NALTREXONE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Naltrexone: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00748-7 1. Naltrexone-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on naltrexone. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON NALTREXONE............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Naltrexone..................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 64 The National Library of Medicine: PubMed ................................................................................ 65 CHAPTER 2. NUTRITION AND NALTREXONE ................................................................................ 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Naltrexone ................................................................................. 109 Federal Resources on Nutrition ................................................................................................. 110 Additional Web Resources ......................................................................................................... 111 CHAPTER 3. ALTERNATIVE MEDICINE AND NALTREXONE.......................................................... 113 Overview.................................................................................................................................... 113 National Center for Complementary and Alternative Medicine................................................ 113 Additional Web Resources ......................................................................................................... 120 General References ..................................................................................................................... 121 CHAPTER 4. DISSERTATIONS ON NALTREXONE ........................................................................... 123 Overview.................................................................................................................................... 123 Dissertations on Naltrexone ...................................................................................................... 123 Keeping Current ........................................................................................................................ 123 CHAPTER 5. PATENTS ON NALTREXONE ...................................................................................... 125 Overview.................................................................................................................................... 125 Patents on Naltrexone................................................................................................................ 125 Patent Applications on Naltrexone............................................................................................ 141 Keeping Current ........................................................................................................................ 148 CHAPTER 6. BOOKS ON NALTREXONE .......................................................................................... 149 Overview.................................................................................................................................... 149 Book Summaries: Online Booksellers......................................................................................... 149 CHAPTER 7. PERIODICALS AND NEWS ON NALTREXONE ............................................................ 151 Overview.................................................................................................................................... 151 News Services and Press Releases.............................................................................................. 151 Academic Periodicals covering Naltrexone................................................................................ 153 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 155 Overview.................................................................................................................................... 155 U.S. Pharmacopeia..................................................................................................................... 155 Commercial Databases ............................................................................................................... 156 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 159 Overview.................................................................................................................................... 159 NIH Guidelines.......................................................................................................................... 159 NIH Databases........................................................................................................................... 161 Other Commercial Databases..................................................................................................... 163 APPENDIX B. PATIENT RESOURCES ............................................................................................... 165 Overview.................................................................................................................................... 165 Patient Guideline Sources.......................................................................................................... 165 Finding Associations.................................................................................................................. 167 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 169 Overview.................................................................................................................................... 169 Preparation................................................................................................................................. 169 Finding a Local Medical Library................................................................................................ 169 Medical Libraries in the U.S. and Canada ................................................................................. 169
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ONLINE GLOSSARIES................................................................................................................ 175 Online Dictionary Directories ................................................................................................... 175 NALTREXONE DICTIONARY................................................................................................... 177 INDEX .............................................................................................................................................. 239
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with naltrexone is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about naltrexone, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to naltrexone, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on naltrexone. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to naltrexone, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on naltrexone. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON NALTREXONE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on naltrexone.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and naltrexone, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “naltrexone” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Naltrexone and Communication Skills in Young Children with Autism Source: Journal of the American Academy of Child and Adolescent Psychiatry. 38(5): 587-593. May 1999. Contact: Available from Lippincott Williams and Wilkins. Subscription Department, P.O. Box 350, Hagerstown, MD 21740-0350. (800) 638-3030. Website: www.aacap.org/journal/journal.htm. Summary: This article reports on a study that examined the impact of naltrexone, a potent oral opiate antagonist, on the communication skills of young children with autism. Autism is characterized by 3 core deficits: qualitative impairments in reciprocal social interactions; qualitative and quantitative impairments in communication; and restricted, repetitive, or stereotyped behaviors, interests, and activities. In the study, 24
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Naltrexone
children with autism (3.0 to 8.3 years old) who were living at home and attending appropriate school programs, participated in a randomized, double blind, placebo controlled, crossover trial. Naltrexone, 1.0 mg per kg, or placebo was administered daily for 2 weeks. Communication was evaluated from videotaped samples of seminaturalistic parent child interaction. Child and parent language were assessed using similar measures. In this heterogeneous sample, the median number of words the child produced on placebo was 9.5 (range 0 to 124). The median proportion of utterances with echolalia was 0.16. No differences were found between the naltrexone and placebo conditions in any of the measures of children or parents' communication. Significant correlations were found between the child's number of words and developmental quotient and between the child's and parent's number of words. Previous studies showed that naltrexone was associated with modest reductions in hyperactivity and restlessness in this group of children with autism. In this short term study, the medication did not lead to improvement in communication, a core deficit of autism. 2 tables. 46 references.
Federally Funded Research on Naltrexone The U.S. Government supports a variety of research studies relating to naltrexone. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to naltrexone. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore naltrexone. The following is typical of the type of information found when searching the CRISP database for naltrexone: •
Project Title: ADDICTION TREATMENT IN RUSSIA:ORAL AND DEPOT NALTREXONE Principal Investigator & Institution: Woody, George E.; Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant): The usual treatment of heroin addiction in Russia involves detoxification and 2-4 weeks of rehabilitation with referral to outpatient followup. Though most patients complete inpatient treatment, few keep follow-up appointments and relapse rates are high. More effective therapies are needed, especially in view of the epidemic of heroin addiction that has resulted in the spread of HIV and other infectious diseases. A recently completed study of 52 patients randomized to oral naltrexone (ON) or oral naltrexone placebo (ONP) has shown efficacy in preventing
2
Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
Studies
5
relapse and reducing HIV risk but dropout was a problem with only 44% of ON patients proven to have not relapsed by 6 months as compared to 16% of ONP patients. A larger study of 280 patients randomized to ON or ONP with or without fluoxetine will further evaluate these early results and determine if adding a SSRI improves outcome. Recruitment into this study is almost completed but is not finished and outcome data are not yet available. We think that retention and outcome can be also improved by depot injectable naltrexone (DIN), and in this study we propose to compare ON with DIN. DIN is not approved for use in Russia and we would like the results of this study to be acceptable to Russian authorities that might approve it for general use. Thus we propose a placebo-controlled, double-blind/double-dummy design since a placebocontrolled trial is required by the Russian equivalent of our FDA as a condition for approval of a pharmacotherapy. Participants will be male and female heroin addicts who have been detoxified in addiction treatment hospitals in St. Petersburg and have a family member willing and able to supervise medication compliance and facilitate follow-up. After giving informed consent and confirming the absence of physiologic dependence, 300 patients will be randomly assigned to a 6-month treatment in one of three groups of 100 each: oral naltrexone (ON) + depot injectable naltrexone placebo (DINP); oral naltrexone placebo (ONP) + depot injectable naltrexone (DIN); or ONP + DINP. All patients will receive biweekly clinical management/compliance enhancement counseling. Assessments will be done at baseline, at each biweekly appointment during the 6-month of medication treatment, and at 3 and 6 months following the end of the medication. Primary outcome will be the relapse free proportion at months 1-6; secondary outcomes will be time to dropout, opioid positive urines, HIV risk, use of alcohol and other drugs, psychiatric symptoms, and other measures of overall adjustment. We hypothesize that outcomes will be better with DIN than ON, and that each will be more effective than placebo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADOPTION & IMPLEMENTATION OF NALTREXONE IN PRIV TX CTRS Principal Investigator & Institution: Oser, Carrie B.; Inst for Behavioral Research; University of Georgia 617 Boyd, Gsrc Athens, Ga 306027411 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-AUG-2004 Summary: (provided by applicant): Prominent on the nation's research agenda on drug abuse treatment is the development of effective behavioral and pharmacological treatment approaches. Likewise, there is concern about transferring this knowledge to practitioners to foster adoption within the service delivery system. The proposed dissertation addresses a facet of this mission using a theoretical framework outlined by Rogers (1995), to examine the impact of managerial characteristics, internal structural characteristics, and external characteristics on the adoption of naltrexone. Data for these analyses will be derived from the National Treatment Center Study (NTSC), a longitudinal national sample of 450 private treatment facilities spanning from 1994 to 2003. The NTCS focuses exclusively on the organization as the unit of analysis, with the administrators and/or clinical directors providing the organizational-level data during on-site interviews. The objectives of the proposed dissertation are two-fold. First, in order to address the adoption of this innovative treatment approach longitudinally, a discrete-time event history analysis will be performed. This approach will allow for the study of the occurrence and timing of events surrounding naltrexone adoption. Second, the focus will turn to treatment centers that have adopted naltrexone and, using Rogers' (1995) theoretical propositions on the diffusion of innovations, create a categorical
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Naltrexone
typology of adopters based on innovativeness. This adopter continuum includes five adopter categories: innovators, early adopters, early majority, late majority, and laggards. After plotting those centers adopting naltrexone by the year of adoption and identifying into which category they should be placed, a multinomial logistic regression will be performed using the five adopter categories as the dependent variable. Organizational-level factors, internal organizational structure, externalities, and stated reasons for adoption, will be the major concepts included in predicting adopter categorization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADOPTION OF BUPHENORPHINE IN OFFICE PRACTICE Principal Investigator & Institution: Wallack, Stanley S.; None; Brandeis University 415 South Street Waltham, Ma 024549110 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-MAY-2005 Summary: (provided by applicant): In October, 2000 the Drug Addiction Treatment Act of 2000 was passed and signed into law, allowing qualified physicians to dispense or prescribe certain narcotic drugs for maintenance or detoxification treatment. According to this legislation, once buprenorphine, a maintenance medication for treatment of opiate addiction, receives FDA approval, physicians may be certified to prescribe it in office practice. Until now physicians have been prohibited from dispensing buprenorphine for opiate addiction, despite evidence of its effectiveness. This legislation is expected to improve access to treatment for thousands who are addicted to opiates by bringing into treatment both people who have rejected use of methadone and for whom methadone has failed, and physicians who wish to treat opiate dependent individuals who are appropriate for office-based treatment. Despite evidence that buprenorphine offers a needed treatment alternative, recent legislative changes and FDA approval alone may not lead to improved access for addicts. For instance, naltrexone, a pharmacological approach to alcoholism treatment, has seen limited acceptance in practice, in spite of clinical evidence of effectiveness and support of policy makers and experts. The factors contributing to the low rates of acceptance are not fully understood, but there is strong evidence that lack of financing and provider knowledge were two main barriers to naltrexone diffusion. These same factors could undermine buprenorphine diffusion into clinical practice. The proposed study seeks to understand factors related to adoption of buprenorphine in office-based practice by surveying a national sample of addiction specialists and general psychiatrists regarding their decision to prescribe buprenorphine or not, and surveying treatment settings regarding adoption and use of buprenorphine. We will examine characteristics of the clinicians, the treatment settings, and financing programs with which they are associated, in order to understand factors associated with moving research to practice, and the links between physicians and their treatment settings in deciding to adopt new treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ALCOHOL DEPENDENCE IN GENERAL MEDICAL SETTINGS Principal Investigator & Institution: Stewart, Scott H.; Medicine; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2004; Project Start 15-MAY-2004; Project End 30-APR-2009 Summary: (provided by applicant): Alcohol dependence is common in general medical settings. While controlled clinical trials have demonstrated the effectiveness of brief advice from medical providers in decreasing consumption for non-dependent heavy
Studies
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drinkers, there is no evidence for effective treatments for alcohol dependence in this setting. This application proposes a five-year period of support for the candidate, providing him with sufficient time and resources to develop as an independent researcher conducting trials of treatments for alcohol dependence in general medical settings. The candidate is currently an Assistant Professor of Medicine at the University at Buffalo, State University of New York. His research background has focused on alcohol-related medical issues, and he has performed several epidemiologic analyses in this area. The career award will allow him to develop additional skills in health-related behavior modification, the use of diagnostic and measurement instruments commonly used in studies evaluating alcohol use and alcoholism, and in conducting trials of treatments for alcohol dependence within a general medical model. Such treatments will be aimed at complementing or providing alternative treatment options to more established standards of care such as referral to self-help groups or addiction specialists. A variety of formal and informal didactics during the early portion of the career development period are planned to facilitate completion of the research objectives. However the majority of the award period will be devoted to the supervised completion of a pilot trial. This trial will evaluate a primary care treatment model for alcohol dependence that includes brief, patient-centered, motivational counseling with optional naltrexone. This will be compared with a traditional medical model based on assessment and expert advice, and also including optional naltrexone. Outcomes will include various measures of medication use, alcohol consumption, and drinking-related adverse consequences. Activities during the award period will be supervised by senior research scientists from the Research Institute on Addictions and and the Department of Social and Preventive Medicine at the University at Buffalo, who have agreed to mentor the candidate over the five-year period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALCOHOL TREATMENT UNDER MANAGED CARE PLANS: ROLE OF HMOS Principal Investigator & Institution: Horgan, Constance M.; Director of Research; None; Brandeis University 415 South Street Waltham, Ma 024549110 Timing: Fiscal Year 2002; Project Start 29-SEP-1996; Project End 31-JUL-2005 Summary: (provided by applicant): Managed care, ranging from health maintenance organizations (HMOs) to preferred provider organizations (PPOs), has become the predominant form of private health insurance in the U.S. The main objective of this study is to further understand how alcohol services are provided in HMOs, one of the earliest and most common forms of managed care. We build on round 1 of our national survey of managed care organizations (MCOs) regarding alcohol service provision in the 1999 benefit year. The specific aims are to: 1. Describe the provision of alcohol services in HMOs for the 2003 benefit year in terms of both administrative factors (including overall plan characteristics, contracting arrangements, payment methods and risk sharing, and benefit design) and clinical factors (including treatment approaches, utilization management, provider selection, entry into treatment, and quality assurance). 2. Document how the provision of alcohol services in HMOs has changed over a fouryear time period, and explore what factors influence these changes. 3. Model why some HMOs provide alcohol services internally within the plan and other HMOs choose to carve out alcohol services to specialty managed care vendors. In round 1, we surveyed a sample of MCOs stratified by type of product offerings (HMO vs. PPO) in 60 market areas with NIAAA funding the HMO and NIDA funding the PPO portions of the study. We surveyed 434 MCOs in round 1, including the 283 MCOs that reported HMO
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Naltrexone
products, and achieved a 92 percent response rate. We will conduct round 2 of a telephone survey of these 434 MCOs, as well as a refresher sample in theses 60 market areas regarding their HMO products. Companion funding has already been obtained from NIDA to conduct round 2 surveys of these same MCOs regarding their PPO products. We will continue to collaborate with longitudinal, nationally representative Community Tracking Study (CTS) conducted by the Center for Studying Health Systems Change which provides the sample frame of health plans in the 60 market areas. The proposed study of alcohol treatment services is the first to combine two rounds of a national survey of MCOs within market areas in a prospective design that will allow us to track how the delivery of alcohol services in HMOs evolves within the changing health care market. These changes include: expansion of federal and state substance abuse parity legislation; increased enrollment in behavioral health specialty vendors; increased managed care regulation, particularly state consumer protection laws regarding managed care; and treatment innovations including the approval of naltrexone. This study will provide systematic information on the nature and extent of HMO changes, and their impact on alcohol service delivery, during this time period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AMINOBENZOMORPHAN: MEDICATIONS
POTENTIAL
COCAINE
ABUSE
Principal Investigator & Institution: Wentland, Mark P.; Professor; Chemistry; Rensselaer Polytechnic Institute 110 Eighth Street Troy, Ny 12180 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 30-JUN-2007 Summary: (provided by applicant): This application is focused on capitalizing on our recent discovery that a carboxamido group (CONH2) can replace the phenolic OH of opioids and ameliorate the rapid clearance of opioids (e.g., duration of action increased from 2 to 15 hours) without compromising intrinsic affinity for opioid receptors or antinociception efficacy. Specifically, we will design, synthesize and characterize novel 8-carboxamido analogues of cyclazocine and ethylketocyclazocine (EKC) as potential anti-cocaine and anti- heroin medications. Cyclazocine is a k opioid agonist and a mu opioid antagonist and is currently in a clinical trial as a possible medication for cocaine abuse. Kappa agonists and mu antagonists decrease dopamine release in the nucleus acumens, a primary pathway involved in the reinforcing effects of drugs of abuse, and thus have the potential to treat drug abuse. EKC was shown to block cocaine selfadministration in non-human primates. Therefore, derivatives of cyclazocine and EKC that do not have major side effects are potential medications for treating cocaine and heroin abuse in humans. We will also characterize novel carboxamido derivatives of other opioids (e.g., naltrindole, naltrexone) used as biochemical tools or for heroin abuse. Due to the uniqueness of this discovery, there is enormous potential to define a new SAR for opioids and we expect to identify new compounds having high affinity for opioid receptors. Taking advantage of computational techniques and our results with 8aminocyclazocine analogues, we will probe an unexplored region of receptor space where an H-bond donor and hydrophobic group in the proper conformation are important for recognition. Based on the excellent preliminary pharmacokinetic and efficacy profile exhibited by these new carboxamides, we expect that the desired pharmacological profile will be attained by rational medicinal chemistry design and synthesis; an extensive pre-clinical work plan has been put in place. Radioligand binding, [35 S]GTP-gamma-S, and mouse antinociceptive assays will be used to characterize new targets pharmacologically. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BEHAVIORAL ALCOHOLISM
AND
PHARMACOLOGIC
Studies
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TREATMENT
OF
Principal Investigator & Institution: Weiss, Roger D.; Professor of Psychiatry and Clinical Dir; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: The primary aim of this proposal is to participate in a multi-site cooperative study to assess the efficacy of combined behavioral and pharmacologic interventions in the treatment of alcohol dependence. As stated in RFA AA-97-004, the goal of the research is to determine if improvement in treatment outcomes can be achieved by implementing therapeutic strategies that integrate various combinations of pharmacotherapy and behavioral interventions. We specifically propose a 2x2x2 factorial design study testing the combination of two pharmacotherapies, their associated placebos, and two behavioral therapies in a sample of 720 subjects (90 subjects per site at each of 8 sites). The pharmacotherapy conditions are (1) naltrexone plus placebo; (2) acamprosate plus placebo; (3) naltrexone plus acamprosate; and (4) placebo plus placebo. The behavioral therapy conditions are (1) brief alcohol counseling (BAC) and (2) motivational enhancement therapy plus cognitive-behavioral coping skills therapy (MET/CBT). Subjects will be randomized with equal probability to one of the following eight treatment cells: 1) naltrexone + acamprosate + BAC; 2) naltrexone + BAC; 3) acamprosate + BAC; 4) placebo + BAC; 5) naltrexone + acamprosate + MET/CBT; 6) naltrexone + MET/CBT; 7) acamprosate + MET/CBT; and 8) placebo + MET/CBT. The study will be conducted in two phases: a six-month active treatment phase and a 12-month posttreatment follow-up phase. The primary measure of drinking outcome throughout the study will be the percentage of days that subjects are abstinent (P.A.). In addition to the main study, we will perform a preliminary study to evaluate whether or not the toxic effects of alcohol are exacerbated by taking a naltrexone/acamprosate combination. We will study this by assessing psychomotor performance and physiological activity after a controlled alcohol challenge in 20 subjects before and after they have taken this medication combination for one week. Subjects in the preliminary study will be occasional drinkers who do not meet criteria for alcohol abuse or dependence. The preliminary study will inform the main trial by enabling the study investigators to learn about the potential effects of combining these two medications with alcohol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BEHAVIORAL ASSAYS IN MONKEYS Principal Investigator & Institution: Ko, Mei-Chuan Holden.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: Pain is a symptom of many clinical disorders, which afflict a large population of humans, and is treated largely by a variety of pharmacological agents. Although most rapid changes and interesting findings in pain research are obtained in rodent species, it is not clear to what extent they can be replicated and applied to primate species. Humans and monkeys have similar thresholds for detecting noxious stimuli and the neural systems responsible for these sensations in the two species are fundamentally similar. Therefore, it is important to conduct monkey studies for characterizing novel experimental compounds, which have been proposed as better analgesics with less side effects in rodents. Both the warm water tail-withdrawal assay and respiration assay have been used to characterize the behavioral effects of various opioid compounds in
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Naltrexone
monkeys. Both assays serve as valid in vivo endpoints for studying the efficacy and selectivity of opioid agonists and the characteristics of opioid antagonists. These assays will be employed during this grant period. In addition, we have established a new experimental pain model (i.e, capsaicin-induced thermal nociception) and an experimental itch model (i.e., central mu opioid receptor-mediated pruritus). These assays facilitate investigating the selective function of opioid receptor types and the sites of action of various opioids in primates. In addition, we have established intrathecal and Intracisternal injection techniques in monkeys, which have provided a valuable opportunity to enhance the pharmacological evaluation of opioids and pain in primates. This series of proposed studies has several aims including developing inflammatory pain models, studying the receptor systems involved in the pain processing, and evaluating distinct opioid agonists and antagonists. These studies will clarify the sites of action and effectiveness of novel analgesics and elucidate the therapeutic potential of experimental agents. The studies, taken together, will make a notable advance in our understanding of pain and analgesia and make a substantial contribution to pain research in primates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BEHAVIORAL FACTORS IN HEROIN'S EFFECT ON NITRIC OXIDE Principal Investigator & Institution: Lysle, Donald T.; Professor; Psychology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: There is a high incidence of infectious disease in heroin-dependent individuals. In spite of the major health issues surrounding heroin use, few studies have examined the impact of heroin on immune status. A wealth of recent data has revealed that the induction of nitric oxide plays a critical role in the immune response to infectious diseases. New data from our laboratory has provided the first evidence that heroin administration produces alterations of inducible nitric oxide synthase (iNOS), the enzyme responsible for the production of nitric oxide. Specific Aim I extensively tests the hypothesis that heroin induces widespread alterations in the in vivo expression of NOS. This specific aim fully evaluates the effect of heroin on lipopolysaccaride (LPS)induced iNOS expression. The experiments establish dose-effect relationships for heroin, as well as the antagonism of those effects with naltrexone. To measure NOS production in vivo, we employ both RT-PCR and western blotting to measure alterations of iNOS mRNA expression and protein in spleen, lung, and liver tissue. We also measure nitrite/nitrate in plasma. Specific Aim II tests the hypothesis that heroininduced alteration of NOS production is conditioned to environmental stimuli paired with drug administration. The demonstration that immune alterations can be induced by the stimuli associated with heroin administration is important for it indicates that the detrimental health consequences of heroin use are conditioned to environmental stimuli and not solely the pharmacological property of the drug. The proposed studies determine whether heroin's effect on nitric oxide production can be elicited by environmental stimuli paired with heroin administration. Control procedures are used to assure that these conditioned alterations are due to conditioning processes per se, and not the result of ancillary factors involved in the conditioning procedure. Tests of extinction and latent inhibition will establish that the effects follow the principles of Pavlovian conditioning. Specific AimIII tests the hypothesis that drug selfadministration is an important behavioral variable controlling heroin's effect on the production of nitric oxide. The self-administration paradigm provides a clinically relevant methodology for the assessment of heroin's effects on nitric oxide production.
