serotonin and dopamine activity and improved brain cell membrane fluidity, and thus significant clinical improvement. [85] [86] [87] The results of a number of clinical studies suggest that SAM is one of the most effective natural antidepressants. [88] [89] [90] [91] Unfortunately, its use is still limited due to its high price. Tables 126.4 and 126.5 summarize double-blind studies comparing SAM with either a placebo or a tricyclic drug such as imipramine. The studies cited in these tables utilized injectable SAM. However, more recent studies using a new oral preparation at a dosage of 400 mg four times daily (1,600 mg total) have demonstrated that SAM is just as effective orally as it is when given intravenously. [92] [93] [94] [95] SAM is better tolerated and has a quicker onset of antidepressant action than tricyclic antidepressants. A recent study compared SAM with the tricyclic desipramine. In addition to clinical response, the blood level of SAM was determined in both groups. At the end of the 4 week trial, 62% of the patients treated with SAM and 50% of the patients treated with desipramine had significantly improved. Regardless of the type of treatment, patients with a 50% decrease in their Hamilton Depression Scale (HAM-D) score showed a significant increase in plasma SAM concentration. These results suggest that one of the ways in which tricyclic drugs exert antidepressive effects is by raising SAM levels. [96] No significant side-effects have been reported with oral SAM. However, because SAM can cause nausea and vomiting in some people, it is recommended that it be started at a dosage of 200 mg twice daily for the first day, increased to 400 mg twice daily on day 3, then to 400 mg three times daily on day 10, and finally to the full dosage of 400 mg four times daily after 20 days. Individuals with bipolar (manic) depression should not take SAM. Because of SAM’s antidepressant activity, these individuals are susceptible to experiencing hypomania or mania. This effect is exclusive to some individuals with bipolar depression.
Reference
Number of patients
Dose (mg/day)
TABLE 126-3 -- Phenylalanine and tyrosine in depression Duration Clinical effects and comments (days)
Yaryura et al (1974)
15
200–400
14
(D,L-P) 10 severely depressed patients responded
Fischer et al (1975)
23
100
1–13
(D, or D,L-P) A complete response was observed in 17 patients previously unresponsive to tricyclics and MAO inhibitors
Beckman et al (1977)
20
75–200
20
(D,L-P) Eight complete remissions, four showed marked improvement; used Hamilton Depression Scale and von Zerssen self-rating questionnaire
Heller (1978)
55
100–400
60–180
(D-P) 73% recovered completely after 15 days, 23% had marked improvement, 4% failed to respond
Heller (1978)
60
100
30
(D-P) Complete remission and improvement in 83% for the phenylalanine group compared with 73% for the imipramine group; double-blind controlled study – no diagnostic criteria or rating scales were reported
Beckman (1979)
27
200
30
(D,L-P) No significant difference between phenylalanine and imipramine groups
Gibson et al (1983)
9
300
Ongoing
(T) Double-blind, placebo-controlled study; tyrosine demonstrated a rate of response (60–70%) typical of most major antidepressants without side-effects
References are from Beckman[83] and Gibson & Gelenberg. [82] P = phenylalanine; T = tyrosine.
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TABLE 126-4 -- Double-blind clinical studies with SAM vs. placebo in depression * SAM responders Placebo responders Conclusion
Authors Fazio et al (1973)
Not quantified
SAM superior to placebo based on Hamilton Depression Scale
Agnoli et al (1976)
20/20
1/10
SAM superior to placebo
Muscettola et al (1982)
4/10
0/10
SAM superior to placebo
Janicak (1982)
5/7
0/5
SAM superior to placebo
Caruso et al (1984)
Not quantified
SAM superior to placebo based on Hamilton Depression Scale
Carney et al (1986)
Not quantified
SAM superior to placebo based on Hamilton Depression Scale and Beck Scale
De Leo (1987)
Not quantified
SAM superior to placebo based on Clinical Global Impression Scale
Total
29/37 (78%)
* References from Janicak et al.
1/25 (4%)
SAM dramatically more effective than placebo
[ 88]
TABLE 126-5 -- Double-blind clinical studies with SAM vs. antidepressant drugs in depression SAM responders Drug responders Conclusion
Authors
*
Mantero et al (1975)
11/16
9/15
SAM comparable to imipramine (75 mg/day)
Barberi et al (1978)
10/10
8/10
SAM more effective than amitryptaline (100 mg/day)
Del Vecchio et al (1978)
5/14
4/10
SAM comparable to clomipramine (100 mg/day)
Miccoli et al (1978)
35/45
30/41
SAM comparable to clomipramine (100 mg/day)
Scarzella et al (1978)
9/10
9/10
SAM comparable to clomipramine (100 mg/day)
Scaggion et al (1982)
18/22
10/18
SAM more effective to nomifensine (200 mg/day)
Kufferle et al (1982)
7/9
6/9
SAM comparable to clomipramine (50 mg/day)
Plotkin (1988)
9/9
2/9
SAM more effective than imipramine (150 mg/day)
Janicak (1988)
5/7
2/3
SAM comparable to imipramine (150 mg/day)
109/142 (76%)
80/124 (61%)
SAM is significantly more effective than antidepressant drugs
Total * References from Janicak et al.
[ 88]
Botanical medicines Hypericum perforatum
Extracts of St John’s wort standardized for hypericin are the most thoroughly researched natural antidepressants. A total of 1,592 patients have been studied in 25 double-blind controlled studies (15 compared with placebo, 10 compared with antidepressant drugs including five studies comparing St John’s wort extract with tricyclics: two vs. imipramine, two vs. amitriptyline, and one vs. desipramine). [97] [98] [99] In these studies, St John’s wort extract was shown to produce improvements in many psychological symptoms, including: • depression • anxiety • apathy • sleep disturbances • insomnia • anorexia • feelings of worthlessness. The main advantage of St John’s wort extract over antidepressant drugs was not so much a difference in therapeutic outcome, but rather a significant advantage in terms of side-effects, cost and patient. For example, in a study of 102 patients there were slightly better results obtained with maprotiline (a tetracyclic) in the HAM-D, D-S, and CGI, but when side-effects and patient tolerance were added to the equation, St John’s wort was considered superior. [100] Maprotiline treatment resulted in the typical side-effects of tricyclics, e.g. tiredness, mouth dryness, and heart complaints. For more information on St John’s wort, consult Chapter 93 . Piper mythisticum
Kava extracts, like St John’s wort, are gaining in popularity in Europe in the treatment of anxiety and depression. Several European countries (e.g. Germany, the United Kingdom, Switzerland, and Austria) have approved kava preparations in the treatment of nervous anxiety, insomnia, depression, and restlessness on the basis of detailed pharmacological data and favorable clinical studies. In fact, kava extract compares quite favorably with benzodiazepines in effectiveness, but does not possess the major drawbacks of these drugs (impaired mental acuity, addictiveness, etc.). [101] [102] [103] These approved kava preparations are extracts standardized for
kavalactone content (usually 30–70%). Kava appears most
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useful in cases of depression with severe anxiety (for more information on kava, see Ch. 104 ). Ginkgo biloba
The extract of Ginkgo biloba leaves standardized to contain 24% ginkgo flavonglycosides and 6% terpenoids exerts good antidepressant effects, especially in patients over the age of 50 years. Researchers became interested in the antidepressive effects of Ginkgo biloba extract as a result of the improvement in mood reported by patients suffering from cerebrovascular insufficiency who were treated with ginkgo in double-blind studies. [104] [105] [106] [107] These observations led to several double-blind studies of the efficacy of ginkgo in depression. In one of the more recent double-blind studies, 40 older patients (age range, 51–78 years) with depression who had not benefited fully from standard antidepressant drugs were given either 80 mg of Ginkgo biloba extract three times daily or a placebo. [108] By the end of the fourth week of the study, the total score on the Hamilton Depression Scale was reduced on average from 14 to 7. At the end of the 8 week study, the total score in the Ginkgo biloba extract group had dropped to 4.5. In comparison, the placebo group only dropped from 14 to 13. This study indicates that Ginkgo biloba extract can be used with standard antidepressants and it may enhance their effectiveness, particularly in patients over 50 years of age. In addition to human studies, Ginkgo biloba extract has also demonstrated antidepressant effects in a number of animal models including the learned helplessness model. The most interesting of these studies demonstrated that Ginkgo biloba extract was able to counteract one of the major changes in brain chemistry associated with aging – the reduction in the number of serotonin receptor sites. [109] Typically, with aging there is a significant reduction in the number of serotonin receptor sites on brain cells. As a result, the elderly are more susceptible to depression, impaired mental function, insomnia, and sleep disturbances. The study was designed to determine whether Ginkgo biloba extract could alter the number of serotonin receptors in old (24-month-old) and young (4-month-old) rats. At the beginning of the study, the older rats had a 22% lower number of serotonin binding sites compared with the younger rats. The results of chronic treatment with Ginkgo biloba extract for 21 consecutive days demonstrated that there was no change in receptor binding in young rats, but in the older rats there was a statistically significant increase (by 33%) in the number of serotonin binding sites. These results indicate that Ginkgo biloba extract may counteract at least some, if not all, of the age-dependent reductions of serotonin binding sites in the aging human brain as well. The exact mechanism of Ginkgo biloba extract’s effect on increasing serotonin receptors has not yet been determined; however, Ginkgo biloba extract may address two major reasons why serotonin receptors decline with age: impaired receptor synthesis, or changes in cerebral neuronal membranes or receptors as a result of free radical damage. Ginkgo biloba extract has demonstrated an ability to increase protein synthesis. In addition, Ginkgo biloba extract is known to be a potent antioxidant. The most likely explanation is that it is a combination of these two effects (and others) rather than one single mechanism (see Ch. 88 for further discussion).
THERAPEUTIC APPROACH Treatment is largely dependent upon accurate determination of which factors are contributing to the patient’s depression; balancing of errant neurotransmitter levels; and optimizing the patient’s nutrition, lifestyle, and psychological health. Diet
Increase the consumption of fiber-rich plant foods (fruits, vegetables, grains, legumes, and raw nuts and seeds). Avoid the intake of caffeine, nicotine, other stimulants, and alcohol. Identify and control food allergies. Increase the consumption of cold water fish to at least twice per week. Lifestyle
• Either refer the patient to a counselor or help them to develop a positive, optimistic mental attitude. This can be accomplished by helping the patient to set goals, use positive self-talk and affirmations, identify self-empowering questions and find ways to inject humor and laughter into his or her life. • Regular exercise: at least 30 minutes at least three times a week. • Relaxation/stress reduction technique: 10–15 minutes each day. Supplements
• High potency multiple vitamins and minerals • Vitamin C: 500–1,000 mg three times/day • Vitamin E: 200–400 IU/day • Flaxseed oil: 1 tbsp/day • 5-HTP: 100–200 mg three times/day • Folic acid and vitamin B 12 : 800 mcg of each daily. Botanical medicines
If under the age of 50, St John’s wort extract (0.3% hypericin) should be used at a dosage of 300 mg three times daily. In severe cases, St John’s wort extract can be used in combination with 5-HTP.
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If over the age of 50, Ginkgo biloba extract (24% ginkgo flavonglycosides) should be used at a dosage of 80 mg three times daily. In severe cases, this can be used in combination with St John’s wort and/or 5-HTP. If anxiety is a significant factor, kava extract standardized for kavalactone content should be used at a dosage of 45–70 mg kavalactones three times daily.
BIPOLAR (MANIC) DEPRESSION AND HYPOMANIA GENERAL CONSIDERATIONS Bipolar depression is a disorder characterized by periods of major depression alternating with periods of elevated mood. If the elevated mood is relatively mild and lasts for 4 days or less it is referred to as hypomania. Mania is longer and more intense. To be diagnosed as a bipolar depressive, an individual would be expected to have at least three of the following symptoms: • excessive self-esteem or grandiosity • reduced need for sleep • extreme talkativeness, excessive telephoning • extremely rapid flight of thoughts along with the feeling that the mind is racing • inability to concentrate, easily distracted • increase in social or work-oriented activities, often with a 60–80 hour working week • poor judgment, as indicated by sprees of uncontrolled spending, increased sexual indiscretions, and misguided financial decisions. A full-blown manic attack requires hospitalization. Manic people have lost control, and they may hurt themselves or others. The standard treatment of bipolar
depression is lithium. Lithium stabilizes mood. It is especially useful in preventing the manic phase. Lithium is used either alone or in combination with an antidepressant like Prozac. However, because Prozac and other antidepressant drugs can occasionally induce mania and hypomania, it is often very difficult to effectively control the lows in bipolar depressives with drug therapy.
THERAPEUTIC CONSIDERATIONS Patients experiencing a manic syndrome usually require hospitalization to prevent impulsive and aggressive behavior from ruining their careers or injuring themselves or others. Lithium has become the drug of choice for these patients. Typically, manic patients are initially hospitalized for 2 weeks and kept under sedation with antipsychotic drugs until lithium levels reach acceptable blood levels. Referral seems warranted for most cases until mood can be stabilized. Many of the principles outlined in the discussion of depression are applicable to mania as well. However, due to the seriousness of this condition, it is more appropriate to use nutritional therapy as an adjunct, rather than as the primary therapy. Also, as serotonin reuptake inhibitors like Prozac, Zoloft, and Paxil are often helpful when used in combination with lithium, 5-HTP and botanical medicines such as St John’s wort extract may prove useful as adjuncts to lithium as well but without the side-effects. Tryptophan
Although patients have responded to tryptophan supplementation, the effective doses were generally quite large, i.e. 12 g/day L-tryptophan. [110] [111] A better choice appears to be 5-HTP, which has been shown to be helpful in the treatment of bipolar depression when used in combination with lithium at a much lower dosage (e.g. 100 mg three times/day) than L-tryptophan. [112] [113] Phosphatidylcholine
Supplementation with large amounts of phosphatidylcholine (15–30 g/day in both the pure form and as lecithin) has shown better results than monoamine precursors in the treatment of mania.[114] [115] [116] Lithium is believed to promote increased CNS cholinergic activity via inhibition of choline flux across the blood–brain barrier. [117] [118] There is evidence that mania is associated with a reduced CNS cholinergic activity. [117] [118] The use of phosphatidylcholine to increase CNS choline may result in significant improvement or amelioration of symptoms in some patients. [114] [115] [116] Details of the basic defect in the one-carbon cycle and the cholinergic system need to be worked out, but it appears to be a valuable clue to the etiology of mania. Vanadium
Vanadium’s role in mania has been researched primarily by Naylor and colleagues. [119] [120] [121] Increased levels of vanadium are found in hair samples from manic patients, and these values fall towards normal levels with recovery. [119] In contrast, depressed patients typically have normal hair concentrations, while whole blood and serum vanadium levels are elevated. [119] Their levels also return to normal upon recovery. Vanadium, as the vanadate ion, is a strong inhibitor of Na + ,K+ ATPase. Lithium has been reported to reduce this inhibition. [119] [120] [121] Therapies designed to reduce vanadate to the less inhibitory vanadyl form have used ascorbic acid, methylene blue, and EDTA separately and in combination. Ascorbic acid (3 g/day) has been shown in a doubleblind cross-over study to result in significant clinical improvement. [120]
[ 120] [ 121]
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The use of a “low-vanadium diet” has also been advocated by Naylor. However, his dietary suggestions for low vanadium intake are not consistent with the vanadium content of foods, as determined by flameless atomic absorption spectroscopy. [122] Using this method, low-vanadium foods (1–5 ng/g) include fats, oils, fresh fruits, and vegetables. Whole grains, sea food, meat, and dairy products are in the range of 5–30 ng/g, while prepared foods, such as peanut butter, white bread, and breakfast cereals, range from 11 to 93 ng/g. [122] The benefit of the low-vanadium diet used in Naylor’s study was probably due to his simultaneous administration of EDTA. If Naylor’s hypothesis is correct, perhaps other factors which are known to affect Na + ,K+ ATPase activity are involved in some cases. Those factors associated with decreased activity would include uremia, hypothyroidism, and catecholamine insensitivity. From a therapeutic aspect, correction of these underlying factors may be of some aid. Vitamins E and B6 have been demonstrated to increase Na + ,K+ ATPase activity in vitro, and vitamin E stabilizes membranes as well. [123] Circadian rhythms
Manic depressive patients have disturbed circadian rhythms, seasonal patterns of exacerbations, and supersensitivity to light, suggesting that alteration of circadian light–dark cycles through light therapy may be of clinical utility (see “Seasonal affective disorder” below). [124]
THERAPEUTIC APPROACH In general, the same dietary and lifestyle guidelines given in the section on depression are appropriate here. Diet
A low-vanadium diet is recommended. This entails eliminating all refined and processed foods and promoting the consumption of fresh fruits and vegetables. Supplements
• Phosphatidylcholine: 10–25 g/day (note that phosphatidylcholine may induce depression in some patients; • Vitamin C: 3–5 g/day in divided doses • Vitamin E: 400–800 IU/day • Pyridoxine: 100 mg/day.
[125]
if this occurs, discontinue immediately)
SEASONAL AFFECTIVE DISORDER GENERAL CONSIDERATIONS Seasonal affective disorder (SAD) is associated with winter depression and summer hypomania. Typically, these individuals feel depressed, they slow down, and generally oversleep, overeat, and crave carbohydrates in the winter. In the summer, these same patients feel elated, active, and energetic.
THERAPEUTIC CONSIDERATIONS Melatonin
Although many variables may be responsible for SAD, light exposure appears the most logical explanation. Many mammals exhibit seasonal variation in activity level, sleep patterns, and appetite, and are extremely sensitive to changes in day length. The key hormonal change may be a reduced secretion of melatonin from the pineal gland and an increased secretion of cortisol by the adrenal glands. Melatonin supplementation may improve SAD because it not only increases brain melatonin levels, but also may suppress cortisol secretion. [126]
Light therapy
The antidepressive effects of full-spectrum light therapy have been demonstrated in well-monitored, controlled studies not only in SAD, but also in clinical depression. [127] [128] [129] The antidepressant effect of light therapy is probably due to restoring proper melatonin synthesis and secretion by the pineal gland leading to re-establishment of the proper circadian rhythm. Light therapy consists of using full-spectrum lighting (Vitalite is a popular brand). The typical protocol used in clinical studies involved placing full-spectrum fluorescent tubes in regular fluorescent fixtures (eight tubes total). Patients were then instructed to sit 3 feet away from the light from 5.00 a.m. to 8.00 a.m. and again from 5.30 p.m. to 8.30 p.m. They were free to engage in activities as long as they glanced at the light at least once per minute. Obviously, to adopt this treatment protocol would greatly restrict social activities. Something that may work just as well is simply replacing standard light bulbs with full-spectrum light bulbs. Hypericum perfoliatum
St John’s wort extract, standardized to contain 0.3% hypericin (see Ch. 93 ), at a dosage of 300 mg three times daily has been shown to improve SAD. [130] However, although effective on its own, St John’s wort extract is more effective when used in combination with light therapy. This was demonstrated in a double-blind study where patients with SAD were randomized in a 4 week treatment study with 900 mg/day of St John’s wort extract (0.3% hypericin content) combined with either bright (3000 lux, n = 10) or dim light ( urtica. However, in certain situations one herbal approach may be more effective than another. In other words, even though we rate urtica lowest, in some cases urtica may produce better results than serenoa. Each plant has a slightly different mechanism of action.
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The chance of clinical success with any of the botanical treatments of BPH appears to be determined by the degree of obstruction as indicated by the residual urine content. For levels less than 50 ml, the results are usually excellent. For levels between 50 and 100 ml, the results are usually quite good. Residual urine levels between 100 and 150 ml will be tougher to produce significant improvements in the customary 4–6 week period. If the residual urine content is greater than 150 ml, saw palmetto extract and other botanical medicines are not likely to produce any significant improvement on their own.
Serenoa repens (saw palmetto)
The liposterolic extract of the fruit of this palm tree (also known as Sabal serrulata), native to Florida, has been shown to significantly improve the signs and symptoms of BPH in numerous clinical studies (see Ch. 110 ). The mechanism of action is related to inhibition of DHT binding to both the cytosolic and nuclear androgen receptors, inhibition of 5-alpha-reductase, and interference with intraprostatic estrogen receptors. As a result of these multitude of effects, excellent results have been produced in numerous double-blind clinical studies. The results from these studies are discussed in Chapter 110 . In summary, it can be stated that roughly 90% of men with mild to moderate BPH experience some improvement in symptoms during the first 4–6 weeks of therapy. All major symptoms of BPH are improved, especially nocturia. Cernilton
Cernilton, an extract of flower pollen, has been used to treat prostatitis and BPH in Europe for more than 35 years. [30] It has been shown to be quite effective in several double-blind clinical studies in the treatment of BPH. [31] [32] The overall success rate in patients with BPH is about 70%. [31] Patients who respond typically have reductions of nocturia and diurnal frequency of around 70% as well as significant reductions in residual urine volume. [32] The extract has been shown to exert some anti-inflammatory action and produce a contractile effect on the bladder while simultaneously relaxing the urethra. In addition, Cernilton contains a substance which inhibits the growth of prostate cells. [33] In the most recent study, the clinical efficacy of Cernilton in the treatment of symptomatic BPH was examined over a 1 year period. [30] Seventy-nine males of an average age of 68 years (range 62–89), with a mean baseline prostatic volume of 33.2 cm, were administered 63 mg Cernilton pollen extract twice daily for 12 weeks. Average urine maximum flow rate increased from 5.1 to 6.0 ml/s. Average flow rate increased from 9.3 to 11 ml/s. Residual urine volume decreased from 54.2 ml to less than 30 ml. Clinical efficacy, based on symptoms, was as follows: • urgency or discomfort – improved by 76.9% • dysuria – improved by 71.4% • nocturia – improved by 56.8% • incomplete emptying – improved by 66.2% • prolonged voiding – improved by 64.1% • delayed voiding – improved by 62.2% • intermittency – improved by 60.6% • post-void dribbling – improved by 42.7%. Overall, 85% of the test subjects experienced benefit: 11% reporting “excellent”, 39% reporting “good”, 35% reporting “satisfactor”, and 15% reporting “poor” as a description of their outcome. Pygeum africanum
Pygeum is an evergreen tree native to Africa whose bark has historically been used in the treatment of urinary tract disorders. The major active components of the bark are fat-soluble sterols and fatty acids. Virtually all of the research on pygeum has featured a pygeum extract standardized to contain 14% triterpenes including beta-sitosterol and 0.5% n-docosanol. This extract has been extensively studied in both experimental animal studies and clinical trials in humans (see Ch. 107 ). Numerous clinical trials in over 600 patients have demonstrated pygeum extract to be effective in reducing the symptoms and clinical signs of BPH, especially in early cases.[34] However, in a double-blind study which compared the pygeum extract with the extract of saw palmetto, the saw palmetto extract produced a greater reduction of symptoms and was better tolerated. [35] In addition, the effects on objective parameters, especially urine flow rate and residual urine content, are better in the clinical studies with saw palmetto. However, there may be circumstances where pygeum is more effective than saw palmetto. For example, saw palmetto has not been shown to produce some of the effects that pygeum has produced on prostate secretion. Of course, as the two extracts have somewhat overlapping mechanisms of actions, they can be used in combination. Urtica dioica (stinging nettles)
Extracts of Urtica dioica have also been shown to be effective in the treatment of BPH. Fewer studies have been done with urtica extract compared with the other botanical medicines discussed. Two double-blind studies have shown it to be more effective than a placebo. [35] [36] However, like pygeum, the results with urtica are less impressive than those with saw palmetto extract (or Cernilton). Like the extract of Serenoa repens, urtica extracts appear to interact with binding of DHT to cytosolic and nuclear receptors. [37]
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THERAPEUTIC APPROACH Therapeutic goals for BPH are to: • normalize prostate nutrient levels • restore steroid hormones to normal levels • inhibit excessive conversion of T to DHT • inhibit DHT receptor binding • limit promoters of the hyperplastic process, e.g. prolactin. Severe BPH resulting in significant acute urinary retention may require catheterization for relief, and a sufficiently advanced case may not respond rapidly enough to therapy and may require the short-term use of an alpha-1 antagonist (e.g. Hytrin or Cordura) or surgical intervention. Diet
Since there have been no clinical trials of the use of diet in the treatment of BPH, the following recommendations are somewhat speculative. Initially the diet should be high in protein, low in carbohydrate, low in animal fats, and high in unsaturated oils. After the patient responds, a more normal diet can be used. The patient should limit alcohol, avoid drug-, pesticide- and hormone-contaminated foods, and limit cholesterol-rich foods. Soy foods should be used regularly. Supplements
• Zinc: 50 mg/day (picolinate preferred, maximum of 6 months; monitor copper status) • Flax oil: 1 tbsp two times/day • Glycine: 200 mg/day • Glutamic acid: 200 mg/day • Alanine: 200 mg/day. Botanicals
• Liposterolic extract (standardized at 85–95% fatty acids and sterols): 160 mg two times/day • Flower pollen extract (e.g. Cernilton): 63 mg two to three times/day.
REFERENCES 1. Oesterling 2. Horton
JE. Benign prostatic hyperplasia: a review of its histogenesis and natural history. Prostate 1996; 6: 67–73
R. Benign prostatic hyperplasia. A disorder of androgen metabolism in the male. J Am Geri Soc 1984; 32: 380–385
3. Kappas
A, Anderson KE, Conney AH et al. Nutrition-endocrine interactions. Induction of reciprocal changes in the delta-5-alpha-reduction of testosterone and the cytochrome P-450–dependent oxidation of estradiol by dietary macronutrients in man. Proc Natl Acad Sci USA 1983; 80: 7646–7649 4. Bush
IM et al. Zinc and the prostate. Presented at the annual meeting of the AMA, 1974
5. Fahim
M, Fahim Z, Der R, and Harman J. Zinc treatment for the reduction of hyperplasia of the prostate. Fed Proc 1976; 35: 361
6. Leake
A, Chrisholm GD, Busuttil A, Habib FK. Subcellular distribution of zinc in the benign and malignant human prostate: evidence for a direct zinc androgen interaction. Acta Endocrinol 1984; 105: 281–288 7. Zaichick 8. Leake
VY, Sviridova TV, Zaichick SV. Zinc concentration in human prostatic fluid. Normal, chronic prostatitis, adenoma and cancer. Int Urol Nephrol 1996; 28: 687–694
A, Chisholm GD, Habib FK. The effect of zinc on the 5-alpha-reduction of testosterone by the hyperplastic human prostate gland. J Steroid Biochem 1984; 20: 651–655
9. Wallace
AM, Grant JK. Effect of zinc on androgen metabolism in the human hyperplastic prostate. Biochem Soc Trans 1975; 3: 540–542
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Judd AM, MacLeod RM, Login IS. Zinc acutely, selectively and reversibly inhibits pituitary prolactin secretion. Brain Res 1984; 294: 190–192
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Login IS, Thorner MO, MacLeod RM. Zinc may have a physiological role in regulating pituitary prolactin secretion. Neuroendocrinology 1983; 37: 317–320
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Farnsworth WE, Slaunwhite WR, Sharma M et al. Interaction of prolactin and testosterone in the human prostate. Urol Res 1981; 9: 79–88
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Farrar DJ, Pryor JS. The effect of bromocriptine in patients with benign prostatic hyperplasia. Br J Urol 1976; 48: 73–75
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DeRosa G, Corsello SM, Ruffilli MP et al. Prolactin secretion after beer. Lancet 1981; 2: 934
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Corenblum B, Whitaker M. Inhibition of stress-induced hyperprolactinaemia. Br Med J 1977; 275: 1328
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Chyou PH et al. A prospective study of alcohol, diet, and other lifestyle factors in relation to obstructive uropathy. Prostate 1993; 22: 253–264
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Hart JP, Cooper WL. Vitamin F in the treatment of prostatic hyperplasia. Report Number 1. Milwaukee, WI: Lee Foundation for Nutritional Research. 1941
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Scott WW. The lipids of the prostatic fluid, seminal plasma and enlarged prostate gland of man. J Urol 1945; 53: 712–718
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Boyd EM, Berry NE. Prostatic hypertrophy as part of a generalized metabolic disease. Evidence of the presence of a lipopenia. J Urol 1939; 41: 406–411
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Dumrau F. Benign prostatic hyperplasia: amino acid therapy for symptomatic relief. Am J Ger 1962; 10: 426–430
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Feinblatt HM, Gant JC. Palliative treatment of benign prostatic hypertrophy: value of glycine, alanine, glutamic acid combination. J Maine Med Assoc 1958; 49: 99–102
22.
Hinman F. Benign prostatic hyperplasia. New York: Springer-Verlag. 1983
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Tilvis RS, Miettinen TA. Serum plant sterols and their relation to cholesterol absorption. Am J Clin Nutr 1986; 43: 92–97
24.
Berges RR et al. Randomized, placebo-controlled, double-blind clinical trial of beta-sitosterol in patients with benign prostatic hyperplasia. Lancet 1995; 345: 1529–1532
25.
Morton MS, Griffiths K, Blacklock N. The preventive role of diet in prostatic disease. Br J Urol 1996; 77: 481–493
26.
Messina M, Barnes S. The roles of soy products in reducing risk of cancer. J Natl Cancer Inst 1991; 83: 541–546
27.
Lahtonen R. Zinc and cadmium concentrations in whole tissue and in separated epithelium and stroma from human benign prostatic hypertrophic glands. Prostate 1985; 6: 177–183
Sinquin G, Morfin RF, Charles JF et al. Testosterone metabolism by homogenates of human prostates with benign hyperplasia: effects of zinc, cadmium, and other bivalent cations. J Steroid Biochem 1984; 20: 733–780 28.
29.
Buck AC. Phytotherapy for the prostate. Br J Urol 1996; 78: 325–336
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Yasumoto R et al. Clinical evaluation of long-term treatment using Cernitin pollen extract in patients with benign prostatic hyperplasia. Clinical Therapeutics 1995; 17: 82–86
31.
Buck AC et al. Treatment of outflow tract obstruction due to benign prostatic hyperplasia with the pollen extract, Cernilton
32.
Dutkiewicz S. Usefulness of Cernilton in the treatment of benign prostatic hyperplasia. Int Urol Nephrol 1996; 28: 49–53
33.
Habib FK, Ross M, Lawenstein A. Identification of a prostate inhibitory substance in a pollen extract. The Prostate 1995; 26: 133–139
34.
Duvia R, Radice GP, Galdini R. Advances in the phytotherapy of prostatic hypertrophy. Med Praxis 1983; 4: 143–148
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Belaiche P, Lievoux O. Clinical studies on the palliative treatment of prostatic adenoma with extract of Urtica root. Phytother Res 1991; 5: 267–269
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Romics I. Observations with Bazoton in the management of prostatic hyperplasia. Int Urol Nephrol 1987; 19: 293–297
37.
Wagner H. Search for the antiprostatic principle of stinging nettle ( Urtica dioica) roots. Phytomedicine 1994; 1: 213–224
®
. A double-blind, placebo-controlled study. Br J Urol 1990; 66: 398–404
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Chapter 139 - Carpal tunnel syndrome Douglas C. Lewis ND
DIAGNOSTIC SUMMARY • Patient complains of numbness, tingling and/or burning pain on the palmar surfaces of the first three digits of the hand • Positive Tinel’s sign (tingling or shock-like pain on volar wrist percussion) • Positive Phalen’s sign (appearance of exacerbation of symptoms caused by flexion of the wrist for 60 seconds and relieved by extension).
GENERAL CONSIDERATIONS Carpal tunnel syndrome (CTS) may be defined as unior bilateral paresthesia in the palmar aspect of the first three digits and the lateral half of the fourth digit of the hand due to median nerve compression within the carpal tunnel. Pain may be felt in the wrist, palm, and/or forearm proximal to the area of compression. There may be loss of strength in abduction and opposition of the thumb and atrophy of the opponens pollicis muscle may develop. Etiology Any condition which increases the volume of the structures within the carpal tunnel or causes a narrowing of the tunnel itself can result in impingement upon the median nerve. Conditions which may decrease the volume in the tunnel include deformity from subluxation of the carpals, separated distal radius and ulna, Colles’ fracture, arthritic spurs, tumor, or thickening of the flexor retinaculum. Those conditions which may increase the volume of the contents of the carpal tunnel include fluid retention, fat deposition, carpal synovitis, or tenosynovitis. A large percentage of cases are idiopathic. Within these idiopathic cases some researchers have found decreased vitamin B 6 levels, [1] [2] while others have seen evidence of collagen dysplasia. [3]
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Risk factors and frequency of occurrence Traumatic injury and occupational injury through repetitive use are the most obvious causes of CTS. A recent study of 501 participants (156 of whom were diagnosed with CTS) showed the following risk factors: repetitive activities with a flexed or extended wrist, hysterectomy without oophorectomy, and last menstrual period in menopausal women 6–12 months earlier.[4] Others have found an increased incidence in pregnant women, women taking oral contraceptives, menopausal women, or patients on hemodialysis. [5] CTS is more prevalent among women and occurs frequently between the ages of 40 and 60 years.
DIAGNOSTIC CONSIDERATIONS Most commonly the patient will complain of pain and tingling or numbness in the hand. Symptoms are often worse at night and will awaken the patient. Patients regularly claim that relief is gained from shaking or rubbing the hand (or hands if the condition is bilateral). Occasionally patients will complain of clumsiness due to an inability to hold or feel an object. Physical examination
Examination will reveal impaired sensation in the distribution of the median nerve. If the condition has existed for a prolonged period, atrophy of the thenar eminence and weakness of the thumb abductor will also be present. Tinel’s and Phalen’s tests have been the accepted tests for diagnosing CTS in the general office. Tinel’s sign is tingling in the distribution of the median nerve when tapping the nerve in the middle of the palm over the transverse carpal ligament. Phalen’s test is positive when symptoms are reproduced by holding the wrist in forced flexion for 60–90 seconds. Katz & Stirrat[6] have devised a self-administered hand diagram that has shown an 80% sensitivity and a 90% specificity for classic or probable CTS. Other diagnostic tests include nerve conduction tests, CT scan, and MR imaging. Differential diagnosis
The paresthesia of CTS may be confused with the paresthesia of the brachial plexus found in thoracic outlet syndrome or with paresthesia of either the radial or ulnar nerves. Likewise, a patient might complain of hand pain which may be the presenting feature of reflex sympathetic dystrophy (shoulder–hand syndrome). Impingement of the median nerve may occur below the elbow where the nerve passes under the pronator teres muscle. The specific dermatome pattern of CTS, without proximal dysfunction, should lead the practitioner to the particular history and tests needed to establish a diagnosis of CTS. When left-sided, CTS may be confused with angina pectoris.
THERAPEUTIC CONSIDERATIONS The majority of patients respond well to nutritional and conservative physical medicine approaches. While a few will require surgical intervention, nutritional support continues to be needed to address the underlying metabolic weakness. Nutrition Vitamin B supplementation
Ellis and Folkers (and co-workers) [1] [7] [8] [9] repeatedly demonstrated the efficacy of vitamin B 6 supplementation in the treatment of CTS. B 6 in the amount of 50 mg initially and increased to 200–300 mg as needed has been shown to be significantly effective in the treatment of CTS in these studies. Another study has shown vitamin B2 to be useful in the treatment of CTS, with an even greater effect seen when B 6 and B2 are given together. [7] This is most likely due to riboflavin-containing enzymes which convert pyridoxine to its more active form, pyridoxal 5'-phosphate. This may support the use of this form of B 6 in the treatment of CTS. The therapeutic response may require up to 3 months of supplementation. The increased incidence of CTS since its initial description by Phalen in 1950 parallels the increased presence of pyridoxine anti-metabolites in the environment.
These include the hydrazine dyes (FD&C yellow no. 5) and drugs (INH and hydralazine), dopamine, penicillamine, oral contraceptives, and excessive protein intake. In an attempt to determine if there is a relationship between vitamin B 6 status and symptoms of carpal tunnel syndrome (CTS), researchers measured vitamin B 6 levels, assessed ulnar and median nerve function in their wrists and hands, and noted CTS symptoms in 125 randomly selected employees at an auto parts plant. About one-third of the employees reported CTS, a quarter had median nerve dysfunction, and 10 had vitamin B 6 deficiency. After statistical analysis, researchers found no correlation between employees’ blood levels of vitamin B 6 and the presence of or improvement in CTS symptoms.
[10]
The study did not analyze the effectiveness of vitamin B 6 therapy, yet several reports in the popular press and JAMA stated that we should “forget the vitamin B 6 ” in the treatment of CTS. Vitamin B6 therapy may prove to be effective in some cases of CTS regardless of the patient’s vitamin B 6 status. Despite the lack of clinical evaluation, the authors of the study concluded that
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“empiric treatment for CTS with vitamin B6 supplementation is not warranted”. Given the safety and positive clinical studies with vitamin B 6 in reasonable dosages (e.g. 25–50 mg three times daily), a trial of vitamin B 6 should still be utilized (especially before opting for surgery). Physical medicine Hydrotherapy
Inflammation and edema are present in CTS, causing compression of the local capillaries with resultant decreased nutrition to the median nerve, thus making the nerve fibers hyperexcitable. [11] Contrast hydrotherapy provides a simple, efficient way to increase circulation to the area. Immersion in hot water for 3 minutes followed by immersion in cold water for 30 seconds, repeated three to five times, will increase local circulation, thereby increasing local nutrition, eliminating waste, and decreasing pain. Immobilization
According to Cailliet, [11] splinting of the wrist in a neutral position is required day and night for several weeks. Night-time splinting only when symptoms appear is ineffective. Manual manipulation
Manipulation of subluxation of the carpals or separation of the distal radius and ulna may relieve pressure in the carpal tunnel, thereby relieving impingement of the median nerve. Acupuncture
In a study of the acupuncture treatment of CTS, a posi-tive response was demonstrated in 35 of 36 patients (14 of whom were previously treated unsuccessfully with surgery). [12] Treatment involved puncture of PC-7 and PC-6 on the affected side. Stretching
In 92 patients, 81 of whom had carpal tunnel syndrome compared with controls, it was found that the mean tunnel pressure was double in those with carpal tunnel syndrome. After 1 minute of stretching–loading exercises, intratunnel pressures dropped to normal levels where they remained for more than 20 minutes. Exercise includes flexing the wrists and fists with the arms extended for 5 minutes. This slow, sustained movement helps to prepare the carpal tunnel nerve for repetitive actions. These exercises should be done before work starts and during every break. The researchers suggested that these exercises might reduce the need for surgery by 50%. [13] Surgery
If all other attempts at treatment fail, surgery may be a last resort. In the past, an incision has been made through the skin overlying the transverse carpal ligament. Chow[14] has developed a less invasive endoscopic technique with a high success rate and decreased morbidity compared with the more commonly performed surgical techniques.
THERAPEUTIC APPROACH Whenever possible, prevention is obviously best. The patient should be instructed to avoid activities which cause trauma to the median nerve through repeated wrist flexion and extension, as well as activities which cause direct trauma to the wrist. All professions that require extensive use of the hands are ones that put the patient at risk. Protecting the hands from injury, as well as maintaining wrist posture, may help in avoiding the onset of CTS. A conservative approach to treatment should be instituted as soon as possible to avoid long term or permanent damage to the median nerve or its associated muscles. All sources of hydrazines should be avoided. If, after several months of treatment, the therapies recommended here do not produce the desired clinical effects, endoscopic surgery should be considered. Anti-inflammatory agents have shown some usefulness in CTS and should be considered as a part of an overall treatment protocol. Diet
Avoid foods containing yellow dyes and limit daily protein intake to a maximum of 0.75 g/kg body weight. Supplements
• Pyridoxine: 50–200 mg/day – use pyridoxal 5'-phosphate if there is no response within 6 weeks • Riboflavin: 10 mg/day. Physical medicine
Contrast hydrotherapy. Immerse for 3 minutes in hot water followed by a 30 second immersion in cold water, three to five times/day. Perform daily. Manipulation. Manipulate carpals and ensure proper spacing of distal radius and ulna. Acupuncture. Needle PC-7 and PC-6 on the affected side. Splint. For severe or unresponsive cases, splint the wrist in the neutral position night and day.
Regular wrist exercises.
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REFERENCES 1. Ellis
JM, Folkers K, Shizukuishi S et al. Response of vitamin B
2. Fuhr
JE, Farrow A, Nelson Jr HS. Vitamin B 6 levels in patients with carpal tunnel syndrome. Arch Surg 1989; 124: 1329–1330
3. Stransky 4. de
6
deficiency and the carpal tunnel syndrome to pyridoxine. Proc Natl Acad Sci USA 1982; 79: 7494–7498
G, Wenger E, Dimitrov L, Weis S. Collagen dysplasia in idiopathic carpal tunnel syndrome. Path Res Pract 1989; 185: 795–798
Krom MCTFM, Kester ADM, Knipschild PG, Spaans F. Risk factors for carpal tunnel syndrome. Am J Epidemiol 1990; 132: 1102–1110
5. Sandez 6. Katz
SC. Carpal tunnel syndrome. Am Fam Phys 1981; 24: 190–204
JN, Stirrat CR. A self-administered hand diagram for the diagnosis of carpal tunnel syndrome. J Hand Surg 1990; 15A: 360–363
7. Folkers
K, Ellis J. Successful therapy with vitamin B 6 and vitamin B 2 of the carpal tunnel syndrome and need for determination of the RDA’s for vitamin B
6
and B2 disease states. Annals NY Acad
Sci 1990; 585: 295–301 8. Ellis
JM, Folkers K. Clinical aspects of treatment of carpal tunnel syndrome with B
9. Folkers
6
. Annals NY Acad Sci 1990; 585: 302–320
KA, Wolaniuk A, Vadhanavikit S. Enzymology of the response of carpal tunnel syndrome to riboflavin and to combined riboflavin and pyridoxine. Proc Nat Acad Sci 1984; 81: 7076–7078
10.
Franzblau A, Rock CL, Werner RA. The relationship of vitamin B
11.
Cailliet R. Soft tissue pain and disability. Philadelphia, PA: FA Davis. 1991: p 228–231
12.
Chen GS. The effect of acupuncture treatment on carpal tunnel syndrome. Am J Acupunct 1990; 18: 5–9
13.
Seradge H. Splints aren’t enough; hand exercises improve carpal tunnel treatment. Modern Med 1996; 64: 14–15
14.
Chow JCY. Endoscopic release of the carpal ligament for carpal tunnel syndrome. 22–month clinical result. Arthroscopy 1990; 6: 288–296
6
status to median nerve function and carpal tunnel syndrome among active industrial workers. JOEM 1996; 38: 485–491
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Chapter 140 - Celiac disease Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • A chronic intestinal malabsorption disorder caused by an intolerance to gluten • Bulky, pale, frothy, foul-smelling, greasy stools with increased fecal fat • Weight loss and signs of multiple vitamin and mineral deficiencies • Increased levels of serum gliadin antibodies • Diagnosis confirmed by jejunal biopsy.
GENERAL CONSIDERATIONS Celiac disease, also known as non-tropical sprue, gluten-sensitive enteropathy, or celiac sprue, is characterized by malabsorption and an abnormal small intestine structure which reverts to normal on removal of dietary gluten. The protein gluten and its polypeptide derivative, gliadin, are found primarily in wheat, barley, and rye grains. Symptoms most commonly appear during the first 3 years of life, after cereals are introduced into the diet. A second peak incidence occurs during the third decade. Breast feeding appears to have prophylactic effect, and breast-fed babies have a decreased risk of developing celiac disease. [1] [2] [3] The early introduction of cow’s milk is also believed to be a major etiological factor. [1] [2] [3] [4] Research in the past few years has clearly indicated that breast feeding, along with delayed administration of cow’s milk and cereal grains, are primary preventive steps that can greatly reduce the risk of developing celiac disease. Epidemiology and genetics
Precise epidemiological data on celiac disease is unavailable, due in part to the fact that asymptomatic disease makes ascertainment of true prevalence rates difficult. Celiac disease appears to have a genetic etiology, as evidenced by an increased frequency of serum histocompatibility antigens, particularly HLA-B 8 and DRw3
1158
types.[3] [5] The HLA-B8 antigen has been found in 85–90% of these celiac patients, as compared with 20–25% in normal subjects. The HLA-B 8 gene locus is believed to be linked to the immunologic recognition of antigens and specific T-cell-regulated immune responses. There is a low prevalence of HLA-B 8 within long-standing agrarian populations, while the frequency in northern and central Europe and the north-west Indian subcontinent is much higher. [3] [6] Wheat cultivation in these high HLA-B 8 areas is a relatively recent development (1000 BC). The prevalence of celiac disease is much higher in these areas compared with other parts of the world (e.g. 1:300 in south-west Ireland compared with 1:2,500 in the United States [estimated]). Chemistry of grain proteins
Gluten, a major component of the wheat endosperm, is composed of gliadins and glutenins. Only the gliadin portion has been demonstrated to activate celiac disease. In rye, barley, and oats, the proteins that appear to activate the disease are termed secalins, hordeins, and avenins, respectively, and prolamines collectively. Cereal grains belong to the family Gramineae. The closer a grain’s taxonomic relationship to wheat, the greater is its ability to activate celiac disease. Rice and corn, two grains that do not appear to activate celiac disease, are further removed taxonomically from wheat. [3] [7] The taxonomic relationship of the grains is shown in Figure 140.1 . Gliadins are single polypeptide chains that range in molecular weight from 30,000 to 75,000, with a very high glutamine and proline content. Gliadins have been divided into four major electrophoretic fractions: alpha-, beta-, gamma-, and omega-gliadin. Alpha-gliadin is believed to be the fraction most capable of activating celiac disease, although beta- and gamma-gliadin are also capable. Omega-gliadin does not appear to activate the disease, although it has the highest content of glutamine and proline. Gliadin that has been subjected to complete hydrolysis does not activate celiac disease in susceptible individuals, suggesting a possible relation to deficient brush border peptidase or similar defect in some other factor involved with protein digestion. [3] Opioid activity
Pepsin hydrosylates of wheat gluten have demonstrated opioid activity. [8] [9] This activity is believed to be the factor responsible for the association between wheat consumption and schizophrenia. [10] [11] [12] The hypothesis that gluten is a pathogenic factor in the development of schizophrenia is substantiated by epidemiological, clinical, and experimental studies. [10] [11] [12] Pathogenesis
Various hypotheses have been proposed to explain the pathogenesis of celiac disease. Currently, the most likely relates to abnormalities in the immune response rather than some “toxic” property of gliadin. [13] Sensitization to gliadin occurs both in humoral and cell-mediated immunity and it appears that T-cell dysfunction is the main factor responsible for the enteropathy. [14] Cell-mediated mechanisms can produce in animals the characteristic lesions seen in celiac disease, i.e. crypt hyperplasia, villous atrophy, and intraepithelial lymphocyte infiltration and mitosis. Although patients with celiac disease have high titers of serum antibodies to gliadin and other food proteins, it appears that these titers are probably secondary to the increased intestinal permeability which is the result of the enteropathy produced by the T-cell defect. [14] Of course, these immune complexes (e.g. antibody + gliadin) also contribute to the enteropathy through antibody-dependent cell-mediated cytotoxicity and activation of complement. [3]
Figure 140-1 Taxonomic relationship of major cereal grains. [3]
[ 24]
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Clinical aspects
The histologic lesions of celiac disease are often indistinguishable from those changes caused by tropical sprue, food allergy, diffuse intestinal lymphoma, and viral gastroenteritis. Furthermore, celiac disease will often lead to a disaccharidase deficiency, causing lactose intolerance, and the increased intestinal permeability usually results in multiple food allergies. As stated earlier, cow’s milk intolerance may precede celiac disease. [1] [2] [3] [4] Associated conditions
Conditions such as thyroid abnormalities, insulin-dependent diabetes mellitus, psychiatric disturbances (including schizophrenia), dermatitis herpetiformis, and urticaria have also been linked to gluten intolerance. [3] A more ominous association is the increased risk for malignant neoplasms seen in celiac patients. [3] [15] [16] This may be a result of decreased vitamin and mineral absorption, particularly vitamin A and carotenoids (see Chs 67 and 121 ). However, it may also be a result of gliadin-activated suppressor cell activity. [17] Alpha-gliadin has demonstrated suppressor cell activation on the cells of celiac patients but has no effect on those of healthy controls or patients with Crohn’s disease. Two other dietary antigens, casein and beta-lactoglobulin, have failed to produce suppressor cell activation in similar experimental settings. This depression in the immune response makes these patients more susceptible to infection and neoplasm. Diagnosis Jejunal biopsy is the definitive diagnostic procedure. However, the presence of the characteristic symptoms along with a positive titer for antibodies against gliadin (anti-alpha-gliadin antibodies) spares the patient the rigor of a small intestine biopsy. The ELISA test for alpha-gliadin antibodies has a diagnostic sensitivity of 100% and a diagnostic specificity of 97%. [18] The fluorescent immunosorbent test has yielded similar impres-sive results (100% sensitivity and 84% specificity). [19] It appears that both IgA and IgG gliadin antibody levels should be taken into consideration rather than relying on just one antibody assay. Anti-endomysium antibodies are now also reliable markers for celiac disease. [20]
THERAPEUTIC CONSIDERATIONS Diet
Once the diagnosis has been established, a gluten-free diet is indicated. This diet does not contain any wheat, rye, barley, triticale, or oats. Buckwheat and millet are often excluded as well. Although buckwheat is not in the grass family, and millet appears to be more closely related to rice and corn, they do contain prolamines with similar antigenic activity to the alpha-gliadin of wheat. A recent study of 52 adults with celiac disease suggests that modest amounts of oats may be tolerated without adverse side-effects.[21] In addition, other foods should be rotated, and milk and milk products should be eliminated until the patient redevelops an intestinal structure and function returns to normal. Patient response
Usually clinical improvement will be apparent within a few days or weeks (30% respond within 3 days, another 50% within 1 month, and 10% within another month). However, 10% of patients only respond after 24–36 months of gluten avoidance. [22] If the patient does not appear to be responding, the following should be considered:
[3] [23]
• incorrect diagnosis • the patient is not adhering to the diet or is being exposed to hidden sources of gliadin • the presence of an associated disease or complication, such as zinc deficiency. The latter highlights the importance of multivitamin and mineral supplementation in these patients. In addition to treating any underlying deficiency, supplementation provides the necessary cofactors for growth and repair. Celiac disease will be refractive to dietary therapy if an underlying zinc deficiency is present. [3] [23] Pancreatic enzymes
The effect of pancreatic enzyme substitution therapy in the 2 months following the initial diagnosis of celiac disease (gluten enteropathy) was investigated in a recent double-blind study. The study sought to clarify the benefit of pancreatic enzyme therapy because previous studies had shown pancreatic insufficiency in 8–30% of celiac patients. The standard treatment of celiac disease is a gluten-free diet. In the study, patients followed a gluten-free diet and received either two capsules of pancreatic enzymes with each meal (six to 10 capsules a day with each capsule containing lipase 5,000 IU, amylase 2,900 IU, and protease 330 IU) or two placebo capsules with meals. Complete nutritional and anthropomorphic evaluations were conducted at days 0, 30, and 60. Results indicated that pancreatic enzyme supplementation enhanced the clinical benefit of a gluten-free diet during the first 30 days, but did not provide any greater benefit than the placebo after 60 days. These results support the use of pancreatic enzyme preparations
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in the first 30 days after diagnosis of celiac disease (see Ch. 101 for a complete discussion). [24]
THERAPEUTIC APPROACH The therapeutic approach is quite straightforward: eliminate all sources of gliadin (see Appendix 5 ), eliminate dairy products initially, correct underlying nutritional deficiencies, treat any associated conditions, and determine and eliminate all food allergens. If the patient does not begin to respond within 1 month, reconsider the diagnosis and search for hidden sources of gliadin. Maintenance of a strict gluten-free diet is quite difficult in the United States, due to the ubiquitous distribution of gliadin and other activators of celiac disease in processed foods. Patients must be encouraged to read labels carefully in order to avoid hidden sources of gliadin, such as is found in some brands of soy sauce, modified food starch, ice cream, soup, beer, wine, vodka, whisky, malt, etc. Patients should also be encouraged to consult resources for patient education and information on gluten-free recipes (see below for a list of patient education resources). Patient resources
American Celiac Society 45 Gifford Avenue Jersey City, NJ 07304 American Digestive Disease Society 7720 Wisconsin Avenue Bethesda, MD 20014 Gluten Tolerance Group of North America PO Box 23053 Seattle, WA 98102 National Digestive Disease Education and Information Clearing House
1555 Wilson Boulevard, Suite 600 Rosslyn, VA 22209
REFERENCES 1. Auricchio
S. Gluten-sensitive enteropathy and infant nutrition. J Ped Gastroenterol Nutr 1983; 2: S304–309
2. Auricchio
S, Follo D, deRitis G et al. Does breast feeding protect against the development of clinical symptoms of celiac disease in children? J Ped Gastroenterol Nutr 1983; 2: 428–433
3. Cole
SG, Kagnoff MF. Celiac disease. Ann Rev Nutr 1985; 5: 241–266
4. Fallstrom
SP, Winberg J, Anderson HJ. Cow’s milk malabsorption as a precursor of gluten intolerance. Acta Paediatrica Scand 1965; 54: 101–115
5. McNicholl
B, Egan-Mitchell B, Stevens FM et al. History, genetics, and natural history of celiac disease – gluten enteropathy. In: Walker DN, Kretchmer N, eds. Food, nutrition and evolution. New York, NY: Masson. 1981: p 169–178 6. Simoons
FJ. Celiac disease as a geographic problem. In: Walker DN, Kretchmer N, eds. Food, nutrition and evolution. New York, NY: Masson. 1981: p 179–200
7. Kasarda
DD. Toxic proteins and peptides in celiac disease: relations to cereal genetics. In: Walker DN, Kretchmer N, eds. Food, nutrition and evolution. New York, NY: Masson. 1981: p 201–216
8. Morley
JE, Levine A, Yamada T et al. Effect of exorphins on gastrointestinal function, hormonal release, and appetite. Gastroenterol 1983; 84: 1517–1523
9. Morley
JE. Food peptides – a new class of hormones. JAMA 1982; 247: 2379–2380
10.
Singh MM, Kay SR. Wheat gluten as a pathogenic factor in schizophrenia. Science 1976; 191: 401–402
11.
Dohan FC, Gasberger JC. Relapsed schizophrenics. Earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatry 1973; 130: 685–688
12.
Dohan FC, Harper EH, Clark MH et al. Is schizophrenia rare if grain is rare? Biol Psychiatry 1984; 19: 385–399
13.
Robbins SL, Cotran RS, Kumar V. Pathologic basis of disease. Philadelphia, PA: WB Saunders. 1984: p 847–848
14.
Ferguson A, Ziegler K, Strobel S. Gluten intolerance (coeliac disease). Annals Allergy 1984; 53: 637–642
15.
Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac disease and malignancy. Lancet 1983; i: 111–115
16.
Cooper BT, Holmes KY, Ferguson R et al. Celiac disease and malignancy. Medicine 1980; 59: 249–261
17.
O’Farrelly C, Whelan CA, Feighery CF, Weir DG. Suppressor-cell activity in coeliac disease induced by alpha-gliadin, a dietary antigen. Lancet 1984; ii: 1305–1306
18.
Stenhammar L, Kilander AF, Nilsson LA et al. Serum gliadin antibodies for detection and control of childhood coeliac disease. Acta Paediatr Scand 1984; 73: 657–663
19.
Burgin-Wolff A, Bertele RM, Berger R et al. A reliable screening test for childhood celiac disease. Fluorescent immunosorbent test for gliadin antibodies. J Pediatr 1983; 102: 655–660
20.
Ferfoglia G et al. Do dietary antibodies still play a role in the diagnosis and follow-up of coeliac disease? A comparison among different serological tests. Panminerva Med 1995; 37: 55–59
21.
Janatuinen ER, Pikkarainen P, Kemppainen TA. A comparison of diets with and without oats in adults with celiac disease. New Engl J Med 1995; 333: 1033–1038
22.
Krause MV, Mahan KL. Food, nutrition and diet therapy. 7th edn. Philadelphia, PA: WB Saunders. 1984: p 452–457
Love AHG, Elmes M, Golden M et al. Zinc deficiency and celiac disease. In: McNicholl B, McCarthy CF, Fotrell PF, eds. Perspectives in celiac disease. Baltimore, MD: University Press. 1978: p 335–342 23.
24.
Carroccio A, Iacono G, Montalto G. Pancreatic enzyme therapy in childhood celiac disease. A double-blind prospective randomized study. Dig Dis Sci 1995; 40: 2555–2560
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Chapter 141 - Cellulite Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Demonstration of the “mattress phenomena”, i.e. pitting, bulging and deformation of the skin • 90–98% of cases occur in women • Symptoms may include feeling of tightness and heaviness in areas affected (particularly the legs) • Tenderness of the skin is quite apparent when the skin is pinched, pressed upon, or vigorously massaged.
GENERAL CONSIDERATIONS The term cellulite is used to describe a cosmetic defect that is cause for great distress among millions of European and American women. This French word was adopted by the lay public in the United States before American physicians and medical literature were educated in a condition that European physicians had been treating for over 150 years. [1] The correct English translation would be cellulitis. However, in the United States, cellulitis is used solely to describe a diffuse, inflammatory or infectious process involving the connective tissue, most commonly of the skin and subcutaneous structures. In cellulite there is no inflammatory or infectious process occurring. This difference in meaning in the translated term was just one source of confusion for American physicians. Researchers have suggested that the terms dermo-panniculois deformans or adiposis edematosa be used to designate the clinical condition. [2] In this chapter, however, the term cellulite will be used. Histological features The subcutaneous tissue is disturbed in cellulite. Since the thighs are the prime area of involvement, the structure of the subcutaneous tissue of the thighs is discussed here in greatest detail. The subcutaneous tissue of the thighs is composed of
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Figure 141-1 The anatomical basis of cellulite.
three layers of fat, with two planes of connective tissue (ground substance) between them. The basic construction of the subcutaneous tissue of the thigh differs in men and women, as shown in Figure 141.1 . In women, the uppermost subcutaneous layer consists of what are termed large “standing fat-cell chambers”, which are separated by radial and arching dividing walls of connective tissue anchored to the overlying connective tissue of the skin (corium). In contrast, the uppermost part of the subcutaneous tissue in men is thinner and has a network of criss-crossing connective tissue walls. In addition, the corium (the connective tissue structure between the dermis and subcutaneous tissue) is thicker in men than in women. [1] [2] These basic differences in subcutaneous tissue structure are the reason cellulite is seen almost exclusively in women. A simple test to illustrate these differences is the “pinch test”. Pinching the skin and subcutaneous tissue of the thighs of women will result in the “mattress phenomenon”, i.e. pitting, bulging, and deformation of the skin, while in most men the skin will fold or furrow, but will not bulge or pit. These structural differences between men and women are responsible for most women producing the mattress phenomenon in response to the pinch test, as illustrated in Figure 141.2 .[1] [2] As women age, the corium (see Figure 141.1 ), which is already thinner in women than in men, becomes progressively thinner and looser. [3] This allows fat cells to migrate into this layer. In addition, the connective tissue walls between the fat-cell chambers also become thinner, allowing the fat-cell chambers to enlarge excessively (hypertrophy). The breaking down or thinning of connective tissue structures is a major contributor to the
Figure 141-2 The “pinch” test.
development of cellulite and is responsible for the granular “buck-shot” feel of cellulite.
[1] [ 2]
The “mattress phenomenon” is brought about by alternating depressions and protrusions in the upper compartment systems of fat tissue. The vertical orientation of women’s fat-cell compartments, in conjunction with the weakening of the tissues noted above, is apparently what allows the protrusion of the fat cells into the lower corium.[1] The anatomical differences between men and women are summarized in Table 141.1 . Histological examination also reveals distension of the lymphatic vessels of the upper corium and a decrease in the number of subepidermal elastic fibers.
CLINICAL FEATURES The basic clinical features of cellulite are well known and are described above as the “mattress phenomenon”. Women comprise 90–98% of the cases, reflecting histological differences between men and women. Symptoms of cellulite include feeling of tightness and heaviness in areas affected (particularly the legs). Tenderness of the skin is quite apparent when the skin is pinched, pressed upon, or vigorously massaged. [1] [2] The areas of the body involved are typically the gluteal and thigh regions, and, to a lesser extent, the lower part of the abdomen, the nape of the neck, and the upper
parts of the arms. These are the areas of the body usually affected in gynecoid (female) obesity. Cellulite is classified in four major stages: • Stage 0 – the skin on the thighs and buttocks has a smooth surface when the subject is standing or lying. When the skin is pinched (pinch test), it folds and 1163
furrows but does not pit or bulge. This stage is the “normal” stage of most men and slim women. • Stage 1 – the skin surface is smooth while a subject is standing or lying, but the pinch test is clearly positive for the mattress phenomenon (pitting, bulging, and deformity of the affected skin surfaces). This is normal for most females, but in a male may be a sign of deficiency of androgenic hormones. • Stage 2 – the skin surface is smooth while a subject is lying, but when standing there is pitting, bulging, and deformity of the affected skin surfaces. This stage is common in women who are obese or over 35–40 years of age. • Stage 3 – the mattress phenomenon is apparent when a subject is lying or standing. It is very common after menopause and in obesity.
TABLE 141-1 -- Sex-typical differences of the skin of the lateral thighs of men and women (16–50 years old) [2] Cutis and subcutis Men Women Epidermis
Thicker (58–77 u)
Thinner (47–62 u)
Corium
Thicker (1159–1798 u)
Thinner (994–1349 u)
Border zone of corium and subcutis
Fewer papillae adiposae
More papillae adiposae
Subcutis
Variably thinner
Variably thicker
Upper zone
Small polygonal fat-cell chambers with criss-crossing septa of connective tissue
Large, standing fat-cell chambers with radially running septa of connective tissue
Status protrusis cutis (so-called mattress phenomenon)
Does not develop
Develops
Although most women consider stage 0 the cosmetic ideal, stage 1 is the best classification most can expect, due to structural predisposition.
THERAPEUTIC CONSIDERATIONS As usual, the best approach is prevention. However, since the number and size of fat cells an individual has are largely determined by maternal prenatal nutritional status, many people have a significant predisposition. The next step is maintaining a slim subcutaneous fat layer. This is best done by exercising and maintaining a normal body weight throughout life. Slim women and female athletes have little or no cellulite. [1] [2] Lifestyle Weight reduction and exercise
Weight reduction and exercise can be employed in the treatment of cellulite, and they should always form the primary mode of treatment. However, weight reduction should be gradual, especially in women over the age of 40. A rapid loss of weight in individuals whose skin and connective tissues are already undergoing changes from aging will often make the mattress phenomena more apparent. Massage
Massage is very beneficial, particularly self-administered massage with the hand or brush. The physical and mechanical effects of massage improve circulation of blood and lymph. The direction of the massage should always be from the periphery to the heart. Botanical medicines Many cosmetic formulas and herbal preparations on the market claim to be effective in “curing” cellulite. However, the majority of these formulas have no scientific basis to support their use. In addition, long-term double-blind studies of some of the more popular cellulite treatments (e.g. Thiomucase, Nemectron, and Alec Eden-Slendertone) demonstrated them to be no more effective than placebo. [3] [4] However, several botanical com-pounds do have confirmed effects in the treatment of cellulite. The comprehensive herbal treatment of cellulite involves both the oral and topical administration of botanical medicines which enhance connective tissue structures. As stated earlier, the breaking down or thinning of connective tissue structures is a major contributor to the development of cellulite. Centella asiatica
An extract of centella containing 70% triterpenic acids (asiatic acid and asiatoside) has demonstrated impressive clinical results when given orally in the treatment of cellulite, venous insufficiency of the lower limbs, and varicose veins. [5] [6] [7] [8] [9] Several experimental studies have demonstrated that centella exerts a normalizing action on the metabolism of connective tissue. Specifically, it enhances connective tissue integrity by stimulating glycosaminoglycan synthesis without promoting excessive collagen synthesis or cell growth. [5] Glycosaminoglycans are the major components of the amorphous intercellular matrix (ground substance) in which collagen fibers are embedded. The net outcome is the development of normal connective tissue that is rich in glycosaminoglycans. The effect of centella in the treatment of cellulite appears to be related to its ability to enhance connective tissue structure and reduce sclerosis, while its action in venous insufficiency and varicose veins is a combination of its connective tissue effects and its ability to improve the blood flow through the affected limbs. Escin
Escin is a compound isolated from the seeds of the Aesculus hippocastanum (horse chestnut). It has anti-inflammatory and anti-edema properties, and it decreases capillary permeability by reducing the number and size of the small pores of the capillary walls. [10] [11] [12] Investigators have also demonstrated that escin has venotonic activity.[13] This has been confirmed in clinical trials that demonstrate a positive effect in the treatment of varicose veins and thrombophlebitis. [11] [14] In the treatment of cellulite, escin can be given orally, or an escin/cholesterol complex can be applied topically. The topical application of escin is also of benefit in the treatment of bruises, due to escin’s ability to decrease capillary fragility and swelling.
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Fucus vesiculosus
Fucus vesiculosus (bladderwrack) is a seaweed that has been used in the treatment of obesity since the 17th century. Its high iodine content is thought to stimulate thyroid function. Bladderwrack has also been used in toiletries and cosmetics for its soothing, softening, and toning effects. [15] Another major topical application of bladderwrack has been in the treatment of cellulite. Its effects in this application have not been confirmed by scientific investigation, but bladderwrack does possess general actions (soothing, softening, and toning effects) which may be of benefit in the treatment of cellulite. Cola species
Cola is a very rich source of caffeine and related compounds. These compounds potentiate the effect of catecholamine-induced lipolysis. Topical administration of caffeine is preferable to oral administration in the treatment of cellulite, since its effects will be primarily local.
THERAPEUTIC APPROACH It must be kept in mind that cellulite is not a disease per se. Instead, it is primarily a cosmetic disorder due to anatomical changes. Excessive subcutaneous adipose tissue or degeneration of subcutaneous connective tissue leads to fat chamber enlargement and greater visibility of the “mattress phenomenon”. The basic therapeutic approach is straightforward, i.e. reduce subcutaneous fat and enhance connective tissue integrity. Varicose veins are often found in conjunction with cellulite, and the two conditions share much in common. In particular, both appear to result largely from a loss of integrity of supporting connective tissue (see Ch. 193 for further discussion). It must be stated again that demonstration of the “mattress phenomenon” in men is a highly probable sign of androgen deficiency. or secondary hypogonadism.
[2]
This may be due to either primary
Diet
A diet high in complex carbohydrates and low in refined carbohydrates and fats is very important. Weight loss should be promoted in obese individuals. Physical measures
• Exercise: 20–30 minutes of aerobic exercise a minimum of 5 days/week • Massage: regular self-massage of the affected area. Botanical medicines
Oral administration • Centella asiatica extract (70% triterpenic acid content): 30 mg three times/day • Aesculus hippocastanum –bark of root: 500 mg three times/day –escin: 10 mg three times/day.
Topical application of salve, ointment, etc. (two times/ day) • Cholesterol/escin complex: 0.5–1.5% • Cola vera extract (14% caffeine): 0.5–1.5% • Fucus vesiculosus: 0.25–75%.
REFERENCES 1. Scherwitz
C, Braun-Falco O. So-called cellulite. J Dermatol Surg Oncol 1978; 4: 230–234
2. Nurnberger
F, Muller G. So-called cellulite: an invented disease. J Dermatol Surg Oncol 1978; 4: 221–229
3. Nurnberger
F, Mende H, Roedel P. Behandlungsergebnisse bei der sog. “Cellulitis” mit verteilerenzymen im einfachen blindversuch. Arch Dermatol Forsch 1972; 29: 173–181
4. Nurnberger
F, Schroter B. Behandlungsergebnisse bei der sog. Zellulitis mit verteilerenzymen im doppelblindversuch. Z Hautkr 1973; 48: 1009–1017
5. Monograph. 6. Allegra
Centella asiatica. Milan, Italy: Indena S.p.A. 1987
C, Pollari G, Criscuolo A et al. Centella asiatica extract in venous disorders of the lower limbs. Comparative clinico-instrumental studies with a placebo. Clin Terap 1981; 99: 507–513
7. Marastoni
F, Baldo A, Redaelli G, Ghiringhelli L. Centella asiatica extract in venous pathology of the lower limbs and its evaluation as compared with tribenoside. Minerva-Cardioangiol 1982; 30:
201–207 8. Allegra
C. Comparative capillaroscopic study of certain bioflavonoids and total triterpenic fractions of Centella asiatica in venous insufficiency. Clin Terap 1984; 110: 555–559
9. Pointel
JP, Boccalon H, Cloarec M et al. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1987; 38: 46–50
10.
Monograph. Escin. Milan, Italy: Indena S.p.A. 1987
Aichinger F, Giss G, Vogel G. Neue befunde zur pharmakodynamik von bioflavoiden und des rosskastanien saponins aescin als grundlage ihrer anwendung in der therapie. Arzniem Forsch 1964; 14: 892 11.
12.
Manca P, Passarelli E. Aspetti farmacologici dell’escina, principio attivo dell’aesculus hyppocastanum. Clin Terap 1965; 297–328
13.
Annoni F, Mauri A, Marincola F, Resele LF. Venotonic activity of escin on the human saphenous vein. Arzneim Forsch 1965; 29: 672–5, 197
14.
Lucas J. Erfahrungen mit Aescin in der internen therapie. Med Welt 1963; 14: 913
15.
Monograph. Bladderwrack. Milan, Italy: Indena S.p.A. 1987
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Chapter 142 - Cervical dysplasia Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Abnormal Papanicolaou smear (stages II–IV) • Positive Schiller test.
GENERAL CONSIDERATIONS Cervical dysplasia is generally regarded as a precancerous lesion with risk factors similar to those of cervical cancer. [1] That being the case, this discussion focuses on the lifestyle and nutritional factors that appear to play a prominent role in the etiology of cervical carcinoma. These include: • early age of first intercourse • multiple sexual partners • herpes simplex type II and papilloma viruses • lower socioeconomic class • smoking • oral contraceptive use • many nutritional factors. [1] [2] All risk factors appear to be closely related, as in other multifactorial diseases. Epidemiology
Although the death rate due to invasive cervical cancer has dropped remarkably in the past 40 years (due primarily to improved screening via the Papanicolaou cytologic test; see Table 142.1 ), cervical cancer still accounts for approximately 7,500 deaths per year. [1] Approximately 16,000 cases of invasive cervical cancer and 45,000 case of carcinoma in situ occur annually in the United States. Cervical cancer is still the second most common malignancy found in women between the ages of 15 and 34 (although it can occur at any age). [1] The peak incidence of invasive lesions occurs at age 45, while in situ lesions peak at around age 30. In contrast to invasive carcinoma, the incidence of carcinoma in situ is increasing dramatically, probably as a result of the
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TABLE 142-1 -- Classification systems for Papanicolaou smears Numerical Dysplasia
CIN
Bethesda system
I
Benign
Benign
Normal
II
Benign with inflammation
Benign with inflammation
Normal
III
Mild dysplasia
CIN I
Low-grade SIL
III
Moderate dysplasia
CIN II
Low-grade SIL
III
Severe dysplasia
CIN III
High-grade SIL
IV
Carcinoma in situ
CIN III
High-grade SIL
V
Invasive cancer
Invasive cancer
Invasive cancer
CIN, cervical intraepithelial neoplasia; SIL, squamous epithelial lesion. increase in risk factors (e.g. early age at first intercourse, multiple sexual partners, oral contraceptive use, and cigarette smoking). Histological considerations
Ninety-five percent of cervix cancers originate in the squamocolumnar junction of the cervical os. [1] In adolescence, glandular epithelium covers much of the exocervix, but as adolescence progresses the columnar epithelium is gradually replaced by squamous cells. This actively growing area seems to be more susceptible to multiple insults and cancer-causing substances, probably due to the metaplastic nature of the conversion process. Risk factors (see Table 142.2 ) Sexual activity
Early age at first intercourse and/or multiple sexual contacts are associated with an increased risk of cervical dysplasia/carcinoma. [1] [2] From this and other evidence, it has been suggested that cervical cancer is a venereal disease, in the sense that the implicated infectious agents appear to be sexually transmitted. Furthermore, an arginine-rich histone or protamine, as well as other substances released by sperm during degradation, could be the transmissible oncogenic agent. [2] TABLE 142-2 -- Risk factors in cervical dysplasia/cancer * Risk factor
Relative risk
Smoking (10+ cigarettes/day)
3.0 [6]
Multiple sexual partners (2–5)
3.4[6]
Age at first intercourse (6.2
Staghorn configuration, light color
Triple phosphate
Infection
Uric acid
6–10
Translucent
pH 30% motile
Normal forms
>60%
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TABLE 169-4 -- Causes of temporary low sperm count[1] [2] • Increased scrotal temperature • Infections, the common cold, the flu, etc. • Increased stress • Lack of sleep • Overuse of alcohol, tobacco, or marijuana • Many prescription drugs • Exposure to radiation • Exposure to solvents, pesticides, and other toxins couples whose sperm counts were below 10 million/ml achieved pregnancy and 40% of those with sperm counts as low as 5 million/ml are able to achieve pregnancy. [1] Because of these confirmed successes in men with low sperm counts, it is recommended that conventional semen analysis be interpreted with caution regarding the likelihood of conception and that more sophisticated functional tests should be used, especially when screening couples for in vitro fertilization. Until recently, pregnancy was the only proof of the ability of sperm to achieve fertilization. Now there are several functional tests in use (see Table 169.5 ). The postcoital test measures the ability of the sperm to penetrate the cervical mucus after intercourse. In vitro variants of this test are also available. One of the most encouraging tests is based on the discovery that human sperm can, under appropriate conditions, penetrate hamster eggs. It was established that fertile males exhibit a range of penetration of 10–100% and that penetration less than 10% is indicative of infertility. The hamster egg penetration test is considered to predict fertility in 66% of the cases compared with about 30% for conventional semen analysis. [1] Another important test in the diagnosis of infertility is the detection of antisperm antibodies. These antibodies, when produced by the man, usually attack the tail of the sperm, thereby impeding the sperm’s ability to move and penetrate the cervical mucus. In contrast, the antisperm antibodies produced by women are typically directed against the head. The presence of antisperm antibodies in semen analysis is usually a sign of past or current infection in the male reproductive tract.
THERAPEUTIC CONSIDERATIONS Standard medical treatment of oligospermia can be quite effective when the cause is known, e.g. increased scrotal temperature, chronic infection of male sex glands, prescription
Test
TABLE 169-5 -- Male fertility tests Fertility prediction accuracy
Semen analysis
30%
Hamster egg penetration test
66%
medicines, and endocrine disturbances (including hypogonadism and hypothyroidism). However, as stated above, in about 90% of the cases of oligospermia, the cause is unknown (idiopathic oligospermia). With regard to azoospermia, if the cause is ductal obstruction, new surgical techniques are showing some good results.
[1]
In the treatment of idiopathic oligospermia or azoospermia, the rational approach is to focus on enhancing those factors which promote sperm formation. In addition to scrotal temperature, sperm formation is closely linked to nutritional status. Therefore, it is critical that men with low sperm counts have optimal nutritional intake. In addition to consuming a healthful diet, there are several nutritional factors that deserve special mention: • vitamin C and other antioxidants • fats and oils • zinc • folate • vitamin B12 • arginine • carnitine. In addition, it appears important for men with low sperm count to avoid dietary sources of estrogens. Some herbs, especially Panax ginseng and Eleutherococcus senticosus, are known to increase sperm counts. And finally, another popular natural treatment of male infertility involves the use of glandular therapy. The concept behind this therapy is discussed below. Controlling sperm-damaging factors Scrotal temperature
The scrotal sac normally keeps the testes at a temperature of between 94 and 96° Fahrenheit. [2] At temperature above 96°F, sperm production is greatly inhibited or
stopped completely. Typically, the mean scrotal temperature of infertile men is significantly higher than that of fertile men. Reducing scrotal temperature in infertile men will often be enough make them fertile. This temperature reduction is best done by not wearing tight-fitting underwear or tight jeans, and avoiding hot tubs. In addition, the following exercises can raise scrotal temperature, especially if a man is wearing synthetic fabrics, exceptionally tight shorts, or tight bikini underwear: rowing machines, simulated cross-country ski machines, treadmills, and jogging. After exercising, a man should allow his testicles to hang free to allow them to recover from heat build-up. Infertile men should wear boxer-type underwear and periodically apply a cold shower or ice to the scrotum. They can also choose to use a device called a testicular hypothermia device or “testicle cooler” to reduce scrotal
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temperatures. Still in its somewhat primitive stage, the testicle cooler looks like a jock strap from which long, thin tubes have been extended. The tubes are attached to a small fluid reservoir filled with cold water that attaches to a belt around the waist. The fluid reservoir is also a pump that causes the water to circulate. When the water reaches the surface of the scrotum, it evaporates and keeps the scrotum cool. Because of the evaporation, the reservoir must be filled every 6 hours or so. It is recommended that the testicle cooler must be worn daily during waking hours. Most users claim that it is fairly comfortable and easy to conceal. [4] Increased scrotal temperature can be due to the presence of a varicocele. A large varicocele can cause scrotum temperatures high enough to inhibit sperm production and motility. Surgical repair may be necessary, but scrotal cooling should be tried first. Infections and infertility
Infections in the male genitourinary tract, including infections of the epididymis, seminal vesicles, prostate, bladder, and urethra, are thought to play a major role in many cases of infertility. [5] The exact extent of the role they play is largely unknown because of the lack of suitable diagnostic criteria coupled with the asymptomatic nature of many infections. The presence of antisperm antibodies is considered to be a good indicator of a chronic infection in the absence of other clinical findings. There are a wide number of bacteria, viruses, and other organisms which can infect the male genitourinary system. It is beyond the scope of this chapter to discuss every type of infection, and therefore the discussion will be limited to Chlamydia trachomatis. Chlamydia is now recognized as the most common as well as the most serious of infections in the male genitourinary tract. [5] Chlamydia is considered a sexually transmitted disease. In women, chlamydia infection can lead to pelvic inflammatory disease (PID) and scarring of the fallopian tubes. Previous chlamydia infection accounts for a large number of cases of female factor infertility. In men, chlamydia infection can lead to equally disabling effects. Chlamydia is the major cause of acute non-bacterial prostatitis and urethritis. Typically the symptoms will be pain or burning sensations upon urination or ejaculation. More serious is chlamydia infection of the epididymis and vas deferens. The resultant damage to these organs parallels the tubal damage in women. Serious scarring and blockage can occur. During an acute chlamydia infection, antibiotics are essential. Chlamydia is sensi-tive to tetracyclines and erythromycin. Unfortunately, because chlamydia lives within human cells it may be difficult to totally eradicate the organism with antibiotics alone. While acute chlamydial infections are usually associated with severe pain, chronic infections of the urethra, seminal vesicles, or prostate can go on with little or no symptoms. It is estimated that 28–71% of infertile men have evidence of a chlamydial infection. [5] Because of the possible link between chlamydia and low sperm counts, there have been several double-blind studies on the effects of antibiotics on sperm counts. These studies have shown only limited improvements in sperm count and sperm quality.[5] However, there have been isolated cases of tremendous increases in sperm counts and sperm quality after antibiotic treatment. If electing this form of treatment, both partners should take the antibiotic. However, it should be used only if there is reason to believe a chronic infection is present and after the recommendations given in Chapter 148 have been employed for at least 3 months. The presence of antisperm antibodies may indicate a chronic chlamydia infection. In the absence of a positive culture, rectal ultrasonography and the detection of antibodies directed against chlamydia can confirm the diagnosis. Avoiding estrogens
According to experts on the impact of the environment and diet on fetal development, we now live in an environment that can be viewed as “a virtual sea of estrogens”.[6] [7] Increased exposure to estrogens during fetal development, as well as during the reproductive years, is suggested to be a major cause of the tremendous increase in the disorders of development and function of the male sexual system. The relationship between estrogens and male sexual development is best viewed by examining the effects of the synthetic estrogen, diethylstilbestrol (DES). Between 1945 and 1971 several million women were treated with DES. By 1970, the side-effects of DES became more known. DES is now recognized to have led to substantial increases in the number of men suffering from developmental problems of the reproductive tract as well as decreased semen volume and sperm counts. [5] As well as being used in humans, DES and other synthetic estrogens were used for 20–30 years in the livestock industry to fatten the animals and help them grow faster. Although many synthetic estrogens like DES are now outlawed, many livestock and poultry are still hormonally manipulated, especially dairy cows. Cow’s milk contains substantial amounts of estrogen due to modern farming techniques. The rise in dairy consumption since the 1940s inversely parallels the drop in sperm counts. Avoidance of hormone-fed animal products and milk products are important for male sexual vitality, especially in men with low sperm counts or low testosterone levels. There are reports that estrogens have been detected in drinking water. [6] [7] Presumably the estrogens are recycled
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from excreted synthetic estrogens (birth control pills) at water treatment plants. These estrogens may be harmful to male sexual vitality as they are more potent since they do not bind to sex-hormone-binding-globulin (SHBG). Purified or bottled water may be a suitable option to prevent exposure. There are other sources of estrogen from the environment (food, water, and air) that can weaken male sexual vitality. For example, many of the chemicals that we have contaminated our environment with in the past 50 years are weakly estrogenic. Most of these chemicals, like PCBs, dioxin, and DDT, are resistant to biodegradation and are recycled in our environment until they find a safe haven in our bodies. For example, even though DDT has been banned for nearly 20 years, it is still often found in the soil and root vegetables such as carrots and potatoes. These toxic chemicals are known to interfere with spermatogenesis, but their effects during sexual development may be more important. All of the estrogenic factors discussed above are thought to have their greatest impact during fetal development. Based on animal studies, these estrogens inhibit the multiplication of the Sertoli cells. The number of Sertoli cells is directly proportional to the amount of sperm that can be produced, as each Sertoli cell can only support a fixed number of germ cells that will develop into sperm. Sertoli cell multiplication occurs primarily during fetal life and before puberty. It is controlled by follicle-stimulating hormone (FSH). In animal studies, estrogens administered early in life inhibit FSH secretion, resulting in a reduced number of Sertoli cells and, in adult life, reduced sperm counts. Evidence exists to indicate that the same events occur in humans.[6] The best example are the sons of women exposed to DES during pregnancy, who, like the animals exposed to estrogens, show reduced sperm counts. Even if a mother did not take DES she may have followed the typically low-fiber, high-fat diet of most Americans. Such a diet is associated with higher levels of estrogens because, without the fiber, excreted estrogens are reabsorbed. If testosterone levels are low or marginal, or if estrogen levels are elevated, a diet rich in legumes (beans), especially soy foods, may be of benefit. Soy is a particularly good source of isoflavonoids. These compounds are also known as “phytoestrogens”, signifying their mild estrogenic activity. The isoflavonoids in soybeans have about 0.2% of the estrogen activity of estradiol, the principal human estrogen. Isoflavones actually bind to estrogen receptors. Their weak estrogenic
action is in actuality an anti-estrogenic effect as it prevents the binding of the body’s own estrogen to the receptor. In addition, phytoestrogens may reduce the effects of estrogens on the body by stimulating the production of SHBG so that the estrogen is bound. [8] Soy, as well as other legumes, nuts, and seeds, is also a good source of phytosterols which may aid in the manufacture of steroid hormones including testosterone. Heavy metals
Sperm are also particularly susceptible to the damaging effects of heavy metals such as lead, cadmium, arsenic, and mercury. A hair mineral analysis for heavy metals should be performed on all men with reduced sperm counts to rule out heavy metals as a cause. Nutritional considerations Vitamin C and other antioxidants
Free radical or oxidative damage to sperm is thought to be responsible for many cases of idiopathic oligospermia, with high levels of free radicals found in the semen of 40% of infertile men.[9] [13] Three factors combine to render sperm particularly susceptible to free radical damage: • a high membrane concentration of polyunsaturated fatty acids • active generation of free radicals • a lack of defensive enzymes. All of these factors combine to make the health of the sperm critically dependent upon antioxidants. Although most free radicals are produced during normal metabolic processes, the environment contributes greatly to the free radical load. Men exposed to increased levels of sources of free radicals are much more likely to have abnormal sperm and sperm counts.[1] [9] [10] [11] [12] Sperm are extremely sensitive to free radicals because they are so dependent upon the integrity and fluidity of their cell membrane for proper function. Without proper membrane fluidity, enzymes are activated, which can lead to impaired motility, abnormal structure, loss of viability, and ultimately death of the sperm. [9] The major determinant of membrane fluidity is the concentration of polyunsaturated fatty acids, particularly omega-3 fatty acids like docosahexanoic acid, which are very susceptible to free radical damage. The sperm have a relative lack of superoxide dismutase and catalase which can prevent or repair oxidative damage. Adding to this more susceptible state is the fact that sperm generate high quantities of free radicals to help break down barriers to fertilization. A common source of oxidants is cigarette smoking, which is associated with decreased sperm counts and sperm motility as well as an increased frequency of abnormal sperm.[12] Cigarette smoking, as well as the increase in environmental pollution, is thought to be a major contributor to the decrease in sperm counts seen in many industrialized nations during the past few decades.