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The study compares the effects of heroin self-administration to those of passive drug administration. Investigation of the effects of self-administered heroin on nitric oxide production is driven by evidence showing that control over drug administration greatly influence it's physiological effects. The demonstration that heroin is differentially efficacious in altering nitric oxide production depending upon whether the drug is selfadministered or passively infused has important implications for the health consequences of heroin use. Collectively, the characterization of heroin-induced modulation of inducible nitric oxide synthase production provides a greater understanding of how opioids impact the immune system and health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BEHAVIORAL PHARMACOLOGY OF NARCOTIC ANTAGONISTS Principal Investigator & Institution: Holtzman, Stephen G.; Professor; Pharmacology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JUN-1975; Project End 31-AUG-2005 Summary: (Applicant's Abstract) Chronic exposure to morphine-like drugs results in physical dependence and marked sensitivity to effects of opioid antagonists. Recent data indicate that pretreatment of rats with a single dose of morphine also increases dramatically sensitivity to opioid antagonists, as measured behaviorally. The proposed research will test the hypothesis that this phenomenon reflects acute physical dependence mediated primarily by the mu-opioid receptor, as well as derivative hypotheses and theoretical models. The pharmacological, neurochemical, and neuroanatomical bases of the phenomenon and its generality across species and drug class will be examined systematically. Several well-validated methodologies will be used in order to obtain converging evidence, for example, a) Drug discrimination: an animal model of subjective drug effects, with resolution to distinguish among effects mediated by different opioid receptors and to detect interoceptive stimuli associated with antagonist-precipitated opioid withdrawal. b) Autotitration intracranial selfstimulation: enables concurrent quantitation of effects of opioid drugs and drug withdrawal on operant responding and threshold for rewarding brain stimulation. c) In vivo microdialysis: a means of correlating behavioral measures with changes in extracellular levels of catecholamines in specific brain regions. d) Tail-flick test: a measure of pain threshold. Compared to chronic opioid dependence, acute dependence has received little research attention despite the fact that it is a robust phenomenon that occurs in humans as well as in laboratory animals. Acute agonist-induced sensitization to opioid antagonists appears to be an exquisite example of neuronal plasticity, reflecting the first hours of the drug-receptor interactions that lead to chronic physical dependence upon opioids. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BEHAVIORAL DEPENDENCE
STUDIES
OF
OPIATE
TOLERANCE
AND
Principal Investigator & Institution: Young, Alice M.; Professor; Psychology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 30-JUN-2007 Summary: (provided by applicant): Current treatments for human opioid abuse incorporate a variety of chronic pharmacotherapies, including methadone maintenance and newer therapies incorporating low efficacy opioid agonists (e.g., buprenorphine) or opioid antagonists (e.g., naltrexone). Preclinical studies of behavioral sequelae of such
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maintenance therapies may be useful in predicting behavioral and subjective effects of repeated opioid use in humans. The proposed projects will use drug discrimination assays and other behavioral assays as model systems to assess how pharmacological and behavioral factors modulate the development and expression of opioid tolerance and dependence during repeated treatment with clinically important opioid agonists. A primary goal during the upcoming period is to evaluate the hypothesis that abstinence precipitated by classical opioid antagonists in dependent organisms arises from inverse agonist actions, rather than from competitive antagonism, per se We will pay particular attention to the possibility that behavioral abstinence responses, as measured in freeoperant, drug discrimination, and place conditioning assays, may represent uniquely sensitive indices of inverse agonist effects. Building on studies conducted during the previous award period, other experiments will evaluate whether the magnitude of dependence varies with the intrinsic efficacy of the agonist used to establish physical dependence Project 1 will define the doses, routes of administration, and pretreatment times over which compounds will function as antagonists of acute agonist actions of the classic f agonists morphine and DAMGO. As controls for potential non-f, or non-opioid, mechanisms in morphine dependence, key antagonists will be compared for their ability to alter effects of ? and k opioid agonists and selected non-opioids. Project 2 will assess the ability of classical and putative neutral opioid antagonists to provoke abstinence in acutely and chronically dependent organisms, focusing on performance altering and discriminative stimulus effects. Project 3 will assess the ability of compounds to produce a functional up regulation of opioid receptors. In order to begin an initial characterization of the potential aversive actions of classical and putative neutral opioid antagonists, Project 4 will assess the ability of promising compounds to establish place aversions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BEHAVIORAL/PHARMACOLOGIC TREATMENT OF ALCOHOLISM Principal Investigator & Institution: Williams, Lauren D.; Assistant Professor; Psychiatry and Behavioral Scis; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: PRELIMINARY STUDY: Noncompliance is the leading cause of nonresponse to drug. This 1-year preliminary study randomly assigns 80 outpatients with alcohol dependence to 2 strategies for monitoring compliance (Medication Event Monitoring System [MEMS] vs. blister pack) in relation to plasma levels of naltrexone and 6-betanaltrexol, and to 2 strategies for enhancing compliance (compliance counseling vs. usual care) in a 2X2 design. All subjects receive 8 weeks of Medication Management Therapy (MMT) and naltrexone to assess acceptability and rate of compliance with the dosing regimen and minimally intensive therapy condition proposed for the main study. MAIN STUDY: New advances in outpatient pharmacologic and behavioral treatments of alcohol dependence have generally occurred independently of each other. The objective of the main study is to evaluate the relative efficacy of combined treatments in a 2X4 multicenter, double-blind, randomized, placebo-controlled comparison of 4 pharmacotherapy conditions (acamprosate, naltrexone, placebo, and acamprosate/naltrexone in combination) administered in conjunction with either the cognitive behavioral therapy typically administered by an alcoholism treatment specialist, or a manualized MMT that may be suitable for managed care settings. Primary outcome measures are time to first drink, time to first heavy drinking day, and cumulative abstinence duration. Treatment duration is 6 months with 1 year of posttreatment follow-up. Subjects for the multicenter study are 1200 outpatients meeting
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DSM IV criteria for alcohol dependence, recruited across 6-8 centers. NONRESPONDER STUDY: A response evaluation will be made at 3 months post-randomization in the main study. Approximately 400 nonresponders to active medication will be available for a 12-week comparison of alternative pharmacotherapy strategies commonly used in general clinical practice. All other subjects will remain in the originally assigned treatment condition in the main study. Nonresponders to monotherapy will be randomized to the alternative monotherapy or combination treatment, nonresponders to combination treatment will be randomized to increased doses of acamprosate or naltrexone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BEHAVIORAL/PHARMACOLOGIC TREATMENT OF ALCOHOLISM Principal Investigator & Institution: Miller, William R.; Distinguished Professor; Psychology; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2003; Project Start 30-SEP-1997; Project End 31-AUG-2005 Summary: (provided by applicant): The present application seeks two years of funding to complete the COMBINE study and its ancillary cost-effectiveness and genetic predictors of treatment response studies. The COMBINE study was initiated in 1997 to answer questions about the benefits of combining behavioral and pharmacological interventions. Two medications, naltrexone and acamprosate, have shown promise in reducing relapse to heavy drinking and improving abstinence in a number of U.S. and European clinical trials. The two behavioral treatments, Medical Management (MM) and Combined Behavioral Intervention (CBI), have potential to be valuable adjuncts to pharmacotherapy. MM appears to be cost-effective and suitable for delivery in primary care or managed care settings by non-specialists. The primary hypothesis is that combining the two medications (naltrexone and acamprosate) with a moderate intensity behavioral treatment (CBI) will yield better outcomes than less intensive approaches (e.g., placebo and MM; acamprosate or naltrexone and MM) for alcohol dependent patients. A total of 1375 subjects from 11 clinical sites comprise the targeted sample. Individuals meeting study criteria have been randomly assigned to one of nine pharmacological (naltrexone and acarnprosate) and behavioral treatment (MM and CBI) combinations to form a complete 2X2X2 factorial design. A ninth cell was later included to test the efficacy of CBI without "pills". Much has been accomplished since COMBINE's initiation. Over 70% of the intended sample has been randomized to the study treatments reflecting gender, ethnic, geographic, and clinical diversity. Drinking assessment interviews have been completed for 84% clients at the 16-week follow-up. Two major pilot studies were successfully completed and the fmdings have been disseminated at conferences and in publications. The requested two-year extension will allow for the recruitment, treatment, and follow-up of the remaining participants, and allow sufficient time for data analysis and manuscript preparation. Results from the COMBINE study are expected to have a major impact on the alcohol treatment delivery system. A common protocol across each of the study sites is submitted. This reflects the cooperative process that has guided the study's efforts across the first five years of operation. However, each study site has provided site-specific information on the budget, budget justifications, listing of key personnel, consultant/consortium agreements, and human subjects sections of their respective proposals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOBEHAVIORAL TRAJECTORIES TO ALCOHOL ABUSE Principal Investigator & Institution: Palmour, Roberta M.; Professor; Mc Gill University James Admin. Bldg., Room 429 Montreal, Pq H3a 2T5 Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): Adolescent alcohol abuse has now reached epidemic proportions, carrying with it a toll of lost opportunity, suffering and death. Many studies document the correlation between early alcohol use and later alcohol dependence, and a widespread belief that delaying the onset of alcohol consumption until the end of adolescence will reduce the risk of pathological drinking. An alternate interpretation is that those who drink early are those who are especially vulnerable, either through biology or circumstance. There are major implications of these conflicting explanations for treatment, for research and for public policy. Yet, to disaggregate the influence of specific biobehavioral and sociocultural variables in any appropriate cross section of the human population is exceedingly difficult. We propose here a pilot study of the feasibility of addressing this question experimentally, capitalizing upon an animal model of spontaneous alcohol abuse. C. aethiops, a non-endangered African primate, is highly homologous with man, lives in social groups, has a distinct adolescent period in its ontogeny, and contains individuals who differ from one another with respect to alcohol consumption and to behavioral traits (sociability, excitability, etc.) In an 18 month cross-sectional study, 96 male and female vervet monkeys will be housed in groups balanced by sex, level of baseline alcohol consumption and temperamental behavioral profile. The manipulated factor will be exposure to ethanol and to drinking or non-drinking role models. The principal outcome measure (9 and 18 months later) will be quantity and pattern of ethanol consumption; weekly social behavioral measures will also be collected in standard primatological fashion. Evaluation of the independent or joint effects of gender, behavioral trait status, and initial propensity to drink and of exposure to ethanol or drinking role models will utilize multivariate regression methods. In a second phase, we will evaluate the utility of specific pharmacological interventions in modifying outcome. The exploratory aspect of this approach is the extent to which it might suggest methods to improve decomposition of the relevant factors in human samples. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BOSTON UNIVERSITY CRU FOR ALCOHOLISM TREATMENT Principal Investigator & Institution: Ciraulo, Domenic A.; Professor and Chairman; Psychiatry; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: This proposal incorporates two studies to assess combined behavioral and pharmacological treatments of alcohol dependence. The preliminary study is designed to examine the effect of acamprosate in combination with a brief intervention (motivational enhancement therapy [MET]) on craving, cue-induced reactivity, and the subjective effects of alcohol following the initiation of drinking behavior compared to placebo-controls receiving only MET. Laboratory-based studies in the US have provided us with evidence that naltrexone decreases cue-induced reactivity and craving, and possibly the rewarding value of alcohol, but similar mechanisms of action for acamprosate have not been explored. The purpose of the preliminary study is to determine whether changes in craving and psychophysiological reactivity mediate the effects of acamprosate on drinking. To this end, subjects will be assigned to the acamprosate or placebo group for 12 weeks. Measures from a laboratory based cue
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reactivity protocol will be evaluated before and after the medication trial. The second phase of the preliminary study will provide all nonresponders with alternative medications to determine the effects of sequencing interventions. After 12 weeks of treatment, nonresponders to acamprosate or placebo will receive either acamprosate plus placebo, acamprosate plus naltrexone, naltrexone plus placebo, or placebo. This phase will allow us to assess whether a combination of medications offers more benefits than either medication alone in sustaining abstinence and whether sequential treatment for nonresponders is helpful in reducing relapse rates. The primary study (11) is designed to examine the relative effectiveness of two behavioral treatments that vary in intensity (MET and cognitive-behavioral treatment [CBT]) combined with one of the following combinations of medications (acamprosate plus placebo, naltrexone plus placebo, acamprosate plus naltrexone, or placebo plus placebo). Subjects will be recruited for a six month treatment trial followed by a 12 month follow-up period that will provide us with the opportunity to evaluate whether behavioral treatments varying in intensity also vary in their effectiveness in treating alcohol dependence. This study will also permit us to examine whether the combination of two medications known to be effective in reducing drinking has benefits over using each medication alone, and whether there are individual patient characteristics that predict treatment outcome. Finally, the proposed primary study will permit an evaluation of the interaction of the two levels of psychological treatment with the varying combination of medications provided. This will be the first study that provides long-term outcome data on the combination of naltrexone with behavior therapy, the combination of more than one medication with behavior therapy, and the combination of a brief intervention with medication in the treatment of alcohol dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BUPRENORPHINE MICROCAPSULES FOR HEROIN ADDICTION Principal Investigator & Institution: Nuwayser, Elie S.; Biotek, Inc. Woburn, Ma 01801 Timing: Fiscal Year 2002; Project Start 05-APR-2002; Project End 31-OCT-2003 Summary: (provided by applicant): The overall objective of the program is to develop a new more economical sustained action injectable formulation of -buprenorphine, based on microcapsules prepared by BIOTEK's air suspension process. The microcapsules will be used in a large placebo controlled study in Phase II of the SBIR program. Recently we tested 30-day buprenorphine microcapsules in five (5) heroin addicts at the Johns Hopkins University School of Medicine, Behavioral Pharmacology Research Unit. For all five subjects the depot buprenorphine medication appeared to provide remarkable relief from opioid withdrawal without evidence of intoxication or respiratory depression over the six weeks of post-depot observation and assessment. Furthermore, the formulation was very effective in dramatically reducing responsiveness to exogenous opioid challenge for a duration of at least several weeks. Clinically, all five participants successfully achieved opioid detoxification, without other medications for withdrawal relief, and without clinically significant withdrawal signs or symptoms. During the subsequent 2-week outpatient phase all patients reported abstinence from opioids and urine toxicology samples were negative for opioids. These remarkable and very exciting findings compel us to drive forward and expand and accelerate the testing of depot buprenorphine in a large population of heroin addicts with appropriate placebo controls. Support is sought under the SBIR program to develop and optimize a more economic formulation of depot buprenorphine microcapsules, by using a new process which produces a much higher yield (5-6 fold increase) of microcapsules in the injectable size range. In preliminary studies detailed in this application, we have
16
Naltrexone
demonstrated significant reduction in manufacturing costs and the equivalency of the buprenorphine release profile from the old and new formulation. During Phase II of the SBIR program, microcapsule development will be completed, a large number of vials will be prepared under cGMP. The current IND will be updated and submitted to the FDA with a clinical protocol to test the formulation in a larger population of heroin addicts with appropriate placebo controls. PROPOSED COMMERCIAL APPLICATION: A sustained action opioid agonist/antagonist formulation, such as microencapsulated buprenorphine would be a significant advance. Once a month treatment is an economic advantage and allows staff members to devote more time to patients and less to dose administration. This formulation will provide opioid antagonism like that of naltrexone, but there would be less motivation for the post addict to drop out of therapy due to the agonistic action similar to that of methadone or LAAM. The overall treatment plan would not need to revolve about a rigid dosing schedule. Rather treatment could be designed to best benefit the patient, and an example of habitual drug taking behavior is eliminated. The drug thus becomes an adjunct not the major aspect of therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GAMBLING
BUPROPION
VS
PLACEBO
TO
TREAT
PATHOLOGICAL
Principal Investigator & Institution: Black, Donald W.; Professor; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2005 Summary: (provided by applicant): Pathological gambling (PG) has become a major health concern, particularly as gambling opportunities have proliferated. Despite its importance, there are few treatment options with proven efficacy. This application is submitted in response to PAR-99- 134 "Exploratory/Development Grants for MH Intervention/Research" The goal of the project is to conduct a randomized, double-blind comparison of bupropion-SR versus placebo in the treatment of PG. Bupropion will be used because of its reported efficacy in treating attention-deficit hyperactivity disorder (ADHD), and clinical similarities between PG and ADHD. This study will be one of the first of its kind, and has the potential to provide pilot data supporting the efficacy of a novel treatment for PG. We propose to recruit approximately 80 adults with DSM-IV PC during the first two years of the project, and to randomize subjects to bupropion-SR or placebo for a 12-week clinical trial. Subjects will be recruited through physician referral, advertisements in the local media, and by word-of-mouth. Subjects will be screened with the 20-item South Oaks Gambling Screen (SOGS) and the NORC DSM Screen for Gambling Problems (NODS). Those screening positive for PG (SOGS score equal to or >5 and NODS score equal to or >5) will be offered inclusion in the trial provided they meet specified inclusion/exclusion criteria. Baseline assessments will include the Structured Clinical Interview for DSM-IV, the Structured Interview for DSM-IV Personality Disorders, the Yale-Brown Obsessive-Compulsive Scale Modified for PG (YBOCS-PG), the Hollingshead Scale, the NORC Gambling Self-Administered Questionnaire, and the Global Assessment Scale. Baseline assessment will also include a physical examination, an electrocardiogram, urine drug screen, and other screening laboratories. Measures to gauge improvement will include the YBOCS-PG, three Clinical Global Impression scale ratings, a patient self-rated scale, the Hamilton Depression Rating Scale, and the Attention Deficit Hyperactivity Disorder (ADHD) Symptom Checklist. Following a two-week screening period, subjects will be randomized to medication or placebo. The dosage of bupropion-SR will begin at 100 mg twice daily and increased weekly to a total of 400 mg daily. Subjects on placebo will be