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Antioxidants such as vitamin C, beta-carotene, selenium, and vitamin E have been shown to be very important in protecting the sperm against damage. Vitamin C plays an especially important role in protecting the sperm’s genetic material (DNA) from damage. Ascorbic acid levels are much higher in seminal fluid compared with other body fluids, including the blood. When dietary vitamin C was reduced from 250 to 5 mg/day in healthy human subjects, the seminal fluid ascorbic acid decreased by 50% and the number of sperm with damage to their DNA increased by 91%. [14] These results indicated that dietary vitamin C plays a critical role in protecting against sperm damage and that low dietary vitamin C levels were likely to lead to infertility. It is now well-documented that cigarette smoking greatly reduces vitamin C levels throughout the body. Even the Food and Nutrition Board, the organization which calculates the recommended dietary allowances (RDAs) acknowledges that smokers require at least twice as much vitamin C than non-smokers. [15] In one study, men who smoked one pack of cigarettes a day received either 0, 200, or 1,000 mg of vitamin C. After 1 month, sperm quality improved proportional to the level of vitamin C supplementation. [16] Non-smokers also appear to benefit from vitamin C as much as smokers. In one study, 30 infertile but otherwise healthy men received either 200 or 1,000 mg vitamin C or placebo daily. [17] There were weekly measurements of sperm count, viability, motility, agglutination, abnormalities, and immaturity. After 1 week, the 1,000 mg group demonstrated a 140% increase in sperm count, the 200 mg group a 112% increase, and the placebo group no change. After 3 weeks both vitamin C groups continued to improve, with the 200 mg group catching up to the improvement of the 1,000 mg group. One of the key improvements was observed in the number of agglutinated sperm. Sperm become agglutinated when antibodies produced by the immune system bind to the sperm. Antibodies to sperm are often associated with chronic genitourinary tract or prostatic infection. When more than 25% of the sperm are agglutinated, fertility is very unlikely. At the beginning of the study all three groups had over 25% agglutinated sperm. After 3 weeks, the agglutinated sperm in the vitamin C groups dropped to 11%. Although this result is significant, the most impressive result of the study was that at the end of 60 days, all of the vitamin C group had impregnated their wives, compared with none of the placebo group. It can be concluded from these results that vitamin C supplementation can be very effective in treating male infertility, particularly if the infertility is due to antibodies against sperm. Other dietary antioxidants, such as vitamin E, selenium, and beta-carotene, are also important and should be supplemented. Vitamin E supplementation appears to be especially warranted as it is the main antioxidant in various cell membranes, including sperm membranes. Vitamin E has been shown to play an essential role in inhibiting free radical damage to the unsaturated fatty acids of the sperm membrane. [18] In addition, vitamin E has been shown to enhance the ability of sperm to fertilize an egg in test tubes. In one study, supplementation with vitamin E was found to decrease malondialdehyde concentration in sperm pellet suspensions. Even more important, however, 11 of 52 treated infertile men impregnated their spouses. [19] Supplementation appears to be indicated based on its physiological effects alone. Vitamin E may prove to exert more beneficial effects on sperm counts or motility when given at higher levels (600–800 IU/day). Fats and oils
Considering the effects of fats and oils on agglutination and cell membrane dynamics, certain fats are best avoided in infertile men while others should be increased. Saturated fats, hydrogenated oils, trans-fatty acids, and cotton, coconut and palm oil should be avoided. Coconut and palm oils are primarily saturated fat, while cotton seed may contain toxic residues, due to the heavy spraying of cotton and its high levels of gossypol, a substance known to inhibit sperm function. In fact, gossypol is being investigated as the “male birth control pill”. Its use as an antifertility agent began after studies demonstrated that men who had used crude cotton seed oil as their cooking oil were shown to have low sperm counts followed by total testicular failure. [20] Excessive consumption of saturated fats combined with inadequate intake of essential fatty acids changes the fatty acid composition of the sperm membranes, thus decreasing fluidity and interfering with sperm motility. The patient must be informed to read food labels carefully and avoid all sources of cotton seed oil and other damaging oils. While the intake of saturated and hydrogenated fats must be eliminated, the intake of polyunsaturated oils should be increased. These oils function in all aspects of sexual function including sperm formation and activity. Zinc
Zinc is perhaps the most critical trace mineral for male sexual function. It is involved in virtually every aspect of male reproduction including the hormone metabolism, sperm formation, and sperm motility.[21] Among many other problems, zinc deficiency is characterized by decreased testosterone levels and sperm counts. Zinc levels are typically much lower in infertile men with low sperm counts, indicating that a low zinc status may be the contributing factor to the infertility.
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Several studies have evaluated the effect of zinc supplementation on sperm counts and motility. [22] [23] [24] The results from all of the studies support the use of zinc supplementation in the treatment of oligospermia, especially in the presence of low testosterone levels. The effectiveness of zinc is best illustrated by a study in 37
men with infertility of greater than 5 years’ duration whose sperm counts were less than 25 million/ml. [24] Blood testosterone levels were also measured. The men received a supplement of zinc sulfate (60 mg elemental zinc daily) for 45–50 days. In the 22 patients with initially low testosterone levels, mean sperm count increased significantly from 8 to 20 million. Testosterone levels also increased and nine out of the 22 wives became pregnant during the study. This result is quite impressive given the long-term nature of the infertility and the rapidity of the results. In contrast, in the 15 men with normal testosterone levels, although sperm count increased slightly, there was no change in testosterone level and no pregnancies occurred. Optimal zinc levels must be attained if optimum male sexual vitality is desired. Although severe zinc deficiency is quite rare in this country, many men consume a diet that does not provide the RDA for zinc (15 mg). Zinc is found in whole grains, legumes, nuts, and seeds. In addition to eating these zinc-containing foods, recommending supplementary zinc (45–60 mg/day) appears warranted. Vitamin B12
Vitamin B12 is involved in cellular replication. A deficiency of B 12 leads to reduced sperm counts and sperm motility. Even in the absence of a vitamin B 12 deficiency, supplementation appears to be worthwhile in men with sperm counts less than 20 million per mL or a motility rate of less than 50%. In one study, 27% of men with sperm counts less than 20 million given 1,000 mcg/day of vitamin B 12 were able to achieve a total count in excess of 100 million. [25] In another study, 57% of men with low sperm counts given 6,000 mcg/day demonstrated improvements.[26] Arginine
The amino acid arginine is required for the replication of cells, making it essential in sperm formation. Arginine supplementation is often, but not always, an effective treatment of male infertility. The critical determinate appears to be the level of oligospermia. If sperm counts are less than 20 million/ml, arginine supplementation is less likely to be of benefit. In order to be effective, it appears that the dosage of L-arginine be at least 4 g/day for 3 months. In perhaps the most favorable study, 74% of 178 men with low sperm counts had significant improvements in sperm counts and motility. [27] L-Arginine therapy should be reserved for use after other nutritional measures have been tried. Carnitine
Carnitine is essential in the transport of fatty acids into the mitochondria. A deficiency of carnitine results in a decrease in fatty acid concentrations in the mitochondria and reduced energy production. Carnitine concentrations are extremely high in the epididymis and sperm, suggesting a role for carnitine in male reproductive function. The epididymis derives the majority of its energy requirements from fatty acids, as do the sperm, during transport through the epididymis. After ejaculation, the motility of sperm correlates directly with carnitine content. The higher the carnitine content, the more motile are the sperm. Conversely, when carnitine levels are low, sperm development, function and motility are drastically reduced. One clinical study found an increase in sperm count and mobility in 37 of 47 men with idiopathic asthenospermia.[28] Supplementing the diet with L-carnitine may be useful in restoring male fertility in some cases. The optimal dosage is 300–1,000 mg of L-carnitine three times daily. However, because L-carnitine tends to be relatively expensive, the other nutritional measures should be tried first. Botanical medicines Ginseng
Current scientific investigation suggests that both Panax ginseng (Chinese or Korean ginseng) and Eleutherococcus senticosus (Siberian ginseng) are likely to be effective in the treatment of male infertility. Both botanicals have a long history of use as male “tonics”. Although human clinical studies are lacking, Panax ginseng has been shown to promote the growth of the testes, increase sperm formation and testosterone levels, and increase sexual activity and mating behavior in studies with animals (see Ch. 100 for references). Siberian ginseng has also shown some benefit to the male reproductive function in animal studies as it has been shown to increase reproductive capacity and sperm counts in bulls (see Ch. 83 for references). These results seem to support the use of either ginseng as a fertility and virility aid. In general, Panax ginseng is regarded as being more potent in its effects (particularly stimulant effects) than Eleutherococcus senticosus. Although Siberian ginseng contains no ginsenosides and is not a true ginseng, it does possess many of the same effects that Panax ginseng exerts, but it is generally regarded as being milder.
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Pygeum africanum
Pygeum may be effective in improving fertility in cases where diminished prostatic secretion plays a significant role. Pygeum has been shown to increase prostatic secretions and improve the composition of the seminal fluid. [29] [30] [31] Specifically, pygeum administration to men with decreased prostatic secretion has led to increased levels of total seminal fluid plus increases in alkaline phosphatase and protein. Pygeum appears to be most effective in cases where the level of alkaline phosphatase activity is reduced (i.e. less than 400 IU/cm 3 ) and where there is no evidence of inflammation or infection (i.e. absence of white blood cells or IgA). The lack of IgA in the semen is a good indicator of clinical success. In one study, the patients with no IgA in the semen demonstrated an alkaline phosphatase increase from 265 to 485 IU/cm3 . [29] In contrast, those subjects with IgA showed only a modest increase from 213 to 281 IU/cm 3 . Pygeum extract has also shown an ability to improve the capacity to achieve an erection in patients with BPH or prostatitis as determined by nocturnal penile tumescence in a double-blind clinical trial. [32] BPH and prostatitis are often associated with erectile dysfunction and other sexual disturbances. Presumably, by improving the underlying condition, pygeum can improve sexual function. Glandular therapy For almost as long as historic records have been kept, glandular therapy has been an important form of medicine. The basic concept underlying the medicinal use of glandular substances from animals is that “like heals like”. In the case of low testosterone levels or low sperm counts, extracts of bovine (beef) orchic or testicular tissues are often recommended by physicians practicing glandular therapy. It is well established that a number of glandular preparations are effective orally because of active hormones (e.g. thyroid, adrenal, and thymus). Presumably, orchic or testicular products may also be of benefit. Unfortunately, dosage, as well as effectiveness, may vary from one manufacturer to another.
THERAPEUTIC APPROACH Male infertility is most often due to an abnormal sperm count or semen quality. Referral to a urologist or fertility specialist for a complete evaluation is often necessary. As elevated scrotal temperature is a common cause of infertility, scrotal cooling through the use of loose underwear made of cotton, avoidance of activities which elevate testicular temperature (e.g. hot tubs) and application of cold water to the testes should be utilized. Nutritional status should be optimized (especially antioxidants and zinc), environmental pollutants identified and eliminated, and fertility-enhancing botanicals such as the ginsengs consumed. General measures
• Maintain scrotal temperatures between 94 and 96°F • Avoid exposure to free radicals • Identify and eliminate environmental pollutants • Stop or reduce all drugs, especially antihypertensives, anti-neoplastics such as cyclophosphamide, and anti-inflammatory drugs such as sulfasalazine.
Diet
• Avoid dietary sources of free radicals, saturated fats, hydrogenated oils, trans-fatty acids, and cottonseed oil • Increase consumption of legumes, especially soy (high in phytoestrogens and phytosterols), good dietary sources of antioxidant vitamins, carotenes, and flavonoids (dark-colored vegetables and fruits), and essential fatty acids and zinc (nuts and seeds) • Recommend the daily consumption of eight to 10 servings of vegetables, two to four servings of fresh fruits, and half a cup of raw nuts or seeds. Nutritional supplements
• Multiple vitamin and mineral • Vitamin C: 1,000–3,000/day in divided doses • Vitamin E: 600–800 IU/day • Beta-carotene: 100,000–200,000 IU/day • Folic acid: 400 µg/day • Vitamin B12 : 1,000 µg/day • Zinc: 30–60 mg/day. Botanical medicines
• Panax ginseng (three times/day dosages) —high quality crude ginseng root: 1.5–2 g/day —standardized extract (5% ginsenosides): 500 mg • Eleutherococcus senticosus —dried root: 2–4 g —tincture (1:5): 10–20 mL —fluid extract (1:1): 2.0–4.0 mL —solid (dry powdered) extract (20:1): 100–200 mg.
The dosage of ginseng is related to the ginsenoside content. The typical dose (taken one to three times daily) should contain a saponin content of at least 25 mg of ginsenosides with a ratio Rb1 to Rg1 of 2:1. For example, for a high-quality ginseng root extract containing 5% ginsenosides, the dose would be 500 mg.
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As each individual’s response to ginseng is unique, care must be taken to observe possible ginseng toxicity (see Ch. 100 ). It is best to begin at lower doses and to increase gradually. The Russian approach for long-term administration of either Panax or Siberian ginseng is to use ginseng cyclically for a period of 15–20 days followed by a 2 week interval without any ginseng. This recommendation appears prudent.
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K, Christiansen E. Male infertility. Current concepts. Annals Med 1992; 24: 259–272
2. Wyngaarden 3. Carlsen
E, Giwercman A, Keiding N. Evidence for decreasing quality of semen during past 50 years. British Med J 1992; 305: 609–613
4. Lauersen 5. Purvis
NH, Bouchez C. Getting pregnant – what couples need to know right now. New York, NY: Fawcett Columbine. 1991
K, Christiansen E. Review: infection in the male reproductive tract. Impact, diagnosis and treatment in relation to male infertility. Int J Androl 1993; 16: 1–13
6. Sharpe 7. Field
JB, Smith LH, Bennett JC, eds. Cecil textbook of medicine. 19th edn. Philadelphia, PA: WB Saunders. 1992
RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproduction tract? Lancet 1993; 341: 1392–1395
B, Selub M, Hughes CL. Reproductive effects of environmental agents. Semen Reprod Endocrinol 1990; 8: 44–54
8. Messina 9. Aitken
M, Messina V. Increasing the use of soyfoods and their potential role in cancer prevention. J Am Diet Assoc 1991; 91: 836–840
RJ. The role of free oxygen radicals and sperm function. Int J Androl 1989; 12: 95–97
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Kaur S. Effect of environmental pollutants on human semen. Bull Environ Contam Toxicol 1988; 40: 102–104
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Steeno OP, Pangkahila A. Occupational influences on male fertility and sexuality. Andrologia 1984; 16: 5–22
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Kulikauskas VD, Blaustein D, Ablin D. Cigarette smoking and its possible effects on sperm. Fertil Steril 1985; 44: 526–528
Zini A, De Lamirande E, Gagnon C. Reactive oxygen species in semen of infertile patients. Levels of superoxide dismutase- and catalase-like activities in seminal plasma and spermatozoa. Int J Androl 1993; 16: 183–188 13.
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Fraga C et al. Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc Natl Acad Sci USA 1991; 88: 11003–11006
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National Research Council. Recommended dietary allowances. 10th edn. Washington, DC: National Academy Press. 1989
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Dawson E, Harris W, Powell L. Effect of vitamin C supplementation on sperm quality of heavy smokers. FASEB J 1991; 5: A915
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Dawson EB et al. Effect of ascorbic acid on male fertility. Ann NY Acad Sci 1987; 498: 312–323
Aitken RJ, Clarkson JS, Hargreave TB. Analysis of the relationship between defective sperm function and the generation of reactive oxygen species in cases of oligospermia. J Androl 1989; 10: 214–220 18.
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Suleiman SA, Ali ME, Zaki ZM et al. Lipid peroxidation and human sperm mobility. Protective role of vitamin E. J Androl 1996; 17: 530–537
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Weller DP, Zaneveld JD, Farnsworth NR. Gossypol. Pharmacology and current status as a male contraceptive. Econ Med Plant Res 1985; 1: 87–112
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Prasad AS. Zinc in growth and development and spectrum of human zinc deficiency. J Am Coll Nutr 1988; 7: 377–384
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Tikkiwal M et al. Effect of zinc administration on seminal zinc and fertility of oligospermic males. Ind J Physiol Pharmacol 1987; 31: 30–34
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Takihara H, Cosentino MJ, Cockett AT. Zinc sulfate therapy for infertile males with or without varicocelectomy. Urology 1987; 29: 638–641
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Netter A, Hartoma R, Nakoul K. Effect of zinc administration on plasma testosterone, dihydrotestosterone and sperm count. Arch Androl 1981; 7: 69–73
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Sandler B, Faragher B. Treatment of oligospermia with vitamin B12. Infertility 1984; 7: 133–138
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Kumamoto Y, Maruta H, Ishigami J. Clinical efficacy of mecobalamin in treatment of oligozoospermia. Results of a double-blind comparative clinical study. Acta Urol Japan 1988; 34: 1109–1132
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Schacter A, Goldman JA, Zukerman Z. Treatment of oligospermia with the amino acid arginine. J Urol 1973; 110: 311–313
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Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia. Clinical results. Drugs Exp Clin Res 1995; 21: 157–159
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Lucchetta G, Weill A, Becker N et al. Reactivation from the prostatic gland in cases of reduced fertility. Urol Int 1984; 39: 222–224
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Menchini-Fabris GF, Giorgi P, Reini F et al. New perspectives of treatment of prostato-vesicular pathologies with Pygeum africanum. Arch Int Urol 1988; 60: 313–322
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Clavert A, Cranz C, Riffaud JP et al. Effects of an extract of the bark of Pygeum africanum on prostatic secretions in the rat and man. Ann Urol 1986; 20: 341–343
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Carani C, Salvioli C, Scuteri A et al. Urological and sexual evaluation of treatment of benign prostatic disease using Pygeum africanum at high dose. Arch Ital Urol Nefrol Androl 1991; 63: 341–345
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Chapter 170 - Menopause Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Cessation of menstruation in older women for 6–12 months • Average age of onset is 51 years • Hot flashes in 65–80% • Atrophic vaginitis • Frequent bladder infections in 15%.
INTRODUCTION Menopause denotes the cessation of menstruation in women, which usually occurs when a woman reaches the age of 50. Six to 12 months without a period is the commonly accepted rule for diagnosing menopause. The time period prior to menopause is referred to as perimenopausal while the time period after menopause is referred to as postmenopausal. During the perimenopausal period, many women ovulate irregularly due to either inadequate secretion of estrogen or resistance of the remaining follicles to ovulatory stimulus. The current medical view of menopause is as a disease rather than as a normal physiological process. This is in stark contrast to the perspective of many cultures in which menopause is a natural part of the life process and a positive event in a woman’s life. In fact, in many cultures of the world, most women do not experience the symptoms associated with menopause. This observation raises some interesting questions about menopause being a sociocultural event. With the prolongation of life expectancy, the menopausal and postmenopausal periods are becoming more significant in a woman’s life. In fact, today’s average woman can expect to live at least one-third of her life in the postmenopausal phase. Current medical treatment of menopause primarily involves hormone replacement therapy, utilizing a combination of estrogen and progesterone. The obvious question is: “Is hormone replacement therapy necessary?” The goal of this chapter is to answer this question and
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provide a natural approach to menopause and the postmenopausal period.
GENERAL CONSIDERATIONS Causes of menopause Menopause is thought to occur when there are no longer any eggs left in the ovaries. This “burning out” of the ovaries reflects the natural course of events. At birth, there are about 1 million eggs (ova). This number drops to 300,000–400,000 at puberty; however, only about 400 of these ova will actually mature during reproductive years. By the time a woman reaches the age of 50, few eggs remain. With menopause, the absence of active follicles results in reduced production of estrogen and progesterone level. In response to this drop in estrogen, the pituitary increases secretion of FSH and LH. After menopause, FSH and LH are secreted in large and continuous quantities. Although there are no longer any follicles to stimulate in the postmenopausal woman, LH and FSH cause the ovaries as well as the adrenal glands to secrete increased amounts of androgens which can be converted to estrogens by the fat cells of the hips and thighs. Converted androgens account for most of the circulating estrogen in postmenopausal women, but the total estrogen levels are still far below the levels in women with reproductive function. Menopause as a social construct
The biomechanical model of health that most physicians adhere to leaves little room for other explanatory models. In the case of menopause, the biomechanical model focuses on the physiological processes resulting from ovarian decline, ignoring the psychological and cultural aspects of menopause. In Western society, menopause is viewed as a deficiency disease. While there is undeniably a physiological process involved in menopause, menopause is much more than simply a biological event. Social and cultural factors contribute greatly to how women react to menopause. [1] Modern society has placed great value on the allure of everlasting youth, resulting in a cultural devaluing of older women. This devaluation is deeply entrenched in our mental programming, as it is found in our children’s books, fairy tales, television programs, and movies. Advocates of a social and cultural explanation of menopause often point to this cultural devaluing of older women as the root of the negativity associated with achieving menopause. In contrast, in many cultures of the world, women look forward to menopause because it brings with it greater respect. Achieving an advanced age is viewed as a sign of divine blessing and great wisdom. Studies of menopausal women in many traditional cultures demonstrate that most will pass through menopause without hot flashes, vaginitis, and other symptoms common to menopausal women in developed countries. Even osteoporosis is extremely rare, despite the fact that the average woman in many traditional societies lives at least 30 years after menopause. Cross-cultural research clearly demonstrates that the cultural view of menopause is directly related to the symptoms of menopause. [2] If the cultural view of menopause is largely negative, as in the United States, symptoms are quite common. In contrast, if menopause is associated with little negativity or viewed in a positive light, symptoms are far less frequent. One of the most detailed studies on the cultural effects on menopause involved studying rural Mayan Indians. [2] Detailed medical histories and examinations which included physical examination, hormone level measurement, and bone density studies were performed on 52 postmenopausal women. According to these results, no woman experienced hot flashes or any other menopausal symptom and not one single woman showed evidence of osteoporosis, despite the fact that their hormonal patterns were identical to postmenopausal women living in the United States. The researchers of this study felt that the attitude of the Mayan women towards menopause was responsible for their symptomless passage. The Mayan women saw menopause as a positive event that would provide them with acceptance as respected elders as well as relief from child-bearing. This attitude is very different from
the dominant attitude towards menopause common to industrialized societies. If our society adopted a different cultural view of older women, it is likely that the symptoms of menopause would cease to exist. The Western view of menopause: feminine forever?
In 1966, Robert A. Wilson MD introduced, in his landmark book, Feminine Forever, the theory that menopause is an estrogen deficiency disease that needs to be treated with estrogen to compensate for the normal decline of estrogen with aging. [3] According to Wilson, without estrogen replacement therapy, women are destined to become sexless “caricatures of their former selves … the equivalent of a eunuch”. Wilson’s theory of menopause as a disease is now the dominant medical view of menopause. This places women entering menopause in a difficult dilemma: should they pass through this period of time naturally or should they remain “forever feminine”? Before a woman can be counseled, the benefits and the risks of estrogen replacement therapy must be considered, as well as the natural alternatives.
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Estrogen replacement therapy The evolution of estrogen replacement therapy
During the 1940s and 1950s, estrogen became a popular prescription for ameliorating the symptoms of menopause. By the 1970s, estrogen replacement therapy became firmly entrenched as the medical treatment of choice for women in menopause. Unfortunately, the consequences of long-term estrogen therapy were not well understood. It is now well established that estrogen replacement therapy is associated with a four to 13 times increased risk of developing endometrial cancer. [4] To combat the link between estrogen and endometrial cancer, drug companies and physicians began recommending that estrogen be combined with progesterone. Estrogen replacement therapy thus became hormone replacement therapy (HRT). The combination of estrogen with progesterone (or more accurately a progestin) appears to have reduced the risk of endometrial cancer, but still carries with it the risk of causing other cancers (discussed below). [5] This stigma looms very large in the minds of many women and some physicians. The benefits of HRT
Hormone replacement therapy (HRT) results in several undeniable benefits: relief of hot flashes and other menopausal symptoms and a significant reduction in osteoporosis. Furthermore, while early studies showed an increased risk for cardiovascular disease with estrogen use, more recent studies are indicating that the estrogen may offer some protection against heart disease and strokes. [6] [7] However, dietary, exercise, and lifestyle factors have also been shown to offer identical benefits without the risks. Furthermore, the use of short-term (less than 6 months) HRT for menopausal symptoms only provides temporary relief. It is not a permanent cure; it only delays the inevitable. Long-term HRT is not justified in most women due to the risks outweighing the benefits. The exception is women who are at high risk of developing osteoporosis. Since both estrogen and progesterone have been shown to exert beneficial effects against bone loss and, in women with established bone loss, actually to increase bone mass, estrogen–progesterone combinations are preferred to estrogen alone. [6] [7] The exception is in women at high risk for breast cancer or women with a disease aggravated by estrogen, such as breast cancer, active liver diseases, and certain cardiovascular diseases, in which case progesterone alone should be used. HRT and cancer
The cancer-causing potential of HRT is a serious concern. Unfortunately, while there have been over 50 studies seeking to determine the cancer risk of HRT, the results have not been clear. [8] [9] [10] [11] The most likely form of cancer adversely affected by HRT is breast cancer, the most common cancer in women. Current estimates are that one in nine women in the United States will develop breast cancer in her lifetime. Since estrogens play a critical role in the development of most breast cancers, it only makes sense that additional estrogens may promote breast cancer. Several studies in postmenopausal women taking estrogen have shown an increased risk for breast cancer. When all are examined collectively, experts have calculated that estrogen replacement therapy is associated with a 1–30% increase in the risk of breast cancer. [9] [10] [11] Most of the positive studies were conducted in European countries and seem to suggest an association that increases with age and length of use. In comparison, only a few studies in the United States have shown that HRT increases the risk of breast cancer. Several hypotheses have been suggested to explain this surprising difference: American researcher bias; and the fact that since American women are already at such a high risk for breast cancer, the effect is difficult to measure. American researcher defensiveness about the positive findings in the European studies makes resolution of this issue difficult, as does the years-long United States medical establishment’s enthusiastic recommendation of estrogen and HRT. Based on the current evidence, and until the issue of whether HRT increases the risk of breast cancer is cleared up, it can be concluded that well-intentioned physicians and their female patients are probably better off avoiding HRT, except in specific cases such as serious osteoporosis. Other side-effects of HRT
The Physicians’ Desk Reference and package inserts for estrogen and progesterone products provide a long list of side-effects. In addition to the risk of cancer, estrogen and progesterone increase the risk of developing gallstones and blood clots and are absolutely contraindicated during the first 4 months of pregnancy. Other side-effects of estrogen and progesterone include: • nausea • breast tenderness • symptoms similar to premenstrual tension syndrome (PMS) • depression • liver disorders • enlargement of uterine fibroids • fluid retention 1390
• blood sugar disturbances • headaches. However, these side-effects are most often linked to estrogen and progesterone-containing birth control pills. Since the doses of estrogen and progesterone used in menopause are much lower than the doses used in oral contraception, these side-effects are usually not as common when used in menopausal women. A newly recognized side-effect was discovered through the evaluation of the more than 23,000 women in the Nurses’ Health Study. Women taking postmenopausal hormones were found to be over twice as likely to suffer adult-onset asthma than women who never took hormones. [12] The researchers also found that the effect was
dose-related. This finding could help explain why severe adult-onset asthma afflicts more women than men. This is not surprising since the number of asthma cases in women soars at the onset of puberty. Types of HRT
If after weighing all the evidence, a woman elects to utilize HRT for short-term relief or if she requires long-term therapy because of a high risk for osteoporosis, it is important that she participates in choosing the right combination and dosage pattern for her needs. There is no well-accepted “best program” among many experts. However, based on the current evidence, a strong case could be made for what is known as combined continuous HRT as being the best in terms of benefits to risk.
[6]
[7]
When estrogen is given alone without a progestin, it is known as unopposed estrogen therapy. This regimen carries with it the high risk for endometrial cancer and possibly other cancers, including breast cancer. Unopposed estrogen can either be given continuously (every day) or during 25 day cycles separated by 3–6 days without estrogen. In an effort to reduce the risk of endometrial cancer, estrogen is often given in combination with a progestin-like progesterone. The hormones can be given either in a cyclical fashion or continuously. The cyclical fashion involves taking estrogen for 25 days and progestin for the last 10–12 days of the cycle. A 3–6 day hormone-free interval follows, during which planned bleeding occurs. In other words, with cyclical administration, menstruation continues in about 90% of women. In order to prevent monthly bleeding, estrogen and progesterone can be given every day without a hormone-free interval. This regimen is known as combined continuous HRT. As shown in Table 170.1 , when administered according to recommended guidelines (the lowest dose of estrogen possible along with 2.5 mg of medroxy-progesterone acetate), combined continuous HRT offers several advantages over other regimens. TABLE 170-1 -- Advantages of combined continuous hormone replacement therapy • Avoidance of cyclical bleeding • Continuous protection of the endometrium against the cancer-causing effects of estrogen • Lower daily and cumulative amounts of progestins are required • Avoidance of symptoms of premenstrual syndrome which often accompany estrogen • Prolongation of the synergistic effects of estrogen and progesterone on bone integrity • Regression of uterine fibroids • Prevention of rare conceptions by promoting endometrial atrophy • Greater convenience and patient compliance
As for the best type of estrogen to use, “natural-type” estrogens are preferred to synthetic versions. Examples of natural estrogens commonly used in HRT include: • conjugated estrogens (Premarin, Genisis) • esterified estrogens (Evex, Menest) • micronized 17-beta-estradiol (Estrace) • transdermal 17-beta-estradiol (Estraderm, Systen). The most commonly used forms are the conjugated estrogens like Premarin. Conjugated estrogens are metabolized in the body to active forms of estrogen like 17-beta-estradiol. Unfortunately, the liver catabolizes much of the active estrogens before they have the opportunity to produce their effects. Therefore, relatively large amounts of conjugated estrogens have to be given, especially since the most active estrogen, 17-beta-estradiol, is not absorbed well orally. It is, however, absorbed very well through the skin and is the form of estrogen used in the newer estrogen patches as well as vaginal creams. Estrogen patches are preferable to conjugated estrogens for several reasons, but primarily because they approximate more accurately the female body’s own natural estrogen secretions by delivering 17-beta-estradiol into the bloodstream in a slow, sustained manner. Estrogen-containing patches appear to be safer than oral estrogens. The patches are applied to the skin and changed twice per week. With regard to the best form of progesterone, the natural derivative, medroxyprogesterone acetate, is preferred to synthetic versions like megesterol, norethindrone, and norgestrel. Examples of medroxyprogesterone products are Provera, Cycrin, and Amen.
THE MAJOR SYMPTOMS The most common complaints of menopause are: • hot flashes • headaches • atrophic vaginitis • frequent urinary tract infections • cold hands and feet 1391
• forgetfulness • an inability to concentrate. Hot flashes
Hot flashes are the most common symptoms of menopause. A hot flash refers to peripheral vasodilation which leads to a rise in skin temperature and flushing of the skin. In the typical hot flash, the skin, especially of the head and neck, becomes red and warm for a few seconds to 2 minutes with cold chills thereafter. Hot flashes can be accompanied by other symptoms, including increased heart rate, headaches, dizziness, weight gain, fatigue, and insomnia. In the United States, 65–80% of menopausal women experience hot flashes to some degree. Hot flashes are often the first sign that menopause is approaching as they may begin prior to the cessation of menses. In most cases, hot flashes are most uncomfortable in the first to second years after menopause. As the body adapts to decreased estrogen levels, hot flashes typically subside. Atrophic vaginitis
After menopause, the vaginal lining may become thin and dry due to the lack of estrogen. As a result, menopausal and postmenopausal women may experience painful intercourse, an increased susceptibility to infection, and symptoms of vaginal itching or burning. Women with atrophic vaginitis should try to avoid substances which tend to dry the mucous membranes, including antihistamines, alcohol, caffeine, and diuretics. In addition, it is critical that the body stays well hydrated.
Clothes made from natural fibers, particularly cotton, are often recommended as they allow the skin to breathe, thus decreasing the incidence of vaginal infections. Regular intercourse is beneficial as it increases blood flow to vaginal tissues which helps to improve tone and lubrication. However, good lubrication, e.g. with oil or K-Y Jelly, must be maintained. Bladder infections
About 15% of menopausal women experience frequent bladder infections. Apparently, there is a breakdown in the natural defense mechanisms which protect against bacterial growth in the urinary tract. The primary goal in the natural approach to treating bladder infections is enhancing normal host protective measures against urinary tract infection. Specifically, this refers to enhancing the flow of urine by achieving and maintaining proper hydration, promoting a pH which will inhibit the growth of the organism, and preventing bacterial adherence to the endothelial cells of the bladder. In addition, there are several botanical medicines that can be employed (see Ch. 145 for further information). Cold hands and feet
Cold hands and feet are common to women in general, not just menopausal women. In most instances, there are three major causes of cold hands and feet: hypothyroidism, low iron levels in the body, and poor circulation. The basal body temperature test (see Appendix 8 ) should be performed to evaluate functional thyroid activity. Serum ferritin levels, the best indicator of body iron stores, along with a CBC (complete blood count) and chemistry panel, including LDL/HDL cholesterol levels, should also be performed. A complete physical examination is also required, paying particular attention to any other signs of vascular insufficiency. Once the cause is identified, the treatment is straightforward. Forgetfulness
Forgetfulness and an inability to concentrate are common symptoms of menopause. Often these symptoms are simply a result of decreased oxygen and nutrient supply to the brain. The brain is highly dependent on a constant supply of oxygen and nutrients. Although weighing only 1.36 kg, the brain utilizes about 20% of the oxygen supply of the entire body. In dealing with the forgetfulness of menopause, the goal is to improve the supply of blood, oxygen, and nutrients to the brain. The role of the hypothalamus and endorphins Many of the symptoms of menopause, especially hot flashes, appear to be a result of altered function of the hypothalamus, which serves as the bridge between the nervous system and the hormonal (endocrine) system. The hypothalamus is responsible for the control of many body functions, including: • body temperature • metabolic rate • sleep patterns • reactions to stress • libido • mood • the release of pituitary hormones. Critical to proper functioning of the hypothalamus are the endorphins. Several natural measures are thought to exert some of their beneficial effects by enhancing endorphin output. Most notable are exercise and acupuncture.
THERAPEUTIC CONSIDERATIONS Rather than use estrogens to artificially counteract the symptoms of menopause, the natural approach focuses on improving physiology. This improvement can be
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accomplished through diet, exercise, nutritional supplementation, and the use of botanical medicines. The baseline evaluation of the menopausal woman should include: • detailed personal and family medical history • breast examination and instructions on self-examination of the breasts • pelvic examination • laboratory tests —complete blood count —blood chemistry panel —cholesterol evaluation, including HDL, LDL, and VLDL —thyroid function panel, including T 3 , T4 , and TSH • baseline mammography (if indicated) • baseline bone densitometry. After this initial evaluation, these tests should be repeated every year. The bone density studies can be used as a gauge to whether HRT is necessary. Diet The most important dietary recommendation may be to increase the amount of plant foods, especially those high in phytoestrogens, while reducing the amount of animal foods in the diet. There is also a protective effect with consumption of fruit and vegetables. Phytoestrogen-containing foods
Fennel, celery, and parsley are members of the Umbelliferous plant family. Foods of this family typically contain phytoestrogens. Fennel is particularly high in these compounds and possesses confirmed estrogenic action. [13] Other foods high in phytoestrogens include soy, nuts, whole grains, apples, and alfalfa. A high intake of phytoestrogens is thought to explain why hot flashes and other menopausal symptoms rarely occur in cultures consuming a predominantly plant-based diet. Several lignans and isoflavonoids are converted by intestinal bacteria to diphenolic estrogenic compounds which decrease hot flashes, increase maturation of vaginal cells and may inhibit osteoporosis. In addition, such a diet results in a decreased incidence of breast, colon, and prostate cancer. [14]
Soy
An especially important dietary recommendation in the relief of atrophic vaginitis and prevention of breast cancer is to increase the consumption of soy foods. The isoflavones (e.g. genistein) and phytosterols of soybeans produce a mild estrogenic effect. One cup of soybeans provides approximately 300 mg of isoflavone. This level would be the equivalent of about 0.45 mg of conjugated estrogens or one tablet of Premarin. [15] However, while estrogen replacement therapy may increase the risk for cancer, the consumption of soy foods is associated with a significant reduction in the risk of cancer. [14] [15] In a study of postmenopausal women, those women consuming enough soyfoods to provide about 200 mg of isoflavone demonstrated signs of estrogenic activity when compared with a control group. [15] Specifically, the women consuming the soyfoods demonstrated an increase in the number of superficial cells which line the vagina. This increase offsets the vaginal drying and irritation that is common in postmenopausal women. The soybean plant (Glycine max) is native to China where it has been cultivated for food for well over 13,000 years. The ancient Chinese considered the soybean their most important crop and a necessity for life. The soybean, thanks largely to the United States which accounts for over 50% of the world’s production, is now the most widely grown and utilized legume as it accounts for well over 50% of the world’s total legume production. The increase in soyfood consumption is attributed to a number of factors, including economics, health benefits, and environmental concerns. [16] Interestingly, the lower the protein content, the higher the level of isoflavonoids. Products made from whole soybeans are higher in isoflavonoid content than those produced from soy protein concentrates. Therefore, in dealing with the symptoms of menopause, lower protein content products made from soy flour and whole soy are superior to high protein isolates. Another useful effect of soy is its protection of LDL cholesterol from oxidation, an effect of great significance for the prevention of cardiovascular disease.
[14]
Dietary fat
There was a clear positive correlation between breast cancer risk and saturated fat intake in postmenopausal women. associated with an increased risk to breast cancer.
[17]
Total caloric intake is apparently not
Nutritional supplements Several nutrients have been shown to be effective in relieving hot flashes and atrophic vaginitis in clinical studies, including vitamin E, hesperidin in combination with vitamin C, and gamma-oryzanol. Vitamin E
In the late 1940s, several clinical studies found vitamin E to be effective in relieving hot flashes and menopausal vaginal complaints when compared with a placebo. [19] [20] Unfortunately, there have been no further clinical investigations.
[18]
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In one study, vitamin E supplementation was shown to improve not only the symptoms, but also the blood supply to the vaginal wall when taken for at least 4 weeks. [18] A follow-up study published in 1949 demonstrated that vitamin E (400 IU/day) was effective in about 50% of postmenopausal women with atrophic vaginitis. [19] Vitamin E oil, creams, ointments, or suppositories can be used topically to provide symptomatic relief of atrophic vaginitis. Vitamin E is usually quite effective in relieving the dryness and irritation of atrophic vaginitis as well as other forms of vaginitis. [3] Hesperidin and vitamin C
Like many other flavonoids, hesperidin is known to improve vascular integrity and relieve capillary permeability. Combined with vitamin C, hesperidin and other citrus flavonoids may be effective in relieving hot flashes. In one clinical study, 94 women suffering from hot flashes were given a formula containing 900 mg of hesperidin, 300 mg of hesperidin methyl chalcone (another citrus flavonoid), and 1,200 mg of vitamin C daily. [21] At the end of 1 month, symptoms of hot flashes were relieved in 53% of the patients and reduced in 34%. Improvements were also noted in nocturnal leg cramps, nose bleeds, and easy bruising. The only side-effect noted was a slightly offensive body odor with a tendency for the perspiration to discolor the clothing. Gamma-oryzanol
Gamma-oryzanol (ferulic acid) is a growth-promoting substance found in grains and isolated from rice bran oil. In the treatment of hot flashes, its primary action is to enhance pituitary function and promote endorphin release by the hypothalamus. Gamma-oryzanol was first shown to be effective in menopausal symptoms, including hot flashes, in the early 1960s. [22] Subsequent studies have further documented its effectiveness. [23] In one of the earlier studies, eight menopausal women and 13 women who had their ovaries surgically removed were given 300 mg/day of gamma-oryzanol. At the end of the 38 day trial, over 67% of the women had a 50% or greater reduction in their menopausal symptoms. [22] In a more recent study, the benefit of a 300 mg/day dose of gamma-oryzanol was even more effective as 85% of the women reported improvement in their symptoms.[23] Gamma-oryzanol is an extremely safe natural substance. No significant side-effects have been produced in experimental and clinical studies. In addition to being helpful in improving the symptoms of menopause, gamma-oryzanol has also been shown to be quite effective in lowering blood cholesterol triglyceride levels. [24] Botanical medicines Many plants have been shown to exert a tonic effect on the female glandular system. As a class, these botanicals are often referred to as “uterine tonics”. Much of their effect is thought to be a result of phytoestrogens in the plants as well as the plant’s ability to improve blood flow to the female organs. The botanicals work to nourish and tone the female glandular and organ system rather than exerting a drug-like effect. This non-specific mode of action makes many botanicals useful in a broad range of female conditions. Phytoestrogens are found in many medicinal herbs with a historical use in conditions which are now treated by estrogens. Phytoestrogen-containing herbs offer significant advantages over the use of estrogens in the treatment of menopausal symptoms. While both synthetic and natural estrogens may pose significant health risks, phytoestrogens have not been associated with these side-effects. In fact, epidemiological data and experimental studies in animals have demonstrated that phytoestrogens are extremely effective in inhibiting mammary tumors, not only because they occupy estrogen receptors, but also by other unrelated anti-cancer mechanisms.[14] [25] Phytoestrogens in herbs are capable of exerting estrogenic effects, although their activity compared with estrogen is only 2% as strong at the most. [26] However, because of this low activity, phytoestrogens have a balancing action on estrogen effects. If estrogen levels are low, since phytoestrogens have some estrogenic activity, they will cause an increase in estrogen effect. If estrogen levels are high, since phytoestrogens bind to estrogen receptor binding sites, thereby competing with estrogen, there will be a decrease in estrogen effects. [27] Because of the balancing action of phytoestrogens on estrogen effects, it is common to find the same plant recommended for conditions of both estrogen excess (e.g.
premenstrual syndrome) and estrogen deficiency (e.g. menopause, menstrual abnormalities). The four most useful herbs in the treatment of hot flashes are: • • • •
Angelica sinensis Glycyrrhiza glabra Vitex agnus-castus Cimicifuga racemosa.
These herbs have been used historically to lessen a variety of female complaints including hot flashes. Angelica sinensis
In Asia, angelica’s (also known as Dong Quai) reputation is perhaps second only to ginseng. Predominantly regarded as a “female” remedy, angelica has been used in menopausal symptoms (especially hot flashes), as well
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as in such conditions as dysmenorrhea, amenorrhea and metrorrhagia, and to assure a healthy pregnancy and easy delivery (see Ch. 65 for a full discussion). Angelica has demonstrated good uterine tonic activity, causing an initial increase in uterine contraction followed by relaxation. [28] In addition, administration of angelica to mice resulted in an increase of uterine weight and of glucose utilization by the liver and uterus. [29] These effects reflect estrogenic activities. Its effectiveness in relieving hot flashes may be a combination of angelica’s mild estrogenic effects and other components acting to stabilize blood vessels.
[ 30]
Glycyrrhiza glabra
The medicinal use of licorice root in both Western and Eastern cultures dates back several thousand years (see Ch. 90 for a full discussion). Licorice is particularly useful in premenstrual syndrome or PMS. PMS has been attributed to an increase in the estrogen:progesterone ratio. Licorice is believed to lower estrogen while simultaneously raising progesterone levels. For menopause, it is thought that the estrogen-like activity of licorice is responsible for many of its beneficial effects, but its effects on progesterone may also be important. [31] [32] Vitex agnus-castus
The chaste tree is native to the Mediterranean. Its berries have long been used for female complaints. As its name suggests, chaste berries were used in suppressing the libido. Scientific investigation has shown chaste berry has profound effects on pituitary function. [33] It is possible that its beneficial effects in menopause are due to altering LH and FSH secretion (see Ch. 123 for a full discussion). Cimicifuga racemosa
Black cohosh was widely used by the American Indians and later by American colonists for the relief of menstrual cramps and menopause. Recent scientific investigation has upheld the use of black cohosh in both dysmenorrhea and menopause. A special extract of Cimicifuga racemosa standardized to contain 1 mg of triterpenes calculated as 27-deoxyacteine per tablet (tradename = Remifemin) is the most widely used and thoroughly studied natural alternative to hormone replacement therapy in menopause. Clinical studies have shown this cimicifuga extract to relieve not only hot flashes, but also depression and vaginal atrophy. [34] For more information see Chapter 75 . Most patients report noticeable benefits within 4 weeks after the onset of cimicifuga therapy. After six to eight weeks complete resolution of symptoms are achieved in most patients. Cimicifuga is very well tolerated and only 7–10% of patients report mild transitory stomach complaints or other mild side-effects. Because there are no contraindications or limitations of use, cimicifuga offers a suitable natural alternative to hormone replacement therapy for menopause, especially where hormone replacement therapy is contraindicated, e.g., women with a history of cancer, unexplained uterine bleeding, liver and gallbladder disease, pancreatitis, endometriosis, uterine fibroids, or fibrocystic breast disease. Ginkgo biloba
Ginkgo biloba extract is often indicated in menopausal and postmenopausal women for its effects on the vascular system. It may be especially useful in improving both cold hands and feet, and the forgetfulness which often accompany menopause. Ginkgo biloba extract has also been shown to improve blood flow to the hands and feet in human clinical trials and has been shown to be effective in the treatment of peripheral vascular disease of the extremities, including Raynaud’s syndrome, a disease characterized by extremely cold fingers or toes. [35] [36] [37] Ginkgo biloba extract has repeatedly been used to improve mental health in patients with cerebral vascular insufficiency and may exert similar effects in menopause. Ginkgo biloba extract appears to work not only by increasing blood flow to the brain, but also by enhancing energy production within the brain, increasing the uptake of glucose by brain cells, and actually improving the transmission of nerve signals. [35] Improving the transmission rate of the nerve signal is critically important to memory. Memory is directly related to the speed at which the nerve impulse can be transmitted. Although the effect of Ginkgo biloba extract on the forgetfulness of menopause has not been studied in a controlled fashion, there is ample evidence to suggest that it is worth a clinical trial in the menopausal woman with forgetfulness and/or an inability to concentrate. Ginkgo has been shown in double-blind studies to significantly improve memory in elderly as well as college-aged women. [38] [39] [40] [41] It must be pointed out that in the treatment of cerebral vascular insufficiency, Ginkgo biloba extract should be taken consistently for at least 12 weeks in order to determine effectiveness. Although most report benefits within a 2–3 week period, some individuals may take longer to respond. It seems that the longer the treatment is continued, the more obvious and lasting the result. Lifestyle factors Exercise
The hypothesis that impaired endorphin activity within the hypothalamus is a major factor in provoking hot
1395
TABLE 170-2 -- Health benefits of regular exercise in menopause • Relief from hot flashes • Decreased bone loss • Improved heart function
• Improved circulation • Reduced blood pressure • Decreased blood cholesterol levels • Improved ability to deal with stress • Improved oxygen and nutrient utilization in all tissues • Increased self-esteem, mood, and frame of mind • Increased endurance and energy levels flashes led researchers in Sweden to design a study to determine the effect of regular physical exercise on the frequency of hot flashes. [42] In the study, the frequency of moderate and severe hot flashes was investigated in 79 postmenopausal women who took part in physical exercise on a regular basis and compared with a control group of 866 postmenopausal women between 52 and 54 years old. The study clearly demonstrated that regular physical exercise definitely decreased the frequency and severity of hot flashes: the women in the exercising group passed through a natural menopause without the use of HRT and the physically active women who had no hot flashes whatsoever spent an average of 3.5 hours/week exercising, while women who exercised less than this amount were more likely to have hot flashes. Similar results, including mood elevation in pre-, periand postmenopausal exercising versus sedentary women have been reported in other studies. [43] The benefits of exercise were experienced in women both on and off HRT. Given the many benefits of regular exercise (see Table 170.2 ) on mood and the health of bone and the cardiovascular system, along with these positive results in reducing the frequency and severity of hot flashes, it is clear that regular physical exercise is a key component of menopause care. Cigarette smoking
Cigarette smoking significantly increases the risk of early menopause, as smokers have approximately double the risk of menopause between the ages of 44 and 55. Those who were former smokers had a lowered risk, showing there could be a partial reversal of the effect. [44]
THERAPEUTIC APPROACH Many natural measures can help to alleviate the most common symptoms of menopause. In most cases, HRT is not necessary. However, in women at high risk for osteoporosis and women who have already experienced significant bone loss, HRT may be indicated. For the immediate treatment of atrophic vaginitis, prescribe topical vitamin E preparations. If the woman is smoking, facilitate a smoking cessation program. Diet
Increase the amount of phytoestrogens in the diet by consuming more soyfoods; fennel, celery, and parsley; high-lignin flaxseed oil; and nuts and seeds. Supplements
• Vitamin E: 800 IU/day until symptoms have improved, then 400 IU/day • Hesperidin: 900 mg/day • Vitamin C: 1,200 mg/day • Gamma-oryzanol: 300 mg/day. Botanical medicines
All dosages are t.i.d. • Angelica sinensis —powdered root or as tea: 1–2 g —tincture (1:5): 4 ml (1 tsp) —fluid extract: 1 ml (¼ tsp) • Glycyrrhiza glabra —powdered root or as tea: 1–2 g —fluid extract (1:1): 4 ml (1 tsp) —solid (dry powdered) extract (4:1): 250–500 mg • Vitex agnus-castus —powdered berries or as tea: 1–2 g —fluid extract (1:1): 4 ml (1 tsp) —solid (dry powdered) extract (4:1): 250–500 mg • Cimicifuga racemosa The dosage of cimicifuga is based on its content of 27-deoxyacteine which serves as an important biochemical marker to indicate therapeutic effect. The dosage of the cimicifuga extract used in the majority of clinical studies has been 2 mg of 27-deoxyacteine twice daily. Here are the approximate dosage recommendations using other forms (non-standardized) of Cimicifuga racemosa: —Powdered rhizome: 1–2 g —Tincture (1:5): 4–6 ml —Fluid extract (1:1): 3–4 ml (1 tsp) —Solid (dry powdered) extract (4:1): 250–500 mg • Ginkgo biloba extract —24% ginkgo flavonglycoside content: 40 mg.
Lifestyle
Facilitate a regular exercise program – at least 30 minutes three times a week.
1396
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SC, Mansfield PK. Menopause: social construction or biological destiny. J Health Educ 1993; 24: 209–213
2. Martin
MC, Block JE, Sanchez SD et al. Menopause without symptoms: the endocrinology of menopause among rural Mayan Indians. Am J Obstet Gynecol 1993; 168: 1839–1845
3. Wilson
RA. Feminine forever. New York: Evans. 1966
4. Rubin
GL, Peterson HB, Lee NC et al. Estrogen replacement therapy and the risk of endometrial cancer. Remaining controversies. Am J Obstet Gynecol 1990; 162: 148–154
5. Whitehead
MI, Townsend PT, Davies-Pryse J et al. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. New Engl J Med 1981; 305:
1599–1685 6. Session
DR, Kelly AC, Jewelewicz R. Current concepts in estrogen replacement therapy in the menopause. Fertil Steril 1993; 59: 277–284
7. Birkenfeld 8. Henrich 9. Tavani
A, Kase NG. Menopause medicine: current treatment options and trends. Comprehen Ther 1991; 17: 36–45
JB. The postmenopausal estrogen/breast cancer controversy. JAMA 1992; 268: 1900–1902
A, Braga C, LaVecchia C et al. Hormone replacement treatment and breast cancer risk: an age-specific analysis. Canc Epidem Biomark Prev 1997; 6: 11–14
10.
Bergkvist L, Persson I. Hormone replacement therapy and breast cancer. A review of current knowledge. Drug Saf 1996; 15: 360–370
11.
Steinberg KK, Thacker SB, Smith SJ et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991; 265: 1985–1990
Toisi RJ, Speizer FE, Willett WC et al. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study. Am J Respir Crit Care Med 1995; 152: 1183–1188 12.
13.
Albert-Puleo M. Fennel and anise as estrogenic agents. J Ethnopharmacology 1980; 2: 337–344
14.
Aldercreutz H, Mazur W. Phyto-estrogens and Western diseases. Ann Med 1997; 29: 95–120
15.
Messina M, Barnes S. The roles of soy products in reducing risk of cancer. J Natl Cancer Inst 1991; 83: 541–546
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Messina M, Messina V. Increasing the use of soyfoods and their potential role in cancer prevention. J Am Diet Assoc 1991; 91: 836–840
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Howe GR, Hirobata T, Hislop TG. Dietary factors and the risk of breast cancer: combined analysis of 12 case-controlled studies. J Natl Cancer Inst 1990; 82: 561–569
18.
Christy CJ. Vitamin E in menopause. Am J Ob Gyn 1945; 50: 84–87
19.
McLaren HC. Vitamin E in the menopause. Br Med J 1949; ii: 1378–1381
20.
Finkler RS. The effect of vitamin E in the menopause. J Clin Endocrinol Metab 1949; 9: 89–94
21.
Smith CJ. Non-hormonal control of vasomotor flushing in menopausal patients. Chic Med 1964; 67: 193–195
22.
Murase Y, Iishima H. Clinical studies of oral administration of gamma-oryzanol on climacteric complaints and its syndrome. Obstet Gynecol Prac 1963; 12: 147–149
23.
Ishihara M. Effect of gamma-oryzanol on serum lipid peroxide levels and climacteric disturbances. Asia Oceania J Obstet Gynecol 1984; 10: 317
24.
Yoshino G, Kazumi T, Amano M et al. Effects of gamma-oryzanol on hyperlipidemic subjects. Current Ther Res 1989; 45: 543–552
25.
Rose DP. Dietary fiber, phytoestrogens, and breast cancer. Nutrition 1992; 8: 47–51
26.
Elghamry MI, Shihata IM. Biological activity of phytoestrogens. Planta Medica 1965; 13: 352–357
27.
Tamaya T, Sato S, Okada H et al. Inhibition by plant herb extracts of steroid bindings in uterus, liver, and serum of the rabbit. Acta Ob Gyn Scand 1986; 65: 839–842
28.
Harada M, Suzuki M, Ozaki Y. Effect of Japanese angelica root and peony root on uterine contraction in the rabbit in situ. J Pharm Dyn 1984; 7: 304–311
29.
Yoshiro K. The physiological actions of tang-kuei and cnidium. Bull Oriental Healing Arts Inst USA 1985; 10: 269–278
Thastrup O, Fjalland B, Lemmich J. Coronary vasodilatory, spasmolytic and cAMP-phosphodiesterase inhibitory properties of dihydropyranocoumarins and dihydrofuranocoumarins. Acta Pharmacol et Toxicol 1983; 52: 246–253 30.
31.
Costello CH, Lynn EV. Estrogenic substances from plants: I. Glycyrrhiza. J Am Pharm Soc 1950; 39: 177–180
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Kumagai A, Nishino K, Shimomura A et al. Effect of glycyrrhizin on estrogen action. Endocrinol Japan 1967; 14: 34–38
33.
Haller J. Animal experimentation with the Lipshutz technique on the activity of a phytohormone on gonadotropin function. Geburt Frauen 1958; 18: 1347
34.
Duker EM, Kopanski L, Jarry H, Wuttke W. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Medica 1991; 57: 420–424
35.
Kleijnen J, Knipschild P. Drug profiles – Ginkgo biloba. Lancet 1993; 340: 1136–1139
Bauer U. Six-month double-blind randomized clinical trial of Ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneim Forsch 1984; 34: 716–721 36.
37.
Rudofsky VG. The effect of Ginkgo biloba extract in cases of arterial occlusive disease – a randomized placebo controlled double-blind cross-over study. Fortschr Med 1987; 105: 397–400
38.
Vorberg G. Ginkgo biloba extract (GBE): a long-term study of chronic cerebral insufficiency in geriatric patients. Clin Trials J 1985; 22: 149–157
Hofferberth B. Effect of Ginkgo biloba extract on neurophysiological and psychometric measurement in patients with cerebroorganic syndrome – a double-blind study versus placebo. Arzneim Forsch 1989; 39: 918–922 39.
Gessner B, Voelp A, Klasser M. Study of the long-term action of a Ginkgo biloba extract on vigilance and mental performance as determined by means of quantitative pharmaco-EEG and psychometric measurements. Arzneim Forsch 1985; 35: 1459–1465 40.
41.
Hindmarch I, Subhan Z. The psychopharmacological effects of Ginkgo biloba extract in normal healthy volunteers. Int J Clin Pharmacol Res 1984; 4: 89–93
42.
Hammar M, Berg G, Lindgren R. Does physical exercise influence the frequency of postmenopausal hot flushes? Acta Obstet Gynecol Scand 1990; 69: 409–412
Slaven L, Lee C. Mood and symptom reporting among middle-aged women: the relationship between menopausal status, hormone replacement therapy, and exercise participation. Health Psychol 1997; 16: 203–208 43.
44.
Midgette AS, Baron JA. Cigarette smoking and the risk of natural menopause. Epidemiology 1990; 1: 474–480
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Chapter 171 - Menorrhagia Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Excessive menstrual bleeding, i.e. blood loss greater than 80 ml, occurring at regular cyclical intervals (cycles are usually, but not necessarily, of normal length) • Often caused by local lesions, e.g. uterine myomas (fibroids), endometrial polyps, endometrial hyperplasia, adenomyosis, and endometritis.
GENERAL CONSIDERATIONS The complaint of menorrhagia is largely subjective, as objective measurement of blood loss is rarely done. Furthermore, there is a poor correlation between measured blood loss and a patient’s assessment of her bleeding (discussed in more detail below). Studies that have measured blood loss have demonstrated that patients with menorrhagia have a considerable increase in menstrual blood flow during the first 3 days (up to 92% of their total menses being lost at this time). This suggests that the mechanisms responsible for cessation of menstruation are as effective in women who have menorrhagia as in normal women, despite the very high blood loss. Etiology
As with any disease, proper determination of the etiology is essential for effective treatment. The appropriate methodology for ruling out pathological causes is beyond the scope of this text and can be found in any good text on gynecology. Table 171.1 lists typical causes of menorrhagia. Abnormalities in prostaglandin metabolism
The etiology of functional menorrhagia is currently believed to involve abnormalities in the biochemical processes of the endometrium which control the supply
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Cause Anovulation
TABLE 171-1 -- Pathological causes of menorrhagia [1] Possible etiology Excessive estrogen Failure of midcycle surge of LH Hypothyroidism Hyperprolactinemia Polycystic ovarian disease
Intrauterine structural defects
Fibroids Polyps Cancer Ectopic pregnancy Intrauterine devices
Bleeding disorders
See Table 171.2
of arachidonic acid for prostaglandin synthesis. [2] [3] Menorrhagic endometrium incorporates arachidonic acid into neutral lipids to a much greater extent than normal, while incorporation into phospholipids is decreased. The increased arachidonic acid release during menstruation results in increased production of series 2 prostaglandins, which are thought to be the major factor both in the excessive bleeding seen at menstruation and in the symptoms of dysmenorrhea. The excessive bleeding during the first 3 days appears to be due to the vasodilatory properties of PGE 2 and PGI2 and the anti-aggregating activity of PGI 2 , while the pain of dysmenorrhea is due to the overproduction PGF 2alpha . Other factors believed to contribute to menorrhagia are: • iron deficiency • hypothyroidism • vitamin A deficiency • intrauterine devices • various local factors, e.g. uterine myomas, endometrial polyps, adenomyosis, endometrial hyperplasia, salpingitis, and endometritis. Estimating menstrual blood loss
Physicians often feel they can assess menstrual blood loss by asking the patient to estimate the number of pads used during each period and the duration of the period. However, studies have demonstrated that there is no correlation between measured blood loss and these assessments. [1] [4] [5] A woman’s assessment of her blood loss is extremely subjective, as demonstrated by one study which found that 40% of women with a menstrual blood loss exceeding 80 ml considered their periods only moderately heavy or scanty, while 14% of those with a measured loss of less than 20 ml judged their periods to be heavy. [5] Serum ferritin levels may be the best indicator of excessive menstrual blood loss from a clinical perspective.
THERAPEUTIC CONSIDERATIONS Psychological
As the complaint of menorrhagia is largely subjective, it is possible that a psychological component may at times be the etiological factor.
[ 6]
However, while it is known
that, as a group, women complaining of menorrhagia are more likely to have received antidepressant medication at some time in the past (and are more likely to have a hysterectomy),[7] the role of iron deficiency and thyroid insufficiency as factors contributing to this association has never been assessed. (The role these can play in disturbances of mood is discussed in Ch. 126 , while their role in menorrhagia is discussed below.) It is the authors’ opinion that women have often been subjected to needless hysterectomy, uterine curettage, and/or antidepressant medication when appropriate diagnostic and therapeutic measures would have revealed the underlying cause. While psychological factors may play a major role in the complaint of menorrhagia, organic factors must always be ruled out first. Iron deficiency
A menstrual blood loss above 60 ml per period is associated with negative iron balance in most cases. [8] Although menstrual blood loss is well recognized as a major cause of iron deficiency anemia in fertile women, it is not as well known that chronic iron deficiency can be a cause of menorrhagia. Taymor et al [9] have suggested this to be the case, based on several observations: • response to iron supplementation alone in 74 of 83 patients (in whom organic pathology had been excluded) 1399
• high rate of organic pathology (fibroids, polyps, adenomyosis, etc.) in the patients who failed to respond to iron supplementation • associated rise in serum iron levels in 44 of 57 patients • decreased response to iron therapy when initial serum iron levels were high • correlation of menorrhagia with depleted tissue iron stores (bone marrow) irrespective of serum iron level • a significant double-blind placebo-controlled study displaying improvement in 75% of those on iron supplementation, compared with 32.5% for the placebo group.
Factor
TABLE 171-2 -- Acquired generalized hemorrhagic disorders [15] Possible cause
Deficiency of vitamin K
Low intake, impaired absorption, antimicrobial inhibition of gut flora that synthesize vitamin K
Drug-induced hemorrhage
Heparin, warfarin
Dysproteinemias
Myeloma, macroglobinemia
Disseminated intravascular coagulation Severe hepatic disease Circulating inhibitors of coagulation Primary fibrinolysis
Hematological screening and serum ferritin determination (which will be the first to indicate decreased iron levels) should be performed for patients complaining of menorrhagia. In one study, menorrhagic women (based on subjective information) displayed significantly lower serum ferritin levels than controls, while hemoglobin concentration, mean corpuscular volume, and mean corpuscular hemoglobin were not significantly different between the two groups. [10] (It was erroneously stated by the authors that these women do not require prophylactic iron supplementation since no hematological abnormalities appeared, despite significantly reduced iron stores.) Iron supplementation, at a daily dose of 100 mg elemental iron, has been recommended as a prophylactic therapy by several researchers, since it appears that chronic iron deficiency may promote menorrhagia , and iron-containing enzymes are depleted before hematological changes are observed. A decreased serum ferritin level is a good indication of the need for iron supplementation. [8] [9] Vitamin A
In one study, serum retinol levels were found to be significantly lower in 71 women with menorrhagia than in healthy controls. After 40 of these were given 25,000 IU of vitamin A twice a day for 15 days, blood loss returned to normal in 23 and was reduced in 14, i.e. 92.5% of these women had either complete relief or significant improvement.[11] Vitamin C and bioflavonoids
Capillary fragility is believed to play a role in many cases of menorrhagia. Supplementation with vitamin C (200 mg t.i.d.) and bioflavonoids (quantity not specified) has been shown to reduce menorrhagia in 14 out of 16 patients. [12] One of the patients failing to respond had endometriosis and the other had metrorrhagia. As vitamin C is known to significantly increase iron absorption, its therapeutic effect could be also due to enhanced iron absorption. Vitamin E
One group of investigators has suggested that free radicals have a causative role in endometrial bleeding, particularly in the presence of an intrauterine device. [13] Vitamin E supplementation (100 IU every 2 days) resulted in improvement in all patients by the end of 10 weeks. [13] Although vitamin E may have produced its effects via its antioxidant activity, it is equally plausible that it affected prostaglandin metabolism in a manner that would reduce bleeding. Vitamin K and chlorophyll
Although bleeding time and prothrombin levels in women with menorrhagia are typically normal, the use of vitamin K (historically in the form of crude preparations of chlorophyll) has clinical and limited research support. [14] Also, some women will be found to have an inherited or acquired bleeding disorder. Table 171.2 lists some causes of acquired hemorrhagic disorders. Thyroid abnormalities
The association of overt hypothyroidism or hyperthyroidism with menstrual disturbances is well known. However, even minimal thyroid dysfunction, particularly minimal, subclinical insufficiency (as determined by the thyroid stimulation (TRH) test) may be responsible for menorrhagia and other menstrual disturbances. [16] Patients with minimal thyroid insufficiency and menorrhagia have responded dramatically to thyroxine. [16] It has been recommended that patients with long-standing menstrual dysfunction (who have no obvious uterine pathology) should be considered for TRH testing. This is preferable to the empirical use of thyroid hormone. Essential fatty acids
Since it now appears that the majority of tissue arachidonic acid is derived from the diet, [17] it is possible that reducing the intake of animal products and/or increasing intake of linoleic, linolenic and di-homo-gamma-linolenic acid could curtail blood loss by decreasing the availability of arachidonic acid . Botanicals
Numerous botanicals have been used in the treatment of menorrhagia, including: • Geranium maculatum
• Trillium pendulum 1400
• • • •
Areca catechu Caulophyllum thalictroides Hamamelis virginiana Capsella bursa pastoris.
The latter (shepherd’s purse) has a long history of use in the management of obstetric and gynecologic hemorrhage. Intravenous and intramuscular injections have been found to be effective (in uncontrolled studies) in menorrhagia due to functional abnormalities and fibroids. [18] [19] Its hemostatic action is believed to be a result of its high concentration of oxalic and dicarboxylic acids. [18] [19] The use of botanicals should be reserved for intractable cases of menorrhagia, those cases where immediate cessation of blood loss is desired, and/or as a short-term adjunct to above-mentioned therapies.
THERAPEUTIC APPROACH The first step in treating a woman with menorrhagia is to rule out serious pathological causes (see Table 171.1 ). When the excessive bleeding has been determined to be functional, prothrombin time, hematological status, and thyroid function should be determined, and any abnormalities corrected. In order to accurately determine the efficacy of therapy, some relatively quantitative method of measuring blood loss should be worked out with the patient. Serum ferritin levels can be used to help monitor the patient’s progress. Diet
The diet should be relatively low in sources of arachidonic acid (animal fats) and high in linolenic and linoleic acids (vegetable oil sources). Green leafy vegetables and other sources of vitamin K should be eaten freely. Supplements
• Vitamin C: 1,000 mg/day • Bioflavonoids: 250 mg/day • Vitamin A: 25,000 IU/day • Vitamin E: 200 IU/day • Chlorophyll: 25 mg/day (use a crude form) • Iron: 25 mg/day. Botanical medicine
• Capsella bursa pastoris: 1 tsp/cup three times/day, if needed to control very heavy bleeding.
REFERENCES 1. Federman 2. Downing 3. Scott
DD. Ovary. In: Dale DC, Federman DD. Scientific American medicine. New York, NY: Scientific American. 1997. p 3: III: 9,10
I, Hutchon DJR, Poyser NL. Uptake of [ 3 H]-arachidonic acid by human endometrium. Differences between normal and menorrhagic tissue. Prostaglandins 1983; 26: 55–69
PC. The outcome of menorrhagia. A retrospective case control study. J Royal Coll Gen Pract 1983; 33: 715–720
4. Chimbira
TH, Anderson ABM, Turnbill AC. Relation between measured blood loss and patients’ subjective assessment of loss, duration of bleeding, number of sanitary towels used, uterine weight and endometrial surface area. Br J Ob Gyn 1980; 87: 603–609 5. Hallberg
L, Hogdahl A, Nilsson L, Rybo G. Menstrual blood loss – a population study. Acta Ob Gyn Scand 1966; 45: 320–351
6. Arvidsson 7. Taymor 8. Lewis
ML, Sturgis SH, Yahia C. The etiological role of chronic iron deficiency in production of menorrhagia. JAMA 1964; 187: 323–327
GJ. Do women with menorrhagia need iron? Br Med J 1982; 284: 1158
9. Lithgow
10.
B, Ekenved G, Rybo G, Solvell L. Iron prophylaxis in menorrhagia. Acta Ob Gyn Scand 1981; 60: 157–160
D, Politzer W. Vitamin A in the treatment of menorrhagia. S Afr Med J 1977; 51: 191–193
Cohen JD, Rubin HW. Functional menorrhagia: treatment with bioflavonoids and vitamin C. Curr Ther Res 1960; 2: 539–542
Dasgupta PR, Dutta S, Banerjee P, Majumdar S. Vitamin E (alpha tocopherol) in the management of menorrhagia associated with the use of intrauterine contraceptive devices (IUCD). Int J Fertil 1983; 28: 55–56 11.
12.
Stoffer CS. Menstrual disorders and mild thyroid insufficiency. Postgraduate Med 1982; 72: 75–82
13.
Sone K, Willis A, Hart M et al. The metabolism of di-homo-gamma-linolenic acid in man. Lipids 1978; 14: 174–180
14.
Schumann E. Newer concepts of blood coagulation and control of hemorrhage. Am J Ob Gyn 1939; 38: 1002–1007
15.
Steinberg A, Segal HI, Parris HM. Role of oxalic acid and certain related dicarboxylic acids in the control of hemorrhage. Annals Oto Rhino Laryngo 1940; 49: 1008–1021
Kelly RW, Lumsden MA, Abel MH, Baird DT. The relationship between menstrual blood loss and prostaglandin production in the human: evidence for increased availability of arachidonic acid in women suffering from menorrhagia. Prostaglandins Leukotrienes Med 1984; 16: 69–78 16.
17.
Greenberg M. The meaning of menorrhagia: an investigation into the association between the complaint of menorrhagia and depression. J Psychosom Res 1983; 27: 209–214
18.
Gubner R, Ungerleider HE. Vitamin K therapy in menorrhagia. South Med J 1944; 37: 556–558
19.
Schrier SL, Lung LLK. Disorders of hemostasis and coagulation. In: Dale DC, Federman DD. Scientific American medicine. New York, NY: Scientific American. 1997. p 5: VI: 41
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Chapter 172 - Migraine headache Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Recurrent, paroxysmal attacks of headache • Headache is typically pounding and unilateral, but may become generalized • Attacks often preceded by psychological or visual disturbances; accompanied by anorexia, nausea, and gastrointestinal upset; and followed by drowsiness.
GENERAL CONSIDERATIONS Migraine headaches are caused by excessive dilation of a blood vessel in the head. Migraines are a surprisingly common disorder, at some time in their life affecting 15–20% of men and 25–30% of women.[1] More than half of the patients have a family history of the illness. Although many migraines come without warning, many migraine sufferers have warning symptoms (auras) before the onset of pain. Typical auras last a few minutes and include: • blurring or bright spots in the vision • anxiety • fatigue • disturbed thinking • numbness or tingling on one side of the body. In vascular headaches, like migraine headaches, the pain is characterized by a throbbing or pounding sharp pain. In non-vascular headaches, like tension headaches, the pain is characterized as a steady, constant, dull pain that starts at the back of the head or in the forehead and spreads over the entire head, giving the sensation of pressure or as if a vise grip has been applied to the skull (see Table 172.1 for primary classifications of headaches). The pain of a headache comes from outside the brain because the brain tissue itself does not have sensory nerves. Pain arises from the meninges and from the scalp and its blood vessels and muscles when these structures are stretched or tensed. The most common non-vascular headache is the
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TABLE 172-1 -- Primary classifications of headache Vascular headache • Migraine headache —classic migraine —common migraine —complicated migraine —variant migraine • Cluster headache —episodic cluster —chronic cluster —chronic paroxysmal hemicrania • Miscellaneous vascular headaches —carotidynia —hypertension —exertional —hangover —toxins and drugs —occlusive vascular disease Non-vascular • Tension headache —common tension headache —temporomandibular joint (TMJ) dysfunction • Increased or decreased intracranial pressure • Brain tumors • Sinus infections • Dental infections • Inner or middle ear infections
tension headache. This headache is usually caused by tightening in the muscles of the face, neck, or scalp as a result of stress or poor posture. The tightening of the muscles results in pinching of the nerve or its blood supply which results in the sensation of pain and pressure. Relaxation of the muscle usually brings about immediate relief. Classification and diagnosis Migraine headache has been subdivided into several types, based on the presence or absence of preceding or concomitant neurological manifestations and the nature of the manifestations. Although there are several subtypes, the three most common ( common, classic, and complicated) comprise the vast majority of patients, and differentiation, while important, does not at this time have any therapeutic significance. The differentiation and diagnosis of these types are summarized in Table 172.2 . Cluster headache was once considered a migraine-type headache, since vasodilation is a key component, but it is now separately classified. Also referred to as histamine cephalgia, Horton’s headache, or atypical facial neuralgia, it is much less common than migraine. Another headache to be considered in this chapter is chronic daily headache (CDH). Approximately 40% of patients seen in headache clinics suffer from CDH. Other terms used to describe CDH by doctors include: • chronic tension headache • migraine with interparoxysmal headache • transformed migraine • evolutive migraine • mixed headache syndrome • tension-vascular headache. To simplify matters, CDH has now been divided into four major types (see Table 172.3 ). Pathophysiology Considerable evidence supports an association between migraine headache and vasomotor instability, but the mechanisms are not yet known. Although most clinicians and researchers believe that the sequence of events is excessive intracranial arterial constriction (causing brain ischemia) followed by rebound dilation of the extracranial vessels (the headache phase), sophisticated studies of sequential cerebral blood flow before, during, and after are inconsistent in their support of this hypothesis.[2] [3] Vasomotor instability
It is a well-known clinical observation that superficial temporal vessels are visibly dilated and local compression of these vessels or the carotid artery temporarily relieves migraine pain. [4] However, other types of extracranial vasodilation (e.g. heat- or exercise-induced) are not associated with migraine. Despite the extracranial vasodilation, the patient appears pale during the headache, suggesting constriction of the small vessels. This is supported by the observation of lower skin temperature on the affected side. The clinical manifestations of focal or diffuse cerebral or brain stem dysfunction have been attributed to intracranial vasoconstriction. A majority, but not all, of the studies measuring cerebral blood flow have confirmed TABLE 172-2 -- Migraine classification Classic
Common
Complicated
Incidence
80%
10%
10%
Pain
Frontal, uni/bilateral
Unilateral
Unpredictable, may be absent
Aura
Unusual
0.5 hour, striking
Neurological aura, vertigo, syncope, diplopia, hemiparesis
Duration of headache
1–3 days
2–6 hours
Unpredictable
Physical examination
Unhappiness
Pallor, vomiting cranial nerve III palsy
Mild neurological signs, speech disorder, hemiparesis, unsteadiness,
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TABLE 172-3 -- The four types of chronic daily headache • Transformed migraine —drug-induced —non-drug-induced • Chronic tension-type headache • New daily persistent headache • Post-traumatic headache a reduction of blood flow, sometimes to very low and critical levels, during the prodromal stage. This is followed by a stage of increased blood flow that can persist for more than 48 hours. There is significant decrease in regional cerebral blood flow in classic, but not common, migraine. [5] The abnormal blood flow appears confined to the cerebral cortex, while deeper structures are perfused normally. There is some evidence that migraine patients have an inherited abnormality of vasomotor control. Migraine patients suffer from orthostatic symptoms more often than normal people, and they seem to be abnormally sensitive to the vasodilatory effects of physical and chemical agents. Platelet disorder
The migraine platelet shows significant differences from the normal platelet both during and between headaches. [6] These differences include a significant increase in spontaneous aggregation, highly significant differences in the manner of serotonin release, and significant differences in platelet composition. The major proponent of the platelet hypothesis is Hanington, [6] who starts with the observation that the most common precipitant of migraine is some type of stressor. This results in a rise in plasma catecholamine levels which triggers the release of serotonin and resultant platelet aggregation and vasoconstriction. The platelets of migraine sufferers aggregate more readily than normal platelets, both spontaneously and when exposed to serotonin (and to adenosine diphosphate and catecholamines). The increase in spontaneous aggregation is similar to that reported in patients suffering from transient cerebral ischemic attacks (TIAs). This is significant, considering the close resemblance of the symptomatology of TIAs and the prodromal phase of the migraine headache. The onset of an attack is accompanied by a significant rise in plasma serotonin levels, followed by an increase in urinary 5-hydroxyindoleacetic acid, the breakdown product of serotonin metabolism. All of the serotonin normally in the blood is stored in the platelets and is released by platelet aggregation and in response to various
stimuli, such as catecholamines. There is no difference in total serotonin content between normal platelets and the platelets of migraine patients. However, the quantity of serotonin released by the platelets of the migraine patient in response to serotonin stimulation, while normal (or even subnormal) immediately after an attack, becomes progressively higher as the next attack approaches. [6] The platelet hypothesis is strengthened by the observation that patients with classic migraine have a twofold increase in incidence of mitral valve prolapse. [7] Using careful clinical and echocardiographic criteria and matched controls, the researchers found in the migraine patients definite mitral prolapse in 16% and possible prolapse in 15%. The controls had 7 and 8%, respectively. This is of significance, since the prolapsing mitral valve is known to damage platelets and increase their aggregation. This work has been confirmed in several studies. [8] [9] Neuronal disorder
A third major hypothesis is that the nervous system plays a role in initiating the vascular events in migraine. [1] It has been suggested that the trigeminovascular neurons, which innervate the pial arteries, release peptide substance P either in direct response to the various initiators or secondarily to changes in the central nervous system.[10] Substance P is an important mediator of pain, and its release into the arteries is associated with vasodilation, mast cell degranulation, and increased vascular permeability. It is thought that the endothelial cells of the arteries respond to substance P by releasing vasoactive substances, such as arachidonic acid metabolites, purine compounds, or molecules containing carbonyl groups. This theory suggests that functional changes within the noradrenergic system constitute the threshold for migraine activation, and it is through modulation of sympathetic activity that potentiators exert their effect. [10] Chronic stress is thought to be an important potentiator in this model. Migraine as a “serotonin deficiency” syndrome
The final hypothesis is that migraine headache represents a serotonin deficiency state. The story of serotonin and headaches began in the 1960s when researchers found that there was an increase in the serotonin breakdown product 5-hydroxyindoleacetic acid (5-HIAA) in the urine during a migraine. [11] Initially it was thought that serotonin excess was the culprit; however, newer information indicates that the factor responsible for the increase in 5-HIAA is more likely the increased breakdown of serotonin as a result of increased activity of monoamine oxidase (MAO). [12] [13] Because migraine sufferers actually have low levels of serotonin in their tissues, it led researchers to refer to migraine as a “low serotonin syndrome”. [14] Low serotonin levels are thought to lead to a decrease
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in the pain threshold in patients with chronic headaches. This contention is strongly supported by over 35 years of research, including positive clinical results in double-blind studies with the serotonin precursor 5-hydroxytryptophan (5-HTP). For more information on the clinical studies with 5-HTP in migraine headaches, see Chapter 92 . The link between low serotonin levels and headache is the basis of many prescription drugs for the treatment and prevention of migraine headaches. For example, the serotonin agonist drug sumatriptan (Imitrex) is now among the most popular migraine prescriptions. In addition to sumatriptan, monoamine oxidase inhibitors (which increase serotonin levels) have also been shown to prevent headaches. The bottom line is that there is considerable evidence that increasing serotonin levels leads to relief from chronic migraine headaches. The effects that 5-HTP, sumatriptan, and other drugs exert on the serotonin system are extremely complex because of the multiple types of serotonin receptors. The manner in which many substances produce their effects on cells is by first binding to receptor sites on the cell membrane. Some serotonin receptors are involved in triggering migraines and others prevent them. This situation is quite clear by looking at the different effects that various drugs exert when binding to these different serotonin receptors. Drugs which bind to serotonin receptors designated as 5-HT 1c trigger migraines, while drugs like methysergide that inhibit 5-HT 1c are used to prevent migraines.[15] In addition, the serotonin receptor 5-HT 1d may prevent migraine headaches since drugs like sumatriptan which bind to these receptors and mimic the effects of serotonin are quite effective in the acute treatment of migraine. [16] 5-HTP supplementation affects these different receptors in several ways. For example, some serotonin receptors appear to undergo desensitization when exposed to higher levels of serotonin. It is thought that by increasing serotonin levels, 5-HT 1c lose their ability or affinity to bind serotonin, resulting in more serotonin binding to the 5-HT1d receptor. In other words, it is thought that what is occurring with 5-HTP in the preventive treatment of migraine headache is that the higher levels of serotonin produced over time result in a decrease in the sensitivity of the 5-HT 1c receptors and an increased sensitivity for 5-HT 1d receptors. [17] As a result, there would be a lowered tendency to experience headache. One of the key pieces of evidence to support this concept is the fact that 5-HTP is more effective over time (better results are seen after 60 days of use than after 30). Unified hypothesis
The mechanism of migraine can be described as a three-stage process: initiation, prodrome, and headache. TABLE 172-4 -- Factors that trigger migraine headaches • Low serotonin levels —genetics —shunting of tryptophan into other pathways • Foods —food allergies —histamine-releasing foods —histamine-containing foods • Alcohol, especially red wine • Chemicals —nitrates —MSG (monosodium glutamate) —nitroglycerin • Withdrawal from caffeine or other drugs which constrict blood vessels • Stress • Emotional changes, especially let-down after stress, and intense emotions, such as anger • Hormonal changes, e.g. menstruation, ovulation, birth control pills • Too little or too much sleep • Exhaustion • Poor posture
• Muscle tension • Weather changes, e.g. barometric pressure changes, exposure to sun • Glare or eyestrain Although a particular stressor may be associated with the onset of a specific attack, it appears that initiation is dependent on the accumulation over time of several stressors. These stressors ultimately affect serotonin metabolism (see Table 172.4 ). Once a critical point of susceptibility (or threshold) is reached, a cascade event is initiated. This susceptibility is probably a combination of decreased tissue serotonin levels, changes in the platelet, alteration in the responsiveness of key cerebrovascular end-organs, increased sensitivity of the intrinsic noradrenergic system of the brain, and the build-up of histamine, arachidonic acid metabolites, or other mediators of inflammation. The platelet changes include increased adhesiveness, enhanced tendency to release serotonin, and increased levels of arachidonic acid in the membranes. Once the platelet is stimulated to secrete serotonin, platelet aggregation, vasospasm, and inflammatory processes result in local cerebral ischemia. This is followed by rebound vasodilation and the release of peptide substance P and other mediators of pain. These events are summarized in Figure 172.1 .
THERAPEUTIC CONSIDERATIONS Modern pharmacological treatment of headache, whether migraine or tension, is ultimately doomed because it fails to address the underlying cause. The first step in treating migraine headache is identifying the precipitating factor. Although food intolerance/allergy is the most important, many other factors must be considered as either primary causes or contributors to the migraine process. In particular, it is very important to assess the
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Figure 172-1 The pathogenesis of migraine.
role that headache medications may be playing, especially in chronic headaches. Drug reaction Several clinical studies have estimated that approximately 70% of patients with chronic daily headaches suffer from drug-induced headaches. [18] There are two main forms of drug-induced chronic daily headaches: analgesic rebound headache and ergotamine rebound headache. [19] Withdrawal of medication results in prompt clinical improvement in most cases. In one study (summarized in Table 172.5 ) of 200 patients suffering from analgesic-rebound headache, discontinuation of these symptomatic medications resulted in 52% improvement in the total headache index, improvements in headache frequency and severity, general well-being, sleep patterns, and a reduction in irritability, depression, and lethargy. [19] These 200 patients were typical in that they sought relief from a variety of drugs. Table 172.6 lists the types
Medications
TABLE 172-5 -- Profile of 200 patients with chronic daily headache Average no. of Range of No. of patients of tablets/week no. tablets/week
Percentage of patients
Butalbital/aspirin, acetaminophen/caffeine with or without codeine
30
14–86
84
42
Codeine
28
10–84
80
40
Aspirin or acetaminophen with caffeine
42
14–108
50
25
Ergotamine
15 mg
6–42 mg
44
22
Acetaminophen
52
15–105
34
17
Propoxyphene
26
14–56
32
16
Nasal decongestants and antihistamines
14
6–30
24
12
Aspirin
28
10–64
8
4
TABLE 172-6 -- Commonly used drugs to prevent migraine headaches Drug Aspirin
Adult daily dosage 650–1950 mg
Common side-effects Gastric irritation, ulcer formation
Propranolol
80–240 mg
Fatigue, lassitude, depression, insomnia, nausea, vomiting, constipation
Amitriptyline and imipramine
10–150 mg
Drowsiness, dry mouth, constipation, weight gain, blurred vision, water retention
Sertraline
50–200 mg
Anxiety, insomnia, sweating, tremor, gastrointestinal disturbances
Fluoxetine
20–60 mg
Similar to those of sertraline
Ergonovine maleate
0.6–2 mg
Nausea, vomiting, abdominal pain, diarrhea
Cyproheptadine
12–20 mg
Sedation, dry mouth, gastrointestinal disturbances
Clonidine
0.2–0.6 mg
Dry mouth, drowsiness, sedation, headache, constipation
Methysergide Calcium-channel blockers (verapamil, nifedipine, diltiazem, etc.)
4–8 mg 80–160 mg
Nausea, vomiting, diarrhea, abdominal pain, cramps, weight gain, insomnia, edema, decreased blood flow to extremities, heart and lung fibrosis Headache, low blood pressure, flushing, water retention, constipation
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of drugs used for symptomatic relief. Most of these patients took at least three of these preparations at the same time. Analgesic-rebound headache
In the early 1980s, it began to be quite apparent in the medical literature that headache medications increase the tendency for headache and perpetuate chronic
headache. Early reports were labeled “paradoxical” in that heavy analgesic users experienced headaches of much greater frequency and intensity. For example, in one study it was found that sufferers of migraine headaches who took more than 30 analgesic tablets per month had twice as many headache days per month as those who took fewer than 30 tablets.[20] This finding led to the recommendation that analgesic use should be restricted in patients with chronic daily headaches. In another study, 70 patients with daily headaches who were consuming 14 or more analgesic tablets per week were told to discontinue their use. 66% of the patients were improved. At the end of the second month, this percentage had grown to 81%.