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administered a similar number o tablets. Subjects will be seen at weeks 1, 2, 4, 6, 8, 10, and 12. Adverse events and concomitant medications will be recorded at each visit. We hypothesize that the subjects receiving bupropion will have better symptomatic improvement than subjects receiving placebo. Further, we hypothesize that symptoms consistent with attention-deficit disorder will improve in parallel to the reduction in PG behavior. If bupropion is confirmed as an effective treatment, future studies will include larger samples to help test whether specific subgroups will improve preferentially, and comparisons of bupropion with the SSRI fluvoxamine, and naltrexone, an opiate antagonist, both shown to have efficacy in treating PG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHIMERIC PEPTIDES AS NOVEL ANALGESICS Principal Investigator & Institution: Kream, Richard M.; Professor of Pharmacology; Biochemistry; Suny Downstate Medical Center 450 Clarkson Ave New York, Ny 11203 Timing: Fiscal Year 2002; Project Start 15-JAN-2001; Project End 31-DEC-2004 Summary: (Adapted from applicant's abstract) Important medically-related issues exist as to why acute pain is perceived with high intensity despite the presence of extensive endogenous pain-modulating systems, and why chronic intractable pain arises from pathophysiological sequelae of nerve injury without consistency of symptomatology, etiological factors; and treatment strategies across patient populations. This necessitates an in depth understanding of how spinal excitatory systems, of which the tachykinin substance P (SP) represents a prototypic regulatory peptide, functionally interact with endogenous opioid systems to maintain functional homeostasis of nociceptive signaling and compensatory antinociceptive responsiveness at spinal and supra spinal levels. The foundation of present proposal is based on recent data obtained from in vivo pharmacological testing, and complementary biochemical analyses, of a chimeric peptide newly synthesized by our group: a heptapeptide consisting of overlapping NH2- and COOH-terminal functional domains of the opioid endomorphin-2(EM-2) and SP, respectively. The chimeric molecule YPFFGLM-NH2, designated ESP7, displays agonist activity at both the u-opioid (MOR) and SP (SPR) receptors. Administration of low concentrations of ESP7 by the intrathecal route produces long-lasting analgesia in the rat tail-flick text that is blocked by prior treatment with the opioid antagonist naltrexone. Repeated administration of ESP7 produces opioid-dependent analgesia without loss of potency over five days. In contrast, repeated administration of ESP7 in the presence of the selective SPR antagonist RP67580 results in a rapid loss of analgesic potency consistent with the development of opioid tolerance observed following administration of MOR-preferring opioids; post-hoc administration of ESP7 also effects partial rescue of opioid responsiveness in tolerant animals. We conclude that in vivo activation of SPR-expressing spinal neurons is functionally linked to inhibition of or delayed onset of opioid tolerance, and further hypothesize that coincident activation of MOR- and SPR-expressing systems mimics an ongoing state of reciprocal excitation and inhibition normally encountered in nociceptive processing. Our overall testable hypothesis is thus: chimeric peptides, composed oftwo independent but overlapping moieties contributed by an opioid peptide and substance P, are novel non-tolerance forming analgesics via their combined agonist action at functionally interactive classes of spinal and supra spinal receptors.Within this framework we propose the following three Specific Aims. 1. To evaluate chimeric peptides as novel analgesic agents through targeting of interactive spinal and supra spinal opioid and tachykinin neural systems, 2. To evaluate chimeric peptides in preclinical models of opioid tolerance and of acute and chronic pain, 3. To develop chimeric peptides with overlapping but distinct functional
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Naltrexone
moieties derived from NH2-terminal domains of delta and kappa opioids and the COOH-terminal domain of SP as novel analgesics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHRONIC ETHANOL EFFECTS ON CNS OPIATE RECEPTORS Principal Investigator & Institution: Saland, Linda C.; Professor; Neurosciences; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Chronic ethanol consumption and its continued reinforcement is an ongoing major health and societal problem. In the Central nervous system, the reinforcement of ethanol intake has been linked to enhanced release of endogenous opiates which act at opiate receptors. A non-selective opiate antagonist drug, naltrexone, is approved for humans to reduce ethanol consumption, craving and relapse. Use of the more selective delta receptor antagonist, naltriben, in animals and human trials, suggests that delta receptors are important in use and abuse of alcohol. However, mechanisms by which endogenous opiates and opiate receptors lead to continued ethanol consumption remain unclear. This proposal outlines the use of both histochemical and pharmacologic techniques to study mechanisms which may link chronic ethanol consumption to modulation of the delta opiate receptor, in a rat animal model. The major hypothesis to be tested is that immunoreactive delta opiate receptor expression in the forebrain and midbrain regions is increased during chronic ethanol intake, and the change in expression is accompanied by a reduction in functional coupling of the receptor to G proteins. Changes in delta receptor expression may affect neuronal intracellular signaling pathways in those brain areas to maintain ethanol consumption. Aim #1: To localize and quantify levels of delta opiate receptor subtype in the nucleus accumbens (NA) of the forebrain, and the midbrain ventral tegmental area (VTA), as well as other brain regions, in rats chronically exposed to ethanol. Confocal microscopy will be used, together with computer-assisted quantification, for immunofluorescent-labeled delta opiate receptors, with comparisons to mu receptor expression. We will compare neurons in brain areas of control and ethanol-consuming animals, and in animals which have been withdrawn from ethanol. Aim #2: To determine if chronic ethanol consumption affects functional coupling of delta receptors to second messenger systems in neurons of the NA and VTA, as well as other brain areas, with comparisons to mu receptor coupling. We will use a recently developed method with [35S]-GTPgammaS, whereby receptor-linked G-protein activation can be measured directly with autoradiographic techniques on sections of the brain areas. The direct effects of delta or mu opiate ligands can be examined to determine if they are functionally linked to G-proteins in the neurons of the selected brain areas. By using both quantitative immunohistochemical methods, and functional coupling studies, to examine the interactions of delta receptor ligands in animals after chronic ethanol consumption, it will be possible to determine receptor subtype-specific effects of chronic ethanol. It will also be possible to study the functional changes that may occur in the receptors after withdrawal from consumption. A future potential may be then to target delta receptors for treating chronic alcoholism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: COCAINE, ALCOHOL, AND COCAETHYLENE--CLINICAL EFFECTS Principal Investigator & Institution: Mccance-Katz, Elinore F.; Associate Professor; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490
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Timing: Fiscal Year 2002; Project Start 20-MAR-1996; Project End 31-JUL-2003 Summary: Epidemiological studies have shown that at least 62% of cocaine abusers and possibly up to 90% in some populations are concomitant alcohol abusers. We conducted a study which investigated the effects of simultaneous consumption of cocaine and alcohol in humans and prospectively demonstrated the formation of cocaethylene, a metabolite formed by ethyl esterification of cocaine which appears to have pharmacological properties similar to cocaine. Subjects experienced prolonged and increased euphoria relative to cocaine or alcohol alone administration and had significant increases in heart rate following cocaine-alcohol administration leading to speculation regarding the role of cocaethylene. Our pilot study in which intranasal cocaethylene was administered to 8 subjects showed it to be similar to cocaine, but with an elimination half-life about twice that of cocaine. our pilot study of acute disulfiram 250 mg treatment followed by cocaine administration showed decreased cocaine craving and increased dysphoria in some subjects. In our open pilot study, outpatients randomized to disulfiram 250 mg daily had a significant decrease in cocaine use as compared to subjects treated with naltrexone. This FIRST application is composed of a series of pharmacologic challenge (study drug administration) studies designed to test the hypothesis that cocaethylene plays a significant role in behavioral and physiological responses during cocaine- alcohol abuse. The 5 proposed studies will each enroll 28 subjects for a total of 140 subjects over 5 years. The studies have been designed to include an analysis of gender differences in responses to study drug administration which may be important to the pathoetiology of cocaine- alcohol abuse and could have important implications for treatment. Study 1 will explore the effects of multiple doses of cocaine in the presence of a steady state of ethanol. Studies 2 and 3 will determine the behavioral, physiological and pharmacokinetic properties of cocaethylene in humans using cocaine as a comparator. Studies 4A and 4B will test the hypothesis that disulfiram is an efficacious pharmacotherapy for cocaine and alcohol abuse using a double-blind, placebo-controlled, limited randomization, dose-response study design. Cocaethylene has been shown to have mush greater selectivity for the dopamine transporter than does cocaine and does not block serotonin reuptake. One hypothesis regarding the high incidence of comorbid cocaine and alcohol abuse is that cocaethylene, with its lack of serotonin reuptake inhibition, alleviates acute abstinence symptoms and dysphoria associated with binge cocaine use. Cocaethylene may be used as a tool to sort out the role of serotonin versus dopamine in mediating the actions of disulfiram on cocaine effects. Cocaethylene will be utilized in Study 4B as a pharmacologic probe in an attempt to deuterium the relative contribution of dopamine and serotonin to cocaine effects and to develop an understanding of possible mechanisms by which disulfiram modifies drug effects. Findings from this study could be important to the development of new pharmacotherapies for cocaine-alcohol abuse. In total, these studies should provide significant contributions to the current state of knowledge regarding the epidemiology of cocaine-alcohol abuse and treatment of these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COGNITIVE MECHANISMS OF ALCOHOL ABUSE Principal Investigator & Institution: Fillmore, Mark T.; Associate Professor; Psychology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-MAY-2004 Summary: (provided by applicant): Excessive alcohol use during a drinking episode (i.e., a binge) contributes to many adverse health and social consequences. Binge
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Naltrexone
drinkers are more likely to drive while intoxicated and to suffer blackouts and hangover. A continued pattern of binge drinking poses immediate health risks (e.g., alcohol poisoning, acute alcoholic hepatitis), and long-term consequences, such as alcohol dependence and liver cirrhosis. Given that even mild doses of alcohol impair cognitive processes that control behavior, it is important to understand how such disturbances also can reduce control over alcohol intake once a drinking episode has begun. The proposed project aims to determine how the inability to curtail alcohol consumption during a drinking episode is linked to alcohol-induced impairment of cognitive processes involved in the self-control and regulation of behavior. The research will examine acute alcohol impairment of cognitive functions in young non-dependent drinkers. The project combines measures of alcohol effects on cognitive inhibitory processes with traditional abuse liability indices based on subjective rewarding effects of the drug and its ability to reinforce self-administration. Studies will determine the degree to which alcohol abuse potential is influenced by two mechanisms of drug action: 1) reward-enhancing effects (i.e., elevation of an approach "go" mechanism); and 2) impairment of cognitive inhibitory processes (i.e., suppression of an avoidance "stop" mechanism). Multiple strategies will test the role of acute cognitive impairment in the abuse liability of alcohol. A drug-reinforcement model will test the degree to which preload alcohol doses "prime" subsequent drug self-administration by impairing inhibitory control processes that regulate behavior. The research also will test an indirect alcohol antagonist drug. caffeine, and an approved medication for alcohol abuse, naltrexone, for their ability to reduce alcohol self-administration by blocking its impairing effects on inhibitory control. The research has several long-term objectives. The findings will provide an understanding of how drinkers' susceptibility to alcohol's acute cognitive-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of cognitive mechanisms in the treatment efficacy of existing pharmacotherapies. such as naltrexone, as well as some investigational medications that might operate via cognitive mechanisms (e.g., acamprosate). Finally, the proposed experiments will provide initial methods and protocols for studying alcohol use in combination with other drugs of abuse that also disrupt cognitive functions, such as cocaine, for which binge use is also a common pattern of drug-taking. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COGNITIVE PHARMACOTHERAPY
PREDICTORS
OF
ALCOHOLISM
Principal Investigator & Institution: Munro-Shelton, Cynthia A.; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2005 Summary: (provided by applicant): Cognitive functioning, known to be variable among alcoholic individuals, has been shown to predict alcohol treatment outcomes in a number of studies regarding psychosocial and cognitive-behavioral treatment for alcohol dependence. A relatively newer option for the treatment of alcohol dependence, pharmacotherapy, represents an alternative treatment option for patients with alcohol use disorders, but not all individuals respond to this type of treatment. Accordingly, studies aimed at predicting which individuals will benefit from pharmaceutical treatment are valuable in informing treatment decisions. Whether cognitive functioning can predict outcomes for pharmacotherapy, however, has not been established. One type of drug used in the treatment of alcohol dependence is an opioid antogonist called
Studies
21
naltrexone. As an adjunct to a 12-week naltrexone clinical trial, the proposed study will add neuropsychological assessment to an existing protocol to determine whether cognitive functioning can predict pharmacotherapy treatment outcomes. Additionally, two separately funded ongoing investigations are being conducted to investigate individual differences in opioid system activity in the same subjects who are part of the clinical drug trial. These investigations will employ responses to a naltrexone challenge and mu opioid receptor binding as measured through PET imaging in investigating opioid system activity. Because these investigations will be conducted with the same pool of subjects, the proposed study will also examine the relation between cognitive functioning and opioid system activity as a secondary aim. This investigation represents an extention of prior work by addressing methodological and conceptual shortcomings of previous studies of cognitive predictors of alcohol treatment outcomes. The primary aims of this investigation are to determine the relation between cognitive test performance and naltrexone treatment outcomes and to examine factors associated with differential patterns of cognitive functioning over time. Secondary aims are to characterize cognitive functioning throughout the withdrawal period, and to examine the relation between cognitive functioning and opioid system activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALCOHOLISM
COMBINED
BEHAVIORAL/PHARMA
TREATMENT
OF
Principal Investigator & Institution: Hosking, James D.; Research Associate Professor; Biostatistics; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 30-SEP-1997; Project End 31-AUG-2005 Summary: (provided by applicant): The present application seeks two years of funding to complete COMBINE and its ancillary cost-effectiveness and genetic predictors of treatment response studies. The COMBINE study was initiated in 1997 to answer questions about the benefits of combining behavioral and pharmacological interventions. Two medications, naltrexone and acamprosate, have shown promise in reducing relapse to heavy drinking and improving abstinence in a number of U.S. and European clinical trials. The two behavioral treatments, Medical Management (MM) and Combined Behavioral Intervention (CBI), have potential to be valuable adjuncts to pharmacotherapy. MM appears to be cost-effective and suitable for delivery in primary care or managed care settings by non-specialists. The primary hypothesis is that combining the two medications (naltrexone and acamprosate) with a moderate intensity behavioral treatment (CBI) will yield better outcomes than less intensive approaches (e.g., placebo and MM; acamprosate or naltrexone and MM) for alcohol dependent patients. A total of 1375 subjects from 11 clinical sites comprise the targeted sample. Individuals meeting study criteria have been randomly assigned to one of nine pharmacological (naltrexone and acamprosate) and behavioral treatment (MM and CBI) combinations to form a complete 2X2X2 factorial design. A ninth cell was later included to test the efficacy of CBI without "pills". Much has been accomplished since COMBINE's initiation. Over 70% of the intended sample has been randomized to the study treatments reflecting gender, ethnic, geographic, and clinical diversity. Drinking assessment interviews have been completed for 84% clients at the 16-week follow-up. Two major pilot studies were successfully completed and the findings have been disseminated at conferences and in publications. The requested two-year extension will allow for the recruitment, treatment, and follow-up of the remaining participants, and allow sufficient time for data analysis and manuscript preparation. Results from the
22
Naltrexone
COMBINE study are expected to have a major impact on the alcohol treatment delivery system. A common protocol across each of the study sites is submitted. This reflects the cooperative process that has guided the study's efforts across the first five years of operation. However, each study site has provided site-specific information on the budget, budget justifications, listing of key personnel, consultant/consortium agreements, and human subjects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMBINED PHARMACOTHERAPIES FOR ALCOHOLISM Principal Investigator & Institution: Johnson, Bankole A.; Wurzbach Distinguished Professor and Dep; Psychiatry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: Recent scientific and clinical interest in combining therapeutic agents for the treatment of alcoholism are based on the fact that derangement of multipleneurotransmitter systems are likely to underlie biological predisposition to the disease. Thus, combining effective medications working at different neurotransmitters should produce a synergistic or at least an added clinical response. In animals, the combination of the 5-HT3 antagonist, ondansetron, and the mu receptor antagonist, naltrexone show synergism of action at reducing ethanol consumption. Alcoholics with an early onset of disease are effectively treated by ondansetron, and those with a family history of alcoholism in first degree relatives may have the best clinical outcome to treatment with naltrexone. Given that family history of alcoholism is associated with an early onset of disease, it reasonable for us to predict that the combination of ondansetron and naltrexone should be more optimal than either alone for the treatment of Early Onset Alcoholics (EOA). Indeed, preliminary clinical data from our group provide strong support that the medication combination is an effective treatment for EOA. We will test this hypothesis by comparing the effectiveness of ondansetron (4 mg/kg) and naltrexone(50 mg/day), both alone and in combination, in treating EOA vs. Late Onset Alcoholics (LOA) (total N of 45 subjects/cell x 8 cells = 360) in a randomized, doubleblind, placebo-controlled, 12-week (1 week of single-blind placebo followed by 11 weeks of the double-blind condition) outpatient clinical trial. All subjects will receive standardized Cognitive Behavioral Therapy, and follow-up at 1, 3, 6, and 9 months posttreatment. Specifically, we predict that: 1) EOA, compared with LOA, will be more responsive to treatment with either ondansetron or naltrexone alone, and 2) that the combination of ondansetron and naltrexone will be superior to either medication alone in the treatment of EOA. We will have the unique opportunity to test with adequate power the secondary hypothesis that the combination of ondansetron and naltrexone will be better tolerated than naltrexone alone, thereby improving compliance. This is because nausea is an important side-effect of naltrexone which can limit compliance, and as shown in our preliminary study, ondansetron by having anti-nausea and antiemetic properties counteracts this naltrexone side-effect. We support NIAAA's mission to develop effective pharmacotherapies as adjuncts to psychotherapy for the treatment of alcoholism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: COMBINED TREATMENT FOR COCAINE-ALCOHOL DEPENDENCE Principal Investigator & Institution: Schmitz, Joy M.; Professor; Psychiatry and Behavioral Scis; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225
Studies
23
Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Treatment seeking patients who are cocaine and alcohol dependent have poor prognosis. While there are no uniquely effective medications, combined pharmaco- and psychotherapy may prove efficacious. Naltrexone (NTX), approved for alcohol dependence, may block cocaine-alcohol rewarding effects at higher doses (> 50 mg/d) but psychotherapeutic context is critical. Our preliminary work indicates potential utility of NTX when combined with Relapse Prevention (RP) therapy and Contingency Management Procedures (CMP). We propose a large, double-blind, placebo-controlled, full factorial study to examine the role of RP + CMP combined with NTX for treatment of cocaine-alcohol dependence. Cocaine-alcohol dependent outpatients (N = 140) will be randomly assigned to NTX 100 mg/d or placebo combined with one of two psychotherapy conditions (RP or RP + CMP). Standardized consent and intake procedures will be followed by a single-blind baseline placebo week and then a 12 week trial with twice weekly visits. Manual-guided RP therapy will be delivered weekly in 60-minute individual sessions. CMP will reinforce abstinence based on cocaine-negative urine screens and negative breath alcohol test results. Medication adherence will be monitored with riboflavin and pill counts. Followup assessments will be conducted at 3, 6, 9, and 12 months after treatment termination. Primary efficacy variables will be measures of substance use (i.e., urine screens, TimeLine Follow-Back methods, collateral informants, change in liver enzymes) and retention (i.e., number of sessions attended, time to dropout). Secondary variables will include addiction severity and adverse event measures. A third set of variables will be tested as possible predictors of therapeutic outcomes. These include measures of motivation, self-efficacy, medication compliance, serum 6-beta naltrexol levels, craving, family history of alcohol problems, and severity of dependence. Power is sufficient to test the main hypothesis that NTX 100 mg/d with RP + CMP will reduce cocaine and alcohol use. Secondarily we will: (1) examine outcome variability as a function of individual differences on a range of potential predictors; (2) evaluate relative reinforcement of cocaine and alcohol using an innovative multiple choice measurement strategy; and (3) examine the relationship between cocaine and alcohol use during treatment and follow-up. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMBINING ALCOHOLISM
BRIEF
AND
PHARMACOTHERAPIES
FOR
Principal Investigator & Institution: Zweben, Allen; Associate Professor; None; University of Wisconsin Milwaukee Graduate School Milwaukee, Wi 532010340 Timing: Fiscal Year 2003; Project Start 30-SEP-1997; Project End 31-AUG-2005 Summary: (provided by applicant): The present application seeks two years of funding to complete COMBINE and its ancillary cost-effectiveness and genetic predictors of treatment response studies. The COMBINE study was initiated in 1997 to answer questions about the benefits of combining behavioral and pharmacological interventions. Two medications, naltrexone and acamprosate, have shown promise in reducing relapse to heavy drinking and improving abstinence in a number of U.S. and European clinical trials. The two behavioral treatments, Medical Management (MM) and Combined Behavioral Intervention (CBI), have potential to be valuable adjuncts to pharmacotherapy. MM appears to be cost-effective and suitable for delivery in primary care or managed care settings by non-specialists. The primary hypothesis is that combining the two medications (naltrexone and acamprosate) with a moderate intensity behavioral treatment (CBI) will yield better outcomes than less intensive approaches
24
Naltrexone
(e.g., placebo and MM; acamprosate or naltrexone and MM) for alcohol dependent patients. A total of 1375 subjects from 11 clinical sites comprise the targeted sample. Individuals meeting study criteria have been randomly assigned to one of nine pharmacological (naltrexone and acamprosate) and behavioral treatment (MM and CBI) combinations to form a complete 2X2X2 factorial design. A ninth cell was later included to test the efficacy of CBI without "pills". Much has been accomplished since COMBINE's initiation. Over 70% of the intended sample has been randomized to the study treatments reflecting gender, ethnic, geographic, and clinical diversity. Drinking assessment interviews have been completed for 84% of participants at the 16-week follow-up. Two major pilot studies were successfully completed and the findings have been disseminated at conferences and in publications. The requested two-year extension will allow for the recruitment, treatment, and follow-up of the remaining participants, and allow sufficient time for data analysis and manuscript preparation. Results from the COMBINE study are expected to have a major impact on the alcohol treatment delivery system. A common protocol across each of the study sites is submitted. This reflects the cooperative process that has guided the study's efforts across the first five years of operation. However, each study site has provided site-specific information on the budget, budget justifications, listing of key personnel, consultant/consortium agreements, and human subjects sections of their respective proposals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROLLED DELIVERY SYSTEM FOR NALTREXONE Principal Investigator & Institution: Akala, Emmanuel O.; Associate Professor; None; Howard University Washington, Dc 20059 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2005 Summary: (provided by applicant): The importance of the problem of alcoholism is shown by the report which indicates that approximately 7.5 percent of the U.S. population (about 14 million Americans) abuse and/or are dependent on alcohol. Alcohol-related deaths account for about five percent of all deaths in the U.S. Aside from human suffering, which is difficult to quantify, it is estimated that alcohol dependence costs the society about 116 billion dollars per year. There are medical complications from alcohol dependence: cardiovascular, neurological, gastrointestinal, immunologic, psychiatric, and obsteric complications. The main approaches to the treatment of alcoholism include detoxification, non-pharmacological, (psychosocial) treatment methods, and pharmacotherapy. The effectiveness of psychosocial treatment approaches has not been established: they have met with little or no success in treating alcoholism. The focus of medication development for addictive disorders, such as alcoholism, has moved from withdrawal to relapse prevention. The effectiveness of naltrexone (already approved by the Food and Drug Administration (FDA) is limited by problem with compliance: alcoholics show particularly low rates of medication compliance. Moreover, naltrexone is a highly extracted drug, with a low amount of the parent drug available in the brain. Consequently, there is need for the development of a controlled delivery system which can, not only sustain the release of the drug for a long time, but can maintain a constant blood level by releasing the drug at a constant rate at the site of absorption. If the delivery system is injectable, naltrexone can escape the first pass effect in the liver. In our preliminary studies, we have developed polymeric injectable nano- and microparticulate naltrexone controlled delivery systems capable of sustaining in vitro availability of naltrexone for a period greater than three months. Our goal is sustained delivery of naltrexone for six to twelve months. Synthesis of biodegradable and biocompatible copolymers and their use in optimizing the fabrication
Studies
25
of naltrexone controlled delivery systems and their evaluation in rats are the focus of this proposal. The use of controlled release naltrexone preparations will ensure compliance because the need for the patient to decide to take his medication would be minimized; it may also increase the likelihood of a therapeutic response by yielding a more predictable and constant plasma concentration of the parent drug and making it available in the brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COST EFFECTIVENESS OF ALCOHOL TREATMENT Principal Investigator & Institution: Zarkin, Gary A.; Director; Research Triangle Institute Box 12194, 3040 Cornwallis Rd Research Triangle Park, Nc 277092194 Timing: Fiscal Year 2002; Project Start 02-AUG-2000; Project End 31-JUL-2005 Summary: Alcohol and drug abuse impose significant costs on society. In 1992, the economic cost of alcohol and drug abuse was estimated to be 246 billion dollars. The majority of these costs arise from alcohol abuse (148 billion dollars). Partly in response to these costs, new pharmacotherapies have recently been developed to treat alcohol abuse and alcoholism. Likewise, important advances have been made in the development of behavioral interventions designed to treat alcohol abuse. While new alcohol abuse therapies have been developed over the last several years, pressures have been developing to identify therapies that are not only efficacious but also cost-effective. Much of this pressure has been driven by managed care, which has placed a premium on economic studies that assess whether the clinical and economic outcomes of new pharmaceutical and behavioral therapies justify their costs. To increase the understanding of the efficacy of two pharmacotherapies (naltrexone and acamprosate) and psychotherapy, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recently funded Project COMBINE, a multi-site, randomized control trial (RCT). This trial is one of the most ambitious clinical trials ever undertaken for the treatment of alcoholism. However, in spite of the importance of economic analysis of clinical trials, the Project COMBINE protocol does not include cost or cost-effectiveness studies. The purpose of this study is to examine the costs and cost-effectiveness of behavioral and pharmacotherapies for alcoholism (and their combination) included in Project COMBINE. Our proposed project builds on Project COMBINE's RCT design, which will provide great credibility of our results in the scientific community. Because of the number of therapies studied, the strength of the study design, and the limited existing literature on the cost and cost-effectiveness of alcohol treatments, the proposed study represents a major advance in the cost and cost-effectiveness analysis of alcohol treatment; our results should have a profound effect on the choice of alcohol treatment in the United States. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEPOT VERSUS ORAL NALTREXONE IN PAROLEES Principal Investigator & Institution: Cornish, James W.; Associate Professor of Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 30-JUN-2007 Summary: (provided by applicant) This project builds on an ongoing funded study (OS) which compares in nonblinded fashion 100 randomly assigned parolees given psychosocial treatment (PT) and 100 randomly assigned to PT plus oral naltrexone for six months. The proposed study (PS) adds a third group of 120 randomly assigned parolees who will be treated with PT plus depot naltrexone as well as 40 additional
26
Naltrexone
parolees treated with PT plus oral naltrexone. The effectiveness of depot naltrexone has never been studied in parolees. All participants will be evaluated at baseline, while in treatment, and at 6- and 12-month outcome evaluations. The primary study outcomes will compare 260 subjects (140 oral naltrexone, 120 depot) with regard to attendance/retention in treatment, urine toxicologies during treatment and at follow-up, re-incarcerations, arrests, and crimes during the one year of study participation, and psychosocial functioning over the study period. It is hypothesized that depot naltrexone will result in improved outcomes vis a vis oral naltrexone. The PS will also examine whether greater criminality/antisociality, psychopathology, gender, or current alcohol abuse problem are predictive of more negative outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DISCRIMINATIVE STIMULUS EFFECTS OF OPIOID WITHDRAWAL Principal Investigator & Institution: France, Charles P.; Professor; Pharmacology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-MAY-1995; Project End 31-MAY-2003 Summary: Despite the availability of several, effective pharmacotherapies, opioid abuse continues to pose a major public health problem worldwide. Currently available pharmacotherapies are effective in only some patients and the need continues for new and better treatments for opioid abuse. Prior research under this grant developed discrimination procedures for studying opioid dependence and withdrawal. Studies in this application will use those, and other, procedures to examine the development of dependence to novel opioids and to test hypotheses regarding drug interactions and the possible attenuation of dependence and withdrawal. Specific Aim I will determine whether opioid or non-opioid tolerance or dependence develops during treatment with the novel fentanyl derivative mirfentanil. Specific Aim II will examine the role of P450 enzymes in the morphine-like effects of codeine and oxycodone and determine whether other drugs (N-methyl-D-aspartate antagonists [NMDA] and nitric oxide synthase [NOS] inhibitors) modify opioid tolerance and dependence. These studies will compare methadone and its stereo isomers because these opioids also have effects at NMDA receptors. Upon completion of a study on LAAM dependence and withdrawal, studies under Specific Aim III will test the hypothesis that variations among mu opioids in their effects on receptor internalization and G-protein coupling will be expressed as differences in tolerance and dependence. Naltrexone will be established as a discriminative stimulus in untreated monkeys (Specific Aim IV) to begin a characterization of behavioral effects that might be important to the therapeutic utility of these drugs (e.g., alcohol abuse). Specific Aim V will use pigeons to study efficacy and selectivity differences among opioids and also to determine whether hypothesized interactions between different opioid receptors has functional consequences for drug dependence and withdrawal. The procedures developed under this grant provide a unique set of conditions for evaluating the effects of other drugs on behaviors related to and predictive of the subjective effects of withdrawal in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DRUG TREATMENT OF ETHANOL SEEKING IN RAT AND MONKEY Principal Investigator & Institution: Czachowski, Cristine L.; None; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2003; Project Start 05-MAY-2003; Project End 30-APR-2007
Studies
27
Summary: (provided by applicant): To identify drugs that are likely to be efficacious at decreasing ethanol abuse, are specific to ethanol, and do not alter behaviors motivated by other reinforcing substances, animal models that closely approximate the human condition are necessary. This project proposes the use of an operant behavioral paradigm that allows for pharmacologically relevant levels of ethanol selfadministration, that procedurally separates reinforcer-seeking from reinforcer drinking, and that uses two species of animals (rats and monkeys) in varying stages of ethanol experience. Experience will range from single daily drinking bouts (rats), to abusive consumption (monkeys), to ethanol-dependence (rats). The overall goal of this project is to develop and expand the behavioral paradigm that separately measures reinforcerseeking and reinforcer consumption to test putative pharmacotherapies for the treatment of alcohol abuse with across-species studies. Three approaches will be utilized: 1) nondependent rats with daily, limited access to sucrose or ethanol, 2) ethanol-dependent rats made dependent in inhalation vapor chambers and tested in operant chambers, and 3) heavy ethanol-drinking monkeys with extended daily access to ethanol. Selectivity for ethanol will be determined by using a sweetened fluid as a control for drug effects on other types of reinforcer-motivated behaviors. Also, since the GABA(A) system has been implicated in the reinforcing and behavioral effects of ethanol, GABA(A) receptor ligands will be tested in this model. The profile of GABA(A) modulatory effects will be compared to the effects of two current pharmacotherapies (naltrexone and acamprosate). A "successful pharmacotherapy" will decrease ethanolseeking behavior and will be selective for ethanol with little to no effect on reinforced responding for the control fluid. Overall, the project allows for the comparison between dependent and nondependent subjects undergoing similar treatments, and the comparison between rats and monkeys in one laboratory. This project responds to 3 of the 5 areas of interest requested in the RFA: testing drugs with known pharmacological properties for therapeutic efficacy, developing a new animal model with high predictive validity, and further research on drugs currently used for the treatment of alcohol abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ELUCIDATING MECHANISMS OF PHARMACOTHERAPY FOR ALCOHOLISM Principal Investigator & Institution: Miranda, Robert; Ctr for Alcohol & Addict Studs; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant): This proposal for a Mentored Patient-Oriented Research Career Award (K-23) is designed to prepare the candidate to carryout high quality research on alcoholism with expertise in conducting human laboratory research to: (a) identify potential pharmacologic agents to treat alcohol use disorders, (b) elucidate biobehavioral mechanisms by which promising medications exert their beneficial effects, and (c) delineate patient characteristics that are associated with differential response to intervention. The candidate will also develop expertise in conducting translational studies which logically extend findings from the human laboratory to appropriate clinical trials research while attending to relevant individual difference factors that may relate to outcome. To this end, the career development plan includes: (a) one-on-one instruction through a multidisciplinary mentor-apprenticeship training model, (b) formal coursework and directed readings, and (c) training in responsible conduct of research. Mentorship will be provided by Damaris Rohsenow, Ph.D. and Robert Swift, MD, Ph.D., and will be supported by an advisory team comprised of Peter Monti, Ph.D., Jennifer Tidey, Ph.D., and Kent Hutchison, Ph.D. To
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Naltrexone
assist didactic and mentorship efforts, this application includes a proposal for a mixed randomized placebo-controlled study to examine whether naltrexone (NAL) and ondansetron (OND) are differentially effective for reducing urge to drink and physiological reactivity in response to alcohol versus psychological stress-related cues. Based on the dissociable putative neurobiological mechanisms involved in stress vs. alcohol cue-related craving, and based on the distinct sites of neurochemical action of each medication, it is hypothesized that stress and alcohol cues will interact differentially with these medications. The proposed study will recruit 132 adult patients with alcohol dependence in substance abuse treatment. Patients will be randomized to receive placebo, NAL only, OND only, or NAL + OND. After ten consecutive days of dosing, participants will attend a laboratory session during which subjective and physiologic responses to personalized imagery conditions involving alcohol and stress cues will be assessed. A finding that NAL and OND are differentially effective at reducing urge to drink and affecting physiologic reactivity based on whether the eliciting stimuli are alcohol cues or are stress related would afford insight into the complex underlying neurobiology of craving, elucidate mechanisms by which agents exert effects, and inform intervention development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROL
ENDOGENOUS
OPIOIDS,
PAIN
AND
BLOOD
PRESSURE
Principal Investigator & Institution: Mccubbin, James A.; Professor and Chair; Psychology; Clemson University 300 Brackett Hall Clemson, Sc 296345702 Timing: Fiscal Year 2002; Project Start 01-AUG-1989; Project End 31-JUL-2004 Summary: This proposal is for continuation of our ongoing research on opioid abnormalities and blood pressure reactivity in persons at risk for hypertension. We are gradually becoming aware that regulation of both blood pressure and pain sensitivity is altered in pre-hypertensive populations. For example, persons at risk for hypertension have decreased opioid inhibition of blood pressure responses to stress. Paradoxically, they also show antinociceptive effects consistent with exaggerated opioid function. The scientific meaningfulness, both basic and clinical, of the links between pain sensitivity alterations and blood pressure dysregulation remains to be clarified. Recent studies by ourselves and others have emphasized the importance of opioids in regulation of 1) neuroendocrine and blood pressure responses to stress in hypertension development, 2) behavioral responses to pain, and 3) the relationship between pain sensitivity and blood pressure. The purpose of this continuation proposal is to further examine the role of endogenous opioids in blood pressure dysregulation by studies of circulatory and behavioral responses to aversive stimuli in persons at enhanced risk for hypertension. This will be accomplished by comparison of the effects of opioid blockade with naltrexone on pain sensitivity and blood pressure reactivity in young men and women with mildly elevated casual blood pressure. We hypothesize that abnormalities of both blood pressure control and pain sensitivity in the early stages of hypertension development are linked to altered opioid peptide function. Persons at risk for hypertension will show exaggerated opioid inhibition of pain sensitivity in the face of diminished opioid inhibition of blood pressure reactivity. Improved understanding of the opioidergic basis of altered pain sensitivity and blood pressure control will clarify the poorly characterized etiology of essential hypertension and possibly offer new preventive, diagnostic and therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ETHANOL DRINKING IN RATS: ACCUMBAL CIRCUIT ACTIVITY Principal Investigator & Institution: Robinson, Donita L.; Psychiatry; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Candidate: Donita L. Robinson, Ph.D., is an Assistant Professor in the Department of Psychiatry and the Center for Alcohol Studies at the University of North Carolina School of Medicine. Her training has been in analytical chemical methodology for brain measurements of dopamine and ethanol in freely-moving animals. Her immediate goal is twofold: (1) to learn multineuron electrophysiological recording in behaving animals and (2) to learn a technique to measure neuronal firing and subsecond dopamine signaling at the same microelectrede in behaving animals. Her long-term goal is to develop a high-quality, independent research program in ethanol neuropharmacology and behavior, funded by independent extramural grants. This Research Career Award will help Dr. Robinson accomplish these goals by providing solid training in the above methods as well as research support to apply these techniques to ethanol studies. Environment: The University of North Carolina provides laboratory space, equipment, and access to faculty and staff that will allow Dr. Robinson to accomplish the training and research proposed herein. The combined electrophysiology electrochemistry technique was developed by Drs. Regina Carelli and Mark Wightman, who are thus best qualified to sponsor this application. The UNC Center for Alcohol Studies contains many well known experts in ethanol pharmacology and self-administration behavior, including Dr. Clyde Hodge. The sponsoring departments and institution are committed and supportive of Dr. Robinson's development of a successful, independent research program at UNC. Research: The nucleus accumbens (NA) is a limbic-motor integrator, assimilating memory and drive input and coordinating responsive behavioral output. Anatomical and pharmacological evidence indicates that the core and shell subregions of the NA perform overlapping but distinct roles in motivated behavior. The proposed experiments will examine NA core and shell functions in ethanol drinking behavior in rats, with particular focus on how dopamine input modulates NA activity on the millisecond timescale. Finding patterns of neurons in the NA core and shell during operant responding for concurrent ethanol and water will be fully characterized using multi-electrode arrays (Specific Aims 1 and 2). Phasic (subsecond) dopamine activity will be evaluated in the NA core and shell during operant responding for concurrent ethanol and water, while simultaneously recording firing patterns of nearby NA neurons (Specific Aims 3 and 4). Finally, opiate modulation of NA cell firing patterns (Specific Aim 2) and phasic dopamine signals (Specific Aim 4) will be assessed with naltrexone administration before the operant session. Together, these experiments will provide new and valuable information on the interaction of physiology, pharmacology and chemistry in the NA during behavior, comparing ethanol to water reinforcement and core to shell. These studies will best train the candidate in a unique and innovative method, and significantly advance our understanding of neural control of ethanol drinking. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ETIOLOGY AND TREATMENT OF ALCOHOL DEPENDENCE Principal Investigator & Institution: Hesselbrock, Victor M.; Vice Chairman for Research; Psychiatry; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2003; Project Start 01-MAR-1978; Project End 30-NOV-2007