[21]
One month later,
Analgesic-rebound headaches should be suspected in any patient with chronic headaches who is taking large quantities of analgesics and who is experiencing daily predictable headache. The critical dosage which can lead to analgesic-rebound headache is estimated to be 1,000 mg of either acetaminophen or aspirin. Analgesic medications typically contain substances in addition to the analgesic such as caffeine or a sedative like butabarbital. These substances further contribute to the problem and may lead to withdrawal headache and related symptoms such as nausea, abdominal cramps, diarrhea, restlessness, sleeplessness, and anxiety. Withdrawal symptoms typically start at 24–48 hours, and in most cases subside in 5–7 days. Ergotamine-rebound headache
Ergotamine is the most widely used drug in the treat-ment of severe acute migraine and cluster headaches. Ergotamine works by constricting the blood vessels of the head, thereby preventing or relieving the excessive dilation of the blood vessels that is responsible for the pain of migraine and cluster headaches. Ergotamine is administered intramuscularly, by inhalation or by suppository since it is poorly absorbed when given orally. Although usually quite effective, ergotamine is also associated with some significant side-effects. Symptoms of acute poisoning include: • vomiting • diarrhea • dizziness • rise or fall of blood pressure • slow, weak pulse • dyspnea • convulsions • loss of consciousness. Symptoms of chronic poisoning include two types of manifestations: those resulting from blood vessel contraction and reduced circulation – numbness and coldness of the extremities, tingling, pain in the chest, heart valve lesions, hair loss, decreased urination, and gangrene of the fingers and toes – and those resulting from nervous system disturbances – vomiting, diarrhea, headache, tremors, contractions of the facial muscles, and convulsions. Regular use of ergotamine in migraine headaches is also associated with a dependency syndrome characterized by severe chronic headache with an increase in headache intensity upon cessation of medication. Because most migraine headaches rarely occur more than once or twice a week, the presence of an almost daily migraine-type headache in individuals taking ergotamine is a good clue for ergotamine-rebound headache. Dosage of ergotamine can also be a clue. In most cases of ergotamine-rebound headache, individuals take weekly dosages in excess of 10 mg. In some cases, patients may be taking dosages as high as 10–15 mg daily. Stopping ergotamine causes predictable, protracted, and extremely debilitating headache usually accompanied by nausea and vomiting. These symptoms usually appear within 72 hours and may last for another 72 hours. Improvement after stopping the medication is very common. Ginger (discussed below) may lessen ergotamine withdrawal symptoms. Diet Food allergy/intolerance
There is little doubt that food allergy/intolerance plays a role in many cases of migraine headache. Many double-blind, placebo-controlled studies have demonstrated that the detection and removal of allergic/intolerant foods will eliminate or greatly reduce migraine symptoms in the majority of patients. What is unclear is the percentage of migraine patients for whom food control is the most important factor. Table 172.7 summarizes the results of several clinical studies. As can be seen, success ranges from 30 to 93%, with the majority of studies showing a remarkably high degree of success. [21] [22] [23] [24] [25] [26] [27] A possible explanation for the large difference between the results of Mansfield et al [21] and the others is that the Mansfield design was carefully selected for food allergy only, while the others included food intolerance. These studies found the incidence of food allergy to be similar for the three major types of migraine. The foods most
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TABLE 172-7 -- Food allergy/intolerance and migraine headache Percentage responding
Study
Method
Mansfield et al [21]
30
Elimination
Carter et al [22]
93
Oligoantigenic diet
Hughes et al [23]
80
Fasting, rotation, elimination
Egger et al[24]
93
Elimination
Monro et al[25]
70
RAST, elimination, sodium cromoglycate
Grant ECG[26]
85
Elimination
commonly found to induce migraine headaches are listed in Table 172.8 . The mechanism by which food allergy/intolerance induces a migraine attack is still unknown. Several theories have been proposed: • idiopathic response to a pharmacologically active substance, such as tyramine • monoamine oxidase deficiency • platelet phenolsulfotransferase deficiency; immunologically mediated food allergy • platelet abnormalities, etc.
TABLE 172-8 -- Foods which most commonly induce migraine headaches Egger et al [24] Hughes et al[23]
Food Cow’s milk
67%
57%
65%
Wheat
52
43
57
Chocolate
55
57
26
Monro et al[25]
Egg
60
24
22
Orange
52
–
13
Benzoic acid
35
–
–
Cheese
32
–
–
Tomato
32
14
–
Tartrazine
30
–
–
Rye
30
–
–
Rice
–
–
30
Fish
22
29 (shell)
17
Grapes
12
33
–
Onion
–
24
–
Soy
17
24
–
Pork
22
–
17
Peanuts
12
29
–
Alcohol
–
29
9
MSG
–
19
–
Walnuts
–
19
–
Beef
20
14
–
Tea
17
–
17
Coffee
15
19
17
Nuts
12
19 (cashew)
17
Goat’s milk
15
14
–
Corn
20
9
–
Oats
15
–
–
Cane sugar
7
19
–
Yeast
12
14
–
Apple
12
–
–
Peach
12
–
–
Potato
12
–
–
Chicken
7
14
–
Banana
7
–
–
Strawberry
7
–
–
Melon
7
–
–
Carrot
7
–
–
Egger et al[24] suggested that migraine headache may result from chronic alteration of the non-specific responsiveness of cerebral vascular end-organ as a result of long-term antigenic stimulation. This mechanism would be analogous to the response in asthma of the bronchioles to exercise or cold after antigen contact. Allergic reactions to foods are known to cause platelet degranulation, with resultant serotonin release. [27] There are several methods which can be used to detect food allergies, most of which are described in Chapter 15 . Although laboratory procedures are probably the most convenient for the patient, challenge testing is thought to be the most reliable. Unfortunately, challenge testing has limitations: some foods evoke a delayed response, which may require several days of repeated challenge to elicit recognizable symptoms; also, ingestion of large amounts of several foods may be necessary to detect those that are marginally reactive. The recommended procedure for the diagnosis and management of food allergy/ intolerance is described in the section on “Therapeutic approach” ( p. 1411 ). Dietary amines
Foods such as chocolate, cheese, beer and wine precipitate migraine attacks in many people because they contain histamine and/or other vasoactive compounds which can trigger migraines in sensitive individuals by causing blood vessels to expand (see Table 172.9 ). [28] [29] [30] Red wine is much more likely than white wine to cause a headache because it contains 20–200 times the amount of histamine and also stimulates the release of vasoactive compounds by platelets. [6] [29] [31] It is also much higher in flavonoids – the antioxidant components shown to help prevent heart disease. These compounds can also inhibit the enzyme (phenolsulfotransferase) which normally breaks down TABLE 172-9 -- Factors involved with histamine-induced headaches Histamine levels increased by: • Histamine in alcoholic beverages (particularly red wine) • Histamine in food • Histamine-releasing foods • Food allergy • Vitamin B6 deficiency Histamine breakdown inhibited by: • Vitamin B6 antagonists —alcohol —drugs —food additives (e.g. yellow dye #5, monosodium glutamate) • Vitamin C deficiency Histamine release prevented by:
• Di-sodium chromoglycate • Quercetin • Antioxidants (e.g. vitamin C, vitamin E, selenium, etc.) Histamine breakdown promoted by: • Vitamin B6 • Vitamin C
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serotonin and other vasoactive amines in platelets. Many migraine sufferers have been found to have significantly lower levels of this enzyme. [32] Since red wine contains substances which are potent inhibitors of this enzyme, it often triggers migraines in these individuals, especially if consumed along with high vasoactive amine foods like cheese or chocolate. The standard treatment of histamine-induced headache is the histamine-free diet along with vitamin B 6 supplementation.[29] [30] The activity of the enzyme diamine oxidase, which breaks down histamine in the lining of the small intestine before it is absorbed into the circulation, appears to play a major role in determining whether or not a person is going to react to dietary histamine. Individuals sensitive to dietary histamine have lower levels (about half) of this enzyme in their tissues compared with control subjects. [29] Diamine oxidase is a vitamin B 6 -dependent enzyme. Not surprisingly, compounds which inhibit vitamin B 6 also inhibit diamine oxidase. [29] These inhibiting factors include food coloring agents (specifically the hydrazine dyes like FD&C yellow #5), some drugs (isoniazid, hydralazine, dopamine, and penicillamine), birth control pills, alcohol, and excessive protein intake. Yellow dye #5 (tartrazine) is often consumed in greater quantities (per capita intake of 15 g/day) than the RDA for vitamin B 6 of 2.0 mg for males and 1.6 mg for females. Vitamin B6 supplementation (usually 1 mg/kg body weight) has been shown to improve histamine tolerance, presumably by increasing diamine oxidase activity. [29] [32] Women have lower levels of diamine oxidase which may explain their higher indicence of histamine-induced headaches. Women are also much more frequently unable to tolerate red wine. [29] Interestingly, the level of diamine oxidase in a woman increases by over 500 times during pregnancy. [33] [34] It is very common for women with histamine-induced headaches to experience complete remission of their headaches during pregnancy. Nutritional supplements 5-HTP
The role of 5-HTP in preventing migraine headaches by increasing serotonin levels was discussed above. In addi-tion to this mechanism of action, 5-HTP also increases endorphin levels. The use of 5-HTP in the prevention of migraine headache offers considerable advantages over drug therapy. Although a number of drugs have been shown to be useful in the prevention of migraine headaches, all of these currently used drugs carry with them significant side-effects. 5-HTP is at least as effective as other pharmacological agents used in the prevention of migraine headaches and is certainly much safer and better tolerated. While some studies have used a dosage of 600 mg/day, equally impressive results have been achieved at a dosage as low as 200 mg/day. The clinical studies with 5-HTP in migraine headaches are discussed in Chapter 92 . EFAs and arachidonic acid
The role of essential fatty acids in the pathogenesis of migraine may be quite important but does not appear to have received much research attention. Considering the significance of platelet aggregation and arachidonic acid metabolites in the mediation of the events leading to the prodromal cerebral ischemia of migraine, manipulation of dietary EFAs may be very useful. It has been well demonstrated that reducing the consumption of animal fats and increasing the consumption of fish will significantly change platelet and membrane EFA ratios and decrease platelet aggregation. [35] [36] [37] Riboflavin
Another hypothesis for explaining migraine headaches is that they are caused by a reduction of energy production within the mitochondria of cerebral blood vessels. If this hypothesis is true, riboflavin, which has the potential of increasing mitochondrial energy efficiency, might have preventive effects against migraine. To test this hypothesis, 49 patients suffering from migraine were treated with a very large dose (400 mg daily) of riboflavin for at least 3 months. [38] Overall improvement after therapy was 68.2% in the riboflavin group as determined by the migraine severity score used in the study. No side-effects were reported. The results from this preliminary study suggest high-dose riboflavin could be an effective, low-cost preventive treatment of migraine. Magnesium
Low magnesium levels may also play a significant role in many cases of headaches as several researchers have provided substantial links between low magnesium levels and both migraine and tension headaches based on both theory and clinical observations. [39] [40] [41] A magnesium deficiency is known to set the stage for the events that can cause a migraine attack as well as a tension headache. Low brain and tissue magnesium concentrations have been found in patients with migraines, indicating a need for supplementation since one of magnesium’s key functions is to maintain the tone of the blood vessels as well as preventing overexcitability of nerve cells.[39] [40] [41] [42] Unfortunately, two recent double-blind studies have given conflicting results in the prevention of migraines in people prone to recurrent migraine headaches. In the first study, 250 mg of magnesium or placebo was given twice daily to 69 patients (35 received magnesium, 34 the placebo) for 12 weeks. [43] The number of responders was
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10 in each group (28.6% under magnesium and 29.4% under placebo). There was no benefit with magnesium compared with placebo in the number of migraine days or migraine attacks. In the other double-blind study, 81 patients suffering from recurrent migraines were given either 600 mg of oral magnesium daily for 12 weeks or placebo. [44] By the ninth week, the attack frequency was reduced by 41.6% in the magnesium group compared with only 15.8% in the placebo group. The number of days with migraine and the drug consumption for symptomatic treatment per patient also decreased significantly in the magnesium group. Side-effects with magnesium supplementation included diarrhea (18.6%) and gastric irritation (4.7%). It appears that magnesium supplementation may only be effective in those individuals with low tissue or low ionized levels of magnesium. Low tissue levels of magnesium are common in patients with migraine, but most cases go unnoticed because most physicians rely on serum magnesium levels to indicate magnesium levels, a very unreliable indicator as most of the body’s store of magnesium lies within cells, not in the serum. A low magnesium level in the serum reflects end-stage deficiency. More sensitive tests of magnesium status are the level of magnesium within the red blood cell (erythrocyte magnesium level) and the level of ionized magnesium (the most biologically active form) in serum. Another possible benefit of magnesium in migraine sufferers may be its ability to improve mitral valve prolapse. Mitral valve prolapse is linked to migraines because it leads to damage to blood platelets, causing them to release vasoactive substances like histamine, platelet-activating factor, and serotonin. [7] [8] [9] Since research has shown that 85% of patients with mitral valve prolapse have chronic magnesium deficiency, magnesium supplementation is indicated. [45] This recommendation is further supported by several studies showing that oral magnesium supplementation improves mitral valve prolapse.
Magnesium bound to citrate, malate, aspartate, or some other Krebs cycle compound is better absorbed and better tolerated than inorganic forms, such as magnesium sulfate, hydroxide, or oxide, which tend to produce a laxative effect. [46] If magnesium produces a loose stool or diarrhea, advise the patient to cut back to a level that is tolerable. Also, it is a good idea to prescribe at least 50 mg of vitamin B 6 daily as this B vitamin has been shown to increase the intracellular accumulation of magnesium.[47] Intravenous magnesium for acute migraine headaches
Intravenous magnesium has been shown to be an extremely effective treatment in some cases of acute migraine, tension, and cluster headaches in three studies. A dosage of 1–3 g of intravenous magnesium (over a 10 minute period) typically resulted in a nearly 90% success rate in patients with low ionized magnesium levels. [48] [49] [50]
In the first study, the efficacy of intravenous infusion of 1 g of magnesium sulfate (MgSO 4 ) was evaluated in 40 patients (16 patients had migraines without aura, nine had cluster headaches, four had chronic tension-type headaches, and 11 had chronic migraine headaches). [48] Complete elimination of pain was observed in 32 (80%) patients within 15 minutes of infusion of MgSO 4 . No recurrence or worsening of pain was observed within 24 hours in 56% of the patients. Patients treated with MgSO4 observed complete elimination of migraine-associated symptoms such as sensitivity to light and sound as well as nausea. No side-effects were observed, except for a brief flushed feeling. The eight non-responders exhibited significantly elevated serum ionized magnesium levels compared with responders prior to the infusion of MgSO4 . In a study of migraine sufferers only, the hypothesis that patients with an acute attack of migraine headache and low serum levels (< 0.54 mmol/L) of ionized magnesium are more likely to respond to an intravenous infusion of magnesium sulfate (MgSO 4 ) than patients with higher serum ionized magnesium levels was tested.[49] Serum ionized magnesium levels were drawn immediately before infusion of 1 g of MgSO 4 in 40 consecutive patients with an acute migraine headache. Pain reduction of 50% or more, as measured on a headache intensity verbal scale of 1–10, occurred within 15 min of infusion in 35 patients. In 21 patients, at least this degree of improvement or complete relief persisted for 24 hours or more. Pain relief lasted at least 24 hours in 18 of 21 patients (86%) with serum ionized magnesium levels below 0.54 mmol/L, and in three of 19 patients (16%) with ionized magnesium levels at or above 0.54 mmol/L. The average ionized magnesium level in patients with relief lasting for at least 24 hours was significantly lower than that in patients with no relief or brief relief. The final study involved patients with cluster headaches. [50] Because previous studies reported that low serum ionized magnesium levels are common in patients with cluster headaches, researchers examined the possibility that patients with cluster headaches and low ionized magnesium levels may respond to an intravenous infusion of magnesium sulfate. Infusions of magnesium sulfate given to 22 patients with cluster headaches produced meaningful improvement in nine (41%) of them – not great numbers, but certainly worth the effort and certainly much safer than the drugs used in the treatment of acute cluster headaches such as ergotamine. Physical medicine Many forms of physical medicine have been used in the treatment of migraine headache. Although most have
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been shown to be effective in shortening the duration and decreasing the intensity of an attack, they appear relatively ineffective in actually curing this disorder. Although very effective for headaches which have a significant muscular contraction component, these methods appear to have more limited success in reducing the frequency of attacks of true migraine. Cervical manipulation
In a 6 month trial in Australia, 85 patients were studied to determine the efficacy of manipulation of the cervical spine by a chiropractor in the treatment of migraine headache. The study was controlled by comparing chiropractic manipulation with manipulation by a medical practitioner or physiotherapist and with simple cervical mobilization. Although the study found no difference in frequency of recurrence, duration, or disability, the chiropractic patients reported greater reduction in the pain associated with the attacks.[51] Temporomandibular joint dysfunction syndrome
Some researchers and clinicians have claimed that a substantial portion of headaches diagnosed as classic or common migraine are in reality the symptoms of temporomandibular joint dysfunction syndrome (TMJ). However, a careful investigation found that the incidence of migraine in patients with TMJ is similar to that in the general population, while the incidence of headache due to muscle tension is much higher. [52] These results suggest that, while correction of TMJ dysfunction may be of use in the treatment of migraine headaches, it is far more important in muscle tension headaches. Transcutaneous electrical stimulation
Transcutaneous electrical stimulation (TENS) has been shown in a placebo-controlled trial to be effective in the treatment of patients with migraine and muscle tension headaches (55% responded to treatment vs. an 18% placebo response). [53] However, the study also found that inappropriately applied TENS, i.e. TENS applied below perception threshold, was ineffective. Acupuncture
The use of acupuncture in the treatment of migraine headache has received considerable research attention. However, assessing its efficacy is difficult since the studies have not been blind, migraine patients were seldom studied separately, and most of the research has been reported in foreign languages, with only summaries available in English. Despite these limitations, sufficient evidence exists to support use of acupuncture to relieve migraine pain. [54] [55] [56] It is interesting to note that the mechanism of relief is apparently not endorphin-mediated. One study found that the injection of saline or naloxone did not affect the efficacy of the therapy, [57] and another found that, while acupuncture increased endorphin levels in controls, the low levels of serum endorphins found in migraine patients did not increase with treatment. [58] The mechanism of action may instead be through normalization of serotonin levels. One study found that acupuncture was effective in relieving pain when it normalized serotonin levels, but was ineffective in relieving pain and in raising serotonin levels in those patients with very low levels of serotonin. [59] Acupuncture appears to have some success in reducing the frequency of migraine attacks, although, as mentioned above, limitations in experimental design make interpretation difficult. One study found that 40% of the subjects experienced a 50–100% reduction in severity and frequency. [57] Although the authors used a double-blind, cross-over design, the patients were only followed for 2 months. Another (uncontrolled) study found that five treatments (over a period of 1 month) decreased recurrence in 45% of the patients over a period of 6 months. [60] Biofeedback and relaxation therapy
The most widely used non-drug therapy for migraine headaches is thermal biofeedback and relaxation training. Thermal biofeedback utilizes a feedback gauge to monitor the temperature of the hands. The patient is then taught how to raise (or lower) the temperature of the hand by the device providing feedback as to what is affecting the temperature. Relaxation training involves teaching patients techniques designed to produce the “relaxation response” – a term used to describe the physiological state that is the opposite of the stress response. This term was originally coined by Harvard professor and cardiologist Herbert Benson MD in his best-selling book, The relaxation response (William Morrow 1975). The effectiveness in reducing the frequency and severity of recurrent migraine headaches with biofeedback and relaxation training has been the subject of over 35
clinical studies. [61] When the results from these studies were compared with studies using the beta-blocking drug Inderal (propranolol), it was apparent that the non-drug approach was as effective as the drug approach, but was without side-effect (see Table 172.10 ). TABLE 172-10 -- Biofeedback/relaxation compared with propranolol – average percentage improvement per patient Biofeedback/relaxation 56.4% Propranolol
55.2%
Placebo
14.3%
Untreated
3.2%
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Botanical medicines Botanical medicines have a long history of use as folk cures for migraine headache. Although many botanicals have been used, few have received careful evaluation. Feverfew (Tanacetum parthenium) and ginger (Zingiber officinalis) are discussed here, as they have the most scientific documentation. Tanacetum parthenium
Perhaps the most popular preventive treatment of migraine headaches is the herb feverfew. Scientific interest in feverfew began when a 1983 survey found that 70% of 270 migraine sufferers who had eaten feverfew daily for prolonged periods claimed that the herb decreased the frequency and/or intensity of their attacks. [62] Many of these patients had been unresponsive to orthodox medicines. This survey prompted several clinical investigations of the therapeutic and preventive effects of feverfew in the treatment of migraine. [62] [63] [64] [65] The first double-blind study was done at the London Migraine Clinic, using patients who reported being helped by feverfew. [62] Those patients who received the placebo (and as a result stopped using feverfew) had a significant increase in the frequency and severity of headache, nausea, and vomiting during the 6 months of the study, while patients taking feverfew showed no change in the frequency or severity of their symptoms. Two patients in the placebo group who had been in complete remission during self-treatment with feverfew leaves developed a recurrence of incapacitating migraine and had to withdraw from the study. The resumption of self-treatment led to renewed remission of symptoms in both patients. The second double-blind study, performed at the University of Nottingham, demonstrated that feverfew was effective in reducing the number and severity of migraine attacks. [63] Follow-up studies to the clinical results have shown that feverfew works in the treatment and prevention of migraine headaches by inhibiting the release of blood vessel-dilating substances from platelets, inhibiting the production of inflammatory substances, and re-establishing proper blood vessel tone. [64] The effectiveness of feverfew is dependent upon adequate levels of parthenolide, the active principle. [65] Zingiber officinalis
The common ginger root has been shown to exert significant effects against inflammation and platelet aggregation. [66] [67] Unfortunately, in relation to migraine headache, there is much anecdotal information but little clinical evidence. For example, a 1990 article described a 42-year-old woman with a long history of recurrent migraines who discontinued all medications for a 3- month period prior to a trial of ginger. [68] For the trial, 500–600 mg of dried ginger was taken mixed with water at the onset of the migraine and repeated every 4 hours for 4 days. Improvement was evident within 30 minutes and there were no side-effects. The woman subsequently began to use uncooked fresh ginger in her daily diet. Migraines became less frequent and, when they did occur, they were at a “much lower intensity” than previously. There remain many questions concerning the best form of ginger and the proper dosage. The most active anti-inflammatory components of ginger are found in fresh preparations and the oil.
THERAPEUTIC APPROACH Migraine headache is a multifaceted disease, and indeed could be accurately described as a symptom rather than as a disease. The challenge for the clinician is to determine which of the several factors discussed here are responsible for each patient’s migraine process. Identification of the precipitating factors, and their avoidance, is important in reducing the frequency of headaches. Avoidance of initiators is particularly significant, considering that they are cumulative in effect. Due to the high incidence (80–90%) of food allergy/ intolerance in patients with migraine headache, diagnosis and management begins with 1 week of careful avoidance of all foods to which the patient may be allergic or intolerant. This can be accomplished through either a pure water fast or the use of an elemental diet (an oligoantigenic diet may be used but is less desirable, since significant allergens may be inadvertently included). All other possible allergens, e.g. vitamins, unnecessary drugs, herbs, etc., should also be avoided. During this procedure, food-sensitive patients will exhibit a strong exacerbation of symptoms early in the week, followed by almost total relief by the end of the fast/modified diet. This sequence is due to the addictive characteristic of the reactive foods. Once the patient is symptom-free, one new food is reintroduced (and eaten several times) each day while symptoms are carefully recorded. Some authors recommend reintroduction on a 4 day cycle. Suspected foods (symptom onset ranges from 20 minutes to 2 weeks) are eliminated, and apparently safe foods are rotated through a 4 day cycle (see Ch. 58 ). Once a symptom-free period of at least 6 months has been established, the 4 day rotation diet should no longer be necessary. Diet
As discussed above, all food allergens must be eliminated and a 4 day rotation diet utilized until the patient is symptom-free for at least 6 months. Foods containing
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vasoactive amines should initially be eliminated. After symptoms have been controlled they can be carefully reintroduced. The primary foods to eliminate are alcoholic beverages, cheese, chocolate, citrus fruits, and shellfish. The diet should be low in sources of arachidonic acid (land animal fats) and high in foods which inhibit platelet aggregation, e.g. vegetable oils, fish oils, garlic, and onion. Supplements
• Magnesium: 250–400 mg three times/day • Vitamin B6 : 25 mg three times/day • 5-HTP: 100–200 mg three times/day. Botanical medicines
• Tanacetum parthenium: 0.25–0.5 mg parthenolide twice daily • Ginger (Zingiber officinalis) —fresh ginger: approximately 10 g/day (6 mm slice) —dried ginger: 500 mg four times/day
—extract standardized to contain 20% of gingerol and shogaol 100–200 mg three times/day for prevention and 200 mg every 2 hours (up to six times daily) in the treatment of an acute migraine.
Physical medicine
• TENS to control secondary muscle spasm • Acupuncture to balance meridians • Biofeedback: The Association for Applied Psychophysiology and Biofeedback 10200 West 44th Avenue, Suite 304 Wheat Ridge, CO 80033 (303) 422-8436 • Guided imagery: The Academy for Guided Imagery PO Box 2070 Mill Valley, CA 94942 1-800-726-2070
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Chapter 173 - Multiple sclerosis Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Sudden, transient motor and sensory disturbances including impaired vision • Diffuse neurologic signs, with remissions and exacerbations • Diagnosis is made almost entirely on characteristic clinical presentation.
GENERAL CONSIDERATIONS The syndrome of progressive diffuse neurological disturbances occurring early in adult life, known as multiple sclerosis, has been recognized since its description by Charcot in 1868. Multiple sclerosis (MS) is an intriguing condition in that, despite considerable research, no coherent theory accounts for all the evidence about the epidemiology, etiology, and pathogenesis of MS. Mainstream medicine has focused on finding a viral etiology for this demyelinating disease, although most current work suggests immune disturbances and autoimmunity. The pathologic hallmark of the disorder consists of zones of demyelination (plaques) that vary in size and location. Symptoms correspond in a general way to the distribution of the plaques. This discussion attempts to encompass all relevant factors in the development and progression of this often debilitating illness. Epidemiology
In about two-thirds of the cases, onset is between ages 20 and 40 (rarely is the onset after 50) and women have a slight preponderance over males (60% female:40% male). One of the more interesting features of MS is the geographic distribution of the disease. Areas with the highest prevalence are all located in the higher latitudes, in both the northern and southern hemispheres (50–100 cases/100,000 vs. 5–10/100,000 in the tropics). These high-risk areas include the northern United States,
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Canada, Great Britain, Scandinavia, northern Europe, New Zealand, and Tasmania. There are interesting exceptions to this geographic distribution, as the disease is uncommon in Japan.[1] [2] It appears that the initial event in the development occurs in early life. This statement is based on the observation that people who move from a low-risk area to a high-risk area before age 15 acquire a high risk of developing MS, whereas those who make the same move after adolescence retain their low risk. [2] The incidence of MS appears to be increasing. There are many possible reasons for the geographic distribution of MS, such as solar exposure, genetics, diet, and other environmental factors. These are discussed below. Etiology The cause of MS remains to be definitively determined. Many causative factors have been proposed, but the data supporting these postulates are fragmentary and indirect. The following etiologies represent only a fraction of the possible explanations of the cause of MS. MS may be the epitome of a multifactorial disease. Virus infection
Viruses cause several demyelinating diseases in humans and animals that are quite similar to MS. The virus-associated demyelinating disease seen most commonly is postinfectious encephalomyelitis. This disease starts 10–40 days after an acute viral infection or after an immunization. Progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis are other human demyelinating diseases caused by the human papovavirus and the measles virus, respectively. In animals, many viruses are capable of producing demyelination. [1] [2] [3] The studies, when considered collectively, have clearly demonstrated that demyelination can occur as a result of viral infection. The demyelination may be direct viral lysis of the myelin-producing cells, or viral infection leading to autoimmunity. In addition, a viral infection may lead to alteration in the balance of suppressor to helper T-cells which may promote immune-mediated demyelination. This information has suggested to many researchers that MS has a viral etiology. However, the viruses that have actually been isolated from cultures of material from patients with multiple sclerosis most likely have represented contamination or were adventitious, rather than causal, agents. Isolated viruses include: [1] [2] [3] • rabies virus • herpes simplex virus • scrapie virus • parainfluenza virus • subacute myelo-opticoneuropathy virus • measles virus • coronavirus. Serological evidence has also pointed to several viruses, particularly the measles virus. As early as 1962, researchers reported that the sera of patients with multiple sclerosis had elevated measles antibody titers. Subsequent studies confirmed this association and also demonstrated that patients with MS had CNS synthesis of measles antibody. Based on this data, MS was at one time believed to be due to an ongoing measles infection. This view has been modified by more recent studies indicating that a high percentage of patients with MS have elevated cerebrospinal fluid antibody titers to two or more viruses. More importantly, studies have shown that the measles-specific antibody in MS patients accounts for only a small percentage of the total IgG. [1] [2] [3] The cerebrospinal fluid of most MS patients contains an elevated level of IgG, the electrophoretic pattern of which is characteristic of an infectious process. One hypothesis states that this pattern is in fact due to an unrecognized infectious agent that causes MS. This hypothesis has been termed the “sense antibody” hypothesis. An alternative hypothesis states that MS is not an infectious disease and that all the IgG in the CNS is non-specific or “non-sense antibody”. At present, the data available do not appear to support a common infectious agent as the antigen for the increased IgG. Hyperactivity of circulating B-cells during acute attacks is
thought to be the factor responsible for the excessive IgG production within the CNS. [1] [2] [3] Autoimmune reaction
The lesions of MS are mimicked by those of experimental allergic encephalomyelitis (EAE), an autoimmune disease induced in animals after immunization with myelin. However, in EAE, T-lymphocyte sensitivity is to a single antigen, i.e. myelin basic protein, while in MS, sensitivity to myelin basic protein cannot be demonstrated. This indicates that if MS is an autoimmune disease, it is due to some other antigen. Attempts to find an antigen to which only MS patients react have failed. [1] [2] A variety of immune system abnormalities have been reported in MS patients that would seem to support an autoimmune etiology. During acute episodes, suppressor T-cell levels have been shown to fall just prior to an attack and to rise when the attack ends. [1] [2] Loss of suppressor cell activity could permit a latent autoimmune condition to become active. However, if this were the case, evidence of other autoimmune diseases
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would be expected to manifest at this time as well. An alternative explanation is that the changes in the T-cell suppressor activity during acute attacks may be secondary to viral suppression. [1] Diet
Many researchers have attempted to correlate various dietary patterns and the geographic distribution of MS. Diets high in gluten [4] and milk[5] [6] are much more common in areas where there is a high prevalence of MS. As intriguing as these associations are, the majority of research concerning nutrition and MS has focused on the role that dietary fat plays in the epidemiology and etiology of MS. [7] [8] [9] [10] Some of the first investigations into diet and MS centered around trying to explain why inland farming communities in Norway had a higher incidence than areas near the coastline.[10] It was discovered that the diets of the farmers were much higher in animal and dairy products than the diets of the coastal dwellers, and the latter’s diet had much higher levels of cold-water fish. Since animal and dairy products are much higher in saturated fatty acids and lower in polyunsaturated fatty acids than fish, researchers explored this association in greater detail. Subsequent studies have upheld a strong association between a diet rich in animal and dairy products and the incidence of MS. [7] Epidemiologic evaluation based on 36 countries between 1983 and 1989 of the relationship between the mortality rates from multiple sclerosis showed that saturated fatty acids, animal fat, animal minus fish fat, and latitude correlated independently and positively with multiple sclerosis mortality. The ratio of polyunsaturated fatty acids to saturated fatty acids (P/S ratio) and the ratio of unsaturated fatty acids to saturated fatty acids correlated independently and negatively with multiple sclerosis mortality.[8] It is interesting to note that the incidence of MS is quite low in Japan, where consumption of marine foods, seeds, and fruit oil is quite high. These foods contain abundant polyunsaturated fatty acids, including the omega-3 oils (alpha-linolenic, eicosapentaenoic, and docosahexanoic acids). Deficiencies of the omega-3 oils are thought to interfere with lipid elongation and permanently impair formation of normal myelin. [11] Individuals with MS are thought to have a defect in essential fatty absorption and/or transport, which results in a functional deficiency state. In addition, consumption of saturated fats increases the requirements for the essential fatty acids, creating a relative deficiency state in some individuals. This is probably significant in patients with MS. The role of diet in the etiology and pathogenesis of MS is discussed further in “Therapeutic considerations” below. Excessive lipid peroxidation
Many studies have demonstrated reduced glutathione peroxidase (GSH-Px) activity in the erythrocytes and leukocytes of patients affected by multiple sclerosis. [12] [13] [14] [15] As GSH-Px is intricately involved in the protection of cells from free radical damage, decreased activity level would leave the myelinated sheath particularly sensitive to lipid peroxidation. GSH-Px is found in two forms, a selenium-dependent enzyme and a non-selenium-dependent enzyme. Since low-selenium areas often overlap high-prevalence areas for MS, it is natural to speculate that there may be a correlation between selenium levels, GSH-Px activity, and MS. Initial studies seemed to support this correlation. [12] [16] However, subsequent studies indicated that the reduced GSH-Px activity found in MS patients is independent of the selenium concentration and is probably due more to genetic factors. [13] [14] [15] There appears to be genetic polymorphism for GSH-Px. In patients with MS, there appears to be an increased occurrence in individuals who inherently possess low GSH-Px activity (GSH-PxL), compared with individuals who possess high GSH-Px activity (GSH-PxH). [13] These studies have utilized erythrocyte GSH-Px activity, but it is not known how this correlates with oligodendrocyte GSH-Px activity. A decreased GSH-Px activity in the myelin-producing cells would render these cells extremely susceptible to lipid peroxidation.
DIAGNOSTIC CONSIDERATIONS Multiple sclerosis is a difficult disease to diagnose early, when it is most effectively treated. The initial symptoms may occur alone or in combination, and they occur in varying frequencies (see Table 173.1 ). Typically, they develop over a few days, remain stable for a few weeks, and then recede. Recurrences are common, although the course of the disease is extremely variable. Although multiple sclerosis is diagnosed primarily TABLE 173-1 -- Early symptoms of multiple sclerosis Type
Frequency Symptoms
Motor
42%
Feeling of heaviness, weakness, leg dragging, stiffness, tendency to drop things, clumsiness
Sensory
18%
Tingling, “pins and needles” sensation, numbness, dead feeling, band-like tightness, electrical sensations
Visual
34%
Blurring, fogginess, haziness, eyeball pain, blindness, double vision
Vestibular
7%
Light-headedness, feeling of spinning, sensation of drunkenness, nausea, vomiting
Genitourinary 4%
Incontinence, loss of bladder sensation, loss of sexual function
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on clinical grounds, some laboratory procedures provide support for the diagnosis. These include measurement of components of the patient’s cerebral spinal fluid and evoked-potential studies. The concentration of IgG in the cerebral spinal fluid is elevated in 80–90% of patients with MS, and agarose electrophoresis reveals the presence of oligoclonal bands in 90%. Unfortunately, these abnormalities are not specific for MS. Assessment of nerve fiber conduction in the visual, auditory, and somatosensory pathways shows abnormalities in 94% of patients with established disease, and 67% of patients with suspected disease. During the past decade, magnetic resonance imaging has become a useful tool for assessing the level of lesions in the nervous system. Essential fatty acid analysis (see Ch. 13 ) for early recognition of lipid abnormalities will result in better therapeutic results, and aids in the determination of the efficacy of fatty acid supplementation.
THERAPEUTIC CONSIDERATIONS From a natural therapeutic standpoint, there appear to be three major approaches: • dietary therapy • nutritional supplements • physical therapy. Obviously, including all three provides the most comprehensive treatment plan. Diet The Swank diet
Dr Roy Swank, Professor of Neurology, University of Oregon Medical School, has provided convincing evidence that a diet low in saturated fats, maintained over a long period of time, tends to retard the disease process and reduce the number of attacks. [9] [17] Swank began successfully treating patients with his low-fat diet in 1948. Swank’s diet recommends:[9] [17] • a saturated fat intake of no more than 10 g/day • a daily intake of 40–50 g of polyunsaturated oils (margarine, shortening, and hydrogenated oils are not allowed) • at least 1 tsp of cod liver oil daily • a normal allowance of protein • the consumption of fish three or more times a week. A diet low in saturated fats significantly restricts many animal sources of protein. The patient will have to derive protein from other sources, e.g. legumes, grains, and vegetables. While meat consumption is contraindicated, fish appears to be particularly indicated due to its excellent protein content and, perhaps more importantly, its oil content. Cold-water fish such as mackerel, salmon, and herring are rich in the beneficial oils eicosapentaenoic and docosahexanoic acid (omega-3 oils). These oils are important in maintaining normal neural function and myelin production. [11] They are incorporated into the myelin sheath where they may increase fluidity and improve neural transmission. Swank’s diet was originally thought to help patients with MS by overcoming an essential fatty acid deficiency. Currently, it is thought that the beneficial effects are probably a result of: [18] [19] • decreasing platelet aggregation • decreasing an autoimmune response • normalizing the decreased essential fatty acid levels found in the serum, erythrocytes, and, perhaps most importantly, the cerebrospinal fluid in patients with MS. Swank’s diet significantly reduces the platelet adhesiveness and aggregation that is observed in atherosclerotic processes as well as in multiple sclerosis. Excessive platelet aggregation and microemboli are thought to result in the following abnormalities observed in MS: damage to the blood–brain barrier, alterations in the microcirculation of the CNS, spontaneous and induced subcutaneous hemorrhage, and cerebral ischemia. [20] [21] MS patients have been shown to have an abnormal blood–brain barrier, presumably as a result of excessive platelet adhesiveness and aggregation. [21] [22] Damage to the blood–brain barrier may allow the influx into the cerebral spinal fluid of plasma constituents, such as bacteria, viruses, antibodies, toxic chemicals, and other compounds, that are toxic to myelin. Ischemia may also be a contributing factor in demyelination, by promoting both the release of lysosomal enzymes and cellular death. [23] The effect of diet on platelets is important in MS, but probably of greater importance is the effect that fatty acids have on the activity of the immune system. Immunosuppressive compounds such as adrenal steroids, cyclophosphamide, and various antimetabolites have yielded good short-term benefits, but are of limited value due to their high risk and lack of demonstrable long-term efficacy. [1] [3] Currently, new immunosuppressive drugs are being tested for use in MS. However, considering the lack of toxicity, Swank’s dietary approach and supplementation with linoleic acid appear to be more appropriate and safer ways of modulating the immune response. Food allergy
The role of food allergies in the pathogenesis and treatment of MS has been popularized.
[ 24]
As mentioned earlier, the consumption of two common allergens,
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gluten and milk, has been implicated in the etiology of MS. Jejunal biopsy in a small group of MS patients indicated an increased frequency of significant villous atrophy similar to that which occurs in celiac disease and food allergies. [25] Clinical evidence for the efficacy of a gluten-free diet is, however, minimal. A clinical trial of a gluten-free diet in 40 patients with MS indicated that the relapse rate was no better than average. [26] Another study demonstrated the absence of gluten antibodies in 35 out of 36 MS patients. [27] While there is no convincing evidence that gluten-free or allergy elimination diets are universally beneficial in the management of MS, it certainly is generally healthful to eliminate food allergens (as long as other dietary measures are also included, i.e. the Swank diet), and there is anecdotal evidence that specific individuals have been helped. Nutritional supplements Linoleic acid
Linoleic acid supplementation for the treatment of MS has been investigated in at least three double-blind trials. [28] [29] [30] Although the results of the studies were mixed (two showed an effect and one did not), combined analysis indicated that patients supplementing with linoleic acid had a smaller increase in disability, and reduced severity and duration of relapses compared with controls. [31] [32] These studies used a sunflower seed oil emulsion at a sufficient dosage to provide a daily supplementation of 17.2 g of linoleic acid. Other vegetable oils which primarily contain linoleic acid include safflower and soy. Better results would probably have been attained in the double-blind studies if dietary saturated fatty acids had been restricted, larger amounts of linoleic acid had been used (at least 20 g/day), [29] and the studies had been of longer duration (one study found that normalization of erythrocyte fatty acid levels required at least 2 years of supplementation). [33] The effectiveness of linoleic acid supplementation in MS is thought to be due to immunosuppression. As mentioned earlier, MS bears a strong resemblance to experimental allergic encephalomyelitis (EAE), an autoimmune disease induced in animals by immunization with myelin. [34] [35] Linoleic acid has been shown to greatly inhibit the severity of EAE in animals with less severe forms of the disease, paralleling the effect of linoleic acid supplementation in humans with MS, i.e. individuals with minimal disability respond better than those with severe disability. Polyunsaturated free fatty acids are known to significantly influence cell-mediated immunity. [36] [37]
Evidence exists to show that the beneficial effects of essential fatty acid supplementation are mediated by prostaglandins and a splenic factor. Inhibitors of prostaglandin synthesis (such as aspirin and similar non-steroidal anti-inflammatory agents) and splenectomy have been shown to prevent the protective effect of linoleic acid in EAE. [38] [39] The spleen is considered to be the major site for the production and release of immunologically active prostaglandins. Non-steroidal anti-inflammatory agents and splenectomy should be avoided in patients with MS. If the effect of essential fatty acid supplementation is related to correcting the lipid composition of oligodendrocytes, Schwann cells, and other myelin-producing cells,
several years of supplementation may be required before complete therapeutic benefits are observed. Electrophoretic mobility studies of erythrocytes from subjects with MS indicate that treatment with unsaturated fatty acids must continue for at least 2 years before they regain normal reactivity. [33] Presumably, since myelin-producing cells have a much longer half-life than erythrocytes, it could take several years before the total benefit of supplementation would be observed. Flax and marine oils
Better results may be attained by using flaxseed oil, as this oil contains both linoleic and alpha-linolenic acid (an omega-3 oil). Linolenic acid has a greater effect on platelets [40] and is required for normal CNS composition. [11] [41] It has been suggested that gamma-linolenic acid, as found in evening primrose oil, is more effective than linoleic acid alone, due to its easier incorporation into brain lipids and its possibly greater effect on immune function. [42] However, due to its cost and the fact that relatively large amounts of the product would have to be consumed to exert a therapeutic effect, supplementation with evening primrose oil may not be indicated at this time. One study demonstrated that daily supplementation with only 340 mg of gamma-linoleic and 2.92 g of linoleic acid (the ratio found in evening primrose oil) had no effect on the clinical course in MS patients. [29] In the same study, those receiving 23 g of linoleic acid demonstrated reduced frequency and severity of acute attacks, even though the study was only 24 months long. There appears to be a strong rationale for supplementation with eicosapentaenoic acid (EPA) and DHA, the so-called “marine lipids”, in the treatment of MS, although no direct clinical investigation has been reported. EPA greatly inhibits platelet aggregation, [43] and DHA is present in large concentrations in lipids of the brain. [44] This is consistent with Swank’s protocol, which included the liberal consumption of fish and supplementation with cod liver oil, a rich source of EPA and DHA. [9] [17] Supplements may be used to increase EPA and DHA, particularly in areas where the availability of cold-water fish is limited.
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Selenium and vitamin E
Selenium’s role as the mineral portion of glutathione peroxidase is discussed above with regard to the increased lipid peroxidation observed in patients with MS. While selenium supplementation will not increase the activity of glutathione peroxidase in the majority of patients with MS, it is a relatively inexpensive supplement that may benefit some. Vitamin E supplementation is definitely indicated, due to the increased lipid peroxidation previously mentioned and the increased consumption of polyunsaturated fats, which increases vitamin E requirements. One study reported that supplementation of 18 MS patients with 6 mg/day of sodium selenite, 2 g/day of vitamin C, and 480 mg/day of vitamin E for 5 weeks increased GSH-Px fivefold.[44] Unfortunately, clinical parameters were not evaluated. Vitamin B12
Acquired deficiency of vitamin B 12 as well as inborn errors of metabolism involving this vitamin are well-known causes of demyelination of nerve fibers in the central nervous system (CNS). There are several reports in the medical literature that vitamin B 12 levels in the serum, red blood cells, and CNS are low in multiple sclerosis. The coexistence of a vitamin B 12 deficiency in MS may aggravate the disease or promote another cause of progressive demyelination. [45] [46] [47] Recently, researchers in Japan sought to clarify the state of vitamin B 12 metabolism in 24 Japanese patients with MS, and to determine if vitamin B 12 in massive doses provided any therapeutic benefit in chronic progressive MS. [48] The researchers found that the level of vitamin B 12 in the serum was normal, but that there was a significant decrease in the unsaturated vitamin B 12 binding capacities in the patients with MS, indicating a defect in the transport of vitamin B 12 into cells. In six patients with severe chronic progressive MS, the oral administration of 60 mg/day of vitamin B 12 (methylcobalamin) improved both visual and brain-stem auditory evoked potentials by nearly 30%. Motor function did not improve, indicating that afferent pathways benefit from vitamin B 12 while efferent pathways do not. The results produced are on a par with those produced by the combination of high-dose intravenous cyclophosphamide and steroids. However, while this drug combination is associated with profound immunosuppression and toxicity, no side-effects have been attributed to high doses of vitamin B 12 . The form of vitamin B12 used in this study was methylcobalamin rather than the standard cyanocobalamin. Hydroxocobalamin was tried in an earlier MS study with no apparent benefit. [49] Methylcobalamin is the main form in the body and is directly related to the function of vitamin B 12 in methylation reactions. Evaluation of vitamin B 12 in CSF and blood levels of 16 MS patients, 20–63 years of age (12 females), revealed that mean values in MS patients were significantly lower than in healthy subjects. Mean homocysteine levels in the serum and CSF in MS patients were significantly higher than in healthy subjects, an indication of impaired B12 nutriture (see Ch. 52 ). [50] However, another study of 38 patients with MS found no differences in the blood levels of B 12 or homocysteine.[51] They did not test CSF. Pancreatic enzymes
Like other autoimmune diseases, MS is associated with an increased level of circulating immune complexes. Experimental and clinical studies have shown that protease enzyme preparations are effective in reducing circulating immune complex levels in several of these diseases. Furthermore, clinical improvements correspond with decreases in immune complex levels. In the treatment of multiple sclerosis, pancreatic enzyme preparations have been shown to produce good effects in reducing the severity and frequency of symptom flare-ups. [52] Especially good results were noted in cases of visual disturbance, urinary bladder and intestinal malfunction, and sensory disturbances. However, it should be pointed out that little effect on spasticity, dizziness, or tremor was reported. Other considerations Malabsorption
A significant number of those with MS may have some degree of malabsorption. [25] [53] In one study, 42% of MS patients were shown to have fat malabsorption, 42% were shown to have high levels of undigested meat fibers in their feces, 27% had an abnormal D-xylose absorption, and 12% had malabsorption of vitamin B 12 .[53] Malabsorption appears to be an important factor to consider, since multiple subclinical deficiency may result. Physical therapy
The patient should be encouraged to lead as normal and active a life as possible. Exercise is physically and psychologically beneficial; however, the patient should avoid overwork and fatigue. Passive movement and massage are indicated for weakened spastic limbs, both for comfort and circulation. Natural alpha-interferon
Recombinant beta-interferon is emerging as a popular medical treatment for multiple sclerosis. However,
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naturally derived alpha-interferon from leukocytes may prove to be as (or more) advantageous. In three preliminary, sequential series conducted between 1987 and 1991, natural leukocyte alpha-interferon was evaluated in 49 multiple sclerosis patients. [54] In the study, patients received 5–30 million international units per week for 3–12 months and were observed for 2 years after their first injection. Although no major toxicity was observed, 13 of the 49 patients initially reported fatigue, flu-like
symptoms, or myalgias. These symptoms tended to abate after 1 month of treatment. In the first year, 80% of the patients improved or stabilized, and in the second year 76% remained improved or stabilized. Better results were seen with higher dosages for longer periods of time. The 83% remission rate in relapsing/remitting patients reported in this study is better than the 30% rate reported for beta-interferon. Further studies with larger patient populations using a double-blind format are needed. Ginkgo biloba
extract
The increased levels of lipid peroxides and other indicators of free radical damage in the central nervous system in patients with MS suggest the need for antioxidant support. [55] Ginkgo biloba extract (GBE) demonstrates impressive results as an antioxidant, exerts positive effects on platelet function, and has been shown to enhance nerve cell functions (see Ch. 88 ). This has now been assessed in a clinical study. This was a randomized, double-blind, placebo-controlled trial in 104 patients for 7 days. Forty-three received a placebo, 29 received 240 mg/day of ginkgolide B, and 32 received 360 mg/day of ginkgolide B. There was no statistically significant difference between the three groups for changes in functional scores. There was, however, a trend in favor of the groups treated with ginkgolide for a change of the Rankin AI scores. [56] While this study seems to demonstrate that ginkgo is not of value for acute exacerbations, it is of far too short a duration to evaluate the value of ginkgo for MS. [56] Hyperbaric oxygen
Early reports described promising results from the use of hyperbaric oxygen (HBO) in the treatment of MS. [57] [58] [59] However, these reports were largely anecdotal or from uncontrolled clinical trials. In 1970, one study reported a small, transient improvement in 16 of 26 patients treated with HBO. [57] Another small study, in 1978, reported an improvement in 11 patients treated with HBO. [58] One year later, a large study found minimal to dramatic improvement in 91% of 250 patients treated with HBO.[59] Several other researchers published similarly encouraging results. The first double-blind, placebo-controlled trial of HBO indicated an apparently beneficial effect in the treatment of MS. [60] Objective improvement was noted in 12 of 17 in the study group, compared with only one of 20 in the placebo group. Although the improvements were mild and transient in most of the patients, it appeared that patients with milder forms of MS and a shorter duration of disease derived a more pronounced and longer-lasting benefit. This was an encouraging preliminary study, yet it was criticized for its small sample and short follow-up period. Subsequently, the Multiple Sclerosis Society commissioned further trials to be performed on a larger number of subjects, with longer periods of follow-up. [61] [62] The results showed no significant improvement, apart from a subjective improvement in bowel and bladder functions in one of the studies. The results from these larger well-designed studies cast substantial doubt on the efficacy of HBO treatment of MS. Recently, a study was published which evaluated the results of 14 controlled trials of hyperbaric oxygen treatment. Of the eight trials considered of reasonably high quality, only one showed favorable results. The patients in the trials had chronic progressive or chronic stable multiple sclerosis. In most of the trials, hyperbaric oxygen was supplied at pressures of 1.75–2 ATA during 20 sessions of 90 minutes over a period of 4 weeks. Side-effects were generally minor but included ear and visual problems. [63] Oral antigen therapy
Perhaps the most exciting new therapy for MS is oral antigen therapy. Because of the striking similarity between the clinical and histopathological features of MS and the experimentally induced disease, experimental autoimmune encephalomyelitis (EAE) researchers began studying oral administration of myelin basic protein (MBP) in humans. EAE is induced by the injection of adjuvants. Oral administration of MBP has been shown to exert a profoundly suppressive effect on EAE induced in the rats.[64] This MBP-induced oral tolerance is characterized by an inhibition of EAE clinical neurologic signs, reduced CNS histopathologic changes, a significant decrease in the T-lymphocyte proliferative response specific for the fed antigen, and a decrease in serum antibody specific for MBP. Preliminary results in humans look equally impressive. [65] However, at this time oral antigen therapy of MS is still in the investigational phase. Hopefully these preliminary results will be confirmed in subsequent studies. Exercise
Whereas in the past conventional physicians cautioned against exercise, it has now been shown to significantly
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improve fitness and have a positive impact on qualityof-life factors of multiple sclerosis patients. In an interesting study, 54 MS patients were assigned to either an exercise or a non-exercise group for 15 weeks. Aerobic training consisted of three 40 minute sessions per week of combined arm and leg ergometry. The exercise group improved in all measures of physical function, social interaction, emotional behavior, home management, total sickness impact profile score and recreation. There was no benefit on fatigue score. [66] Electromagnetic fields
Extracerebral applications of picotesla low-frequency electromagnetic fields have been suggested as a way of rapidly reversing the conduction blocks in demyelinating fibers. Reversal of the conduction block is believed to change the axonal sodium and potassium channels and synaptic nerve transmitter release, which may account for the immediate improvement in vision and other neurologic deficits reported in MS patients following this therapy. [67] While this therapy may have value (immediate improvements in fine and large muscle control, speech, balance, fatigue, body image, cataplexy, and mood), evaluation is impossible at this time as all the published reports are small in number (one to five patients), uncontrolled, authored by a single clinician, and published in a single journal.
THERAPEUTIC APPROACH Treatment of MS with diet, lifestyle modification, and supplementation should begin as soon as possible, as the earlier in the disease process this therapy is initiated, the better the results will be. Several non-specific measures are important, including avoidance of excessive fatigue, emotional stress, and marked temperature changes. The natural therapy of MS, while not proven to be highly effective, will help, and poses no threat to the patient’s health. In fact, it is quite healthful, since the recommendations decrease the risk of atherosclerosis and other degenerative diseases. However, once MS has progressed to significant disability, it is unlikely to be affected to any great degree by these measures. Diet
Swank’s dietary protocol is recommended: • saturated fat intake should be no more than 10 g/day • daily intake of polyunsaturated oils should be 40–50 g (margarine, shortening, and hydrogenated oils are not allowed) • normal amounts of protein are recommended • fish should be eaten three or more times per week. Fresh whole foods should be emphasized and animal foods (with the exception of cold-water fish) should be reduced, if not completely eliminated.
Supplements
• EPA: 1.8 g/day; or flaxseed oil: 1 tbsp/day • Selenium: 200 mcg/day • Vitamin E: 800 IU/day • Vitamin B12 (methylcobalamin): 60 mg/day • Pancreatin (10X): 350–700 mg three times/day (on an empty stomach). Botanical medicines
• Ginkgo biloba extract (24% ginkgo flavonglycosides): 40 to 80 mg three times/day.
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Chapter 174 - Nausea and vomiting of pregnancy Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Morning or evening nausea and vomiting occurring during the first trimester of pregnancy.
GENERAL CONSIDERATIONS Many physiologic and psychogenic mechanisms have been proposed to explain the high incidence of nausea and vomiting during pregnancy (morning sickness). It has been estimated that 50% of women complain of these symptoms at some time during pregnancy. Considering the multitude of hormonal and metabolic changes which occur during pregnancy, the existence of these symp-toms is not surprising; nonetheless, emotional factors undoubtedly contribute to the perceived, and actual, severity of the nausea and vomiting. Effective psychological support is paramount to any effective metabolic therapy.
THERAPEUTIC CONSIDERATIONS Pyridoxine
Vitamin B6 is often recommended in the treatment of nausea and vomiting of pregnancy. A pyridoxine deficiency, coupled with estrogen-mediated alterations in tryptophan metabolism, may be the etiologic factor in many cases of nausea and vomiting of pregnancy (for further discussion, see Ch. 183 ). Support for the use of vitamin B 6 in nausea and vomiting of pregnancy in the medical literature prior to the 1990s consisted primarily of uncontrolled studies in the 1940s.[1] [2] In 1979, the American Medical Association Council on Drugs went so far as to say that “there was no solid evidence that vitamin B 6 is effective against nausea”. Two double-blind studies in the 1990s appear to provide the necessary support for this popular (and seemingly effective) recommendation to pregnant women. In the first study, 59 women were randomly assigned to receive either 25 mg of vitamin B 6 every 8 hours or a
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placebo. After 72 hours, only eight of 31 B 6 treated patients had nausea compared with 15 of 28 in the placebo group. [3] In the other, more recent, double-blind study, 342 pregnant women (less than 17 weeks gestation) were randomized to receive either 30 mg of vitamin B 6 or placebo in a double-blind fashion. [4] Patients graded the severity of their nausea by a visual analog scale and recorded the number of vomiting episodes over the previous 24 hours before treatment and again during five consecutive days on treatment. Compared with the placebo group, there was a statistically significant reduction in nausea scores and vomiting episodes. Vitamin B 6 was recommended as a first-line treatment of nausea and vomiting of pregnancy. Although a positive effect was reported in the trial, the results were not all that impressive. More than one-third of the patients still experienced vomiting and significant nausea with B 6 supplementation. Perhaps a larger dosage would have been more effective. Or perhaps ginger is a better recommendation (alone or in combination with vitamin B6 ). Vitamins K and C
Vitamins K and C, when used together, have shown considerable clinical efficacy, with 91% of patients in one study showing complete remission within 72 hours. The mechanism for this effect is unknown, and both vitamins administered alone show little effect.
[5]
Zingiber officinale (Ginger)
Ginger has a long tradition of being very useful in alleviating the symptoms of gastrointestinal distress, including the nausea and vomiting typical of pregnancy. Although the mechanism of action has yet to be elucidated, current thought is that it is due more to its aromatic and carminative effects on the gastrointestinal tract than to any CNS effects.[6] Ginger’s anti-emetic actions have been studied in hyper-emesis gravidum, the most severe form of pregnancy-related nausea and vomiting. This condition usually requires hospitalization. In a double-blind, randomized cross-over trial, ginger root powder at a dose of 250 mg four times a day brought about a significant reduction in both the severity of the nausea and the number of attacks of vomiting in 19 of 27 cases of early pregnancy (less than 20 weeks). [7] These clinical results, along with the safety and the relatively small dose of ginger required and the problems (e.g. teratogenicity) with anti-emetic drugs in pregnancy, support the use of ginger in nausea and vomiting in pregnancy. This recommendation is becoming a well-accepted prescription even in orthodox obstetrical practices: ginger (as well as vitamin B6 ) was recommended as an effective treatment of early nausea and vomiting of pregnancy. Psychological aspects
Many studies have been performed in an attempt to understand why 50% of normal women experience no nausea and vomiting during pregnancy and why in some women this symptom continues beyond the first trimester.[8] Although many theories have been proposed, the lack of consistent data has hampered the development of a widely accepted viewpoint. There appears to be general agreement that mild symptoms of nausea and vomiting during the first trimester have a strong physiological basis (linked to hormone changes during pregnancy) and are predictive of positive pregnancy adjustment and outcome. More serious or longer-lasting symptoms are thought more likely to have a psychological component. A prospective study of 86 pregnant women showed a significant increase in both nausea and vomiting in the first trimester in women who reported more unplanned, undesired pregnancies and negative relationships with their own mothers. Those with problems continuing into the third trimester were also significantly more negative in their assessment of their relationships with their mothers. [9] Acupressure
A prospective, controlled clinical trial examined the efficacy of acupressure therapy for morning sickness, using a two-group, random assignment, cross-over design. Subjects in group 1 (n = 8) used acupressure wristbands for 5 days, followed by 5 days without therapy. Subjects in group 2 ( n = 8) had no therapy for 5 days, followed by 5 days’ use of wristbands. The Multiple Affect Adjective Checklist and Sickness Impact Profile were used, and extent of nausea was assessed at baseline, day 5, and day 10. Use of acupressure wristbands relieved morning sickness for 12 of 16 subjects. Acupressure therapy also resulted in statistically significant ( P < 0.05) reductions in anxiety, depression, behavioral dysfunction, and nausea. [10]
THERAPEUTIC APPROACH Diet
• Small, frequent meals • Dry toast immediately after rising. Supplements
• Vitamin B6 : 25 mg two to three times/day • Vitamin C: 250 mg two to three times/day • Vitamin K: 5 mg/day.
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Botanical medicines
Zingiber officinale (Ginger). There remain many questions concerning the best form of ginger and the proper dosage. Most research studies have utilized 1 g of dry powdered ginger root, a relatively small dose. For example, ginger is commonly consumed in India at a daily dose of 8–10 g. Furthermore, although most studies have used powdered ginger root, fresh (or possibly freeze-dried) ginger root or extracts concentrated for gingerol at an equivalent dosage may yield even better results. In the treatment of nausea and vomiting of pregnancy, a dosage of 1–2 g of dry powdered ginger or as a decoction may be effective. For ginger extracts standardized to contain 20% gingerol and shogaol, an equivalent dosage would be 100–200 mg. Counseling
Women who are having an unplanned or undesired pregnancy or who report a poor relationship with their own mother should be referred to a qualified counselor for assistance in resolving these conflicts.
REFERENCES 1. Gaby
A. The doctor’s guide to B 6 . Emmaus, PA: Rodale Press. 1984: ch. 3
2. Weinstein
B, Wohl Z, Mitchell M et al. Oral administration of pyridoxine hydrochloride in the treatment of nausea and vomiting of pregnancy. Am J Ob Gyn 1944; 47: 389–394
3. Sahakian
V, Rouse D, Sipes S et al. Vitamin B 6 is effective for nausea and vomiting of pregnancy. A randomized, double-blind placebo-controlled study. Obstet Gynecol 1991; 78: 33–36
4. Vutyananich
T, Wongtra-ngan S and Rung-aroon R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 1995; 173:
881–884 5. Merkel
R. The use of menadione bisulfite and ascorbic acid in the treatment of nausea and vomiting of pregnancy. Am J Ob Gyn 1952; 64: 416–418
6. Mowrey
D and Clayson D. Motion sickness, ginger, and psychophysics. Lancet 1982; i: 655–657
7. Fischer-Rasmussen 8. Wolkind
S, Zajicek E. Psycho-social correlates of nausea and vomiting in pregnancy. H Psychosom Res 1978; 22: 1–5
9. FitzGerald
10.
W, Kjaer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 1990; 38: 19–24
CM. Nausea and vomiting in pregnancy. Br J Med Psycho 1984; 57: 159–165
Hyde E. Acupressure therapy for morning sickness. A controlled clinical trial. J Nurse Midwifery 1989; 34: 171–178
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Chapter 175 - Obesity Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY Obesity is defined as: • Being greater than 10% above “normal” weight • Having a body fat percentage greater than 30% for women and 25% for men.
GENERAL CONSIDERATIONS According to the results of The National Health and Nutrition Examination Survey III, the frequency of obesity (defined as greater than 20% above the ideal weight for height) in adults living in the United States is now greater that one in three. [1] Even more alarming is the number of obese children – the number doubled from 1960 to 1991.[2] This situation is serious as the odds are 4:1 against a child ever achieving normal weight as an adult if they enter their teenage years obese, and 28:1 if they end their teenage years obese. Obesity is such a problem for American adults as most eat a diet high in fat and sugar, and are physically inactive. Increased television viewing and decreased physical activity are thought to be primary causes of the growing number of obese children. [2] Obesity defined
The simplest definition of obesity is an excessive amount of body fat. It must be distinguished from overweight, which refers to an excess of body weight relative to height. A muscular athlete may be overweight, yet have a very low body fat percentage. With this in mind, it is obvious that using body weight alone as an index of obesity is not entirely accurate. Nonetheless, obesity is classically identified as being of a weight greater than 20% more than the average desirable weight for men and women of a given height (see the Metropolitan Life tables in Ch. 44 ). In terms of body fat percentage, obesity is defined as a body fat percentage greater than 30% for women and 25% for men. [1]
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TABLE 175-1 -- Indirect methods of analyzing body fat composition • Visual observation (somatotypes) —anthropometric measurements —height and weight —circumferences and diameters —skinfold thickness • Isotope or chemical dilution • Body water • Body potassium • Body fat • Body density and body volume • Conductivity • Total body electrical conductivity • Bioelectric impedance • Neutron activation • Imaging techniques • Ultrasound • Computer tomography • Nuclear magnetic resonance • Nuclear magnetic spectroscopy
DETERMINATION OF BODY COMPOSITION The significance of accurately determining body fat composition and classifying obesity cannot be overstated as it offers valuable monitoring, prognostic, and therapeutic information. Since direct analysis of body composition cannot at this time be performed on live subjects, indirect methods must be employed, such as those listed in Table 175.1 . Visual observation Superficial visual observation is often all that is required for a qualitative analysis of obesity. One popular way of classifying body types is somatotyping, a physical anthropological classification of physique based on body size and proportion: • The endomorph has a relatively large body and short arms and legs.
• The mesomorph has a large muscular chest that dominates over the abdomen and has prominent bony joints. • The ectomorph has a relatively small frame (a slender and delicate bone structure) and long arms and legs. The endomorph is at greatest risk of developing obesity, the mesomorph is at moderate risk, and the ectomorph is extremely unlikely to develop obesity. The distribution of body fat is also important in the classification of obesity. Two basic distribution patterns exist: gynecoid and android or female and male patterned obesity. These types are discussed in greater detail under “Classification of obesity” ( p. 1431 ). Anthropometric measurements Anthropometric measurements involve measurements of height and weight, various body circumferences or diameters (waist, chest, or hip circumferences and distances between the ileac crests, greater trochanters or acromioclavicular joints), and skinfold thickness. Height and weight
Height and weight indices are the most common measurements made in the determination of obesity. The indices in widest use are the tables of desirable weights for height provided by the Metropolitan Life Insurance Company (see Ch. 44 ). The Metropolitan tables are often criticized for three major shortcomings: • the stated weight ranges merely reflect the weights of those with lowest mortality of insured persons, which may not reflect the US population • weight ranges for lowest mortality do not necessarily reflect optimal healthy weight for height • the standard values make it difficult to assess degree of obesity, e.g. a person within the proper weight range may have excess body fat and lower than optimal lean body mass, or an individual with increased muscular development may be “overweight” despite having a low body fat percentage. Again, it is important to recognize that weight alone is a poor reflector of body fat composition. In addition to the Metropolitan table, the Fogarty table of desirable weights for height is also widely used. It is simply a modification of the Metropolitan data, i.e. it represents an adaptation of the table in which the mean weight for the medium frame size is used as a reference point, with acceptable body weight ranging between the lowest level for the small frame and the highest level for the large frame. Body mass indices
Body mass indices (BMIs) are often calculated for more precise estimates of adiposity. A number of body mass indices have been developed from weight and height measurements. The most popular BMIs include the weight–height ratio (W/H), Quetelet index (W/H 2 ), Khosla-Lowe index (W/H 3 ), and Benn index (W/H P ). These indices are widely used in large epidemiologic and health investigations due to the simplicity of their computation and their cost-effectiveness. The Quetelet index is the most widely accepted method and generally correlates well with skinfold thickness measurements of body fat (see below). Quetelet’s index, W/H 2 (W = weight in kg; H = height in meters), has been found to have the least correlation with body height and the highest correlation with independent measures of body fatness. [3] [4] A Quetelet value of 27 or greater
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for either sex is indicative of obesity, while a score of between 24 (for females) or 25 (for males) and 27 is considered to indicate that the person is overweight. It should be kept in mind, once again, that measures of relative weight are generally unable to distinguish between adiposity, muscularity, and edema, but the Quetelet index correlates well with hydrostatic and skinfold measurements. Skinfold thickness
The amount of total body fat can be estimated by measuring the thickness of the subcutaneous fat (skinfold or fatfold thickness). Skinfold thickness is measured with skinfold calipers at several sites on the body to improve accuracy. The most common measurement sites are the triceps, biceps, subscapular, and suprailiac skinfolds. While skinfold thickness measurements are easy to obtain and are generally accurate in estimating body fat percentage, there are some limitations, including the inability to control inter- and intra-subject variation in skinfold compressibility, the inability to palpate the fat–muscle interface, and the impossibility of obtaining interpretable measurements on very obese individuals. Additionally, interobserver variability, as well as the use of different types of skinfold calipers, may contribute to measurement errors. However, for most clinical purposes, skinfold measure-ments provide the easiest and least expensive method for estimating body fat percentage. For more precise estimations, other methods (e.g. bioelectrical impedance, ultrasound, total body electrical conductivity [TOBEC], and hydrostatic weighing) offer significant advantages. Body density Measurement of body density provides a quantitative technique for measuring body fat. Density is determined from the specific gravity, which is calculated through measuring the different weight of the body in and out of water. In this procedure, individuals are weighed under water and out of water, taking into account the residual volume of the lungs. This information is used to fractionate the body into its fat and non-fat components, since fat is lighter than water and other tissues are heavier than water. The method is relatively easy if appropriate facilities are available. However, with the advent of more sophisticated body composition analyzers, the procedure has generally fallen out of favor, although many experts still consider it to be the “gold standard” of body composition determination. The major limitation of hydrostatic weighing is that it requires considerable subject cooperation. The test subject must exhale completely and then submerge totally under water up to 10 times, making the method impossible for use with the elderly, the ill, or hospitalized patients. Bioelectric impedance The bioelectrical impedance method for determining body composition is based on measuring the conduction of an applied electrical current through body tissues. In biological structures, application of a constant low-level alternating current results in an impedance to the flow of the current that is frequency-dependent, according to the type of tissue. Intracellular and extracellular fluids behave as electrical conductors, while the cell membranes act as electrical condensers. At low frequencies, such as 1 kHz, the current mainly passes through the extracellular fluids, whereas at higher frequencies, such as 500–800 kHz, it penetrates the intra- and extracellular fluids. Thus body fluids and electrolytes function as electrical conductors, while cell membranes behave as capacitors. Since fat-free mass has a much greater conductivity than does fat, there is a strong relationship between conductance and lean body mass. Body composition analysis, as determined by bioelectrical impedance, is a safe non-invasive procedure that provides rapid measurement. Home scales equipped with bioelectrical impedance units to assess body fat percentage at the same time as weight are now available. These scales typically cost between $150 and $200.
TYPES OF OBESITY Obesity is divided into several different categories based on the size and number of fat cells and also on how the fat is distributed in the body (e.g. in the abdomen
versus the hips). Hyperplastic obesity
In hyperplastic obesity, there is an increased number of fat cells throughout the body. The number of fat cells that a person has is primarily dependent on the diet of the mother while the person was still in the womb as well as early infant nutrition. An excess of calories during these early stages of development can lead to the formation of an increased number of fat cells for the rest of the baby’s life. Because it is harder to develop new fat cells in adulthood, hyperplastic obesity usually begins in childhood. Fortunately, hyperplastic obesity tends to be associated with fewer serious health effects compared with other types of obesity. Hypertrophic obesity is characterized by an increase in the size of each individual fat cell and is linked to diabetes, heart disease, high blood pressure, and other serious disturbances of metabolism. [5] Usually with hypertrophic obesity the fat distribution is around the waist. This fat cell distribution is referred to as male-patterned
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or android since it is typically seen in the obese male. If the waist is larger than the hips, a person is said to have android obesity. If the hips are larger, then a person has female-patterned or gynecoid obesity. In hyperplastic–hypertrophic obesity there is an increase in both the number and size of fat cells.
CAUSES OF OBESITY There are basically two areas on which to focus in trying to understand what causes obesity: psychological factors and physiological factors. Psychological factors In the past, psychological factors were thought largely responsible for obesity. A popular theory proposed that overweight individuals were insensitive to internal signals for hunger and satiety while simultaneously being extremely sensitive to external stimuli (sight, smell, and taste) which can increase the appetite. One source of external stimuli that has definitely been shown to be associated with obesity is watching television. Watching television has been demonstrated to be linked to the onset of obesity, and there is a dose-related effect. In addition to leading to childhood obesity, [5] television viewing also contributes to being overweight in adults. In one study of 4,771 adult women, the relationship between time spent watching television per week and obesity demonstrated that twice as many women who reported 3 or more hours of television viewing per day were obese compared with the reference group of women who watched less than 1 hour of television per day. [6] Although watching television fits very nicely with the psychological theory (increased sensitivity to external cues), there are also several physiological effects of watching televison that promote obesity, such as reducing physical activity and the actual lowering of resting (basal) metabolic rate to a level similar to that experienced during trance-like states. These factors clearly support the physiological view. Physiological factors While the psychological theories primarily propose that obese individuals have a decreased sensitivity to internal cues of hunger and satisfaction, an emerging theory of obesity states almost the opposite: obese individuals appear to be extremely sensitive to specific internal cues. [4] The physiological theories of obesity are tied to: • brain serotonin levels • diet-induced thermogenesis • the activity of the sympathetic nervous system • the metabolism of the fat cells • sensitivity to the hormone insulin. All of these models (discussed below) support the theory that obesity is not just a matter of overeating, and explain why some people can consume very large quantities of calories and not increase their weight substantially, while for others just the reverse is true. The low serotonin theory
A considerable body of scientific evidence demonstrates that brain serotonin plays a major role in influencing eating behavior. Much of the initial research was conducted at the Massachusetts Institute of Technology by Judith Wurtman PhD and her husband, Richard Wurtman PhD. These pioneers in brain chemistry have made many valuable contributions to the understanding of the effects of amino acids (including melatonin) on mood and behavior. The Wurtmans and other researchers have shown that when animals and humans are fed diets deficient in tryptophan, appetite is significantly increased, resulting in binge eating of carbohydrates. [7] [8] The diet low in tryptophan leads to low brain serotonin levels, a condition the brain interprets as starvation, resulting in the stimulation of the appetite control centers. This stimulation results in a preference for carbohydrates. Feeding animals or humans a carbohydrate meal leads to increased tryptophan delivery to the brain, resulting in the elevated manufacture of serotonin. This scenario has led to the idea that low serotonin levels leads to “carbohydrate craving” and plays a major role in the development of obesity. Furthermore, it has been demonstrated that concentrations of tryptophan in the bloodstream and subsequent brain serotonin levels plummet with dieting. [9] In response to severe drops in serotonin levels, the brain simply puts out such a strong message to eat that it cannot be ignored. This situation sets up the scenario to explain why most diets do not work. Cravings for carbohydrate due to low serotonin levels can be very mild or quite severe. They may range in severity from the desire to nibble on a piece of bread or a cookie to uncontrollable binging. At the upper end of the spectrum of carbohydrate addiction is bulimia, a potentially serious eating disorder characterized by binge eating and purging of the food through forced vomiting or the use of laxatives. The medical consequences of bulimia can be quite severe, e.g. rupture of the stomach, erosion of the dental enamel, and heart disturbances due to loss of potassium. The set point theory
The “set point” is the weight that a body tries to maintain by regulating the amount of food and calories consumed. Research with animals and humans has found that
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each person has a programmed “set point” weight. [4] It has been postulated that individual fat cells control this set point: when the fat cell becomes smaller, it sends a powerful message to the brain to eat. Since the obese individual often has both more and larger fat cells, the result is an overpowering urge to eat. The existence of this set point helps to explain why most diets do not work. While the obese individual can fight off the impulse to eat for a time, eventually the signal becomes too strong to ignore. The result is rebound overeating with individuals often exceeding their previous weight. In addition, their set point is now set at a higher level, making it even more difficult to lose weight. This effect has been termed the “ratchet effect” and “yo-yo dieting”. The set point seems to be tied to fat cell insulin sensitivity. When cells become insensitive to insulin, not only is transport of blood sugar (glucose) into the cells
impaired, but there is also impaired burning of fat for energy. Both obesity and diabetes are strongly linked to the Western diet, presumably due to the negative effects saturated fats and refined carbohydrates have on internal mechanisms that control blood sugar levels (see Ch. 147 ). The key to overcoming the fat cell’s set point appears to be increasing the sensitivity of the fat cells to insulin. This sensitivity apparently can be improved, and the set point lowered, by exercise, a specially designed diet, and several nutritional supplements which are discussed below. The set point theory suggests that a diet that does not improve insulin sensitivity will most likely fail to provide long-term results. Increasing the body’s sensitivity to insulin results in less insulin being secreted. This effect is very important as elevated insulin levels increase the transport of fatty acids into fat cells and, when the fat cells are replete with high levels of fat, triggers the body to manufacture more fat cells. While the body is able to add new fat cells, it is impossible to reduce the number of existing fat cells via natural means. The set point of the fat cells not only predisposes an individual to be overweight, it also leads to an increased susceptibility to gain weight following weight loss, due to the ratchet effect. It is this physiology that is largely responsible for the “ratchet effect” and “yo-yo dieting”; however, the loss of muscle mass (the prime burner of fat in the body) caused by dieting is also a factor. Diet-induced thermogenesis
A certain amount of excess consumed calories is converted immediately to heat, a process labeled “diet-induced thermogenesis”. There is some evidence that the level of diet-induced thermogenesis determines an individual’s susceptibility to weight gain. In lean individuals a meal may stimulate up to a 40% increase in heat production. In contrast, overweight individuals often display only a 10% or less increase in heat production. The excess food energy is stored instead of being converted to heat. [10] A major factor for the decreased thermogenesis in overweight people is, once again, insulin insensitivity. to re-establishing normal thermogenesis as well as resetting the set point in overweight individuals.
[11]
Therefore, enhancing insulin sensitivity may go a long way
Another cause of the decreased thermogenesis in overweight individuals is impaired sympathetic nervous system activity. described below, can activate the sympathetic nervous system, thereby increasing the metabolic rate and thermogenesis.
[12]
Several natural plant stimulants,
Researchers have also shown that even after weight loss has been achieved, individuals predisposed to obesity will still have decreased diet-induced thermogenesis compared with a lean individual. [13] It is therefore important to continue to support insulin sensitivity and proper metabolism indefinitely if weight loss is to be maintained. In addition to insulin insensitivity and reduced sympathetic nervous system activity, another factor determines diet-induced thermogenesis – the amount of brown fat. Most fat in the body is “white fat”, consisting of an energy reserve containing triglycerides stored in a single compartment. Tissue composed of white fat will look white or pale yellow. Brown fat cells contain multiple fat storage compartments. The triglycerides are localized in smaller droplets surrounding numerous mitochondria. An extensive blood vessel network and the density of the mitochondria give the tissue its brown appearance as well as its increased capacity to metabolize fatty acids. [14] Brown fat does not metabolize fatty acids to ATP as efficiently as other tissues of the body, including white fat. This inefficiency results in increased heat produc-tion. Brown fat plays a major role in diet-induced thermogenesis. Some theories suggest that lean people have a higher ratio of brown fat to white fat than overweight individuals. There is evidence to support this theory. The amount of brown fat in modern humans is extremely small (estimates are 0.5–5% of total body weight), but because of its profound effect on diet-induced thermogenesis, as little as 1 ounce of brown fat (0.1% of body weight) could make the difference between maintaining body weight or putting on an extra 10 pounds/year. [14] Lean individuals also tend to respond differently to excess calories than overweight individuals. In one experiment, lean individuals were overfed to increase their weight. In order to maintain the excess weight, they had to increase their caloric intake by 50% over their previous intake. [15] The opposite appears to be the
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case in overweight and formerly overweight individuals. In addition to requiring fewer calories to gain and maintain their weight, studies have shown that in order to maintain a reduced weight, formerly obese persons must restrict their food intake to approximately 25% less than a lean person of similar weight and body size. [16] Individuals predisposed to obesity because of decreased diet-induced thermogenesis have been shown to be extremely sensitive to marked weight gain when consuming a high-fat diet compared with lean individuals. [17] These individuals are not only more sensitive to the weight gain-promoting effects of a high-fat diet, they tend to consume much more dietary fat than lean individuals and they tend to exercise less.
THERAPEUTIC CONSIDERATIONS Long-term, successful control of obesity is one of the greatest clinical challenges. Few people want to be overweight, yet only 5% of markedly obese individuals are able to attain and maintain “normal” body weight, while 66% of those just a few pounds or so overweight are able to do the same. The successful program for obesity is consistent with the basic foundations of good health – a positive mental attitude, a healthy lifestyle (especially important is regular exercise), a health-promoting diet, and supplementary measures. All of these components are interrelated, creating a situation where no single component is more important than the other. Improvement in one facet may be enough to result in some positive changes, but impacting all components yields the greatest results. There are literally hundreds of diets and diet programs that claim to be the answer to the problem of obesity. Dieters are constantly bombarded with new reports of a “wonder” diet to follow. However, the basic equation for losing weight never changes. In order for an individual to lose weight, energy intake must be less than energy expenditure. This goal can be achieved by de-creasing caloric intake or by increasing the rate at which calories are metabolized. To lose 1 pound, a person must consume 3,500 fewer calories than he or she expends. The loss of 1 pound each week requires a negative caloric balance of 500 calories/day. This can be achieved by decreasing the amount of calories ingested or by exercise. Reducing a person’s caloric intake by 500 calories is often difficult, as is increasing metabolism by an additional 500 calories/day by exercise (accomplished by a 45 minute jog, playing tennis for an hour, or a brisk walk for 1.25 hours). The most sensible approach to weight loss is to both decrease caloric intake and increase energy expenditure through exercise. Most individuals will begin to lose weight if they decrease their caloric intake below 1,500 calories/day and do aerobic exercise for 15–20 minutes three to four times per week. Starvation and crash diets usually result in rapid weight loss (largely muscle and water), but cause rebound weight gain. The most successful approach to weight loss is gradual weight reduction (0.5–1 pound/week) through adopting long-standing dietary and lifestyle habits that promote health and the attainment and maintenance of ideal body weight. There are several natural weight loss aids that can be very useful in helping either to reduce appetite or to enhance metabolism. In decreasing order of efficacy, we rate these items as follows: • 5-hydroxytryptophan • thermogenic formulas • fiber supplements • chromium • medium-chain triglycerides • hydroxycitrate • coenzyme Q10
• thyroid hormone. 5-HTP
Over two decades ago, researchers demonstrated that administering 5-HTP to rats who were genetically bred to overeat and be obese resulted in a significant reduction in food intake. [6] Further research revealed that these rats have decreased activity of tryptophan hydroxylase, which converts tryptophan to 5-HTP, itself subsequently converted to serotonin. In other words, these rats are fat as a result of a genetically determined low level of activity of the enzyme that starts the manufacture of serotonin from tryptophan. As a result, these rats never get the message to stop eating until they have consumed far greater amounts of food than normal rats. There is much circumstantial evidence that many humans are genetically predisposed to obesity. This predisposition may involve the same mechanism as rats genetically predisposed to obesity, i.e. decreased conversion of tryptophan to 5-HTP and, as a result, decreased serotonin levels. By providing preformed 5-HTP, this genetic defect is bypassed and more serotonin is manufactured. (For a complete discussion of this interesting nutrient, see Ch. 92. ) The early animal studies with 5-HTP as a weight loss aid have been followed by a series of three human clinical studies in overweight women. [18] [19] [20] The first study showed that 5-HTP was able to reduce calorie intake and promote weight loss despite the fact that the women made no conscious effort to lose weight. [18] The average amount of weight loss during the 5 week period of 5-HTP supplementation was a little more than 3 pounds. The second study sought to determine if 5-HTP helped overweight individuals adhere to dietary recommendations.