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Naltrexone
Summary: (provided by applicant): Since 1978, the Center on the Etiology and Treatment of alcohol Dependence (UConn ARC) has been devoted to a systematic exploration of the etiology and the treatment of alcohol dependence. This application requests five years of continued funding for the Center's research programs on vulnerability to alcohol dependence and promising biological and psychosocial treatment interventions. The Administrative/Scientific Cores describe the UConn ARC's organizational framework, quality control mechanisms related to research and publications, and core research facilities. Project 0027 describes the continuation of a prospective longitudinal study of Deviance Proneness as a model for predicting alcohol use behaviors, including pathological alcohol involvement, among older adolescents and young adults. Personality traits, cognitive factors, and conduct problems are examined as predictors of pathological alcohol involvement. Project 0032, a second study of vulnerability, will focus on several motivational pathways that may increase the susceptibility for developing heavy drinking and alcohol-related problems among college students. Using a multi-wave, cohort-sequential design, daily process information will be collected via web-based data methods at three different sites. Continuing our Center's emphasis on novel treatments for alcohol dependence, we have proposed two research components in this area. Project 0033 will evaluate the efficacy of contingency management (CM) procedures versus standard case management for reducing chronic alcoholic recidivism. A variety of alcohol use and behavioral outcomes will be examined, and an economic analysis of CM for reducing recidivism will be conducted. Project 0034 is a placebo-controlled trial of targeted vs. daily administration of naltrexone treatment for early problem drinkers. In addition to drinking behavior, mood, desire to drink and self-efficacy will be measured daily to examine possible mechanisms of naltrexone's effects. A pilot studies component will support five studies that relate directly to the Center's themes of vulnerability and novel treatments for alcohol dependence. Three studies will use animal models to examine neurobiological substrates of vulnerability, while two studies will provide an examination of the effects of two pharmacologic agents (finasteride, naltrexone). Finally, this application describes educational activities, information dissemination, a visiting scholars program, and consulting and mentoring activities that strengthen the role of the UConn ARC as a regional and national resource. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EVALUATION DEPENDENCE
OF
NMDA
ANTAGONIST
FOR
OPIATE
Principal Investigator & Institution: Bisaga, Adam M.; Assistant Professor of Psychiatry; Psychiatry; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 30-JUN-2004 Summary: The prevalence of heroin use has been increasing. However, the availability of efficacious treatments is limited, and relapse rates remain high. The development of more effective pharmacotherapies that reverse the physiologic effects of opioid dependence and prevent relapse to heroin use remains a priority. This application for a mentored research career award aims to enhance the research skills of Adam Bisaga, MD, by focusing on a systematic laboratory and clinical evaluation of memantine, an NMDA antagonist, for the treatment of opioid dependence. Dr. Bisaga, a Board Certified psychiatrist, is a research fellow in the Division on Substance Abuse at Columbia University. As a psychiatric resident and fellow, Dr. Bisaga has been exploring the theoretical basis for the clinical use of NMDA antagonists in the treatment of addictions and has collected pilot data using memantine to treat the opioid abstinence syndrome.
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In the next several years, he plans to carry out studies that would systematically evaluate the efficacy of memantine for opioid dependence. Two aspects of pharmacotherapy will be addressed: detoxification and relapse prevention. This novel approach to treatment will be initially evaluated using a laboratory model, and will be followed by a controlled clinical trial. Unique expertise and resources available at the Division on Substance Abuse make possible comprehensive training in such translational research. Under the sponsorship and guidance of Dr. Marian Fischman, together with the resources available at Columbia University, Dr. Bisaga will be able to achieve his long-term career goal of becoming a clinical research scientist with expertise in multiple approaches in addiction research and medication development. His training plan includes an extensive program of individualized instruction by major experts in the field, both at Columbia and elsewhere, in addition to formal course work. Training is planned specifically in the following areas: methods of new medications development for opioid dependence, including methodology and logistics of conducting clinical treatment trials; methodology and ethics of conducting research with opioids in the human laboratory; psychology of learning and conditioned responses; psychotherapy with substance abusers; integration of psychosocial interventions into medication treatment trials, and biostatistics. The research plan specifically includes the following: a laboratory study examining the effect of memantine on naloxone-precipitated opiate withdrawal, followed by a controlled clinical opioid detoxification trial comparing memantine with clonidine; a laboratory study of the effects of memantine pretreatment on cue-induced opioid craving in opioid-dependent subjects maintained on naltrexone; and a placebo-controlled trial of adjunctive memantine in the population of patients receiving naltrexone and cognitive behavioral therapy for opioid addiction. Taken together, the proposed plans will provide Dr. Bisaga with the opportunity to receive state-of-the-art training and research experience that will enable him to become an independent researcher in the field of addiction psychiatry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTIONAL NEUROMAGING OF CUE-INDUCED HEROIN CRAVING Principal Investigator & Institution: Langleben, Daniel D.; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): This is an application for a Mentored PatientOriented Research Career Development Award (K23) entitled "Functional neuroimaging of cue-induced heroin craving". The candidate's previous training and experience was in clinical psychiatry and nuclear medicine. Through this proposal, the candidate seeks to gain advanced training in: (1) functional magnetic resonance imaging (fMRI) and cognitive neuroscience methodology relevant to addiction research; (2) clinical research design and analysis, with a special emphasis on advanced statistical analysis of fMRI data and power analyses. The research project that is designed to complement this training program will use fMRI and experimental psychology methods to investigate the regional cerebral blood flow (CBF) changes during drug craving induced by heroinrelated cues to identify the brain networks mediating opiate craving. Studies by the investigators at candidates' laboratory and institution laid out the principles of drugrelated conditioned response in opiate-dependent patients and of Arterial Spin Labeling (perfusion) fMRI. Perfusion fMRI is particularly well suited for imaging of relatively prolonged states (e.g. cue-induced craving) and protocols involving repeated withinsubject experiments separated by days or weeks, such as the study of chronic
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medication effects. The candidate has extensive experience in the management of opiate dependence. An on-going pilot study by the candidate suggests an association between activation of the ventral tegmental area and heroin craving induced by opiate-related cues in methadone-maintained patients. The proposed project will expand and elaborate upon the previous findings and technological developments. Specific Aim 1 is to use fMRI to characterize the pattern of CBF response to cue-induced heroin craving and determine the specificity of this pattern in opiate-dependent subjects, building on the pilot data obtained by the candidate. Specific Aim 2 is to determine whether the CBF response to opiate-related cues in methadone-maintained patients is modulated by the fluctuation in methadone plasma levels. Specific Aim 3 is to characterize the effect of the opiate antagonist naltrexone on the CBF response to opiate-related cues in abstinent formerly opiate-dependent patients. The research plan will help determine the role of specific brain structures that mediate cue-induced craving to opiates and potentially to other drugs abuse acting on the mesocorticolimbic reward system. This data would improve our understanding of the mechanisms underlying dependence, treatment resistance and relapse. Furthermore, it may point the way for the development of novel methods for evaluation of the efficacy of pharmacotherapies and individual treatment response prediction in drug dependence. Implementation of this training and research plan will help the candidate to become an independent investigator in the neuropsychiatry of addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GABAPENTIN AS AN ADJUNCT TO NALTREXONE FOR ALCOHOLISM Principal Investigator & Institution: Anton, Raymond F.; Professor of Psychiatry; Psychiatry and Behavioral Scis; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 31-AUG-2007 Summary: (provided by applicant): Experience gained conducting numerous clinical trials with alcoholics has provided the infrastructure and knowledge for us to address novel treatments in a scientifically vigorous manner. In particular, we have found naltrexone to be efficacious when combined with cognitive behavioral therapy (CBT) and are currently investigating its efficacy when combined with either CBT or motivational enhancement therapy. In both studies, comprising over 250 individuals, most relapse occurs during early treatment (during the first six weeks) during which individuals complain of sleep difficulty, irritability and nervousness. These symptoms are indicative of brain dysregulation and may be related to "protracted alcohol withdrawal". Gabapentin, a safe and effective FDA approved antiseizure compound used in millions of individuals worldwide, can reduce glutamate and increase GABA neurotransmission in the brain. This unique pharmacology is well suited to the treatment of alcohol withdrawal and could normalize the brain dysregulation seen during the early abstinence period. A number of pre-clinical and clinical studies at our Center have indicated that it can reduce alcohol withdrawal symptoms, reduce drinking in dependent animals, and is safe to use in the clinic. We purpose a randomized double blind clinical trial, to evaluate the adjunctive use of gabapentin with naltrexone for the treatment of alcohol dependent individuals using a three group (placebo alone, placebo plus naltrexone, gabapentin plus naltrexone) design. Gabapentin or placebo will be added to naltrexone for the first six weeks of treatment (the time of greatest relapse and of potential 'protracted withdrawal" symptoms). Naltrexone and/or placebo treatment will last 16 weeks and all subjects will receive Combined Behavioral Intervention as
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developed for the COMBINE study (in which we are participating). It is predicted that alcoholics receiving naltrexone and adjunctive gabapentin will have less relapse than those treated with naltrexone alone. Measures of mood, sleep, irritability, and anxiety will be compared between treatment groups. Evaluations occur during treatment and 12 weeks and 24 weeks post-treatment. This evaluation of a novel treatment will allow us to better understand combined pharmacotherapy and develop a new paradigm for medications development for alcoholism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GALANIN-OPIATE INTERACTIONS Principal Investigator & Institution: Picciotto, Marina R.; Associate Professor; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 30-MAR-2007 Summary: (provided by applicant): We have shown that although the neuropeptide galanin potentiates morphine analgesia in the spinal cord, galanin and galanin agonists can antagonize morphine reinforcement and withdrawal in the brain. Our hypothesis is that the galanin system in the brain protects against opiate reinforcement by attenuating opiate-induced dopamine (DA) signaling in the ventral tegmental area and nucleus accumbens (Nac) and protects against opiate withdrawal by down-regulating noradrenergic signaling in the locus coeruleus (LC) and its targets. Thus, galanin agonists may be useful for potentiating opiate analgesia while minimizing its abuse liability. The effects of galanin are mediated through activation of a family of G proteincoupled receptors (GaIR1, GalR2 and GaIR3). GalR1 and GalR2 are expressed in brain areas associated with drug addiction, such as the mesolimbic DA system and the LC, as well as in the spinal cord. The distribution and second messenger coupling of GalR1 and GalR2 are distinct, suggesting that they have different roles in galanin neurotransmission. This study will analyze the interactions between galanin and morphine in the CNS. Our first aim is to determine whether the galanin system attenuates morphine place preference by modulating the DA system and to identify the galanin receptor subtypes that affect morphine reward. We will determine whether morphine-induced DA release or morphine place preference is altered in mice lacking galanin or in mice treated with the systemic galanin agonist Galnon. Galanin binding will be used to determine whether any of the pharmacological, behavioral or genetic manipulations used alter GalR levels. The second aim is to determine whether galanin attenuates opiate withdrawal by modulating the noradrenergic system and to identify the GalR subtypes regulated during opiate withdrawal. Transgenic mice overexpressing galanin in the noradrenergic system will be used to identify the role of galanin in these neurons in modulating opiate withdrawal. Using in situ hybridization we will determine whether GalR1, 2 and 3 mRNA levels are regulated by chronic morphine treatment or naltrexone-precipitated withdrawal in brain and spinal cord. We have already shown that GalR1 is upregulated following opiate withdrawal in the LC but it is not known whether GalR2 or 3 are also regulated. Since there are not selective antagonists for GalR subtypes, we will also generate mice lacking GalR1 to use in behavioral studies to elucidate the role of GalR1 in opiate analgesia and dependence. These experiments are designed to characterize an endogenous system that opposes opiate reward and withdrawal. The proposed studies will identify the pathways in the brain involved in galanin's actions on these processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Naltrexone
Project Title: GENDER PHARMACOLOGY
INFLUENCE
ON
PRECLINICAL
ALCOHOL
Principal Investigator & Institution: Middaugh, Lawrence D.; Professor; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The proposed experiments utilize a C5713L/6 (B6) murine model to determine if gender and/or estrus state influence the response to ethanol and ethanol conditioned stimuli or influence the impact of potential therapeutic agents on the response to ethanol-related stimuli. Although both positive and negative reinforcing stimuli regulate behavior directed toward obtaining and consuming ethanol and other abused drugs, we focus on evaluating the influence of gender on the effect on the positive reinforcing stimuli related to ethanol. Such information is basic and applicable to conditions reflective of "craving", "loss of control", or "relapse after abstinence", all of which have ethanol-related stimuli as a component. Although female members of our society contribute to the alcoholic population, preclinical investigations on potential therapeutic agents focus almost exclusively on young male rats. The general hypothesis guiding the proposed research is that gender and estrus state will (1) influence the rewarding effects of ethanol and ethanol -conditioned stimuli and (2) influence the ability of potential therapeutic agents to reduce the reward value of these stimuli. The strategy for testing this hypothesis is to compare the impact of ethanolrelated stimuli in male and female mice as well as female mice during two distinct stages of estrus. The effect of estrus cycle on the effect of potential therapeutic agents (Naltrexone, Onclansetron, Vigabatrin) will be measured using behavioral evaluations of the rewarding effects of ethanol and ethanol-conditioned stimuli. Opioid antagonists (Naltrexone) 5-HT3 antagonists (Ondansetron) and GABA transaminase inhibitors (Vigabatrin) have all been shown to attenuate the rewarding effects of ethanol in male monkeys, rats, and mice and can also reduce the rewarding effects of ethanolconditioned stimuli in male rats and mice. Whether effects on female members of the different species follow those noted for males is unknown, and is the focus of this proposal. An important aspect of the proposed work is to establish whether the drugs can attenuate the rewarding effects of ethanol and ethanol-conditioned stimuli with few unwanted side effects in female mice as we have demonstrated for male mice. Although the experiments are for ethanol reward, they should be generalized to treatment in paradigms for other drugs of abuse such as cocaine, heroin and morphine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HIV RISK REDUCTION AND DRUG ABUSE TREATMENT IN MALAYSIA Principal Investigator & Institution: Schottenfeld, Richard S.; Professor; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): Combining drug abuse and HIV risk reduction counseling with opioid agonist maintenance treatment (OMT) or antagonist maintenance treatment with naltrexone (NMT) is effective for reducing illicit drug use and preventing HIV transmission associated with heroin dependence, but support for NMT remains tenuous and OMT is not currently available in many Western Pacific countries (e.g., Malaysia, Indonesia and Singapore) where heroin addiction and HIV infection are epidemic and closely linked with injection drug use (IDU) and high-risk sexual behaviors among addicts. Promising results of NMT in Malaysia have created
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35
interest in evaluating OMT using buprenorphine (BMT) and comparing the efficacy of counseling alone and counseling combined with BMT or NMT. We are proposing a 24week, randomized double blind clinical trial to evaluate the efficacy for maintaining abstinence and reducing HIV risk behaviors of manual-guided, HIV risk reduction and drug counseling (DC-HIV) alone or when combined with BMT or NMT for recently detoxified and currently abstinent heroin dependent patients (N=l80) in Malaysia (Specific Aim 1). The study will allow evaluation of 3 hypotheses: DC-HIV plus naltrexone is superior to DC-HIV alone; DC-HIV plus buprenorphine is superior to DCHIV alone; and DC-HIV plus naltrexone is superior to DC-HIV plus buprenorphine. Primary outcome measures, assessed by 3x/wk urine toxicology testing and self-report, include resumption of heroin use, 1 or 3 weeks continuous relapse and reductions in HIV risk behaviors. The project will also evaluate the characteristics of treatmentseeking heroin addicts in Malaysia (including specific risk behaviors and patterns of HIV risk behaviors; prevalence of psychiatric and other medical comorbidity; and patterns of social, family, vocational, and criminal activity and service needs--Specific Aim 2). This data will be used to revise the DC-HIV manual to address the specific circumstances and risk behaviors of Malaysian heroin addicts. Finally, the project will also provide clinical training for health professionals and training and mentoring in drug abuse treatment and HIV prevention research to clinical researchers who will continue development, implementation, evaluation and dissemination of HIV prevention and drug abuse treatment approaches in Malaysia after the project ends (Specific Aim 3). The results of the study will inform government policy and support for HIV prevention and drug abuse treatment efforts in Malaysia and possibly also in other Western Pacific countries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND ALCOHOLISM Principal Investigator & Institution: Wand, Gary S.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 30-APR-2005 Summary: Rodent studies suggest a link between stress, mesolimbic dopamine generation and abnormal reinforcement from drugs of abuse. It has been posited that the ability of stress to increase mesolimbic dopamine production results in sensitization of the reward pathway to drugs of abuse. Indeed, rats will consume more alcohol and other drugs following stress and post-stress alcohol drinking is attenuated by adrenalectomy. During the last funding period, we established that persons at increased risk for alcoholism (e.g., offspring of alcoholics) are more sensitive to Naloxone, have altered HPA axis dynamics and altered hypothalamic opioid activity, which can be identified before the onset of heavy drinking. Moreover, we had shown that chronic heavy drinking induces even more dramatic derangement in HPA axis dynamics, affecting mood and perhaps increasing the chances of relapse following withdrawal. Lastly, we showed that chronic Naltrexone administration blunted alcohol-induced activation of the HPA axis as well as blunting subjective "liking" of alcohol "high". We hypothesize that hypercortisolemia induced by alcoholism or family history of alcoholism alters mesolimbic dopamine production leading to abnormal reinforcement. The experiments outlined in this competitive renewal are a direct extension of our findings from the previous funding period. As well as interacting with 3 other RO-1 proposals through the IRPG, the experiments outlined in this application "stand alone". Fist, we will extend our previous findings and determine if high- risk subjects have a more labile HPA axis in response to a psychological stress. Second, we will ascertain