[19]
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TABLE 175-2 -- Impact of 5-HTP on weight loss Placebo 5-HTP group Weight (pounds) Baseline
207.68
229.46
After 6 weeks
206.58
225.94
After 12 weeks
205.4
219.12
After 6 weeks
1.1
3.52
After 12 weeks
2.28
10.34
Total weight loss (pounds)
The 12 week study was divided into two 6 week periods. For the first 6 weeks there were no dietary recommendations, and for the second 6 weeks the women were placed on a 1,200 calorie diet. As shown in Table 175.2 , the women taking the placebo lost 2.28 pounds, while the women taking the 5-HTP lost 10.34 pounds. Like the previous study, 5-HTP appeared to promote weight loss by promoting satiety, leading to fewer calories being consumed at meals. Every women taking 5-HTP reported early satiety. The third study with 5-HTP was similar to the second study: for the first 6 weeks there were no dietary restrictions, and for the second 6 weeks the women were placed on a diet of 1,200 calories/day. [20] The group receiving the 5-HTP lost an average of 4.39 pounds after the first 6 weeks and an average of 11.63 pounds after 12 weeks. In comparison, the placebo group lost an average of only 0.62 pounds after the first 6 weeks and 1.87 pounds after 12 weeks. The lack of weight loss during the second 6 week period in the placebo group obviously reflects the fact that the women had difficulty adhering to the diet. Early satiety was reported by 100% of the subjects during the first 6 week period. During the second 6 week period, even with severe caloric restriction, 90% of the women taking 5-HTP reported early satiety. Many of the women receiving the 5-HTP (300 mg three times daily) reported mild nausea during the first 6 weeks of therapy. However, the symptom was never severe enough for any of the women to drop out of the study. No other side-effects were reported. Thermogenic formulas
When properly combined, plant stimulants like ephedrine and caffeine can activate the sympathetic nervous system, thereby increasing the metabolic rate and diet-induced thermogenesis. This results in weight loss by helping to normalize a possible underlying defect in metabolism. These formulas must be used in a rational manner and not abused, as they are not panaceas, not for everyone, and may induce side-effects. Although ephedrine has demonstrated an appetite-suppressing effect, its main mechanism for promoting weight loss appears to be increasing the metabolic rate of adipose tissue. [21] [22] Its weight-reducing effects are greatest in those individuals with a low basal metabolic rate and/or decreased diet-induced thermogenesis. The thermogenic effects of ephedrine can be enhanced by methylxanthines. Botanicals rich in these active ingredients can be used in a similar fashion to the isolated principles. Good methylxanthine sources include coffee ( Coffea arabica), tea (Camellia sinensis), cola nut (Cola nitida), and guarana (Paullinea cupana). The optimum dosage of the crude plant preparation or extract depends on their content of active constituents. Standardized preparations may produce more dependable results. Although more recent studies have used a daily dosage of 60 mg of ephedrine and 600 mg of caffeine, these high dosages may not be necessary. [21] [22] [23] [24] [25] [26] In one study, a daily dosage of 22 mg ephedrine, 30 mg caffeine and 50 mg theophylline was shown to greatly increase the basal metabolic rate and diet-induced thermogenesis.[27] One of the key benefits of thermogenic formulas appears to be their ability to promote fat breakdown and not loss of lean muscle mass. For example, in one study of 16 obese women on a weight-reducing diet given either a combination of ephedrine (20 mg) and caffeine (200 mg) twice daily or a placebo, no real significant differences in overall weight loss were demonstrated. [28] However, upon closer examination it was determined that the ephedrine–caffeine group lost 9.9 pounds more body fat and 6.16 pounds less lean body mass compared with the placebo group. These results indicate that ephedrine and caffeine combinations promote fat loss and preserve lean body mass during weight reduction diets. As an added bonus, subjects in the study taking the ephedrine–caffeine combination had higher energy levels and burned more calories than the placebo group. Although effective, these formulations are not without side-effects. Thermogenic formulas containing ephedrine and caffeine combinations can produce increased blood pressure, increased heart rate, insomnia, and anxiety. The FDA advisory review panel on non-prescription drugs recommended that ephedrine should not be taken by patients with heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate. In addition, ephedrine should not be used by patients on antihypertensives or antidepressants. There is tremendous variation in the response to ephedrine and caffeine. Some people can tolerate high levels quite easily while others (most likely with slow liver phase I detoxification – see Ch. 16 ) are extremely sensitive to the CNS stimulatory effects. The side-effects reported in the studies using a daily dosage of 60 mg of ephedrine and 600 mg of caffeine tend to decrease with time, suggesting tolerance or
1436
induction of liver phase I detoxification. Although at week 4, 60% of subjects taking the ephedrine–caffeine combination typically reported side-effects such as dizziness, headache, insomnia, heart palpitations, and headache, by week 8 the rate of side-effects was substantially reduced to the same as the placebo group. A significant concern with this dosage schedule is an elevation of blood pressure. Surprisingly, systolic and diastolic blood pressure actually decreased, indicating that the effect of weight loss more than compensated for any increase in blood pressure caused by the ephedrine and caffeine. Blood glucose, triglycerides, and cholesterol levels also decreased with weight loss and were not affected by ephedrine and caffeine. Fiber supplements
Increasing the amount of dietary fiber promotes weight loss. The best fiber sources for weight loss are psyllium, chitin, guar gum, glucomannan, gum karaya, and pectin, because they are rich in water-soluble fibers. When taken with water before meals, these fiber sources bind to the water in the stomach to form a gelatinous mass which induces a sense of satiety. As a result, individuals will be less likely to overeat. The benefits of fiber go well beyond this mechanical effect, however. Fiber supplements have been shown to enhance blood sugar control, decrease insulin levels, and reduce the number of calories absorbed by the body. [29] In some of the clinical studies demonstrating weight loss, fiber supplements were shown to reduce the number of calories absorbed by 30–180 calories/day. While modest, this reduction in calories would, over the course of a year, result in a 3–18 pound weight loss. There are two important recommendations to make to patients to assist their choice of fiber supplements: • avoid products that contain a lot of sugar or other sweeteners to camouflage the taste • be sure to drink adequate amounts of water when taking any fiber supplement, especially if it is in a pill form. The most impressive results in weight loss studies have been achieved with guar gum, a water-soluble fiber obtained from the Indian cluster bean ( Cyamopsis tetragonoloba) (see Table 175.3 ). In one study, nine women weighing between 160 to 242 pounds were given 10 g of guar gum immediately before lunch and dinner. They were told not to consciously alter their eating habits. After 2 months, the women reported an average weight loss of 9.4 pounds. Reductions were also noted for cholesterol and triglyceride levels. [30] Studies with soluble fiber in the treatment of elevated cholesterol levels have shown a dose-dependent effect. [29] Dietary fiber supplements appear to exert a dose-dependent effect in weight loss studies as well. Therefore, to achieve the greatest benefit, the dosage should be as high as possible. As water-soluble fibers are fermented by intestinal bacteria, a great deal of gas can be produced, leading to increased flatulence and abdominal discomfort. Advise the patient to start out with a dosage between 1 and 2 g before meals and at bedtime and gradually increase the dosage to 5 g. Chromium
One of the key goals for enhancing weight loss is to increase the sensitivity of the cells throughout the body to insulin. Chromium plays a key role in cellular sensitivity to insulin. Chromium has lately gained a great deal of lay attention as an aid to weight loss. The importance of this trace mineral in human nutrition was not discovered until 1957 when it was shown that it was essential to proper blood sugar control. Although there is no recommended dietary allowance (RDA) for chromium, health requires a dietary intake of at least 200 mcg/day.
Fiber
No. of subjects
Length of study
TABLE 175-3 -- Clinical studies with dietary fiber supplements Dosage Calorie Average weight loss (fiber, (g/day) restriction lbs)
Guar
9
2 months
20
None
9.4
No placebo group
30
Guar
7
1 year
20
None
61.9
No placebo group
31
Guar
21
2.5 months
20
None
15.6
No placebo group
32
Guar
33
2.5 months
15
None
5.5
0.9 lbs in placebo group
33
Glucomannan 20
2 months
3
None
5.5
Weight gain of 1.5 lbs
34
Glucomannan 20
2 months
3
None
8.14
0.44 lbs in placebo group
35
Citrus Pectin
14
4 weeks
5.56
Yes
12.8
No placebo group
36
Mixture A
60
12 weeks
5
Yes
18.7
14.7 lbs in placebo group
37
Mixture A
89
11 weeks
10
Yes
13.9
9.2 lbs in placebo group
38
Mixture B
45
3 months
7
Yes
13.6
9 lbs in placebo group
39
Mixture B
97
3 months
7
Yes
10.8
7.3 lbs in placebo group
40
Mixture B
52
6 months
7
Yes
12.1
6.1 lbs in placebo group
41
Average weight loss (placebo)
Reference
Mixture A = 80% fiber from grains, 20% fiber from citrus; mixture B = 90% insoluble and 10% soluble fiber from beet, barley, and citrus fibers.
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Chromium levels can be depleted by refined sugars, white flour products, and lack of exercise. [42] In some clinical studies in diabetics, supplementing the diet with chromium has been shown to decrease fasting glucose levels, improve glucose tolerance, lower insulin levels, and decrease total cholesterol and triglyceride levels, while increasing HDL-cholesterol levels. [43] Obviously chromium is a critical nutrient in diabetes, but it is also very important in hypoglycemia. In one study, eight female patients with hypoglycemia given 200 mcg/day for 3 months demonstrated alleviation of their symptoms.[44] In addition, glucose tolerance test results were improved and the number of insulin receptors on red blood cells were increased. Chromium supplementation has been demonstrated to lower body weight yet increase lean body mass, presumably as a result of increased insulin sensitivity. [45] In one study, patients were given chromium bound to picolinic acid (chromium picolinate) in one of three doses daily for 2.5 months: placebo, 200 mcg, or 400 mcg. [46] Patients taking the 200 and 400 mcg doses lost an average of 4.2 pounds of fat. The group taking the placebo lost only 0.4 pounds. Even more impressive was the fact that the chromium groups gained more muscle (1.4 vs. 0.2 pounds) than those taking the placebo. The results were most striking in elderly subjects and in men. The men taking chromium picolinate lost more than seven times the amount of body fat as those taking the placebo (7.7 vs. 1 pound). The 400 mcg dose is more effective than the 200 mcg dose (see Table 175.4 ). The results of these preliminary studies with chromium are encouraging. Particularly interesting is the fact that in these initial studies chromium picolinate promoted an increase in lean body weight percentage, as it led to fat loss but also to muscle gain. [47] Greater muscle mass means greater fat burning potential. All of the effects of chromium appear to be due to increased insulin sensitivity. There is evidence that marginal chromium deficiency is quite common in the United States. Chromium supplementation will often not only improve blood sugar control, but also lower cholesterol and triglyceride levels. [48] There are several forms of chromium available on the market. Chromium picolinate, chromium polynicotinate, chromium chloride, and chromium-enriched yeast are each touted by their respective suppliers to provide the greatest benefit. There is no firm evidence to indicate that one is a significantly better choice than another, although there was one small study of six women and six men given either 400 mcg of chromium picolinate or chromium polynicotinate. The test subjects were
enrolled in an aerobics class for 3 months. Those taking the chromium picolinate increased muscle mass by three times as much as those taking chromium polynicotinate (women: 4 vs. 1.3 pounds; men: 4.6 vs. 1.5 pounds). [22] Medium-chain triglycerides
Medium-chain triglycerides (MCTs) are saturated fats (extracted from coconut oil) that range in length from 6 to 12 carbon chains. MCTs are used by the body differently from the long-chain triglycerides (LCTs) which are the most abundant fats found in nature. LCTs are the storage fats for both humans and plants that range in length from 18 to 24 carbons. This difference in length makes a substantial difference in how MCTs and LCTs are metabolized. Unlike regular fats, MCTs appear to promote weight loss rather than weight gain. MCTs may promote weight loss by increasing thermogenesis. [49] In contrast, the LCTs are usually stored in the fat deposits, and since their energy is conserved, a high fat diet tends to decrease the metabolic rate. In one study, the thermogenic effect of a high calorie diet containing 40% fat as MCTs was compared with one containing 40% fat as LCTs. [50] The thermogenic effect (calories wasted 6 hours after meal) of the MCTs was almost twice as high as the LCTs – 120 vs. 66 calories. The researchers concluded that the excess energy provided by fats in the form of medium-chain triglycerides would not be efficiently stored as fat, but rather would be wasted as heat. A follow-up study demonstrated that MCT oil given over a 6 day period can increase diet-induced thermogenesis by 50%. [50] In another study, researchers compared single meals of 400 calories composed entirely of MCTs or LTCs. [51] The thermic effect of MCTs over 6 hours was three times greater than that of LCTs. In addition, while the LCTs elevated blood fat levels by 68%, MCTs had no effect on the blood fat level. Researchers concluded that substituting MCTs for LCTs would produce weight loss as long as the calorie level remained the same. In order to gain the benefit from MCTs, a diet must remain low in LCTs. MCTs can be used as an oil for salad dressing, a bread spread, or simply taken as a supplement. A good dosage recommendation for MCTs is 1–2 tablespoons/day.
Dosage
TABLE 175-4 -- Effects of 200 vs. 400 mcg/day for 2.5 months Fat loss Muscle gain
Total weight loss
200 mcg chromium picolinate
-3.3 lbs
+1.5 lbs
-1.8 lbs
400 mcg chromium picolinate
-4.6 lbs
+1.1 lbs
-3.5 lbs
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Diabetics and individuals with liver disease should be monitored very closely when using MCTs as they may develop ketoacidosis. Hydroxycitrate
Hydroxycitrate is a natural substance isolated from the fruit of the Malabar tamarind ( Garcinia cambogia). The Malabar tamarind is a yellowish fruit that is about the size of an orange, with a thin skin, and deep furrows similar to an acorn squash. It is native to southern India where it is dried and used extensively in curries. The dried fruit contains about 30% hydroxycitric acid. Hydroxycitrate has been shown to be a powerful lipogenic inhibitor in animals. [52] [53] Whether or not it demonstrates this effect in humans has not yet been proven. The weight loss-promoting effects in animals are perhaps best exemplified in a study that shows hydroxycitrate producing a “significant reduction in food intake, and body weight gain” in rats. [54] Hydroxycitrate may not only be a powerful inhibitor of fat production; it may also suppress appetite. It is critical when using a hydroxy-citrate formula that a low-fat diet be maintained as it only inhibits the conversion of carbohydrates into fat. By itself, hydroxycitrate may offer a safe, natural aid for weight loss when taken at a dosage of 500 mg three times daily. However, combining it with chromium and a thermogenic formula should produce a greater effect because in addition to inhibiting the production of fat, fat catabolism would increase. Coenzyme Q 10
Coenzyme Q10 is an essential compound required in the transport and breakdown of fatty acids into energy. Clinical studies have shown that CoQ 10 may help to promote weight loss. For example, in one study CoQ 10 levels were found to be low in 52% (14 of 27) of overweight subjects tested. [55] Nine subjects (five with low CoQ10 levels, and four with normal levels) were given 100 mg/day of CoQ 10 along with a low-calorie diet. After 9 weeks, mean weight loss in the CoQ 10 -deficient group was 29.7 pounds, compared with 12.8 in those with initially normal levels of CoQ 10 .
THERAPEUTIC APPROACH A successful program for weight loss must be consistent with the four cornerstones of good health: • proper diet • adequate exercise • a positive mental attitude • the right support for the body through natural measures. All of these components are critical and interrelated. Diet
Follow the recommendations given in Chapter 44 . Psychological support
Consider referral for counseling. The overweight individual tends to suffer a great deal of assaults on their self-esteem and self-image. Lifestyle
Exercise is absolutely critical to an effective weight loss program. Follow the recommendations given in Chapter 38 . Supplements
Follow the recommendations given in Chapter 44 . • 5-HTP: begin at 50–100 mg 20 minutes before meals for 2 weeks and then double the dosage (to a maximum of 300 mg) if weight loss is less than1 pound/week. Higher dosages of 5-HTP (e.g.300 mg) are associated with nausea, but this symptom disappears after 6 weeks of use • Chromium: 200–400 mcg/day • Medium-chain triglycerides: incorporate 1–2 tbsp into the diet • Hydroxycitrate: 500 mg three times/day
• Coenzyme Q10 : 100–300 mg/day. Botanical medicines
Combinations of an ephedrine source such as Ephedra sinica with a methylxanthine source such as coffee (Coffea arabica), tea (Camellia sinensis), cola nut (Cola nitida), or guarana (Paullinea cupana) can be used at a dosage to provide 20–30 mg/day of ephedrine and 80–100 mg/day of methylxanthines.
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Chapter 176 - Osteoarthritis Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Clinical symptoms– mild early-morning stiffness, stiffness following periods of rest, pain that worsens on joint use, and loss of joint function • Clinical signs – local tenderness, soft tissue swelling, joint crepitus, bony swelling, restricted mobility, Heberden’s (proximal interphalangeal joints) and/or the less common Bouchard’s (distal interphalangeal joints) nodes, and other signs of degenerative loss of articular cartilage • X-ray findings – narrowed joint space, osteophytes, increased density of subchondral bone, subchondral sclerosis, bony cysts, soft tissue swelling, and periarticular swelling.
GENERAL CONSIDERATIONS Osteoarthritis or degenerative joint disease is characterized by joint degeneration, loss of cartilage, and alterations of the subchondral bone. The most common form of arthritis, osteoarthritis (OA) probably has the highest morbidity rate of any illness. [1] Although primarily seen in the elderly, there is a 35% incidence in the knee as early as age 30 (often diagnosed as chondromalacia patellae). [2] Its incidence increases dramatically with age. Surveys have indicated that over 40 million Americans have osteoarthritis, including 80% of persons over the age of 50. Under the age of 45, osteoarthritis is much more common in men, while after age 45 it is much more common in women.[1] Table 176.1 TABLE 176-1 -- Diseases thought to be osteoarthritis of specific joints Joint
Disease
Hands
Heberden’s and Bouchard’s nodes
Hip
Malum coxae sinilis
Temporomandibular Costen’s syndrome Knee
Chondromalacia patellae
Spine
Ankylosing hyperostosis (interstitial skeletal hyperostosis)
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lists some of the diseases which are now thought to be osteoarthritis of specific joints. The weight-bearing joints and peripheral and axial articulations are the joints principally affected by the degenerative changes associated with osteoarthritis. There is much hyaline cartilage destruction followed by hardening and the formation of large bone spurs (calcified osteophytes) in the joint margins. Pain, deformity, and limitation of joint motion result from this degeneration. Inflammation is usually minimal. [1] Osteoarthritis is divided into two categories, primary and secondary. In primary osteoarthritis, the degenerative “wear-and-tear” process occurs after the fifth and sixth decades, with no apparent predisposing abnormalities. The cumulative effects of decades of use lead to the degenerative changes by stressing the collagen matrix of the cartilage. Damage to the cartilage results in the release of enzymes that destroy collagen components. With aging, the ability to restore and synthesize normal collagen structures decreases. [1] [2] [3] Secondary osteoarthritis is associated with some predisposing factor which is responsible for the degenerative changes. Predisposing factors in secondary osteoarthritis include: • congenital abnormalities in joint structure or function (e.g. hypermobility and abnormally shaped joint surfaces) • trauma (obesity, fractures along joint surfaces, surgery, etc.) • crystal deposition • presence of abnormal cartilage • previous inflammatory disease of joint (rheumatoid arthritis, gout, septic arthritis, etc.). The many factors involved in the pathogenesis of OA are summarized in Table 176.2 .
DIAGNOSIS The onset of osteoarthritis can be subtle. Morning joint stiffness is often the first symptom. As the disease progresses, there is pain on motion of the involved joint that is made worse by prolonged activity and relieved by rest. There are usually no signs of inflammation. [1] TABLE 176-2 -- Multifactorial etiology of osteoarthritis • Hypermobility/joint instability • Age-related changes in collagen matrix repair mechanisms • Hormonal and sex factors • Altered biochemistry • Genetic predisposition • Inflammation • Fractures and mechanical damage • Inflammatory joint disease • Acromegaly
• Others
The specific clinical picture varies with the joint involved. Disease of the hands leads to pain and limitation of use. Knee involvement produces pain, swelling, and instability. Osteoarthritis of the hip causes local pain and a limp. Spinal osteoarthritis (which is very common) may result in compression of nerves and blood vessels, causing pain and vascular insufficiency. [1] The classic presentation of OA is easy to distinguish from other arthritides, especially rheumatoid arthritis which is usually associated with much more inflammation of surrounding soft tissues. After a detailed medical history and physical examination, the best diagnostic tool to confirm the diagnosis of osteoarthritis is an X-ray of the suspected joint. The classic finding in joints affected with osteoarthritis is joint space narrowing, loss of cartilage, and the presence of bone spurs (osteophytes). [1] Important causes of misdiagnosis of osteoarthritis are given in Table 176.3 . Pain One of the most interesting clinical features of osteoarthritis is the lack of correlation between severity of osteoarthritis as determined by X-ray and the degree of pain. In some cases the joint will appear normal, with little if any joint space narrowing, yet the pain can be excruciating. Conversely, there are cases where there TABLE 176-3 -- Important causes of misdiagnosis of osteoarthritis The source of the pain is not osteoarthritis, but: • Arthritis of other origin • Pathological changes of the adjacent bone (tumor, osteomyelitis, metabolic bone disease, etc.) • Mechanical injuries • Pathological fractures • Referred pain of neuritis, neuropathy, or radiculopathy • Other neurological disorders causing stiffness of joints The source of the pain is osteoarthritis, but not at the joint suspected • OA of the hip, pain localized to the knee • OA of the cervical spine, causing pain in the shoulder • OA of the lumbar spine, causing pain in the hip, knee, or ankle • OA of the shoulder, causing pain in the elbow The source of pain is caused by secondary soft tissue alterations of OA • Tendonitis or ligamentitis (especially of the knee) • Enthesopathy, tendinopathy, due to joint contracture • Bursitis Misinterpretation of deformity • Pseudohypertrophic osteoarthropathy • Psoriatic arthritis • Flexion contracture of the joints • Mucopolysaccharidoses • Neurogenic arthropathies • Calcium pyrophosphate dihydrate crystal deposition disease • Genu varum and valgum Misinterpretation of X-ray films • Arthritis with previous OA changes • Initial stage of osteoarthritis; may have normal X-ray • Flexion contracture can cause a virtual loss of joint space width • Neurogenic and metabolic arthropathies
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TABLE 176-4 -- Potential causes of pain in osteoarthritis • Bone —periosteal elevation by osteophytes —trabecular microfractures —pressure on subchondral bone —hypertension in bone marrow • Articular —synovial inflammation —pinching of synovial villi —joint capsule distension • Periarticular —ligament damage —muscle spasm —bursitis • Psychological factors —anxiety —depression
—lack of social support —secondary gain • Physical demands —occupational —obesity • Neuromuscular integrity —protective reflexes —muscle weakness is tremendous deformity, yet very little if any pain. In fact, about 40% of individuals with the worst X-ray classification for osteoarthritis are pain-free. [3] The exact cause of the pain in osteoarthritis is still not well-defined, but there are numerous potential causes ( Table 176.4 ). Depression and anxiety appear to increase the experience of the pain of osteoarthritis.
THERAPEUTIC CONSIDERATIONS Data collected from the earliest lesions to the most advanced stages of clinical OA suggest that cellular and tissue response is purposeful and is aimed at repair of the anatomic defects. The process contributing to OA appears to be arrestable, and sometimes reversible. [2] The major therapeutic goal appears to be enhancing collagen matrix repair and regeneration by the connective tissue cells. Several studies have attempted to determine the “natural course” of OA. [2] [4] One group of researchers studied the natural course of OA of the hip over a 10-year period. All subjects had pseudocystic changes suggestive of advanced osteoarthritis, yet the researchers reported marked clinical improvement and radiologic recovery of the joint space in 14 of 31 hips. [4] The authors purposely applied no therapy and regarded their results as reflecting the natural course of the disease. These results, as well as others, raise the serious concern that medical intervention may actually promote disease progression. Aspirin and nonsteroidal anti-inflammatory drugs
The first drug generally employed in the allopathic treatment of osteoarthritis is aspirin. It is often quite effective in relieving both the pain and inflammation. It is also relatively inexpensive. However, since the therapeutic dose required is relatively high (2–4 g/day), toxicity often occurs. Tinnitus (ringing in the ears) and gastric irritation are early manifestations of toxicity. [1] [2] Other non-steroidal anti-inflammatory drugs (NSAIDs) are often used as well, especially when aspirin is ineffective or not tolerated. The following are representative of this class of drugs: • ibuprofen (Motrin) • fenoprofen (Nalfon) • indomethacin (Indocin) • naproxen (Naprosyn) • tolmetin (Tolectin) • sulindac (Clinoril). These drugs are associated with such side-effects as gastrointestinal upset, headaches, and dizziness, and are therefore recommended for only short periods of time. While these drugs provide short-term symptomatic relief, unexpected side-effects may be increasing the rate of degeneration of the joint cartilage. Experimental studies have shown that aspirin and other NSAIDs inhibit collagen matrix synthesis and accelerate cartilage destruction. [5] Retrospective clinical studies have shown that NSAID use is associated with acceleration of osteoarthritis and increased joint destruction. [6] [7] [8] [9] Simply stated, NSAIDs appear to suppress the symptoms but accelerate the progression of osteoarthritis. Hormonal considerations There is a considerable amount of evidence that endocrine forces may initiate or accelerate the development of OA by altering the chondrocyte’s microenvironment. Virtually all hormones act, directly or indirectly, on connective tissue cells: fibroblasts, osteoblasts and chondrocytes. [2] Estrogen
The higher prevalence of OA in women suggests that estrogens may play a role. Estradiol worsens, and tamoxifen, an anti-estrogen drug, improves experimental OA by decreasing erosive lesions. This suggests a therapeutic role for estrogen blockade. Several botanicals (e.g. Glycyrrhiza glabra and Medicago sativa) commonly used in the treatment of OA contain compounds with phytoestrogen activity capable of binding to estrogen receptors and acting as estrogen antagonists. However, although phytoestrogen-containing herbs may be of value in osteoarthritis, perhaps the best way to increase the intake of phytoestrogens is to increase the intake of food sources of phytoestrogens. Good food sources of
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phytoestrogens include soy, fennel, celery, parsley, nuts, whole grains, and apples. Insulin growth hormone and somatomedin
Diabetic patients have a greater incidence and more severe form of OA than non-diabetics. [2] Diabetes is characterized by insulin insensitivity or deficiency, increased growth hormone levels, and decreased somatomedin levels (somatomedins are insulin-like growth factors secreted by the liver in response to growth hormone). Insulin stimulates chondrocytes to increase the synthesis and assembly of proteoglycans. [2] As the most prominent early change seen in the articular cartilage is a decrease in both proteoglycan content and state of aggregation, insulin insensitivity or deficiency predisposes to OA. Excessive growth hormone has detrimental effects on bone and joint structures, as demonstrated by the increased incidence of OA in acromegaly. Women with primary osteoporosis have been shown to have significantly higher basal growth hormone levels than controls. [10] Growth hormone appears to be detrimental to chondrocytes, while somatomedins appear to mediate normal chondrocyte activity. [2] Impaired hepatic function, diabetes, malnutrition, and other metabolic abnormalities suppress the liver’s secretion, in response to growth hormone, of somatomedin. This could lead to increased risk of developing OA. Thyroid
Patients with hypothyroidism have been shown to have an increased risk of OA compared with age- and sex-matched population samples. [2] Clearly, correction of
underlying endocrine imbalance or liver dysfunction is of critical importance in normalizing chondrocyte function. Dietary considerations Dietary therapy primarily involves the achievement of normal body weight, as excess weight means increased stress on weight-bearing joints affected with osteoarthritis. [11] [12] A general healthy diet, rich in complex carbohydrates and dietary fiber, is recommended (for further discussion see Ch. 175 ). Nightshade vegetables
Childers, a horticulturist, popularized a diet that treated osteoarthritis by eliminating foods from the genus Solanaceae (nightshade family). He arrived at this method after finding that this simple dietary elimination cured his own osteoarthritis. [13] Childers developed a theory that genetically susceptible individuals might develop arthritis, and other complaints, from long-term, low-level consumption of the solanum alkaloids found in tomatoes, potatoes, eggplant, peppers, and tobacco. Presumably, these alkaloids inhibit normal collagen repair in the joints or promote inflammatory degeneration of the joint. Although as yet unproven, this diet has been of benefit to some individuals (the authors have seen osteoarthritis in several patients respond well to such a diet) and is certainly worth a try. Antioxidant nutrients
Results from the Framingham Osteoarthritis Cohort Study indicate that a high intake of antioxidant nutrients, especially vitamin C, may reduce the risk of cartilage loss and disease progression in people with osteoarthritis. [14] A threefold reduction in the risk of osteoarthritis progression was found in both the middle tertile and highest tertile of vitamin C intake. These results highlight the importance of a diet rich in plant-based antioxidant nutrients protecting against chronic degenerative diseases including osteoarthritis. Nutritional supplements Glucosamine sulfate
Glucosamine is a simple molecule composed of glucose and an amine. The main physiological function of glucosamine on joints is to stimulate the manufacture of glycosaminoglycans.[15] [16] Glucosamine also promotes the incorporation of sulfur into cartilage. It appears that as some people age, they lose the ability to manufacture sufficient levels of glucosamine. The result is that cartilage loses its gel-like nature and ability to act as a shock absorber. The inability to manufacture glucosamine may be the major factor leading to osteoarthritis. The clinical benefits of glucosamine sulfate in the treatment of osteoarthritis are impressive. In one of the more recent studies comparing glucosamine sulfate with a placebo, 252 patients with osteoarthritis of the knee were given either a placebo or 500 mg glucosamine sulfate three times daily for 4 weeks. [17] Glucosamine sulfate was significantly more effective than the placebo in improving pain and movement after only 4 weeks of use. Previous studies have shown that the longer glucosamine sulfate is used, the more obvious the therapeutic benefit. The rate and severity of side-effects with glucosamine did not differ from the placebo. These results are consistent with other double-blind studies versus a placebo. [18] [19] [20] [21] [22] Head-to-head double-blind studies have shown glucosamine
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sulfate to produce better long-term results than NSAIDs in relieving the pain and inflammation of osteoarthritis despite the fact that glucosamine sulfate exhibits very little direct anti-inflammatory effect and no direct analgesic or pain-relieving effects. [23] [24] [25] While NSAIDs offer purely symptomatic relief and may actually promote the disease process, glucosamine sulfate appears to address the cause of osteoarthritis. By treating the root of the problem through the promotion of cartilage synthesis, glucosamine sulfate not only improves the symptoms, including pain, but also helps the body to repair damaged joints. The clinical effect is impressive, especially when glucosamine’s safety and lack of side-effects are considered. In one of the earlier comparative studies, glucosamine sulfate (1,500 mg/day) was compared with the common anti-inflammatory drug ibuprofen (1,200 mg/day). While pain scores decreased faster in the first 2 weeks in the ibuprofen group, by week 4 the group receiving the glucosamine sulfate improved more than the ibuprofen group.[23] Physicians rated the overall response as good in 44% of the glucosamine sulfate-treated patients as compared with only 15% of the ibuprofen group. Two more recent studies designed to further evaluate the comparative effectiveness of glucosamine sulfate to NSAIDs provide even better evidence. The first study consisted of 200 subjects with osteoarthritis of the knee given either glucosamine sulfate (500 mg three times daily) or ibuprofen (400 mg three times daily) for 4 weeks.[24] Consistent with previous studies, the ibuprofen group experienced quicker pain relief. However, by the end of the second week the group taking glucosamine sulfate experienced as good results as the ibuprofen group with one major exception – while the rate of side-effects with glucosamine were mild and only affected 6% of the group, ibuprofen produced more significant side-effects much more frequently, with 35% of the group experiencing side-effects. In the second study, 329 patients were given one of 1,500 mg glucosamine sulfate; 20 mg piroxicam; both compounds; or a placebo for 90 days. [25] The main efficacy variable was represented by the Lequesne index, a common assessment of disease activity. The results of the study were strikingly in favor of glucosamine sulfate alone. These impressive results with glucosamine sulfate were achieved without side-effects. In fact, patients on glucosamine sulfate had fewer side-effects than the placebo and no drop-outs. In addition to showing benefit in double-blind studies, oral glucosamine sulfate was shown to offer significant benefit in an open trial involving 252 doctors and 1,506 patients in Portugal. [26] The patients received 500 mg of glucosamine sulfate three times daily over a mean period of 50 days. Symptoms of pain at rest, on standing, and on exercise and limited active and passive movements improved steadily throughout the treatment period. Objective therapeutic efficacy was rated by doctors as “good” in 59% of patients, and “sufficient” in an additional 36%. Therefore, a total of 95% of patients achieved benefit from glucosamine sulfate. The results with glucosamine sulfate were rated by both doctors and patients as being significantly better than those obtained with previous treatment including NSAIDs, vitamin therapy, and cartilage extracts. Glucosamine sulfate produced good benefit in a significant portion of patients who had not responded to any other medical treatment. In the study, obesity was associated with a significant shift from good to fair. This finding may indicate that higher dosages may be required for obese individuals or that oral glucosamine is not enough to counteract the stress of obesity on the joints. Patients with peptic ulcers and individuals taking diuretics were also associated with a shift from good to sufficient in efficacy, as well as tolerance. Individuals with current peptic ulcers should try to take glucosamine sulfate with foods. Individuals taking diuretics may need to increase the dosage to compensate for the reduced effectiveness. The improvement with glucosamine lasted for a period of 6–12 weeks after the end of treatment. This result indicates that glucosamine may have to be taken for long periods of time or in repeated short-term courses. Given the safety and excellent tolerability of glucosamine, it is suitable for long-term use, even if continuous. (For additional discussion about the physiological effects and clinical efficacy of glucosamine sulfate, see Ch. 89. ) Chondroitin sulfate
Chondroitin sulfate, as well as shark cartilage, bovine cartilage extracts, and sea cucumber, contains a mixture of intact or partially hydrolyzed GAGs of molecular weights ranging from 14,000 to over 30,000. Chondroitin sulfate is composed of repeating units of derivatives of glucosamine sulfate with attached sugar molecules. While the absorption rate of glucosamine sulfate is 90–98%, the absorption of intact chondroitin sulfate is estimated to be anywhere from 0 to 13%. [27] [28] [29] The difference in absorption is largely due to the difference in size. Chondroitin sulfate is at least 50–300 times larger than glucosamine sulfate, too large to pass the normal intact intestinal barrier. If chondroitin sulfate molecules were absorbed intact or partially digested, they are still unlikely to produce any significant benefit as the chondroitin sulfate molecules are too large to be delivered to cartilage cells. One of the key reasons why glucosamine sulfate is so effective is that its small molecular size allows it to penetrate the joint cartilage and be delivered to the
chondrocyte and stimulate GAG synthesis. It would be nearly impossible for large chondroitin sulfate molecules
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to produce this effect. Furthermore, chondroitin sulfate levels are typically elevated in the synovial tissues in patients with osteoarthritis. [30] These absorption problems suggest that any direct effect of these compounds in osteoarthritis is highly unlikely. Any clinical benefit from chondroitin sulfate is most likely due to the absorption of sulfur or smaller GAG molecules broken down by the digestive tract. [23] However, even this is controversial as in one human study, 1 g of chondroitin sulfate failed to increase serum GAG concentration at all based on a highly sensitive measure of intact or depolymerized GAG absorption. These results prompted the researchers to conclude: “We suggest that chondroprotection by orally administered chondroitin sulfate is a biologically and pharmacologically unfounded theory.” [28] In a further analysis, these experts on chondroitin sulfate further concluded: [31] Pooled literature on chondroitin sulfate biochemistry offers enough information to assert that neither intact, nor polymerized chondroitin sulfate is absorbed by the mammalian gastrointestinal tract. Therefore, any direct action of orally administered chondroitin sulfate on cartilage and chondrocytes is not possible. The few clinical studies that have been done with orally administered chondroitin sulfate demonstrate that it is less effective than glucosamine sulfate. more impressive results have been achieved with glucosamine sulfate. Glucosamine sulfate is faster acting and provides much greater overall benefit.
[32] [33] [34] [35]
Far
Niacinamide
In the 1940s and 1950s, Dr William Kaufman, and later Dr Abram Hoffer, reported very good clinical results in the treatment of hundreds of patients with rheumatoid arthritis and osteoarthritis using high-dose niacinamide (i.e. 900–4,000 mg/day in divided doses). [36] [37] Dr Kaufman documented improvements in joint function, range of motion, increased muscle strength and endurance, and reduction in the sedimentation rate. Most patients achieved noticeable benefits within 1–3 months of use, with peak benefits noted between 1 and 3 years of continuous use. These clinical results were recently evaluated in a well-designed double-blind, placebo-controlled trial. [38] Seventy-two patients with osteoarthritis were randomized for treatment with niacinamide (3,000 mg daily in six divided dosages) or placebo for 12 weeks. Outcome measures included global arthritis impact and pain, joint range of motion and flexibility, erythrocyte sedimentation rate (ESR), complete blood count, liver function tests, serum cholesterol, serum uric acid, and fasting blood sugar. The researchers found that niacinamide produced a 29% improvement in global arthritis impact compared with a 10% worsening in the placebo group. Pain levels did not change, but those on niacinamide reduced their NSAID use. Niacinamide supplementation reduced the ESR by 22% and increased joint mobility by 4.5° over controls (8° vs. 3.5°), otherwise there were no other changes in blood chemistry. Side-effects, primarily mild gastrointestinal complaints, were more common in the niacinamide group, but could be effectively managed by recommending the pills be taken with food or fluids. Niacinamide at this high dose can result in significant side-effects (e.g. glucose intolerance and liver damage) and therefore requires strict supervision. Methionine
S-Adenosylmethionine (SAM) is an important physiological agent formed in the body by combining the essential amino acid methionine to adenosyl-triphosphate (ATP). A deficiency of SAM in the joint tissue, just like a deficiency of glucosamine, leads to loss of the gel-like nature and shock-absorbing qualities of cartilage. SAM appears to be useful in the treatment of osteoarthritis. SAM has been shown to be very important in the manufacture of cartilage components. [39] In one double-blind study, supplemental SAM increased cartilage formation, as determined by magnetic resonance imaging (MRI), in 14 patients with osteoarthritis of the hands. [40] In addition to this effect, SAM has also demonstrated some mild pain-relieving and anti-inflammatory effects in animal studies. A total of 21,524 patients with osteoarthritis have been treated with SAM in published clinical trials. In double-blind trials, SAM has demonstrated similar reductions in pain scores and clinical symptoms to NSAIDS like ibuprofen, indomethacin, naproxen, and piroxicam. In one double-blind study, SAM was compared with the popular drug ibuprofen (Advil, Motrin, Nuprin, etc.). [41] The 36 subjects with osteoarthritis of the knee, hip, and/or spine received a daily oral dose of 1,200 mg of SAM or 1,200 mg of ibuprofen for 4 weeks. Morning stiffness, pain at rest, pain on motion, swelling, and limitation of motion of the affected joints were assessed before and after treatment. The total score of the individual clinical parameters improved to the same extent in patients treated with SAM or ibuprofen. In two other studies SAM was shown to produce slightly better results than ibuprofen. [42] [43] SAM has been compared with naproxen (Naprosyn) in several studies. In one double-blind study, 20 patients with osteoarthritis of the knee were given either SAM or naproxen for 6 weeks.[44] During the first week, SAM was administered at a dose of 400 mg three times daily and afterwards at a dose of 400 mg twice daily, whereas the dose of naproxen during the first week was 250 mg three times daily and subsequently 250 mg twice daily. During the first 2 weeks, the patients were allowed to
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take the drug paracetamol as an additional analgesic if the pain was severe. The patients were examined at the beginning of the study and after 2, 4, and 6 weeks. The parameters tested were: pain, joint swelling, circumference of joint, extent of motility and walking time over 10 m. At the end of the sixth week no statistically significant difference between the two patient groups treated was found; both groups exhibited a marked improvement on all parameters. Another double-blind study compared SAM with both naproxen and placebo in the treatment of osteoarthritis of the hip, knee, spine, and hand. [45] The study involved 33 rheumatologic and orthopedic medical centers and a total of 734 subjects. SAM administered orally at a dose of 1,200 mg daily was shown to exert the same analgesic (pain-relieving) activity as naproxen at a dose of 750 mg daily. However, SAM was significantly more effective than naproxen, both in terms of physicians’ and patients’ judgments and in terms of the number of patients with side-effects. In fact, SAM was better tolerated than the placebo. Ten patients in the SAM group and 13 in the placebo group withdrew from the study because of intolerance to the drug. Other double-blind studies have shown SAM to offer the pain-relieving and anti-inflammatory benefit of drugs like indomethacin (Indocin and Indometh) and piroxicam (Feldene), but it is generally much better tolerated than these potent NSAIDs. [46] [47] Perhaps the most meaningful study of SAM in the treatment of osteoarthritis was a long-term multicenter open 2 year trial of 97 patients with osteoarthritis of the knee, hip, and spine. [48] The patients received 600 mg of SAM for the first 2 weeks and thereafter 400 mg daily until the end of the 24th month of treatment. Separate evaluations were made for osteoarthritis of the knee, hip, cervical spine, and dorsal/lumbar spine. The severity of the clinical symptoms (morning stiffness, pain at rest, and pain on movement) was assessed using scoring before the start of the treatment, at the end of the first and second weeks of treatment, and then monthly until the end of the 24 month period. Clinical improvement was evident after the first week of treatment and continued to the end of the 24th month. Non-specific side-effects occurred in 20 patients, but in no case did therapy have to be discontinued. Most side-effects disappeared during the course of therapy. Moreover, during the last 6 months of treatment, no adverse effect was recorded. Detailed laboratory tests carried out at the start and after six, 12, 18, and 24 months of treatment showed no pathologic changes. SAM administration also helped to relieve the depression often associated with osteoarthritis. The largest study evaluated 20,641 patients with osteoarthritis of the knee, hip, and spine and also with osteoarthritic polyarthritis of the fingers over an 8 week period.[49] The patients were given 400 mg three times of SAM daily for the first week, 400 mg twice daily for the second week, and 200 mg twice daily from the third week on. No additional analgesic/anti-inflammatory treatment was allowed. The efficacy of SAM was comparable to results achieved with NSAIDs. Efficacy was described as very good or good in 71% of cases, moderate in 21%, and poor in 9% of cases. The tolerance was assessed as very good or good in 87%, moderate in 8%, and poor in 5% of cases.
All of these studies indicate that SAM appears to offer significant advantages over NSAIDs. While the drugs are associated with a significant risk of toxicity, side-effects, and actual promotion of the disease process in osteoarthritis, SAM offers similar benefits without risk or side-effect. Superoxide dismutase
Intra-articular injections of superoxide dismutase (SOD) have demonstrated significant therapeutic effects in the treatment of OA. are absorbed orally is yet to be determined. Preliminary indications are that they probably are not. [52]
[50] [51]
Whether oral SOD preparations
Vitamin E
A clinical trial using 600 IU of vitamin E in patients with osteoarthritis demonstrated significant benefit. [53] The benefit was thought to be due to vitamin E’s antioxidant and membrane-stabilizing actions. In vitro studies have shown that vitamin E has an ability to inhibit the activities of lysosomal enzymes and stimulate increased deposition of proteoglycan. [54] Vitamin C
Deficient intake of vitamin C is common in the elderly, resulting in altered collagen synthesis and compromised connective tissue repair. [54] Several in vitro studies have demonstrated that vitamin C has an anabolic effect on cartilage. [55] [56] Research has confirmed the importance, indeed necessity, for an excess of ascorbic acid in human chondrocyte protein synthesis. [57] One in vivo study of experimental OA in guinea pigs found that cartilage erosion was much less and the overall histologic and biochemical changes in and around the OA joint much milder in animals kept on high doses of vitamin C. [54] Vitamins C and E appear to possess synergistic effects. [54] The researchers concluded: Thus, both vitamins E and C appear to enhance the stability of sulfated proteoglycans in the complex structure comprising articular cartilage. Judicious use of these vitamins in the treatment of osteoarthritis, either alone or in combination with other therapeutic means, may thus be of great benefit to the patient population by retarding the erosion of cartilage.
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Pantothenic acid
Acute deficiency of pantothenic acid in the rat causes a pronounced failure of cartilage growth and eventually produces lesions similar to osteoarthritis. Clinical improvement in OA symptomatology with the administration of 12.5 mg pantothenic acid has been reported. [58] [59] Results often did not manifest until 7–14 days. However, a larger, double-blind study in patients with primarily rheumatoid arthritis displayed no significant benefit from administration of 500 mg of pantothenic acid. [60] Vitamins A and E, pyridoxine, zinc, copper, and boron
These nutrients are required for the synthesis of collagen and maintenance of normal cartilage structures. A deficiency of any one of these would allow accelerated joint degeneration. In addition, supplementation at appropriate levels may promote cartilage repair and synthesis. For example, boron supplementation has been used in the treatment of osteoarthritis in Germany since the mid-1970s. This use was recently evaluated in a small double-blind clinical study and an open trial. In the double-blind study, of the patients given 6 mg of boron (as sodium tetraborate decahydrate), 71% improved compared with only 10% in the placebo group. [61] In the open trial, boron supplementation (6–9 mg daily) produced effective relief in 90% of arthritis patients including patients with osteoarthritis, juvenile arthritis and rheumatoid arthritis. [62] The preliminary indication is that boron supplements are of value in arthritis with many people with osteoarthritis experiencing complete resolution. Physical therapy Various physical therapy modalities (exercise, heat, cold, diathermy, ultrasound, etc.) are often beneficial in improving joint mobility and reducing pain in OA, especially when administered regularly ( Table 176.5 ). Much of the benefit of physical therapy is thought to be a result of achieving proper hydration within the joint capsule. Clinical and experimental studies seem to indicate that TABLE 176-5 -- Non-pharmacological approaches to pain in osteoarthritis • Acupuncture • Psychological aids • Exercise • Physical therapy —ultrasound —transcutaneous nerve stimulation —laser therapy —diathermy —thermal baths —massage • Weight loss short-wave diathermy may be of the greatest benefit. [63] [64] [65] Combining short-wave diathermy therapy with periodic ice massage, rest, and appropriate exercises appears to be the most effective approach. Ultrasound and laser therapy have also been shown to be helpful. [66] [67] The best exercises are isometrics and swimming. These types of exercises increase circulation to the joint and strengthen surrounding muscles without placing excess strain on joints. Increasing quadriceps strength has been shown to improve the clinical features and reduce pain in osteoarthritis of the knee. [68] Walking programs help to improve functional status and relieve pain in patients with osteoarthritis of the knee. [69] Botanical medicines Many herbs have historically been used in the treatment of osteoarthritis. When inflammation is present, those botanicals and nutritional factors possessing anti-inflammatory activity are indicated. Examples include bromelain, curcumin, and ginger. Yucca
A double-blind clinical trial found that a saponin extract of yucca demonstrated a positive therapeutic effect. [70] Results were of gradual onset and no direct joint effects of the yucca saponin were noted. The researchers suggested that the clinical improvement was due to indirect effects on the gastrointestinal flora. This is an interesting suggestion, since bacterial lipopolysaccharides (endotoxins) have been shown to depress the biosynthesis of proteoglycans. [71] It is entirely possible that
yucca decreases bacterial endotoxin absorption and thus reduces this inhibition of proteoglycan synthesis. If this is the mechanism of action, then other saponin-containing herbs, and other ways of reducing endotoxin load, may be useful. Harpagophytum procumbens (Devil’s
claw)
Several pharmacological studies utilizing experimental animal models of inflammation have reported that Devil’s claw possesses an anti-inflammatory and analgesic effect comparable to phenylbutazone. [72] However, other studies have indicated that Devil’s claw has little, if any, anti-inflammatory activity in experimental inflammation.[73] [74] The equivocal research results may reflect a mechanism of action that is inconsistent with current anti-inflammatory models or a lack of quality control (standardization) of the preparations used. Since the main components of Devil’s claw are saponins, its therapeutic effect in OA may be similar to that observed for yucca.
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Boswellia serrata
Another herb historically used in the treatment of osteo-arthritis is Boswellia serrata, a large branching tree native to India. Boswellia yields an exudative gum resin known as salai guggul. Although salai guggul has been used for centuries, newer preparations concentrated for the active components (boswellic acids) are giving better results. Boswellic acid extracts have demonstrated anti-arthritic effects in a variety of animal models. There are several mechanisms of action including inhibition of inflammatory mediators, prevention of decreased glycosaminoglycan synthesis, and improved blood supply to joint tissues. [75] [76] Clinical studies using herbal formulas with Boswellia have yielded good results in both osteoarthritis and rheumatoid arthritis. [77] The standard dosage for boswellic acids in arthritis is 400 mg three times daily. No side-effects due to boswellic acids have been reported.
THERAPEUTIC APPROACH Although there appear to be several worthwhile approaches to control of OA through natural therapies, a direct clinical study of a comprehensive, integrated program has yet to be conducted. The therapeutic approach recommended here is based on reducing joint stress and trauma, promoting collagen repair mechanisms, and eliminating foods and other factors which may inhibit normal collagen repair. All diseases or predisposing factors (see Table 176.1 ) should, of course, be controlled. Non-steroidal anti-inflammatory drugs, such as aspirin, should be avoided as much as possible. If aspirin must be used, deglycyrrhizinated Glycyrrhiza glabra (or Robert’s formula) should be used to help protect the gastrointestinal tract from its damaging effects and its use should be discontinued as soon as possible. Diet All simple, processed, and concentrated carbohydrates must be avoided; complex-carbohydrate, high-fiber foods should be emphasized; and fats should be kept to a minimum. Plants of the Solanaceae family should be eliminated (tomatoes, potatoes, eggplant, peppers, and tobacco). Liberal consumption of flavonoid-rich berries or extracts is also important. Supplements
• Glucosamine sulfate: 1,500 mg/day • Niacinamide: 500 mg six times/day (under strict supervision – liver enzyme must be regularly assayed) • Vitamin E: 600 IU/day • Vitamin A: 5,000 IU/day • Vitamin C: 1,000–3,000 mg/day • Vitamin B6 : 50 mg/day • Pantothenic acid: 12.5 mg/day • SAM: 400 mg three times/day • Zinc: 45 mg/day • Copper: 1 mg/day • Boron: 6 mg/day. Botanical medicines
• Medicago sativa: equivalent to 5–10 g/day • Yucca leaves: 2–4 g three times/day • Harpagophytum procumbens —dried powdered root – 1–2 g three times/day —tincture (1:5) – 4–5 ml three times/day —dry solid extract (3:1) – 400 mg three times/day • Boswellia serrata: equivalent to 400 mg boswellic acids three times/day. Physical therapy and exercise Physical activity that induces physiologic or traumatic strain, such as occupational or recreational overuse of a joint, must be avoided. Normalization of posture and orthopedic correction of structural abnormalities should be utilized to limit joint strain. Daily non-traumatic exercise (isometrics and swimming) is important, but should be carefully monitored. Short-wave diathermy, hydrotherapy, and other PT modalities which improve joint perfusion are indicated.
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Chapter 177 - Osteoporosis Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Usually asymptomatic until severe backache • Most common in postmenopausal white women • Spontaneous fractures of the hip and vertebra • Decrease in height • Demineralization of spine and pelvis as confirmed by X-ray techniques.
GENERAL CONSIDERATIONS Osteoporosis literally means porous bone. Normally there is a decline in bone mass after the age of 40 in both sexes (about 2% loss/year), but women are at a much greater risk for osteoporosis because of lower bone density prior to the age of 40. Many factors can result in excessive bone loss and different variants of osteoporosis exist, but postmenopausal osteoporosis is the most common form of osteoporosis. Approximately one in four postmenopausal women has osteoporosis (see Table 177.1 for other major risk factors in women).[1] Osteoporosis affects more than 20 million people in the United States. Although the entire skeleton may be involved in postmenopausal osteoporosis, bone loss is usually greatest TABLE 177-1 -- Major risk factors for osteoporosis in women • Postmenopausal • White or Asian • Premature menopause • Positive family history • Short stature and small bones • Leanness • Low calcium intake • Inactivity • Nulliparity • Gastric or small-bowel resection • Long-term glucocorticosteroid therapy • Long-term use of anticonvulsants • Hyperparathyroidism • Hyperthyroidism • Smoking • Heavy alcohol use
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in the spine, hips, and ribs. Since these bones bear a great deal of weight, they are then susceptible to pain, deformity or fracture. At least 1.5 million fractures occur each year as a direct result of osteoporosis, including 250,000 hip fractures, the most catastrophic of fractures. Hip fracture is fatal in 12–20% of cases and precipitates long-term nursing home care for half of those who survive. Nearly one-third of all women and one-sixth of all men will fracture their hips in their lifetime. [2] Etiology Osteoporosis involves both the mineral (inorganic) and the non-mineral (organic matrix composed primarily of protein) components of bone. This basic physiology clearly indicates that there is more to osteoporosis than simply a lack of dietary calcium. In fact, lack of dietary calcium in the adult results in a separate condition known as osteomalacia or “softening of the bone”. The two conditions, osteomalacia and osteoporosis, are different in that in osteomalacia there is only a deficiency of calcium in the bone. In contrast, in osteoporosis there is a lack of both calcium and other minerals as well as a decrease in the non-mineral framework (organic matrix) of bone. Little attention has been given to the important role that this organic matrix plays in maintaining bone structure. Bone is dynamic living tissue that is constantly being broken down and rebuilt, even in adults. Normal bone metabolism is dependent on an intricate interplay of many nutritional and hormonal factors, with the liver and kidney having a regulatory effect as well. Although over two dozen nutrients are necessary for optimal bone health, it is generally thought that calcium and vitamin D are the most important nutritional factors. However, hormones are also critical, as the incorporation of calcium into bone is dependent upon the estrogen. Gastric acid
The absorption of calcium is dependent on becoming ionized in the intestines. The poor ionization of calcium has been the major problem with calcium carbonate, which is the most widely utilized form of calcium for nutritional supplementation. In order for calcium carbonate to be absorbed, it must first be solubilized and ionized by stomach acid. In studies with postmenopausal women, it has been shown that about 40% are severely deficient in stomach acid. [3] It has been shown that patients with insufficient stomach acid output can only absorb about 4% of an oral dose of calcium as calcium carbonate, while a person with normal stomach acid can typically absorb about 22%.[3] Patients with low stomach acid secretion need a form of calcium that is already in a soluble and ionized state, such as calcium citrate, calcium lactate, or calcium gluconate. About 45% of the calcium is absorbed from calcium citrate in patients with reduced stomach acid compared with 4% absorption for calcium
carbonate. [4] This difference in absorption clearly demonstrates that ionized soluble calcium is much more beneficial than insoluble calcium salts like calcium carbonate in patients with reduced stomach acid secretion. It has also been demonstrated that calcium is more bioavailable from calcium citrate than from calcium carbonate in normal subjects.[5] Vitamin D
It is well known that vitamin D stimulates the absorption of calcium. Since vitamin D can be synthesized by the action of sunlight on 7-dehydrocholesterol in the skin, many experts consider it more of a hormone than a vitamin. The sunlight changes the 7-dehydrocholesterol into vitamin D 3 (cholecalciferol). It is then transported to the liver and converted into 25-hydroxycholecalciferol (25-(OH)D 3 ) which is five times more potent than cholecalciferol (D 3 ). The 25-hydroxycholecalciferol is then converted by the kidneys to 1,25-dihydroxycholecalciferol (1,25-(OH) 2 D3 ), which is 10 times more potent than cholecalciferol and the most potent form of vitamin D 3 (see Table 177.2 ). Disorders of the liver or kidneys result in impaired conversion of cholecalciferol to more potent vitamin D compounds. Many patients with osteoporosis have a high level of 25-OH-D 3 but quite a low level of 1,25-(OH) 2 D3 . This signifies an impairment of the conversion of 25-(OH)D 3 to 1,25-(OH)2 D3 within the kidneys in people with osteoporosis. [6] [7] Many theories have been proposed to account for this decreased conversion, including relationships to estrogen and magnesium deficiency. Recently, the trace mineral boron has been theorized to play a role in this conversion. All of these theories are discussed below. Hormonal factors
The concentration of calcium in the blood is strictly maintained within very narrow limits. If levels start to decrease, there is an increase in the secretion of parathyroid
Form
TABLE 177-2 -- Relative activities of vitamin D forms Relative activity
Vitamin D3
1
Vitamin D2
1
25-(OH)D3
2–5
25-(OH)D2
2–5
1,25-(OH) 2 D3
10
1,25-(OH) 2 D2
10
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hormone by the parathyroid glands and a decrease in the secretion of calcitonin by the thyroid and parathyroids. If calcium levels in the blood start to increase, there is a decrease in the secretion of parathyroid hormone and an increase in the secretion of calcitonin. An understanding of how these hormones increase (parathyroid hormone) and decrease (calcitonin) serum calcium levels is necessary in understanding osteoporosis. Parathyroid hormone increases serum calcium levels primarily by increasing the activity of the osteoclast catabolism of bone, although it also decreases the excretion of calcium by the kidneys and increases the absorption of calcium in the intestines. In the kidneys, parathyroid hormone increases the conversion of 25-(OH)D 3 to 1,25-(OH) 2 D3 . One of the theories relating bone loss to estrogen deficiency is that an estrogen deficiency makes the osteoclasts more sensitive to parathyroid hormone, resulting in increased bone breakdown and thereby raising blood calcium levels. This elevation in blood calcium leads to a decreased parathyroid hormone level that results in diminished levels of active vitamin D and increased calcium excretion as well. This theory appears to best explain the hormonal effects in osteoporosis.
DIAGNOSTIC CONSIDERATIONS Osteoporosis is best diagnosed by bone densiometry. There are several different techniques, but the one with the greatest support and popularity is dual energy X-ray absorptiometry (DEXA).[8] There are other methods (some of which are promising because they indicate not only bone density but also bone quality and structure, such as some of the computerized tomography [CT] scans), but DEXA is currently considered the gold standard. In addition to providing the most reliable measurement of bone density, the DEXA test requires less radiation exposure than other X-ray procedures for measuring bone density. Usually the DEXA examination measures both the hip and the lumbar spine densities. We recommend that women of high risk get a baseline bone density measurement and then monitor the rate of bone loss by urine tests that measure breakdown products of bone such as cross-linked N-telopeptide of type I collagen or deoxypyridium. These tests of bone resorption can be used to monitor the rate of bone loss and success (or failure) of therapy. They provide quicker feedback compared to DEXA which can take up to 2 years to detect a therapeutic response. The DEXA test is best used to measure bone density, while urinary bone resorption assessments can be used to measure the rate of bone loss. Reducing urinary levels of these markers of bone breakdown over a 2-year period has produced increases in bone density measurements.[9]
THERAPEUTIC CONSIDERATIONS Recently, there has been considerable public advocation of an increase in dietary calcium to prevent osteoporosis. While this appears to be sound medical advice for many, osteoporosis is much more than simply a lack of dietary calcium. It is a complex condition involving hormonal, lifestyle, nutritional, and environmental factors. A comprehensive plan that addresses these factors offers the greatest protection against developing osteoporosis. The primary goals in the treatment and prevention of osteoporosis are: • to preserve adequate mineral mass • to prevent loss of the protein matrix and other structural components of bone • to assure optimal repair mechanisms to remodel damaged areas of bone. Hormone replacement therapy One of the most publicized effects of hormone replacement therapy (combination of estrogen and progesterone) in menopause is its role in maintaining bone health and preventing osteoporosis. The research clearly demonstrates that the benefits of hormonal therapy significantly outweigh its risks in women who are susceptible to osteoporosis and women who have already experienced significant bone loss. Since both estrogen and progesterone exert beneficial effects against bone loss and, in women with established bone loss, actually increase bone mass, estrogen– progesterone combinations are preferred to estrogen alone. The exception is in women at high risk for breast cancer or women with a disease aggravated by estrogen, including breast cancer, active liver diseases, and certain cardiovascular diseases, in which case progesterone alone should be used.
Lifestyle factors Certain lifestyle factors significantly impact bone health. For example, coffee, alcohol, and smoking cause a negative calcium balance and are associated with an increased risk of developing osteoporosis, while regular exercise reduces the risk. [10] [11] In fact, as important as hormonal and dietary factors are, exercise is more critical for maintaining healthy bones. Numerous studies have demonstrated that physical fitness is the major determinant of bone density. Physical exercise consisting of 1 hour of moderate activity three times a week has been shown to prevent bone loss and actually increase bone mass in postmenopausal women. [11] [12] [13] [14] [15] [16] In contrast to exercise, immobilization doubles the rate of urinary and fecal calcium excretion, resulting in a significant negative calcium balance. [17]
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Although nutritional factors are important, the most effective practice for strengthening bones is physical activity. General dietary factors Many dietary factors have been suggested as a cause of osteoporosis, a few of which are: [18] [19] • low calcium-high phosphorus intake • high protein diet • high acid-ash diet • high salt intake • trace mineral deficiencies, to name a few. A vegetarian diet (both lacto-ovo and vegan) is associated with a lower risk of osteoporosis. [20] [21] Although bone mass in vegetarians does not differ significantly from omnivores in the third, fourth, and fifth decades, there are significant differences in the later decades. These findings indicate that the decreased incidence of osteoporosis in vegetarians is not due to increased initial bone mass, but rather to decreased bone loss. Several factors are probably responsible for the decrease in bone loss observed in vegetarians. The most important of these is probably a lowered intake of protein. A high-protein diet or a diet high in phosphates is associated with increased excretion of calcium in the urine. Raising daily protein from 47 to 142g doubles the excretion of calcium in the urine. [22] A diet this high in protein is common in the United States and may be a significant factor in the increased number of people suffering from osteoporosis in this country. [23] Another dietary factor which increases the loss of calcium from the body is refined sugar. Following sugar intake, there is an increase in the urinary excretion of calcium.[24] Considering that the average American consumes, in 1 day, 125 g of sucrose, 50 g of corn syrup plus other refined simple sugars, and a glass of a carbonated beverage loaded with phosphates, along with the high amount of protein, it is little wonder that there are so many suffering from osteoporosis in this country. Soft drinks
Soft drink consumption may be a major factor for osteoporosis as they are high in phosphates but contain virtually no calcium. This leads to lower calcium levels and higher phosphate levels in the blood. The United States ranks first among countries for soft drink consumption with a per capita consumption of approximately 15 ounces/day. The link between soft drink consumption and bone loss is going to be even more significant as children practically weaned on soft drinks reach adulthood. Soft drink consumption in children poses a significant risk factor for impaired calcification of growing bones. Since there is such a strong correlation between maximum bone mineral density and the risk of osteoporosis, the rate of osteoporosis may reach even greater epidemic proportions. The severe negative impact that soft drinks exert on bone formation in children was clearly demonstrated in a study that compared 57 children, aged 18 months to 14 years, with low blood calcium to 171 matched controls of children with normal calcium levels. [25] The goal of the study was to assess whether the intake of at least 1.5 quarts/week of soft drinks containing phosphates is a risk for the development of low blood calcium levels. Of the 57 children with low blood calcium levels, 38 (66.7%) drank more than four bottles (12–16 ounces) per week, but only 48 (28%) of the 171 children with normal serum calcium levels drank as many soft drinks. For all 228 children, a significant inverse correlation between serum calcium level and the number of bottles of soft drink consumed each week was found. [26] Green leafy vegetables
Consumption of green leafy vegetables (kale, collard greens, parsley, lettuce, etc.) offers significant protection against osteoporosis. These foods are a rich source of a broad range of vitamins and minerals important to maintaining healthy bones, including calcium, vitamin K 1 , and boron. Vitamin K1 is the form of vitamin K that is found in plants. A function of vitamin K 1 that is often overlooked is its role in converting inactive osteocalcin to its active form. Osteocalcin, the major non-collagen protein in bone, anchors calcium molecules into the protein matrix. [27] A deficiency of vitamin K leads to impaired mineralization of bone due to inadequate osteocalcin levels. Very low blood levels of vitamin K 1 have been found in patients with fractures due to osteoporosis. [28] The severity of fracture strongly correlated with the level of circulating vitamin K. Other studies have shown that the lower the level of circulating vitamin K, the lower the bone density. [29] This evidence clearly indicates the importance of vitamin K 1 . The richest sources of vitamin K 1 are dark green leafy vegetables, broccoli, lettuce, cabbage, spinach, and green tea. Good sources are asparagus, oats, whole wheat, and fresh green peas. In addition to vitamin K 1 , the high levels of many minerals like calcium and boron in green leafy vegetables may also be responsible for this protective effect. Boron is a trace mineral gaining recent attention as a protective factor against osteoporosis (see Ch. 68 ). [30] Supplementing the diet of postmenopausal women with 3 mg/day of boron reduced urinary calcium excretion by 44% and dramatically increased the levels of 17-beta-estradiol,
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the most biologically active estrogen. It appears boron is required to activate certain hormones, including estrogen and vitamin D. Boron is also apparently required for the conversion of vitamin D to its most active form (1,25-(OH) 2 D3 ) within the kidney. A boron deficiency may contribute greatly to osteoporosis as well as menopausal symptoms. As fruits and vegetables are the main dietary sources of boron, diets low in these foods may be deficient in boron. Typically, the standard American diet is severely deficient in these foods. According to several large surveys, including the US Second National Health and Nutrition Examination, fewer than 10% of Americans met the minimum recommendation of two fruit servings and three vegetable servings per day, and only 51% ate one serving of vegetables per day. [31] In order to guarantee adequate boron levels, supplementing the diet with a daily dose of 3–5 mg of boron is indicated. Boron has been shown to mimic some of the effects of estrogen therapy in postmenopausal women. [32]
Nutritional supplements As stated several times previously, but worth repeating, osteoporosis involves much more than calcium. Bone is dependent on a constant supply of many nutrients. A deficiency of any one of these nutrients will adversely affect bone health. In addition to vitamin K and boron (discussed above), there are other key nutrients critical to bone health, which are discussed below. Calcium
Supplementation of calcium has been shown to be effective in reducing bone loss in postmenopausal women. [33] [34] [35] [36] [37] [38] [39] Although, by itself, calcium supplementation does not completely halt calcium loss, it does slow the rate down by at least 30–50% and offers significant protection against hip fractures. Combined with exercise and the dietary recommendations given above, calcium is clearly part of an effective treatment for most women. While menopausal and postmenopausal women are often told that without hormone replacement therapy they will most definitely get osteoporosis, several studies provide strong evidence of the inaccuracy of this commonly held view. In one study, 118 healthy white women who had experienced the onset of menopause 3–6 years previously were randomly allocated to receive either 1,700 mg of calcium as calcium carbonate, a placebo, or Premarin with 1,700 mg of calcium. [38] The nearly 3-year-long study indicated that calcium supplementation alone significantly prevented bone loss. Using a more absorbable form of calcium like calcium citrate or calcium bound to other Krebs cycle intermediates may have provided greater benefit compared with calcium carbonate due to enhanced absorption (discussed below). Although calcium alone was less effective than the Premarin– calcium combination, because calcium supplementation carries with it no significant health risks this study reinforces the opinion that hormone replacement therapy should definitely be reserved for women at significant risk for osteoporosis. In another study, 86 postmenopausal women received, for 4 years, either 1 g of elemental calcium from an effervescent form containing 5.24 g calcium-lactate-gluconate and 0.8 g calcium carbonate or a placebo of an identical effervescent tablet containing no calcium. [39] Clinical status, calcium intake, physical activity, and bone mineral density were assessed at baseline and every 6 months. The study found that continued calcium supplementation produces a sustained reduction in the rate of loss of total bone mineral density in healthy postmenopausal women. As a result, the incidence of bone fractures was far lower in the group taking calcium (two out of 38) compared with the placebo (nine out of 40). And finally, in another 4 year study, the long-term effect of calcium supplementation on bone density was determined in 84 elderly women (54–74 years) more than 10 years past the menopause. [35] A placebo group who did not take calcium supplements at all during the 4 year study served as a comparison. Changes in bone density at the lumbar spine, hip, and ankle sites, current calcium intake and activity were monitored. Over the 4 years, the calcium supplement group (average calcium intake of nearly 2,000 mg/day) did not lose bone at the hip and ankle sites. The control group (average calcium intake, 950 mg/day) lost significantly more bone than the calcium supplement group at all sites of the hip and ankle. No overall bone loss was seen at the spine, in either group, over the 4 years of this study. There is a strong correlation between premenopausal bone density and the risk of osteoporosis. That being the case, building strong bones should be a lifelong goal, beginning in childhood. However, most women probably are not concerned about osteoporosis until a few years before menopause. Fortunately, calcium supplementation does improve bone density in perimenopausal women. In a 2 year study, 214 perimenopausal women received either 1,000 or 2,000 mg of calcium provided in an effervescent mixture as described above. [40] While the control group actually lost 3.2% of the bone density of their spine, the calcium-treated groups increased their density by 1.6% (there was no difference between the two calcium groups). These results highlight the importance of calcium supplementation prior to menopause in the battle against osteoporosis. The best form of calcium is certainly neither oyster shell nor bone meal. Studies have indicated that these
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calcium supplements may contain substantial amounts of lead. [41] (For a discussion of the toxic effects of lead in children and adults, see Chs 18 , 37 , and 135 .) In 1981, the FDA cautioned the public to limit their intake of calcium s derived from either dolomite or bone meal because of the potentially high lead levels in these calcium supplements. More recent studies have shown that other calcium sources such as carbonate (from oyster shells) and various chelates may also contain high amounts of lead.[41] One study measured the lead level in 70 brands of calcium supplements and found some forms and brands to have high levels. [41] The 70 products were divided into five categories: • refined calcium carbonate produced in a laboratory ( n = 17) • unrefined calcium carbonate derived from limestone or oyster shells ( n = 25) • calcium bound to various organic chelates such as citrate, gluconate, lactate, etc. ( n = 13) • dolomite (n = 9) • bone meal (n = 6). The results (lead content in mcg/800 mg calcium) are listed in Table 177.3 . None of the products tested in the dolomite and bone meal groups, and only two out of 25 in the unrefined calcium carbonate group, had lead levels below the recommended level of 1 mcg/800 mg of calcium. The group that displayed the greatest range of lead content was the unrefined calcium carbonate group (the source was oyster shells) – while two products contained very little lead, most contained higher levels, and one product contained 25 mcg of lead per 800 mg of calcium, a cause for great concern. As the total tolerable daily intake of lead for children aged 6 years and under is less than 6 mcg/day, young children should utilize refined calcium carbonate or chelated calcium products as calcium sources for supplementation. Since chelated calcium, especially calcium citrate, is better absorbed than calcium carbonate, the best recommendation for calcium supplementation are products which feature calcium bound to citrate, gluconate, or some other organic molecule. This recommendation is appropriate for older children and adults as well. Natural oyster shell calcium, dolomite, and bone meal TABLE 177-3 -- Lead content of calcium supplements Supplement
Lead content
Refined calcium carbonate
0.92
Calcium chelate
1.64
Dolomite
4.17
Unrefined calcium carbonate
6.05
Bone meal
11.33
products should be avoided unless the manufacturer can provide reasonable assurance that lead levels are below acceptable levels. Refined calcium carbonate has the lowest lead content, but calcium chelates are better absorbed, especially in women with low gastric acid output. Calcium bound to citrate and other Krebs cycle intermediates such as fumarate, malate, succinate, and aspartate is probably the best form. The Krebs cycle
intermediates fulfill every requirement for an optimum calcium chelating agent: • they are easily ionized • they are almost completely degraded • they have virtually no toxicity • they have been shown to increase the absorption of not only calcium, but other minerals as well. One popular calcium supplement is calcium hydroxyapatite – basically a purified bone meal. It is interesting to note that among calcium supplements tested for absorption, this form tested at 20% absorption compared with 30% for either calcium carbonate or calcium citrate. [42] Vitamin D
In addition to studies that utilized calcium supplementation alone, there have been several studies that used calcium in combination with vitamin D (usually vitamin D 3 ) as well as vitamin D alone. One study using vitamin D 3 alone found that supplementation with 700 IU/day will reduce the annual rate of hip fracture from 1.3 to 0.5% – nearly a 60% reduction. [43] In another study, 348 women aged 70 and older received either 400 IU/day of vitamin D 3 or a placebo for 2 years. [44] Bone density at the hip (femoral neck) increased by 1.9% in the left hip and 2.6% in the right hip in the vitamin D-treated group. In comparison, the placebo group demonstrated decreases of 0.3% in the left hip and 1.4% in the right hip. Studies that combined vitamin D with calcium produced slightly better results. For example, in one study of 3,270 elderly women living in nursing homes, the hip fracture rate in those receiving 1,200 mg/day of calcium and 800 IU/day of vitamin D 3 was reduced by 43% compared with the placebo group. [45] In another study, the effects of 3 years of dietary supplementation with calcium and vitamin D 3 on bone mineral density and the incidence of hip fractures in 176 men and 213 women aged 65 years or older who were living at home was evaluated. [46] The participants received either 500 mg/day of calcium plus 700 IU/day of vitamin D 3 (cholecalciferol) or placebo. Bone mineral density was measured by DEXA, and cases of hip fracture were ascertained by means of interviews and verified using hospital records. The average changes in bone mineral density in the calcium–vitamin D group were
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+0.5% for the hip, +2.12% for the spine, and +0.06% for the whole body. In contrast, the values for the placebo group were –0.70, +1.22, and –1.09%, respectively. Of 37 subjects who had hip fractures, 26 were in the placebo group and 11 were in the calcium–vitamin D group. These studies imply that vitamin D can be helpful, especially in elderly people living in nursing homes, people living further away from the equator, and those who do not regularly get outside. We recommend a dosage of 400 IU/day of vitamin D 3 rather than higher dosages, as the level of active vitamin D does not differ substantially from 400–800 IU. Taking higher dosages offers no significant benefit and may adversely effect magnesium levels. Magnesium
Magnesium supplementation may turn out to be as important as calcium supplementation in the prevention and treatment of osteoporosis. Women with osteoporosis have lower bone magnesium content and other indicators of magnesium deficiency than people without osteoporosis. [47] [48] In human magnesium deficiency, there is a decrease in the serum concentration of the most active form of vitamin D (1,25-(OH) 2 D3 ) which has been observed in osteoporosis. [49] This finding could be due either to the enzyme responsible for the conversion of 25-(OH)D 3 to 1,25-(OH)2 D3 being dependent on adequate magnesium levels, or to magnesium’s ability to mediate parathyroid hormone and calcitonin secretion. The benefits of magnesium supplementation were investigated in a small 2 year trial in 31 postmenopausal women. [50] The women received an initial dosage of either 250 mg of magnesium (as magnesium hydroxide) or a placebo. Dosages were increased to a maximum of 750 mg for the first 6 months followed by a maintenance dosage of 250 mg for the remaining 18 months of the trial. After 1 year, the women in the magnesium-treated group showed a slight improvement in the bone density. In contrast, the placebo group showed a slight decrease in bone density. Hopefully there will be follow-up studies to this preliminary study to better assess the benefits of magnesium in osteoporosis. Vitamin B6 , folic acid, and vitamin B 12
Low levels of these nutrients are quite common in the elderly population and may contribute to osteoporosis. These vitamins are important in the conversion of the amino acid methionine to cysteine. If deficient in these vitamins or if a defect exists in the enzymes responsible for this conversion, there will be an increase in homocysteine. This compound has been implicated in a variety of conditions, including atherosclerosis and osteoporosis (see Ch. 52 for a complete discussion). Increased homocysteine concentrations in the blood have been demonstrated in postmenopausal women and are thought to play a role in osteoporosis by interfering with collagen cross-linking leading to a defective bone matrix. Since osteoporosis is known to be a loss of both the organic and inorganic phases of bone, the homocysteine theory has much validity as it is one of the few theories that addresses both factors. Folic acid supplementation has been shown to reduce homocysteine levels in postmenopausal women even though none of the women were deficient in folic acid according to standard folic acid laboratory criteria. [51] Vitamins B6 and B12 are also necessary in the metabolism of homocysteine. Combinations of these vitamins will produce better results than either one of them alone. [52] Silicon
Silicon is necessary for cross-linking collagen strands, thereby contributing greatly to the strength and integrity of the connective tissue matrix of bone. [53] Since silicon concentrations are increased at calcification sites in growing bone, recalcification in bone remodeling may be dependent on adequate levels of silicon. It is not known whether the typical American diet provides adequate amounts of silicon. In patients with osteoporosis or where accelerated bone regeneration is desired, silicon requirements may be increased and therefore supplementation may be indicated. Fluoride
Fluoride administration is a popular therapy in many parts of the world, but its validity is still in question. Early studies showed that fluoride is largely ineffective. [54] Fluoride’s predominant effects are stimulation of osteoblastic activity and positive calcium balance. Fluoride is incorporated into the crystalline structure of bone as fluoroapatite, but the bone matrix is poorly formed and weak, and long-term excessive exposure typically results in more fragile bones. The therapeutic index for fluoride is quite narrow, and at the recommended daily dose of 60–75 mg, sodium fluoride causes side-effects in 33–50% of patients. Joint pain is the most common, but stomach aches, nausea, and vomiting also occur, although they are less troublesome if the fluoride is taken with meals. Newer sodium fluoride preparations, i.e. enteric-coated and timed-release to prevent digestion in the stomach, are showing better results in terms of both fewer side-effects and better clinical results. [55] However, at this time we do not recommend fluoride supplementation in the treatment of osteoporosis.
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Phytoestrogens
Plant estrogenic substances or “phytoestrogens” are components of many medicinal herbs with a historical use in conditions which are now treated with synthetic
estrogens. They may be suitable alternatives to estrogens in the prevention of osteoporosis in menopausal women (see Ch. 170 for further description). A semi-synthetic isoflavonoid similar in structure to soy isoflavonoids has been approved in Japan, Hungary, and Italy for the treatment and prevention of osteoporosis. [56] The compound, ipriflavone, has shown impressive results in a number of clinical studies. For example, in one study, ipriflavone (200 mg three times daily) increased bone density measurements by 2 and 5.8% after 6 and 12 months, respectively, in 100 women with osteoporosis. [57] In another 1 year study in women with osteoporosis, ipriflavone (600 mg/day) produced a 6% increase in bone mineral density after 12 months, while the bone density of the placebo group was reduced by 0.3%. [58] Longer-term studies are showing equally promising results given the safety and apparent efficacy of ipriflavone. [59] [60] The effectiveness of ipriflavone suggests that naturally occurring isoflavonoids like genistein and diadzein in soy may exert similar benefits. Given the benefits of soy isoflavonoids against breast cancer alone, the regular consumption of soyfoods is encouraged. The mechanism of action appears to be due to enhancement of calcitonin effects (see above) on calcium metabolism as ipriflavone exerts no estrogen-like effects. [61]
THERAPEUTIC APPROACH Osteoporosis is a preventable illness if appropriate dietary and lifestyle measures are followed. Women of all ages, from the very young to the very old, should make building healthy and strong bones a lifelong priority. This involves avoiding those dietary and lifestyle practices that leach calcium from the bone and choosing those dietary and lifestyle factors which promote bone health. Although calcium intake is highlighted by most physicians, strong bones require much more than this important mineral. Bone is dynamic, living tissue that requires a constant supply of high-quality nutrition and regular stimulation (exercise). The primary goal in the treatment of osteoporosis is prevention. In severe cases of osteoporosis, the recommendations given in this chapter should be used in conjunction with appropriate medical care, which may include the use of a variety of prescription drugs. Although drugs like Fosamax, as well as natural hormonal therapies like calcitonin, have side-effects, the benefits (prevention of hip fracture) usually outweigh these side-effects in severe cases. [62] [63] Diet
Follow the guidelines given in Chapter 44 . Recommend that patients avoid those dietary factors that promote calcium excretion such as salt, sugar, protein, and soft drinks. Supplements
• High potency multiple vitamin and mineral formula • Calcium: 800–1,200 mg/day • Vitamin D: 400 IU/day • Magnesium: 400–800 mg/day • Boron (as sodium tetrahydraborate): 3–5 mg/day.
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Bourgoin BP, Evans DR, Cornett JR et al. Lead content in 70 brands of dietary calcium supplements. Am J Public Health 1993; 83: 1155–1160
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Dawson-Hughes B, Harris SS, Krall EA et al. Rates of bone loss in postmenopausal women randomly assigned to one of two dosages of the vitamin D. Am J Clin Nutr 1995; 61: 1140–1145
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Ooms ME, Roos JC, Bezemer PD et al. Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind study. J Clin Endocrinol Metabol 1995; 80: 1052–1058
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Chapuy MC, Arlot ME, Delmas PD et al. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. Br Med J 1994; 308: 1081–1082
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Dawson-Hughes B, Harris SS, Krall EA et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. New Engl J Med 1997; 337: 701–702
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Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two-year controlled trial of peroral magnesium in osteoporosis. Magnesium Res 1993; 6: 155–163
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Rude RK, Adams JS, Ryzen E et al. Low serum concentration of 1,25-dihydroxyvitamin D in human magnesium deficiency. J Clin Endo Metabol 1985; 61: 933–940
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Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two-year controlled trial of peroral magnesium in osteoporosis. Magnesium Res 1993; 6: 155–163
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Brattstrom LE, Hultberg BL, Hardebo JE. Folic acid responsive postmenopausal homocysteinemia. Metabolism 1985; 34: 1073–1077
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Ubbink JB, van der Merwe WJ, Delport R. Hyperhomocysteinemia and the response to vitamin supplementation. Clin Invest 1993; 71: 993–998
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Fessenden RJ, Fessenden JS. The biological properties of silicon compounds. Adv Drug Res 1987; 4: 95
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Riggs B, Seeman E, Hodgson S et al. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. New Engl J Med 1982; 306: 446–450
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Murray TM, Ste-Marie LG. Fluoride therapy for osteoporosis. Can Med Assoc J 1996; 155: 949–954
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Brandi ML. New treatment strategies. Ipriflavone, strontium, vitamin D metabolites and analogs. Am J Med 1993; 95(suppl 5A): 69S–74S
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Moscarini M, Patacchiola F, Spacca G et al. New perspectives in the treatment of postmenopausal osteoporosis. Ipriflavone Gynecol Endocrinol 1994; 8: 203–207
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Passeri M, Biondi M, Costi D et al. Effect of ipriflavone on bone mass in elderly osteoporotic women. Bone Miner 1992; 19(suppl 1): S57–62
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Chapter 178 - Otitis media Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY Acute otitis media
• Earache or irritability • History of recent upper respiratory tract infection or allergy • Red, opaque, bulging ear drum with loss of the normal features • Fever and chills. Chronic or serous otitis media
• Painless hearing loss • Dull, immobile tympanic membrane.
GENERAL CONSIDERATIONS Otitis media occurs as a result of inflammation, swelling, or infection of the middle ear. There are basically two types of otitis media: chronic and acute. Acute otitis media is usually preceded by an upper respiratory infection or allergy. The organisms most commonly cultured from middle ear fluid during acute otitis media include Streptococcus pneumoniae (40%) and Haemophilus influenzae (25%). Chronic otitis media – also known as serous, secretory, or non-suppurative otitis media; chronic otitis media with effusion; and “glue ear” – refers to a constant swelling of the middle ear. Acute otitis media affects two-thirds of American children by 2 years of age, and chronic otitis media affects two-thirds of children under the age of 6. [1] Otitis media is the most common diagnosis in children and accounts for over 50% of all visits to pediatricians. It has been conservatively estimated that approximately $8 billion are spent annually on medical and surgical treatment of earache in the United States. Standard medical treatment The standard medical approach to otitis media in children is antibiotics, analgesics (e.g. acetaminophen),
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and/or antihistamines. If the ear infection is long-standing and unresponsive to the drugs, surgery is performed. The surgery involves the placement of a tiny plastic myringotomy tube through the ear drum to assist the normal drainage of fluid into the throat via the Eustachian tube. It is not a curative procedure as children with myringotomy tubes in their ears are in fact more likely to have further problems with otitis media. Myringotomies are currently being performed on nearly 1,000,000 American children each year. It appears that the unnecessary surgery of the past, the tonsillectomy, has been replaced by this new procedure. In fact there is a direct correlation between the decline of the tonsillectomy and the rise of the myringotomy. Over 2 million myringotomy tubes are inserted into children’s ears each year, along with 600,000 tonsillectomies and adenoidectomies. These surgeries are unnecessary for most children. A 1994 evaluation of the appropriateness of myringotomy tubes in children under 16 years of age in the United States found that only 42% were judged as being appropriate. [2] These results mean that several hundred thousand children are subjected to a procedure that will do them little good and possibly significant harm. A number of well-designed studies have demonstrated that there are no significant differences in the clinical course of acute otitis media when conventional treatments were compared with placebo. Specifically, no differences were found between non-antibiotic treatment, ear tubes, ear tubes with antibiotics, and antibiotics alone. [3] [4] [5] [6] [7] Interestingly, in some studies, children not receiving anti-biotics did have fewer recurrences than those receiving antibiotics. This reduced recurrence rate is undoubtedly a reflection of the suppressive effects antibiotics have on the immune system as well as disturbing the normal flora of the upper respiratory tract. Although some reviews showed a slight benefit with antibiotics, in the most recent analysis, a group of eight international experts from the United States, Britain, and the Netherlands reported that antibiotics are not recommended for the otitis media in most children. [7] Their extensive review of the scientific literature on the value of antibiotics in the treatment of otitis media over the past 30 years led to the following conclusions: We conclude that the benefit of routine antimicrobial use for otitis media, judged by either short-term or long-term outcomes, is unproven. We conclude that existing research offers no compelling evidence that children with acute otitis media routinely given antimicrobials have a shorter duration of symptoms, fewer recurrences, or better long-term outcomes than those who do not receive them. Although preventing mastoiditis and meningitis is a rationale for antimicrobial treatment, little evidence exists that routine treatment is effective for this purpose. Antimicrobials did not improve outcome at 2 months, and no differences in rates of recovery were found for either antimicrobial type or duration. These results are not likely to be readily accepted by most pediatricians in the United States, who rely heavily on antibiotics to treat otitis media. Instead of antibiotics, this group of experts recommended using analgesics (e.g. acetaminophen) and close observation by the parent, as over 80% of the children with acute otitis media will respond to a placebo within 48 hours. In addition to not being very effective in otitis media, the widespread use and abuse of antibiotics is becoming increasingly alarming for many other reasons, including the near-epidemic proportion of sufferers of chronic candidiasis as well as the development of “superbugs” that are resistant to currently available antibiotics. According to many experts as well as the World Health Organization, we are coming dangerously close to arriving at a “post-antibiotic era” where many infectious
diseases will once again become almost impossible to treat because of an over-reliance on antibiotics (see Ch. 53 for further information). [8] The risks and failure with antibiotics, when coupled with the high rate of recurrent otitis media following insertion of ear tubes, suggest that conservative (non-antibiotic, non-surgical) treatment alone would reduce the frequency rate and decrease the yearly financial costs of otitis media. Although standard antibiotic and surgical procedures may not be statistically effective, each child must be evaluated individually before a decision not to use these procedures is taken. Causes The primary risk factors for otitis media are: [1] • day care attendance • wood-burning stoves • parental smoking or exposure to other second-hand smoke • food allergies • not being breast-fed. All of these factors share a common mechanism – abnormal Eustachian tube function, the underlying cause in virtually all cases of otitis media. The Eustachian tube regulates gas pressure in the middle ear, protects the middle ear from nose and throat secretions and bacteria, and clears fluids from the middle ear. Swallowing causes active opening of the Eustachian tube due to the action of the surrounding muscles. Infants and small children are particularly susceptible to Eustachian tube problems since it is smaller in diameter, and more horizontal. Obstruction of the Eustachian tube leads first to fluid build-up and then, if the bacteria present are pathogenic
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and the immune system is impaired, to bacterial infection. Obstruction results from collapse of the tube (due to weak tissues holding the tube in place and/or an abnormal opening mechanism), blockage with mucus in response to allergy or irritation, swelling of the mucous membrane, or infection.