36
Naltrexone
whether high cortisol reponders to Naloxone will also be high cortisol responders to "real life" stress. Third, we will determine whether 1) family history of alcoholism, 2) personality measures or 3) anxiety measures interact to alter HPA axis dynamics. Fourth, using PET imaging, we will determine if high-risk nonalcoholics make more dopamine compared to low risk subjects. We will test the hypothesis that high cortisol secretors are also high dopamine releasers as the rodent literature predicts. Finally, 5 and 10-year follow-up studies will determine if high cortisol production or high dopamine release is independent risk factors for alcoholism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOREGULATION BY ENDOGENOUS OPIOIDS Principal Investigator & Institution: Moynihan, Jan A.; Associate Professor; Psychiatry; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-MAY-2001; Project End 30-APR-2005 Summary: (applicant's abstract): The sense of smell is highly developed in rodents, and odors provide a critical set of stimuli that are necessary for reproduction, neuroendocrine responses and recognition of conspecifics, predators, and prey. We have shown that olfactory cues can also alter type 2 cytokine and antibody production following immunization with a protein antigen. This effect appears to be mediated by endogenous opioid production. The following specific aims have been designed to explore the role of endogenous opioids on immune function in our unique aNd naturalistic stress pheromone model. The central hypothesis is: Stress odor exposure (SOE) induces an endogenous opioid response that is immunomodulatory. Specific Aim 1: To test the hypothesis that type 2 cytokine production and immune effector functions in BALB/c mice immunized with KLH are preferentially altered by SOE via endogenous opioids. Specific Aim 2a: To test the hypothesis that the immunomodulatory effects of SOE may depend upon the antigen used to elicit the immune response. Specific Aim 2b: To test the hypothesis that administration of the opioid receptor antagonist naltrexone will abrogate SOE-induced changes in anti-HSV immunity. Specific Aim 3a: To determine whether endogenous opioid-induced changes in immune function are mediated centrally, resulting in an indirect effect on peripheral immune function, and/or peripherally, thereby directly affecting the immune system. Specific Aim 3b: To determine the specific class(es) of opioid receptors that are involved in stress odor-induced immune changes. Specific Aim 4: To determine if C57B1/6 mice, which do not have altered immune responses to KLH following stress odor exposure, have evidence of elevated endogenous opioids following odor exposure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMPROVING DRUG ABUSE TREATMENT BY RESEARCH AND TRAINING Principal Investigator & Institution: Kleber, Herbert D.; Professor of Psychiatry and Director; Psychiatry; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (Provided by Applicant) The overall aim of this K-05 proposal is to support and expand the applicant's work in developing and improving pharmacotherapy and psychotherapy for substance abuse as well as mentoring scientists embarking on such a career. The applicant has had a productive career in both areas, developing such programs first at Yale and currently at Columbia. During his eight years at Columbia
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the applicant has, in addition to these activities, served as Executive Vice President and Medical Director of CASA, a policy research center he and Joseph Califano founded in 1992. Receiving the K05 award would provide financial support for the candidate so that he could relinquish his CASA position with its administrative duties and policy research, and devote himself full time to biomedical research and training at the medical school. The applicant's current research has two major themes: 1) treating opioid withdrawal, 2) developing and improving medications and behavioral approaches for treating cocaine, heroin and marijuana dependence. Current funding for these areas is in hand for the first three years of this award. The applicant will direct a study comparing Anesthesia Rapid Opioid Detox (AROD) to Buprenorphine Rapid Opioid Detox to Clonidine Assisted Opioid Detox. The popularity of AROD has not been matched by evaluation of the technique, side effects and long term follow-up. This is the first controlled study to do so. In addition, the applicant will be PI at the Columbia site of a NIDA multi-site phase III trial of lofexidine, an alpha-adrenergic agonist with possible better efficacy than clonidine, and his Center will run an outpatient trial of a new Depot Naltrexone. Also focused on antagonist therapy is a Stage II Trial where he is CoInvestigator, testing a newly developed manualized psychotherapy for naltrexonemaintained individuals, which will also be the 1st study to test the usefulness of the new Depot Naltrexone in a clinical study. The Medication Development Research Center, where he is PI, focuses on targeting subgroups of addicts as well as development and/or utilization of models to improve testing potential medications. It includes human laboratory research on heroin, PET imaging, a large scale medication trial for cocaine, and testing potential medications for marijuana withdrawal and craving. In addition, the applicant plans to expand his time mentoring young scientists, including fellows on his training grant as well as young faculty. Additional time would also be spent in increasing collaborative research with other investigators at Columbia and developing new medication development projects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LEPTIN AND NEUROENDOCRINE GENE REGULATION IN OBESITY Principal Investigator & Institution: Korner, Judith; Medicine; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAR-2006 Summary: (adapted from the application) The long-term objectives of this application are to understand the regulation of genes expressed in the hypothalamus that encode anorectic and orexigenic peptides, and their interactions with the leptin-leptin receptor axis. This information will guide the study in rats of potential medical therapies for obesity, that will be translated to the study and treatment of human obesity. In Aim 1, the effect of the leptin receptor mutations, Lepr-fa-f ("Koletsky") and Lepr-fa ("Zucker"), on the hypothalamic expression of proopiomelanocortin (POMC, the gene which encodes the anorectic peptide alpha-MSH), agouti related protein (AGRP, a potent antagonist of alpha-MSH), and neuropeptide Y (NPY,an orexigenic peptide coexpressed in the same neurons as AGRP), will be studied within the same brain dissections using a very sensitive solution hybridization assay. The effect of gene dosage of Lepr-fa-f on neuroendocrine gene expression in the hypothalamus, body composition and leptin production per adipocyte will also be studied. The hypothesis that the administration of low dose leptin will reduce or eliminate the endocrine, metabolic and behavioral adjustments to reduced body weight will be tested in several Aims in both rodents and humans. In the rodent experiments, leptin will be co-administered with other known
38
Naltrexone
anorectic agents: sibutramine (a norepinephrine and serotonin reuptake inhibitor); naltrexone (an opioid receptor antagonist known to stimulate hypothalamic POMC expression); and pergolide (a dopamine agonist). In human experiments, low dose leptin will be co-administered with sibutramine, or administered after a period of 10 percent loss in body weight. The effects of these treatments on neuroendocrine gene expression, CSF levels of neuropeptides, energy homeostasis, and body composition will be analyzed. I plan an investigative career in academic medicine. Although my background in molecular research is fairly extensive, I have no formal experience in conducting clinical research and relevant statistical analysis. As part of my career development plan, I will enroll in courses at Columbia University in clinical research study design and statistics. In Aims 3 and 4, I will be part of ongoing clinical research projects, working closely with experienced investigators, while pursuing my own aspects of the projects. My sponsors, Dr. Leibel and Dr. Wardlaw, are experienced in basic and clinical research. They are easily accessible, enthusiastic about my projects, and will facilitate my transition to status as an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MEASURING AND MODIFYING ETHANOL'S REINFORCING EFFECTS Principal Investigator & Institution: Winger, Gail D.; Research Professor; Pharmacology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): In rhesus monkeys, the reinforcing effects of intravenously delivered ethanol lead to high ethanol intake, high ethanol blood levels, marked intoxication, and, under continuous access conditions, "binge" patterns of ethanol consumption, physiological dependence, and withdrawal signs. These are some of the characteristics of severe human alcoholism, a condition that is likely to result, at least in part, from this pharmacologically based reinforcing effect of ethanol. We suggest that response-contingent delivery of i.v. ethanol is a fairly "pure" measure of these reinforcing effects of ethanol, relatively unmodified by the aspects of taste, fluid volume, and gastrointestinal absorption that appear to prevent consumption by monkeys of equally large amounts of ethanol by the oral route. We propose to use behavioral economic procedures (demand curves) to quantify these reinforcing effects of i.v. ethanol and to compare them with those of other intravenously delivered drugs. In further studies, these procedures will be used to determine how the combination of ethanol and other drugs of abuse changes the reinforcing effects of both drugs. Because demand functions are unaltered by changes in drug potency, but are modified by changes in drug effectiveness, the measurements should indicate whether the various drug combinations result in a greater reinforcing effectiveness than either drug alone, or whether the potencies of the drugs as reinforcers are enhanced when they are combined. Finally, this same analysis will be used to determine how the treatment drugs of naltrexone and acamprosate modify the reinforcing effects of intravenous ethanol, again either by decreasing its reinforcing effectiveness or by decreasing its potency as a reinforcer. These studies will provide information not currently available on how ethanol compares with other drugs in terms of its reinforcing effectiveness, information that could impact policy decisions regarding legalization or decriminalization of other drugs of abuse. Data relevant to the behavioral and pharmacological mechanisms underlying polydrug abuse involving ethanol, and underlying pharmacological treatment of alcoholism will also be obtained.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MEDICATION DEVELOPMENT FOR PROTRACTED ABSTINENCE IN ALCO Principal Investigator & Institution: Mason, Barbara J.; Associate Professor; Psychiatry and Behavioral Scis; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 25-SEP-1999; Project End 31-MAY-2003 Summary: Protracted abstinence can be defined as a state of heightened reactivity to aversive and appetitive stimuli long after acute withdrawal that conveys a vulnerability to relapse in individuals with a history of dependence. The purpose of this proposal is to establish animal and human models of protracted abstinence that can predict efficacy of medications to treat the protracted abstinence stage of the alcoholic syndrome and protect against relapse. Animal models exist for all stages of the addiction cycle and have been useful in elucidating the neurobiological basis for vulnerability to alcoholism. Preliminary studies have shown that rats can be trained to self-administer alcohol and, when made dependent, increase their consumption during acute withdrawal and long after acute withdrawal. Studies are proposed to further characterize and develop this animal model of protracted abstinence and to attempt to manipulate alcohol intake with appetitive and aversive stimuli (Specific Aim 1). Neuropharmacological agents known to alter reward dysregulation will be tested on these models (Specific Aim 1). Optimal parameters from this model will be used to identify novel potential treatments for human laboratory testing (Specific Aim 2). In parallel, a human experimental model of protracted abstinence will be developed using cue reactivity and mood induction techniques (Specific Aim 3). Primary outcome measures are affective state and urge to drink with confirmatory physiological measures. The optimal parameters of the human laboratory model will be used to evaluate potential treatments for the protracted abstinence syndrome (Specific Aim 4), drawing on the pharmacological agents identified in the animal models of Specific Aim 2. The state of protracted abstinence in alcoholism is critical to vulnerability to relapse, and the results of the present proposed studies will provide novel treatments for protracted abstinence and thus unique approaches to alcoholism treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RESOURCES
MEDICATION/PSYCHOTHERAPY
TAILORED
TO
PATIENT
Principal Investigator & Institution: Swift, Robert M.; Associate Professor; Ctr for Alcohol & Addict Studs; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2003; Project Start 30-SEP-1997; Project End 31-AUG-2005 Summary: (provided by applicant): The present application seeks two years of funding to complete COMBINE and its ancillary cost-effectiveness and genetic predictors of treatment response studies. The COMBINE study was initiated in 1997 to answer questions about the benefits of combining behavioral and pharmacological interventions. Two medications, naltrexone and acamprosate, have shown promise in reducing relapse to heavy drinking and improving abstinence in a number of U.S. and European clinical trials. The two behavioral treatments, Medical Management (MM) and Combined Behavioral Intervention (CBI), have potential to be valuable adjuncts to pharmacotherapy. MM appears to be cost-effective and suitable for delivery in primary care or managed care settings by non-specialists. The primary hypothesis is that combining the two medications (naltrexone and acamprosate) with a moderate intensity
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behavioral treatment (CBI) will yield better outcomes than less intensive approaches (e.g., placebo and MM; acamprosate or naltrexone and MM) for alcohol dependent patients. A total of 1375 subjects from 11 clinical sites comprise the targeted sample. Individuals meeting study criteria have been randomly assigned to one of nine pharmacological (naltrexone and acamprosate) and behavioral treatment (MM and CBI) combinations to form a complete 2X2X2 factorial design. A ninth cell was later included to test the efficacy of CBI without "pills." Much has been accomplished since COMBINE's initiation. Over 70% of the intended sample has been randomized to the study treatments, reflecting gender, ethnic, geographic, and clinical diversity. Drinking assessment interviews have been completed for 84% clients at the 16-week follow-up. Two major pilot studies were successfully completed and the findings have been disseminated at conferences and in publications. The requested two-year extension will allow for the recruitment, treatment, and follow-up of the remaining participants, and allow sufficient time for data analysis and manuscript preparation. Results from the COMBINE study are expected to have a major impact on the alcohol treatment delivery system. A common protocol across each of the study sites is submitted. This reflects the cooperative process that has guided the study's efforts across the first five years of operation. However, each study site has provided site-specific information on the budget, budget justifications, listing of key personnel, consultant/consortium agreements, and human subjects sections of their respective proposals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MU OPIOID RECEPTOR AND IMMUNE FUNCTION Principal Investigator & Institution: Roy, Sabita; Associate Professor; Pharmacology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-MAY-1999; Project End 30-APR-2008 Summary: (provided by applicant): Opiate abuse is a major public health problem and a controversial social issue imparting considerable economic and personal costs to societies both in the US and internationally. Opioid addicts are prone to both bacterial and viral infections. Chronic morphine treatment has been shown to alter a number of immune parameters including suppression of cellular immunity. Opioid withdrawal exacerbates this cellular immune defect. Differentiation of T-helper cells toward Th2 effectors cells results in impaired cellular immunity. It is thought that T-helper cell differentiation into Th2 effector cell populations is a major contributing factor to impaired cellular immunity following injury, infection and addiction. We have recently shown that chronic morphine treatment in-vitro directs T-helper cells towards Th2 differentiation. The control of T-helper cell differentiation is a function of a number of factors; the most important of which is cytokine environment. Cytokine environment is controlled by regulation of key transcriptional "switches" (GATA-3, T-bet) that regulate T-helper cell differentiation. The central hypothesis in this proposal is that chronic morphine treatment differentially modulates the transcriptional "switches" GATA-3 and T-bet, which then directs CD4+ differentiation. In this proposal we will investigate the following: Specific Aim 1: We will investigate mediators of signal transduction pathway by which chronic morphine treatment in-vivo regulate the transcriptional "switches" Tbet and GATA 3 in CD4+ T-cells. Specific Aim 2: We will investigate the signal transduction mechanisms by which chronic morphine treatment in vitro regulates the transcriptional "switches" T-bet and GATA 3 in CD4+ T-cells. Specific Aim 3: We will investigate the signal transduction mechanisms by which morphine withdrawal in-vivo and in-vitro regulate the transcriptional "switches" T-bet and GATA 3 in CD4+ T-cells. Experiments outlined in these specific aims will help identify how morphine modulates
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T-helper cell cytokine responses and T-helper cell differentiation and may explain defects observed in cellular immune response in the drug abuse population. Therapies that prevent Th2 differentiation and promote Th1 cytokine synthesis may therefore prove beneficial in the immunosuppressed drug abuse population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MU RECEPTORS AND ETHANOL/DOPAMINE INTERACTIONS Principal Investigator & Institution: Gonzales, Rueben A.; Professor; Neurobiology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2004; Project Start 12-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): The neurochemical and cellular mechanisms that contribute to the control of ethanol drinking behavior are not fully understood, but the involvement of dopamine in the mesolimbic system has been hypothesized for some time. Many neurochemical systems are known to regulate the activity of the mesolimbic dopamine system, e.g., the opiate peptides and their receptors. Naltrexone, a clinically effective drug used to reduce relapse in alcoholism, is a broad spectrum opiate receptor antagonist, but its mechanism is not known in detail. Mu opiate receptors are anatomically located in the ventral tegmental area (VTA) and are known to control VTA dopamine neuron activity through the inhibition of GABA interneurons. However, the role of this mechanism in ethanol's regulation of dopamine release, and the role of particular opiate receptor subtypes has not been firmly established. Our preliminary studies show that mu opiate receptors are involved in the mechanism by which ethanol stimulates dopamine release in the ventral striatum, one of the terminal areas of the mesolimbic system. We propose to determine whether genetic deletion or irreversible blockade of the mu opiate receptor alters the dose-response curve for ethanol-stimulated dopamine release in the ventral striatum (aim 1). The genetic model we propose to use will be congenic mu receptor knockouts and wild-type controls that have been established on a C57BL/6 background. These studies will be complemented by investigation of effects of irreversible blockade of mu receptors with the use of naloxonazine. We also will determine whether the deletion of the mu receptor or irreversible blockade alters ethanol consumption using a two bottle choice procedure (aim 2). Moreover, we propose to determine whether mu receptors in the ventral tegmental area or the ventral striatum are involved in the inhibitory effects of loss of mu receptor function on ethanol stimulated dopamine release (aim 3). This will be done by microinjection of naloxonazine into either area and measuring the ethanol response. The role of mu receptors in the control of VTA-dopamine neurons will be examined using electrophysiological measures of cellular and synaptic activity in GABAergic interneurons (aim 4). These studies will utilize both the genetic and pharmacological approaches as described above. Together, the proposed experiments will elucidate the role of mu opiate receptors in the modulation of mesolimbic dopamine activity by ethanol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NALTREXONE & SSRI THERAPY FOR ALCOHOL DEPENDENCE Principal Investigator & Institution: O'malley, Stephanie S.; Professor; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 23-SEP-1999; Project End 31-AUG-2004 Summary: Alcoholism is a problem of significant proportion in Alaska and among Alaska Natives in particular. Due to remote nature of Alaska the provision of care is