THERAPEUTIC CONSIDERATIONS The primary treatment goals are to ensure patency of Eustachian tubes and to promote drainage by identifying and addressing causative factors. In addition, it is very important to support the immune system. The recommendations given below are to be used along with those recommendations given in Chapter 53 . Bottle feeding
Recurrent ear infection is strongly associated with early bottle feeding, while breast-feeding (minimum of 4 months) has a protective effect. [9] Whether this is due to cow’s milk allergy or to the protective effect of human milk against infection has not yet been conclusively determined. It is probably a combination of both. In addition, bottle feeding while a child is lying on his or her back (bottle propping) leads to regurgitation of the bottle’s contents into the middle ear and should be avoided. Whatever the “causative” organism in otitis media – viral (respiratory syncytial virus or influenza A) or bacterial ( Streptococcus pneumonia or Haemophilus influenza) – human milk offers protection due to its high antibody content which helps to inhibit infectious agents. [10] Breast-fed infants also have a thymus gland (the major organ of the immune system) roughly 20 times larger than formula-fed infants (see Ch. 53 for further information). [11] Food allergy
The role of allergy as the major cause of chronic otitis media has been firmly established in the medical literature. these children have allergies: 16% to inhalants only, 14% to food only, and 70% to both.
[12] [ 13] [14] [ 15] [16] [ 17]
Most studies show that 85–93% of
One of the ways in which prolonged breast-feeding prevents otitis media may be by the avoidance of food allergies, particularly if the mother avoids sensitizing foods (i.e. those to which she is allergic) during pregnancy and lactation. In addition to breast-feeding, also of value is the exclusion or limited consumption of the foods to which children are most commonly allergic – wheat, egg, fowl, and dairy – particularly during the first 9 months. Since a child’s digestive tract is quite permeable to food antigens, especially during the first 3 months, careful control of eating patterns (no frequent repetitions of any food, avoiding the common allergenic foods, and introduction of foods in a controlled manner, i.e. introduction of one food at a time and carefully watching for a reaction) will reduce and prevent the development of food allergies. The allergic reaction causes blockage of the Eustachian tube by two mechanisms: inflammatory swelling of the mucous membranes lining the tube and inflammatory swelling of the nose, causing the Toynbee phenomenon (swallowing when both mouth and nose are closed, forcing air and secretions into the middle ear). In chronic earaches, an allergic cause should always be considered, and the offending allergens determined and avoided. One illustrative study of 153 children with earaches demonstrated that 93.3% of the children (using the RAST test for diagnosis – see Chs 15 and 61 for further discussion) were allergic to foods, inhalants, or both. The 12 month success rate for 119 of the children, when treated with serial dilution titration therapy for inhalant sensitivities and an elimination diet for food allergens, showed that 92% improved. This compares favorably with the surgically treated control group (ear tubes and, as indicated, removal of the tonsils and adenoids), which showed only a 52% response. [12] In another study, a total of 104 children with recurrent otitis media ranging in age from 1.5 to 9 years were evaluated for food allergy by means of skin-prick testing, specific IgE tests, and food challenge. [17] Results indicated a statistically significant association between food allergy and recurrent otitis media in 81/104 patients (78%). The elimination diet led to a significant amelioration of chronic otitis media in 70/81 (86%) patients as assessed by detailed clinical evaluation. The challenge diet with the suspected offending food(s) provoked a recurrence of serous otitis media in 66/70 patients (94%). The frequency distribution of allergies to individual foods is listed in Table 178.1 , while the frequency distribution according to number of food allergens is listed in Table 178.2 . Thymus gland extract
The thymus gland secretes a family of hormones which act on white cells to ensure their proper development TABLE 178-1 -- Food allergy in children with chronic otitis media Percentage of patients
Food
No. of patients
Cow’s milk
31
38
Wheat
27
33
Egg white
20
25
Peanut
16
20
Soy
14
17
Corn
12
15
Tomato
4
5
Chicken
4
5
Apple
3
4
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No. of food allergens
TABLE 178-2 -- The frequency distribution according to number of food allergens No. of allergic patients/total
Percentage
1
11/81
13.6
2–4
66/81
81.5
5–7
3/81
3.7
8–10
1/81
1.3
and function. Studies with calf thymus extracts given orally have demonstrated impressive clinical results in a variety of clinical conditions in children. [18] [19] [20] Specifically, thymus extracts have been shown to improve immune function, decrease children’s food allergies, and improve a child’s resistance to chronic respiratory infections. Thymus extracts may be of particular benefit in chronic otitis media. For more information, see Chapter 53 . Humidifiers
Humidifiers are popular treatments for otitis media and upper respiratory tract infections in children. This may be justified according to a 1994 study which evaluated the role of low humidity in this disorder. [21] The study examined the effect of low humidity on the middle ear using a rat model. Twenty-three rats were housed for 5 days in a low-humidity environment (10–12% relative humidity) and 23 control rats were housed at 50–55% relative humidity. Microscopic ear examinations were graded for otitis media before testing and on test days 3 and 5. The lining of the middle ears and Eustachian tubes were examined by biopsy. Significantly more effusions (fluid in the Eustachian tubes) were observed in the low-humidity group on both days 3 and 5, but biopsy results were similar in both groups. This study indicated that low humidity may be a contributing factor in otitis media. Possible explanations are that low humidity may induce nasal swelling and reduced ventilation of the Eustachian tube, or that it may dry the Eustachian tube lining which could lead to an inability to clear fluid as well as to increased secretions. The mast cells that reside in the lining of the Eustachian tubes may also come into play by releasing histamine and producing swelling. Although preliminary, this research indicates that increasing humidity with the help of a humidifier may be an important goal in the treatment of otitis media with effusion.
THERAPEUTIC APPROACH The key factor in the natural approach to chronic otitis media in children appears to be the recognition and elimination of allergies, particularly food allergies, and support for the immune system. Diet
Since it is usually not possible to determine the exact allergen during an acute attack, the most common allergic foods should be eliminated from the diet, i.e.: • milk and dairy products • eggs • wheat • corn • oranges • peanut butter. The diet should also eliminate concentrated simple carbohydrates – sugar, honey, dried fruit, concentrated fruit juice, etc. – since they inhibit the immune system. These simple dietary recommendations will bring relief to most children in a matter of days. Nutritional supplements
• Children’s multiple vitamin and mineral formula • Vitamin A: 50,000 IU/day for up to 2 days in children under 6 years of age, and 4 days in children over 6 years of age • Beta-carotene (natural mixed carotenoids): age in years × 20,000 IU/day (up to 200,000 IU/day) • Vitamin C: age in years × 50 mg every 2 hours • Bioflavonoids: age in years × 50 mg every 2 hours • Zinc: age in years × 2.5 mg daily (up to 30 mg) • Thymus extract: the equivalent of 120 mg pure polypeptides with molecular weights less than 10,000 or roughly 500 mg of the crude polypeptide fraction daily. Botanical medicines
• Echinacea sp.: one-half the adult dosage is appropriate for children under the age of 6, and the full adult dosage (given below) is appropriate for children over the age of 6 (Echinacea is very safe for children). All dosages below can be given up to three times daily —dried root (or as tea): 0.5–1 g —freeze-dried plant: 325–650 mg —juice of aerial portion of E. purpurea stabilized in 22% ethanol: 2–3 ml —tincture (1:5): 2–4 ml —fluid extract (1:1): 2–4 ml —solid (dry powdered) extract (6.5:1 or 3.5% echinacoside): 150–300 mg
Physical medicine
Local application of heat is often very helpful in reducing discomfort. It can be applied as a hot pack, with warm
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oil (especially mullein oil), or by blowing hot air into the ear with the aid of a straw and a hair dryer. These treatments help to reduce the pressure in the middle ear and promote fluid drainage. REFERENCES 1. Daly
KA. Epidemiology of otitis media. Otolaryngol Clin North Am 1991; 24: 775–786
2. Kleinman
LC, Kosecoff J, Dubois RW. The medical appropriateness of tympanostomy tubes proposed for children younger than 16 years in the United States. JAMA 1994; 271: 1250–1255
3. Bluestone 4. Van
CD. Otitis media in children: to treat or not to treat. New Engl J Med 1982; 306: 1399–1404
Buchen FL, Dunk JH, van Hof MA. Therapy of acute otitis media: myringotomy, antibiotics, or neither? Lancet 1981; 2: 883–887
5. Williams
RL, Chalmers TC, Stange KC. Use of antibiotics in preventing recurrent acute otitis media and in treating ottitis media with effusion. JAMA 1993; 270: 1344–1351
6. Rosenfeld 7. Froom
RM, Vertrees JE, Carr J. Clinical efficacy of antimicrobial drugs for acute otitis media. Metaanalysis of 5400 children from thirty-three randomized trials. J Pediatr 1994; 124: 355–367
J et al. Antimicrobials for acute otitis media? A review from the International Primary Care Network. Br Med J 1997; 315: 98–102
8. Woodhead 9. Saarinen
M. Antibiotic resistance. Brit J Hosp Med 1996; 56: 314–315
UM. Prolonged breast feeding as prophylaxis for recurrent otitis media. Acta Ped Scand 1982; 71: 567–571
10.
Editor. Breast feeding prevents otitis media. Nutr Rev 1983; 41: 241–242
11.
Hasselbalch H, Jeppesen DL, Engelmann MD. Decreased thymus size in formula-fed infants compared with breastfed infants. Acta Periatr 1996; 85: 1029–1032
12.
McMahan JT, Calenoff E, Croft DJ et al. Chronic otitis media with effusion and allergy: modified RAST analysis of 119 cases. Otol Head Neck Surg 1981; 89: 427–431
13.
Viscomi GJ. Allergic secretory otitis media: an approach to management. Laryngoscope 1975; 85: 751–758
14.
Van Cauwenberge PB. The role of allergy in otitis media with effusion. Ther Umschau 1982; 39: 1011–1016
15.
Bellionin P, Cantani A, Salvinelli F. Allergy: a leading role in otitis media with effusion. Allergol Immunol 1987; 15: 205–208
Hurst DS. Association of otitis media with effusion and allergy as demonstrated by intradermal skin testing and eosinophil protein levels in both middle ear effusions and mucosal biopsies. Laryngoscope 1996; 106: 1128–1137 16.
17.
Nsouli TM, Nsouli SM, Linde RE. Role of food allergy in serous otitis media. Annals Allergy 1994; 73: 215–219
Fiocchi A, Borella E, Riva E et al. A double-blind clinical trial for the evaluation of the therapeutic effectiveness of a calf thymus derivative (Thymomodulin) in children with recurrent respiratory infections. Thymus 1986; 8: 831–839 18.
19.
Genova R, Guerra A. Thymomodulin in management of food allergy in children. Int J Tissue Reac 1986; 8: 239–242
Cazzola P, Mazzanti P, Bossi G. In vivo modulating effect of a calf thymus acid lysate on human T lymphocyte subsets and CD4+/CD8+ ratio in the course of different diseases. Curr Ther Res 1987; 42: 1011–1017 20.
21.
Lovejoy HM, McGuirt WF, Ayres PH. Effects of low humidity on the rat middle ear. Laryngoscope 1994; 104: 1055–1058
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Chapter 179 - Pelvic inflammatory disease Nancy Roberts ND
DIAGNOSTIC SUMMARY • Dyspareunia, leukorrhea • Severe cramp-like, non-radiating lower abdominal pain; adnexal tenderness • Chills with moderately high, intermittent fever typical, but not invariably present • Cervical motion tenderness • WBC 20,000/ul, with marked leukocytosis and/or elevated sedimentation rate • Neisseria gonorrhea and Chlamydia trachomatis most common, followed by Ureaplasma urealyticum, Mycoplasma hominis, Streptococcus sp., E. coli, H. influenzae, Peptostreptococcus, and Peptococcus.
GENERAL CONSIDERATIONS Pelvic inflammatory disease (PID) is a categorical name for a range of pelvic infections and inflammations. Although salpingitis is the particular condition under the general label of PID (the adnexa are by definition always involved), non-infectious states such as pelvic adhesions and chronic salpingitis are also included. PID causes women to make an estimated 2.5 million outpatient visits to health care providers each year. One-fourth of these women will suffer serious long-term sequelae and all are at risk for recurrence. [1] The social and physical costs of PID are also significant: the risk of ectopic pregnancy increases sixfold after a single episode of PID, and there is an estimated 13% risk of infertility after one infection – 70% after three. [2] Although many of us have been numbed to increases in the costs of health care in the past two decades, such statistics about sequelae are unsettling. For this reason, prevention and aggressive full-spectrum care of the acute phase cannot be undervalued. History Inflammatory processes of the adnexal structures were
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not recognized until the 19th century. Prior to this time the uterus was thought to be the primary site for inflammation, although tubal and ovarian pathology were noted at autopsy. In l843, Simpson wrote about pelvic cellulitis; 19 years later, Virchow described perimetritis. [3] Neisseria gonorrhea (GC) was regularly listed as the bacterial cause of the inflammatory effect, but until about the 1960s, the causal agent named most frequently was unknown. Even laboratory identification of GC was not very reliable at that time. Etiology It is now recognized that several organisms (listed in Table 179.1 ) are implicated in the etiology of PID. Because of the complexities of and inconsistencies in sampling and laboratory verification, it is difficult to make definitive statements about the causal agents in PID. Asymptomatic chlamydial infections are a big cause of PID. A higher proportion of PID has been ascribed to Chlamydia trachomatis than to Neisseria gonorrhea.[4] Neisseria gonorrhea (GC)
The incidence of GC in the United States increased by a factor of 2.7 from 1960 to 1980. [6] In 1975, there were approximately 1 million cases of GC reported in the US. The infection has reached pandemic proportions in the US, where it is estimated that for each reported case, four go unreported. [3] Gonococci have been recovered from the urethra of 2.2% of sexually active servicemen who had minimal or no symptoms and from 40% of asymptomatic males who had contact with symptomatic women.[7] In addition, an estimated 80% of the men and women exposed to Gonococcus will develop infections. [62] For a seemingly delicate and fastidious species, Neisseria has impressive infective abilities, preferring human columnar and transitional epithelia. In less than 1 hour after intercourse, Gonococcus can establish itself on the urethral mucosa where it successfully resists the flow of urine. [8] Favored sites in the lower female genital tract are the Bartholin’s and Skene’s glands, the urethra, and the endocervical canal. [3] Direct spreading can occur from the endocervix across the endometrial surface to the tubal mucosa, or there can be migration through subendothelial vascular and lymphatic channels. [2] Perhaps the most common method of spreading, however, is TABLE 179-1 -- Microorganisms involved in PID [5] Organism
Incidence (%)
Neisseria gonorrhea
40–60
Chlamydia trachomatis
30
Mycoplasma hominis
8
Ureaplasma urealyticum
4
by vector: GC attached to spermatozoa are physically carried to the fallopian tubes. [3] Primary pathogens can also enter the upper tract from retrograde menstruation or uterine contractions during intercourse. [9] In the acute state, the gonococci and polymorphonucleocytes accumulate in the subepithelial connective tissue, resulting in patchy destruction of the overlying mucosa.[8] [10] The consequent thinning of the mucosal lining is thought to facilitate GC penetration into deeper tissue. [8] It is probably for this reason that gonococci are reported to survive only a short time in the fallopian tubes. [11] However, they may not only be surviving, but thriving. The descent of the microbe beyond the surfaces being examined makes it difficult to detect. [11] Concomitant infections are known to occur with GC. [12] Some researchers have even proposed that GC’s primary role appears to be paving the way for secondary invaders from normal vaginal flora, allowing access to the upper tract. [13] The associated infection will frequently be Chlamydia trachomatis (CT), but a superinfection
can also be present, in which case one will find that anaerobic bacteria have colonized as well.
[ 12]
Chlamydia trachomatis (CT)
In the United States it is estimated that 20–30% of PID cases are caused by CT. [5] [14] Further, one study found that acute chlamydial PID may be subclinical or silent in 66–75% of the cases. [15] Laboratory diagnosis of chlamydial infection is difficult, which, combined with CT’s asymptomaticity, renders thorough assessment of the scope of these infections nearly impossible. A 5 year study conducted in urban Sweden showed that, despite a decrease in the numbers of gonococcal PID, the total cases of acute PID were unchanged or even increased in the last year of the study. [16] Another European study, conducted in 1977, found that 62% of women with acute salpingitis had elevated (titer 1:64 or higher) chlamydial IgG antibodies. [17] However, most of the other studies completed to date show much lower percentages. These numbers will no doubt change as diagnostic technology improves and the clinical presentation of Chlamydia is more widely understood. Anaerobic infections
Anaerobes are the organisms most commonly isolated from the fallopian tubes or cul-de-sacs of patients with PID. [18] Anaerobic bacteria are probably not the chief causative agents, but rather are opportunists, establishing themselves in unsuccessfully defended tissues. Anaerobic infections are commonly found in immunocompromised hosts and are generally of endogenous origin. [19] The cervix and vagina of normal healthy women contain both anaerobic and aerobic bacteria. [20] Anaerobic
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infections establish themselves more often in older patients and in women with a history of prior PID. [6] Other organisms
Facultative aerobic organisms found in tuboperitoneal fluids from women with salpingitis have included coliforms, Haemophilus influenzae, streptococci, and Mycoplasma hominis.[21] Mycoplasma hominis has not been demonstrated as a sole etiologic agent, but rather seems to be a common contributor to the polymicrobial milieu that is often discovered in PID. One study found Mycoplasma hominis in cervical cultures from 81% of women patients with GC, and 64% of those without GC. [22] Ramifications There are serious physical consequences for women who have had PID. It has been estimated that, in the post-infection state, one of four women will suffer from one or more sequelae, such as abdominal pain, infertility, or ectopic pregnancy. [6] Dyspareunia is a symptom which is often not investigated, but which, when relevant questions are asked, is frequently found in the post-PID sufferer. Death from salpingitis is rare, and is generally due to rupture of the tubo-ovarian abscess with subsequent peritonitis. A mortality rate of 5.2–5.9% has been calculated for tubo-ovarian abscesses, and prior to 1950, mortality was 80–100%. [23] [24] Better diagnostic understanding of this complication, treatment with antibiotics, and prompt surgical intervention have phenomenally improved both morbidity and mortality statistics. The Fitz-Hugh–Curtis syndrome is a perihepatitis complicating the primary condition of PID. There are characteristic violin-string adhesions attaching the liver to the abdominal wall.[19] [25] These adhesions are due to local peritonitis involving the anterior liver surface and the adjacent abdominal wall. [26] Historically, GC was thought to be the main contributor to this syndrome, but CT is now found more frequently. [19] [20] Infertility is a serious concern. Once a woman has had PID, she is at risk for additional attacks. This is in part because, after the fallopian tubes have been damaged by the infectious process, normal defense mechanisms are impaired. Reinfection has been found to be the most important cause of infertility after PID. [27] One study comparing the rate of non-surgical infertility in 1973 with that of 1976 noted a 45% increase. This translates to 122,000 infertile couples per year. [28] This increased incidence is consistent with the concurrent epidemic of STD-associated PID. An alarming statistical analysis has shown that for each 1,000 girls born in 1950, 138 had one or more bouts of PID by age 30; 26 are infertile because of the PID; and nine have had surgery for ectopic pregnancy. [6] Further, it has been postulated that by the year 2000 there will be one episode of salpingitis for each two women reaching reproductive age in 1970. [20] Ectopic pregnancy is a severe sequel and any woman with a history of PID faces a seven- to 10-fold increased risk. [6] Ectopic pregnancies tripled in the United States from 1967 to 1977. In 1977, ruptured ectopic pregnancies accounted for 12% of maternal deaths and were the leading cause of maternal death in non-white women.[28] In another study, which followed women with PID for 9.5 years, 12.8% were infertile after one infection, 35.5% after two, and 75% after three infections. The same study showed that one in 24 women will have an ectopic pregnancy. [29] Risk factors Besides the obvious factor of sexual contact, the main risk factors are age, use or history of use of an IUD, and previous history of PID. An earlier “sexual debut” puts a young woman in a very high-risk group for PID, especially when there are multiple sexual partners. The risk in sexually active 15-year-olds is one in eight, while in the average 24-year-old it is one in 80. [6] One interesting hypothesis for these data is that the cervical mucus in the younger woman may be estrogen-dominated, creating an environment which is more accessible to pathogens. [21] Women with multiple partners have 4.6 times greater risk than women in monogamous relationships. [20] A woman bears a substantial risk of PID if she uses an IUD. Oral contraceptive (OC) users are somewhat less likely to have GC but, on the other hand, are at increased risk for chlamydial invasion. Birth control remains a potent issue, with barrier methods being techniques of choice because of their decreased PID risk. It should also be noted that one author included his own clinical observation that women in his practice who had vasectomized men as partners were only seldom in his office with PID.[30] The last risk factor to be considered is iatrogenic. This occurs when invasive procedures have introduced pathogens, or in some other way disturbed the tract flora, and induced PID. Among these procedures are: • cervical dilation • abortion • curettage • tubal insufflation • hysterosalpingography • insertion of an IUD. A hospital in Lund, Sweden, reported that 15% of its PID cases were iatrogenic. This indicates that PID may not be strictly an STD.
[19]
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Pathogen access to the upper female tract The route by which the pathogens gain access to the upper female tract has only recently been explored. Menstruation, sperm, and trichomonads have all been shown to be important in the transportation of pathogens into the salpinx. Often, the onset of menses corresponds with the onset of an episode of PID. Infections occurring around the menses tend to be GC rather than CT, a clinical curiosity which may ultimately illuminate more about the etiology. One hypothesis is that menstrual regurgitation facilitates the inflammatory response by carrying sloughed endometrial epithelium which may have attached GC or intracellular CT. These organisms are then able to proliferate in the tubal epithelium or on peritoneal surfaces.[9] [31] Human sperm has proved an interesting and multifaceted variable in the precipitation of PID. Some of the research targets bacteriospermia as a cause of infertility in men, findings which are clearly relevant to PID. Increasingly, STD research is noting the incidence of asymptomatic male carriers. [3] [7] [30] [32] [33] [34] [35] A very large population study discovered that 66–75% of the men who tested positive for GC were asymptomatic. [7] Designed to travel during intercourse, sperm also serve as effective vectors. Researchers took a very interesting look at this most basic interaction between man and woman by means of a laboratory experiment. They introduced organisms into capillary tubes containing cervical mucus, either alone or with added spermatozoa, and observed microbial motility. Cervical mucus had already been considered an effective mechanical and immunologic barrier between the abundant flora of the vagina and the upper tract, and the test results confirmed this idea. However, they also demonstrated that organisms attached to sperm could easily traverse the length of the mucus column. This may be particularly important during menses since sperm migration has been observed through menstrual plasma, but not during the luteal phase or through the cervical mucus of pregnancy. Electron microscopy has produced amazing photographic evidence of organisms attached to sperm. [3] [36] The mechanism observed with piliated GC is that pili twist together with the tails of the spermatozoa in a rope-ina-spider-web arrangement around the bacteria. Sperm have also been found intimately associated with cytomegalovirus, Toxoplasma, Ureoplasma urealyticum, [31] and Chlamydia. [37] Motile trichomonads serve as another transporter of PID. They are capable of ascending from the vagina to the fallopian tubes, carrying additional invaders. In fact, it has been observed that trichomonads are never isolated from humans when heavy bacterial contamination is absent. [31]
DIAGNOSIS Pelvic or lower abdominal pain is the most dependable symptom of PID but, unfortunately, is not specific. Rebound tenderness is not reliably reported; cervical motion tenderness and adnexal tenderness are much more common. The clinical picture of the various types of PID can easily mislead: in a large study the clinical diagnosis of PID was confirmed at laparoscopy in only 65% of the patients. Appendicitis, hemorrhagic corpus luteum, pelvic endometriosis, ectopic pregnancy, mesenteric adenitis, and ovarian tumors accounted for 12%, while 23% were found to be normal. [38] Many PID patients have atypical signs and symptoms and some have no signs and symptoms at all. [6] Table 179.2 lists those most commonly found. The woman with GC may appear more toxic and febrile and manifest leukocytosis, while CT-caused PID may give her an elevated sedimentation rate (ESR). Most episodes of gonococcal PID occur at or shortly after menses. [39] Gonococcal PID has a generally more severe clinical picture, but as discussed in Chapter 143 , tissue damage and long-term sequelae can be more severe in CT. This attempt to differentiate clinical pictures becomes meaningless, of course, in the presence of mixed infections. Any putrid discharge should yield oxygen-sensitive organisms since offensive odor is considered diagnostic of anaerobic infection. Any woman who has such a discharge probably has well-developed PID, with opportunistic anaerobes following the primary invaders. [27] The differential diagnosis of PID is shown in Table 179.3 . TABLE 179-2 -- Common signs and symptoms in acute PID[5] Symptom
Incidence (%)
Lower abdominal pain
90
Adnexal tenderness on palpation
90
Pain on movement of the cervix
90
Vaginal discharge
55
Adnexal mass or swelling
50
Fever or chills
40
Irregular vaginal bleeding
35
Anorexia, nausea, and vomiting
25
TABLE 179-3 -- Differential diagnosis of PID • Acute appendicitis • Acute cholecystitis • Acute pyelonephritis • Ectopic pregnancy • Endometriosis • Hemorrhagic ovarian cysts • Intrauterine pregnancy • Mesenteric lymphadenitis • Ovarian cyst with torsion • Ovarian tumor • Pelvic thrombophlebitis • Septic abortion
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In light of the Fitz-Hugh–Curtis syndrome, symptoms from the upper right quadrant in a sexually active woman may be an indirect sign of genital infection. The pain usually has a sudden onset and can overshadow the signs and symptoms of the underlying PID. [26] In the event of rupture of a tubulo-ovarian abscess, a sudden severe exacerbation of the pain can be observed. The pain is referred to the side of the rupture and is
typically followed by generalized peritonitis and collapse. Shoulder pain may be present. The pulse will likely be elevated out of proportion to the fever and is frequently as high as 170. [24] Surgery must be performed within 12 hours or mortality becomes probable. A careful history is, as always, invaluable. STDs, birth control methods used, sexual activity, recent medical procedures, and the nature and onset of symptoms are key factors to consider. Laboratory diagnosis Laboratory findings during active PID are inconsistent in the research literature. Such confusion may be inevitable since we lack knowledge of the normal flora of the female upper genital tract. Historically, this tract had been considered a sterile environment, but researchers have now begun to question this. [1] In the large number and variety of laboratory and surgical examinations performed by physicians over the last 20 years, there has been a consistent lack of correlation between the organisms found in the different sectors of the female anatomy.[11] [13] [20] [40] Pathogens cultured from the cervix are frequently not retrieved from the adnexa, and gonococci from the peritoneum are not found in the upper tract. Some researchers report the adnexa as being free from an organism because they cannot isolate it from the exudate, but since Chlamydia is intracellular and gonococci are thought to be below the submucosa by the second day, these findings are unreliable. [11] It is difficult to determine the most appropriate diagnostic approach. As has been eloquently stated, [18] PID results from infection of the endometrium and fallopian tubes by a wide array of bacterial pathogens, often in synergistic combination, and the inaccessible site of infection makes microbiologic confirmation difficult. Perhaps the best guideline to recommend is a conservative search. Invasive sampling of exudate and tissue should only be employed as a last resort. Diagnostic laparoscopies have a death rate of 5.2/ 100,000 and major complications in 4.6/1,000 procedures. [41] The most recent and least invasive technique is an upper tract culture via cervical entrance utilizing a double-lumen, catheter-protected brush. [42] [44] Perhaps with more studies this procedure can be improved or elaborated; however, currently it is poorly correlated and frequently compromised by lower tract contamination. A CBC and ESR are absolutely essential. The sedimentation rate in pregnancy is elevated from the increased plasma fibrinogen and globulin levels [44] and will also be increased in anemia due to the higher plasma-to-erythrocyte ratio. An infection should be suspected with a sedimentation rate above 35 in the absence of pregnancy and anemia. The C-reactive protein (CRP) has been investigated as a diagnostic tool in pelvic infections. [45] [46] [47] The evaluation is based on the local inflammatory reaction that follows cell death in internal organs. This reaction induces an increased synthesis of a series of plasma proteins. The C-reactive protein is one of these acute-phase reactants and its levels increase 1–2 days after any tissue injury that affects more than the epithelial layer. The increase of CRP is quantitatively matched with the degree of tissue injury. This non-specific test does not stand alone, however, and should be evaluated with the WBC and the ESR. Other diagnostic procedures to consider are: • endocervical smears and cultures (a good approach but can be misleading for reasons previously discussed) • urinalysis (to help with the differential diagnosis) • serum human chorionic gonadotropin (to help rule out pregnancy) • abdominal ultrasound (useful where displaced pregnancy is a possibility). Liver enzymes will not be elevated with a chlamydial perihepatitis as the parenchyma is not involved. [26] Finally, however a case of PID is being worked up, the physician should always consider the possibility that the infection is polymicrobial. Mixed infections are very common; isolation of a particular microbe from the cervix does not absolutely establish it as the sole etiologic agent of the PID, nor does isolation rule out other organisms.
THERAPEUTIC CONSIDERATIONS Hospitalization is recommended for patients who are pregnant, are suspected of having a pelvic abscess, have adnexal masses, or show signs of peritoneal involve-ment. Referral is necessary if the diagnosis is uncertain or a surgical emergency threatens. Should the physician decide not to hospitalize, a regimen of antibiotic therapy, combined with the supportive therapies discussed below, can be tried if the patient’s clinical and laboratory status can be reassessed in 48–72 hours. Laboratory values and objective patient criteria should direct all acute-phase treatment. Antibiotics As is well known, antibiotic therapy is not itself curative. Yet the literature is awash with big gun antibiotic
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TABLE 179-4 -- Antibiotic treatment of mild to moderate acute PID [5] • Cefoxitin (2 g i.m.) plus probenecid (1 g PO) in a single dose, or ceftriaxone (250 mg i.m.) plus doxycycline (100 mg PO b.i.d.) for 14 days or • Ofloxacin (400 mg PB b.i.d.) for 14 days plus either clindamycin (450 mg PO q.i.d.) or metronidazole (500 mg PO b.i.d.) for 14 days protocols. Additional antibiotics are suggested for the anaerobic contingency; and such use quickly becomes complex, expensive, potentially dangerous, and often contradictory. For example, drugs which deter Gonococcus do not affect Chlamydia. Some protocols suggest switching drugs every 2 days until the desired therapeutic result is achieved, while others suggest simultaneous use of several antibiotics (see Table 179.4 ). Mid-century literature predicted an end to GC with the fine-tuning of available chemotherapy:
[ 48]
Unless one succeeds in producing more virulent and resistant bacterial strains by present methods of treatment, it is possible to predict almost complete therapeutic success by means of both bacteriostatic and bactericidal agents. We are no longer so optimistic. Antibiotic resistance has been increasing at a rapid rate. Research now shows that 2–3% of all GC in Holland produces beta-lactamase, as do 30–40% of all strains in Singapore, Malaysia, and Thailand. [49] The 1985 United States STD treatment guidelines note that there is: [50] … increasing incidence of infections due to both penicillinase producing N. gonorrhoeae (PPNG) and chromosomal-mediated resistant N. gonorrhoeae (CMRNG), and there are published reports of the emergence of tetracycline-resistant gonococci in some geographic areas. Fifteen per cent of women with PID fail to respond to primary antimicrobial treatment, 20% have at least one recurrence, and 15% are rendered infertile.
[18]
Given the polymicrobial nature of PID, the complexities of isolation, antibiotic-resistant strains of microorganisms, and the realities of recurrence rate with antibiotic use, a more fundamental approach combining immune system enhancement and non-toxic therapies is more sound. Antibiotics, whether herbal or pharmaceutical, can help with the first phase of treatment, but do not offer sufficient intervention for the devastation that regularly occurs in the wake of the primary infection.
Physical medicine Diathermy
Pulsed high-frequency diathermy is very beneficial in the treatment of women with PID. [51] [52] [53] Pulsing electric energy for a short duration (65 µs every 1600 µs) at high intensity achieves the desired therapeutic result without the hyperpyrexia typically associated with diathermy. Local recovery is enhanced, the reticuloendothelial system is stimulated, and gamma-globulin fractions are increased. [20] Sitz baths
Traditionally, sitz baths have been an important component of the naturopathic treatment of PID. The contrast sitz bath is primarily used to increase pelvic circulation and drainage (for further discussion, see Ch. 42 ). Nutritional supplements Chlorophyll
Chlorophyll derivatives are cell-stimulating agents which aid in the regeneration of tissues the added benefit of being non-toxic. It has been suggested that: [56]
[54] [55]
and enhance production of hemoglobin and erythrocytes. They have
… the action of chlorophyll consists for the most part of increasing the resistance of cells in some physiochemical manner so that enzymatic digestion of the cell membrane by invading bacteria or their toxin is checked. Chlorophyll is theorized to break down carbon dioxide, resulting in the liberation of oxygen which inhibits anaerobic bacteria. [57] Careful vaginal douching with chlorophyll is recommended in every case of PID to forestall or diminish the inevitable anaerobic population and to encourage cervical and possibly upper tract healing. These tissues must be healed to reduce the risk of infertility or ectopic pregnancy. One researcher reported that the discharge from several leukorrhea cases was cleared up in almost every instance, with comparatively few applications of chlorophyll. [56] Vitamin C
Vitamin C is very useful in the treatment of women with PID, for the following reasons: • Its anti-inflammatory effects help to decrease tissue destruction. • Its support of collagen tissue repair helps to prevent the spread of infection (especially important in GC infections which can spread through the subepithelial connective tissue, resulting in disorganization of the collagen matrix [62] ). • Its fibrinolytic activity helps to prevent pelvic scarring. Beta-carotene
The normal ovary has a high concentration of beta-carotene. As these structures are bombarded by inflammation and the unwelcome company of aggressive
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microbes, it is essential to maintain optimal levels of carotene to allow for an optimal defense. Beta-carotene potentiates the beneficial effects of interferon and enhances numerous other immune functions such as antibody levels and white blood cell activity. [58] [59] It is also important as an antioxidant, helping to limit the cell damage induced by the inflammatory process (see Ch. 67 for a full discussion of this nutrient). Bromelain
Bromelain is an important component of the treatment regimen. Adnexal exudate in PID frequently suppurates to form abscesses. If during the acute stage, tissue irritation is relieved or ameliorated, much of the exudate can be absorbed and fewer adhesions formed. [51] Adhesions will form as the exudate lingers, the structures being over-whelmed by the inflammation. Also, upon resolution, agglutination of the villous fold in the lumen of the tube may occur, resulting in scarring and tubal occlusion. [3] Bromelain activates fibrinolysis which can greatly diminish the enduring sequelae of the inevitable exudate. Bromelain also demonstrates antimicrobial properties, and an Italian study has shown that it penetrates the salpinx [60] (see Ch. 69 for further discussion). Botanical medicines Vaginal depletion packs
The use of the vaginal depletion pack is recommended as an integral part of PID treatment, as it promotes the drainage of exudate from the involved tissues. (The vaginal depletion pack is discussed in more detail in Appendix 12.) Hydrastis canadensis
The immune-potentiating, specific anti-chlamydial properties and the general antibacterial nature of goldenseal make it indispensable in the care of PID. Since Hydrastis canadensis is also a trophorestorative to mucous membranes, the herb should be used throughout the rehabilitation period. ( Hydrastis is discussed in more detail in Ch. 91. ) Symphytum officinale
Comfrey is a soothing demulcent that is best used in the second phase of treatment. Its allantoin content encourages cell regeneration which is crucial for un-complicated recovery from PID. [61] Prevention STD prevention is an extremely important issue for all heterosexually and bisexually active women. The woman with no history of PID still should be concerned about the significant population of asymptomatic male carriers of STDs. The choice of birth control is pivotal. Oral contraceptives
A surprising number of articles laud the use of oral contraceptives (OC) for their apparent inhibition of gonococci. [20] Burnham [18] suggests OC use after a first episode of PID to prevent recurrence. Apparently, estrogens create a thicker cervical plug, which offers protection against gonococci. [9] [62] OCs also decrease the length and volume of menstrual blood flow, thus decreasing the exposure of the GC to this handy culture medium. On the other hand, users of OCs have a higher risk of chlamydial infections. [39] [63] [62] [31] Progesterone induces hyperplasia and hypersecretion which can then produce
cervical eversion, exposing the endocervical columnar epithelium – the target tissue of Chlamydia.[39] Estradiol has been implicated in suppressing endocervical antibodies necessary for resolution of the CT. [39] Animal experimentation finds that estrogen-treated individuals have a higher number of infected cervical cells and a longer duration of infection. [64] Since women are probably not selectively exposed to GC versus CT, OCs are not recommended. Intrauterine devices
The IUD is an STD disaster. [6] [15] [18] [21] [26] [65] [66] The reasons are straightforward – an IUD allows the colonization of bacteria on its surface while simultaneously reducing local immunologic capacity. [67] Senanayake & Kramer[68] suggest that if a woman is not concerned about child-bearing or possibly would “welcome the subfertility”, the IUD may be a good choice. The IUD is not recommended. Barrier methods
Barrier methods of contraception are excellent choices for the prevention of PID. The condom is preferred to cervical protectors, as with this method the sperm more rarely reach the vaginal vault. Douching
Haphazard douching is to be avoided since it disturbs the vaginal flora. However, if a woman believes that she has had intercourse with an infected partner, douching with a water-soluble chlorophyll solution may be a good supportive measure. However, douching must be used with caution. One study compared 100 consecutive patients hospitalized for pelvic inflammatory disease with 762 controls and 119 women suspected of having PID.[69] Current douching
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(defined as any douching during the previous 2 months) was more common among those with PID than among those in both control groups. Among current douchers, PID was related to the frequency of douching. Those who douched three or more times per month were 3.6 times more likely to get PID than those who douched less than once per month. A much larger study surveyed 6,984 women over the age of 18 and found that 32% said they had douched within the past week, and 13% reported regular douching more than once a week.[70] Intercourse during menses
Intercourse during menses is not recommended unless a condom is used. GC risk is increased by the loss of the protective cervical mucus plug and by the prevalence of blood, a medium of choice for Gonococcus. The endometrium is also thought to offer local protection against bacterial invasion, and it is this layer which is being sloughed off during menses. Smoking
When 197 women hospitalized for their first pelvic inflammatory disease infection were compared with 667 controls with non-gynecologic conditions, it was found that cigarette smokers, compared with women who had never smoked, had an elevated risk of PID of 1.7 and former cigarette smokers had an elevated risk of 2.3. There was not a dose–response relationship. [71] A more rigorous study found similar results. This was a case-controlled, population-based study of 131 women between 18 and 40 years of age who were treated for their first episode of PID compared with 294 randomly selected patients from the same HMO. Current smokers, compared with those who had never smoked, had an increased risk of PID. Women who smoked 10 or more cigarettes a day had a higher risk than those who smoked less. [72] Education
A physician should review the signs and symptoms of PID with all sexually active women, and should encourage any woman to seek counsel if she appears to fit the clinical picture for PID. The diagnosis is easier to make and the recovery more rapid when treatment is instituted early.
THERAPEUTIC APPROACH There are two phases to the treatment, both of which are important. The first therapeutic goal is to eliminate all pathogens and normalize the microflora of the adnexa. The second is to rehabilitate the damaged tissues. Women should avoid intercourse until all signs and symptoms are resolved and their male partners have been examined and treated. In addition, all partners from up to 2 months prior to the illness should be examined. [18] Increased bed rest must also accompany all forms of treatment. Note. Referral for aggressive antibiotic treatment or hospitalization is necessary if the patient does not quickly respond to therapy. Diet
All dietary inhibitors of immune function (sugar, alcohol, and processed and allergic foods) should be limited during the both phases of treatment. Supplements
• Beta-carotene: 100,000 IU/day for 2+ months • Vitamin E: 400 IU/day for 3 months • Vitamin C: 500 mg four times/day for the first week of treatment and then decrease over 3 days to250 mg three times/day • Chlorophyll: 10 mg of fat/oil soluble four/day for1 month • Bromelain: 250 mg (1,800 mcu) four times/day for the first week and three times/day for 6 weeks. Botanical medicines
• Symphytum officinale (after the acute phase) —500 mg of freeze dried herb three times/day —1:1 fluid extract, 30 drops two times/day • Hydrastis canadensis: 400 mg of the solid extract three times/day during the acute phase; 200 mg three times/day during recovery • Chlorophyll: douches alternating with vag packs • Vag packs: daily during the acute phase until there is adequate clinical and laboratory response. After the acute phase, vag packs need to be used three times/week, alternating with chlorophyll douches, for 3 weeks.
Physical medicine
• Diathermy: pulsed, high-intensity diathermy for10 minutes over the suprapubic area, 10 minutes over the liver, and 10 minutes in the area of the left adrenal (the right being presumably stimulated with the liver) • Sitz baths: one to two times/day throughout the acute phase. Contrast sitz baths are given in groups of three alterations of hot to cold. Two separate tubs are necessary to facilitate this process. The hot is at 105–115°F, the cold at 55–85°F, with the temperatures 1477
dependent on the strength of the patient. Standard treatment is 3 minutes hot and 30 seconds cold. The water level in the hot tub is set 1 inch higher than in the cold. Adequate draping is necessary to prevent chilling. As with all hydrotherapy treatments, one always finishes with the cold.
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Trehearne JD, Ripa KT, Mardh P-A. Antibodies to Chlamydia trachomatis in acute salpingitis. Br J Vener Dis 1979; 55: 26–29
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Burnham RC. Therapy for acute pelvic inflammatory disease. A critique of recent treatment trials. Am J Ob Gyn 1984; 148: 235–240
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Mardh PA. An overview of infectious agents of salpingitis, their biology and recent advances in methods of detection. Am J Ob Gyn 1980; 138: 933–951
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Mickal A, Sellmann A, Beebe J. Ruptured tuboovarian abscess. Am J Ob Gyn 1968; 100: 432–436
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Urnes A, Stray-Pedersen B, Raknerud N. Case report: massive ascites as a complication to subclinical perihepatitis and pelvic inflammatory disease. Acta Obstet Gyn Scand 1986; 65: 277–278
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Wolner-Hanssen P, Westrom L, Mardh PA. Perihepatitis and chlamydial salpingitis. Lancet 1980; i: 901–903
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Bartlett J. Anaerobic infections of the pelvis. Clin Ob Gyn 1979; 21: 351–359
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Curran J. Economic consequences of pelvic inflammatory disease in the U.S. Am J Ob Gyn 1980; 138: 848–851
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Westrom L. Effect of acute pelvic inflammatory disease on fertility. Am J Ob Gyn 1975; 121: 707–713
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Toth A, O’Leary W, Ledger W. Evidence for microbial transfer by spermatozoa. Ob Gyn 1982; 59: 556–559
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Kinghorn GR, Waugh MA. Oral contraceptive use and prevalence of infection with Chlamydia trachomatis in women. Br J Vener Dis 1981; 57: 187–190
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Lang D, Kummer J. Cytomegalovirus in semen: observation in selected populations. J Inf Dis 1975; 132: 472–473
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Dahlberg B. Asymptomatic bacteriospermia. Urology 1976; VIII: 563–566
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Lang D, Kummer J. Demonstration of cytomegalovirus in semen. New Engl J Med 1972; 287: 756–758
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Gomez C, Stenback W, James A et al. Attachment of Neisseria gonorrhoea to human sperm. Br J Ven Dis 1979; 55: 245–255
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Friberg J. Chlamydia attached to spermatozoa. J Inf Dis 1985; 152: 854
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Jacobson L, Westrom L. Objectivized diagnosis of acute pelvic inflammatory disease: diagnostic and prognostic value of routine laparoscopy. Ob Gyn 1969; 105: 1088
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Cromer B, Heald F. Pelvic inflammatory disease associated with Neisseria gonorrhoeae and Chlamydia trachomatis. Clinical correlates. Sex Trans Dis 1987; 14: 125–129
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Sweet R, Mills J, Hadley K et al. Use of laparoscopy to determine the microbiologic etiology of acute salpingitis. Am J Ob Gyn 1979; 134: 68–70
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Phillips J, Hulka J, Keith D et al. Laparoscopic procedures. a national survey for 1975. J Repro Med 1977; 18: 219–226
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Lehtinen M, Laine S, Heinonen P. Serum C-reactive protein determination in acute pelvic inflammatory disease. Am J Ob Gyn 1980; 154: 158–159
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Jacobson L, Laurell CB, Gennser G. Plasma protein changes induced by acute inflammation of the fallopian tubes. In J Gyn Ob 1975; 13: 249–256
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Angerman N, Evans M, Moravec W et al. C-reactive protein in the evaluation of antibiotic therapy for pelvic infection. J Repro Med 1980; 25: 63–66
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Mattingly R. Office management of acute pelvic and urinary tract infections. Clin Ob Gyn 1962; 5: 275–285
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Catterall RD. Biological effects of sexual freedom. Lancet 1981; i: 315–319
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US Dept of Health and Human Services. 1985 STD treatment guidelines. Morb Mort Wkly Report Sup 1985; 34: 1–35
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Gellhorn G. Diathermy in gynecology. JAMA 1928; March: 1005–1008
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Horowitz E, Derow D, Bierman W. Temperature determination in the female pelvis during diathermy. Am J M Sc 1935; 189: 555–556
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Kottke F, Gullickson G, Erickson H et al. Study of the reactive value of long wave diathermy and microwave diathermy for heating the pelvis. Arch Phys Med Rehab 1955; March: 137–140
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Rafsky H, Krieger C. The treatment of intestinal disease with solutions of water soluble chlorophyll. Rev Gastro Ent 1945; 15: 549–553
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Gruskin B. Chlorophyll – its therapeutic place in acute and suppurative disease. Am J Surg 1940; XIIX: 49–55
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Smith L. Chlorophyll: remarks upon the history, chemistry, toxicity and antibacterial properties of water-soluble chlorophyll derivatives as therapeutic agents. 1944; 207: 647–654
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Rhodes J. Human interferon action: reciprocal regulation by retinoic acid and beta-carotene. J Natl Cancer Inst 1983; 70: 833–837
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Alexander M, Newmark H, Miller RG. Oral beta-carotene can increase the number of OKT4+ cells in human blood. Immunol Letters 1985; 9: 221–224
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Luerti M, Vignali M. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Exp Clin Res 1978; 4: 45–48
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Priest AW, Priest LR. Herbal medication. London: LN Fowler. 1982
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Ringsdorf W, Cheraskin E. Vitamin C and human wound healing. Oral Surgery 1985; March: 231–233
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Washington AE, Gove S, Schachter J et al. Oral contraceptives, Chlamydia trachomatis infection and pelvic inflammatory disease. JAMA 1985; 253: 2446–2450
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Rank R, White H, Hough A. Effect of estradiol on Chlamydial genital infection of female guinea pigs. Inf Imm 1982; 38: 699–705
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Burkman R. Intrauterine device use and the risk of pelvic inflammatory disease. Am J Ob Gyn 1980; 138: 861–863
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Eschenbach D, Harnisch J, Holmes K. Pathogenesis of acute pelvic inflammatory disease. Role of contraception and other risk factors. Am J Ob Gyn 1980; 128: 838–850
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Keith L, Berger G, Edelman D et al. On the causation of pelvic disease. Am J Ob Gyn 1984; 149: 215–224
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Senanayake P, Kramer D. Contraception and the etiology of pelvic inflammatory disease: new perspectives. Am J Ob Gyn 1980; 138: 852–860
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Wolner-Hanssen P. Association between vaginal douching and acute pelvic inflammatory disease. JAMA 1990; 263: 1936–1941
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Marchbanks P, Lee NC, Peterson HB. Cigarette smoking as a risk factor for pelvic inflammatory disease. Am J Ob Gyn 1990; 162: 639–644
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Scholes D. Current cigarette smoking and risk of acute pelvic inflammatory disease. Am J Pub Health 1992; 82: 1352–1355
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Chapter 180 - Peptic ulcer – duodenal and gastric Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Epigastric distress 45–60 minutes after meals, or nocturnal pain. Both relieved by food, antacids, or vomiting • Epigastric tenderness and guarding • Symptoms chronic and periodic • Gastric analysis shows acid in all cases, with hypersecretion in about half the patients with duodenal ulcers • Ulcer crater or deformity usually occurring at the duodenal bulb (duodenal ulcer) or pylorus (gastric ulcer) on X-ray or fiber-optic examination • Positive test for occult blood in stool.
GENERAL CONSIDERATIONS Peptic ulcer formation occurs in the stomach (gastric ulcer) and the first portion of the small intestine (duodenal ulcer). Duodenal ulcers are more common, with an estimated prevalence of 6–12% in the United States. Approximately 10% of the US population has clinical evidence of duodenal ulcer at some time in their lifetime. It is four times more common in men than in women and four to five times more common than clinically evident benign gastric ulcer. Although symptoms of a peptic ulcer may be absent or quite vague, most peptic ulcers are associated with abdominal discomfort noted 45–60 minutes after meals or during the night. In the typical case, the pain is described as gnawing, burning, cramp-like, or aching, or as “heartburn”. Eating or using antacids usually results in great relief. Even though duodenal and gastric ulcers occur at different locations, they appear to be the result of similar mechanisms. Specifically, the development of a duodenal or gastric ulcer is a result of some factor damaging the protective factors which line the stomach and duodenum. In the past, the focus has primarily been on the acidic secretions of the stomach as the primary cause of both
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gastric and duodenal ulcers. However, more recently the focus has been on the bacteria Helicobacter pylori and non-steroidal anti-inflammatory drugs. Gastric acid is extremely corrosive with a pH of 1–3. To protect against ulcers, the lining of the stomach and small intestine is protected by a layer of mucin. In addition, the constant renewing of intestinal cells and the secretion of factors which neutralize the acid when it comes in contact with the stomach and intestinal linings also protect against ulcer formation. Excessive gastric acid output is rarely a factor in gastric ulcers as in these patients gastric acid output is usually normal or reduced. In contrast, almost half of patients with duodenal ulcers have increased gastric acid output. This increase may be due to an increased number of parietal cells. As a group, patients with duodenal ulcers have twice as many parietal cells as normal controls. Even with an increase in gastric acid output, under normal circumstances there are enough protective factors to prevent the ulcer formation. However, when the integrity of these protective factors is impaired, an ulcer can form. A loss of integrity can be a result of H. pylori, NSAIDs, alcohol, nutrient deficiency, stress, and many other factors. Of these factors, H. pylori and NSAIDs are by far the most significant. Helicobacter pylori
The role of H. pylori in peptic ulcer disease has been extensively investigated. It has been shown that 90–100% of patients with duodenal ulcers, 70% with gastric ulcers, and about 50% of people over the age of 50 test positive for H. pylori.[1] The presence of H. pylori is determined by determining the level of antibodies to H. pylori in the blood or saliva, or by culturing material collected during an endoscopy as well as measuring the breath for urea. Low gastric output as well as low antioxidant content in the gastrointestinal mucosa is thought to predispose to H. pylori colonization. H. pylori colonization increases gastric pH, thereby setting up a positive feedback scenario and increasing the likelihood for the colonization of the stomach and duodenum with other organisms. [2] Aspirin and other NSAIDs
Aspirin and other non-steroidal anti-inflammatory drugs are associated with a significant risk of peptic ulcer. While most studies documenting the relative frequency of peptic ulcers as a consequence of aspirin and NSAIDs have focused on their use in the treatment of arthritis and headaches, recently the risk of gastrointestinal bleeding due to peptic ulcers was evaluated for aspirin at daily dosages of 300, 150, and 75 mg – dosages commonly recommended to prevent heart attacks and strokes.[3] One study, conducted at five test hospitals in England, found an increased risk of gastrointestinal bleeding due to peptic ulcer at all dosage levels. However, the dosage of 75 mg/day was associated with 40% less bleeding than 300 mg/day, and 30% less bleeding than 150 mg/day. The researchers concluded: “No conventionally used prophylactic aspirin regimen seems free of the risk of peptic ulcer complications.” The combination of NSAID use and smoking is particularly harmful to the ulcer patient. [4]
THERAPEUTIC CONSIDERATIONS Individuals experiencing any symptoms of a peptic ulcer need competent medical care. Peptic ulcer complications such as hemorrhage, perforation, and obstruction represent medical emergencies that require immediate hospitalization. Obviously, the best treatment of a peptic ulcer involves identification of the causative factor and its appropriate elimination. Lifestyle factors
Stress and emotions
Stress is universally believed to be an important factor in the pathogenesis of peptic ulcers. However, this belief is based on uncontrolled observations. The medical literature is controversial, and every substantial attempt to examine this assumption has been fraught with methodological errors. [5] This problem is further complicated by the observation that men and women with peptic ulcers appear to have distinctly different psychological profiles. In addition, several studies have shown that the number of stressful life events is not significantly different in peptic ulcer patients as compared with carefully selected, ulcer-free controls. These data suggest that it is not simply the amount of stress, but rather the patient’s response to it that is the significant factor. A very large prospective study of 4,000 persons who had no history of peptic ulcer disease revealed that those who perceived stress in their lives are at increased risk of developing peptic ulcers[6] (see Ch. 60 for a more complete discussion). It is probable that psychological factors are important in some patients with peptic ulcer disease, but not in others. As a group, ulcer patients have been characterized as tending to repress emotions. At the very least, patients should be encouraged to discover enjoyable outlets of self-expression and emotions. Smoking
Increased frequency, decreased response to peptic ulcer therapy, and an increased mortality due to peptic ulcers
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are all related to smoking. Three postulated mechanisms for this association are: [6] • decreased pancreatic bicarbonate secretion (an important neutralizer of gastric acid) • increased reflux of bile salts into the stomach • acceleration of gastric emptying into the duodenum. Bile salts are extremely irritating to the stomach and initial portions of the duodenum. Bile salt reflux induced by smoking appears to be the most likely factor responsible for the increased peptic ulcer rate in smokers. However, the psychological aspects of smoking are also important, since the chronic anxiety and psychological stress associated with smoking appear to worsen ulcer activity. Nutritional factors Food allergy
Clinical and experimental evidence points to food allergy as a prime etiological factor. [7] [8] [9] [10] The lesions of peptic ulcers and the Arthus Reaction show the same microanatomical changes. [1] In one study, 98% of patients with radiographic evidence of peptic ulcer had coexisting lower and upper respiratory tract allergic disease. [9] In another study, 25 of 43 allergic children had X-ray-diagnosed peptic ulcers. [10] Clinically, an elimination diet has been used with great success in treating and preventing recurrent ulcers. [8] [9] Food allergy is also consistent with the high recurrent rate of peptic ulcers. It is ironic that many people with peptic ulcers soothe themselves by consuming milk, a highly allergic food. Milk should be avoided on this basis alone. However, there is additional evidence suggesting that milk should be avoided in patients with peptic ulcers; for example, population studies show that the higher the milk consumption, the greater the likelihood of ulcer, and milk significantly increases stomach acid production. [11] Fiber
A diet rich in fiber is associated with a reduced rate of duodenal ulcers as compared with a low-fiber diet. The therapeutic use of a high-fiber diet in patients with recently healed duodenal ulcers reduces the recurrence rate by half. [12] This is probably a result of fiber’s ability to delay gastric emptying of the liquid phase, counteracting the rapid movement of this phase into the duodenum normally seen in ulcer patients. Although several fibers often used to supplement the diet (e.g. pectin, guar gum, psyllium, etc.) have been shown to produce beneficial effects, a diet rich in plant foods is best. [13] [14] Cabbage
Raw cabbage juice has been well documented as having remarkable success in treating peptic ulcers. [15] [16] [17] One liter per day of the fresh juice, taken in divided doses, resulted in total ulcer healing in an average of only 10 days. Further research has shown that the high glutamine content of the juice is probably responsible for the efficacy of cabbage in treating these ulcers. In a double-blind clinical study of 57 patients, 24 using 1.6 g/day of glutamine and the rest using conventional therapy (antacids, antispasmodics, diet, milk, and bland diet), glutamine proved to be the more effective treatment. Half of the glutamine patients showed complete healing (according to radiographic analysis) within 2 weeks, and 22 of the 24 showed complete relief and healing within 4 weeks. [19] Although the mechanism for these results is not known, it is postulated by the authors to be due to the role of glutamine in the biosynthesis of the hexosamine moiety in certain mucoproteins. This could stimulate mucin synthesis which would benefit peptic ulcer patients. Bismuth subcitrate
Bismuth is a naturally occurring mineral that can act as an antacid as well as exerting activity against H. pylori. The best known and most widely used bismuth preparation is bismuth subsalicylate (Pepto-Bismol). However, bismuth subcitrate has produced the best results against H. pylori and in the treatment of peptic ulcers. [18] [19] In the United States, bismuth subcitrate preparations are available through compounding pharmacies (to find a compounding pharmacist in your area, call the International Academy of Compounding Pharmacists 1-800-927-4227). One of the key advantages of bismuth preparations over standard antibiotic approaches to eradicating H. pylori is that while the bacteria may develop resistance to various antibiotics it is very unlikely to develop resistance to bismuth. The usual dosage for bismuth subcitrate is 240 mg twice daily before meals. For bismuth subsalycilate, the dosage is 500 mg four times daily. Bismuth preparations are extremely safe when taken at prescribed dosages. Bismuth subcitrate may cause a temporary and harmless darkening of the tongue and/or stool. Bismuth subsalicylate should not be taken in children recovering from the flu, chicken pox, or other viral infection as it may mask the nausea and vomiting associated with Reye’s syndrome, a rare but serious illness. Flavonoids
Flavonoids are known to counteract both the production and secretion of histamine, an important factor in ulcer formation. They are generally regarded as anti-allergy compounds. The use of these compounds seems particularly indicated, due to the probable allergic etiology of peptic ulcers.
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Catechin, via its ability to inhibit histidine decarboxylase, offers anti-ulcer activity. Experimental studies in guinea pigs and rats have demonstrated that catechin has significant anti-ulcer activity in various models. [20] [21] In a human clinical study, oral administration (1,000 mg five times/day) resulted in reduced histamine levels in the gastric tissue (determined by biopsy) of normal patients and those with gastric and duodenal ulcers and acute gastritis. [21] It was also demonstrated that the histamine levels, which significantly increase in patients with urticaria and food allergy after the local application of the antigen to the gastric mucosa, could be decreased by the
prior administration of catechin. In a recent study, several flavonoids were shown to inhibit H. pylori in a clear-cut concentration-dependent manner. [22] In addition, unlike antibiotics the flavonoids were also shown to augment natural defense factors which prevent ulcer formation. The activity of flavone, the most potent flavonoid in the study, was shown to be similar to that of bismuth subcitrate. Miscellaneous Vitamins A and E have been shown to inhibit the development of stress ulcers in rats and are important factors in maintaining the integrity of the mucosal barrier. Zinc increases mucin production in vitro, and has been shown to have a protective effect on peptic ulcers in animals [25] and a curative effect in humans. [26]
[23] [ 24]
Botanical medicines
Glycyrrhiza glabra. Licorice has historically been regarded as an excellent medicine for peptic ulcer. However, due to the known aldosterone-like side-effects of glycyrrhizinic acid (GA), a procedure was developed to remove GA from licorice and form deglycyrrhizinated liquorice (DGL). The result is a very successful anti-ulcer agent without any known side-effects (see Ch. 90 ). [2] [27] [28] [29] [30] [31] The proposed mechanism of DGL is that it stimulates and/or accelerates the differentiation to glandular cells, as well as mucus formation and secretion. [27] Clinical studies have demonstrated no significant differences in recurrence rates between cimitidine and DGL drug regimens, and rat and human studies have shown its efficacy in preventing aspirin-induced ulceration and gastric bleeding. [29] [30] [31] An obvious question related to DGL is: “Does DGL have any effect on Helicobacter pylori?”. The answer appears to be “yes” as DGL is composed of several flavonoids which have been shown to inhibit H. pylori. [22] It appears that in order to be effective in healing peptic ulcers, DGL must mix with saliva. DGL may promote the release of salivary compounds which stimulate the growth and regeneration of stomach and intestinal cells. DGL in capsule form has not been shown to be effective. The standard dosage for DGL is two to four 380 mg chewable tablets between or 20 minutes before meals. Taking DGL after meals is associated with poor results. DGL therapy should be continued for at least 8–16 weeks after there is a full therapeutic response. Rhubarb. In cases of active intestinal bleeding, rhubarb ( Rheum sp.) preparations can be extremely effective. In one double-blind study, three kinds of alcohol-extracted rhubarb tablets were studied ( Rheum officinale Baill; Rheum palmatum L.; Rheum tanguticum Maxim ex Balf).[32] Their efficacies in a group of 312 cases of bleeding gastric and duodenal ulcers were 90.7, 93.7, and 92.8%, respectively. The time taken for the stool occult blood to change from positive to negative was 57.1, 53.4, and 56 hours, respectively. The beneficial actions are due to the presence of astringent anthraquinones and flavonoids. Plantain banana. In rats, the dried extract of the unripe plantain banana has been found to have anti-ulcerogenic activity against a variety of experimentally induced ulcers. [33] [34] This effect appears to be similar to that of DGL, i.e. stimulation of mucosal cell growth rather than inhibition of gastric acid secretion.
THERAPEUTIC APPROACH Peptic ulcer disease should be recognized as a heterogeneous group of disorders with a common final pathway leading to an ulcerative lesion in either the gastric or duodenal mucosa. Patients must be carefully evaluated to determine which of the above factors is most relevant to their health problem. This is, however, difficult; a more general approach may be necessary. The first step is to identify and eliminate or reduce all factors implicated in the etiology of peptic ulcers: food allergy, cigarette smoking, stress, and drugs – especially aspirin and other non-steroidal analgesics. Once the causative factors have been controlled, attention should be directed at healing the ulcers, inhibiting exacerbating factors (e.g. reducing excess acid secretion if present), and promoting tissue resistance. Finally, the proper diet and lifestyle should be developed to prevent further recurrence. Peptic ulcer complications – hemorrhage, perforation, and obstruction – represent medical emergencies that require immediate hospitalization. Psychological
Assist the patient in developing an effective stress reduction program – eliminating or controlling of stressors, and designing a regular relaxation plan.
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Diet
Eliminate allergic food, promote foods high in dietary fiber, and utilize various members of the cabbage family. Supplements
• Vitamin A: 20,000 IU three times/day • Vitamin C: 500 mg three times/day • Vitamin E: 100 IU three times/day • Flavonoids: 500 mg three times/day • Zinc: 20 mg/day • Glutamine: 500 mg three times/day • Bismuth subcitrate: 240 mg twice daily before meals. Botanical medicine
• Deglycyrrhizinated licorice root (DGL): 380–760 mg 20 minutes before meals three times/day.
REFERENCES 1. Berstad 2. Sarker
K, Berstad A. Helicobacter pylori infection in peptic ulcer disease. Scand J Gastroenterol 1993; 28: 561–567
SA, Gyr K. Non-immunological defense mechanisms of the gut. Gut 1992; 33: 987–993
3. Weil
J, Colin Jones D, Langman M. Prophylactic aspirin and risk of peptic ulcer bleeding. Brit Med J 1995; 310: 827–830
4. Gray
GM. Peptic ulcer diseases. In: Dale DC, Federman DD, eds. Scientific American medicine New York, NY: Scientific American. 1995
5. Feldman
EJ, Sabovich KA. Stress and peptic ulcer disease. Gastroenterol 1980; 78: 1087–1089
6. Anda
RF, Williamson DF, Escobedo L et al. Self-perceived stress and the risk of peptic ulcer disease. Arch Int Med 1992; 152: 829
7. Siegel
J. Gastrointestinal ulcer – Arthus reaction! Ann Allergy 1974; 32: 127–130
8. Andre
C, Moulinier B, Andre F, Daniere S. Evidence for anaphylactic reactions in peptic ulcer and varioliform gastritis. Ann Allergy 1983; 51: 325–328
9. Siegel
J. Immunologic approach to the treatment and prevention of gastrointestinal ulcers. Ann Allergy 1977; 38: 27–29
10.
Rebhun J. Duodenal ulceration in allergic children. Ann Allergy 1975; 34: 145–149
11.
Kumar N, Kumar A, Broor SL et al. Effect of milk on patients with duodenal ulcers. Brit Med J 1986; 293: 666
12.
Rydning A, Berstad A, Aadland E, Odegaard B. Prophylactic effects of dietary fiber in duodenal ulcer disease. Lancet 1982; 2: 736–739
13.
Kang JY, Tay HH, Guan R. Dietary supplementation with pectin in the maintenance treatment of duodenal ulcer. Scand J Gastroenterol 1988; 23: 95–99
14.
Harju E, Larme TK. Effect of guar gum added to the diet of patients with duodenal ulcers. J Parenteral Enteral Nutr 1985; 9: 496–500
15.
Cheney G. Rapid healing of peptic ulcers in patients receiving fresh cabbage juice. Cal Med 1949; 70: 10–14
16.
Cheney G. Anti-peptic ulcer dietary factor. J Am Diet Assoc 1950; 26: 668–672
17.
Shive W, Snider RN, DuBiler B et al. Glutamine in treatment of peptic ulcer. Tex J Med 1957; 53: 840–843
18.
Kang JY et al. Effect of colloidal bismuth subcitrate on symptoms and gastric histology in non-ulcer dyspepsia. A double blind placebo controlled study. Gut 1990; 31: 476–480
Marshall BJ, Valenzuela JE, McCallum RW. Bismuth subsalicylate suppression of Helicobacteria pylori in non-ulcer dyspepsia. A double-blind placebo-controlled trial. Dig Dis Sci 1993; 38: 1674–1680 19.
20.
Parmar N, Ghosh M. Gastric anti-ulcer activity of (+)-cyanidanol-3, a histidine decarboxylase inhibitor. Eur J Pharmacol 1981; 69: 25–32
Wendt P, Reiman H, Swoboda K et al. The use of flavonoids as inhibitors of histidine decarboxylase in gastric diseases. Experimental and clinical studies. Naunyn-Schmiedeberg’s Arch Pharma (Supplement) 1980; 313: 238 21.
22.
Beil W, Birkholz, Sewing KF. Effects of flavonoids on parietal cell acid secretion, gastric mucosal prostaglandin production and Helicobacter pylori growth. Arzneim Forsch 1995; 45: 697–700
23.
Schumpelik VV, Farthmann E. Untersuchung zur protektiven wirkung von vitamin A beim stressulkus der ratte. Arzneim Forsch (Drug Res) 1976; 26: 386
24.
Harris PL et al. Dietary production of gastric ulcers in rats and prevention by tocopherol administration. Proc Soc Exp Biol Med 1947; 4: 273–277
25.
Oner G, Bor NM, Onuk E, Oner ZN. The role of zinc ion in the development of gastric ulcers in rats. Eur J Pharmacol 1981; 70: 241–243
26.
Formmer DJ. The healing of gastric ulcers by zinc sulphate. Med J Austr 1975; 2: 793
27.
Marle J et al. Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium. Eur J Pharm 1981; 72: 219
28.
Morgan A et al. A comparison between cimitidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982; 23: 545
29.
Tewari S, Trembalowicz F. Some experience with deglycyrrhizinated liquorice in the treatment of gastric and duodenal ulcers with special reference to its spasmolytic effect. Gut 1968; 9: 48
30.
Balakrishnan V et al. Deglycyrrhizinated liquorice in the treatment of chronic duodenal ulcer. J Asso Phys Ind 1978; 26: 811–814
31.
Rees WD et al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scan J Gastro 1979; 14: 605–607
32.
Zhou H, Jiao D. 312 cases of gastric and duodenal ulcer bleeding treated with 3 kinds of alcoholic extract rhubarb tablets. Chung Hsi I Chieh Ho Tsa Chih 1990; 10: 150–151, 131–132
33.
Best R, Lewis DA, Nasser N. The anti-ulcerogenic activity of the unripe plantain banana (Musa species). Br J Pharmacol 1984; 82: 107–116
34.
Sanyal AK, Gupa KK, Chowdhury NK. Banana and experimental peptic ulcer. J Pharm Pharmac 1963; 15: 283–284
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Chapter 181 - Periodontal disease Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Gingivitis – inflammation of the gingiva characterized by erythema, contour changes and bleeding • Periodontitis – localized pain, loose teeth, demonstration of dental pockets, erythema, swelling and/or suppuration. X-ray may reveal alveolar bone destruction.
GENERAL CONSIDERATIONS Periodontal disease is an inclusive term used to describe an inflammatory condition of the gingiva (gingivitis) and/or periodontium (periodontitis). Periodontal disease usually refers to a disease process that typically progresses from gingivitis to periodontitis. [1] [2] Periodontal disease may be a manifestation of a more systemic condition, such as diabetes mellitus, collagen diseases, leukemia or other disorders of leukocyte function, anemia, or vitamin deficiency states. [1] An association with atherosclerosis has also been reported. Since alveolar bone loss may be non-inflammatory, our definition of periodontal disease excludes the processes causing only tooth loss (the majority of which are due to osteoporosis or endocrine imbalances). [1] These conditions reflect systemic disease, with local factors playing only a minor role; therefore, the focus should be on treating the underlying condition rather than the “periodontal disease”. In this context, non-inflammatory alveolar bone loss should be viewed as a separate entity, as it involves a different etiology (see Ch. 177 ). The focus of this chapter is the use of nutrition and lifestyle improvement as an adjunctive therapy to aid in the control and prevention of the causes of inflammatory periodontal disease. This is a good example of a condition that is probably best treated with combined expertise, i.e. a dentist or periodontist and a nutritionally minded physician. Although oral hygiene is of great importance in treating and preventing periodontal disease,
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it is not sufficient in many cases. The host defense must be normalized if development and progression of the disease are to be controlled. nutritional status of the individual determines the status of host defense factors.
[1] [3]
To a large extent, the
Prevalence and epidemiology
The prevalence of periodontal disease increases directly with age. The rate of periodontal disease is approximately 15% at age 10, 38% at age 20, 46% at age 35, and 54% at age 50. As a group, men have a higher prevalence and severity of periodontal disease than women. Periodontal disease is inversely related to increasing levels of education and income. Rural inhabitants have a higher level of severity and prevalence than their urban counterparts. [1] Pathophysiology Understanding the underlying pathophysiology of any disease process leads to a more effective treatment plan. In periodontal disease this involves understanding the normal host protective factors in the periodontium. It has been concluded that: “Clearly bacteria are essential agents, but their presence is in itself insufficient; host factors must be involved if the disease is to develop and progress.” [3] Factors involved in host resistance include: • the environment of the gingival sulcus • bacterial factors • leukocyte function • complement activation • IgE and mast cell function • amalgam restoration • miscellaneous local factors • the structure and integrity of the collagen matrix of the periodontium and gingiva. Gingival sulcus
The gingival sulcus is the V-shaped crevice that surrounds each tooth, being bounded by the surface of the tooth on one side and the epithelium lining the free margin of the gingiva on the other. The anatomy of the gingival sulcus is ideal for growth of bacteria as it is resistant to the washing and cleaning action of saliva. Furthermore, the gingival fluid (sulcular fluid) provides a rich nutrient source for microorganisms. The clinical determination of the depth of the gingival sulcus is an important diagnostic parameter. Patients with periodontal disease should be monitored; biannual visits to the dentist should be sufficient in most cases. Bacterial factors
Bacterial plaque has long been considered the etiological agent in most forms of periodontal disease. [1] However, an appreciation of host defense factors has now developed.[1] [3] Bacteria are known to produce and secrete numerous compounds that are quite detrimental to the status of the host’s defense mechanisms. These compounds include:[1] • endotoxins and exotoxins • free radicals and collagen-destroying enzymes • leukotoxins • bacterial antigens, waste products, and toxic compounds. Polymorphonuclear leukocytes
Neutrophils (PMNs) constitute a first line of defense against microbial overgrowth. Defects in PMN functions are “catastrophic” to the periodontium. [1] [3] PMN functions are depressed in the geriatric population as a whole, and in patients with diabetes, Crohn’s disease, Chediak–Higashi syndrome, Down’s syndrome, and juvenile periodontitis. [1] [3] These patients are at extremely high risk for developing rapidly progressing periodontal disease, as are people with transient neutropenia. Transient
defects in PMN function may be responsible for the periods of quiescence and exacerbation noted in periodontal disease. As well as serving a vital role in protecting against periodontal disease, PMNs also play a major role in tissue destruction. PMNs release numerous free radicals, collagenases, hyaluronidases, inflammatory mediators, and an osteoclast stimulator. [1] [3] Macrophages and monocytes
These leukocytes are found in increased numbers in periodontal disease. As well as serving to phagocytize bacteria and debris, these cells are the primary source of prostaglandins in the diseased gingiva and release large quantities of enzymes believed to play a major role in collagen destruction. [1] [3] Lymphocytes
The major role lymphocytes play in periodontal disease is via lymphokine production. Their role in periodontal disease is overshadowed by the roles of the other immune system components discussed, but lymphokines are involved in promoting PMN and monocyte chemotaxis, fibroblast destruction, and osteoclast activation. [1] [3]
Complement
The complement system is composed of at least 22 proteins and accounts for more than 10% of the total serum
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globulin. Upon activation, complement components act in a cascade fashion. Complement can be activated via the classical or alternative pathway. The complement system plays a critical role in immunological and non-specific resistance to infection and in the pathogenesis of tissue injury. The products of complement activation regulate a number of events, including the release of mediators from mast cells; promotion of smooth muscle contraction; chemotaxis of PMNs, monocytes, and eosinophils; and phagocytosis by immune adherence. [4] The net effect is an increase in gingival permeability, resulting in increased penetration of bacteria and bacterial by-products and, in essence, the initiation of a positive feedback cycle. [1] [3] Other effects of complement activation include solubilization of immune complexes, cell membrane lysis, neutralization of viruses, and the killing of bacteria. periodontal disease, activation of complement via the alternative pathway within the periodontal pocket is possibly the major factor in tissue destruction.
[4]
In
Mast cells and IgE
Mast cell degranulation is also a major factor in periodontal disease. Degranulation results in the release of inflammatory mediators, i.e. histamine, prostaglandins, leukotrienes, kinins, serotonin, heparin, and serine proteases. [1] Mast cell degranulation can be initiated by IgE complexes, complement components, mechanical trauma, endotoxins, and free radicals. The finding of increased IgE concentrations in the gingiva of patients with periodontal disease suggests that allergic reactions may be a factor in the progression of the disease in some patients. [5] Amalgam restorations
Faulty dental restorations and prostheses are common causes of gingival inflammation and periodontal destruction. [1] Overhanging margins provide an ideal location for the accumulation of plaque and the multiplication of bacteria. If the restoration is a silver amalgam filling there may be even more involvement, due to decreased activities of antioxidant enzymes. Mercury accumulation results in a depletion of the free radical-scavenging enzymes, glutathione peroxidase, superoxide dismutase, and catalase. [6] The proteoglycans and glycosaminoglycans of the collagen matrix are particularly sensitive to free radical damage. [7] Miscellaneous local factors
Numerous local factors favor the progression of periodontal disease. These include: • food impaction • unreplaced missing teeth • malocclusion • tongue thrusting • bruxism • toothbrush trauma • mouth breathing • tobacco (discussed below). Tobacco
Tobacco smoking is associated with increased susceptibility to severe periodontal disease and tooth loss. [1] [8] [9] (Tobacco smoking is associated with increased susceptibility to virtually every major chronic disease.) Many of the harmful effects of tobacco smoking are a result of free radical damage, particularly to epithelial cells. Furthermore, smoking greatly reduces ascorbic acid levels, thereby potentiating its damaging effects. [10] Carotenes and flavonoids have been shown to greatly reduce some of the toxic effects of smoking.[11] [12] Structure and integrity of collagen matrix
The collagen matrix of the periodontal membrane serves as periosteum to the alveolar bone and allows the dissipation of the tremendous amount of pressure exerted during mastication.[13] The status of the collagen matrix of the periodontium, specifically the extracellular proteoglycans of the gingival epithelium, determines the rate of diffusion and the permeability of inflammatory mediators, bacteria and their by-products, and destructive enzymes from the oral cavity. [14] [15] Due to the high rate of protein turnover in periodontal collagen, the integrity of the collagen matrix in this area is extremely vulnerable to atrophy when the necessary cofactors for collagen synthesis (e.g. protein, vitamin C, B 6 and A, zinc, copper, etc.) are absent or deficient. [13] The collagen of the periodontium is particularly rich in glycosaminoglycans. [13] [14] [15] [16] Heparin sulfate, dermatan sulfate, and chondroitin 4-sulfate are the major glycosaminoglycans present. Stabilization of collagen is the major treatment goal outlined below.
THERAPEUTIC CONSIDERATIONS Therapeutic goals in treating periodontal disease from a nutritional perspective are: • decrease wound healing time (the time span for wound healing is longer in patients who are more susceptible to periodontal disease • improve membrane and collagen integrity • decrease inflammation and free radical damage (inflammation can induce a vicious cycle and promote periodontal disease) • enhance immune status (defects in the immune 1488
system, particularly PMNs, are catastrophic to the periodontium).
[17]
)
Individual nutrients will be discussed below in the context of their role in achieving these therapeutic goals. Vitamin C
Vitamin C (ascorbic acid) plays a major role in preventing periodontal disease, as is evident from many experimental studies. [1] [18] [19] [20] [21] [22] The classical symptom of gingivitis seen in scurvy illustrates the vital function vitamin C plays in maintaining the membrane and collagen integrity and immunocompetence. Deficiency of vitamin C is associated with defective formation and maintenance of collagen, ground substance, and intercellular cement substance in mesenchymal tissue. [1] The defi-ciency effects on bone include retardation or cessation of osteoid formation, impaired osteoblastic activity, and osteoporosis. Subclinical vitamin C deficiency plays a significant role in periodontal disease via these effects and its role in delaying wound healing. [1] [18] [19] [20] [21] [22] Decreased vitamin C levels are also associated with increased permeability of the oral mucosa to endotoxin and bacterial by-products, as well as impaired leukocyte functions (particularly PMNs). The role vitamin C plays in increasing chemotaxis and phagocytosis by PMNs is best exemplified by its effect on Chediak–Higashi syndrome. This autosomal recessive trait is associated with compromised PMN and monocyte chemotaxis and phagocytosis, all of which are responsive to vitamin C supplementation. [23] This syndrome is also associated with an extremely rapidly progressing periodontitis. [1] [3] Vitamin C’s other effects on immune status include enhancing lymphoproliferative response to mitogens and increasing interferon levels, antibody response, immunoglobulin levels, and secretion of thymic hormones. Vitamin C also possesses significant antioxidant and anti-inflammatory properties and decreases wound healing time. [24] Sucrose
Sugar is known to significantly increase plaque accumulation while simultaneously decreasing PMN chemotaxis and phagocytosis. is due to osmotic effects and competition with vitamin C.
[1] [ 25]
This inhibition of PMN function
Vitamin C and glucose are known to compete for intracellular transport sites, with this intracellular transport being largely insulin-dependent (see Ch. 53 for further information on nutrient factors and immune function). Considering the fact that the average American consumes in excess of 175 g/day of sucrose and other refined carbohydrates, it is safe to say that most Americans have a chronically depressed immune status which puts them at increased risk for periodontal disease. [26] Vitamin A
A vitamin A deficiency predisposes to periodontal disease. Deficiency of vitamin A is associated with:
[1]
• keratinizing metaplasia of the gingival epithelium • early karyolysis of gingival epithelial cells • inflammatory infiltration and degeneration • periodontal pocket formation • gingival calculus formation • increased susceptibility to infection • abnormal alveolar bone formation. Vitamin A is necessary for collagen synthesis and wound healing, maintaining the integrity of epithelial and mucosal surfaces and their secretions, and enhancing numerous immune functions.[24] Beta-carotene may be a more advantageous supplement due to its affinity for epithelial tissue and potent antioxidant activity. [12] Zinc and copper
Zinc functions synergistically with vitamin A in many metabolic processes. [27] The severity of periodontal disease is positively associated with increased serum copper levels while zinc levels are significantly decreased, i.e. an increased copper to zinc ratio. [28] This is consistent with other causes of chronic inflammation and signifies activation of metallothionein, which increases ceruloplasmin formation while increasing zinc sequestration in response to inflammation. [27] Zinc’s importance in treating periodontal disease cannot be overstated. In the United States, marginal zinc deficiency is widespread, particularly in the elderly. [28] [29] This may be a factor in the increasing prevalence of periodontal disease with age, although the geriatric population as a whole is at higher risk for development of numerous nutrient deficiencies. Zinc functions in the gingiva and periodontium include: [24] [27] [29] [30] [31] • stabilization of membranes • inhibition of calcium influxes • antioxidant activity • metallo-component in at least 40 enzymes including enzymes for DNA, RNA, and collagen synthesis • inhibition of plaque growth • inhibition of mast cell degranulation • numerous immune activities, including increased PMN chemotaxis and phagocytosis. Zinc is also known to significantly reduce wound healing time. [24] [27] Zinc’s positive effects in established periodontal disease are also due to its action on calcium- and calmodulin-mediated
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processes such as mast cell degranulation, tissue damage induced by endotoxin, and increased vascular permeability. responsible for much of the tissue destruction seen in periodontal disease. [32]
[27]
These calcium-mediated events are
Regular (twice daily) use of a mouthwash that contains a 5% zinc solution inhibits plaque growth. [30] However, lower concentrations or less frequent mouth washing are not particularly successful. Vitamin E and selenium
These two nutrients function synergistically in antioxidant mechanisms and seem to potentiate each other’s effect. Vitamin E alone has been demonstrated to be of considerable value in patients with severe periodontal disease. [1] [33] This can largely be attributed to the decreased wound healing time associated with vitamin E. [34] The antioxidant effects of vitamin E are particularly needed if silver amalgam is present. Mercury depletes the tissues of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. In animal studies, this toxic effect of mercury is prevented by supplementation with vitamin E. [6] Selenium and vitamin E’s antioxidant activities also deter periodontal disease, as the effects of free radicals are extremely damaging to gingival proteo- and glycosaminoglycans. [7] Coenzyme Q
Ubiquinone, an essential coenzyme involved in mitochondrial oxidative phosphorylation, is also an effective antioxidant. [35] [36] Coenzyme Q is widely used in Japan for many conditions, including periodontal disease. A review of seven studies using coenzyme Q found that 70% of the 332 patients involved responded favorably to supplementation. [35] A double-blind study comprising 56 subjects found the supplemented group to respond significantly, while the placebo group displayed very little
change in periodontal pocket depth and tooth mobility. [36] Flavonoids
As a group, these compounds are perhaps the most important components of an anti-periodontal disease program. Flavonoids are extremely effective in reducing inflammation and stabilizing collagen structures. Flavonoids affect collagen structure by: [37] [38] [39] [40] [41] [42] • decreasing membrane permeability, thereby decreasing the load of inflammatory mediators and bacterial products • preventing free radical damage with their potent antioxidant properties • inhibiting enzymatic cleavage by hyaluronidases and collagenases • inhibiting mast cell degranulation • cross-linking with collagen fibers directly. The more biologically active flavonoids, i.e. quercetin, catechin, anthocyanidins, and proanthocyanidins, should be supplemented, as rutin has very little collagenstabilizing effect. Remarkable effects have been displayed by 3-0-methyl-(+)-catechin in the treatment of hamsters with experimentally induced periodontitis. Large doses of this flavonoid derivative significantly retarded plaque growth and alveolar bone resorption. [43] Folic acid
The use of folate, either topically or systemically, in double-blind studies produced significant reductions of gingival inflammation as determined by reduction in color changes, bleeding tendency, gingival exudate flow, and plaque scores. [44] [45] [46] [47] [48] The folate mouthwash, 0.1% folic acid, is significantly more effective than the oral supplementation of either 2 or 5 mg/day, suggesting a local mechanism of action. [46] [47] Folate has been demonstrated to bind plaque-derived endotoxin. [46] [47] [48] The use of folate mouthwash is particularly indicated for pregnant women and oral contraceptive users, and for other conditions associated with an exaggerated gingival inflammatory response or folate anti-metabolites (e.g. phenytoin, methotrexate). [46] [47] Epithelial cells of the cervix and the oral cavity appear to suffer from a similar “end-organ” deficiency of folic acid under the hormonal influences of pregnancy and oral contraceptive use. [47] [49] [50] The cervical dysplasia associated with oral contraceptive use also responds to pharmacological doses of folic acid, i.e. 8–30 mg/day. [49] [50] (Whitehead’s work [49] was the inspiration for the use of folic acid by Pack & Thomson [46] [47] in the treatment of gingivitis of pregnancy.) The sera and leukocytes of pregnant women and oral contraceptive users contain a macromolecule that binds folate, which, more than malabsorption or decreased intake, appears to be the major factor for the “end-organ” folate deficiency. [51] (It should be noted, however, that folic acid deficiency is the most common deficiency in the world. [24] ) Double-blind studies have shown that the beneficial effects of folic acid are not limited to women, periodontitis improves as well. [48]
[44] [45] [48]
and the positive effects are not limited to just gingivitis, since
Botanical medicines A number of botanical compounds have shown an ability to inhibit plaque formation, including green
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tea polyphenols and glycyrrhetinic acid from licorice, but the most extensively studied compound is an alcoholic extract of Sanguinaria canadensis. Sanguinaria canadensis
Bloodroot contains a mixture of benzophenanthridine alkaloids, but chiefly sanguinarine is available in commercial toothpastes and mouth rinses. Sanguinarine demonstrates properties useful in preventing dental plaque formation. It has broad antimicrobial activity as well as anti-inflammatory properties. In vitro studies indicate that the anti-plaque action of sanguinaria is due to its ability to inhibit bacterial adherence. Electron microscopic studies of bacteria exposed to sanguinarine demonstrate that bacteria aggregate and become morphologically irregular. [52] Sanguinarine appears to be less effective than chlorhexidine mouthwash, but it is effective in many cases and does have the advantage of being a natural compound versus a synthetic. [52] [53] Centella asiatica
An extract containing the triterpenoids of Centella asiatica (gotu kola) has demonstrated impressive wound healing properties (see Ch. 74 ). These properties can be put to good use in severe periodontal disease or if there is a requirement for surgery. One study demonstrated that centella extract was quite helpful in speeding up recovery after laser surgery for severe periodontal disease. [54]
THERAPEUTIC APPROACH As discussed above, many factors are involved in the initiation and promotion of periodontal disease. Effective therapy requires that all relevant factors be controlled. Since there are as yet no clear guidelines for determining which factors are most important for a given patient, a general approach is recommended here. All smoking patients should be assisted in stopping as continued smoking greatly decreases the success of any therapy for periodontal disease. Hygiene
Periodic visits to a dentist, as needed, to eliminate plaque and calculus accumulation. Brushing after meals and daily flossing are necessary. Diet
A diet high in dietary fiber may have a protective effect via increased salivary secretion.
[ 18]
Avoidance of sucrose and all refined carbohydrates is extremely important.
Supplements
• Vitamin C: 3–5 g/day in divided doses • Vitamin E: 400–800 IU/day • Beta-carotenes: 250,000 IU/day (higher doses if indicated) for up to 6 months (although not clinically tested in this condition, beta-carotenes are recommended instead of vitamin A due to their similar effects and greater safety) • Selenium: 400 mcg/day • Zinc: 30 mg/day of Zn picolinate (60 mg/day if another form); wash mouth with 15 ml of a 5% solution two times/day • Folic acid: 2 mg/day; wash mouth with 15 ml of a 0.1% solution two times/day • Quercetin: 500 mg three times/day. Botanical medicines
High-flavonoid-containing extracts, such as those from bilberry ( Vaccinium myrtillus), hawthorn (Crataegus sp.), grape seed (Vitis vinifera), or green tea (Camellia sinensis), can be used according to the dosages in the corresponding chapter. Of these extracts, green tea extract or the liberal consumption of green tea as a
beverage may be the most cost-effective. For a green tea extract with a 50% polyphenol content, the dosage would be 200–300 mg twice daily. • Sanguinaria canadensis: use toothpaste containing extract • Centella asiatica triterpenoids: 30 mg twice daily of pure triterpenoids.
REFERENCES 1. Carranza 2. Robbins 3. Page
F. Glickman’s clinical periodontology. Philadelphia, PA: WB Saunders. 1984
S, Cotran R. Pathologic basis of disease. Philadelphia, PA: WB Saunders. 1979: p 893–895
R, Schroeder H. Current status of the host response in chronic marginal periodontitis. J Periodontal 1981; 52: 477–491
4. James
K. Complement. Activation, consequences, and control. Am J Med Tech 1982; 48: 735–743
5. Hyyppa 6. Addya
T. Gingival IgE and histamine concentrations in patients with periodontitis. J Clin Periodontal 1984; 11: 132–137
S, Chakravarti K, Basu A et al. Effects of mercuric chloride on several scavenging enzymes in rat kidney and influence of vitamin E supplementation. Acta Vitaminol Enzymol 1984; 6:
103–107 7. Bartold
P, Wiebkin O, Thonard J. The effect of oxygen-derived free radicals on gingival proteoglycans and hyaluronic acid. J Periodontal Res 1984; 19: 390–400
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8. Schenkein 9. Kaldahl
HA, Gunsolley JC, Koertge TE. Smoking and its effects on early-onset periodontitis. J Am Dental Assoc 1995; 126: 1107–1113
WB et al. Levels of cigarette consumption and response to periodontal therapy. J Periodont 1996; 67: 675–681
10.
Pelletier O. Smoking and vitamin C levels in humans. Am J Clin Nutr 1968; 21: 1259–1267
11.
Prerovsky I, Hladovec J. Suppression of the desquamating effect of smoking on the human endothelium by hydroxyethylrutosides. Blood Vessels 1979; 16: 239–240
12.
Burton G, Ingold K. Beta-Carotene. An unusual type of lipid antioxidant. Science 1984; 224: 569–573
13.
Junqueira L, Carneiro J. Basic histology. Los Altos, CA: Lange Medical. 1980: p 312
14.
Bartold P, Wiebkin O, Thonard J. The active role of gingival proteoglycans in periodontal disease. Med Hypothesis 1983; 12: 377–387
15.
Bartold P, Wiebkin O, Thonard J. Proteoglycans of human gingival epithelium and connective tissue. Biochem J 1983; 11: 119–127
16.
Bartold P, Wiebkin O, Thonard J. Glycosaminoglycans of human gingival epithelium and connective tissue. Connective Tissue Research 1981; 9: 99–106
17.
Abbas F, van der Velden U, Hart A. Relation between wound healing after surgery and susceptibility to periodontal disease. J Clin Periodontal 1984; 11: 221–229
18.
Alvares O. Nutrition, diet and oral health. In: Worthington-Roberts B, ed. Contemporary developments in nutrition. St Louis, MI: Mosby. 1981: ch. 14
19.
Alvares O, Altman L, Springmeyer S et al. The effect of subclinical ascorbate deficiency on periodontal disease in nonhuman primates. J Periodontal Res 1984; 16: 628–636
20.
Woolfe S, Hume W, Kenney E. Ascorbic acid and periodontal disease: a review of the literature. J Western Soc Periodontal 1980; 28: 44–60
21.
Alfano M, Miller S, Drummond J. Effect of ascorbic acid deficiency on the permeability and collagen biosynthesis of oral mucosal epithelium. Ann NY Acad Sci 1975; 258: 253–263
22.
Alvares O, Siegel I. Permeability of gingival sulcular epithelium in the development of scorbutic gingivitis. J Oral Path 1981; 10: 40–48
23.
Stephens C, Snyderman R. Cyclic nucleotides regulate the morphologic alterations required for chemotaxis in monocytes. J Immunol 1982; 128: 1192–1197
24.
Krause M, Mahan L. Food, Nutrition and Diet Therapy. Philadelphia, PA: WB Saunders. 1984
25.
Ringsdorf W, Cheraskin E, Ramsay R. Sucrose, neutrophil phagocytosis and resistance to disease. Dent Surv 1976; 52: 46–48
26.
Sanchez A, Reeser J, Lau H et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr 1973; 26: 1180–1184
27.
Prasad A. Clinical, biochemical and nutritional spectrum of zinc deficiency in human subjects: an update. Nutr Rev 1983; 41: 197–208
28.
Freeland J, Cousins R, Schwartz R. Relationship of mineral status and intake to periodontal disease. Am J Clin Nutr 1976; 29: 745–749
29.
Nordstrom J. Trace mineral nutrition in the elderly. Am J Clin Nutr 1982; 36: 788–795
30.
Harrap G, Saxton C, Best J. Inhibition of plaque growth by zinc salts. J Periodontal Res 1983; 18: 634–642
31.
Hsieh S, Hayali A, Navia J. Zinc. In: Curzon M, Cutress T, eds. Trace elements in dental disease. Boston, MA: John Wright PSG. 1983: p 99–220
32.
Aleo J, Padh H, Subramoniam A. Possible role of calcium in periodontal disease. J Periodontal 1984; 55: 642–647
33.
Hazan S, Cowan E. Diet, nutrition and periodontal disease. Chicago, IL: Am Soc Prev Dent. 1975
34.
Kim J, Shklar G. The effect of vitamin E on the healing of gingival wounds in rats. J Periodontal 1983; 54: 305–308
35.
Folkers K, Yamamura Y. Biomedical and clinical aspects of coenzyme Q, vol 1. Amsterdam: Elsevier/North Holland Biomedical Press. 1977: p 294–311
36.
Folkers K, Yamamura Y. Biomedical and clinical aspects of coenzyme Q, vol 3. Amsterdam: Elsevier/North Holland Biomedical Press. 1981: p 109–125
37.
Monboisse J, Braquet P, Borel J. Oxygen-free radicals as mediators of collagen breakage. Agents Actions 1984; 15: 49–50
38.
Rao C, Rao V, Steinman B. Influence of bioflavonoids on the metabolism and cross linking of collagen. Ital J Biochem 1981; 30: 259–270
39.
Ronziere M, Herbage D, Garrone R, Frey J. Influence of some flavonoids on reticulation of collagen fibrils in vitro. Biochem Pharm 1981; 30: 1771–1776
40.
Jones C, Cummings C, Ball J, Beighton P. A clinical and ultrastructural study of osteogenesis imperfecta after flavonoid (Catergen) therapy. S Afr Med J 1984; 66: 907–910
41.
Pearce F, Befus A, Bienenstock J. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allerg Clin Immunol 1984; 73: 819–823
42.
Busse W, Kopp D, Middleston E. Flavonoid modulation of human neutrophil function. J Allerg Clin Immunol 1984; 73: 801–809
43.
Gineste M, de Grousaz P, Duffort JF et al. Influence of 3-methoxy 5,7,3´4´-tetrahydroxyflavan (ME) on experimental periodontitis in the golden hamster. J Biol Buccale 1984; 12: 259–265
44.
Vogel R, Fink R, Schneider L et al. The effect of folic acid on gingival health. J Periodontal 1976; 47: 667–668
45.
Vogel R, Fink R, Schneider L et al. The effect of topical application of folic acid on gingival health. J Oral Med 1978; 33: 20–22
46.
Pack A, Thomson M. Effects of topical and systemic folic acid supplementation on gingivitis in pregnancy. J Clin Periodontal 1980; 7: 402–404
47.
Pack A, Thomson M. Effects of extended systemic and topical folate supplementation on gigivitis of pregnancy. J Clin Periodontal 1982; 9: 275–280
48.
Pack A. Folate mouthwash. Effects on established gingivitis in periodontal patients. J Clin Periodontal 1984; 11: 619–628
49.
Whitehead N, Reyner F, Lindenbaum J. Megaloblastic changes in the cervical epithelium association with oral contraceptive therapy and reversal with folic acid. JAMA 1973; 226: 1421–1424
50.
Butterworth C, Hatch K, Gore H et al. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982; 35: 73–82
51.
da Costa M, Rothenberg S. Appearance of folate binder in leukocytes and serum of women who are pregnant or taking oral contraceptives. J Lab Clin Med 1974; 83: 207–214
52.
Godowski KC. Antimicrobial action of sanguinarine. J Clin Dent 1989; 1: 96–101
Grossman E, Meckel AH, Isaacs RL. A clinical comparison of antibacterial mouthrinses. Effects of chlorhexidine, phenolics, and sanguinarine on dental plaque and gingivitis. J Periodontol 1989; 60: 435–440 53.
Benedicenti A, Galli D, Merlini A. The clinical therapy of periodontal disease: the use of potassium hydroxide and the water-alcohol extract of Centella asiatica in combination with laser therapy in the treatment of severe periodontal disease. Parodontol Stomatol 1985; 24: 11–26 54.
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Chapter 182 - Pneumonia: bacterial, mycoplasmal, and viral Michael T. Murray ND Joseph E. Pizzorno Jr ND
GENERAL CONSIDERATIONS Acute pneumonia is still the fifth leading cause of death in the United States. It is particularly dangerous in the elderly. Although pneumonia may appear in healthy individuals, it is usually seen in immune-compromised individuals, particularly in drug and alcohol abusers. The growing population of those with chronic lung diseases and other debilitating illnesses and the use of respiratory therapy, immunosuppressive drugs, and other such technologies have contributed to further increase of nosocomial and opportunistic pneumonias, which have very high mortality rates. In healthy individuals, pneumonia most often follows an insult to the host defense mechanisms: viral infection (especially influenza), cigarette smoke and other noxious fumes, impairment of consciousness (which depresses the gag reflex, allowing aspiration), neoplasms, and hospitalization (see Table 182.1 ). The airway distal to the larynx is normally sterile due to several protective mechanisms, both mechanical and humoral. The mucus-covered ciliated epithelium which lines the lower respiratory tract propels sputum to the larger bronchi and trachea, evoking the cough reflex. The respiratory secretions contain substances which exert non-specific antimicrobial actions: alpha- 1-antitrypsin, lysozyme, and lactoferrin. At the level of the alveoli, potent defense mechanisms are present, including alveolar macrophages, a rich vasculature TABLE 182-1 -- Etiologies of common pneumonias[1] Type
Percentage
Viral
20
(influenza)
(3)
Mycoplasmal
10–20
Bacterial
12
Bacterial superimposed on viral
6
Chlamydia
10
Unknown cause (legionnaires’, toxic)
38
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capable of rapidly delivering lymphocytes and granulocytes, and an efficient lymphatic drainage network. Immunoglobulin respiratory system defenses IgA
IgA is present in high concentrations in the secretions of the upper respiratory tract, and protects against viral infection. In the lower tract, IgA aids in: • agglutinating bacteria • neutralizing microbial toxins • reducing bacterial attachment to mucosal surfaces • activating the alternative complement pathway when complexed with an antigen. IgG
IgG is present in the lower respiratory tract. It: • serum agglutinates and opsonizes bacteria • activates complement • promotes chemotaxis of granulocytes and macrophages • neutralizes bacterial toxins and viruses • lyses Gram-negative bacteria.
THERAPEUTIC CONSIDERATIONS FOR ALL TYPES OF PNEUMONIA Expectorants
Botanical expectorants have a long history of use in pneumonia. They act to increase the quantity, decrease the viscosity, and promote expulsion of the secretions of the respiratory mucous membranes. Many also have antibacterial and antiviral activity. Some expectorants are also antitussives; however, Lobelia inflata, a commonly used expectorant, actually helps promote the cough reflex. [2] Therefore, lobelia is much more effective at clearing the lungs than an expectorant like Glycyrrhiza glabra (licorice) which also exerts some antitussive effect. If the cough is productive, use lobelia. If it is non-productive use licorice. Other useful expectorants include balsam of Peru, senega root, grindelia, wild cherry bark, and horehound. In addition, bromelain (the proteolytic enzyme complex from pineapple) can be used as a mucolytic (discussed under “Pneumococcal pneumonia”). Vitamin C
In the early part of this century, before the advent of effective antibiotics, many controlled and uncontrolled studies demonstrated the efficacy of large doses of vitamin C, but only when started on the first or second day of infection. [3] If administered later, vitamin C tended only to lessen the severity of the disease. Researchers also demonstrated that in pneumonia white cells take up large amounts of vitamin C. [3] The value of vitamin C supplementation in elderly patients with pneumonia was demonstrated quite clearly in a recent double-blind study of 57 elderly patients
hospitalized for severe acute bronchitis and pneumonia. [4] The patients were given either 200 mg/day of vitamin C or a placebo. Patients were assessed by clinical and laboratory methods (vitamin C levels in the plasma, white blood cells, and platelets; sedimentation rates; and white blood cell counts and differential). Patients receiving the modest dosage of vitamin C demonstrated substantially increased vitamin C levels in all tissues even in the presence of an acute respiratory infection. Using a clinical scoring system based on major symp-toms of respiratory infections, results indicated that the patients receiving the vitamin C fared significantly better than those on placebo. The benefit of vitamin C was most obvious in patients with the most severe illness, many of whom had low plasma and white blood cell vitamin C levels on admission. Vitamin A
Vitamin A supplementation appears to be of value in pneumonia, especially in children with measles. This may be due to the increased rate of excretion of vitamin A found during severe infections such as pneumonia. An interesting study evaluated 29 patients with pneumonia and sepsis and found their mean excretion rate of vitamin A was 0.78 µmol/day. Subjects with fever excreted significantly more retinol than did those without fever. A remarkable 34% of the patients excreted more than 1.75 µmol/day of retinol, which is equivalent to 50% of the US RDA. [5] This may be particularly important for children. A randomized double-blind trial of 189 children with measles (average age 10 months) in South Africa evaluated the efficacy of vitamin A in reducing complications. Providing 400,000 IU (120 mg retinyl palmitate), half on admission and half a day later, reduced the death rate by more than 50%, and the duration of pneumonia, diarrhea and hospital stay by 33%. [6] However, another study did not show any benefit from vitamin A supplementation. The difference may be due to the lower dosage (100,000 IU) or to the fact that it was not limited to children with pneumonia as a complication of measles, a condition known to also decrease vitamin A levels. [7] Vitamin E
Patients with influenza complicated by pneumonia experience a sharp rise in lipid peroxidation (LPO) products,
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especially those who are seriously ill. Administration of alpha-tocopherol promotes a significant decrease in LPO levels and more apparent clinical response.
[ 8]
Bromelain
Bromelain is a useful adjunct therapy for pneumonia due to its fibrinolytic, anti-inflammatory, and mucolytic actions and enhancement of antibiotic absorption. Bromelain’s mucolytic activity is responsible for its particular effectiveness in respiratory tract diseases including pneumonia, bronchitis, and sinusitis. [10]
[9]
THERAPEUTIC APPROACH FOR ALL TYPES OF PNEUMONIA The general approach to all pneumonias includes enhancement of the immune system and support of respiratory tract drainage (for a full discussion of immune system stimulation, see Ch. 53 ). Drainage is supported by the use of local heat, massage, and expectorants. For more discussion on cause-specific therapies for the various pneumonias, see the subsections below. Supplements
• Vitamin A: 50,000 IU/day for 1 week; or beta-carotene: 200,000 IU/day (Note: do not use vitamin A in menstruating women, due to teratogenic effect) • Vitamin C: 500 mg every 2 hours • Vitamin E: 200 IU/day • Bioflavonoids: 1,000 mg/day • Zinc: 30 mg/day • Thymus extract: the equivalent to 120 mg pure polypeptides with molecular weights less than 10,000 or roughly 500 mg of the crude polypeptide fraction. Botanicals
• Lobelia inflata —dried herb: 0.2–0.6 grams three times/day —tincture: 15–30 drops three times/day —fluid extract: 8–10 drops three times/day • Echinacea sp. —dried root (or as tea): 0.5–1 g —freeze-dried plant: 325–650 mg —juice of aerial portion of Echinacea purpurea stabilized in 22% ethanol: 2–3 ml —tincture (1:5): 2–4 ml —fluid extract (1:1): 2–4 ml —solid (dry powdered) extract (6.5:1 or 3.5% echinacoside): 150–300 mg
Physical therapy
• Diathermy to chest and back: 30 min/day • Mustard poultice: once/day • Lymphatic massage: three times/day • Postural drainage: three times/day. For best results, use diathermy, then lymphatic massage, and finally postural drainage.
MYCOPLASMAL PNEUMONIA DIAGNOSTIC SUMMARY • Most commonly occurs in children or young adults • Insidious onset over several days • Non-productive cough, minimal physical findings, temperature generally less than 102°F
• Headache and malaise are common early symptoms • WBC is normal or slightly elevated • X-ray pattern patchy or inhomogeneous.
THERAPEUTIC CONSIDERATIONS Mycoplasma are bacteria that lack cell walls. Mycoplasma pneumoniae is the most frequent cause of community-acquired, non-pyogenic pneumonia. Trachobronchitis is more common than pneumonia, often with pharyngitis (especially in children). Slow recovery is the general rule, but the course is quite variable. As there are no specific natural medicine recommendations for mycoplasmal infections available at this time, an antibiotic, typically an erythromycin, is indicated. Enhancement of general immune function is recommended.
ADDITIONAL THERAPIES Antibiotic
• Erythromycin: 250–500 mg four times/day.
PNEUMOCOCCAL (STREPTOCOCCAL) PNEUMONIA DIAGNOSTIC SUMMARY • Pneumonia usually preceded by upper respiratory tract infection • Sudden onset of shaking, chills, fever, and chest pain • Sputum is pinkish or blood-specked at first, then becoming rusty at the height of the infection, and finally yellow and mucopurulent during resolution • Gram-positive diplococci are present in the sputum smear • Initially chest excursion is diminished on the 1496
involved side, breath sounds suppressed, and fine inspiratory rales are heard • Later classic signs of consolidation appear (bronchial breathing, crepitant rales, dullness) • Leukocytosis • X-ray shows lobar or segmental consolidation.
THERAPEUTIC CONSIDERATIONS Pneumococcal pneumonia (Streptococcus pneumoniae) is the most common bacterial pneumonia and the most common cause of pneumonia requiring hospitalization. Careful clinical judgment is necessary in determining the severity of the disease and the status of the patient’s immune system, since it is often necessary to administer antibiotics or to refer for hospitalization. A blood culture is a more accurate method of diagnosis than sputum culture, since 15–25% of all cultures are positive early in the disease, regardless of whether the patient has a bacterial pneumonia or not. This is not surprising, since the nasopharynx is the natural habitat of the pneumococcus (humans are the only known hosts). Bovine spleen extracts
The most specific natural medicine for pneumococcal pneumonia appears to be bovine spleen extracts (see Ch. 41 ). The importance of spleen function in preventing pneumococcal pneumonia is demonstrated by examining post-splenectomy syndrome. One of the hallmark features of this syndrome is an increased risk of pneumococcal pneumonia. About 2.5% of patients having their spleen removed will die from pneumococcal pneumonia within 5 years of splenectomy. It is often recommended that a child that has undergone a splenectomy receive a pneumococcal vaccine and receive long-term antibiotic treatment. Use of spleen extracts, especially those rich in tuftsin, may be an effective natural alternative. As far back as the 1930s, orally administered bovine spleen extracts were shown to possess some physiological action in increasing white blood cell counts in patients with extreme deficiencies of white blood cells, as well as being of some benefit in patients with malaria and typhoid fever. [11] [12] [13] Hydrastis canadensis
Hydrastis canadensis and probably other berberine-containing botanicals are very important in treating this difficult infection. Berberine has well documented antibiotic activity against pathogenic streptococci. [14] In addition, its sparing effect on the normal gastrointestinal microbial flora is an advantage as compared with conventional antibiotics. Antibiotics
Bacterial pneumonia is one of the conditions in which the conventional antibiotic approach, typically penicillin G or V, is clearly of great value for the patient. In general, an appropriately prescribed course of antibiotics will lead to substantial clinical improvement within a few days.
ADDITIONAL THERAPIES Supplements
• Bovine spleen extracts: hydrolyzed (predigested) products concentrated for tuftsin and splenopentin content are preferable to crude preparations – 50 mg/day tuftsin and splenopentin or roughly 1.5 g/day of total spleen peptides • Bromelain (1,200 to 1,800 mcu): 500–750 mg three times/day between meals. Botanical medicines
Hydrastis canadensis. The dosage should be based on berberine content. As there is a wide range of quality in goldenseal preparations, standardized extracts are recommended. Three times a day dosages as follows: • dried root or as infusion (tea): 2–4 g • tincture (1:5): 6–12 ml (1.5–3 tsp) • fluid extract (1:1): 2–4 ml (0.5–1 tsp) • solid (powdered dry) extract (4:1 or 8–12% alkaloid content): 250–500 mg. Antibiotic
• Penicillin V: 500 mg four times/day (for uncomplicated cases).
VIRAL PNEUMONIA DIAGNOSTIC SUMMARY • Onset typical of influenza: fever, myalgia, and headache • Other symptoms, signs, and X-ray findings are similar to mycoplasmal pneumonia.
THERAPEUTIC CONSIDERATIONS In addition to the treatment recommendations given under the general discussion of pneumonia, Glycyrrhiza glabra (licorice) is useful for its antiviral properties, immune-enhancing effects, and expectorant effects (see Ch. 90 ). Note, however, that glycyrrhiza does have some antitussive effect. In the case of viral pneumonia, this action is usually warranted. However, if the cough is productive, use lobelia.
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ADDITIONAL THERAPY • Glycyrrhiza glabra (licorice) —powdered root: 1–2 g —fluid extract (1:1): 2–4 ml —solid (dry powdered) extract (4:1): 250 to 500 mg.
REFERENCES 1. Branch
WT Jr. Office practice of medicine Philadelphia, PA: WB Saunders. 1982: p 57–76
2. Cambar
P, Shore S, Aviado D. Bronchopulmonary and gastrointestinal effects of lobeline. Arch Int Pharmacodyn 1969; 177: 1–27
3. Bicknell
F, Prescott F. The vitamins in medicine Lee Foundation, 1953.
4. Hunt
C, Chakravorty NK, Annan G. The clinical effects of vitamin C supplementation in elderly hospitalized patients with acute respiratory infections. Internat J Vit Nutr Res 1994; 64: 212–219
5. Stephensen 6. Hussey
CB, Alvarez JO, Kohatsec J. Vitamin A is excreted in the urine during acute infection. Am J Clin Nutr 1994; 60: 388–392
GD, Klein MM. A randomized, controlled trial of vitamin A in children with severe measles. New Engl J Med 1990; 323: 160–164
7. Kjolhede
CL, Chew FJ, Gadomski AM, Marroquin DP. Clinical trial of vitamin A as adjuvant treatment for lower respiratory tract infections. J Pediatr 1995; 126: 807–812
8. Nagibina
MV, Neifakh EA, Krylov VF et al. The treatment of pneumonias in influenza using antioxidants. Ter Arkh 1996; 68: 33–35
9. Kelly
GS. Bromelain. A literature review and discussion of its therapeutic applications. Alt Med Rev 1996; 1: 243–257
10.
Rimoldi R, Ginesu F, Giura R. The use of bromelain in pneumological therapy. Drugs Exp Clin Res 1978; 4: 55–66
11.
Minter MM. Agranulocytic angina: treatment of a case with fetal calf spleen. Texas State J Med 1933; 2: 338–343
12.
Gray GA. The treatment of agranulocytic angina with fetal calf spleen. Texas State J Med 1933; 29: 366–369
13.
Greer AE. Use of fetal spleen in agranulocytosis: preliminary report. Texas State J Med 1932; 28: 338–343
14.
Hahn F, Ciak J. Berberine. Antibiotics 1976; 3: 577–584
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Chapter 183 - Premenstrual syndrome Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Recurrent signs and symptoms that develop during the 7–14 days prior to menstruation • Typical symptoms include: decreased energy, tension, irritability, depression, headache, altered sex drive, breast pain, backache, abdominal bloating, and edema of the fingers and ankles.
GENERAL CONSIDERATIONS Premenstrual syndrome (PMS) is a recurrent condition of women characterized by troublesome symptoms 7–14 days before menstruation. [1] Typical symptoms include (see also Table 183.1 ): • decreased energy • tension • irritability • depression • headache • altered sex drive • breast pain • backache • abdominal bloating • edema of the fingers and ankles.
TABLE 183-1 -- Signs and symptoms of the premenstrual syndrome Behavioral • Nervousness, anxiety, and irritability • Mood swings and mild to severe personality change • Fatigue, lethargy, and depression Gastrointestinal • Abdominal bloating • Diarrhea and/or constipation • Change in appetite (usually craving of sugar) Female • Tender and enlarged breasts • Uterine cramping • Altered libido General • Headache • Backache • Acne • Edema of fingers and ankles
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PMS is estimated to affect between 30 and 40% of menstruating women, with peak occurrences among women in their 30s and 40s. In most cases symptoms are relatively mild; however, in about 10% of women symptoms can be quite severe. Severe PMS with depression, irritability, and severe mood swings is referred to as premenstrual dysphoric disorder. [2] Although PMS has been a well-defined clinical entity for over 60 years, many physicians argue that it really does not exist. [3] As a result many women suffering from PMS do not receive proper treatment. Instead they are told that it is “all in your head”. This view is gaining even more momentum as large pharmaceutical companies have recognized the huge market potential and began to sponsor clinical trials using psychotropic drugs (e.g. antidepressant drugs like Prozac and Zoloft; anti-anxiety drugs related to Valium; and gonadotropin-releasing hormone) to treat PMS symptoms despite the fact that risks due to side-effects appear to far outweigh the benefit. [4] A more rational approach to the problem of PMS is identification of the causative factors and appropriate treatment using dietary therapy, nutritional supplementation, and exercise. Hormonal patterns in women with PMS Although there is a wide spectrum of symptoms, there are common hormonal patterns in PMS patients when compared with women who have no symptoms of PMS. The primary finding is that estrogen levels are elevated and plasma progesterone levels are reduced 5–10 days before the menses, or the ratio of estrogen to progesterone is increased. In addition to this hormonal abnormality, hypothyroidism and/or elevated prolactin levels are common; FSH levels are typically elevated 6–9 days prior to the onset of menses and aldosterone levels are marginally elevated 2–8 days prior to the onset of menses. [1] [5] [6]
Corpus luteum insufficiency and PMS
PMS symptoms occur during the luteal phase of the menstrual cycle. During this phase, the corpus luteum plays an important role in the production of progesterone primarily, but also of estrogen. It is theorized by many researchers and clinicians that PMS reflects “corpus luteum insufficiency”. Corpus luteum insufficiency is usually diagnosed by measuring the level of progesterone in the blood 3 weeks after onset of menstruation. If the level in the blood is below 10–12 ng/ml, corpus luteal insufficiency is a strong possibility. In addition to PMS, corpus luteal insufficiency has also been linked to abnormal menstruation (excessive blood loss, absent, persistent, and more frequent menstruation), elevations in prolactin, and low thyroid function. [7]
DIAGNOSIS AND CLASSIFICATIONS Diagnosis of PMS is usually made by the association of the symptoms attributed to PMS and their occurrence during the luteal phase of the menstrual cycle. To aid in the diagnosis, symptom questionnaires are often used. Since recalled information is less accurate, in addition to a symptom questionnaire, it is a good idea to have the patient keep a menstrual symptom diary. The diary will help in documenting improvement as well as further clarifying the symptom pattern. Both a questionnaire and diary are provided in Appendix 9 . PMS classifications In an attempt to bring some order to the clinically and metabolically confusing picture of PMS, several experts have created classification systems that identify PMS sufferers into subgroups. [8] The system recommended here is the one developed by Dr Guy Abraham which divides PMS into four distinct subgroups. [9] Each subgroup is linked to specific symptoms, hormonal patterns, and metabolic abnormalities. Following is a brief discussion of the individual subgroups. Please note that rarely do women experience a particular subgroup in a pure form; usually there are aspects of two or more subgroups that a woman with PMS experiences. A PMS questionnaire based on Dr Abraham’s classifications can be found in Appendix 9 . PMS-A
PMS-A (A = anxiety) is the most common symptom category and is found to be strongly associated with excessive estrogen and deficient progesterone during the premenstrual phase. Common symptoms in patients in this category are anxiety, irritability, and emotional instability. PMS-C
PMS-C (C = carbohydrate craving) is associated with increased appetite, craving for sweets, headache, fatigue, fainting spells, and heart palpitations. Glucose tolerance tests (GTT) performed on PMS-C patients during the 5–10 days before their menses show a flattening of the early part of the curve (which usually implies excessive secretion of insulin in response to sugar consumption), whereas during other parts of the menstrual cycle their GTT is normal. [2] Currently, there is no clear explanation
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for this phenomenon, although an increased cellular capacity to bind insulin has been postulated. This increased binding capacity for insulin appears to be hormonally regulated, but other factors may also be involved, such as a high salt intake or decreased magnesium or prostaglandin levels. PMS-D
PMS-D (D = depression) is the least common and is relatively rare in its pure form. Its key symptom is depression which is usually associated with low levels of neurotransmitters in the central nervous system. In PMS-D patients this is most likely due to increased breakdown of the neurotransmitters as a result of decreased levels of estrogen (in contrast to PMS-A which shows just the opposite results). The decreased ovarian estrogen output has been attributed to a stress-induced increase in adrenal androgen and/or progesterone secretion. PMS-H
PMS-H (H = hyperhydration) is characterized by weight gain (greater than 1.5 kg), abdominal bloating and discomfort, breast tenderness and congestion, and occasional swelling of the face, hands and ankles. These symptoms are due to an increased fluid volume secondary to an excess of the hormone aldosterone which causes increased fluid retention. Aldosterone excess during the premenstrual phase of PMS-H patients may arise due to stress, estrogen excess, magnesium deficiency, or excess salt intake. An alternative classification system and diagnostic hierarchy Abraham’s system is very useful in quickly identifying possible causes in a given case of PMS based on symptoms. However, an alternative is to classify patients according to cause. Of course, in order to classify the patient the causative factor(s) must be identified. The most common causative factors are discussed under “Therapeutic considerations”. The detection of these causative factors involves a diagnostic hierarchy based upon the clinical picture and history. Following the steps listed below should lead to the proper identification of the causative factor (if necessary). As a result, a more effective treatment plan can be tailored for the specific needs and as a result better relief achieved: 1. Begin following the recommendations summarized in “Therapeutic approach” ( p. 1510 ). 2. Rule out hypothyroidism. Have the patient determine their basal body temperature (discussed in Ch. 160 ). If the basal body temperature is below 97.8°F, or if other symptoms associated with hypothyroidism are present, perform blood measurement of TSH and T 4 . 3. Rule out depression. 4. If the patient has followed the recommendations in step 1, ruled out or addressed hypothyroidism or depression, and has not improved after 2–3 cycles, perform a complete blood count and chemistry panel (including serum ferritin, thyroid panel, and estrogen, progesterone, and prolactin levels) on day 21 of her cycle. The test should include: a. complete blood count (CBC) b. chemistry panel c. thyroid panel (i) T 3 uptake (ii) thyroxine (iii) free thyroxine index
d. ferritin e. progesterone f. estrogen
g. prolactin. 5. If there are no apparent abnormalities in the CBC and chemistry panel, additional recommended tests include: liver detoxification profile (see Ch. 16 ), adrenal stress index and food allergy detection (see Ch. 15 ).
THERAPEUTIC CONSIDERATIONS PMS represents a “heterogenous” or “multifactorial” condition as there is no single cause that explains PMS in every case. Many factors appear to play a role, with some factors being more important in one case than another. However, there is tremendous overlap. Table 183.2 lists the most common factors causing or contributing to PMS. Estrogen and progesterone One of the most common findings in women with PMS is an elevated estrogen to progesterone ratio. [1] [10] [11] [12] [13] [14] Most commonly this derangement is caused by a combined mild estrogen excess and mild progesterone deficiency. The physiological effects of such an imbalance are listed in Table 183.3 . TABLE 183-2 -- The primary causes of PMS • Estrogen excess • Progesterone deficiency • Elevated prolactin levels • Hypothyroidism • Stress, endogenous opioid deficiency, and adrenal dysfunction • Depression • Nutritional abnormalities —macronutrient disturbances/excesses —micronutrient deficiency
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TABLE 183-3 -- Physiological effects of an increased estrogen to progesterone ratio • Impaired liver function • Reduced manufacture of serotonin • Decreased action of vitamin B 6 • Increased aldosterone secretion • Increased prolactin secretion
Estrogen excess and liver function
In the early 1940s, Dr Morton Biskind observed an apparent relationship between B vitamin deficiency and PMS. [15] [16] He postulated that PMS, as well as excessive menstruation and fibrocystic breast disease, was due to an excess in estrogen levels caused by decreased detoxification and elimination in the liver due to B vitamin deficiency. The liver utilizes various B vitamins to detoxify estrogen and excrete it in the bile. There appears to be support for Dr Biskind’s theory. Estrogen excess is known to produce cholestasis, a term which signifies diminished bile flow or stasis of bile. Naturopathic physicians often refer to this condition as a “sluggish liver”. It reflects minimal impairment of liver function because normal indicators of liver status (such as liver enzymes: alkaline phosphatase, SGOT, SGPT, and GGTP) are not elevated. These enzymes, the conventional means of assessing liver status, are not very useful as they really only indicate liver damage, as they are only elevated when the liver is damaged. They have little correlation with liver function. Because of the liver’s important role in numerous metabolic processes, even minor impairment of liver function can have profound effects. Cholestasis can be caused by a large number of factors besides estrogen excess (see Table 183.4 ). The presence of cholestasis may be a predisposing factor to PMS, as with cholestasis there is reduced estrogen detoxification and clearance. Hence, a positive feedback scenario is produced. The high incidence of gallstones is a clear indication that many American women suffer from cholestasis. Effects of estrogen on neurotransmitters
Another possible result of the increase in the estrogen to progesterone ratio is impairment of neurotransmitter TABLE 183-4 -- Causes of cholestasis • Estrogen excess or birth control pills • Pregnancy • Presence of gallstones • Alcohol • Endotoxins • Hereditary disorders such as Gilbert’s syndrome • Anabolic steroids • Various chemicals or drugs • Nutritional deficiencies synthesis and endorphin activity. This is one reason antidepressant drug therapy of PMS is gaining increased popularity, even though it does not address the underlying cause of the neurotransmitter dysfunction. It is interesting to note that the majority of the over 12 million patients on Prozac are women between the ages of 25 and 50 – the same population that has a high frequency of PMS. Estrogen excess and endorphin levels
Estrogen excess during the luteal phase also negatively affects endorphin levels. One study found a direct correlation between an increased estrogen to progesterone ratio and endorphin activity in the brain. [11] In essence, when the estrogen to progesterone ratio was increased there was a decline in endorphin levels. This reduction is significant considering the known ability of endorphins to normalize or improve mood. Other studies have shown that low endorphin levels during the luteal phase
are common in women with PMS.[17] Endorphins are lowered by stress and raised by exercise. The role of endorphins are further discussed below. Estrogen impairs vitamin B 6
The way in which estrogen excess during the luteal phase negatively affects neurotransmitter and endorphin levels may be secondary to impairment of vitamin B 6 action. It is well known that estrogens negatively affect vitamin B 6 function. Vitamin B 6 levels are typically quite low in depressed patients, especially women taking estrogens (birth control pills or Premarin). [18] [19] Vitamin B 6 supplementation has been shown to exert positive effects on all PMS symptoms (particularly depression) in many women (discussed in greater below). The improvement is achieved via a combined reduction in mid-luteal estrogen levels and an increase in mid-luteal progesterone levels. Estrogen effects on aldosterone
In many cases of PMS, aldosterone levels are marginally elevated 2–8 days prior to the onset of menses. This elevation may be a result of estrogen excess increasing the secretion of aldosterone. Estrogen and prolactin secretion
Excessive levels of prolactin are implicated in many cases of PMS, especially in women experiencing breast pain or fibrocystic breast disease (discussed in Ch. 151 ).[20] [21] Estrogens, both internally produced and ingested as birth control pills or Premarin, are known to increase prolactin secretion by the pituitary gland. Following the
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recommendations given below for lowering the luteal phase estrogen to progesterone ratio may be all that is necessary to lower prolactin levels. In particular, the herb Vitex agnus-castus (chaste berry) may prove to be very useful in cases of high prolactin levels due to corpus luteum insufficiency (discussed below). Vitamin B 6 and zinc supplementation also lower prolactin levels and are discussed below. Prolactin levels also tend to be elevated in low thyroid function. Reducing the estrogen to progesterone ratio Central to effective treatment in most cases of PMS is lowering of the luteal phase estrogen to progesterone ratio. An elevation in this ratio may be the underlying factor in the hormonal, neurotransmitter, endorphin, and other physiological disturbances in most cases of PMS. Effective treatment usually involves six components. Diet
A number of dietary factors are known to reduce circulating estrogens or block the attachment of estrogen to receptor sites. Chief among these dietary recommendations are the following: • increase the consumption of plant foods (vegetables, fruits, legumes, whole grains, nuts, and seeds) • limit consumption of meat and dairy products • reduce fat and sugar intake • increase consumption of soy foods. In addition, it is important to reduce the load of environmental estrogens by avoiding foods sprayed with pesticides and herbicides. Gastrointestinal flora
One of the key ways in which the liver detoxifies cancer-causing chemicals as well as the body’s hormones such as estrogen is via attaching glucuronic acid to the toxin and excreting it in the bile. Beta-glucuronidase is a bacterial enzyme which uncouples (breaks) the bond between excreted toxins and glucuronic acid. Not surprisingly, it has been found that excess beta-glucuronidase activity is associated with an increased cancer risk, particularly estrogen-dependent breast cancer, and presumably PMS. The activity of this enzyme can be reduced by establishing a proper bacterial flora. [22] The dietary guidelines go a long way toward this goal. In addition, supplementation with probiotics helps to establish a normal intestinal flora. Probiotics, literally translated, means “for life”, and is a term used to signify the health-promoting effects of “friendly bacteria”. The most important friendly bacteria are Lactobacillus acidophilus and Bifidobacterium bifidum. The dosage of a commercial probiotic supplement is based upon the number of live organisms. The ingestion of 1–10 billion viable L. acidophilus or B. bifidum cells daily is a sufficient dosage for most people. Amounts exceeding this may induce mild gastrointestinal disturbances, while smaller amounts may not be able to colonize the gastrointestinal tract. Probiotics are extremely safe and are not associated with any side-effects. Nutritional supplements
Estrogen excess is known to stress nutritional needs for B vitamins, magnesium, and possibly other nutrients. In addition, B vitamins and magnesium are also necessary for the proper detoxification of estrogens. Liver detoxification
Supporting liver function focuses on protecting the liver by following the dietary guidelines above and the nutritional supplement recommendations below. In addition, most naturopathic physicians often use formulas containing “lipotropic factors”. Lipotropic factors are, by definition, substances that hasten the removal or decrease the deposition of fat and bile in the liver through their interaction with fat metabolism. In essence, they produce a “decongesting” effect on the liver and promote improved liver function and fat metabolism. Compounds commonly employed as lipotropic agents include choline, methionine, betaine, folic acid, and vitamin B 12 , along with herbal cholagogues and choleretics. Most major manufacturers of nutritional supplements offer lipotropic formulas. The typical daily doses are 1,000 mg of choline and 500 mg of methionine and/or cysteine. Botanical medicines
Chaste berry (Vitex agnus-castus) and phytoestrogen-containing herbs like dong quai, black cohosh, and licorice are popular herbal recommendation for PMS. Their appropriate use is described below. Progesterone therapy
Although progesterone administration is a popular recommendation made by many physicians (MDs and NDs alike), we have some reservations. First of all, although progesterone administration has been the most common prescription for PMS by the medical community, controlled clinical trials have failed to consistently demonstrate the superiority of progesterone therapy over a placebo (there is a significant placebo response in PMS). [23] [24] [25] [26] [27] [28] The studies that are positive have used
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dosages which far exceed the normal levels for progesterone (200–400 mg twice daily as a vaginal or rectal suppository from 14 days before the expected onset of
menstruation until the onset of vaginal bleeding). [27] [28] Side-effects, although generally mild, are common. In one of the more recent double-blind studies that did show a positive effect with progesterone therapy (400 mg twice a day by vaginal or rectal administration), adverse events were reported by 51% of patients in the progesterone treatment group (compared with 43% in the placebo group). [28] Irregularity of menstruation, vaginal itching, and headache were reported more frequently by the women taking the progesterone. Secondly, philosophically we would rather help the body to naturally improve the estrogen and progesterone ratio by addressing the underlying causative factors such as reduced detoxification or clearance of estrogen along with reduced corpus luteum function rather than artificially and drastically tipping the ratio in favor of progesterone. We do not recommend progesterone creams as the first step for treating PMS, but rather as a possible last choice after other natural measures have failed. Thyroid function Low thyroid function (hypothyroidism) has been shown to affect a large percentage of women with PMS. [29] [30] For example, in one study, 51 of 54 PMS subjects demonstrated low thyroid status compared with 0 of 12 for the control group. [29] In another study, seven of 10 in the PMS group were low compared with 0 of 9 for the control group. [30] Other studies have also shown hypothyroidism to be only slightly more common in women with PMS compared with controls. [31] [32] Many women with PMS and confirmed hypothyroidism given thyroid hormone experience complete relief of symptoms. [29] For more information see Chapter 162 . Stress, endorphins, and exercise Like many common conditions associated with “modern” living, stress definitely plays a role in PMS. When stress is extreme, unusual, or long-lasting, it triggers biological changes in the brain largely as a result of altered adrenal gland function and endorphin secretion or action. These changes produce a domino effect as they lead to alterations in normal physiology. Effective treatment of PMS must include stress management (see Ch. 60 ). Exercise
Several studies have shown that women engaged in a regular exercise program do not suffer from PMS nearly as often as sedentary women. [33] [34] [35] In one of the more thorough studies, mood and physical symptoms during the menstrual cycle were assessed in 97 women who exercised regularly and in a second group of 159 female non-exercisers. [33] Mood scores and physical symptoms assessed throughout the menstrual cycle revealed significant effects for exercise on negative mood states and physical symptoms. The regular exercisers obtained significantly lower scores on impaired concentration, negative mood, behavior change, and pain. In another study, 143 women were monitored for 5 days in each of the three phases of the cycle (mid-cycle, premenstrual and menstrual). [34] The women were 35 competitive athletes, two groups of exercisers (33 high exercisers and 36 low exercisers) and 39 sedentary women. The high exercisers experienced the greater positive mood scores and sedentary women the least. The high exercisers also reported the least depression and anxiety. The differences were most apparent during the premenstrual and menstrual phases. These results are consistent with the belief that women who frequently exercise (but not competitive athletes) are protected from PMS symptoms. In particular, regular exercise protects against the deterioration of mood before and during menstruation. These studies provide evidence that women with PMS need to exercise. One of the ways exercise may be positively impacting PMS is through elevations in endorphin levels and lowering of cortisol levels. Coping style
Many women with PMS tend to employ “negative” coping styles. [36] Examples of negative coping mechanisms are listed in Table 183.5 . It is important to identify the manner in which the patient deals with stress and to counsel them on more positive ways of coping. Psychotherapy
Various psychotherapy methods have been successful in improving the psychological aspects of PMS. In particular, psychotherapy in the form of biofeedback or short-term individual counseling (especially cognitive therapy) has documented clinical efficacy. [37] [38] One of the advantages that cognitive therapy in the treatment TABLE 183-5 -- Negative coping styles in women with PMS • Feelings of helplessness • Overeating • Too much television • Emotional outbursts • Overspending • Excessive behavior • Dependence on chemicals —drugs, legal and illicit —alcohol —smoking
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of PMS has over antidepressant drug therapy is that learning techniques such as cognitive-behavioral coping skills can produce excellent results that will be maintained over time. Depression and low serotonin
There are some important relationships between PMS and depression. Depression is a common feature in many cases of PMS, and PMS symptoms are typically more severe in depressed women. [1] The reason appears to be a decrease in the brain level of various neurotransmitters, with serotonin and gamma-aminobutyric acid (GABA) being the most significant. [39] [40] Use of antidepressant drugs like Prozac is quickly becoming the dominant medical treatment for PMS. [1] Approximately 80% of the 12 million Americans on Prozac are women between the ages of 25 and 50. Not surprisingly, this also represents the highest frequency of PMS. Dietary considerations Women suffering from PMS typically eat a diet which is even worse than the standard American diet. Guy Abraham MD reports that, compared with symptom-free women, PMS patients consume:[9] • 62% more refined carbohydrates • 275% more refined sugar • 79% more dairy products • 78% more sodium • 53% less iron • 77% less manganese
• 52% less zinc. In addition to providing benefits against PMS symptoms, the dietary recommendations given below also provide significant protection against the development of breast cancer, other cancers, heart disease, strokes, osteoporosis, diabetes, and virtually every other chronic degenerative disease. The seven most important dietary recommendations for PMS are listed in Table 183.6 . Vegetarian diet and estrogen metabolism
Vegetarian women have been shown to excrete two to TABLE 183-6 -- Dietary recommendations for women suffering from PMS • Vegetarian or predominantly vegetarian diet • Reduce the intake of fat • Eliminate sugar • Reduce exposure to environmental estrogens • Increase the intake of soy foods • Eliminate caffeine • Keep salt intake low three times more estrogen in their feces and have 50% lower levels of free estrogen in their blood compared with omnivores. [41] [42] These differences are thought to be a result of the lower fat and higher fiber intake of the vegetarian women. These dietary differences may also explain the lower incidence of breast cancer, heart disease, and menopausal symptoms in vegetarian women. At the very least, recommend a diet lower in saturated fat and cholesterol (achieved by reducing or eliminating the amounts of animal products) and higher in fiberrich plant foods (fruits, vegetables, grains, and legumes). Limit the intake of animal protein sources to no more than 110–170 mg/day and recommend fish, skinless poultry, and lean cuts rather than fat-laden choices. It appears that many of the effects that a vegetarian diet has on lowering circulating estrogen levels are related to a higher intake of dietary fiber. The fiber promotes the excretion of estrogens directly and indirectly by promoting a more favorable bacterial flora with lower levels of beta-glucuronidase activity. Fat intake and estrogen metabolism
Decreasing the percentage of calories as fat, in particular saturated fat, has dramatic effects on reducing circulating estrogen. [43] [44] In one study, when 17 women switched from the SAD, composed of 40% of calories as fat and only 12 g as fiber, to a low-fat, high-fiber diet consisting of 25% of the calories as fat and 40 g as fiber daily, there was a 36% reduction in blood estrogen levels, with 16 out of the 17 women demonstrating significant reductions in only 8–10 weeks. [45] A low-fat diet has also been shown to improve PMS symptoms.[45] Besides possibly improving PMS symptoms, another good reason to reduce the intake of fat is that there is a great deal of research linking a diet high in saturated fat and cholesterol to numerous cancers, heart disease, and strokes. Both the American Cancer Society and the American Heart Association have recommended a diet containing less than 30% of calories as fat. The easiest way for most people to achieve this goal is to eat less animal products and more plant foods. With the exception of nuts and seeds, most plant foods are very low in fat. With regard to nuts and seeds, while they do contain high levels of fat calories, the calories are derived largely from polyunsaturated essential fatty acids. It is also very important to eliminate the intake of margarine and foods containing trans-fatty acids and partially hydrogenated oils. Sugar
Sugar has several detrimental actions in PMS. Eating foods high in simple sugars increases insulin secretion and can be harmful to blood sugar control, especially if
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the patient is hypoglycemic or diabetic. Sugar, especially when combined with caffeine, also has a detrimental effect on PMS and mood (discussed below). The most significant symptom-producing food in PMS appears to be chocolate. [46] A high intake of sugar also impairs estrogen metabolism. The evidence is based on the higher frequency of PMS symptoms in women consuming a high-sugar diet and the fact that a high sugar intake is also associated with higher estrogen levels. [47] Encourage patients to read food labels carefully for clues about sugar content. If the words sucrose, glucose, maltose, lactose, fructose, corn syrup, or white grape juice concentrate appear on the label, extra sugar has been added. Environmental estrogens
Widespread environmental contamination has occurred with a group of compounds known as “halogenated hydrocarbons”. Included in this group are the toxic pesticides DDT, DDE, PCB, PCP, dieldrin, and chlordane. These molecules are hard to break down and are stored in fat cells. These chemicals mimic estrogen in the body and are thought to be a major factor in the growing epidemics of estrogen-related health problems such as PMS, breast cancer, and low sperm counts. [48] [49] Soy foods
Soy and soy foods contain compounds referred to as “phytoestrogens” because they are capable of binding to estrogen receptors. Phytoestrogens are also often referred to as “anti-estrogens” because their estrogenic effect is only 2% as strong as estrogen at the very most. However, because of this low activity, phytoestrogens have a balancing action on estrogen effects. If estrogen levels are low (as in menopause), since phytoestrogens have some estrogenic activity, they will cause an increase in estrogen effect. If estrogen levels are high (as in PMS), since phytoestrogens bind to estrogen receptor binding sites, thereby competing with estrogen, there will be a decrease in estrogen effects. Caffeine
Caffeine must be avoided by patients with PMS, especially if anxiety or depression, or breast tenderness and fibrocystic breast disease are major symptoms. [50] [51] There is considerable evidence demonstrating that caffeine consumption is strongly related to the presence and severity of PMS. The effect of caffeine is particularly significant in the psychological symptoms associated with PMS such as anxiety, irritability, insomnia, and depression. The effect of caffeine on fibrocystic breast disease is discussed in Chapter 151 . Salt
Excessive salt (sodium chloride) consumption, coupled with diminished dietary potassium, greatly stresses the kidney’s ability to maintain proper fluid volume. As a result some people are “salt-sensitive”, in that high salt intake increases blood pressure and/or water retention. Patients who experience more water retention during the mid-luteal phase may be especially sensitive to salt intake. However, it is simply not a matter of reducing salt intake, as potassium intake must be simultaneously
increased. This is easily done by increasing the intake of high-potassium foods (i.e. fruits and vegetables) and decreasing high-sodium foods (most processed foods). Total daily sodium intake should be below 1,800 mg. Micronutrients Although all essential nutrients are critical to good health and in dealing with PMS symptomatology, our discussion focuses on the six key nutrients followed by some practical recommendations. Vitamin B6
The first use of vitamin B 6 in the management of cyclical conditions in women was in the successful treatment of depression caused by birth control pills as noted in several studies in the early 1970s. These results led researchers to try and determine the effectiveness of vitamin B 6 in relieving PMS symptoms. Since 1975 there have been at least a dozen double-blind clinical trials. [52] [53] The majority of these studies have demonstrated a positive effect. For example, in one double-blind cross-over trial, 84% of the subjects had a lower symptomatology score during the B 6 treatment period.[54] Although PMS has multiple causes, B 6 supplementation alone appears to benefit most patients. It is important to note, however, that not all double-blind studies of vitamin B 6 have been positive.[52] [53] These negative results may have been caused by many factors, such as the inability of some women to convert B 6 to its active form due to a deficiency in another nutrient (e.g. vitamin B 2 or magnesium) which was not supplemented. These results suggest that supplementing pyridoxine by itself may not result in adequate clinical results for all women suffering from this disorder and that some women may have difficulty converting vitamin B 6 into its active form, pyridoxal-5-phosphate. To overcome this conversion difficulty, it may be necessary to use a broader-spectrum nutritional supplement or to use injectable pyridoxal-5-phosphate. For most indications, the therapeutic dosage of vitamin B 6 is 50–100 mg daily. This dosage level is generally regarded as being safe, even for long-term use. When using
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dosages greater than 50 mg, it may be important to divide it into 50 mg dosages throughout the day. A single dosage of 100 mg of pyridoxine did not lead to a significant increase in pyridoxal-5-phosphate levels in the blood, indicating that a 50 mg oral dosage of pyridoxine is about all the liver can handle at once. [55] Vitamin B6 is one of the few water-soluble vitamins that is associated with some toxicity when taken in large doses or moderate dosages for long periods of time. One-time doses greater than 2,000 mg/day can produce symptoms of nerve toxicity (tingling sensations in the feet, loss of muscle coordination, and degeneration of nerve tissue) in some individuals. Chronic intake of dosages greater than 500 mg daily can be toxic if taken daily for many months or years. [56] There are also a few rare reports of toxicity occurring at chronic long-term dosages as low as 150 mg/day. [56] [57] [58] The toxicity is thought to be a result of supplemental pyridoxine overwhelming the liver’s ability to add a phosphate group to produce the active form of vitamin B 6 (pyridoxal-5-phosphate). As a result it is speculated that either pyridoxine is toxic to the nerve cells or it actually acts as an anti-metabolite by binding to pyridoxal-5-phosphate receptors, thereby creating a relative deficiency of vitamin B6 . Another possibility is that minute amounts of contaminants or vitamin B 6 analogs may have been introduced during synthesis. While at normal dosages these are not a problem, at larger dosages they may block B 6 activation sites. Again, it appears to make sense to limit dosages to 50 mg at a time. If more than 50 mg/day is desired, then the dosages should be spread out throughout the day. There are extensive interactions between vitamin B 6 and magnesium as they work together in many enzyme systems. In fact, one of the ways in which vitamin B6 may improve the symptoms of PMS is by increasing the accumulation of magnesium within the cells of the body. [59] In fact, without vitamin B 6 , magnesium will not get inside the cell. Magnesium
Magnesium deficiency is strongly implicated as a causative factor in premenstrual syndrome. [60] Red blood cell magnesium levels in PMS patients have been shown to be significantly lower than in normal subjects. [9] [61] As magnesium plays such an integral part in normal cell function, magnesium deficiency may account for the wide range of symptoms attributed to PMS. Furthermore, magnesium deficiency and PMS share many common features, and magnesium supplementation has been shown to be an effective treatment of PMS. [62] A recent study designed to better understand the association between magnesium and the menstrual cycle measured plasma, red blood cell (RBC), and mononuclear blood cell (MBC) magnesium in 26 women with confirmed PMS and in a control group of 19 women during the follicular, ovulatory, early luteal, and late luteal phases of the menstrual cycle. [63] The principal findings of the study were as follows: • There were no significant differences in plasma magnesium levels in PMS patients compared with controls, nor was there a menstrual cycle effect on plasma magnesium in either group. • PMS patients had significantly lower RBC and MBC magnesium concentrations compared with controls. • These lower RBC and MBC magnesium concentrations were consistent across the menstrual cycle. • Magnesium measures did not correlate with the severity of mood symptoms. The observation of low RBC magnesium concentrations in PMS patients has now been confirmed by four independent studies. In general, it is thought that women with PMS have a “vulnerability to luteal phase mood state destabilization” and that chronic, and enduring intracellular magnesium depletion serves as a major predisposing factor towards destabilization. In addition to emotional instability, magnesium deficiency in PMS is characterized by excessive nervous sensitivity with generalized aches and pains, and a lower premenstrual pain threshold. One clinical trial of magnesium in PMS showed a reduction of nervousness in 89%, breast tenderness in 96%, and weight gain in 95%. [9] In another double-blind study, high-dosage magnesium supplementation (360 mg three times daily) was shown to dramatically relieve PMS-related mood changes. [62] While magnesium has been shown to be effective on its own, even better results may be achieved by combining it with vitamin B 6 and other nutrients. Several studies have shown that when PMS patients are given a multivitamin and mineral supplement containing high doses of magnesium and pyridoxine they experience a substantial reduction in PMS symptoms. [64] [65] The optimum intake for magnesium should be based on body weight, 6 mg/kg. For a 50 kg woman, the recommendation would be 300 mg, 420 mg for a 154 pound woman, and 540 mg for a 90 kg woman. As this is difficult to achieve by diet alone, supplementation is recommended. In the treatment of PMS, a dosage of twice this amount, 12 mg/kg, may be needed. Magnesium bound to aspartate or one of the Krebs cycle intermediates (malate, succinate, fumarate, or citrate) is preferred to magnesium oxide, gluconate, sulfate, and chloride due to better absorption and fewer side-effects (laxative effects). [66] [67] Calcium
Calcium appears to be a bit of a double-edged sword in PMS. High calcium intake due to high milk consumption
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is linked as a possible causative factor perhaps by the combination of calcium, vitamin D, and phosphorus of milk reducing the absorption of magnesium. [9] At the same time, there are studies showing positive improvements in PMS symptomatology with calcium supplementation (1,000–1,336 mg). [68] [69] In one of the more recent studies, calcium and manganese supplementation (1,336 and 5.6 mg, respectively) improved mood, concentration, and behavior. In another study, 1,000 mg/day improved mood and water retention.[68] It is theorized, based primarily on animal research, that calcium improves the altered hormonal patterns, neurotransmitter levels, and smooth muscle responsiveness noted in PMS. Further support for the importance of calcium supplementation in PMS was the finding that women with PMS have reduced bone mineral density (based on dual-photon absorptiometry). [70] Zinc
Zinc levels have been shown to be low in women with PMS. [71] Zinc is required for proper action of many body hormones, including the sex hormones, as well as in the control of the synthesis and secretion of hormones. In particular, zinc serves as one of the control factors for prolactin secretion. [72] When zinc levels are low, prolactin release increases, while high zinc levels inhibit this release. Hence, in high prolactin states, zinc supplementation is very useful. An effective dosage range for zinc supplementation for elevated prolactin levels in women is 30–45 mg in the picolenate form. Vitamin E
Although vitamin E research concerning PMS has focused primarily on breast tenderness, significant reduction of other PMS symptomatology has also been demonstrated in double-blind studies. [9] [73] Nervous tension, headache, fatigue, depression, and insomnia were all significantly reduced. In one double-blind study, patients receiving vitamin E (400 IU/day) demonstrated a 33% reduction in physical symptoms (such as weight gain and breast tenderness), a 38% reduction in anxiety, and a 27% reduction in depression after 3 months of use. In contrast, the placebo group only reported a 14% reduction in physical symptoms. The group taking vitamin E also noted higher energy levels, fewer headaches, and less cravings for sweets. Essential fatty acids
Women with PMS have been shown to exhibit essential fatty acid and prostaglandin abnormalities, with the chief abnormality most often reported being a decrease in gamma-linolenic acid (GLA). [74] Gamma-linolenic acid is derived from linoleic acid. This conversion requires adequate vitamin B 6 , magnesium, and zinc levels as these nutrients function in the key enzyme responsible for this conversion, delta-6-desaturase. Given the fact that deficiency of one or more of these nutrients is common in PMS, decreased GLA levels could almost be expected. Evening primrose, blackcurrant, and borage oil contain GLA, with typical levels being 9, 12, and 22%, respectively. Although these essential fatty acid sources are quite popular, the research on GLA supplements is controversial in the treatment of PMS. Specifically, the double-blind studies with GLA supplements like evening primrose oil in PMS are largely negative in that they showed no greater benefit over a placebo. A meta-analysis of the clinical trials of evening primrose oil for the treatment of PMS concluded that evening primrose is of little value in the management of PMS. [75] The three most well-controlled studies failed to show any beneficial effects for evening primrose. [76] [77] [78] A better approach to the essential fatty acid and prostaglandin abnormalities of PMS may be to provide the necessary nutrients required for proper essential fatty acid metabolism along with providing adequate levels of the essential fatty acids and GLA. In other words, it may be more appropriate to provide a broader range of support than simply trying to increase GLA levels. Multiple vitamin and mineral supplements
A high-quality multiple vitamin and mineral supplement providing all of the known vitamins and minerals serves as a foundation upon which to build. For women with PMS there are two very sound reasons for taking a high potency multiple: • Nutritional deficiency is relatively common among women with PMS • High potency multiple vitamin and mineral formulations have been shown to produce significant benefits in PMS. When compared with normal women, the frequency of nutritional supplementation and the calculated intake of selected nutrients by PMS patients have been shown to be much lower. Although women with PMS have been shown to consume vitamins in their food at levels that are close to the recommended daily allowance, compared with women who did not have PMS their intake levels were only 2.2% as much for thiamin, 2.2% for riboflavin, 16.7% for niacin, 8.7% for pantothenic acid, and 2.7% for pyridoxine. [9] Several double-blind studies have shown that PMS patients given a multivitamin and mineral supplement containing high doses of magnesium and pyridoxine experience reductions (typically at least a 70% reduction) in both pre- and postmenstrual symptoms. [64] [65]
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Botanical medicines Although a wide variety of herbs have been used in folk medicine for the many disorders of menstruation, and many have been evaluated for their “phytoestrogen” effects, few have been specifically evaluated for their efficacy in relieving premenstrual symptoms. The herbs which are most likely to be useful are probably those which exhibit a tonic effect on the female glandular system. This tonic effect is thought to be a result of phytoestrogens in the plants or other compounds which help to improve the hormonal balance of the female system, as well as the plant’s ability to improve blood flow to the female organs. Although phytoestrogens are capable of exerting estrogenic effects, the activity is only 2% as strong as estrogen. However, because of this low activity, phytoestrogens have a balancing action on estrogen effects. If estrogen levels are low, since phytoestrogens have some estrogenic activity, they will cause an increase in estrogen effect. If estrogen levels are high, since phytoestrogens bind to estrogen receptor binding sites, thereby competing with estrogen, there will be a decrease in estrogen effects. Because of the balancing action of phytoestrogens on estrogen effects, it is common to find the same plant recommended for conditions of estrogen excess (like PMS) and conditions of estrogen deficiency (like menopause, menstrual abnormalities). Many of these herbs have been termed “uterine tonics” because they work to nourish and tone the female glandular and organ system rather than exerting a drug-like effect. This non-specific mode of action makes many herbs useful in a broad range of female conditions including PMS. The four most useful herbs in the treatment of PMS and related symptoms (as well as menopause) are Angelica sinensis (angelica or dong quai), Glycyrrhiza glabra (licorice root), Cimicifuga racemosa (black cohosh), and Vitex agnus-castus (chaste berry). These herbs have been used historically to lessen a variety of female complaints including hot flashes. Angelica sinensis
In Asia, angelica’s reputation is perhaps second only to ginseng. Predominantly regarded as a “female” remedy, angelica has been used in menopausal symptoms (especially hot flashes), as well as in such conditions as dysmenorrhea (painful menstruation), amenorrhea (absence of menstruation), metrorrhagia (abnormal menstruation), and to assure a healthy pregnancy and easy delivery.
Angelica has demonstrated good uterine tonic activity, causing an initial increase in uterine contraction followed by relaxation. [79] In addition, administration of angelica to mice resulted in an increase of uterine weight and an increase of glucose utilization by the liver and uterus. [80] These effects reflect phytoestrogenic activities. Angelica is particularly helpful when, in addition to PMS, a woman experiences painful menstruation (dysmenorrhea). The typical dosage schedule is to start angelica on day 14 and continue until menstruation begins, unless the woman typically experiences dysmenorrhea, in which case it should be continued until menstruation has stopped. Glycyrrhiza glabra
The medicinal use of licorice in both Western and Eastern cultures dates back several thousand years. In addition to being used for a variety of female disorders, it was used primarily as an expectorant and antitussive in respiratory tract infections and asthma. Other traditional uses include treating peptic ulcers, malaria, abdominal pain, insomnia, and infections. Many of these uses have been substantiated by modern research. Licorice is particularly useful in premenstrual syndrome as it is believed to lower estrogen while simultaneously raising progesterone levels. [81] [82] It raises progesterone levels by inhibiting the enzyme responsible for breaking it down. Licorice is also useful in reducing water retention by blocking the hormone aldosterone. Licorice works to block the effects of aldosterone much in the same way that it impacts estrogen. [83] [84] Its chief component, glycyrrhetinic acid, binds to aldosterone receptors, but its activity is only about 25% as strong as the body’s own aldosterone. This lower level of activity means that in cases of high aldosterone (such as often occurs in PMS), licorice may actually reduce the aldosterone effect by competing with aldosterone for binding sites. If aldosterone levels are normal, the chronic ingestion of licorice in large doses may cause symptoms of aldosterone excess, namely high blood pressure due to sodium and water retention. Prevention of the side-effects of glycyrrhizin may be possible by following a high-potassium, low-sodium diet. Although no formal trial has been performed, patients who normally consume high-potassium foods and restrict sodium intake, even those with high blood pressure and angina, have been reported to be free from the aldosterone-like side-effects of glycyrrhizin. [85] Licorice should probably not be used in patients with a history of hypertension, renal failure, or current use of digitalis preparations. The typical dosage schedule is to begin licorice on day 14 of the cycle and continue till menstruation. Cimicifuga racemosa
Black cohosh was widely used by the American Indians and later by American colonists for the relief of menstrual cramps and menopause. Recent scientific
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investigation into Remifemin, an extract of black cohosh standardized to contain 1 mg of triterpenes calculated as 27-deoxyacteine per tablet which has been used in Germany for over 40 years, has shown that it is a safe and effective natural alternative to hormone replacement therapy in the treatment of menopause and may offer some benefits in PMS as well. In one study of 135 women, Remifemin was judged to have “performed very well” in PMS in that it reduced feelings of depression, anxiety, tension, and mood swings.[86] Vitex agnus-castus
The chaste tree is native to the Mediterranean, where its berries have long been used for female complaints. As its name signifies, chaste berries were used in suppressing the libido. While black cohosh is the more popular herbal approach to menopausal symptoms in Germany, chaste berry extract is probably the most popular herbal approach to PMS. In two surveys of gynecological practices in Germany, physicians graded chaste berry extract as good or very good in the treatment of PMS. More than 1,500 women participated in the studies. [87] [88] One-third of the women experienced complete resolution of their symptoms while another 57% reported significant improvement. Chaste berry extract appears to be particularly useful in cases of corpus luteum insufficiency or prolactin excess. [89] It appears that its beneficial effects in PMS and these other conditions are related to altering gonadotropin-releasing hormone (GnRH) and follicle-stimulating hormone-releasing hormone (FSH-RH). In other words, it appears that chaste berry extract has profound effects on the hypothalamus and pituitary function. As a result it is able to normalize the secretion of other hormones, e.g. reducing the secretion of prolactin and reducing the estrogen to progesterone ratio. Chaste berry extract may also be useful in certain cases of amenorrhea (absence of menstruation) due to prolactin excess, one of the most frequent causes of amenorrhea. This application, however, requires patience as 3 months of use is necessary to lower prolactin levels. [89]
THERAPEUTIC APPROACH The approach to the woman with PMS first involves evaluation of symptoms and identifying possible causes and hormonal disturbances. In an effort to clarify the treatment approach, here are seven key steps to consider: 1. Evaluate PMS symptoms by having the patient complete the questionnaire in Appendix 9 . 2. Rule out hypothyroidism and/or depression. 3. Begin following the dietary recommendations for PMS: a. follow a vegetarian or predominantly-vegetarian diet b. reduce the intake of fat c. eliminate sugar d. reduce exposure to environmental estrogens e. increase the intake of soy foods f. eliminate caffeine g. keep salt intake low 4. Follow the guidelines for nutritional supplementation given above. 5. Select the appropriate herbal support: a. if the patient has PMS-associated breast pain, infrequent periods, or a history of ovarian cysts, utilize Vitex agnus-castus b. if the patient typically experiences menstrual cramps, utilize Angelica sinensis c. if the patient is bothered by PMS water retention, utilize Glycyrrhiza glabra d. if the patient suffers from uterine fibroids, utilize Cimicifuga racemosa. 6. Establish a program for stress reduction and recommend regular exercise. 7. If after at least three complete periods the patient is not experiencing a significant improvement or complete resolution of symptoms, work to identify additional causative factors as detailed above. Nutritional supplements
• Multivitamin and mineral • Vitamin B6 : 100 mg/day • Magnesium: 500 mg/day • Vitamin E: 400 IU/day.
Botanical medicines
• Angelica sinensis —three times a day —powdered root or as tea: 1–2 g —tincture (1:5): 4 ml (1 tsp) —fluid extract: 1 ml (¼ tsp) • Glycyrrhiza glabra —three times a day —powdered root or as tea: 1–2 g —fluid extract (1:1): 4 ml (1 tsp) —solid (dry powdered) extract (4:1): 250–500 mg • Cimicifuga racemosa —twice a day —standardized extract (4 mg 27-deoxyacteine): 1 tablet (2 for menopausal women) • Vitex agnus-castus —daily dosage —standardized extract (0.5% agnuside): 175–225 mg daily —liquid extract: 2 ml.
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Chapter 184 - Psoriasis Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Sharply bordered reddened rash or plaques covered with overlapping silvery scales • Characteristically involves the scalp, the extensor surfaces (backside of the wrists, elbows, knees, buttocks, and ankles), and sites of repeated trauma • Family history in 50% of cases • Nail involvement results in characteristic “oil drop” stippling • Possible arthritis.
GENERAL CONSIDERATIONS Psoriasis is an extremely common skin disorder. Its rate of occurrence in the United States is between 2 and 4% of the population. Psoriasis affects few blacks in tropical zones but is more common among blacks in temperate zones. It appears commonly among Japanese but is rare in American Indians. Psoriasis affects men and women equally, and the mean onset is 27.8 years of age, although 2% show onset by 2 years of age. Psoriasis is the classic example of a hyperproliferative skin disorder. The rate of cellular division rate in psoriatic lesions is very high (1,000 times greater than in normal skin), exceeding the rate in squamous cell carcinoma. Even in uninvolved skin, the number of proliferating cells is up to two and one-half times greater than in non-psoriatics. The basic defect lies within the skin cells themselves. The incidence of psoriasis is increased in HLA-B 13 , HLA-B16 , and HLA-B 17 , reflecting a possible genetic error in mitotic control which is confirmed by the observation that 36% of patients have one or more family members with psoriasis. [1] The rate at which cells divide is controlled by a delicate balance between two internal control compounds – cyclic AMP and cyclic GMP. Increased levels of cyclic GMP (cGMP) are associated with increased cell proliferation; conversely, increased levels of cyclic AMP (cAMP) are associated with enhanced cell
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maturation and decreased cell proliferation. Both decreased cAMP and increased cGMP have been measured in the skin of individuals with psoriasis. is excessive cell proliferation.
[2] [3]
The result
THERAPEUTIC CONSIDERATIONS Although psoriasis may have a significant genetic component, rebalancing the cyclic AMP:GMP ratio can be substantially achieved through natural medicine intervention. A number of controllable factors appear to cause or contribute to psoriasis, including: • incomplete protein digestion • bowel toxemia • impaired liver function • alcohol consumption • excessive consumption of animal fats • nutritional deficiencies • stress. These are briefly discussed below. Incomplete protein digestion Incomplete protein digestion or poor intestinal absorption of protein breakdown products can result in elevated levels of amino acids and polypeptides in the bowel. These are metabolized by bowel bacteria into several toxic compounds. The toxic metabolites of the amino acids arginine and ornithine are known as polyamines (e.g. putrescine, spermidine, and cadaverine) and have been shown to be increased in individuals with psoriasis. Polyamines inhibit the formation of cyclic AMP and therefore contribute to the excessive rate of cell proliferation ( Fig. 184.1 ). [4] [5] [6] Lowered skin and urinary levels of polyamines are associated with clinical improvement in psoriasis. [4] There are a number of natural compounds which can inhibit the formation of polyamines that may be of benefit in the treatment of psoriasis. For example, vitamin A and the alkaloids of Hydrastis canadensis (goldenseal) such as berberine inhibit bacterial decarboxylase, the enzyme which converts the amino acids into polyamines.[7] [8] However, the best way to prevent the excessive formation of polyamines is to evaluate digestive function with the aid of Heidelburg Gastric Analysis and/or a Comprehensive Digestive Stool Analysis and then take the action necessary (e.g. hydrochloric acid supplementation) to ensure complete protein digestion and absorption (chapters on these assessment methods are available in Section 2). Bowel toxemia A number of gut-derived toxins are implicated in the development of psoriasis, including endotoxins (cell wall components of Gram-negative bacteria), streptococcal products, Candida albicans, yeast compounds, and IgE and IgA immune complexes.[9] [10] [11] These compounds lead to increases in cyclic GMP levels within skin cells, thereby increasing the rate of proliferation dramatically. Candida albicans overgrowth in the intestines (chronic candidiasis) may play a major role in many cases. A diet low in dietary fiber is associated with increased levels of gut-derived toxins. [9] Dietary fiber is of critical importance in maintaining a healthy colon. Many fiber components bind bowel toxins and promote their excretion in the feces. It is therefore essential that the diet of an individual with psoriasis be rich in beans, fruits, and vegetables. Natural compounds which bind endotoxins and promote their excretion may also be used. For example, an aqueous extract of the herb Smilax sarsaparilla was found in a 1942 study to be effective in psoriasis, particularly the more chronic, large plaque-forming variety. [12] In this controlled study of 92 patients, sarsaparilla greatly improved the psoriasis in 62% of the patients and resulted in complete clearance in another 18% (i.e. 80% of the subjects experienced significant benefits). This benefit is apparently due to sarsaparilla components binding to and promoting the excretion of bacterial endotoxins. Since clinical severity as well as therapeutic response have been shown to correlate well with the level of circulating endotoxins, control of gut-derived toxins is
Figure 184-1 Amino acids, polyamines, and inhibition of adenylate cyclase.
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critical in the treatment of psoriasis. Every effort should be made to promote proper binding and elimination of these compounds through supporting the excretion in the feces as well as proper handling of absorbed endotoxins by the liver. Liver function Correcting abnormal liver function is of great benefit in the treatment of psoriasis. [13] The connection between the liver and psoriasis relates to one of the liver’s basic tasks – filtering and detoxifying the blood returning through the portal circulation from the bowels. As mentioned above, psoriasis has been linked to the presence of several microbial by-products in the blood. If the liver is overwhelmed by excessive levels of these toxins from the bowel, or if there is a decrease in the liver’s detoxification ability, the systemic toxin level will increase and the psoriasis will get worse. Alcohol consumption is known to significantly worsen psoriasis. [14] Alcohol has this effect since it both increases the absorption of toxins from the gut (by damaging the gut mucosa) and impairs liver function. Alcohol intake must be eliminated in individuals with psoriasis. Silymarin, the flavonoid component of Silybum marianum, has been reported to be of value in the treatment of psoriasis. [13] Presumably this is a result of its ability to improve liver function, inhibit inflammation, and reduce excessive cellular proliferation. [15] [16] Nutrition Omega-3 fatty acids
The manipulation of dietary oils is extremely important in the management of psoriasis since serum free fatty acid levels are typically abnormal in these patients. [17] Of particular benefit are the omega-3 fatty acids. Most of the clinical research has utilized fish oils rich in eicosapentaenoic acid (EPA) and docosohexanoic acid (DHA). Several double-blind clinical studies have demonstrated that supplementing the diet with 10–12 g of fish oils (providing 1.8 g EPA and 1.2 g DHA) results in significant improvement.[18] [19] [20] This amount of EPA and DHA would be equivalent to the amount of EPA in about 150 g of salmon, mackerel, or herring. Consumption of cold-water fish and the daily supplementation with one tablespoon of flaxseed oil may be more advantageous than fish oil supplementation, given the problem with lipid peroxides in many commercially available fish oil supplements. The improvement in psoriasis from EPA is largely due to the competition of EPA for arachidonic acid binding sites, which results in the inhibition of the production of inflammatory compounds. In the skin of individuals with psoriasis, the production of inflammatory leukotrienes from arachidonic acid is many times greater than normal.[21] Leukotrienes are potent inflammatory agents and promoters of guanylate cyclase activity. In the involved epidermis, the cellular contents of free arachidonic acid and 12-HETE (a product of lipoxygenase metabolism of arachidonic acid) are 250 and 810 times greater, respectively, than in uninvolved epidermal tissue. [21] These elevations appear to be due to the presence in the plaques of a yet-to-be-defined inhibitor of cyclooxygenase, which normally metabolizes arachidonic acid to less inflammatory compounds. Trauma also induces the release of free arachidonic acid and may account for the common clinical observation of plaques at the sites of repeated trauma. These observations are significant, since the increase in 12-HETE stimulates the 5-lipoxygenase pathway, promoting leukotriene formation. This pathway is inhibited by EPA and glutathione peroxidase, suggesting that a selenium deficiency may be a contributory factor (see below under nutritional considerations). As might be expected, cyclooxygenase inhibitors (e.g. aspirin and most other non-steroidal anti-inflammatory agents) may exacerbate psoriasis, while lipoxygenase inhibitors (e.g. benoxaprofen) may cause improvement. [22] Naturally occurring substances, such as quercetin (the ubiquitous plant flavonoid), vitamin E, onion, and garlic, are known to inhibit lipoxygenase and therefore may be of benefit. Since arachidonic acid is found only in animal tissues, it is necessary to limit the intake of animal products, particularly animal fats and dairy products. Diet, fasting, and food allergy control
The evaluation of 316 psoriasis patients with 366 controls, both groups being in the age range 16–65 years, found that psoriasis was positively associated with body mass index and inversely related to intake of carrots, tomatoes, fresh fruits, and the index of beta-carotene intake. [23] Research at a Swedish hospital studying the effects of fasting and vegetarian regimens on chronic inflammatory disease found that such diets helped psoriatic patients. [24] The improvement was probably due to decreased levels of gut-derived toxins and polyamines. Patients have also benefited from gluten-free and elimination diets. [25] [26] Individual nutrients
Decreased levels of vitamin A and zinc are common in patients with psoriasis. [27] [28] [29] Given vitamin A and zinc’s critical role in the health of skin, supplementation might be warranted even without this association. Chromium supplementation may be indicated to increase insulin receptor sensitivity as psoriatics typically have increased serum levels of both insulin and glucose.
[30]
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Glutathione peroxidase (GP) levels are low in psoriatic patients, possibly due to such factors as alcohol abuse, malnutrition, and the excessive skin loss of the hyperproliferative disease. The depressed levels of GP normalize with oral selenium and vitamin E therapy. [31] Another study compared 113 patients with moderate to severe psoriasis with 104 healthy controls and found that male psoriatic patients between 20 and 49 years of age and women with the disease of longer than 20 years had particularly low serum concentrations in whole blood selenium. The lowest whole blood selenium values were found in the subgroup of male patients with widespread disease of long duration who also required treatment with methotrexate and retinoids. [32] There is a growing body of evidence that indicates that the active form of vitamin D (1,25-dihydroxycholecalciferol) has a role in controlling cellular proliferation and differentiation. This recognition has led to clinical trials of both oral and topical forms of vitamin D in the treatment of psoriasis. One controlled study found that 2–5 weeks of topical 1,25-dihydroxycholecalciferol resulted in definite to total improvement in all five patients treated. [33] Another study by the same researchers, this one uncontrolled, found that four of seven patients had complete remission (after 1–3 months) with daily oral doses of 1.0 µg of 1alpha(OH)D 3 .[34] Patients with severe psoriasis have also been found to have significantly low serum levels of 1,25-dihydroxycholecalciferol which normalized after treatment with oral 1alpha(OH)D 3 .[35] Fumaric acid
Over the past three decades, fumaric acid therapy has become increasingly popular in western Europe for psoriasis. Therapy consists of the oral intake of dimethylfumaric acid (240 mg daily) or monoethylfumaric acid (720 mg daily) and the topical application of 1–3% of monoethylfumaric acid. Clinical studies have shown that it is useful in many patients with psoriasis, but side-effects such as flushing of the skin, nausea, diarrhea, general malaise, gastric pain, and mild liver and
kidney disturbances can occur. [36] We recommend using fumaric acid therapy only after other natural therapies have proven ineffective. Psychological aspects A large number (39%) of patients with psoriasis report a specific stressful event occurring within 1 month prior to their initial episode. Such patients have a better prognosis. [37] A few case histories have been reported which document the successful treatment of psoriasis with hypnosis and biofeedback alone. [38] Physical therapeutics Sunlight (ultraviolet light) is extremely beneficial for individuals with psoriasis. The standard medical treatment of psoriasis typically involves the use of the drug psoralen and ultraviolet A (PUVA therapy). However, ultraviolet B (UVB) exposure alone leads to inhibition of cell proliferation and has been shown to be as effective as PUVA therapy with fewer side-effects. [1] [39] [40] [41] Ultraviolet exposure may also benefit through its induction of vitamin D synthesis in the skin. The induction of localized elevation of temperature (42–45°C) to the affected area by ultrasound and heating pads has been shown to be an effective treatment of psoriasis. [42] [43] Topical treatments A number of natural proprietary formulas as well as over-the-counter preparations can be used to provide symptomatic relief. Three botanical agents are worth discussing as alternatives to hydrocortisone: glycyrrhetinic acid from licorice ( Glycyrrhiza glabra), chamomile (Matricaria chamomilla), and capsaicin from cayenne pepper (Capsicum frutescens). Glycyrrhiza glabra (licorice
root)
The licorice component glycyrrhetinic acid exerts an effect similar to that of topical hydrocortisone in the treatment of psoriasis and eczema. In fact, in several studies, glycyrrhetinic acid was shown to be superior to topical cortisone, especially in chronic cases. For example, in one study in patients with eczema, 93% of the patients applying glycyrrhetinic acid demonstrated improvement compared with 83% using cortisone. [44] Glycyrrhetinic acid can also be used to potentiate the effects of topically applied hydrocortisone by inhibiting the 11-beta-hydroxy-steroid dehydrogenase which catalyzes the conversion of hydrocortisone to an inactive form. [45] Matricaria chamomilla (chamomile)
Chamomile preparations are widely used in Europe for the treatment of a variety of common skin complaints including psoriasis, eczema, and dry, flaky, irritated skin. The flavonoid and essential oil components of chamomile possess significant anti-inflammatory and anti-allergy activity. [46] Capsicum frutescens (cayenne
pepper)
Capsaicin is the active component of cayenne pepper ( Capsicum frutescens). When topically applied, capsaicin is known to stimulate and then block small-diameter pain fibers by depleting them of the neurotransmitter substance P. Substance P is thought to be the principal chemomediator of pain impulses from the periphery.
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In addition, substance P, which is elevated in the skin of psoriatics, has been shown to activate inflammatory mediators in psoriasis. Several clinical studies have found that the topical application of 0.025 or 0.075% capsaicin is effective in improving psoriasis. [47] [48] In one double-blind study, 44 patients with symmetrically distributed psoriasis lesions applied topical capsaicin to one side of their body and a placebo to the other side. [28] After 3–6 weeks, significantly greater reductions in scaling and redness were observed on the capsaicin side. Burning, stinging, itching, and skin redness were noted by nearly half of the patients initially, but this diminished or vanished upon continued application. [48] In a more recent study, patients applied capsaicin 0.025% cream (n= 98) or vehicle alone (n = 99) four times a day for 6 weeks. [47] Efficacy was based on a physician’s global evaluation and a combined psoriasis severity score including scaling, thickness, erythema, and pruritus. Capsaicin-treated patients demonstrated significantly greater improvement in global evaluation and in pruritus relief, as well as a significantly greater reduction in combined psoriasis severity scores. Aloe vera
A recent, very exciting, double-blind, placebo-controlled study found that topical application of an Aloe vera extract in a hydrophilic cream was highly effective in psoriasis vulgaris. Sixty patients with slight to moderate chronic plaque-type psoriasis, PASI (psoriasis area and severity index) scores of between 4.8 and 16.7 (mean 9.3), and mean duration of the disease of 8.5 years (range 1–21) applied either the aloe or a placebo gel three times a day. The treatment was well tolerated by all the patients, with no adverse drug-related symptoms and no drop-outs. By the end of the study (4–12 months of treatment), the Aloe vera extract cream had cured 25/30 patients (83.3%) compared with the placebo cure rate of only 2/30 (6.6%), resulting in significant clearing of the psoriatic plaques (328/396 (82.8%) vs. placebo 28/366 (7.7%), and a decreased PASI score to a mean of 2.2. [49]
THERAPEUTIC APPROACH Despite the complexity of this disease, the therapeutic approach is fairly straightforward: decrease bowel toxemia, rebalance fatty acid levels and inflammatory processes in the skin, and utilize the listed therapeutic regimen to further balance the abnormal cell proliferation. Diet
• Limit sugar, meat, animal fats, and alcohol • Increase intake of dietary fiber and cold water fish and, if necessary, bring weight to normal levels • Eliminate sources of gluten • Identify and address any food allergies. Supplements
• High potency multiple vitamin and mineral formula • Flaxseed oil: 1 tbsp/day • Vitamin A: 50,000 IU/day (do not use in pregnant or women at risk for pregnancy) • Vitamin E: 400 IU/day • Chromium: 400 mcg/day • Selenium: 200 mcg/day • Zinc: 30 mg/day • Water-soluble fiber (psyllium, pectin, guar gum, etc.): 5 g at bedtime. Botanical medicines
• Hydrastis canadensis (goldenseal) —the dosage should be based on berberine content; as there is a wide range of quality in goldenseal preparations, standardized extracts are preferred three times/day
—dried root or as infusion (tea): 2–4 g three times/day —fluid extract (1:1): 2–4 ml (0.5–1 tsp) three times/day —solid (powdered dry) extract (4:1 or 8–12% alkaloid content): 250–500 mg three times/day • Smilax sarsaparilla —dried root or by decoction: 1–4 g three times/day —liquid extract (1:1): 8–16 ml (2–4 tsp) three times/day —solid extract (4:1): 250–500 mg three times/day • Silybum marianum (milk thistle) —silymarin: 70–210 mg three times/day.