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often difficult. Pharmacological adjuncts may provide an important tool for augmenting the effectiveness of existing treatments. Naltrexone, an opioid antagonist, has been shown to be efficacious in preventing relapse among Caucasian and African American patients, but the efficacy of this treatment has not been established in Native populations. In addition, not all patients benefit from naltrexone suggesting that combination pharmacotherapy may be useful, particularly if the additional agent targets a different neurobiological system affected by alcoholism. In this regard, serotonin reuptake inhibitors (SSRI), which address hypothesized serotonin deficiencies in alcoholism, have been shown to be modestly successful in reducing drinking in heavy drinkers although the response in alcohol dependent subjects has been mixed. However, there are promising preclinical and human preliminary studies suggesting that the combination of naltrexone and an SSRI may be more effective in reducing alcohol consumption than naltrexone alone. As a result, the proposed study has two primary aims: The first is to replicate previous findings in Caucasians and African Americans regarding the ability of naltrexone to reduce the risk of relapse in Alaska Natives with alcohol dependence. The second is to test whether combination therapy with naltrexone and sertraline yields better abstinence rates than monotherapy with naltrexone in this population. The efficacy of these pharmacological interventions will be tested when provided in conjunction with a model of counseling that could be used in remote rural locations. One hundred ninety-eight alcohol dependent individuals of Alaska Native heritage will participate in a double blind, double dummy placebo controlled study and will receive either 1) Combination therapy (naltrexone + sertraline), 2) Naltrexone monotherapy (naltrexone + placebo sertraline) or 3) Placebo (placebo naltrexone + placebo sertraline). Participants will be recruited from the townships of Sitka, Juneau/Ketchikan and village areas and evaluated centrally in Sitka. Participants will receive compliance enhancement, counseling and pharmacotherapy for 12 weeks and followed 6 and 12 months after treatment Secondary aims are to evaluate whether the combination therapy is better tolerated than monotherapy, 2) the durability of improvement during following and 3) the acceptability/implementation of the treatment components. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NALTREXONE AND CBT FOR PATIENTS WITH ALCOHOLISM AND PTSD Principal Investigator & Institution: Foa, Edna B.; Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 19-SEP-2000; Project End 31-JUL-2005 Summary: APPLICANT'S ABSTRACT: This proposed investigation extends prior research efforts by Edna Foa and Joseph Volpicelli in the evaluation of pharmacological and cognitive-behavioral treatments for alcohol dependence (AD) and post- traumatic stress disorder (PTSD), and capitalizes on their combined expertise in evaluating a comprehensive treatment program developed for patients with comorbid AD and PTSD. The comorbidity of AD and PTSD is a significant public mental health problem because the risk for AD dramatically increases among individuals with trauma history or PTSD and vice versa. The two disorders are thought to form a vicious cycle in which PTSD leads to abuse of alcohol; alcohol abuse impedes recovery from the traumatic experience thus contributing to the maintenance of PTSD; and PTSD in turn further escalates and entrenches alcohol abuse. Although promising treatments for AD and PTSD have been identified, comprehensive programs that address both disorders simultaneously have not been empirically tested. Specifically, the opiate antagonist naltrexone has been well
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established as an efficacious treatment for AD, but research has not specifically addressed its efficacy in patents with PTSD, who are especially prone to treatment attrition and noncompliance. Similarly, cognitive- behavioral treatment of PTSD by prolonged exposure (PE) is the most validated psychosocial treatment for PTSD; however, its efficacy in patients who abuse alcohol is unknown because AD is typically an exclusion criterion in such research. In the proposed study we will evaluate the efficacy of combining these empirically validated treatments for a group of patients who exhibit comorbid AD and PTSD. The proposed study compares four, 6-month treatment conditions in a 2 (naltrexone vs. placebo) by 2 (PE vs. No PE) research design. The four conditions are: 1) 100mg. naltrexone with PE; 2) naltrexone alone; 3) pill placebo with PE; 4) pill placebo alone. An enhanced medication management intervention will accompany all treatment conditions. PE will be provided by experienced psychologists trained in manual protocols. The study will include 200 patients (50/group) diagnosed with AD and comorbid PTSD. Symptoms will be evaluated before, during, and at the end of treatment, and at 9 and 12 months following study entry. Our primary study objective is to compare the short and long term effects of the combined treatments to those of each treatment in isolation on symptoms of AD and of PTSD. This study offers a model for combining and evaluating interventions in diverse treatment modalities for addressing comorbidity in AD, in a major step toward the development of theoretically driven and empirically validated treatments for difficult to treat populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NALTREXONE BLOCKADE OF NMDA Principal Investigator & Institution: Krystal, John H.; Kent Professor and Deputy Chair for Rese; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 29-SEP-2000; Project End 31-JUL-2003 Summary: (Adapted from the Investigator's Abstract) The capacity of ethanol to block N-methyl-D-aspartate (NMDA) glutamate receptors contributes to its behavioral effects in animals and humans. Recent preclinical data indicate that NMDA receptors and u opiate receptors are co-localized and have opposing actions in several brain regions involved in reward, such as the nucleus accumbens, the amygdala, and the raphe nucleus. These finds lead to the prediction that the mu receptor antagonist, naltrexone, would block the rewarding effects of NMDA antagonists, such as ketamine and ethanol. The capacity of naltrexone to attenuate the rewarding effects of ethanol contributes to its capacity to prevent episodes of drinking from becoming relapses to alcohol abuse. Similarly, our pilot data suggest that naltrexone reduces the euphoric and ethanol-like effects of subperceptual doses of ketamine. However, the mechanisms underlying the interactions of ethanol and naltrexone are not well understood. It is timely to explore the interactions of human opiate and glutamate receptor systems. Acamprostate, another promising pharmacotherapy for alcoholism, may act, in part, via glutamate receptor systems. The NIAAA multicenter study, Project COMBINE, will test the interactive effects of naltrexone and acamprostate. Better understanding of the interactions of opiate and glutamate systems may provide insights into findings from this study. In this application, we test the hypothesis that naltrexone attenuates the euphoric and ethanol-like effects of the NMDA antagonist, ketamine. We propose to examine the interactive effects of naltrexone and ketamine in 36 healthy human subjects using a randomized, balanced, placebo-controlled, within subjects design. The primary outcome measures include the visual analog scale measuring similarity to ethanol and the visual analog scale measuring "high." In our previous studies, we found that the
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rewarding effects of ketamine were remarkably resistant to antagonism by pretreatment with haloperidol or facilitation by pretreatment with lorazepam or amphetamine. We hypothesize that ketamine may mimic some aspects of the actions of ethanol at the NMDA receptor. Thus, the blockade of the rewarding effects of ketamine by naltrexone may provide insight into an important mechanism underlying the psychopharmacology of ethanol and the treatment of alcoholism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NALTREXONE IN DRINKERS SMOKING RESPONSE Principal Investigator & Institution: King, Andrea C.; Assistant Professor; Psychiatry; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2003 Summary: The candidate is a clinical and biological psychologist who seeks to acquire the skills in conducting clinical trials outcome research for nicotine, alcohol, and other drug dependencies. This award will allow the candidate to advance science-based treatment into clinical practice, by providing training, mentorship, and experience in relevant methodologies to combine pharmacotherapy and psychosocial treatment. The candidate will also expand her previous laboratory research background to study subjective, behavioral, and physiological factors involved in alcohol and drug reinforcement and their relation to clinical outcome. Throughout the award, Dr. King will engage in course work, workshops, laboratory and pilot clinical trial research, and have ongoing mentorship from experts in the field. Concurrent heavy use of alcohol and tobacco is common. However, the mechanisms of combined reinforcement and the optimal treatment strategies for heavy users of both drugs have not been delineated. The proposed study will examine the effects of combining naltrexone with standard smoking cessation treatment in heavy smokers with moderate-to-heavy drinking patterns. The rationale for this study derives from the candidate's recent preliminary data. These data indicate that naltrexone significantly reduced heavy smokers' craving for cigarettes after smoking one cigarette and a subsequent one hour rest period. Also in heavy smokers, naltrexone decreased the number of choice cigarettes smoked, lowered carbon monoxide (CO) levels, and acutely increased cortisol response to the first cigarette compared to placebo, suggesting a potential mechanism of reduced craving. We hypothesize that naltrexone will be particularly efficacious as an adjunctive treatment in moderate-to-heavy drinking smokers, an historically treatment refractory subgroup. Naltrexone might directly reduce craving or number of cigarettes smoked, or decrease alcohol intake and indirectly reduce cigarette smoking, since studies have shown that alcohol drinking enhances subsequent urge to smoke. Consumption patterns and quit rates for both substances will be monitored throughout the study. We will also investigate the relationship between response to naltrexone in the laboratory to response in a clinical trial, which will enable us to explore potential mechanisms for heightened response to opioid antagonists. Examining a targeted treatment combining pharmacotherapy and behavioral treatment for this subgroup is of great importance, as alcohol abusers show increased mortality more due to tobacco than alcohol-related illness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NALTREXONE PRODRUGS FOR TRANSDERMAL DELIVERY Principal Investigator & Institution: Stinchcomb, Audra L.; Assistant Professor; Pharmaceutical Sciences; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506
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Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: Naltrexone, an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. Most recently, naltrexone has been indicated as an adjunct in the treatment of alcohol dependence, as well as reported to reduce alcohol craving in certain alcoholic populations. Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. We plan to continue designing and synthesizing derivatives (prodrugs), which are more skin permeable than naltrexone, in order to make a therapeutically successful drug delivery system. We hypothesize that prodrugs of naltrexone will improve the transdermal delivery rate of naltrexone, and that these prodrugs will make excellent research tools for investigating quantitative structurepermeability relationships (QSPRs) for transdermal flux and concurrent metabolism. These prodrugs should improve naltrexone delivery rates across the skin, because they are more lipophilic, less crystalline, and therefore more soluble than naltrexone. The specific aims of this project include: (1) to synthesize a series of naltrexone prodrugs designed to elucidate fundamental QSPRs for transdermal flux and concurrent metabolism of the prodrugs, (2) to characterize the physicochemical parameters of the naltrexone prodrugs, including molecular weight, molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, and solubilities in select solvents, (3) to measure the naltrexone prodrugs' penetration and concurrent metabolism through human skin in vitro, (4) to characterize the pharmacokinetics of the naltrexone prodrugs in guinea pigs in vivo, and (5) to characterize the pharmacokinetics of the most promising naltrexone prodrugs in pigs in vivo. Correlation of our in vitro data with the in vivo models will aid in the creation of a reliable QSPR database, as well as help to identify the most promising prodrug for eventual human use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NALTREXONE TREATMENT FOR ALCOHOLISM--PREDICTING OUTCOMES Principal Investigator & Institution: Mccaul, Mary E.; Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2005 Summary: APPLICANT'S ABSTRACT: Preclinical research on endogenous opioid system involvement in alcohol reinforcement has led to studies of the effectiveness of the opioid antagonist naltrexone for treatment of alcohol dependence. In two clinical trials, naltrexone decreased alcohol craving and drinking in alcohol dependent subjects. Recently, naltrexone has been studied under more diverse conditions, including heterogeneous subject populations, longer medication periods, different dose levels and different therapy conditions. Results have been more variable than those of the original clinical trials and it is now clear that many alcohol dependent patients do not benefit from naltrexone as administered under current practice standards. These recent studies highlight the need for research to identify predictors of naltrexone treatment response. Our research has identified a negative relationship between serum 6-beta naltrexol level (naltrexone's major metabolite) and alcohol consumption in patients on 50 or 100 mg naltrexone. Above a level of 40 ng/ml 6-beta-naltrexol, alcohol consumption was fully suppressed; however, as reported in earlier studies on naltrexone metabolism, 6-betanaltrexol levels were highly variable across patients. The proposed research will examine the effectiveness of several opioid-related variables as predictors of naltrexone
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treatment outcomes. First, we will measure endogenous opioid system activity by naloxone challenge test as a marker of opioid system dysfunction resulting from chronic drinking. Second, we will measure unblocked mu opioid receptor binding at the 24-hr nadir of steady-state naltrexone levels using Positron Emission Tomography (PET). Third, we will obtain daily serum 6-beta-naltrexol levels during naltrexone induction as a marker of individual differences in naltrexone bioavailability. Fourth, we will measure self-reported alcohol craving, withdrawal and mood. Alcohol-dependent subjects (N= 192) with no other substance abuse or psychiatric disorders will be randomized to: placebo, once daily naltrexone 100 mg, or twice daily naltrexone 50 mg. All subjects will undergo a 2-week inpatient protocol, including alcohol withdrawal, naloxone challenge test, naltrexone induction according to dose condition, and PET imaging. After discharge, subjects will participate in a 12-week outpatient clinical trial with regular measurement of drinking, craving and mood, and 6-beta-naltrexol. Follow-up will be conducted 6 and 12 months post-enrollment. Results will provide new scientific and clinical knowledge on predictors of naltrexone treatment response and the interrelationships of endogenous opioid activity, mu opioid receptor blockade by naltrexone, serum 6-beta-naltrexol levels and alcohol craving and mood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NALTREXONE TREATMENT IN PATHOLOGIC GAMBLING DISORDER Principal Investigator & Institution: Kim, Suck W.; Psychiatry; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-MAY-2005 Summary: (provided by applicant): This R21 application proposes a novel use of naltrexone as treatment for Pathological Gambling Disorder (PGD) patients with severe urge symptoms. Although PGD is a prominent and growing social problem, there is no established drug treatment for this disorder. Our preliminary investigations demonstrate statistically significant findings that an opioid antagonist, may serve as a viable treatment option for PGD patients with severe urges. In 1994, naltrexone was approved to treat alcoholism (at a dose limited to 50 mg/day, but the use of naltrexone has since languished. In an effort to further pursue the use of naltrexone, we adopted a novel alternative approach. First, we focused our efforts only on a subset of PGD patients who had severe urge symptoms, as opposed to the entire PGD population. Second, we tested naltrexone at doses higher than 50 mg/day (up to 250 mg/day). Third, we addressed the side effect of hepatic transaminase revelation, an established adverse effect of naltrexone at doses above 50 mg/day, and we found a solution, such that dosages up to 250 mg/day were well tolerated and safe during an 11-week time period of use. In our three preliminary investigations, we found statistically significant results in our case study, open study, and double blind study, showing that naltrexone doses above 50 mg/day are effective in treating PGD patients with severe urges. We present the design of our proposed double-blind study, placebo-controlled, dose-finding study, which will expand upon our preliminary work and will establish the optimal dose for efficacy, whether efficacy is maintained for 16 weeks, and whether efficacy is disrupted in a male: female ratio analogous to that of the PGD population in the U.S. The implications of our study expand from PGD to other impulse control disorders, including compulsive shopping, kleptomania and possible alcoholism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NALTREXONE TREATMENT OF ADOLESCENT ALCOHOLICS Principal Investigator & Institution: Deas, Deborah V.; Psychiatry and Behavioral Scis; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Alcohol use among adolescents is a major public health concern given its illegal nature in this age group as well as its associated negative psychological, physical, and social consequences. Some surveys indicate that binge drinking (five or more drinks in a row in one sitting) occurs in almost fifty percent (50%) of the adolescents that consume alcohol. Treatment of these adolescents is critical because early intervention may prevent the progression of alcohol dependence into adulthood. Current treatments explored for adolescents are limited to psychosocial treatments; however, the adult alcohol field has explored and is now utilizing pharmacological interventions for alcohol dependence. Recently, the opiate antagonist, naltrexone, has been found to be safe and efficacious in reducing alcohol consumption and craving in adults. This led to the Food and Drug Administration's (FDA) approval of naltrexone for the treatment of alcohol dependence. While naltrexone has been used to treat other child and adolescent disorders, it has not been explored to treat adolescents with alcohol dependence. A few case reports, as well as a small pilot study we conducted, indicate that naltrexone is safe and leads to a reduction in alcohol consumption in adolescents. In order to expand on these preliminary findings, the proposed research is designed to evaluate the efficacy, safety, and tolerability of naltrexone, an opiate antagonist, in the treatment of adolescents with alcohol dependence. The design is a double-blind, placebo-controlled, twelve-week, medication trial with adjunctive, weekly, individual cognitive- behavioral therapy, and with sixmonth and nine-month follow-ups. A total of 100 male and female adolescent subjects, aged 15 - 18, will be recruited over a four year period for a target sample size of 50 randomized subjects per group. Data from the proposed trial may assist in the development of guidelines for the use of pharmacotherapy in the treatment of adolescents with alcohol dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NALTREXONE SCHIZOPHRENIA
TREATMENT
OF
ALCOHOL
ABUSE
IN
Principal Investigator & Institution: Batki, Steven L.; Professor and Director of Research; Psychiatry and Behavioral Scis; Upstate Medical University Research Administration Syracuse, Ny 13210 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The long-term goal of the proposed project is to improve the treatment of alcohol abuse and dependence in patients with schizophrenia and schizoaffective disorder. Alcohol use disorders are common among patients with severe mental illness. It is estimated that there may be as many as 750,000 individuals in the United States with comorbid schizophrenia and alcohol disorders. Alcohol disorder comorbidity requires treatment because it is associated with adverse consequences such as increased rates of hospitalization. Yet, to date, there are no reports of controlled trials testing the efficacy of pharmacological treatments for alcohol abuse or dependence in this population. Naltrexone pharmacotherapy is an effective treatment for alcohol dependence, but it has not been systematically applied to the care of patients with schizophrenia. The specific aims of this study are: To test the efficacy of naltrexone in reducing alcohol use among individuals with schizophrenia and schizoaffective