Psychological
Evaluate stress levels and utilize stress reduction techniques as appropriate. Physical medicines
• Ultrasound: 42–45°C, 20 minutes, three times/week • UVB: 295–305 nm, 2 mW/cm2 , 3 minutes, three times/week. Topical treatment
Preparations containing one or more of the ingredients described above. Apply to affected areas of the skin two to three times/day.
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REFERENCES 1. Katayama
H, Hori H. The influence of UVB irradiation on the excretion of the main urinary metabolite of prostaglandin F1a and F2a in psoriatic and normal subjects. Acta Derm Vener (Stockh) 1984;
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E, Belew P. Microbial factors in psoriasis. Arch Dermatol 1982; 118: 1434–1444
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Rao M, Field M. Enterotoxins and anti-oxidants. Biochem Soc Trans 1984; 12: 177–180
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Juhlin L, Vahlquist C. The influence of treatment and fibrin microclot generation in psoriasis. Br J Dermatol 1983; 108: 33–37
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Thurmon FM. The treatment of psoriasis with sarsaparilla compound. New Engl J Med 1942; 227: 128–133
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Weber G, Galle K. The liver, a therapeutic target in dermatoses. Med Welt 1983; 34: 108–111
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Monk BE, Neill SM. Alcohol consumption and psoriasis. Dermatologica 1986; 173: 57–60
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Hikino H, Kiso Y, Wagner H et al. Antihepatotoxic actions of flavanolignans from Silybum marianum fruits. Planta Medica 1984; 50: 248–250
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Adzet T. Polyphenolic compounds with biological and pharmacological activity. Herbs Spices Medicinal Plants 1986; 1: 167–184
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Zlatkov NB, Ticholov JJ, Dourmishev AL. Free fatty acids in the blood serum of psoriatics. Acta Derm Vener (Stockh) 1984; 64: 22–25
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Bittiner SB, Tucker WFG, Cartwright I et al. A double-blind, randomized, placebo-controlled trial of fish oil in psoriasis. Lancet 1988; i: 378–380
Grimmunger F, Mayser P, Papavassilis C. A double-blind, randomized, placebo-controlled trial of n-3 fatty acid based lipid infusion in acute, extended guttate psoriasis. Clin Invest 1993; 71: 634–643 19.
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Maurice PDL, Allen BR, Barkley ASJ et al. The effects of dietary supplementation with fish oil in patients with psoriasis. Br J Dermatol 1987; 1117: 599–606
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Editorial. Leukotrienes and other lipoxygenase products in the pathogenesis and therapy of psoriasis and other dermatoses. Arch Dermatol 1983; 119: 541–547
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Kragballe K, Herlin MD. Benoxaphren improves psoriasis. Arch Dermatol 1983; 119: 548–552
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Naldi L et al. Dietary factors and the risk of the risk of psoriasis. Results of an Italian case-controlled study. Br J Dermatol 1996; 134: 101–106
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Lithell H, Bruce A, Gustafsson B et al. A fasting and vegetarian diet treatment trial on chronic inflammatory disorders. Acta Derm Vener (Stockh) 1983; 63: 397–403
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Bazex A. Diet without gluten and psoriasis. Ann Derm Symp 1976; 103: 648
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Douglass JM. Psoriasis and diet. Calif Med 1980; 133: 450
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Majewski S et al. Decreased levels of vitamin A in serum of patients with psoriasis. Arch Dermatol Res 1989; 280: 499–501
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Hinks LJ, Young S, Clayton B. Trace element status in eczema and psoriasis. Clin Exp Dermatol 1987; 12: 93–97
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Donadini A, Dazzaglia A, Desirello G. Plasma levels of Zn, Cu and Ni in healthy controls and in psoriatic patients. Acta Vitamin Enzymol 1980; 1: 9–16
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Fratino P, Pelfini C, Jucci A, Bellazi R. Glucose and insulin in psoriasis: the role of obesity and genetic history. Panminerva Medica 1979; 21: 167
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Juhlin L, Bedquist L, Echman G et al. Blood glutathione-peroxide levels in skin diseases. Effect of selenium and vitamin E treatment. Acta Derm Vener (Stockh) 1982; 62: 211–214
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Michaelsson G, Berne B, Calmark B. Selenium in whole blood and plasma is decreased in patients with moderate and severe psoriasis. Acta Derm Vener (Stockh) 1989; 69: 29–34
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Morimoto S, Takamoto S, Onishi T et al. Therapeutic effect of 1,25–dihydroxyvitamin D3 for psoriasis. Report of five cases. Calcif Tissue Int 1986; 38: 119–122
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Takamoto S, Onishi T, Morimoto S et al. Effect of 1-alpha-hydroxycholecalciferol on psoriasis vulgaris. A pilot study. Calcif Tissue Int 1986; 39: 360–364
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Staberg B, Oxholm A, Klemp P, Christiansen C. Abnormal vitamin D metabolism in patients with psoriasis. Acta Derm Vener (Stockh) 1987; 67: 65–68
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Nieboer C et al. Systemic therapy with fumaric acid derivates: new possibilities in the treatment of psoriasis. J Am Acad Dermatol 1989; 20: 601–608
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Seville RH. Psoriasis and stress. Br J Dermatol 1977; 97: 297
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Winchell SA, Watts RA. Relaxation therapies in the treatment of psoriasis and possible pathophysiologic mechanisms. J Am Acad Dermatol 1988; 18: 101–104
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Parrish J. Phototherapy and photochemotherapy of skin diseases. J Incest Dermatol 1981; 77: 1: 167–171
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Larko O, Swanbeck G. Is UVB treatment of psoriasis safe? Acta Derm Vener (Stockh) 1982; 62: 507–512
Boer J, Hermans J, Schothorst A, Suurmond D. Comparison of phototherapy (UV-B) and photochemotherapy (PUVA) for clearing and maintenance therapy of psoriasis. Arch Dermatol 1984; 120: 52–57 41.
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Urabe H, Nishitani K, Kohda H. Hyperthermia in the treatment of psoriasis. Arch Dermatol 1981; 117: 770–774
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Orenberg E, Deneau D, Farber E. Response of chronic psoriatic plaques to localized heating induced by ultrasound. Arch Dermatol 1980; 116: 893–897
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Evans FQ. The rational use of glycyrrhetinic acid in dermatology. Br J Clin Pract 1958; 12: 269–279
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Teelucksingh S, Mackie AD, Burt D. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990; 335: 1060–1063
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Mann C, Staba EJ. The chemistry, pharmacology, and commercial formulations of chamomile. Herbs, Spices, and Medicinal Plants 1984; 1: 235–280
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Ellis CN, Berberian B, Sulica VI. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol 1993; 29: 438–442
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Bernstein JE, Parish LC, Rapaport M. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986; 15: 504–507
49.
Syed TA, Ahmad SA, Holt AH et al. Management of psoriasis with Aloe vera extract in a hydrophilic cream: a placebo-controlled, double-blind study. Trop Med Int Health 1996; 1: 05–509
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Chapter 185 - Rheumatoid arthritis Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Fatigue, low-grade fever, weakness, weight loss, joint stiffness, and vague joint pain may precede the appearance of painful, swollen joints by several weeks • Severe joint pain with considerable inflammation that begins insidiously in the small joints and progresses to affect all joints • X-ray findings usually show soft tissue swelling, erosion of cartilage, and joint space narrowing • Rheumatoid factor usually present in serum • Extra-articular manifestations are common, including vasculitis, muscle atrophy, subcutaneous and systemic granulomas, pleurisy, pericarditis, pulmonary fibrosis, lymphadenopathy, splenomegaly, anemia, and leukopenia.
GENERAL CONSIDERATIONS Rheumatoid arthritis (RA) is a chronic inflammatory condition that affects the entire body but especially the synovial membranes of the joints. The joints typically involved are the hands, feet, wrists, ankles, and knees. Between 1 and 3% of the population is affected; female patients outnumber males almost 3:1; and the usual age of onset is 20–40 years, although rheumatoid arthritis may begin at any age. [1] [2] The onset of RA is usually gradual, but occasionally it is quite abrupt. Fatigue, low-grade fever, weakness, joint stiffness, and vague joint pain may precede the appearance of painful, swollen joints by several weeks. Several joints are usually involved at the onset, typically in a symmetrical fashion, i.e. both hands, wrists, or ankles. In about one-third of persons with RA, initial involvement is confined to one or a few joints. [1] [2] Involved joints will characteristically be quite warm, tender, and swollen. The skin over the joint will take on a ruddy purplish hue. As the disease progresses, deformities develop in the joint of the hands and feet.
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Colloquial terms used to describe these deformities include swan neck, boutonnière, and cock-up toes.
[ 1] [ 2]
Pathogenesis There is abundant evidence that RA is an autoimmune reaction, where antibodies develop against components of joint tissues. Yet what triggers this autoimmune reaction remains largely unknown. Speculation and investigation have centered around genetic susceptibility, abnormal bowel permeability, lifestyle and nutritional factors, food allergies, and microorganisms. RA is a classic example of a multifactorial disease where an assortment of genetic and environmental factors contribute to the disease process. Genetic factors
The histocompatibility antigen HLA-DRw 4 is found in 70% of patients with RA compared with 28% of controls. This strongly implies that susceptibility to RA is influenced by genetic factors which govern immune response. Severe RA is also found at four times the expected rate in first-degree relatives of probands with seropositive disease. As strong as these genetic associations are, environmental factors are necessary for the development of the disease. This is evident from the discordance demonstrated in monozygotic twin studies. [1] Abnormal bowel permeability
An interesting association between rheumatoid arthritis and abnormal bowel function may provide a unified theory as to the cause of RA. Individuals with RA have increased intestinal permeability to dietary and bacterial antigens as well as alterations in bacterial flora. [3] [4] [5] Food allergies may contribute greatly to the increased permeability of the gut in RA. Non-steroidal anti-inflammatory drugs have also been implicated. This altered permeability to gut-derived antigens contributes greatly to the increased levels of circulating endotoxins (lipopolysaccharide components of the cell walls of Gram-negative bacteria) and immune complexes characteristic of RA. The increased gut permeability and inappropriate bacterial flora could also result in the absorption of antigens that are very similar to antigens in joint tissues. Antibodies formed to microbial antigens are hypothesized to cross-react with the antigens in the joint tissues. Increasing evidence appears to support this concept. For example, antibodies to Campylobacter, Salmonella, and Shigella have been shown to cross-react with collagen, while antibodies to Klebsiella pneumoniae, Proteus vulgaris and Yersinia enterocolitica have been shown to cross-react with other joint tissues. [6] [7] Dysbiosis and small intestinal bacterial overgrowth
Perhaps more important than specific causative organisms is the fact that many patients with rheumatoid arthritis exhibit altered microbial flora and small intestinal bacterial overgrowth (SIBO). In fact, the degree of SIBO has been shown to be associated with the severity of symptoms and disease activity. [8] For more information on SIBO, see Chapter 7 . The presence of abnormal antibodies and immune complexes
The serum and joint fluid of nearly all individuals with RA contain the rheumatoid factor (RF). The RF is the number of antibodies against the Fc fragment of IgG. RF antibodies belong to the IgM, IgG, and IgA classes, but only IgM RF is readily measured by currently available methods, which include latex agglutination, bentonite flocculation, and sensitized sheep or human red blood cell test. Most of the RF is formed locally in the affected joints by the inflammatory infiltration of activated B-cells and plasma cells. The serum titer of RF usually correlates well with the severity of arthritis symptoms. The presence of circulating immune complexes is one of the major factors thought to contribute to the pathogenesis of RA. The cell-mediated, humoral, and non-specific immune responses to the immune complexes lead to much of the proliferative inflammation seen in RA.
These abnormalities are quite similar to the Arthus reaction and serum sickness, immune complex-induced reactions dependent upon neutrophils, and complement activation. Although the amount of circulating immune complexes has not correlated well with disease activity, there is little doubt that the formation of immune complexes and abnormal antibodies and the sequelae of events that follow are major factors in the progression of RA. Microbial hypotheses
As interesting as the various microbial hypotheses are, they are not in themselves comprehensive enough to explain all of the events observed in RA. A variety of microorganisms (e.g. Epstein–Barr virus, rubella virus, amebic organisms, and Mycoplasma) have been sug-gested to be causative factors in the pathogenesis of RA, despite the fact that no microbial agent has been consistently isolated in RA patients. [9] The fact that studies have focused on attempting to isolate whole organisms from synovial fluids and on the presence of antibodies to viable and whole organisms, coupled with the failure to isolate any offending organisms, has prompted many researchers committed
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to the “germ theory” to suggest that some atypical viral-like agent(s) may be responsible in RA. [9] Microbial factors, particularly their role in increasing the level of circulating immune complexes, definitely contribute to the pathogenesis of RA, but at this time it appears highly unlikely that there is a single causative microbe in RA. Nonetheless, researchers continue to search for a causative agent. One popular microbial hypothesis, which was later disproved, involved the Epstein–Barr virus (EBV). basic immunopathologic observations:
[ 10]
The link between EBV and RA was initially based on three
• EBV is a polyclonal activator of B-cells, which induce autoantibody and rheumatoid factor production both in vitro and in vivo. • Lymphocytes from patients with RA show evidence of impaired regulation of EBV infection in vitro. • Antibodies to EBV-determined antigens such as rheumatoid arthritis nuclear antigen (RANA), EBV nuclear antigen, and viral capsid antigen are elevated in sera from patients with RA. Researchers have subsequently concluded that EBV is an unlikely etiological agent, based on the prevalence of EBV antibodies in healthy controls.
[ 10]
Mycoplasmas have also received some attention as possible etiologic factors in RA. [11] Mycoplasmas can infect joints and induce arthritis. Mycoplasmal antigens have been detected in the synovial fluid of RA patients, implying that frequent and persistent colonization of mycoplasmas may lead to host sensitization and IC formation. However, these effects are not specific to mycoplasmas alone. Another popular microbial hypothesis is based on the work of Dr Roger Wyburn-Mason. [12] During the 1960s, Dr Wyburn-Mason routinely identified an amebic organism in the synovial fluid of patients with arthritic conditions. The potent antibiotic metronidazole (Flagyl) was shown to be active against the organism and is part of the protocol recommended by the Rheumatoid Disease Foundation (Route 4, Box 137, Franklin, TN 37064; tel: 615-646-1030), an organization which promotes additional research in this area. In summary, it appears that the presence of high levels of circulating immune complexes containing microbial antigens in general, as well as the increased microbial antigenic load observed in RA patients, are of greater significance than antibodies to one particular organism or group of organisms. Decreased DHEA levels
Defective androgen synthesis has been proposed as a potential predisposing factor for rheumatoid arthritis. For example, in one large study dehydroepiandrosterone sulfate (DHEAS) levels were measured in 185 postmenopausal women (aged 45–65 years) with rheumatoid arthritis. [13] Compared with 518 postmenopausal women in the control group, DHEAS levels were below normal in the 120 patients with RA who had never taken corticosteroids, and levels were even lower in the 39 patients who were currently taking corticosteroids. Supplemental DHEA has shown therapeutic benefits in patients with systemic lupus erythematosus (SLE) in studies conducted at Stanford Medical Center. [14] [15] In the double-blind study, 28 female patients with mild to moderate SLE were given DHEA (200 mg/day) or placebo for 3 months. [15] Outcomes were assessed using the SLE Disease Activity Index (SLEDAI) score, patient’s and physician’s overall assessments of disease activity, and concurrent corticosteroid usage. In the patients receiving DHEA, the SLEDAI decreased by nearly two points, while the placebo group’s average score increased by almost a full point. Patient and physician assessments also showed improvements in the SLE group and exacerbation in the placebo group. The average dosage of corticosteroids decreased by 30% in the SLE group and increased by 40% in the control group. The number of lupus flare-ups was three in the SLE group, compared with eight in the placebo group. Mild acne was a frequent side-effect of DHEA. Given DHEA’s positive effects in SLE, [14] [15] even in the absence of double-blind clinical studies in rheumatoid arthritis, DHEA supplementation appears warranted. For conservative practitioners it should be used at least to correct the physiological deficit, which can be determined with a 24 hour urinary measure. For more aggressive practitioners, it can be used to try to significantly impact disease activity. In the later goal, the dosage required will likely be above 50 mg. The major side-effect at this dosage and above is mild to severe acne and possibly increased androgenization in women.
DIAGNOSIS RA is easily recognized in its most advanced and characteristic form. However, diagnosis of early RA is often much more difficult. The American Rheumatism Association has established criteria for the diagnosis of “classic”, “definite”, “probable”, and “possible” RA, which are listed in Table 185.1 .[16] Laboratory and X-ray findings Rheumatoid factor
A variety of non-rheumatoid diseases will show elevated levels of RF. These diseases usually share the common feature of chronic inflammation with persistent antigenic challenge and include other connective tissue diseases
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TABLE 185-1 -- Criteria for the classification of RA Classic RA The diagnosis of RA requires seven of the following criteria to be observed by a physician. In criteria 1–5 the joint signs or symptoms must be continuous for at least 6 weeks. Any one of the features listed under exclusions will exclude a patient from this and other categories. 1. Morning stiffness 2. Pain on motion or tenderness in at least one joint 3. Swelling (soft tissue thickening or fluid, not bony overgrowth alone) in at least one joint
4. Swelling of at least one other joint with any interval free of joint symptoms between the joint involvement may not be more than 3 months 5. Symmetric joint swelling with simultaneous involvement of the same joint on both sides of the body (bilateral involvement of proximal interphalangeal, metacarpophalangeal, or metatarsophalangeal joints is acceptable without absolute symmetry). Terminal phalangeal joint involvement will not fulfill this criteria 6. Subcutaneous nodules over bony prominences, on extensor surfaces, or in juxta-articular regions 7. X-ray changes typical of RA, which must include bony decalcification localized to or most marked adjacent to the involved joints and not just degenerative changes. Degenerative changes do not exclude patients from any group classified as having RA 8. Positive agglutination test – demonstration of the “rheumatoid factor” by an acceptable method 9. Poor mucin precipitate from synovial fluid or an inflammatory synovial effusion with 2,000 or more white cells/mm 3 and without crystals 10. Characteristic histologic changes in synovium with three or more of the following: marked villous hypertrophy; proliferation of superficial synovial cells often with palisading; marked infiltration of chronic inflammatory cells with tendency to form lymphoid nodules; deposition of compact fibrin either on the surface or interstitially; foci of necrosis 11. Characteristic histologic changes in nodules showing granulomatous foci with central zones of cell necrosis, surrounded by a palisade of proliferated mononuclear and peripheral fibrosis and chronic inflammatory cell infiltration Definite RA This diagnosis requires five of the above criteria. In criteria 1–5, the joint signs must be continuous for at least 6 weeks Probable RA This diagnosis requires three of the above criteria. In at least one of the criteria 1–5, the joint signs or symptoms must be continuous for at least 6 weeks Possible RA This diagnosis requires two of the following criteria and total duration of joint symptoms must be at least 3 months: 1. Morning stiffness 2. Tenderness or pain on motion with history of recurrence or persistence of 3 weeks 3. History or observation of joint swelling 4. Elevated sedimentation rate or C-reactive protein 5. Iritis (e.g. systemic lupus erythematosus, Sjögren’s syndrome, polymyositis, and scleroderma), as well as infectious diseases (e.g. tuberculosis, leprosy, syphilis, viral hepatitis, bacterial infections, infectious mononucleosis, and influenza). Positive results are also found in patients with idiopathic pulmonary fibrosis, sarcoidosis, chronic active hepatitis and cirrhosis, lymphomas, cryoglobulinemia, and repeated blood transfusions. [1] RF may also be transiently elevated after immunizations and other assaults to the immune system. Studies of apparently healthy individuals demonstrate that the overall prevalence is about 4%, but in persons over the age of 60 some surveys have demonstrated a prevalence rate of over 40%. However, titers of RF in the elderly and apparently healthy individuals are typically quite low, less than 1:80. [1] Antinuclear antibodies
Antinuclear antibodies (ANA) are found in 20–60% of RA patients. Titers specific for native DNA are typically normal, while titers to single-stranded or denatured DNA are usually elevated. ANA titers are typically lower in RA than systemic lupus erythematosus. [1] EBV antibodies
Antibodies to an Epstein–Barr virus antigen can be identified by immunodiffusion or by immunofluorescence in the serum of most patients with RA. These antibodies are referred to as anti-rheumatoid arthritis precipitin (anti-RAP) and anti-rheumatoid arthritis nuclear antigen (anti-RANA). The significance of these antibodies remains to be determined. Other laboratory abnormalities
Anemia is quite common, usually normocytic and normochromic or hypochromic. Decreased erythropoiesis is common in chronic inflammatory conditions like RA. Although the serum iron level and total iron binding capacity are usually low, supplemental iron is of no value
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and may actually promote further free radical damage. [1] [17] Therefore, iron supplementation is not indicated unless the anemia is due specifically to blood loss. Serum ferritin levels may be useful in determining the appropriateness of iron therapy; however, it must be kept in mind that ferritin is elevated during acute inflammation and correlates well with other indicators of disease activity such as the erythrocyte sedimentation rate and C-reactive protein. The erythrocyte sedimentation test (ESR) is commonly elevated and may be used as a rough estimator of disease activity in patient monitoring with the caveat that occasionally the ESR does not accurately reflect disease activity. Synovial fluid
Synovial fluid findings usually reflect the degree of inflammation. The high content of fibrinogen may lead to spontaneous clotting of the fluid, but this should not be confused with the mucin clot. Adding 1% acetic acid will dissolve the fibrin. In RA the mucin clot is poor because of smaller-than-normal polymers of hyaluronic acid. Neutrophils are the primary cells found in the fluid and may range from 10,000 to 50,000/mm 3 . Complement levels are generally low and the neutrophils typically contain cytoplasmic inclusion bodies with ingested immune complexes. X-rays
X-ray findings usually show soft tissue swelling, erosion of cartilage, and subtle joint space narrowing early in the disease process. As the disease progresses, the erosion of joint spaces is more pronounced, as is the evidence of diffuse osteoporosis. Standard medical therapy Standard medical therapy is of limited value in most cases of RA as it fails to address the complex underlying causes of this disease. Standard medical treatment of RA involves, in addition to drugs, such physical therapy modalities as exercise, heat, cold, massage, diathermy, lasers, and paraffin baths. [1] [2] Non-steroidal anti-inflammatory drugs
The first drug generally employed is aspirin. It is often quite effective in relieving both the pain and inflammation and is also relatively inexpensive. Since the
therapeutic dose required is relatively high, toxicity often occurs. Tinnitus and gastric irritation are early manifestations of toxicity.
[1] [2]
Other non-steroidal anti-inflammatory drugs (NSAIDs) are often used as well, especially when aspirin is ineffective or is not well tolerated. Typical representatives of this class of drugs include: • ibuprofen (Motrin, Advil, Nuprin, piroxicam (Feldene)) • diclofenac (Voltarin) • fenoprofen (Nalfon) • indomethacin (Indocin) • naproxen (Naprosyn) • tolmetin (Tolectin) • sulindac (Clinoril). While more expensive, none of these drugs have demonstrated superior efficacy over aspirin. Like the use of these drugs in osteoarthritis, use of these drugs in the treatment of rheumatoid arthritis is a classic example of suppression of symptoms, while accelerating the factors which promote the disease process. In the case of rheumatoid arthritis, NSAIDs have been shown to greatly increase the already hyperpermeable gastrointestinal tract of rheumatoid arthritis sufferers. [18] The use of NSAIDs in rheumatoid arthritis is also a significant cause of serious gastrointestinal tract reactions, including ulcers, hemorrhage, and perforation. Approximately 20,000 hospitalizations and 2,600 deaths occur as a result of NSAIDs each year in individuals with rheumatoid arthritis. [19] If NSAIDs are not effective, corticosteroids may be used. However, most experts and medical textbooks clearly state that long-term use of corticosteroids in rheumatoid arthritis is not advised due to the side-effects. Nonetheless, long-term corticosteroid use is quite common in patients with rheumatoid arthritis. If NSAID and cortisone therapy does not offer benefit, more aggressive and potentially more toxic treatments are used along with continued use of NSAIDs and corticosteroids. Hydroxychloroquine, gold therapy, penicillamine, azathioprine, methotrexate, and cyclophosphamide are examples of drugs currently in use. Unfortunately, in most cases, the benefit produced by these drugs is greatly outweighed by the significant toxicity they possess. The use of these drugs often requires the use of additional drugs to deal with side-effects. It is not uncommon for individuals with rheumatoid arthritis to be on 12 or more prescription drugs at one time. And finally, joint surgery and replacement are reserved for the most severe cases. Corticosteroids
Prednisone is by far the most frequently prescribed oral corticosteroid. Other drugs in this category include prednisolone, methyl-prednisolone, dexamethasone, and betamethasone. Prednisone blocks many key steps in
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the allergic and inflammatory response including the production and secretion of the inflammatory mediators such as histamine, prostaglandins, and leukotrienes by white blood cells. This disruption of the normal defense functions of the white blood cells is effective in stopping the inflammatory response, but essentially cripples the immune system. Although prednisone is often of great benefit in the short-term management of many chronic inflammatory diseases, long-term use generally causes more problems than benefits. As long-term corticosteroid use has many significant side-effects, most physicians try to reserve the use of prednisone for acute worsening of the rheumatoid arthritis. Because long-term treatment with corticosteroids suppresses the natural production of the corticosteroids produced by the adrenal gland, sudden withdrawal of the drugs may lead to collapse, coma, and death. The side-effects of oral corticosteroids are a function of dosage levels and length of time on the medication. Most of the problems of side-effects are not due to taking too much of the drug for a short period of time, but rather reflect long-term use. At lower doses (less than 10 mg/day), the most notable side-effects are usually increased appetite, weight gain, retention of salt and water, and increased susceptibility to infection. Common side-effects of long-term corticosteroid use at higher dosage levels include: • depression and other mental/emotional disturbances (up to 57% of patients being treated with high doses of prednisone for long periods of time develop these symptoms) • high blood pressure • diabetes • peptic ulcers • acne • excessive facial hair in women • insomnia • muscle cramps and weakness • thinning and weakening of the skin • osteoporosis • susceptibility to the formation of blood clots. The other drugs used in rheumatoid arthritis are often referred to as “disease-modifying drugs”. These drugs include hydroxychloroquine, gold therapy, penicillamine, azathioprine, methotrexate, and cyclophosphamide. Hydroxychloroquine (Plaquinil)
Hydroxychloroquine was originally used in the treatment of malaria. In the treatment of rheumatoid arthritis, hydroxychloroquine is thought to work via inhibiting the immune system. Hydroxychloroquine must be used for at least 6 months to determine if it is going to be of value in rheumatoid arthritis. Since hydroxychloroquine is associated with a high rate of side-effects, use is often discontinued before this time period. Mild adverse effects include skin rashes, loss of hair, headache, blurring of vision, ringing in the ears, loss of appetite, nausea, vomiting, stomach cramps, and diarrhea. More severe side-effects include emotional or psychotic mental changes, seizures, excessive muscle weakness, damage to the eyes with significant impairment of vision, anemia, decreased white blood cell counts, and frequent infections. Gold therapy
Gold salt injection aids about 50% of patients, but severe side-effects occur in nearly one-third of patients. Oral gold salts are slightly less toxic, but still cause skin rashes, painful mouth ulcers, bone marrow suppression, and, in some cases, even more serious side-effects such as kidney damage. Like hydroxychloroquine, a trial of 6 months is required to determine the likely benefit of gold therapy. Penicillamine
Penicillamine was originally used in the treatment of copper, mercury, and lead poisoning. It works by binding to these metals and promoting their excretion. Penicillamine has been used in the treatment of rheumatoid arthritis since the early 1960s. Its use has fallen out of favor in the 1990s because of a growing concern for its safety as well as questionable effectiveness. Penicillamine can cause kidney damage, blood and bone marrow toxicity, and severe muscular weakness. Like other disease-modifying drugs, it must be used for at least 6 months to determine if it is effective.
Azathioprine
Azathioprine is a drug which suppresses the immune system. It is often used to severely impair the immune system after organ transplantation in an attempt to prevent tissue rejection. Azathioprine is more powerful than the previously discussed disease-modifying drugs and provides more immediate benefits. With this increased potency comes significant toxicity. Side-effects include skin rash, loss of appetite, nausea, vomiting, diarrhea, sore on lips and mouth, bone marrow suppression, weakness, and fatigue. Azathioprine is also associated with increasing the risk of certain cancers. Methotrexate
Methotrexate is used primarily in the treatment of cancer and a severe disabling form of psoriasis. It works by inhibiting the utilization of folic acid which is required for cell reproduction. Without the ability to utilize folic
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acid, cells are unable to divide and multiply. The goal in the case of rheumatoid arthritis is to inhibit the replication of white blood cells and thus the immune system. Methotrexate is the next step in potency and toxicity. Side-effects include gastrointestinal ulceration and bleeding; loss of hair; mouth and throat ulcers; severe bone marrow suppression; damage to the lungs, liver, and kidneys; increased rate of infections; and increased risk for developing cancer. Cyclophosphamide
Cyclophosphamide is used primarily in the treatment of various forms of cancer. It is more powerful than all the previously described disease-modifying drugs. Toxicity is a major problem with side-effects being comparable to methotrexate, but more severe.
THERAPEUTIC CONSIDERATIONS There is little argument that rheumatoid arthritis is an aggressive disease which calls for aggressive measures. There is also little argument that current medical treatment of rheumatoid arthritis is aggressive. The big question is: Is aggressive chemotherapy for rheumatoid arthritis actually providing benefit? And at what cost to the patient? Research is only beginning to determine the effects of treatment on the long-term outcome of rheumatoid arthritis because in order to fully answer the questions raised in the previous paragraph patients must be followed for at least 20 years. Many of the disease-modifying drugs have only been used for the last two or three decades. A revealing study evaluated the long-term outcome of therapy in 112 patients with rheumatoid arthritis treated with conventional drug therapy. [20] After 20 years, despite aggressive therapy with standard drug regimens, only 18% of all patients were able to lead a normal life. Most patients (54%) were either dead (35%) or severely disabled (19%). Most mortalities were directly related to rheumatoid arthritis. The results of this study clearly indicate that, although current drug therapy may be effective in providing short-term benefit, this approach is not providing long-term benefits to patients with rheumatoid arthritis. Rheumatoid arthritis as a multifactorial condition requires a comprehensive therapeutic approach which focuses on reducing those factors known to be involved in the disease process (gut permeability, circulating immune complexes, free radicals, immune dysfunction, etc.), controlling inflammation and promoting joint regeneration. The natural approach involves improving poor digestion, food allergies, increased gut permeability, increased circulating immune complexes, and excessive inflammatory processes. Foremost in the natural approach is the use of diet to control inflammation. Diet Diet has been strongly implicated in rheumatoid arthritis for many years, in terms of both cause and cure. Population studies have demonstrated that rheumatoid arthritis is not found in societies that eat a more “primitive” diet and is found at a relatively high rate in societies consuming the so-called “Western” diet. [21] Therefore, a diet rich in whole foods, vegetables, and fiber, and low in sugar, meat, refined carbohydrate, and saturated fat appears to offer some protection against developing rheumatoid arthritis. In addition, dietary therapy is showing tremendous promise in the treatment of rheumatoid arthritis. [22] [23] [24] The major focus in dietary therapy is: • eliminating food allergies • following a vegetarian diet • modifying the intake of dietary fats and oils • increasing the intake of antioxidant nutrients. Food allergy
Elimination of allergic foods has been shown to offer significant benefit to some individuals with rheumatoid arthritis. [25] [26] [27] [28] Virtually any food can result in aggravating rheumatoid arthritis, but the most common offending foods are wheat, corn, milk and other dairy products, beef, and nightshade family foods (tomato, potato, eggplants, peppers, and tobacco) as well as food additives. A well-designed study highlights the effectiveness of eliminating food allergens as part of a healthy diet and lifestyle program in the treatment of rheumatoid arthritis.[29] In a 13 month study, two groups of patients suffering from rheumatoid arthritis were studied to determine the effect of diet on their condition. One group followed a therapeutic diet, the other group continued to eat as they wished. Both groups started the study by visiting a spa for 4 weeks. The treatment group began their therapeutic diet by fasting for 7–10 days. Dietary intake during the fast consisted of herbal teas, garlic, vegetable broth, decoction of potatoes and parsley, and the following juices: carrots, beets, and celery. No fruit juices were allowed. Patients with rheumatoid arthritis have historically benefited from fasting; however, strict water fasting should only be done under direct medical supervision. Fasting decreases the absorption of allergic food components as well as reducing the levels of inflammatory mediators. A juice fast or a fast similar to the one used in this study is probably safer than a water fast and may actually yield better results. Short-term fasts of 3–5 days’ duration are recommended during acute worsening of rheumatoid arthritis (see Ch. 47 for a full discussion of therapeutic fasting.)
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After the fast, the patients reintroduced a “new” food item every second day. If they noticed an increase in pain, stiffness, or joint swelling within 2–48 hours, this item was omitted from the diet for at least 7 days before being reintroduced a second time. If the food caused worsening of symptoms after the second time, it was omitted permanently from the diet. The results of the study further supported the positive results noted in other studies showing that shortterm fasting followed by a vegetarian diet results in “a substantial reduction in disease activity” in many patients. [30] [31] [32] The results indicated a therapeutic benefit beyond elimination of food allergies alone. The authors suggested that the additional improvements were due to changes in dietary fatty acids (discussed below). In addition, other studies have shown that improvements with a vegetarian diet are associated with improvements in fecal flora (also discussed below). In a 1 year follow-up to this important study, all the patients who responded to the diet still followed the diet. [33] Significant benefits were noted in the patients who responded to the diet compared with those subjects who did not respond and with the control group on an omnivorous diet. These long-term results support
recommending a vegetarian diet in the treatment of rheumatoid arthritis. Fecal flora
Altered gastrointestinal tract flora has been linked to rheumatoid arthritis and other autoimmune diseases (see above). Two recent randomized, clinical studies demonstrate that significant changes in microbial flora are associated with clinical improvements. [34] [35] In the first study, researchers sought to determine the effect of vegetarian diet-induced improvement of RA on fecal flora in 53 patients. [34] Rather than the traditional method of isolating, identifying, and enumerating different bacterial species in fecal samples, the researchers examined bacterial fatty acid profiles. Human fecal flora is a very complex ecosystem with over 400 different species, making it very difficult to isolate and identify the species. Because of the lack of reproducibility and the fact that many bacteria do not grow well on selective culture media and many prevent the growth of other species, classic bacteriological techniques are generally regarded as being unsuitable for the study of the microecology of the human gut. Instead of focusing on specific species, the researchers used another approach to detect overall changes in bacterial flora of stool cultures collected at baseline, 4 weeks, and thereafter every 3 months for 1 year. The technique used was computerized comparison of bacterial fatty acid profiles produced by gas–liquid chromatography of stool samples. The fatty acids extracted are structural components of bacterial cell membranes. Each bacterial species has its own characteristic composition. In a stool sample, the profile of fatty acids represents all the bacteria present in the sample. This technique has proven to be more sensitive than classical quantitative culture in detecting microecological changes in stool samples. In the first study, the 53 patients, based on repeated clinical assessments, were assigned to either a high-improvement index (HI) or a low-improvement index (LI). Significant alteration in the intestinal flora was observed when the patients changed from the omnivorous to the vegetarian diet. These results further document a direct association between intestinal flora and disease activity in rheumatoid arthritis. The second study, of 43 patients, provided additional support for the positive effects of a vegetarian diet producing clinical improvements in RA. [35] Forty-three RA patients were divided into a treatment group or a control group. The treatment group followed a vegetarian diet for 1 month, the control group consumed their normal diet. At the end of only 30 days, positive changes in fecal flora correlated with improvements in RA. These finding are not surprising. Fecal flora undoubtedly play a major role in health. The total surface area of the gastrointestinal system is approximately 300–400 m . Only a single epithelial layer separates the host from enormous amounts of dietary and microbial antigens. Fortunately, the gut-associated lymphoid tissue, the largest lymphoid organ, helps to protect the individual from antigens that pass through this epithelial layer. Alterations in intestinal flora change the antigenic challenge. In an autoimmune condition like rheumatoid arthritis, this change may significantly impact disease activity. Gas–liquid chromatography of stool samples may prove to be a relatively quick and easy method of forecasting clinical improvement in rheumatoid arthritis. Digestion
Proper digestion is a requirement for optimum health, and incomplete or disordered digestion can be a major contributor to the development of many diseases including rheumatoid arthritis. The problem is not only that ingestion of foods and nutritional substances is of little benefit when breakdown and assimilation are inadequate, but also that incompletely digested food molecules can be inappropriately absorbed. Since many individuals with rheumatoid arthritis are deficient in digestive factors, including hydrochloric acid and pancreatic enzymes, incomplete digestion may be a major factor in rheumatoid arthritis. [36] [37] Supplementation with appropriate digestive aids appears warranted. Beyond its physiological role in digestion, pancreatic enzymes may offer additional
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benefits. Specifically, the proteases in pancreatin have been shown to reduce circulating levels of immune complexes in autoimmune diseases such as:
[38] [39]
• rheumatoid arthritis • lupus erythematosus • periarteritis nodosa • scleroderma • ulcerative colitis • Crohn’s disease • multiple sclerosis • AIDS. Since clinical improvements usually correspond with decreases in immune complex levels (the erythrocyte sedimentation rate can be used as a rough indicator), pancreatin or bromelain (discussed below) supplementation is often warranted. Dietary fats
Fatty acids are important mediators of allergy and inflammation through their role as precursors of inflammatory prostaglandins, thromboxanes, and leukotrienes. Altering dietary oil intake can significantly increase or decrease inflammation depending on the type of balance of fatty acids. The basic goal is twofold: • reduce the level of arachidonic acid • increase the level of DHGLA and EPA. Vegetarian diets are often beneficial in the treatment of many chronic allergic and inflammatory conditions, including rheumatoid arthritis, presumably as a result of decreasing the availability of arachidonic acid for conversion to inflammatory prostaglandins and leukotrienes, while simultaneously supplying linoleic and linolenic acids. An important nutritional approach to decreasing the inflammatory response is the consumption of cold-water fish such as mackerel, herring, sardines, and salmon. These fish are rich sources of eicosapentaenoic acid (EPA) which competes with arachidonic acid for prostaglandin and leukotriene production. The net effect of consumption of these fish is a significantly reduced inflammatory/ allergic response. To test the hypothesis that omega-3 fatty acids may protect against the development of RA, a population-based case–control study in women living in the Seattle area compared fish consumption in 324 cases of RA with 1,245 controls. [40] Consumption of broiled or baked fish was associated with a decreased risk of rheumatoid arthritis. An apparent dose-dependent response was noted in that consuming more than two servings per week offered greater protection compared with one serving per week. Based on this study and the one described previously on the benefits of a vegetarian diet, it appears that the best diet for the prevention of rheumatoid arthritis is a vegetarian diet with the exception of cold-water fish. Flaxseed oil supplementation (discussed below) may also be useful. Nutritional supplements GLA
Evening primrose, blackcurrant, and borage oil contain gamma-linolenic acid, an omega-6 fatty acid that eventually acts as a precursor to the anti-inflammatory prostaglandins of the 1 series. Although quite popular, the research on GLA supplements in rheumatoid arthritis is controversial and not as strong as the research on omega-3 oils. Studies have actually shown that over the long term GLA supplementation will increase tissue arachidonic acid levels while decreasing tissue levels of
2
EPA.[41] Obviously, this effect is contrary to the treatment goal of trying to reduce inflammation by reducing tissue levels of arachidonic acid and raising levels of EPA. Some studies in rheumatoid arthritis have shown benefit with GLA supplementation, while others have not. [42] [43] [44] The key factor appears to be whether or not subjects are allowed to take their anti-inflammatory drugs. These drugs inhibit the formation of inflammatory prostaglandins and would mask the negative effects of the altered tissue fatty acid profile produced by GLA supplements. Although positive results have been reported with GLA supplementation, closer examination is required. For example, in one double-blind study, 37 patients with rheumatoid arthritis were given either GLA (1.4 g/day) or placebo for 24 weeks. GLA supplementation reduced the number of tender joints by 36%, the tender joint score by 45%, swollen joint count by 28%, and the swollen joint score by 41%. [44] In contrast, no patients in the placebo group showed significant improvement in any measure. The superficial results of this study indicate that borage oil may be useful in reducing the inflammatory process of rheumatoid arthritis. However, in this study the subjects continued to take their anti-inflammatory drugs and probably masked the detrimental effects on tissue arachidonic acid and EPA levels. The recommended daily dosage for GLA in the treatment of rheumatoid arthritis is 1.4 g. Since evening primrose oil is 9% GLA, this means that approximately 31 500 mg capsules of evening primrose oil would have to be consumed each day. This dosage would typically cost a person nearly $100 per month to attain. Taking less than the recommended dosage is not likely to produce benefit. For several reasons, including cost, omega-3 oils appear to be a better choice.
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Also, another controversial aspect is the fact that because GLA can be formed from linoleic acid, it is difficult to determine to what extent the effects are due to GLA vs. linoleic acid. Most sources of GLA are much richer in linoleic acid than GLA. For example, evening primrose contains only 9% GLA, but contains 72% linoleic acid. Omega-3 fatty acids
The studies of fish oil supplementation in the treatment of rheumatoid arthritis have demonstrated far better and more consistent responses than the studies with GLA supplementation. The first double-blind, placebo-controlled study of rheumatoid arthritis patients using 1.8 g/day of EPA showed less morning stiffness and tender joints.[45] These results led to considerable scientific interest as well as numerous popular press accounts of the possible benefits of fish oil for allergic and inflammatory conditions. Over a dozen follow-up studies have consistently demonstrated positive benefits. [46] [47] [48] [49] [50] [51] [52] [53] As well as improvements in symptoms (morning stiffness and joint tenderness), fish oil supplementation has produced favorable changes in suppressing the production of inflammatory compounds secreted by white blood cells. Unfortunately, since it has been shown that commercially available fish oils contain very high levels of lipid peroxides and greatly stress antioxidant defense mechanisms, at this time it makes the most sense to rely on cold-water fish and flaxseed oil for the omega-3 oils rather than fish oil capsules. [54] [55] [56] Although several studies have shown that flaxseed oil is not as effective in increasing tissue concentrations of EPA and lowering tissue concentrations of arachidonic acid as fish oils, these studies failed to address an important factor. [57] [58] The studies were all performed on subjects continuing to consume a diet rich in omega-6 fatty acids. Although the desaturation and elongation enzymes prefer alpha-linolenic acid to the omega-6 oils, in these studies only relatively small amounts of alpha-linolenic acid were converted to EPA because of the much higher concentrations of omega-6 oils. A more recent study was undertaken to determine the potential for dietary flaxseed oil to increase tissue EPA concentration in healthy human subjects. [59] Unlike the previous studies, this study incorporated a diet low in omega-6 oils by restricting the use of other vegetable oils while supplementing the diet with 13 g (approximately 1 tbsp) of flaxseed oil daily. The results of the study indicated that flaxseed oil supplementation, along with restriction of linoleic acid, will raise tissue EPA levels comparable to fish oil supplementation. Furthermore, several human and animal studies have demonstrated that flaxseed oil supplementation can inhibit the autoimmune reaction as well as EPA.[60] Unfortunately, a small, 22 patient double-blind study over a 2 month period did not show any benefit with flaxseed oil (30 g/day) versus the same amount of safflower oil. [61] However, upon examination of the data, a possible explanation presents itself. In order to provide clinical benefit, flaxseed oil would have to reduce the tissue concentration of arachidonic acid while simultaneously increasing the tissue concentration of EPA and DHA. Tissue analysis in patients involved in this study who were taking flaxseed oil did not demonstrate significant changes in tissue levels of either arachidonic acid or EPA and DHA. Previous studies have shown that it is possible to raise tissue levels of EPA and DHA and lower levels of arachidonic acid with flaxseed oils if the intake of omega-6 oils is restricted. The failure to improve tissue lipid concentrations in this study led to the ineffectiveness of flaxseed oil. The reason behind the failure to improve lipid concentrations is either failure to restrict the use of other vegetable oils while supplementing the diet with flaxseed oil or failure to correct an underlying zinc deficiency. Evidence to support a failure to restrict the intake of omega-6 oils is offered by the fact that there was no significant change in the alpha-linolenic acid to linoleic acid ratio in test subjects. Evidence to support failure to correct an underlying zinc deficiency comes from serum zinc analysis on test subjects. Zinc functions in delta-6-desaturase, the enzyme involved in the conversion of alpha-linolenic acid to EPA and DHA. Zinc deficiency is common in rheumatoid arthritis. In fact, several studies have shown zinc supplementation to improve rheumatoid arthritis. The fact that tissue levels of alpha-linolenic acid increased while on the flaxseed oil and that EPA and DHA levels did not suggests zinc deficiency. This led researchers to measure serum zinc in the patients in the study. The researchers concluded: Low conversion of alpha-linolenic acid to EPA and DHA [due to a zinc deficiency], together with a low alpha-linolenic acid to linoleic acid ratio, might explain why a short term alpha-linolenic acid supplementation did not alter the RA disease activity. At this time, our recommendation is to follow the dietary recommendations of a vegetarian diet with the exception of cold-water fish, restrict omega-6 fatty acids, and supplement the diet with one tablespoon of flaxseed oil daily. Dietary antioxidants
The importance of consuming a diet rich in fresh fruits and vegetables cannot be overstated in the dietary treatment of rheumatoid arthritis. These foods are the best sources of dietary antioxidants. While the benefits of vitamin C, beta-carotene, vitamin E, selenium, and zinc
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as antioxidant nutrients are becoming well-recognized and well-accepted, there are still other plant compounds which promote healthy joints. Of particular benefit in rheumatoid arthritis are flavonoids, due to their neutralization of inflammation and support of collagen structures. [62] In short, the antioxidant benefits of fresh fruits and vegetables go well beyond the antioxidant effects of vitamins and minerals. Several studies have shown that the risk of RA is highest in people with the lowest levels of nutrient antioxidants (e.g. serum concentrations of alpha-tocopherol, beta-carotene, and vitamin C). For example, in one study, persons with rheumatoid arthritis and systemic lupus erythematosus that developed 2–15 years after donating blood for a serum bank in 1974 were designated as cases. [63] For each case, four controls were selected from the serum bank donors, matched for race, sex, and age. Stored serum samples from cases and controls were assayed for alpha-tocopherol, beta-carotene, and retinol. Cases of both diseases had lower serum concentrations of alpha-tocopherol, beta-carotene, and retinol in 1974 than their matched controls. Selenium and vitamin E
Selenium levels are low in patients with rheumatoid arthritis. [64] [65] Low selenium levels may be a significant nutritional factor as selenium plays an important role as an antioxidant and serves as the mineral cofactor in the free radical scavenging enzyme glutathione peroxidase. This enzyme is especially important in reducing the
production of inflammatory prostaglandins and leukotrienes. As free radicals, oxidants, prostaglandins, and leukotrienes cause much of the damage to tissues seen in rheumatoid arthritis, a deficiency of selenium would result in even more significant damage. Clinical studies have not yet clearly demonstrated that selenium supplementation alone improves the signs and symptoms of rheumatoid arthritis. However, one clinical study indicated that selenium combined with vitamin E had a positive effect. [66] The best food sources are Brazil nuts, fish, and grains. However, the amount of selenium in grains and other plant foods is directly related to the amount of selenium available in the soil. Zinc
Zinc has antioxidant effects and is a cofactor to the antioxidant enzyme superoxide dismutase (copper–zinc SOD). Zinc levels are typically reduced in patients with rheumatoid arthritis and several studies have used zinc in the treatment of rheumatoid arthritis, with some of the studies demonstrating a slight therapeutic effect. [67] [68] [69] Most of the studies utilized zinc in the form of sulfate. Better results may be produced by using a form of zinc with a higher absorption rate such as zinc picolinate, zinc monomethionine, or zinc citrate. Foods rich in zinc include oysters, whole grains, nuts, and seeds. Manganese and superoxide dismutase
Manganese functions in a different form of the antioxidant enzyme superoxide dismutase (manganese SOD). Manganese-containing SOD is deficient in patients with rheumatoid arthritis. [70] The injectable form of this enzyme (available in Europe) has been shown to be effective in the treatment of rheumatoid arthritis. [71] However, it is not clear if any orally administered SOD can escape digestion in the intestinal tract and exert a therapeutic effect. In one study, oral SOD was shown not to affect tissue SOD levels. [72] Perhaps a better and more economical method of raising SOD is to supplement the diet with additional manganese. Manganese supplementation has been shown to increase SOD activity. [73] Although no clinical studies have been conducted to determine the effectiveness of manganese supplementation in rheumatoid arthritis, it appears to be indicated based on the low levels seen in patients with rheumatoid arthritis as well as its biochemical functions. Good dietary sources include nuts, whole grains, dried fruits, and green leafy vegetables. Meats, dairy products, poultry, and seafood are considered poor sources of manganese. Vitamin C
Vitamin C functions as an important antioxidant. The white blood cell and plasma concentrations of vitamin C are significantly decreased in rheumatoid arthritis patients. [74] Supplementation with vitamin C increases SOD activity, decreases histamine levels, and provides some anti-inflammatory action. [75] [76] Foods rich in vitamin C include broccoli, Brussels sprouts, cabbage, citrus fruits, tomatoes, and berries. Pantothenic acid
Whole blood pantothenic acid levels have been reported to be lower in rheumatoid arthritis patients compared with normal controls. [77] In addition, disease activity was inversely correlated with pantothenic acid levels. Correction of low pantothenic acid levels to normal brings about some alleviation of symptoms. In one double-blind study, subjective improvement was noted in patients receiving 2 g/day of calcium pantothenate. [78] Patients noted improvements in duration of morning stiffness, degree of disability, and severity of pain. Good dietary sources of pantothenic acid are whole grains and legumes.
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Copper
Copper aspirinate (salicylate) is a form of aspirin that yields better results in reducing pain and inflammation than standard aspirin preparations. These copper-containing substances may be indicated in RA patients requiring aspirin. [79] [80] The wearing of copper bracelets has been a long-time folk remedy which appears to have some scientific support, as found in a double-blind study performed in Australia. Presumably, copper is absorbed through the skin and is chelated to another compound which is able to exert anti-inflammatory action. [81] Copper is a component, along with zinc, in one type of superoxide dismutase (copper–zinc SOD). Deficiency may result in significant susceptibility to free radical damage as a result of decreased SOD levels. However, an excess intake of copper may be detrimental due to its ability to combine with peroxides and damage joint tissues.[80] [82] Sulfur
The sulfur (cysteine) content in fingernails of arthritis sufferers is lower than that of healthy controls. [83] Normalizing the sulfur content of the nails by administering intravenous or intragluteal colloidal sulfur was reported to alleviate pain and swelling according to clinical data from the 1930s. [84] [85] Presumably, increasing the sulfur content of the body through increased consumption of sulfur-rich foods like legumes, garlic, onions, Brussels sprouts, and cabbage or through supplementation may be of equal benefit. Niacinamide
Dr William Kaufman and Dr Abram Hoffer have reported very good clinical results in the treatment of hundreds of patients with rheumatoid arthritis and osteoarthritis using high-dose niacinamide (i.e. 900–4,000 mg in divided doses daily). [86] [87] While these promising results have been confirmed in osteoarthritis (see Ch. 176 ), they have never been fully evaluated in detailed clinical studies of rheumatoid arthritis patients. Niacinamide has been shown to impact the autoimmune process involved in insulin-dependent diabetes mellitus (see Ch. 147 ). Botanical medicines Many botanicals possess significant anti-inflammatory action and are useful in the treatment of rheumatoid arthritis. The suggestions below represent some of the more popular and better researched of these botanical medicines. Several herbs are also discussed in relation to their ability to enhance the function or secretion of endogenous corticosteroids as well as their ability to prevent or reverse some of the negative effects of orally administered cortisone. Curcuma longa
Curcumin, the yellow pigment of Curcuma longa (turmeric), exerts excellent anti-inflammatory and antioxidant effects. [88] [89] [90] [91] [92] [93] Curcumin is as effective as cortisone or the potent anti-inflammatory drug phenylbutazone in models of acute inflammation. However, while phenyl-butazone and cortisone are associated with significant toxicity, curcumin is without side-effects. Curcumin exhibits many direct anti-inflammatory effects including inhibiting the formation of leukotrienes and other mediators of inflammation. However, curcumin also appears to exert some indirect effects. In models of chronic inflammation, curcumin is much less active in animals that have had their adrenal glands removed. This observation suggests that curcumin works to enhance the body’s own anti-inflammatory mechanisms. Possible mechanisms of action include: • stimulation of the release of adrenal corticosteroids • “sensitizing” or priming cortisone receptor sites, thereby potentiating cortisone action
• preventing the breakdown of cortisone. Curcumin has demonstrated some beneficial effects in human studies comparable to standard drugs. In one double-blind clinical trial in patients with rheumatoid arthritis, curcumin (1,200 mg/day) was compared with phenylbutazone (300 mg/day). [94] The improvements in the duration of morning stiffness, walking time, and joint swelling were comparable in both groups. However, it must be pointed out that while phenylbutazone is associated with significant adverse effects, curcumin has not been shown to produce any side-effects at the recommended dosage level. In another study which used a new human model for evaluating NSAIDs, the postoperative inflammation model, curcumin was again shown to exert comparable anti-inflammatory action to phenylbutazone. [95] It must be pointed out that while curcumin has an anti-inflammatory effect similar to phenylbutazone and various NSAIDs, it does not possess direct analgesic action. The results of these studies indicate that turmeric or curcumin may provide benefit in the treatment of acute exacerbations of inflammation in rheumatoid arthritis. Furthermore, the safety and excellent tolerability of curcumin compared with standard drug treatment is a major advantage. Toxicity reactions to curcumin have not been reported. Animals fed very high levels of curcumin (3 g/kg body weight) have not exhibited any significant adverse effects. [96] The recommended dosage for curcumin as an anti-inflammatory
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is 400–600 mg three times a day. To achieve a similar amount of curcumin using turmeric would require a dosage of 8,000–60,000 mg. Because there remains a question on the absorption of orally administered curcumin, curcumin is often formulated in conjunction with bromelain to possibly enhance absorption. In addition, bromelain also has anti-inflammatory effects (see below). If a curcumin–bromelain combination is used, it is important to take it on an empty stomach 20 minutes before meals or between meals. Providing curcumin in a lipid base such as lecithin, fish oils, or essential fatty acids may also increase absorption. Bromelain
Bromelain refers to a mixture of enzymes found in pineapple. Bromelain was introduced as a medicinal agent in 1957, and since that time over 200 scientific papers on its therapeutic applications have appeared in research literature. [97] Bromelain has been reported to exert a wide variety of beneficial effects, including reducing inflammation in rheumatoid arthritis. [98] Several mechanisms may account for bromelain’s anti-inflammatory effects, including the inhibition of proinflammatory compounds. Much of bromelain’s anti-swelling effects are due to activating compounds which break down fibrin. Fibrin’s role in the promotion of the inflammatory response is to form a matrix that walls off the area of inflammation, resulting in blockage of blood vessels and inadequate tissue drainage and edema. Bromelain also blocks the production of kinins, compounds produced during inflammation which increase swelling as well as cause pain. Zingiber officinalis
Ginger possesses numerous pharmacological properties, the most relevant in rheumatoid arthritis being its antioxidant effects; its inhibition of prostaglandin, thromboxane, and leukotriene synthesis; and its antiinflammatory effects. Fresh ginger may be more effective in the treatment of rheumatoid arthritis over dried preparations as it contains a protease that may have similar action to bromelain on inflammation. [99] Ginger’s ability to inhibit the formation of inflammatory mediators along with its strong antioxidant activities and protease component suggest a possible benefit in inflammatory conditions. [100] To test this hypothesis, a preliminary clinical study was conducted on seven patients with rheumatoid arthritis, in whom conventional drugs had provided only temporary or partial relief. [101] All patients were treated with ginger. One patient took 50 g/day of lightly cooked ginger while the remaining six took either 5 g/day of fresh ginger or 0.1–1 g/day of powdered ginger. Despite the difference in dosage, all patients reported a substantial improvement, including pain relief, joint mobility, and a decrease in swelling and morning stiffness. In the follow-up to this study, 28 patients with rheumatoid arthritis, 18 with osteoarthritis, and 10 with muscular discomfort who had been taking powdered ginger for periods ranging from 3 months to 2.5 years were evaluated. [102] Based on clinical observations, it was reported that 75% of the arthritis patients and 100% of the patients with muscular discomfort experienced relief in pain or swelling. The recommended dosage was 500–1,000 mg/day, but many patients took three to four times this amount. Patients taking the higher dosages also reported quicker and better relief. There remain many questions concerning the best form of ginger and the proper dosage. Most studies have utilized 1 g of dry powdered ginger root. This amount is a relatively small dose of ginger compared with the average daily dietary dose of 8–10 g consumed in India. Although most scientific studies have used powdered ginger root, fresh (or possibly freeze-dried) ginger root at an equivalent dosage may yield better results because it contains higher levels of gingerol as well as the active protease. In an effort to provide some practical application of the information presented here on ginger, it can be recommended that a daily dosage of 2–4 g of dry powdered ginger may be effective. This amount would be equivalent to approximately 20 g or two-thirds of an ounce of fresh ginger root, roughly a 0.5 inch slice. These amounts of ginger can easily be incorporated into the diet in fresh fruit and vegetable juices. There do not appear to be any side-effects with ginger at these levels. Bupleuri falcatum
Chinese thoroughwax root is an important component in various Chinese traditional medicine prescriptions, particularly in remedies for inflammatory conditions. Recently these formulas have also been used in combination with corticosteroid drugs like prednisone. [103] Chinese thoroughwax has been shown to enhance the activity of cortisone. The active constituent components of Chinese thoroughwax are steroid-like compounds known as saikosaponins. These compounds have diverse pharmacological activity including significant anti-inflammatory action. [104] The saikosaponins apparently both increase the release of cortisone and other hormones by the adrenal gland and potentiate their effects. Saikosaponins have also been shown to prevent the adrenal gland atrophy caused by corticosteroids. [105] It has been recommended that patients on corticosteroid drugs should take herbal formulas containing Chinese thoroughwax to help protect the adrenal gland. [106]
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Glycyrrhiza glabra and Panax ginseng appear to enhance the action of Chinese thoroughwax and the three are almost always used together in traditional Chinese herbal formulas. Both licorice root and ginseng have components with anti-inflammatory activity. [106] In addition, these herbs have also been shown to improve the activity of the adrenal glands. Perhaps licorice’s major effect is its ability to inhibit the breakdown of adrenal hormones by the liver. When used in combination with Chinese thoroughwax, the net effect is increased corticosteroids in the circulation, as a result of Chinese thoroughwax promoting secretion of these hormones by the adrenal glands combined with licorice root’s ability to inhibit the liver breakdown. Preparations containing Chinese thoroughwax, licorice, and Panax ginseng may help to restore adrenal function in patients with a history of long-term or high-dosage corticosteroid use. Physical medicine
Physical therapy has a major role in the management of patients with rheumatoid arthritis. While not curative, proper physical management can improve patient comfort and preserve joint and muscle function. Heat is typically used to help relieve stiffness and pain, relax muscles, and increase range of motion. Moist heat (e.g. moist packs, hot baths) is more effective than dry heat (e.g. heating pad), and paraffin baths are used if skin irritation from regular water immersion develops. Cold packs are of value during acute flare-ups. Strengthening and range-of-motion exercises are important for improving and maintaining joint function, as well as general health. Patients with well-developed disease and significant inflammation should begin with progressive, passive range-of-motion and isometric exercises. As inflammation is ameliorated, active range-of-motion and isotonic exercises are more appropriate. Balneotherapy
Balneotherapy, the therapeutic use of mineral baths and mud packs, is a form of physical therapy often recommended in cases of rheumatoid arthritis in Europe. A study conducted in Israel provides some evidence of benefit. [107] The study was along the western shore of the Dead Sea at the Ein Gedi Spa. This area along the Dead Sea is renowned for its many hot, thermomineral springs and a large natural concentration of mud useful for therapeutic purposes. The area is also popular to persons with rheumatoid arthritis because of its unique climatic conditions — high barometric pressures, low humidity, high temperatures, paucity of rainfall, and absence of air pollution. Standard spa therapy for rheumatoid arthritis in this region consists of mud packs, sulfur baths, and bathing in the waters of the Dead Sea. In a previous study, it was shown that sulfur and mud pack therapy, alone or in combination, are effective in reducing inflamma-tion and pain in active rheumatoid arthritis. A recent study was conducted to determine whether there was any treatment advantage to sulfur baths or bathing in the Dead Sea, alone or in combination, in the treatment of active rheumatoid arthritis. Thirty-six patients with active rheumatoid arthritis were treated for 12 days at the spa. The patients were divided randomly into four study groups: group 1 was treated with daily baths in the Dead Sea; group 2 was treated with daily sulfur baths; group 3 was treated with a combination of daily Dead Sea bathing and sulfur baths; and group 4 served as a control group. All patients were assessed by a rheumatologist who was blinded to the treatment modalities and group allocation. Clinical parameters assessed included: duration of morning stiffness, 15 m walk time, grip strength, activities of daily living assessment, patient’s assessment of disease activity, number of active joints, and the Ritchie articular index. The study found a statistically significant improvement lasting up to 3 months in only the three treatment groups. In morning stiffness, 15 m walk time, grip strength, activities of daily living assessment, and patient’s assessment of disease activity, there was an advantage shown for Dead Sea baths, either alone or in combination with sulfur baths. The number of active joints and the Ritchie index improved to a similar degree in all three treatment groups. Table 185.2 lists the results on the Ritchie index by treatment group. Several research studies have attempted to determine why the Dead Sea baths were so effective. The Dead Sea is extremely saline – 10 times greater than the Mediterranean Sea. However, this is not the most likely explanation, since a double-blind study in rheumatoid arthritis that compared Dead Sea bath salts with regular table salt dissolved in the patient’s home bath heated to 35°C for 20 minutes a day for 2 weeks showed statistically significant improvements in most of the clinical variables in the group using the Dead Sea bath salts compared with the group using table salt. Although muscle tone, joint mobility, and pain intensity are somewhat influenced by hydromechanical and thermal stimuli, the improvement noted with Dead Sea bathing is generally superior to regular hot baths. A possible TABLE 185-2 -- Results of spa therapy for rheumatoid arthritis Baseline End of treatment
1 month
3 months
Group 1
27.3
13.1
12.6
15.9
Group 2
23.2
10.1
14.8
11.2
Group 3
21.4
7.8
12.7
19.3
Group 4
25.4
28
28.5
27.1
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explanation may be in the trace mineral content of the Dead Sea. It is possible that trace elements such as zinc and copper – key components in the antioxidant enzyme superoxide dismutase – as well as boron, selenium, rubidium, and other minerals may be absorbed through the skin. Below normal levels of several trace minerals have been reported in patients with rheumatoid arthritis. The results of the present study are quite impressive in that most patients had severe active rheumatoid arthritis, yet no patient in the treatment group experienced any side-effect or aggravation of the disease. Compare this result with standard drug therapy for rheumatoid arthritis. Hopefully, there will be further studies to help understand the beneficial effects of Dead Sea baths.
THERAPEUTIC APPROACH RA is a disease known to have many contributing factors. Effective treatment using natural therapies requires controlling as many of these factors as possible. Foremost is the use of dietary measures to reduce the causes and ameliorate the symptoms of RA. Symptom relief can also be attained through the use of standard physical therapy techniques (i.e. exercise, heat, cold, massage, diathermy, lasers, and paraffin baths), anti-inflammatory botanicals and nutrients and, in appropriate patients, bowel detoxification. Rheumatoid arthritis is often an aggressive disease that needs aggressive treatment. In mild to moderate rheumatoid arthritis, the measures listed above are extremely effective on their own. In severe cases, NSAIDs and other drugs may be necessary, at least in the acute phase. However, encourage patients not to abandon the natural measures as they will actually enhance the effectiveness of the drugs, resulting in lower dosages. When the drugs are necessary, prescribe deglycyrrhizinated licorice (DGL) to protect against developing peptic ulcers. Diet
The first step is a therapeutic fast or an elimination diet followed by careful reintroduction of foods to detect those which determine symptoms. Virtually any food can result in aggravating RA, but the most common offenders are: • wheat • corn • milk and other dairy products • beef • nightshade (Solanum) family foods – tomato, potato, eggplants, peppers, and tobacco. After isolating and eliminating all allergens, a general healthy diet rich in whole foods, vegetables, and fiber, and low in sugar, meat, refined carbohydrates, and animal fats is indicated. Foods particularly beneficial for the RA patient include cold-water fish (mackerel, herring, sardines, and salmon) and flavonoid-rich berries (cherries, hawthorn berries, blueberries, blackberries, etc.) and their extracts. Supplements
• DHEA: 50–200 mg/day • EPA: 1.8 g/day; or flaxseed oil: 1 tbsp/day • Niacinamide: 500 mg four times/day (monitor liver enzymes) • Pantothenic acid: 500 mg four times/day • Quercetin: 250 mg between meals three times/day • Tryptophan: 400 mg three times/day • Vitamin C: 1–3 g/day in divided doses • Vitamin E: 400 IU/day • Copper: 1 mg/day • Manganese: 15 mg/day • Selenium: 200 mcg/day • Zinc: 45 mg/day • Betaine HCl: 5–70 grains with meals (see Appendix 7 ) • Pancreatin (10 × USP): 350 mg–750 mg between meals three times/day; or bromelain: 250–750 mg (1,800–2,000 mcu) between meals three times/day. Botanical medicines
The following botanicals may be used alone or in combination with others. Severe inflammation and joint destruction require more aggressive therapy. Patients with a history of corticosteroid use (e.g. prednisone) and those being weaned off corticosteroids need the botanicals Bupleuri falcatum, Glycyrrhiza glabra, and Panax ginseng, which prevent and/or reverse the adrenal gland atrophy induced by these drugs. Dosages are as follows: • Curcumin: 400 mg three times/day; or ginger: incorporate 8–10 g of fresh ginger into the diet each day or recommend ginger extracts standardized to contain 20% gingerol and shogaol at a dosage of 100–200 mg three times/day • Bupleuri falcatum —dried root: 2–4 g —tincture (1:5): 5–10 ml —fluid extract (1:1): 2–4 ml —solid extract (4:1): 200–400 mg • Panax ginseng —crude herb: 4.5–6 g/day —standardized extract (5% ginsenosides): 100 mg one to three times/day • Glycyrrhiza glabra —dried root: 2–4 g
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—tincture (1:5): 10–20 ml —fluid extract (1:1): 4–6 ml —solid extract (4:1): 250–500 mg.
Physical medicine
• Heat (moist packs, hot baths, etc.): 20–30 minutes one to three times/day • Cold packs for acute flare-ups • Paraffin baths (if skin irritation is caused by hot water) • Active (or in severe cases passive) range-of-motion exercises: 3–10 repetitions one to two times/day • Progressive isometric (and isotonic as the joints improve) exercise: 3–10 repetitions several times per day with generous periods of rest Massage: one to three times/week.
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Hoffer A. Treatment of arthritis by nicotinic acid and nicotinamide. Canadian Medical Association Journal 1959; 81; 235–239
88.
Ammon HPT, Wahl MA. Pharmacology of Curcuma longa. Planta Medica 1991; 57: 1–7
89.
Sharma OP. Antioxidant properties of curcumin and related compounds. Biochem Pharmacol 1976; 25: 1811–1825
90.
Toda S, Miyase T, Arich H et al. Natural antioxidants. Antioxidative compounds isolated from rhizome of Curcuma longa L. Chem Pharmacol Bull 1985; 33: 1725–1728
91.
Srimal R, Dhawan B. Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent. J Pharm Pharmac 1973; 25: 447–452
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92.
Srivastava R. Inhibition of neutrophil response by curcumin. Agents Actions 1989; 28: 298–303
Flynn DL, Rafferty MF. Inhibition of 5-hydroxy-eicosatetraenoic acid (5-HETE) formation in intact human neutrophils by naturally-occurring diarylheptanoids. Inhibitory activities of curcuminoids and yakuchinones. Prost Leukotri Med 1986; 22: 357–360 93.
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Deodhar SD, Sethi R, Srimal RC. Preliminary studies on antirheumatic activity of curcumin (diferuloyl methane). Ind J Med Res 1980; 71: 632–634
Satoskar RR, Shah SJ, Shenoy SG. Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol 1986; 24: 651–654 95.
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Shankar TNB, Shantha NV, Ramesh HP et al. Toxicity studies on turmeric (Curcuma longa): acute toxicity studies in rats, guinea pigs & monkeys. Indian J Exp Biol 1980; 18: 73–75
97.
Taussig S, Batkin S. Bromelain: the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update. J Ethnopharmacol 1988; 22: 191–203
98.
Cohen A, Goldman J. Bromelain therapy in rheumatoid arthritis. Penn Med J 1964; 67: 27–30
99.
Leung A. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York, NY: John Wiley. 1980
100. Kiuchi
F et al. Inhibition of prostaglandin: and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull 1992; 40: 387–391
101. Srivastava
KC, Mustafa T. Ginger (Zingiber officinale) and rheumatic disorders. Med Hypothesis 1989; 29: 25–28
102. Srivastava
KC, Mustafa T. Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. Med Hypothesis 1992; 39: 342–348
103. Shimizu
K, Amagaya S, Ogihara Y. Combination of shosaikoto (Chinese traditional medicine) and prednisolone on the anti-inflammatory action. J Pharmaco Dyn 1984; 7: 891–899
104. Yamamoto 105. Hiai
M, Kumagai A, Yokoyama Y. Structure and actions of saikosaponins isolated from Bupleurum falcatum L. Arzniem Forsch. 1975; 25: 1021–1040
S, Yokoyama H, Nagasawa T et al. Stimulation of the pituitary-adrenocortical axis by saikosaponin of Bupleuri radix. Chem Pharm Bull 1981; 29: 495–499
106. Hikino
H. Recent research on Oriental medicinal plants. Economic and Medicinal Plant Research 1985; 1: 53–85
107. Sukenik
S. Balneotherapy for rheumatoid arthritis at the Dead Sea. Isr Med J 1995; 31: 210–214
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Chapter 186 - Rosacea Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Chronic acneiform eruption on the face of middle-aged and older adults associated with facial flushing and telangiectasia • The acneiform component is characterized by papules, pustules, and seborrhea; the vascular component by erythema and telangiectasia; and the glandular component by hyperplasia of the soft tissue of the nose (rhinophyma) • The primary involvement occurs over the flush areas of the cheeks and nose More common in women (3:1), but more severe in men.
GENERAL CONSIDERATIONS Rosacea is a chronic skin disorder in which the nose and cheeks are abnormally red and may be covered with pimples similar to those seen in acne (see Ch. 125 ). Rosacea is a relatively common skin disorder in adults between the ages of 30 and 50, with women being affected about three times as often as men. Many factors have been suspected of causing acne rosacea: • alcoholism • menopausal flushing • vasomotor neurosis • seborrheic diathesis • local infection • B-vitamin deficiencies • gastrointestinal disorders. Most cases are associated with moderate to severe seborrhea, although sebum production is not increased in many. Vasomotor lability is prevalent, and migraine headaches are three times more common than in age- and sex-matched controls.
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THERAPEUTIC CONSIDERATIONS Hypochlorhydria
Gastric analysis of rosacea patients has led to the postulate that it is the result of hypochlorhydria. [1] Psychological factors, i.e. worry, depression, stress, etc., often reduce gastric acidity. [2] Hydrochloric acid supplementation results in marked improvement in those rosacea patients who have achlorhydria or hypochlorhydria. [1] [2] Rosacea patients have also been shown to have decreased secretion of lipase (although bicarbonate and chymotrypsin secretion were normal) and to benefit from pancreatic supplementation. [3] Helicobacter pylori
Given the high incidence of hypochlorhydria, it is perhaps not surprising that a high incidence of Helicobacter pylori infection in the stomach has also been found in rosacea patients. [4] In a pilot study, H. pylori was found in the serum of 46 of 94 rosacea patients, 38 of 88 patients with other inflammatory diseases and five of 14 patients without an inflammatory disease. These researchers believe that the flushing reaction in rosacea is caused by gastrin or vasoactive intestinal peptides. They also quote an Irish study which found that 19 of 20 patients with acne rosacea were positive for H. pylori. Another study which evaluated histological sections of the stomach mucosa found that 84% of 31 patients were H. pylori-positive. [5] Interestingly, 20% of these histologically positive patients were serologically negative. The consistency between clinical success in the treatment of rosacea with metronidazole and the abatement of H. pylori isolates and serology after treatment provides additional evidence suggesting an etiologic relationship between rosacea and H. pylori infection. Food allergy
The statistically significant incidence of migraine headaches accompanying rosacea points to food intolerance, as does the reflex flushing caused by vasodilator substances. B vitamins
The administration of large doses of B vitamins has been shown to be quite effective, [6] with riboflavin appearing to be the key factor. [7] The mite Demodex folliculorum has been considered a causative factor, but it is a normal inhabitant of follicles. Although it may account for the more granulomatous response of some patients, it is interesting to note that researchers were able to infect the skin of riboflavin-deficient rats with Demodex, but not the skin of normal rats. [7] While B vitamins are important for rosacea patients, some care must be exercised as some patients’ rosacea may be aggravated by large dosages of these common nutrients. There is a case report of a 53-year-old female who presented to a dermatology clinic with a 9 month history of a facial eruption which resembled acne rosacea. Treatment with oral hydroxychloroquine, ibuprofen, terfenadine, prednisone, erythromycin and tetracycline had been tried during the 9 months without success. Topical desoximethasone, hydrocortisone, and cosmetic elimination also yielded no benefit. Patch test revealed a positive reaction to nickel. The eruption began at the time of a personal stress when she went through a marital separation. To help with her stress, she began taking 100 mg/day of pyridoxine and 100 mcg/day of B12 . Discontinuation of the vitamins resulted in dramatic improvement and with rechallenge her condition reappeared. The authors noted that inflammation and exacerbations of acne related to vitamins B 2 , B6 , and B12 have been reported in the European literature. [8]
THERAPEUTIC APPROACH Although the cause(s) has not yet been determined, sufficient information is available to adequately treat most patients. The control of hypochlorhydria and food
intolerance forms the basis of therapy. This is supported with B-complex supplementation and the avoidance of vasodilating foods. General recommendations
See Chapter 125 for general recommendations. Diet
Avoid coffee, alcohol, hot beverages, spicy foods, and any other food or drink that causes a flush. Eliminate from the diet all refined and/or concentrated sugars, foods containing trans-fatty acids such as milk, milk products, margarine, shortening and other synthetically hydrogenated vegetable oils as well as fried foods. Avoid milk and foods high in iodized salt. Supplements
• B-complex: 100 mg/day (avoid niacin) • Pancreas extract (8–10 × USP): 350–500 mg before meals • Hydrochloric acid: provided in Appendix 6 .
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REFERENCES 1. Ryle
J, Barber H. Gastric analysis in acne rosacea. Lancet 1920; ii: 1195–1196
2. Poole
W. Effect of vitamin B complex and S-factor on acne rosacea. S Med J 1957; 50: 207–210
3. Barba
A, Rosa B, Angelini G et al. Pancreatic exocrine function in rosacea. Dermatologica 1982; 165: 601–606
4. Baker
B. Helicobacter pylori strikes again: this time it’s rosacea. Family Practice News 1994; Sept 1: 6
5. Rebora
A, Drago F, Parodi A. May Helicobacter pylori be important for dermatologists? Dermatology 1995; 191: 6–8
6. Tulipan
L. Acne rosacea: a vitamin B complex deficiency. NY State J Med 1929; 29: 1063–1064
7. Johnson
L, Eckardt R. Rosacea keratitis and conditions with vascularization of the cornea treated with riboflavin. Arch Ophth 1940; 23: 899
8. Sherertz
E. Acneiform eruption due to ‘mega dose’ vitamin B
6
and B12 . Cutis 1991; 48: 119–120
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Chapter 187 - Seborrheic dermatitis Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Superficial erythematous papules and scaly eruptions occurring on the scalp, cheeks, and intertrigo of the axilla, groin, and neck • Usually non-pruritic • Seasonal, worse in winter.
GENERAL CONSIDERATIONS Seborrheic dermatitis is a common papulosquamous condition with an appearance similar to eczema. Clinically it may be associated with excessive oiliness (seborrhea) and dandruff. The scale may be yellowish and either dry or greasy. The erythematous, follicular, scaly papules may coalesce to form large plaques or circinate patches. Flexural involvement is often complicated with Candida infection. The condition occurs either in infancy (usually between 2 and 12 weeks of age) or in the middle-aged or elderly and has a prognosis of lifelong recurrence. The cause of seborrheic dermatitis is unknown. Genetic predisposition, emotional stress, diet, hormones, and infection with yeast-like organisms have all been implicated. Seborrheic dermatitis is now recognized as one of the most common manifestations of AIDS, affecting as many as 83%. This recent observation has given increased credence to the infection theory of seborrheic dermatitis.
THERAPEUTIC CONSIDERATIONS Food allergy
Seborrheic dermatitis usually begins as “cradle cap” and, although not primarily an allergic disease, has been associated with food allergy (67% develop some form of allergy by 10 years of age). [1] Biotin
The underlying factor in infants appears to be a biotin deficiency. [2] A syndrome clinically similar to seborrheic
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dermatitis has been produced by feeding rats a diet high in raw egg white (high in avidin, a glycoprotein that binds biotin, making it unavailable for absorption). Since a large portion of the human biotin supply is provided by intestinal bacteria, it has been postulated that the absence of normal intestinal flora may be responsible for biotin deficiency in infants. [2] A number of articles have demonstrated successful treatment of seborrheic dermatitis with biotin in both the nursing mother and the infant. [2] [3] In adults, treatment with biotin alone is usually of no value. It has been postulated that long-chain fatty acid synthesis is impaired in seborrheic lesions. B vitamins (biotin, pyridoxine, pantothenic acid, niacin, and thiamin and the lipotropics) are vital for fatty acid metabolism. Pyridoxine
Both the administration of desopyridoxine, which induces pyridoxine deficiency in humans, and the placing of rats on a pyridoxine-deficient diet cause dermatological lesions indistinguishable from seborrheic dermatitis. [4] Despite these results, oral and parenteral applications of pyridoxine have shown little success. However, in the sicca form of the disorder (involvement of the scalp – dandruff – brow, nasolabial folds, and bearded area with varying degrees of greasy adherent scales on an erythematous base), all patients cleared completely within 10 days with local application of a water-soluble ointment containing 50 mg/g of pyridoxine. Other types of seborrheic dermatitis, particularly flexural and infected, did not respond to this mode of therapy. In patients with elevated levels of urinary xanthurenic acid, oral, parenteral, and local applications of pyridoxine all returned excretion levels to normal, implying transcutaneous absorption of pyridoxine. [4] [8] These results are clouded, however, by the results of another study which indicate that the improvement from topical application may be due more to reduction in sebaceous secretion rate from the ointment itself, the added pyridoxine having no effect. [9] The patient should be checked for exposure to pyridoxine antimetabolites. Examples include the hydrazine dyes (FD&C yellow #5) and drugs (INH and hydralazine), dopamine, penicillamine, oral contraceptives, and excessive protein intake. [10] Folic acid
Oral treatment with folic acid has been only moderately successful (the use of the tetrahydro form showed dramatic results for one patient who became unresponsive to folic acid after childbirth). Patients with the sicca form were unresponsive. [5] Parenteral injections of vitamin B 12 , both synthetic and liver-extracted, have been shown to be very effective in many cases. [6] This may be due to vitamin B12 ’s role as a cofactor (with choline) in 5-methyl-tetrahydro folate methyltransferase, which regenerates tetrahydrofolate. It has been hypothesized that folate becomes trapped as 5-methyltetrahydrofolate by a lack of B 12 and/or choline. Miscellaneous factors
Other B vitamins have also been shown to be involved in seborrheic dermatitis; experimentally induced ariboflavinosis produces the sicca form of the disorder.
[7]
THERAPEUTIC APPROACH Although the optimal approach to treating all patients with seborrheic dermatitis is not clear at this time, effective therapy is available for most patients. In infants, alleviation of the biotin deficiency and control of the food allergies are the keys. For adults, correcting the impaired long-chain fatty acid synthesis by supplementing with large doses of vitamin B complex is the primary therapy. To maximize therapeutic results, we recommend a broad-spectrum approach. (Note that the following dosages are for adults; children’s doses should be modified according to weight.)
Diet
Detect and treat food allergens. In nursing infants, the food allergies of the mother should be considered. Supplements
• Biotin: 3 mg two times/day • B complex: 50 mg two times/day • Zinc: 25 mg/day (picolinate) • Flaxseed oil: 1 tbsp/day. Topical treatment
• Pyridoxine ointment: 50 mg/g (in water soluble base).
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REFERENCES 1. Eppic
J. Seborrhea capitis in infants: a clinical experience in allergy therapy. Ann Allergy 1971; 29: 323–324
2. Nisenson
A. Seborrheic dermatitis of infants and Leiner’s disease: a biotin deficiency. J Ped 1957; 51: 537–549
3. Nisenson
A. Treatment of seborrheic dermatitis with biotin and vitamin B complex. J Ped 1972; 81: 630–631
4. Schreiner
A, Slinger W, Hawkins V et al. Seborrheic dermatitis. A local metabolic defect involving pyridoxine. J Lab Clin Med 1952; 40: 121–130
5. Schreiner
A, Rockwell E, Vilter R. A local defect in the metabolism of pyridoxine in the skin of persons with seborrheic dermatitis of the “sicca” type. J Invest Dermatol 1952; 19: 95–96
6. Effersoe 7. Roe
H. The effect of topical application of pyridoxine ointment on the rate of sebaceous secretion in patients with seborrheic dermatitis. Acta Dermatol 1954; 3: 272–277
DA. Drug-induced nutritional deficiencies. Westport, CT: AVI Publ. 1976: p 168–177
8. Callaghan 9. Andrews
10.
T. The effect of folic acid on seborrheic dermatitis. Cutis 1967; 3: 584–588
G, Post C, Domonkos A. Seborrheic dermatitis: supplemental treatment with vitamin B
12
. N Y State J M 1950: p 1921–1925
Bicknell F, Prescott F. The vitamins in medicine . Milwaukee, WI: Lee Foundation for Nutritional Research. 1962: p 309
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Chapter 188 - Senile cataracts Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Clouding or opacity in the crystalline lens of the eye • Absence or altered red reflex (small cataracts stand out as dark defects) • Gradual loss of vision.
GENERAL CONSIDERATIONS Cataracts are the leading cause of impaired vision and blindness in the United States. Approximately 4 million people have some degree of vision-impairing cataract, and at least 40,000 people in the US are blind due to cataracts. Cataracts are a source of a tremendous financial burden on our society; cataract surgery is the most common major surgical procedure done in the United States each year (600,000 per annum) for persons on Medicare. Cataracts may be classified by location and appearance of the lens opacities, by cause or significant contributing factor, and by age of onset. Many factors may cause or contribute to the progression of lens opacity, including ocular disease, injury, or surgery, systemic diseases (e.g. diabetes mellitus, galactosemia), toxin, ultraviolet and near-ultraviolet light, or radiation exposure, and hereditary disease. Aging-related (or senile) cataracts are discussed in this chapter and diabetic- and galactose-induced cataracts (sugar cataracts) are discussed in Chapter 147 . The crystalline lens is, obviously, a vital component of the optical system due to its ability to focus light (via changes in shape) while maintaining optical transparency. Unfortunately, this transparency decreases with age. The majority of the geriatric population display some degree of cataract formation. In the normal aging eye there is a progressive increase in size, weight, and density of the lens throughout life. Cataract formation is characterized histopathologically by: • fibrous metaplasia of the epithelium • liquefaction of fibers resulting in Morgagnian globule 1546
formation (drops of fluid beneath the capsule and between the lens fibers) • sclerosis (melding of fibers) • posterior migration and swelling of the epithelium. By a topoanatomic classification these basic alterations result in five types of cataracts: • anterior subcapsular cataract – fibrous metaplasia of lens epithelium (usually follows iritis and adherence of the iris to the lens – posterior synechia) • anterior cortical cataract – liquefaction of lens fibers occurs and Morgagnian globules form in the cortex anteriorly • nuclear cataract – an exaggeration of the normal, aging-related, melding of fibers in the nucleus • posterior cortical cataract – liquefaction and globular degeneration of the posterior lens cortex • posterior subcapsular cataract – epithelial cells migrate posteriorly under the capsule and form large irregular nucleated cells. About 75% of senile cataracts are cortical and the rest are nuclear. Clinically, cortical cataracts take three forms: • spoke wheel, beginning in the periphery and coursing anteriorly and posteriorly to the nucleus • perinuclear punctate opacities • granular opacities under the posterior capsule (subcapsular cataracts).
THERAPEUTIC CONSIDERATIONS The etiology of cataract formation is ultimately related to an inability to maintain normal homeostatic concentrations of Na + , K+ , and Ca2+ within the lens. These abnormalities are apparently the result of decreased Na + , K+ -ATPase activity, [1] [2] [3] [4] [5] [6] a defect usually due to free radical damage to some of the sulfhydryl proteins in the lens, including Na + , K+ -ATPase which contains a sulfhydryl component. In cataract formation, the normal protective mechanisms are unable to prevent free radical damage. The lens, like many other tissues of the body, is dependent on adequate levels and activities of superoxide dismutase (SOD), catalase, and glutathione (GSH), and adequate levels of the accessory antioxidants vitamins E and C and selenium, to aid in preventing free radical damage. Individuals with higher dietary intakes of vitamin C and E, selenium, and carotenes have a much lower risk for developing cataracts. [7] These compounds are discussed individually below. Antioxidants Vitamin C
In addition to preventing cataracts, antioxidant nutrients like vitamin C may offer some therapeutic effects as well. Several clinical studies have demonstrated that vitamin C supplementation can halt cataract progression and, in some cases, significantly improve vision. For example, in one study conducted in 1939, 450 patients with cataracts were placed on a nutritional program that included 1 g/day of vitamin C, resulting in a significant reduction in cataract development. [1] Though similar patients had previously required surgery within 4 years, in the vitamin C-treated patients only a small handful of patients required surgery and in most patients there was no evidence that the cataract progressed over the 11 year period of the study. It appears the dosage of vitamin C necessary to increase the vitamin C content of the lens is 1,000 mg. [2] The lens of the eye and active tissue of the body require higher concentrations of vitamin C. The level of vitamin C in the blood is about 0.5 mg/dl, whereas in the adrenal and pituitary glands, the level is 100 times this concentration. In the liver, spleen, and lens of the eye, it is concentrated by at least a factor of 20. In order for these concentrations to be maintained in these tissues, the body has to generate enormous amounts of energy to pull vitamin C out of blood against this tremendous gradient. By keeping blood vitamin C levels elevated,
you are helping the body to concentrate vitamin C into active tissue by reducing the gradient. That is probably why dosages of at least 1,000 mg are required to increase the vitamin C content of the lens. In another study, 450 patients with incipient cataract were placed on a nutritional program that included 1 g/day of vitamin C, resulting in a significant reduction in cataract development.[3] Glutathione
This tripeptide composed of glycine, glutamic acid, and cysteine is found at very high concentrations in the lens. GSH plays a vital role in maintaining a healthy lens and has been postulated as a key protective factor against toxins of both intra- and extralenticular origin. It functions as an antioxidant, maintains reduced sulfhydryl bonds within the lens proteins, acts as a coenzyme of various enzyme systems, participates in amino acid transport with gamma-glutamyl transpeptidase, and is involved in cation transport. [4] GSH levels are diminished in virtually all forms of cataracts. Ascorbic acid and glutathione interactions
These two antioxidants work in close conjunction and are the most important of all the host protective factors against the induction of cataracts. The reactions are as follows:
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Light may also cause oxidation of AA, leading to hydrogen peroxide formation:
An interesting cycle is then set into motion. The dehydroascorbate and hydrogen peroxide produced are reduced by selenium-containing glutathione peroxidase:
The oxidized glutathione (GSSG) serves as an inducer of the hexose monophosphate shunt, which provides the NADPH necessary for reducing GSSG via riboflavin-dependent glutathione reductase:
The NADP is reduced by hexose monophosphate dehydrogenase as follows:
This combination of enzymatic and non-enzymatic scavenging of free radicals is a key mechanism for the protection of the lens from damage due to photochemical and other forms of oxidative damage. Selenium and vitamin E
These antioxidants are known to function synergistically and are therefore discussed together. Maintaining proper selenium levels appears to be especially important as human lens glutathione peroxidase is selenium-dependent. Low selenium levels would greatly promote cataract formation. Previous studies have shown the selenium content in human lens with a cataract is only 15% of normal levels. [5] A more recent study was conducted to better examine the role of selenium in cataract formation.[6] Selenium levels in the serum, lens, and aqueous humor were determined in 48 patients with cataracts and compared with matched controls. The selenium levels of the serum and aqueous humor were found to be significantly lower in the patients with cataracts (serum, 0.28 vs. 0.32 mcg/ml; aqueous humor, 0.19 vs. 0.31 mcg/ml). However, the selenium levels in the lens itself did not significantly differ in patients with cataracts and normal controls. The most important finding of the study was the decreased level of selenium in the aqueous humor in patients with cataracts. Excess hydrogen peroxide levels, up to 25 times the normal levels, are found in the aqueous humor in patients with cataracts. An excess of hydrogen peroxide is associated with increased lipid peroxidation and altered lens permeability as a result of damage to the sodium–potassium pump. These changes ultimately leave the lens unprotected against free radical and sun damage. As a result, a cataract is formed. Since selenium-dependent glutathione peroxidase is responsible for the breaking down of hydrogen peroxide, it is quite obvious that low selenium levels appear to be a major factor in the development of a cataract. Superoxide dismutase
The activity of SOD in the human lens is lower than it is in other tissues as a result of the increased ascorbate and glutathione levels. A progressive decrease in SOD is encountered in cataract progression. Oral supplementation is probably of little value, as it has been demonstrated that it does not affect tissue SOD activity. [8] Of greater value is supplementation with the trace mineral cofactors of SOD, as the levels of these cofactors are greatly reduced in the cataractous lens (copper, over 90%; manganese, 50%; and zinc, over 90%). [9] Catalase
Catalase is concentrated in the epithelial portion of the lens (anterior surface), with very low levels found in the rest of the lens. Its primary function is to reduce (to water and oxygen) the hydrogen peroxide formed from the oxidation of ascorbate. Tetrahydrobiopterin
Pteridine compounds are believed to play a protective role against cataract formation via prevention of oxidation and damage by ultraviolet light. This prevents the formation of high molecular weight proteins in the lens. Tetrahydrobiopterin functions as an essential coenzyme in the hydroxylation of monoamines such as phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase. Studies of human senile cataracts have demonstrated decreased levels of pteridine-synthesizing enzymes and tetrahydrobiopterin. [10] Supplemental folic acid may help to compensate for this deficiency.
Other nutritional factors Riboflavin
Lenticular GSH requires flavin adenine dinucleotide (FAD) as a coenzyme for glutathione reductase. [11] [12] Deficiency of riboflavin, the precursor of FAD, is believed to enhance cataract formation due to depressed glutathione reductase activity. While riboflavin deficiency is fairly common in the geriatric population (33%), original studies demonstrating an association between riboflavin deficiency and cataract formation were followed by
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studies demonstrating no association. The patient’s riboflavin status can be determined by measuring RBC glutathione reductase activity before and after flavin adenine dinucleotide (FAD) stimulation. [12] Although correction of the deficiency is warranted, no more than 10 mg/day of riboflavin should be prescribed for cataract patients, since it is a photosensitizing substance, i.e. superoxide radicals are generated by the interaction of light, ambient oxygen, and riboflavin/ FAD. Riboflavin and light (at physiological levels) have been used experimentally to induce cataracts. The evidence appears to suggest that excess riboflavin does more harm than good in the cataract patient. Amino acids
Methionine is a component of the lenticular antioxidant enzyme methionine sulfoxide reductase and a precursor of cysteine, a component of GSH. Cysteine, along with the other amino acid precursors of GSH, has been shown to be of some aid in cataract treatment. [13] Zinc, vitamin A and beta-carotenes
These nutrients are known antioxidants and are vital for normal epithelial integrity. Adequate status of these nutrients is important for the epithelial portion of the lens. In particular, beta-carotene may act as a filter, protecting against light-induced damage to the fiber portion of the lens. Beta-carotene is the most significant of the singlet oxygen free radical scavengers and is used in treating photosensitive disorders. [14] Melatonin
Melatonin is a very efficient free radical scavenger and antioxidant which can neutralize hydroxyl and peroxyl radicals as well as enhancing endogenous and exogenous antioxidant efficiency. In animal models, melatonin has been an effective inhibitor of DNA damage, lipid peroxidation and cataract formation. Melatonin is present at significant levels in the cell nucleus, the aqueous cytosol, and lipid-rich cellular membranes. [15] Diet Evaluation of 207 patients with cataracts compared with 706 controls found a protective action from some vegetables, fruit, calcium, folic acid, and vitamin E. The study also found an increased incidence with elevated salt and fat intake. [16] Dairy products
Cataracts often develop in infants with a homozygous deficiency of either galactokinase or galactose-1-phosphate uridyl transferase and in laboratory animals fed a high galactose diet. Abnormalities of galactose metabolism can be identified by measurements of the activity of these enzymes in red blood cells. It has been suggested that this is an important mechanism in approximately 30% of cataract patients. [12] However, this mechanism of cataract formation appears only to be significant in diabetic cataract formation and is probably not relevant to senile cataract formation (for further discussion, see Ch. 147 ). Heavy metals A number of heavy metals have been shown to have increased concentrations in both the aging lens and the cataractous lens. Although the levels are higher in the latter, the significance of this is unknown. [9] Cadmium
The cadmium concentration in the cataractous lens is two to three times higher than in age-matched controls. Since cadmium displaces zinc from binding in enyzmatic proteins by binding to the sulfhydryl groups, it may contribute to deactivation of free radical quenching and other protective/repair mechanisms. Other elevated elements of unknown significance include bromine, cobalt, iridium, and nickel.
[9]
Botanical medicines There are a number of excellent choices from the botanical world to help with antioxidant mechanisms. Flavonoid-rich extracts
Among the best may be flavonoid-rich extracts from Vaccinium myrtillus (bilberry), Vitis vinifera (grape seed), and Pinus maritima (pine bark) as well as curcumin from Curcuma longa. The occurrence of cataracts in rats can be retarded by changing their diet from a commercial laboratory chow to a “well-defined diet”. [17] Preliminary research suggests that flavonoid components in the well-defined diets may be responsible for the protective effects. [18] Of the flavonoid-rich extracts, bilberry anthocyanosides may offer the greatest protection. In one human study, bilberry extract plus vitamin E stopped progression of cataract formation in 97% of 50 patients with senile cortical cataracts. [19] Hachimijiogan
An ancient Chinese formula, Hachimijiogan, has been shown to increase the antioxidant level of the lens of
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the eye.[20] This activity may explain its use in treating cataracts for hundreds of years. According to clinical research, its therapeutic effect is quite impressive in the early stages of cataract formation. In one study, 60% of the subjects on Hachimijiogan noted significant im-provement, 20% of the group showed no progression and only the remaining 20% of the group displayed progression of the cataract. Hachimijiogan contains the following eight herbs (per 24 g): • • • •
Rehmania glutinosa – 6,000 mg Poria cocos sclerotium – 3,000 mg Dioscorea opposita – 3,000 mg Cormus officinalis – 3,000 mg
• • • •
Epimedium grandiflorum – 3,000 mg Alisma plantago – 3,000 mg Astragalus membranaceus – 2,000 mg Cinnamonum cassia – 1,000 mg.
THERAPEUTIC APPROACH In cases of marked vision impairment, cataract removal and lens implant may be the only alternative. As with most diseases, prevention or treatment at an early stage is most effective. Since free radical damage appears to be the primary factor in the induction of senile cataracts, avoidance of oxidizing agents and promotion of free radical scavenging are critically important to successful treatment. The patient should avoid direct ultraviolet light, bright light, and photosensitizing substances; wear protective lenses when outdoors; and greatly increase intake of antioxidant nutrients. Progression of the pathological process can be stopped and early lesions can be reversed. However, significant reversal of well-developed cataracts does not appear possible at this time. Since the geriatric population is especially susceptible to nutrient deficiencies, every effort should be made to ensure that the patient is ingesting and assimilating adequate macro- and micronutrients. Diet
Avoid rancid foods and other sources of free radicals. Increase consumption of legumes (high in sulfur-containing amino acids), yellow vegetables (carotenes), and vitamin E and C rich foods. Supplements
• Vitamin C: 1 g three times/day • Vitamin E: 600 to 800 IU/day • Selenium: 400 mcg/day • Beta-carotene: 200,000 IU/day • L-Cysteine: 400 mg/day • L-Glutamine: 200 mg/day • L-Glycine: 200 mg/day. Botanical medicines
• Bilberry extract (25% anthocyanidin content): 80 mg three times/day • Hachimijiogan formula: 150 mg three times/day.
REFERENCES 1. Bouton
S. Vitamin C and the aging eye. Arch Int Med 1939; 63: 930–945
2. Ringvold
A, Johnsen H, Blika S. Senile cataract and ascorbic acid loading. Acta Ophthalmol 1985; 63: 277–280
3. Atkinson
D. Malnutrition as an etiological factor in senile cataract. Eye, Ear, Nose and Throat Monthly 1952; 31: 79–83
4. Rathbun
W, Hanson S. Glutathione metabolic pathway as a scavenging system in the lens. Ophthal Res 1979; 11: 172–176
5. Swanson
A, Truesdale A. Elemental analysis in normal and cataractous human lens tissue. Biochem Biophys Res Comm 1971; 45: 1488–1496
6. Karakucuk 7. Taylor
S, Ertugrul Migra G, Faruk Ekinciler O. Selenium concentrations in serum, lens, and aqueous humour of patients with senile cataract. Arch Ophthalmol Scand 1995; 73: 329–332
A. Cataract: relationships between nutrition and oxidation. J Am Coll Nutr 1993; 12: 138–146
8. Whanger
P, Weswig P. Effects of selenium, chromium and antioxidants on growth, eye cataracts, plasma cholesterol and blood glucose in selenium deficient, vitamin E supplemented rats. Nutr Rep Int 1975; 12: 345–358 9. Swanson
A, Truesdale A. Elemental analysis in normal and cataractous human lens tissue. Biochem Biophys Res Comm 1971; 45: 1488–1496
Rao GN, Cotlier E. The enzymatic activities of GTP cyclohydrolase, sepiapterin reductase, dihydropteridine reductase and dihydrofolate reductase; and tetrahydrobiopterin content in mammalian ocular tissues and in human senile cataracts. Comp Biochem Physiol 1985; 80B: 61–66 10.
11.
Skalka H, Prchal J. Cataracts and riboflavin deficiency. Am J Clin Nutr 1981; 34: 861–863
12.
Prchal J, Conrad M, Skalka H. Association of pre-senile cataracts with heterozygosity for galactosemic states and riboflavin deficiency. Lancet 1978; 1: 12–13
13.
Hockwin O. Drug treatment of senile lens opacities, analysis of possible ways and means from the aging lens. Amsterdam Elsevier/North-Holland Biomedical Press. 1980: p 281
14.
Burton G, Ingold K. Beta-carotene: an unusual type of lipid antioxidant. Science 1984; 224: 569–573
15.
Reiter RJ. Oxygen radical detoxification processes during aging. The functional importance of melatonin. Aging Clinical Exp Res 1995; 7: 340–351
16.
Tavani A, Negri E, LaVecchia C. Food and nutrient intake and risk of cataract. Ann Epidem 1996; 6: 41–46
17.
Hess H, Knapka JJ, Newsome DA et al. Dietary prevention of cataracts in the pink-eyed RCS rat. Lag Anim Sci 1985; 35: 47–53
18.
Pautler EL, Maga JA, Tengerdy C. A pharmacologically potent natural product in the bovine retina. Exp Eye Res 1986; 42: 285–288
19.
Bravetti G. Preventive medical treatment of senile cataract with vitamin E and anthocyanosides. Clinical evaluation. Ann Ophthalmol Clin Ocul 1989; 115: 109
20.
Yoshida H. The effects of Ba-wei-wan (Hachimijiogan) on plasma levels of high density lipoprotein-cholesterol and lipoperoxide in aged individuals. Am J Clin Med 1985; 13: 71–76
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Chapter 189 - Streptococcal pharyngitis Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Abrupt onset of sore throat, fever, malaise, nausea, and headache • Throat red and edematous, with or without exudation • Tender cervical lymph nodes • Positive rapid detection of streptococcal antigen • Group A streptococci on throat culture.
GENERAL CONSIDERATIONS Throat cultures yield group A beta-hemolytic streptococci in 10% of patients presenting clinically with a sore throat. Signs and symptoms of “strep throat” resemble viral pharyngitis, requiring a culture for definitive diagnosis. However, 10–25% of the general, asymptomatic population are carriers for group A streptococci. Rapid strep screens which detect the presence of group A streptococcal antigens are a major clinical advancement. Since definitive diagnosis with a positive culture usually takes 2 days, antibiotic therapy during this time period for presumed group A strep throat leads to unnecessary exposure to antibiotics and an increased likelihood of developing antibiotic-resistant organisms. “Second-generation” rapid strep screens, such as the Strep A OIA test, are showing excellent sensitivity and specificity. [1] The hope is that the use of these rapid strep screens will likely eliminate the unnecessary use of antibiotics. Even in positive cases, antibiotics may not be necessary.[2] Strep throat is usually a self-limiting disease. Although standard medical textbooks strongly assert that antibiotics are highly effective in preventing the sequelae of strep infections, recent research has shown that clinical recovery is similar in both cases where antibiotics are prescribed and those where they are not. [4] The primary concern with not using antibiotics is the development of the “non-suppurative post-streptococcal syndromes” (rheumatic fever, post-streptococcal glomerulonephritis,
[3]
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etc.). However, antibiotic administration does not significantly reduce the incidence of these sequelae. Most cases of rheumatic fever and glomerulonephritis due to group A beta-hemolytic strep throat are the result of the afflicted not consulting a physician. [3] At this time, it appears that the use of antibiotics should be reserved for those patients who are suffering from severe infection, or who are unresponsive to therapy (i.e. no response after 1 week of immune supportive therapy), and those with a prior history of rheumatic fever or glomerulonephritis. Even then, antibiotics like penicillin fail to eradicate the streptococci in over 20% of patients. The primary reason is the presence of beta-lactase-positive organisms ( Staphylococcus aureus and Bacteroides sp.) which shield streptococci by deactivating the penicillin. [5] Antibiotics are often praised for their role in effectively eliminating rheumatic fever as a serious concern. However, the dramatic decrease in the incidence of rheumatic fever began before the advent of effective antibiotics. [6] Improved socioeconomic, hygienic, and nutritional factors were, as in most infectious diseases, more important than the liberal use of penicillin. The present attack rates after a streptococcal infection are 0.4–2.8% for rheumatic fever and 0.2–20% for glomerulonephritis. Obviously, such a wide range of reported sequelae makes accurate evaluation of the risk difficult.
THERAPEUTIC CONSIDERATIONS The primary therapeutic consideration is the status of the patient’s immune system. If the patient’s immune system is in good function, the illness will be short-lived. Enhancing general immune function as described in Chapter 53 may shorten the course. In cases of poor immune function, every effort should be made to strengthen the immune system by following the recommendations given in Chapter 53 . Vitamin C
During the 1930s there was considerable interest in the relationship between malnutrition and the development of the sequelae of streptococcal pharyngitis. Both experimental animal work and epidemiological surveys demonstrated a correlation between vitamin C deficiency and the development of sequelae. Rheumatic fever is virtually non-existent in the tropics where vitamin C intake is higher, and 18% of children in high-risk groups have subnormal serum vitamin C levels. Vitamin C supplementation of streptococcal-infected, vitamin C-deficient, rheumatic fever-susceptible, guinea pigs totally prevents their development of rheumatic fever.[7] [8] Uncontrolled clinical studies demonstrated very positive results when children were given orange juice supplementation. Unfortunately, this promising line of research appears to have been dropped, probably due to the advent of, supposedly effective, antibiotics. Hydrastis canadensis and Echinacea augustifolia
The guidelines for enhancing the immune system, as presented in Chapter 53 , are particularly well indicated for streptococcal pharyngitis, particularly the botanicals Hydrastis canadensis and Echinacea augustifolia. The berberine alkaloid of hydrastis exerts antibiotic activity against streptococci and, perhaps more importantly, has been shown to inhibit the attachment of group A streptococci to pharyngeal epithelial cells. To promote the spread of colonies, streptococci secrete large amounts of hyaluronidase. This enzyme is inhibited by echinacea and bioflavonoids. Echinacea also promotes increased phagocytosis, natural killer cell activity, and properdin levels (see Chs 82 and 91 for more discussion of these botanical effects). Bacteriotherapy
Colonizing the throat with group A non-beta-hemolytic streptococci may prove to be an effective treatment for recurrent group A beta-hemolytic streptococci pharyngitis. In a double-blind study, 130 patients with recurrence of group A beta-hemolytic streptococci pharyngotonsillitis received antibiotic treatment for 10 days, followed by 10 days of group A non-beta-hemolytic streptococci alpha-streptococci. [9] The clinical recurrences (bacteriologically verified) in the alpha- and placebo-treated patient groups were 2 and 23%, respectively, in patients given spray for at least 5 days. No side-effects were reported.
THERAPEUTIC APPROACH
For further information, consult Chapter 53 . If antibiotics are used, follow the recommendations for Lactobacillus acidophilus supplementation given in Chapter 105 . Supplements
• Vitamin A: 50,000 IU/day for 1 week; or beta-carotene: 200,000 IU/day (Note: do not use vitamin A in menstruating women due to its teratogenic effect) • Vitamin C: 500 mg every 2 hours • Bioflavonoids: 1,000 mg/day • Zinc: 30 mg/day • Thymus extract: the equivalent of 120 mg pure polypeptides with molecular weights less than10,000 or roughly 500 mg of the crude polypeptide fraction.
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Botanical medicines
• Echinacea sp. —dried root (or as tea): 0.5–1 g —freeze-dried plant: 325–650 mg —juice of aerial portion of E. purpurea stabilized in 22% ethanol: 2–3 ml —tincture (1:5): 2–4 ml —fluid extract (1:1): 2–4 ml —solid (dry powdered) extract (6.5:1 or 3.5% echinacoside): 150–300 mg • Hydrastis canadensis – the dosage should be based on berberine content. As there is a wide range of quality in goldenseal preparations, standardized extracts are recommended. Three times a day dosages are as follows: —dried root or as infusion (tea): 2–4 g —tincture (1:5): 6–12 ml (1.5–3 tsp) —fluid extract (1:1): 2–4 ml (0.5–1 tsp) —solid (powdered dry) extract (4:1 or 8–12% alkaloid content): 250–500 mg.
Local treatment
Gargle with salt water twice daily: 1 tbsp salt/240 ml of warm water.
REFERENCES 1. Badgett
JT, Hesterberg LK. Management of group A streptococcus pharyngitis with a second-generation rapid strep screen. Strep A OIA. Microb Drug Resist 1996; 2: 371–376
2. Dagnelie
CF, van der Graaf Y, De Melker RA. Do patients with sore throat benefit from penicillin? A randomized double-blind placebo-controlled clinical trial with penicillin V in general practice. Br J Gen Pract 1996; 46: 589–593 3. McIsaac
WJ et al. Reconsidering sore throats. Part I: Problems with current clinical practice. Can Fam Physician 1997; 43: 485–493
4. McIsaac
WJ et al. Reconsidering sore throats. Part 2: Alternative approach and practical office tool. Can Fam Physician 1997; 43: 495–500
5. Brook
I. Treatment of group A streptococcal pharyngotonsillitis. JAMA 1982; 247: 2496
6. McKowen 7. Rinehart
T. The role of medicine. Dream, mirage, or nemesis? London: Nuffield Provincial Hospitals Trust. 1975
JF. Studies relating vitamin C deficiency to rheumatic fever and rheumatoid arthritis. Experimental, clinical, and general considerations. I. Rheumatic fever. Ann Int Med 1935; 9: 586–599
8. Rinehart
JF. Studies relating vitamin C deficiency to rheumatic fever and rheumatoid arthritis: experimental, clinical, and general considerations. II. Rheumatoid (atrophic) arthritis. Ann Int Med 1935; 9: 671–689 9. Roos
K et al. Recolonization with selected alpha-streptococci for prophylaxis of recurrent streptococcal pharyngotonsillitis – a randomized placebo-controlled multicenter study. Scand J Infect Dis 1996; 28: 459–462
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Chapter 190 - Trichomoniasis Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Profuse, malodorous, white to green colored discharge from vagina • Discharge usually has a pH greater than 4.5, a weak amine odor, and large numbers of WBCs and trichomonads on wet mount • Vulvovaginal pruritus, burning, and/or irritation • Vulva and introitus usually show erythema • Cervix may or may not have a mottled erythema “strawberry cervix” (less than 5%) • Dysuria and/or dyspareunia may be present • R/O trichomoniasis in males exhibiting signs of prostatitis, urethritis, or epididymitis.
GENERAL CONSIDERATIONS Trichomoniasis is a remarkably common disease: [1] [2] [3] • one in five women in the United States will have trichomoniasis at some time in her life • approximately 2.5 million women acquire this infection annually • trichomonas is present in 3–15% of asymptomatic women attending gynecological clinics and 20–50% of women attending clinics for sexually transmitted diseases. In addition, gonorrhea and trichomoniasis are common coexisting infections, with up to 40% of women with trichomonas having gonorrhea and vice versa. Aside from these alarming statistics, there are other reasons for taking trichomonal infections seriously:
[4]
[2]
• Trichomoniasis is a frequent cause (90%) of cervical erosion and therefore may be a factor in malignant transformation. • Trichomoniasis may complicate interpretation of Pap smears, increasing the number of false-positivetests. • Trichomoniasis increases the rate of sterility among males and females, the latter due to salpingitis and the 1556
former because of toxic products decreasing motility of spermatozoa. • There is increased postpartum fever and discharge in women who contract Trichomonas vaginalis at delivery. • Neonates infected via the birth canal may manifest serious illness (rare). • Prostatitis and epididymitis are common in infected males. • Infection may confuse and/or complicate other urinary or genital tract problems. • Metronidazole (Flagyl), the most commonly used anti-trichomonal agent, has been found to be carcinogenic and teratogenic in rodents.
DIAGNOSIS Trichomonas vaginalis is a flagellate 15–18 microns in length. It is shaped like a turnip, with three to four anterior and one posterior flagella mounted in an undulating membrane.[5] Transmission is via sexual intercourse. Although women have in the past been thought to be the reservoir for Trichomonas and men merely the vector, current information suggests that men may also be reservoirs. [6] [7] [8] Diagnosis is made by clinical signs and symptoms (see “Diagnostic summary”), saline wet mount, and culture. Trichomonal cultures (using the Feinberg Trichomonas medium) have recently been advocated to increase diagnostic sensitivity. Errors [9] reported in 1972 that only 50% of women with Trichomonas, as defined by a positive culture, have the organism identified by microscopic wet mount. Among patients with trichomonal vaginitis, the organism can be cultured from the vagina and para-urethral glands in 98%, from the urethra in 82%, and from the endocervix in 13%. In 65%, T. vaginalis can be seen on a Pap smear.[10] Trichomonal vaginitis In women, T. vaginalis usually infests the vagina and urethra. However, infection may involve the endocervix, Bartholin’s glands, Skenes glands, or bladder. The vagina appears to be a good reservoir for the organism. Under stimulation of estrogen, the vaginal walls are well glycogenated – essential for T. vaginalis to thrive. Prepubescent and postmenopausal women seldom have symptomatic trichomonal infections. [6] In addition to estrogen, an elevated pH increases susceptibility to Trichomonas. The normal adult vagina maintains a pH of 3.5–4.5 due to the metabolism of free glucose into lactic acid by vaginal Lactobacillus acidophilus. A decrease in the number of lactobacilli will increase pH. Trichomonas organisms grow optimally at a vaginal pH of 5.5–5.8. [11] Other conditions also increase vaginal pH: [6] • progesterone, which increases in the latter half of the menstrual cycle and during pregnancy • excess intravaginal secretions (i.e. cervical mucus) • overgrowth of certain bacteria such as Streptococcus and Proteus. Trichomonas in the male Although the incidence is lower in men, it is estimated that 5–15% of non-gonococcal urethritis is caused by trichomonal infections. [2] [6] Men suffering from T. vaginalis are most often asymptomatic, yet mild cases of urethritis, prostatitis, and epididymitis have been reported. [8] Trichomonads have been identified in semen, urethral discharge, urine, and prostatic fluid and have been found in the prostatic secretions and semen of up to 23% of men with chronic non-gonococcal prostatitis. [12] [13] Although men are thought to be only vectors for Trichomonas, the parasite is now known to persist in the male reproductive tract. The reinfection of treated females who are sexually active is well-documented. [8] [14] Therefore, treatment of both sexual partners is necessary.
THERAPEUTIC CONSIDERATIONS
Diet Dietary factors affect the body’s ability to defend itself against foreign bodies and substances both directly and indirectly. As with any infection, it is not the pathogenicity of the organism but rather the “fertility of the soil” that allows the organism to grow and flourish. A well-balanced diet high in natural fiber (vegetable, fruits) and low in fat, sugar, and refined carbohydrates aids immune function (see Ch. 53 for more discussion). Lifestyle Depression and anxiety have been associated with exacer-bations of trichomonal infections. [6] Therefore, reducing stress is definitely indicated. This may be achieved by a variety of means, including exercise and meditation. The practice of safe sex or abstinence (while infected) will also lower incidence of infection and reinfection. Greater than 66% of prostitutes who do not practice safe sex have trichomonal infections. [14] Nutritional supplements For years, it has been the view of many alternative health care providers that the supplementation of vitamins and minerals is beneficial in the prevention and treatment of disease. Although considerable research has supported this view, it is only recently that such groups as the American Medical Association (AMA) have considered
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the importance of single nutrients in disease. An interesting report sponsored by the AMA summarizes how nutrients such as iron, zinc, B-complex, and vitamins A and C, as well as calcium and magnesium, increase immune function. [15] B-complex
Pyridoxine, pantothenic acid, vitamin B 12 , and folate aid the phagocytic and bactericidal effects of neutrophils and B- and T-cell activity.
[16]
Ascorbic acid
Vitamin C aids in phagocytic cell migration and killing functions. [17] In addition, vitamin C preserves cell integrity by inactivating free radicals and oxidants produced during phagocytosis. [18] Vitamin A
Secretory IgA production appears to be impaired in vitamin A-deficient humans. Many studies indicate that modest increases in vitamin A enhance resistance to infection. [19] [20] [21] Vitamin A maintains the composition of external cell membranes and surface glycoproteins, decreasing susceptibility to infectious organisms. [15] Excess vitamin A is a known teratogen and can be toxic in high dosages. Therefore, particular caution must be taken in treating pregnant women, children, and the elderly (see Ch. 121 for a full discussion). Vitamin E
Vitamin E in doses two- to 10-fold greater than the minimum requirements have been found to enhance antibody responses and accelerate the clearance of particulate matter by the reticuloendothelial system (RES), as well as enhancing host resistance. [22] Conversely, one study found that megadoses of vitamin E in healthy volunteers will inhibit multiple immune functions. [23] Calcium and magnesium
Many minerals, especially divalent cations, have regulatory influences on the external membrane functions of all body cells. Calcium and magnesium ions also participate in the activation of the complement pathway. [15] This may be important for the prevention and treatment of T. vaginalis. Trichomonas activates the alternate complement pathway which can lead to parasite lysis. [24] Unlike the classical complement pathway, which requires both calcium and magnesium, the alternate pathway requires only magnesium. Zinc
Zinc supplementation is important in the treatment of trichomonal infections of both men and women. The antimicrobial spectrum of zinc is broad and includes many potential genitourinary pathogens: Gram-positive and -negative bacteria, T. vaginalis, Candida albicans, and Chlamydia trachomatis, as well as many viruses. [25] [26] Of particular significance is the fact that trichomonads are readily killed by zinc at a concentration of 0.042% (6.4 mmol/L), [8] a concentration which can occur in the prostatic fluid of men. The zinc concentration of prostatic fluid ranges from 0.015 to 0.10% (2.3–15.3 mmol/L). [27] [28] This suggests that persistent trichomonal infections in men may be due to a low-level zinc deficiency. Zinc sulphate (220 mg two times/day for 3 weeks) has been recommended as a possible treatment for trichomonal infections refractory to metronidazole. [29] For women with drug-resistant trichomoniasis, zinc douches in combination with metronidazole may provide welcome relief. In a small study, the women suffering from recalcitrant trichomoniasis (4 months to 4 years culture-positive despite conventional treatment), all became culture-negative through the use of a combination of 1% zinc sulfate douching (for 3 days after each menstrual period) and 1.6–2.2 g/day of metronidazole (suppositories plus oral). [30] Iron
Iron deficiency, often too small to lower hemoglobin values, causes immune dysfunctions. [31] Iron-deficient humans demonstrate defective macrophage and neutrophil functions. [15] Too much iron can, however, increase availability to microorganisms, leading to increased growth of the pathogen. [32] Botanical medicines Trichomonas, as mentioned earlier, activates the alternate complement pathway. [24] Complement has the ability to lyse T. vaginalis in vitro and in vivo. [33] [34] There are several botanical medicines which activate the alternate complement pathway. Of these, Angelica sp. and Echinacea purpura are the most widely used. Angelica spp. contain coumarin compounds which have been shown to activate both classical and alternate pathways (see Ch. 65 ). Inulin, an active constituent of Echinacea, also activates complement and promotes chemotaxis of neutrophils, monocytes, and eosinophils (see Ch. 82 ). Topical trichomonacides Betadine (povidone-iodine)
Iodine has long been recognized as being a highly potent
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trichomonacide. Povidone-iodine (PVP) has a broad therapeutic effect in killing a large number of different microorganisms causing vaginitis, including Trichomonas vaginalis.[35] [36] Povidone-iodine (iodine which is absorbed into polyvinyl pyrrolidone) has several advantages over iodine in that it has little sensitizing potential, does not sting, is water-soluble, and washes out of clothing. A success rate of 98.1% has been reported in patients with intractable trichomonal, monolial, non-specific, and mixed vaginitis with a 2 week treatment regimen using Betadine preparations. [37] [38] Other studies suggest a 28 day course of Betadine pessaries, particularly if the patient is using oral contraceptives. [39] Propolis
An ethanol extract of propolis (150 µg/ml) has been shown to have a 100% lethal effect in vitro on the protozoans Trichomonas vaginalis and Toxoplasma gondii after 24 hours of contact. [40] This extract has also been shown to decrease the inflammation associated with trichomonal vaginitis. Essential oils
The diverse antimicrobial action of essential oils has been well demonstrated. Many possess strong antitrichomonal properties. In a study of 40 essential oils tested for their ability to kill Trichomonas, Mentha piperita (peppermint) and Lavandula angustifolia (lavender) had the fastest killing effects (20 and 15 minutes, respectively).[41] Melaleuca alternifolia
Melaleuca alternifolia (tea tree) oil is a powerful cidal agent (see Ch. 96 ). Commonly used as a germicidal agent in Great Britain and Australia, a 40% solution of tea tree oil has been found to be a highly effective treatment. [42] The 40% solution of the oil produced no irritation, burning, or other side-effects. Daily vaginal douches with a 0.4% solution of melaleuca oil in 1 litre of water was also found to be an effective treatment. [43] Berberine-containing botanicals
The plant alkaloid, berberine sulphate, has been shown in vitro to inhibit the growth of several protozoa, including Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis.[44] [45] No clinical trials have been reported in trichomonas vaginalis (see Ch. 91 for further discussion).
THERAPEUTIC APPROACH Discussion with the patient of such factors as diet, sexual habits, and lifestyle is a must. Inform the patient that Trichomonas is a sexually transmitted disease (STD) and that treatment of the sexual partner(s) is necessary to prevent reinfection. During the treatment, sexual intercourse should be avoided. If intercourse does occur, use of a condom is necessary. Diet
Decrease refined carbohydrates, alcohol, and fats and increase fiber. Nutritional supplements
• Vitamin A: 25,000 IU/day; or beta carotene:200,000 IU/day • Vitamin C: 500–1,000 mg every 4 hours • B-complex: 20–50 mg/day • Zinc (picolinate): 10–15 mg/day • Vitamin E: 200 IU/day • Lactobacillus acidophilus: 2 caps two times/day. If effective, L. acidophilus treatment will change the quantity and quality of the stool. If this change does not occur, check the quality of the L. acidophilus product being used (see Ch. 105 for further discussion). Botanical medicines
The following are three times/day doses: • Hydrastis canadensis —dried root: 0.5–1.0 g —tincture (1:10): 6–12 ml —fluid extract (1:1): 1–2 ml —solid extract (4:1): 250 mg • Echinacea angustifolia —dried root: 1–2 g —tincture (1:10): 8–12 ml —fluid extract: 1.5–3.0 ml —solid extract (6.5:1): 250 mg • Angelica sp. —dried root or rhizome: 1–2 g —tincture (1:5): 3–5 ml —fluid extract (1:1): 0.5–2 ml
Topical treatment
• Betadine douche, pessary, or saturated tampon: two times/day for 14 days • Melaleuca alternifolia oil (40% solution): swab on affected area two times/day, or —douche: 1 litre of a 0.4% solution two times/day
—suppository: one at night • Zinc sulphate douche: 1% solution two times/day • Lactobacillus culture yogurt douches daily, preferably in the morning.
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PJ, Jones OG, Blount JH. World trends in STDs: the situation in the US. In: Catterall RD, Nicol CS, eds. Sexually transmitted diseases. New York, NY: Academic Press. 1976: p 5–17
JC. Trichomoniasis – eight reasons why you should take it seriously. Med Times 1978; 106: 59–63
MF, Chapel TA. Trichomonas, candidiasis and the minor venereal diseases. Clin Obstet Gyn 1975; 18: 73
4. Fonts
AC, Kraus ST. Trichomonas vaginalis. Reevaluation of its clinical presentation and laboratory diagnosis. J Infect Dis 1980; 141: 137–139
5. Robbins
SL, Cotran RS, Kumar V. Pathologic basis of disease. 3rd edn. Philadelphia, PA: WB Saunders. 1984: p 365
6. Hildebrandt 7. Jirovev
O, Petru M. T. vaginalis and trichomoniasis. Adv Parasit 1968; 6: 117–188
8. Langley 9. Errors
RJ. Trichomoniasis: always with us – but controllable. Med Times 1978; 106: 44–48
JG, Goldsmid JM, Davies N. Venereal trichomoniasis: role of men. Genitour Med 1987; 63: 264–267
PG. Diagnosis of T. vaginalis infection as observed in 1199 patients. Obstet Gyn 1972; 39: 7
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Karchmer AW. Sexually transmitted diseases. In: Dale DC, Federman DD, eds. Scientific American medicine. New York, NY: Scientific American. 1997: p 7:XXII: 13–14
11.
Trussel RE, Plass ED. The pathogenicity and physiology of a pure culture of T. vaginalis. Am J Obstet Gyn 1940; 40: 883
12.
Andreeva N, Tzvetkova A, Gikov D et al. Studies on the etiological role of trichomonas in chronic prostatitis and efficacy of diagnostic methods employed. Folia Med 1981; 23: 36–40
13.
Gardner WA, Culberson DE, Bennet BD. Trichomonas vaginalis in the prostate gland. Arch Pathol Lab Med 1986; 110: 430–432
14.
Dunkelberg WE, Skaggs R, Kellogg DS, Domesick GK. Relative incidence of H. vaginalis, N. gonorrhea and T. vaginalis among women attending STD clinics. Br J Vener Dis 1970; 46: 187
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Biesel WR, Edelman R, Nauss K, Suskind RM. Single nutrient effects on immunologic functions. JAMA 1981; 245: 53–58
16.
Axelrod AE. Immune processes in vitamin deficient states. Am J Clin Nutr 1971; 24: 265–271
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Thomas WR, Holt PG. Vitamin C and immunity. Clin Exp Immunol 1978; 32: 370–379
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Stankova L, Gerhardt NB, Nagel L, Bigley RH. Ascorbate and phagocyte function. Infect Immun 1975; 12: 252–256
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Darip MD, Sirisinka S, Lamb AJ. Effect of vitamin A deficiency on susceptibility of rats to Angiostrongylus canlonensis. Proc Soc Exp Biol Med 1979; 161: 600
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Dowling JE, Waid G. Biological function of vitamin A. Proc Natl Acad Sci 1960; 46: 587
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Sinsinka S, Darip MD, Moongkarundi P, Lamb AJ. Impaired local immune response in vitamin A deficient rats. Clin Exp Immunol 1980; 40: 127–135
22.
Nockels CF. Protective effects of supplemental vitamin E against infection. Fed Proc 1979; 38: 2134–2138
23.
Prasad JS. Effect of vitamin E supplementation on leukocyte function. Am J Clin Nutr 1980; 33: 606–608
24.
Gillin FD, Sher A. Activation of alternate complement pathway by T. vaginalis. Infec and Immun 1981; 34: 268–273
25.
Tennican P, Carl G, Frey J, Thies C. Topical zinc in the treatment of mice infected intravaginally with Herpes virus. Proc Soc Exp Biol Med 1980; 164: 593–597
Greenberg SB, Harris D, Martin RR. Zinc inhibits Chlamydia trachomatis in prostate cells. In: Program and abstracts of the 20th interscience conference on antimicrobial agents and chemotherapy. Washington, DC: American Society of Microbiology. 1980 26.
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Krieger JN, Rein MF. Zinc sensitivity of T. vaginalis: in vitro studies and clinical implications. J Inf Disease 1982; 146: 341
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Pfeiffer CC. Mental and elemental nutrients. New Canaan, CN: Keats. 1975: p 472
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Willmott F, Say J, Downey D, Hookman A. Zinc and recalcitrant trichomonads. Lancet 1983; i: 1053
Houang ET, Ahmet Z, Lawrence AG. Successful treatment of four patients with recalcitrant vaginal trichomoniasis with combination of zinc sulfate douche with metronidazole therapy. Sex Transm Dis 1997; 24: 116–119 30.
31.
Chandru RK, Woodford G et al. Iron status, immune response and susceptibility to infection. In: Kies H, ed. Iron metabolism. CIBA Foundation Symposium 51. 1979: p 249–268
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Murray MJ, Murray AB. Adverse effect of iron in the course of infection. Br Med J 1978; ii: 1113–1115
33.
Demes P, Gombosova A, Valent M. Fewer trichomonads in vaginas of infected women during menstruation. Genitour Med 1988; 64: 22–24
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Demes P, Gombosova A, Valent M. Differential susceptibility of T. vaginalis isolates to complement in menstrual blood and cervical mucus. Genitour Med 1988; 64: 176–179
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Gershenfeld L. Povidone-iodine (PVP) as a trichomonacide. Am J Pharm 1962; 134: 324
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Gershenfeld L. Povidone-iodine as an antiseptic. Am J Pharm 1957; 94: 938
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Shook DM. Clinical study of povidone-iodine regimen for resistant vaginitis. Curr Ther Res 1963; 5: 256
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Mayhew SR. Vaginitis. A study of the efficacy of povidone-iodine in unselected cases. 1981; 9: 157–159
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Henderson JN, Tait IB. Use of betadine pessaries in treatment of candida and trichomonas. Curr Med Res Opinion 1975; 3: 157–162
40.
Starzyk J, Scheller S, Szaflarski J et al. Biological properties and clinical application of propolis. II. Studies on the antiprotozoan activity of ethanol extract of propolis. Arzneim Forsch Drug Res
1977; 27: 1198–1199 41.
Jankov N, Baltova E, Topalov V et al. Action of some essential oils on T. vaginalis. Folia Med 1968; 10: 308
42.
Humphrey EM. New Australian germicide. Med J Aus 1930; 1: 417
43.
Pena EF. Melaleuca alternifolia oil – its use for Trichomonal vaginalis and other vaginal infections. Obstet Gyn 1962; 19: 793–795
Kaneda Y, Torii M, Tanaka T, Aikawa M. In vitro effects of berberine sulphate on the growth and structure of Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis. Ann Trop Med Parasitol 1991; 85: 417–425 44.
45.
Kaneda Y, Tanaka T, Saw T. Effects of berberine, a plant alkaloid, on the growth of anaerobic protozoa in axenic culture. Tokai J Exp Clin Med 1990; 15: 417–423
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Chapter 191 - Urticaria Michael T. Murray ND Joseph E. Pizzorno Jr ND
DIAGNOSTIC SUMMARY • Urticaria (hives): well-circumscribed erythematous wheals with raised serpiginous borders and blanched centers which may coalesce to become giant wheals. Limited to the superficial portion of the dermis • Angioedema: similar eruptions to urticaria, but with larger well-demarcated edematous areas that involve subcutaneous structures as well as the dermis • Chronic versus acute: recurrent episodes of urticaria and/or angioedema of less than 6 weeks’ duration are considered acute, while attacks persisting beyond this period are designated chronic • Special forms: special forms have characteristic features – dermographism, cholinergic urticaria, solar urticaria, cold urticaria.
INTRODUCTION Urticaria is localized pruritic edema of the skin characterized by white or pink papules or plaques with surrounding axon flare. The lesions are consistent with lesions of histamine-induced wheals. The lesions may develop variable erythema and coalesce to form plaques. About 50% of patients with urticaria develop angioedema – a deeper, less-defined edema of the subcutaneous and soft tissues. Urticaria and angioedema are relatively common conditions: it is estimated that 15–20% of the general population has had hives at some time. Although persons in any age group may experience acute or chronic urticaria and/or angioedema, young adults (post-adolescence through the third decade of life) are the most often affected.[1] [2] The basic pathophysiology involves the release of inflammatory mediators from mast cells or basophilic leukocytes. Although classically this occurs as a result of IgE–antigen complexes interacting with these cells, other mechanisms are probably more important in the majority of patients. The true incidence of IgE-mediated
1562
urticaria is probably quite low when compared with non-immunologic urticaria. [1] [3]
PATHOPHYSIOLOGY The signs and symptoms of acute and chronic urticaria show consistent patterns despite the many diverse etiologic and initiating factors (see below) that have been found, yet the pathogenesis of urticaria cannot be entirely ascribed to any one mechanism. However, at the present time, it appears that mast cells and mast cell-dependent mediators play the most prominent role in the pathogenesis of urticaria. [3] Mast cells are widely distributed throughout the body and are found primarily near small blood vessels, particularly in the skin. The granule-containing mast cell is a secretory cell capable of releasing both preformed and newly synthesized molecules, termed mediators. These mediators (listed in Table 191.1 ) play key roles in the pathogenesis of both immunologic and non-immunologic inflammatory reactions. There are three distinct sources of mediators: • preformed mediators, which are contained in the granules and are released immediately • secondarily formed mediators, which are generated immediately or within minutes by the interaction of the primary mediators and nearby cells and tissues • granule matrix-derived mediators, which are preformed but slowly dissociate from the granule after discharge and remain in the tissues for hours.
TABLE 191-1 -- Mast cell-derived mediators [3] Preformed, rapidly released • Histamine • Eosinophil chemotactic factors of anaphylaxis (ECF-A) • Eosinophil chemotactic oligopeptides • Neutrophil chemotactic factor • Superoxide anions • Exoglycosidases (beta-hexosaminidase, beta-delta-galactosidase, * beta-glucuronidase) • Serotonin* • Arylsulfatase A Secondary or newly generated • Slow-reacting substances (SRS-A): LTC, LTD, LTE • Prostaglandins • Monohydroxyeicosatetraenoic acids (HETEs) • Hydroperoxyeicosatetraenoic acids (HPETEs) • Thromboxanes • Platelet-activating factor (PAF) * • Prostaglandin generating factor of anaphylaxis (PGF-A) Preformed, granule-associated • Heparin • Proteases (chymotrypsin/trypsin)
• Peroxidase* • Superoxide dismutase* • Arylsulfatase B • Inflammatory factors of anaphylaxis (IFA) * * Found in mast cells of species other than human.
The most common immunological mechanism is mediated by IgE. The early vascular changes appear to be the result of mast cell-dependent vasoactive mediators, particularly histamine and some secondarily generated end-products of arachidonic acid metabolism. The wheal and flare reactions occur within minutes of initiation and last 30–60 minutes. The more prolonged, and delayed, reactions reflect leukocytic infiltration in response to the release of mast cell granule-derived chemotactic factors. These late-phase reactions develop over time and are characterized by erythema, edema, and induration beginning within 2 hours and lasting 12–24 hours. Leukocyte infiltration may contribute to the urticarial tissue response by inducing a second wave of mast-cell activation, or by releasing toxic lysosomal enzymes and mediators characteristic of the type of infiltrating cell. The actual events initiated by the mediators also depend on the tissues into which they are released. For example, the release of histamine into the skin primarily produces pruritus and vascular permeability, while hista-mine release into the lung may induce bronchospasm.
CAUSES OF URTICARIA Fundamental to the treatment of urticaria is the recognition and control of causative factors. Physical Urticaria can be produced as a result of reactions to various physical stimuli. The most common forms of physical urticarias are dermographic, cholinergic, and cold urticarias ( Table 191.2 ). These are briefly described below. Less common types of physical urticarias or angioedema are: [1] • contact • solar • pressure • heat contact • aquagenic • vibratory • exercise-induced. Dermographism
Dermographism or dermographic urticaria is a readily elicited whealing of the skin which evolves rapidly when moderate amounts of pressure are applied. This may occur as a result of simple contact with furniture, garters, bracelets, watch bands, towels, or bedding. The incidence of dermographic urticaria has been estimated at 1.5–5% in the general population. It is the
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Type
Eliciting stimulus
TABLE 191-2 -- Clinical aspects of physical urticarias [1] Time of Duration of Diagnostic test onset lesion
Associated symptoms
Dermographic urticaria (tarda)
Stroking, scratching (rubbing for red dermographism)
2–5 min (0.5–5 h)
1–5 h (48 h)
Firm stroking of skin
Headache, malaise
Cholinergic urticaria
Physical exercise + overheating mental stress
2–20 min
30–60 min
Bicycling, running, sauna Headache, gastrointestinal upset, wheezing, salivation, lacrimation, syncope
Cold urticaria
Cold contact
2–5 min
1–2 h
Ice cube, cold arm bath, cold air
Wheezing, syncope
Solar urticaria
Light of varying wavelengths
2–15 min
0.25–3 h
Phototest
Wheezing, dizziness, syncope
Pressure urticaria
Pressure
3–8 h
8–24 h
Locally applied weights
Flu-like syndrome, fever, leukocytosis, arthralgias
Heat contact urticaria
Contact with heat
2–15 min
30–60 min
Hot arm bath
Gastrointestinal upset, dizziness, fatigue, wheezing, dyspnea
Aquagenic urticaria
Contact with water
2–30 min
30–60 min
Bath, compresses
Vibratory angioedema
Vibration
0.5–4 min
1h
Vibrating motor
Faintness, headache
Exercise-induced anaphylaxis
Exercise after a heavy meal
2–5 min
10–30 min
Exercise
Flushing, headache, disorientation, glottis edema, dyspnea, collapse
Familial cold urticaria
Cold wind, change from cold to warm air
0.5–3 h
48 h
Cold wind and subsequent rewarming
Tremor, headache, arthralgias, fever
most frequent type of physical urticaria and is found twice as frequently in women as in men, with the average age of onset in the third decade. The incidence is much greater among the obese, especially those who wear tight clothing. Dermographic lesions usually start within 1–2 minutes of contact as an erythema, which is replaced within 3–5 minutes by edema and surrounding reflex urticaria. Maximal edema is usually produced within 10–15 minutes. While the erythema generally regresses within an hour, the edema can persist up to 3 hours. Dermographism may be associated with other diseases, including: [1] • parasitosis • insect bites • neuropsychiatric disorders • hormonal changes • thyroid disorders
• pregnancy • menopause • diabetes • immunological alterations • other urticarias • during or following drug therapy • Candida albicans • angioedema • hypereosinophilia. Cholinergic urticaria
Cholinergic, or heat reflex, urticaria is the second most frequent physical urticaria. These lesions, which depend upon the stimulation of the sweat gland via cholinergic afferent fibers, consist of pinpoint wheals surrounded by reflex erythema. The wheals arise at or between follicles and develop preferentially on the upper trunk and arms. The three basic types of stimuli that may produce cholinergic urticaria include passive overheating, physical exercise, and emotional stress. Typical eliciting activities, besides physical exercise, may include taking a warm bath or sauna, eating hot spices, or drinking alcoholic beverages. The lesions usually arise within 2–10 minutes after provocation and last for 30–50 minutes. A variety of systemic symptoms may also occur, suggesting a more generalized mast cell release of the mediators than in the skin. Headache, periorbital edema, lacrimation, and burning of the eyes are common symptoms. Less frequent symptoms include nausea, vomiting, abdominal cramps, diarrhea, dizziness, hypotension, and asthmatic attacks. [1] Cold urticaria
Cold urticaria is an urticarial and/or angioedematous reaction of the skin when it comes into contact with cold objects, water, or air. Lesions are usually restricted
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to the area of exposure, and develop within a few seconds to minutes after the removal of the cold object and rewarming of the skin. The lower the object’s or element’s temperature, the faster the reaction. Widespread local exposure and generalized urticaria can be accompanied by: • flushing • headaches • chills • dizziness • tachycardia • abdominal pain • nausea • vomiting • muscle pain • shortness of breath • wheezing • unconsciousness. Cold urticaria has been observed to accompany a variety of clinical conditions including:
[ 1]
• viral infections • parasitic infestations • syphilis • multiple insect bites • penicillin injections • dietary changes • stress. The association of cold urticaria with infectious mononucleosis is well-established. Other conditions asso-ciated with cold urticaria include cryoglobulinemia and myeloma where cold urticaria may precede the diagnosis by several years. [1] Drugs Drugs are the leading cause of urticarial reactions in adults. In children, they are usually due to foods, food additives, or infections.
[1]
Most drugs are composed of small molecules incapable of inducing antigenic/allergenic activity on their own. Typically, they act as haptens which bind to endogenous macromolecules, ultimately causing the production of hapten-specific antibodies. Alternately, drugs can interact directly with mast cells to induce degranulation. Many drugs have been shown to produce urticaria. Table 191.3 provides a condensed list. The two most common urticaria-inducing drugs, penicillin and aspirin, are briefly discussed below. Penicillin
Antibiotics, including penicillin and related compounds, are the most common cause of drug-induced urticaria. TABLE 191-3 -- Drugs which can cause urticaria [4] • Acetylsalicylic acid • Allopurinol • Antimony • Antipyrines • Barbiturates • Bismuth • Chlorhydrate • Chlorpromazine • Corticotropin (ACTH)
• Eucalyptus • Fluorides • Gold • Griseofulvin (cold urticaria) • Insulin • Iodines • Liver extract • Menthol • Meprobamate • Mercury • Morphine, opium • Para-aminosalicylic acid • Penicillin • Phenacetin • Phenobarbital • Pilocarpine • Poliomyelitis vaccine • Potassium sulfocyanate • Procaine • Promethazine • Quinine • Reserpine • Saccharin • Thiamine chloride • Thiouracil The allergenicity of penicillin in the general population is thought to be at least 10%. Nearly 25% of these individuals will display urticaria, angioedema, or anaphylaxis upon ingestion of penicillin. [1] [5] An important characteristic of penicillin is that it cannot be destroyed by boiling or steam distillation. This is a problem since penicillin and related contaminants can exist undetected in foods. It is not known to what degree penicillin in the food supply contributes to urticarial reactions. However, urticaria and anaphylactic symptoms have been traced to penicillin in milk, [6] soft drinks, [7] and frozen dinners. [8] In one study of 245 patients with chronic urticaria, 24% had positive skin tests and 12% had positive RAST tests for penicillin sensitivity. [9] Of those 42 patients sensitive to penicillin, 22 improved clinically on a dairy product-free diet while only two out of 40 patients with negative skin tests improved on the same diet. This study would seem to provide indirect evidence of the importance of penicillin in the food supply in urticaria. In an attempt to provide direct evidence, penicillin-contaminated pork was given to penicillin-allergic volunteers. No significant reactions were noted other than transient pruritus in two volunteers. [10] Penicillin in milk appears to be more allergenic than penicillin in
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meat.[6] Presumably this is due to the fact that penicillin can be degraded into more allergenic compounds in the presence of carbohydrate and metals, suggesting that penicillin in milk may be more allergenic than artificially contaminated meat. [6] Aspirin
Urticaria is a more common indicator of aspirin sensitivity than is asthma (see Ch. 132 ). The incidence of aspirin sensitivity in patients with chronic urticaria is at least 20 times greater than in normal controls. [11] [12] [13] [14] [15] Studies (summarized in Table 191.4 ) have demonstrated that 2–67% of patients with chronic urticaria are sensitive to aspirin. Aspirin inhibition of cyclooxygenase apparently shunts eicosanoid metabolism towards leukotriene synthesis, thereby increasing smooth muscle contraction and vascular permeability. In addition, aspirin and other NSAIDs have been shown to dramatically increase gut permeability and may alter the normal handling of antigens.[38] [43] The daily administration of 650 mg of aspirin for 3 weeks has been shown to desensitize patients with urticaria and aspirin sensitivity. While taking the aspirin, patients also became non-responsive to foods to which they usually reacted, e.g. pineapple, milk, egg, cheese, fish, chocolate, pork, strawberries, and plums. [44] Others have noted this effect in patients with asthma, but they have also found that the effect disappears within 9 days after stopping the treatment, suggesting the loss of effect or a possible placebo response. [45] Food allergy IgE-mediated urticaria can occur upon the ingestion of a specific reaginic antigen. Although any food can be the agent, the most common offenders are milk, fish, meat, eggs, beans, and nuts.[1] [5] [46] [47] [48] [49] [50] Individuals with atopy are most likely to experience urticaria as a result of IgE-related mechanisms. A basic requirement for the development of a food allergy is the absorption of the allergen through the intestinal barrier. Several factors are known to significantly increase gut permeability, including vasoactive amines ingested in foods or produced by bacterial action on essential amino acids, alcohol, NSAIDs, and possibly many food additives (see Ch. 21 for a full discussion). In addition, several investigators have reported alterations in gastric acidity, intestinal motility, and the function of the small intestine and biliary tract in up to 85% of patients with chronic urticaria. [51] [52] [53] [54] [55] Selective IgA deficiency, gastroenteritis, hypochlorhydria or achlorhydria, and other disruptive factors reported in patients with chronic urticaria, may temporarily or
Authors
TABLE 191-4 -- Provocation tests with food additives in chronic urticaria Year No. of patients Percent positive tests Tartrazine
Samter & Beers[16]
1969 40
8
Other azo dyes –
Annatto Benzoates BHA/BHT Aspirin –
–
–
–
Michaelsson & Juhlin[17]
1973 52
36
20
–
44
–
67
Thune & Granholt[18]
1975 100
21
14
–
10
14
33
Doeglas[19]
1975 23
30
–
–
23
–
24
Warin & Smith[20]
1976 108
12
–
–
16
–
–
Settipane et al[21]
1976 38
8
–
–
–
–
–
Kaaber[22]
1978 65
5
5
8
3
–
–
Fujita et al [23]
1978 57
–
–
–
23
–
–
Neuman et al[24]
1978 30
23
–
–
–
–
–
August[25]
1979 86
23
–
–
22
–
–
Meynadier et al [26]
1979 24
24
46
–
25
–
–
Lindemayr & Schmidt[27]
1979 90
19
16
–
29
–
–
Mikkelsen et al [28]
1979 24
24
46
26
–
–
–
Wutrich & Hacki-Herrmann [29]
1980 81
21
–
–
18
11
–
Gibson & Clancy [30]
1980 76
28
–
–
34
–
54
Juhlin [31]
1981 330
–
18
11
11
15
10
Wutrich & Fabro [32]
1981 306
6
–
–
6
–
–
Kirchoff et al[59]
1981 100
15
10
–
8
–
–
Egyedi & Torok[33]
1982 40
37
7
–
17
–
37
Merk & Gorez[34]
1983 25
24
–
–
–
–
–
Hannuksela [35]
1983 137
1
–
–
4
–
18
Ortolani et al [36]
1984 75
13
–
–
21
10
43
Simon[37]
1984 25
0
–
–
–
–
–
Genton et al [38]
1985 17
59
–
–
30
–
–
Pigatto et al [39]
1985 61
10
–
–
–
15
–
Kemp & Schembri[40]
1985 23
7
–
–
7
–
36
Zieger & Hamstein [41]
1986 100
10
–
–
–
–
–
Supramaniam & Warnor[42]
1986 43
26
–
–
15
–
2
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permanently alter the barrier and immune function of the gut wall and predispose an individual to allergic sensitization. In one study of 77 patients with chronic urticaria, 24 (31%) were diagnosed as achlorhydric and 41 (53%) were shown to be hypochlorhydric. [53] Treatment with HCl and a vitamin B-complex gave impressive clinical results, highlighting the importance of correcting any underlying factor in the treatment of chronic urticaria (see Ch. 19 for further discussion). Although IgE-mediated reactions are thought to predominate in immunologic urticaria, it has been suggested that IgG-mediated reactions are probably responsible for the majority of adverse reactions to foods seen in general practice (see Ch. 51 ). IgG antigen–antibody complexes are capable of promoting complement activation and subsequent generation of anaphylatoxins which promote mast cell degranulation. This could be a significant factor in some cases of urticaria. Figure 191.1 summarizes the basic aspects of a hypothetical model of immune defense in the normal and urticarial gut. Food colorants Food additives are a major factor in many cases of chronic urticaria in children. Colorants (azo dyes), flavorings (salicylates, aspartame), preservatives (benzoates, nitrites, sorbic acid), antioxidants (hydroxytoluene, sulfite, gallate), and emulsifiers/stabilizers (polysorbates, vegetable gums) have all been shown to produce urticarial reactions in sensitive individuals. [1] [5] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [39] [40] [41] [42] [50] [56] [57] [58] [59] [60] [61] The importance of the control of food additives is well demonstrated in a recent study of 64 patients with common urticaria. Within 2 weeks on an additive-free diet, 73% of the patients had a significant reduction in their symptoms. The diet strictly forbade preservatives, dyes, or antioxidants. No fruits were allowed except honey. Rice, potatoes, and unprocessed cereals were allowed as well as fresh milk. [62] Tartrazine
In 1959, the azo dye tartrazine (FD&C yellow #5) was the first food dye reported to induce urticaria. [63] Tartrazine
Figure 191-1 Hypothetical model of immune defense in the normal and urticarial gut.
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is one of the most widely used colorants. It is added to almost every packaged food as well as many drugs, including some antihistamines, antibiotics, steroids, and sedatives.[64] Reactions to this food additive are so common that its use has been banned in Sweden. [65] In the United States, the average daily per capita consumption of certified dyes is 15 mg, of which 85% is tartrazine. Among children, consumption is usually much higher. Tartrazine sensitivity has been calculated as occurring in 0.1% of the population. [64] Tartrazine sensitivity is extremely common (20–50%) in individuals sensitive to aspirin. [5] [64] Like aspirin, tartrazine is also a cyclooxygenase inhibitor and known inducer of asthma, urticaria, and other allergic conditions, particularly in children. [64] Inhibition of cyclooxygenase by tartrazine or aspirin apparently shunts eicosanoid
metabolism towards leukotriene synthesis, thereby increasing smooth muscle contraction and vascular permeability. In addition, tartrazine, as well as benzoate and aspirin, increases the production of the lymphokine leukocyte inhibitory factor. [66] This results in an increase in perivascular mast cells and mononuclear cells. Histological examination of patients with urticaria shows that greater than 95% have an increase in perivascular mast cells and mononuclear cells. [67] Table 191.4 summarizes the findings in studies using provocation tests to determine sensitivity to tartrazine and other food additives in patients with urticaria. Results have varied from 5 to 46%. Diets eliminating tartrazine as well as other azo dyes and food additives in sensitive individuals have in many cases been shown to be of great benefit. These studies are summarized in Table 191.5 . Table 191.6 shows a recommended test battery.[61]
Authors
TABLE 191-5 -- Response to a diet free from added dyes and benzoates Year No. of patients
Percentage Free of urticaria
Better Same
Michaelsson & Juhlin[17]
1973 16
81
6
13
Thune & Granholt[18]
1975 100
12
50
38
Ros et al [56]
1976 75
24
57
19
Warin & Smith[20]
1976 58
75
75
25
Douglas[57]
1977 18
67
67
33
Kaaber[22]
1978 23
44
30
26
August[25]
1979 22
45
23
32
Meynadier et al [26]
1979 98
80
12
8
Lindemayr & Schmidt[27]
1979 90
20
55
25
Gibson & Clancy [30]
1980 65
75
15
10
Valverde et al [58]
1980 258
62
22
16
Wutrich & Fabro [32]
1981 51
31
57
12
Kirchoff et al[59]
1981 41
44
29
27
Verschave et al[60]
1983 67
73
73
37
Kemp & Schembri[40]
1985 18
39
39
22
Day
Substances
1
Control (lactose)
2
Azo dyes
TABLE 191-6 -- Test battery for patients with recurrent urticaria [31] [61] Amount (mg) 100,000
Tartrazine
0.1*, 1, 10
New coccine
0.1*, 1, 10
Sunset yellow
0.1*, 1, 10
3
Control (lactose)
100, 100
4
Benzoates Sodium benzoate
50, 500
4-Hydroxybenzoic acid
50, 200
Carotene
50, 100, 100
Canthazanthine
10, 200, 200
6
Annatto
5, 10
7
BHT-BHA
1, 10, 50, 50
8
Yeast extract
600
9
Control (lactose)
100, 100
10
Aspirin
0.1, 1, 10, 100, 250+, 500+
11
Sorbic acid
50, 200, 200
12
Control
13
Sodium nitrite
100
Sodium nitrate
100
14
Sodium glutamate
100, 200
15
Quinoline yellow
1, 5, 10
16
Potassium metabisulfate
1, 5, 10, 50
5
Food flavorings Salicylates
A broad range of salicylic acid esters are used to flavor foods such as cake mixes, puddings, ice cream, chewing gum, and soft drinks. The mechanism of action of these agents is thought to be similar to that of aspirin. [5] Salicylates are also found naturally in many foodstuffs. It is estimated that daily salicylate intake from foods is in the range of 10–200 mg/day. to the level of salicylate used in clinical testing (usually 300 mg), dietary salicylate may be a significant factor in aspirin-sensitive individuals.
[ 68]
As this is very close
Most fruit, especially berries and dried fruits, contain salicylates. Raisins and prunes have the highest amounts. Salicylates are also found in appreciable amounts in candies made of licorice and peppermint. Moderate levels of salicylate are found in nuts and seeds. Vegetables, legumes, grains, meat, poultry, fish, eggs, and dairy products typically contain insignificant levels of salicylates. Salicylate levels are especially high in some herbs and condiments, including curry powder, paprika, thyme, dill, oregano, and turmeric. Although the intake of these herbs and spices is relatively small, they can make a significant contribution to dietary salicylate. [68]
Other flavoring agents
Other flavoring agents such as cinnamon, vanilla, menthol, and other volatile compounds may produce urticaria in some individuals. aspartame has been shown to induce urticaria. [69]
[5]
Recently the artificial sweetener
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Food preservatives Benzoates
Benzoic acid and benzoates are the most commonly used food preservatives. Although for the general population the incidence of adverse reactions to these compounds is thought to be less than 1%, the frequency of positive challenges in patients with chronic urticaria varies from 4 to 44%, as illustrated in Table 191.4 . Fish and shrimp frequently contain extremely high quantities of benzoates. This may be one reason why adverse reactions to these foods are so common in patients with urticaria. BHT and BHA
Butylated hydroxytoluene (BHT) and butylated hydroxyanisol (BHA) are the primary antioxidants used in prepared and packaged foods. Typically, 15% of patients with chronic urticaria test positive to oral challenge with BHT. [18] [31] [37] [41] The use of chewing gum containing BHT was enough to induce urticaria in one patient. [70] Sulfites
Sulfites, like tartrazine, have been shown to induce asthma, urticaria, and angioedema in sensitive individuals. [71] The source may be varied, as these compounds are ubiquitous in foods and drugs. They are typically added to processed foods to prevent microbial spoilage and to keep them from browning or changing color. The earliest known use of sulfites was in the treatment of wines with sulfur dioxide by the Romans. Sulfites are sprayed on fresh foods such as shrimp, fruits, and vegetables. They are also used as antioxidants and preservatives in many pharmaceuticals. Sulfites have caused such a wide range of health problems, such as asthma and urticaria, that their use on fruits and vegetables has been banned in the US. [65] The average person consumes an average of 2–3 mg/ day of sulfites. Wine and beer drinkers typically consume up to 10 mg/day and individuals who rely on restaurants for meals may ingest up to 150 mg/day. [71] Normally, the enzyme sulfite oxidase metabolizes sulfites to safer sulfates which are excreted in the urine. Those with a poorly functioning sulfoxidation system, however, have an increased ratio of sulfite to sulfate in their urine. Sulfite oxidase is dependent on the trace mineral molybdenum. Although most nutrition textbooks list molybdenum as an uncommon deficiency, an Austrian study of 1,750 patients found that 41.5% were molybdenum-deficient. [72] Food emulsifiers and stabilizers A variety of compounds is used to emulsify and stabilize many commercial foods to ensure that the solids, oils, and liquids do not separate out. Most of the foods containing these compounds are heterogeneous, as they usually contain antioxidants, preservatives, and dyes. Polysorbate in ice cream has been reported to induce urticaria, and vegetable gums such as acacia, gum arabic, tragacanth, quince, and carrageenin may also induce urticaria in susceptible individuals. [5] Infections Infections are a major cause of urticaria in children. [1] Apparently in adults immunological tolerance occurs to many microorganisms due to repeated massive antigen exposure. The role of bacteria, viruses, and yeast ( Candida albicans) in urticaria is briefly reviewed below. Chronic Trichomonas infections have also been found to cause urticaria. Bacteria
Bacterial infections contribute to urticaria in two major settings: in acute streptococcal tonsillitis in children, and in chronic dental infections in adults. In the first setting acute urticaria predominates, while in the second, chronic urticaria predominates. [1] Viruses
Hepatitis B is the most frequent cause of viral-induced urticaria. One study found that 15.3% of patients with chronic urticaria had anti-hepatitis B surface antibodies. [73] Urticaria has also been strongly linked to infectious mononucleosis and may develop several weeks before clinical manifestation. The incidence of urticaria during infectious mononucleosis is 5%. [1] Candida albicans
The association between Candida albicans and chronic urticaria has been suggested in several clinical studies. The number of patients with chronic urticaria who react positively to an immediate skin test with Candida antigens is 19–81% compared with 10–15% of normals. [20] [74] [75] [76] [77] [78] [79] [80] It appears that sensitivity to Candida albicans is an important factor in at least 25% of patients with chronic urticaria. [77] Approximately 70% of patients with a positive skin reaction also react to oral provocation tests using foods prepared with yeasts. Treatment with nystatin has proven that elimination of the organism can achieve a cure in a number of individuals with positive skin tests, although a placebo response cannot be ruled out. More patients responded to a “yeast-free” diet than to simple elimination of the organism. The yeast-free diet employed excluded bread,
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buns, sausage, wine, beer, cider, grapes, sultanas, marmite, bovril, vinegar, tomato, ketchup, pickles, and prepared foods containing food yeasts. In a study of 49 patients with positive sensitivity to Candida, nine responded to a 3 week course of nystatin, while 18 became symptom-free only after adopting the yeast-free diet. [75] This would seem to support the importance of diet along with eliminating the yeast. Further support for the importance of diet can be found in a study of 36 patients with a positive skin-prick test to Candida. Only three patients became asymptomatic from nystatin alone, compared with 23 on diet therapy following the nystatin therapy. Desensitizing patients to Candida albicans with the use of a Candida cell wall extract has also demonstrated encouraging results in some patients, although the treatment of these individuals also included increasing gastrointestinal fermentation and acidity, as well as elimination of yeast. [79] [80]
OTHER CONSIDERATIONS
Psychological aspects In one retrospective study involving 236 cases of chronic urticaria, psychological factors, i.e. stress, were reported to be the most frequent primary cause. appears to play an important role by decreasing intestinal secretory IgA levels.
[ 81]
Stress
In one study of 15 patients with chronic urticaria, relaxation therapy and hypnosis was shown to provide significant benefit. [82] Patients were given an audio tape and asked to use the relaxation techniques described on the tape at home. At a follow-up examination 5–14 months after the initial session, six patients were free of hives and an additional seven reported improvement. Ultraviolet light therapy
Ultraviolet light has been shown to be of some benefit to patients with chronic urticaria. [83] [84] Both ultraviolet A (UVA) and ultraviolet B (UVB) have been used. Patients with cold, cholinergic, and dermographic urticaria display the greatest therapeutic response. Thyroid
One study reported that thyroid hormone replacement therapy dramatically improved chronic urticaria in patients who had normal thyroid function but had evidence of thyroid autoimmunity. In seven patients with chronic urticaria, five were begun on thyroid hormone and two had their dosages increased. Their urticaria resolved within 2–4 weeks, at which time the thyroid therapy was discontinued. In five patients, their symptoms returned within 4 weeks, then resolved within 4 weeks of restarting the hormone therapy. Antithyroid antibodies did not correlate with clinical response. [85] Supplements Vitamin B12
Vitamin B12 has been anecdotally reported to be of value in the treatment of acute and chronic urticaria. [86] [87] Although serum B12 levels are normal in most patients, additional B 12 appears to be of value. However, since injectable B 12 was used, the placebo effect (see Ch. 4 ) cannot be ruled out. Quercetin
Considering the importance of mast cell degranulation in the pathogenesis of urticaria, quercetin’s significant in vitro activity as a mast cell stabilizer (and inhibitor of many of the pathways of inflammation; see Ch. 87 ) suggests that it may be very useful in treating urticaria. This possibility is strengthened by the observation that sodium cromoglycate (at 200–400 mg four times/day), a compound similar to quercetin, confers excellent protection against the development of urticaria and angioedema in response to ingested food allergens. [88]
THERAPEUTIC APPROACH The basic therapeutic approach is identification and control of all factors which promote the patient’s urticarial response. Obtaining a careful and thorough history is paramount to this process. Acute urticaria is usually a self-limiting disease, especially once the eliciting agent has been removed or reduced. Chronic urticaria also responds to the removal of the eliciting agent(s). In severe anaphylaxis, appropriate emergency care procedures should be followed. Diet
An elimination or oligoantigenic diet is of utmost importance in the treatment of chronic urticaria (see Chs 15 and 51 ). The diet should not only eliminate suspected allergens, but also all food additives. The strictest elimination diets allow only water, lamb, rice, pears, and vegetables. Those foods most commonly associated with inducing urticaria (i.e. milk, eggs, chicken, fruits, nuts, and additives) should definitely be avoided. [50] Foods containing vasoactive amines should be eliminated even if no direct allergy to them is noted. The primary foods to eliminate are cured meat, alcoholic beverages, cheese, chocolate, citrus fruits, and shellfish. The importance of eliminating food additives cannot be overstated. If food additives do in fact increase the
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number of perivascular mast cells in the skin, they may also do the same in the small intestine, thereby greatly increasing the risk of developing a “leaky” gut. Also of value is control of arachidonic acid-dependent prostaglandins through the use of a low animal fat diet. Supplements
• Vitamin C: 1 g three times/day • Vitamin B12 : 1,000 mcg/i.m. per week • Quercetin: 250 mg 20 minutes before meals. Psychological
Perform relaxation techniques daily. Listening to audio-taped relaxation programs may be an appropriate way to induce the desired state. Physical medicine
Daily sunbathing for 15–20 minutes or the use of a UVA solarium, especially in chronic physical urticaria, is recommended.
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Egyedi K, Torok L. Nachweis einer intoleranz von lebensmittel-additvstoffen durch proben mit salizylaten bei chronischer urticaria. Allergologie 1982; 5: 234–235
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Hannuksela M. Food allergy and skin diseases. Ann Allergy 1983; 51: 269–271
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Ortolani C, Pastorello E, Luraghi MT et al. Diagnosis of intolerance to food additives. Ann Allergy 1984; 53: 587–591
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Simon RA. Adverse reactions to drug additives. J Allergy Clin Immunol 1984; 74: 623–630
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Genton C, Frei PC, Pecoud A. Value of oral provocation tests to aspirin and food additives in the routine investigation of asthma and chronic urticaria. J Allergy Clin Immunol 1985; 76: 40–45
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Pigatto PD, Riva F, Cattaneo A et al. Orticaria cronica. G Ital Derm Venereol 1985; 120: 113–117
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Kemp AS, Schembri G. An elimination diet for chronic urticaria of childhood. Med J Aust 1985; 143: 234–235
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Ziegler B, Haustein UF. Intoleranzreaktionen anf nicht-steroidale antiphogistika und analgetika bei chronisch recidivierendes urtikaria. Derm Mschr 1986; 172: 313–317
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Supramaniam G, Warner JO. Artificial food additive intolerance in patients with angio-oedema and urticaria. Lancet 1986; ii: 907–909
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Bjarnason I, Williams P, Smethurst P et al. Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut 1986; 27: 1292–1297
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Asad SI, Youlten LJF, Lessof MH. Specific desensitization in aspirin sensitive urticaria. Clin Allergy 1983; 13: 459–466
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Kowalski ML, Grzelewski-Ryzmowski I, Roznieki J, Szmidt M. Aspirin-induced tolerance in aspirin sensitive asthmatics. Allergy 1984; 39: 171–178
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Galant SP, Bullock J, Frick OL. An immunological approach to the diagnosis of food sensitivity. Clin Allergy 1973; 3: 363–372
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Pachor ML, Andri L, Nicolis F et al. Elimination diet and challenge test in diagnosis of food intolerance. Italian J Med 1986; 2: 1–6
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Rawls WB, Ancona VC. Chronic urticaria associated with hypochlorhydria or achlorhydria. Rev Gastroenterol 1951; 18: 267–271
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Baird PC. Etiology and treatment of urticaria: diagnosis, prevention and treatment of poison-ivy dermatitis. NEJM 1941; 224: 649–658
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Allison JR. The relation of hydrochloric acid and vitamin B complex deficiency in certain skin diseases. Southern Med J 1945; 38: 235–241
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Gloor M, Henkel K, Schulz U. Zur pathogenetischen bedeutung von magenfunktionsstoringen bie allergish bedingter chronischer urtikaria. Derm Msch 1972; 158: 96–102
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Husz S, Berko G, Szabo R, Simon N. Immunoelectrophoresis in the dermatologic practice. III. Dysproteinemias (chronic urticaria, drug allergy). Derm Msch 1974; 160: 93–100
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Doeglas HMG. Dietary treatment of patients with chronic urticaria and intolerance to aspirin and food additives. Dermatologica 1977; 154: 308–310
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Valverde E, Vich JM, Garcia-Calderon JV et al. In vitro stimulation of lymphocytes in patients with chronic urticaria induced by additives and food. Clin Allergy 1980; 10: 691–698
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Verschave A, Stevens E, Degreef H. Pseudo-allergen free diet in chronic urticaria. Dermatologica 1983; 167: 256–259
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Juhlin L. Additives and chronic urticaria. Ann Allergy 1987; 59: 119–123
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Chapter 192 - Vaginitis and vulvovaginitis Paul Reilly ND
DIAGNOSTIC SUMMARY • Increased volume of vaginal secretions • Abnormal color, consistency, or odor of vaginal secretions • Vulvovaginal itching, burning, or irritation • Introitus may show patchy erythema, and vaginal mucosa may exhibit congestion, or petechiae • Dysuria or dyspareunia may be present.
GENERAL CONSIDERATIONS Vaginitis is one of the most common reasons for women to seek medical attention, accounting for approximately 7% of all visits to gynecologists. [1] A recent study reported that 72% of young sexually active females had one or more forms of vulvovaginitis. [2] Another study of 821 women found vaginal infections to be six times more common than urinary tract infections. [3] In fact, patients with dysuria are more likely to have vaginitis than a rurinary tract infection (rUTI). Furthermore, when questioned carefully, most women can distinguish between “internal” dysuria of a UTI and the “external” dysuria felt when urine passes over inflamed labial tissues. Thus, it seems appropriate to question patients with dysuria more specifically about symptoms of vaginal discharge or irritation.
[ 3]
In addition to causing physical discomfort and embarrassment, vaginitis is medically important for several reasons. It may be a symptom of a more serious underlying problem, such as chronic cervicitis or a sexually transmitted disease. If infectious in nature, the agent may cause an ascending infection of the genital tract, leading to endometritis, salpingitis, and pelvic inflammatory disease. These may in turn lead to tubal scarring, infertility or ectopic pregnancies. Chronic asymptomatic vaginal infections have been implicated in recurrent urinary tract infections by their action as a reservoir of the infectious agent. [4] [5] Some types of vaginal infections during pregnancy increase the risk of miscarriage, and,
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if present at delivery, increase the incidence of neonatal infections, with potentially serious or fatal consequences. Finally, evidence is accumulating which links some forms of vaginitis to cervical cellular abnormalities and increased risk of cervical dysplasia.
TYPES OF VAGINITIS There are three general types of vaginitis: hormonal, irritant, and infectious. Each is further divided into several specific subgroups based on etiology. Hormonal vaginitis Atrophic vaginitis
This is primarily a problem of postmenopausal women and those whose ovaries have been surgically removed. The vaginal epithelium becomes thin and atrophic due to the lack of estrogenic stimulation, which may result in formation of adhesions, dyspareunia, and increased susceptibility to infection. The most commonly reported symptoms are itching or burning and a thin watery discharge that may occasionally be blood-tinged. (Note that any vaginal bleeding in a postmenopausal woman requires a complete work-up to rule out the presence of carcinoma.) For a more extensive discussion, see Chapter 170 . Increased vaginal discharge
When increased quantities of normal secretions exist in the absence of other symptomatology, the diagnosis of “physiological vaginitis” is often applied. This is inappropriate, since no inflammation actually exists. The increased discharge frequently reflects increased hormonal stimulation, such as occurs during pregnancy or at some stages of the menstrual cycle. It is primarily a diagnosis of exclusion after ruling out other causes. In most cases, no further treatment is required other than reassurance that the discharge is normal. Overly zealous douching or washing will briefly alleviate symptoms, but may ultimately aggravate the situation by causing an irritant vaginitis. Irritant vaginitis Irritant vaginitis is caused by physical or chemical agents which damage the delicate membranes of the vagina. In most cases, the cause is easily identified by careful history and examination. Chemical vaginitis
This type is due to the use of medications or hygiene products which directly irritate the vaginal mucosa. A variant of this subgroup is allergic vaginitis where the damage is elicited by an immunologic reaction to a product rather than direct toxic reaction. Traumatic vaginitis
Injury caused by physical agents or sexual activity can cause vaginitis. Foreign body vaginitis
A foul-smelling discharge may signal the presence of a foreign body in the vagina – the most common being a forgotten tampon. Contraceptive devices, pessaries, and a wide variety of other items may also be found upon examination. Infectious vaginitis Infectious vaginitis may be sexually transmitted or may arise from a disturbance to the delicate ecology of the healthy vagina. Vaginal “infections” frequently involve common organisms found in the cervix and vagina of many healthy, asymptomatic women.[6]
The unifying factor in the pathogenesis of pelvic infections is not so much which organisms are present in the patient’s genital tract but rather what happens to the patient to make her susceptible to infection. Factors influencing the vaginal environment include the pH, glycogen content, glucose level, the presence of other organisms (particularly lactobacilli), the natural flushing action of vaginal secretions, the presence of blood, and the presence of antibodies and other compounds in the vaginal secretions. Many of these factors are, in turn, affected by the woman’s internal milieu and general health. Immune dysfunction will predispose a woman to increased infections, including vaginal infections. Depressed immunity may occur as a result of nutritional deficiencies, medications (e.g. steroids), pregnancy, or serious illness. Other factors may predispose to infectious agents: diabetes mellitus, the wearing of synthetic pantihose (which tend to retain moisture), and a suspected but still unproven link between birth control pills and Candida infections. [7] Risk factors for sexually transmitted infections include increased numbers of sexual partners, unusual sexual practices, and the type of birth control (barrier methods reduce risk of infection). Approximately 90% of vulvovaginitis will be associated with one of three organisms, Trichomonas vaginalis, Gardnerella vaginalis, or Candida albicans.[8] The relative frequency of each form varies with the population studied, as well as with sexual activity levels. Less frequent causes of vaginitis include Neisseria gonorrhea, herpes simplex,
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Candida Keynote symptoms
TABLE 192-1 -- Diagnostic differentiation of common causes of infectious vaginitis NSV Trichomonas Gonorrhea Herpes
Chlamydia
Itching
Odor
Odor and itching
Asymptomatic or cervicitis
Vesicles or ulcers
Asymptomatic
pH
4.5
>5.0