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disorder who also have alcohol abuse or dependence. We will test hypothesis 1: Naltrexone will be more effective than placebo in reducing alcohol use. Our primary outcome measure will be the number of drinking days over the course of the treatment trial. To test naltrexone's efficacy in reducing psychiatric symptom severity and medical utilization by reducing alcohol use. We will test hypothesis 2: Patients responding to naltrexone by reducing alcohol use will also show reductions in severity of psychiatric symptoms and utilization of inpatient and emergency psychiatric services. To determine the relationship between a) changes in alcohol use, and b) psychiatric symptom severity and inpatient and emergency service utilization. We will test hypothesis 3: Severity of psychiatric symptoms and amount of service utilization will correlate positively with alcohol use. The proposed research will study a cohort of 150 subjects in a double-blind, randomized, placebo-controlled trial of naltrexone using three times per week directly observed administration of medication. The study will be 6 months in duration, consisting of a 12-week course of naltrexone or placebo plus 3 monthly follow-up interviews after discontinuation of medication. Voucher incentives contingent on attendance will be provided to all subjects to ensure attendance for medication administration. Weekly motivational enhancement counseling sessions will also be provided to all subjects. Study outcomes will consist of self-report and biological measures of alcohol use as well as measures of psychiatric symptom severity and medical service utilization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NALTREXONE TREATMENT OF ALCOHOL DEPENDENCE Principal Investigator & Institution: Volpicelli, Joseph R.; Associate Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-APR-1989; Project End 31-DEC-2002 Summary: APPLICANT'S ABSTRACT: The long range goal of this ongoing program of research is to find more effective treatments for alcohol dependence through combining medication with the appropriate psychosocial support. Naltrexone when used in conjunction with psychosocial therapy, reduces relapse to clinically significant drinking in compliant subjects. The present proposal extends our previous research by comparing the efficacy of naltrexone treatment administered in two types of primary care settings: one using simple medication management and a second using medication management with compliance enhancement techniques. In addition, we will compare these two conditions with cognitive behavioral therapy--a combination that has been successfully used to demonstrate naltrexone efficacy in prior research. This proposal has 3 specific aims: 1) To compare the effectiveness of naltrexone in 3 types of treatment settings; 2) Assess the effects of psychosocial support on medication compliance and treatment retention; and 3) To investigate the subject characteristics that may predict who is likely to benefit from additional psychosocial support versus simple medication management. To this end, 240 alcohol dependent outpatients who are, currently involved in outpatient alcohol rehabilitation at the University of Pennsylvania's Treatment Research Center will be randomly assigned to treatment with either naltrexone (100 mg per day) or placebo in double-blind fashion over a six-month period. Medication will be administered in three types of settings: 1) simple medication management by a research physician, 2) simple medication management plus Compliance Enhancement Techniques (CET) administered by a nurse practitioner, and 3) simple medication management plus Cognitive Behavioral Therapy (CBT) administered by a trained psychologist using the Project MATCH, CBT manual. The primary outcome measures are time to relapse to clinically significant drinking (5 or more in one day) and percent
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days of clinically significant drinking. Other alcohol use related measures include, alcohol craving, percent of abstinent days, and blood chemistries including liver enzymes. The outcome measures will be evaluated during the medication phase and at follow-up points 12 and 18 months after entrance into treatment. In addition, medication and treatment compliance will be evaluated during the trial. Medication compliance will be assessed by pill counts, urine screens for riboflavin and for those subjects on active medication by serum levels of naltrexone and beta-naltrexol. Treatment compliance will be evaluated by the percent of research visits attended. The results of this trial will provide important information on the clinical use of naltrexone in the treatment of alcohol dependence as alcohol dependence treatment moves into primary care settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NALTREXONE, CRAVING AND DRINKING: ECOLOGICAL ASSESSMENT Principal Investigator & Institution: Monti, Peter M.; Professor; Ctr for Alcohol & Addict Studs; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2002; Project Start 01-AUG-1988; Project End 30-APR-2005 Summary: APPLICANT'S ABSTRACT: Naltrexone treatment reduces drinking rates for alcoholics, especially for those who lapse. However, the mechanisms that may mediate naltrexone's effects on drinking are not well understood. Effects on urges may provide one mediating mechanism. Clinical trials suggest that naltrexone reduces urges to drink, and lab studies with alcohol showed that naltrexone reduced the probability of experiencing cue-elicited urges to drink. Effects on the reinforcing effects of alcohol after taking a drink may provide another set of mediating mechanisms. Lab studies with heavy drinkers found brief administration of naltrexone to decrease the pleasurable effects of drinking, increase latency to a second drink, and reduce drinking rates. Naltrexone may thus reduce additional drinking due to reductions in positive reinforcement. The overall primary objectives are to determine whether naltrexone: (1) reduces urges to drink and initial reactions to drinking among heavy drinkers in the natural environment, using ecological momentary assessments (EMA), and in laboratory assessments of urge in response to alcohol cues, and (2) reduces drinking rates in this population. Therefore, we propose to provide 3 weeks of naltrexone (50 mg/day) or placebo administration to heavy drinkers in a 2-group randomized placebo-controlled design. All will participate in a week of baseline recording, a week of placebo leadin, then 3 weeks randomized to medication condition with medication management sessions. All participants will use palmtop computers daily to record urges to drink, environmental circumstances in which urges occur, drinking behavior, and reactions to drinking. All will participate in a lab assessment of alcohol cue reactivity after one week on the medication. This study will be the first to investigate the effects of naltrexone with heavy drinkers in a fine-grained analysis in the natural environment. The results will add important information about some of the hypothesized mechanisms of naltrexone's effects and about the relationships among environmental circumstances, urges and drinking behavior. Since heavy drinkers pose a substantial risk to other people and cost to society, investigation of the effects of naltrexone on this population may ultimately lead to interventions for heavy drinkers who need to modify their drinking rates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEUROBIOLOGY OF ENDOMORPHINS IN SPINAL DORSAL HORN Principal Investigator & Institution: Dun, Nae; Professor and Chairman; Pharmacology; East Tennessee State University Box 70565 Johnson City, Tn 37601 Timing: Fiscal Year 2002; Project Start 01-DEC-1999; Project End 30-NOV-2002 Summary: Substantia gelatinosa (SG) neurons in the spinal cord are the principal site of termination of primary afferents, many of which innervate nociceptors. Endogenous opiates or synthetic compounds are thought to produce their anti-nociceptors. Endogenous opiates or synthetic compounds are thought to produce their antinociception by interacting with subtypes of opiate receptors on SG neurons. Two recently isolated tetrapeptides endomorphin (Endo) 1 and 2 are believed to be the endogenous ligand for the mu-subtype of opioid receptors. Preliminary results showed endomorphin-like immunoreactivity (Endo-LI) subtype of opioid receptors. Preliminary results showed that endomorphin-like immunoreactivity (Endo-LI) is localized to dense networks of nerve fibers in the superficial layers of the rat dorsal horn. Thus, the rat dorsal horn offers a unique opportunity to test the hypothesis that Endo-1/Endo-2 is released endogenously and that it may modulate the activity of SG neurons. Two major issues will be addressed. First, release of endogenous of endogenous endomorphins will be evaluated in anesthetized rats in vivo or isolated rat spinal cords in vitro by the radioactive microprobe techniques. Electrical stimulation of afferent fibers of painful stimulus to the hindpaw will be employed to evaluate whether or not endomorphin release is altered under these conditions. Second, whole-cell patch recording techniques will be used to study the cellular action and the signal transduction mechanism underlying the action of Endo on single SG neurons in rat transverse spinal cord slices. Our preliminary results show that Endo inhibits the activity of SG neurons by hyperpolarizing the membrane and/or attenuating synaptic transmission. In this proposal, the pre- and post-synaptic actions of Endo will be evaluated electrophysiologically and pharmacologically. The subtype(s) of K+ channels that may underlie the hyperpolarizing action of Endo will be examined. Similarly, the subtype(s) of Ca2+ and/or K+ channels coupled to the presynaptic opiate receptor that may mediate the synaptic depressant action of Endo will be evaluated. The long term goal of this project is to improve our current understanding of the site and mechanism of action of this new class of opioid peptides on dorsal horn neurons, with the aim toward developing a novel class of opiate compounds with therapeutic potentials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ONDANSETRON AND NALTREXONE:CUE REACTIVITY AND DRINKING Principal Investigator & Institution: Rohsenow, Damaris J.; Professor and Associate Director; Ctr for Alcohol & Addict Studs; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Investigating mechanisms can help determine which medications show the most promise for alcoholism treatment. Naltrexone (NAL) results in improved treatment outcomes but there are no studies of the effects of 100 mg dose on mechanisms such as urges or responses to drinking. Ondansetron (OND) shows considerable promise with little information about its mechanisms. The combination of OND with NAL reduces drinking but has never been tested against each medication alone. Certain individual difference variables have shown promise for moderating the effects of some medications. The objective of this research is to evaluate the value of
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OND (0.5 mg/day), NAL (100 mg/day) and both together on several mechanisms along with several hypothesized moderating variables. The specific aims are to investigate: (1)whether these doses of OND, NAL or the combination results in reduced cue-elicited responses to alcohol cues among abstinent alcoholics in treatment (Study 1); (2) whether OND and/or NAL results in reduced pleasurable effects and craving after alcohol ingestion among non-treatment-seeking alcoholics (Study 2); (3) whether OND and/or NAL results in less alcohol consumption in a bar and in the natural environment (Study 2); (4) the extent to which the effects in the above aims are moderated by early vs. lateonset alcoholism, family history of alcoholism, or presence of the 7-repeat allele of the D4 dopamine receptor. Two studies will be conducted. The first will investigate the effects of 7 days on each medication on reactivity to alcohol cues among recently abstinent alcoholics in treatment, using a 2 X 2 (NAL vs. placebo; OND vs. placebo) between-groups randomized placebo-controlled design. The second will investigate the effects of 7 days on each medication on reactions to alcohol ingestion in a bar-lab and on amount consumed both in the bar-lab and the home environment among non-treatmentseeking heavy drinkers, using a 2 X 2 within-subject placebo-controlled cross-over design. Results will provide evidence for the relative promise of these medications separately and in combination on measures relevant to relapse and severity of drinking. Evidence will also be provided about subpopulations more likely to benefit from each medications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OPIATE AND NICOTINE DEPENDENCE--MEDICATIONS AND THERAPY Principal Investigator & Institution: Sullivan, Maria A.; Psychiatry; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 30-JUN-2004 Summary: Heroin and nicotine dependence are two addictions for which new combined pharmacotherapy/behavioral therapy interventions are possible. The goal of this mentored clinical scientist award is to promote the developing research skills of Maria A. Sullivan, M.D., Ph.D., by providing two areas of clinical research for testing novel combined medication/therapy strategies for opiate and nicotine dependence. Dr. Sullivan, a Board-Certified Psychiatrist, has completed a successful research fellowship in the Division on Substance Use at Columbia University/New York State Psychiatric Institute (NYSPI). As a fellow, Dr. Sullivan has begun studying patterns of smoking among schizophrenic patients and carried out a pilot intervention using bupropion/behavioral therapy to treat nicotine dependence among patients with chronic psychosis. This year Dr. Sullivan has joined the staff in the Division as an Assistant Professor of Clinical Psychiatry. She is currently serving as the Co-Director for the NIDA funded grant, "Opiate Dependence: Combined Naltrexone/Behavior Therapy." In the next several years, Dr. Sullivan plans to carry out clinical treatment trials to explore novel combined pharmacotherapy/psychotherapy approaches to opiate and nicotine dependence. Her proposed research plan will enable her to develop skills in two specific areas of addiction psychiatry: (1)conducting double-blind pharmacotherapeutic trials of agents which target specific mood symptoms in opiate or nicotine dependence or withdrawal; and (2)developing manualized psychotherapies tailored to promote abstinence and relapse prevention for individuals abusing certain classes of drugs. In this way, Dr. Sullivan will be well prepared to achieve her long-term research career goal of developing treatment approaches for comorbid substance use/psychiatric disorders. Under the sponsorship and guidance of Dr. Herbert Kleber,
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together with the faculty and resources available at Columbia University, Dr. Sullivan's training plan combines formal course work with clinical research experience at several sites of the New York State Psychiatric Institute. She will be working closely with several preceptors to receive training in the following areas: design and methods of clinical treatment studies; controlled medication trials; developing and implementing manual-guided relapse prevention therapies for opiate and nicotine dependence in selected populations; and biostatistics and epidemiology. Her specific research plan includes double-blind placebo-controlled trials of bupropion for nicotine dependence and nefazodone with open-label naltrexone for opiate dependence. For both treatment studies, manual-guided relapse prevention therapies will be developed and implemented. Dr. Sullivan's planned research will provide her with unique training and will afford her the opportunity to develop a clinical research career focused on developing new combined medication/therapy approaches to the treatment of substance abuse disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OPIATE DEPENDENCE: COMBINED NALTREXONE/BEHAVIOR THERAPY Principal Investigator & Institution: Nunes, Edward V.; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 100321098 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 30-JUN-2005 Summary: (Applicant's Abstract) The goal of this Stage II project (NIDA Behavioral Therapies Development Program PA-99-107) is to test the efficacy of a new combination of behavioral therapy with oral naltrexone maintenance for the treatment of heroin addiction, and to test a new long-acting depot parenteral formulation of naltrexone in initiating treatment. Antagonist maintenance with naltrexone is an important alternative to agonist maintenance or drug-free treatment, but it has not, to date, lived up to its potential. During the first two years of a Stage I project, Behavioral Naltrexone Therapy (BNT) was developed to address four limitations of naltrexone maintenance: 1) Difficulty transitioning patients from opiates to naltrexone; 2) Poor compliance; 3) Possible dysphoric effects; and 4) Inadequate psychotherapeutic context. After hospitalization for rapid transition from opiates to naltrexone, therapy sessions over six months draw elements from Network Therapy, the Community Reinforcement Approach, and voucher incentives contingent on compliance with naltrexone and abstinence from opiates. A significant other attends sessions and monitors compliance. Depression is identified early and treated. A treatment manual and therapy adherence instrument were developed. Results of a pilot trial are promising, although naltrexone discontinuation and relapse during the first month remains a significant problem. At the same time, a depot parenteral formulation of naltrexone was studied which produces therapeutic blood levels and blockade of opiate effects for 3 to 4 weeks after injection. It is hypothesized that a dose of depot naltrexone, administered after transition to oral naltrexone and before discharge from hospital, will prevent attrition during the initial outpatient weeks, allowing the behavioral regimen to take hold and substantially improving the long-term efficacy of our combination of behavioral therapy and oral naltrexone. In the proposed Stage II trial 160 heroin dependent patients will be randomly assigned to one of four conditions in a 2 by 2 factorial design: 1) BNT plus a dose of depot naltrexone prior to hospital discharge; 2) BNT plus a placebo injection; 3) Compliance Enhancement (CE), a control condition simulating standard treatment with naltrexone, plus depot naltrexone; and 4) CE plus placebo injection. Specific Aims are: 1) To test the efficacy of Behavioral Naltrexone Therapy (BNT) compared to control
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therapy for the maintenance treatment of opiate dependence; and 2) To test the efficacy of depot naltrexone in reducing early attrition, improving initial stabilization on oral naltrexone, and improving long term outcome of Behavioral Naltrexone Therapy (BNT). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OPIOID AND ALCOHOL REGULATED IMMUNE FUNCTION Principal Investigator & Institution: Sarkar, Dipak K.; Professor Ii and Director; None; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2002; Project Start 10-JUL-1999; Project End 31-MAR-2004 Summary: (Adapted from the Investigator's Abstract) High alcohol intake has been shown to compromise cell-mediated and humoral immunity by altering the function of various lymphocytes, including the natural killer (NK) cells, which participate in the defense against infection, tumor development and metastasis. How alcohol alters NK cell function is not known. Preliminary studies using male rats as an animal model demonstrate that alcohol consumption can suppress splenic NK cytolytic activity and decrease hypothalamic and plasma B-endorphin levels. Furthermore, opioid peptide Bendorphin stimulates NK cell cytolytic activity in vitro. Since levels of endogenous Bendorphin are reduced following alcohol treatment, a question arises as to whether the abnormality in NK cell activity in alcohol-treated animals is secondary to altered endogenous opioid activity. The goal of this proposal is to examine the role of opioid peptide B-endorphin in ethanol-modulated NK cell function. Three specific aims are proposed: 1) to further characterize the effects of ethanol on central and peripheral B-EP by determining the effects on B-EP production and secretion in the hypothalamus and pituitary and ethanol's effects on NK cell cytolytic activity by using NK-enriched splenocytes and 51Cr release assays; 2) to identify the mediatory role of B-EP by determining the actions of B-EP and its antagonist naltrexone on ethanol-modulated NK cell activity, and 3) to determine the neurochemical mechanisms by studying the role of corticotropin-releasing hormone and norepinephrine in B-EP-regulated NK cell activity in alcohol-treated rats. These studies have the potential to elucidate important neuroendocrine mechanisms mediating ethanol-induced immune dysfunction and may indicate potential therapeutic uses of the opiate antagonist naltrexone, in controlling alcohol-induced immune dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OPIOID ANTAGONISTS WITH MORPHINE FOR NEUROPATHIC PAIN Principal Investigator & Institution: Burns, Lindsay H.; Pain Therapeutics, Inc. 416 Browning Way South San Francisco, Ca 94080 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 31-MAY-2005 Summary: (provided by applicant): The proposed work will test the efficacy of proprietary combinations of opioid agonists and ultra-low-dose opioid antagonists in a rat model of neuropathic pain. A large body of work in rodent nociception assays has established that the addition of an ultra-low-dose opioid antagonist enhances the analgesic potency of the opioid agonist and also alleviates the analgesic tolerance and somatic withdrawal effects that accompany chronic administration of opioid agonists. These opioid agonist/antagonist combinations are currently in development by Pain Therapeutics, Inc. for non-neuropathic pain. Eiectrophysiological work supports the theory that ultra-low-dose opioid antagonists prevent opioid tolerance by blocking
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opioid receptors that have switched their signaling from an inhibitory to an excitatory mode that elicits hyperalgesia. In addition, it is hypothesized that similar excitatory signaling of opioid receptors underlies the paradoxical hyperalgesia caused by low doses of opioid agonists; ultra-low doses of opioid antagonists also convert this hyperalgesia to analgesia. Importantly, neuropathic pain and hyperalgesia from either morphine tolerance or low doses of morphine activate descending pain facilitatory pathways and cause release of dynorphin in the spinal cord. In addition to assessing efficacy of opioid agonist/antagonist combinations in a neuropathic pain model, it is the aim of this proposal to measure the effects of this drug treatment on mechanisms of neuropathic pain and opioid tolerance. Efficacy will be assessed by measuring thermal hyperalgesia and tactile allodynia in L5/L6 spinal nerve ligated rats administered morphine or morphine + ultra-low-dose naltrexone for 7 days. Mechanistically, coimmunoprecipitation of the receptor and G alpha subunits will define G-protein signaling changes that may occur in opioid tolerance and/or in neuropathic pain; these studies will measure the activity of opioid agonist/antagonist combinations to prevent such cellular changes. Finally, on a systems level, quantification of spinal dynorphin will assess whether this opioid agonist/antagonist treatment can prevent the increase in spinal dynorphin that is a result of activation of descending pain facilitatory pathways in neuropathic pain and in opioid antinociceptive tolerance. Moreover, analgesia for neuropathic pain is a large unmet medical need, and there is strong rationale for this investigation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PET IMAGING OF BRAIN OPIOID RECEPTORS IN ALCOHOLISM Principal Investigator & Institution: Frost, J James.; Professor; Radiology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 31-MAR-2005 Summary: Alcohol abuse and alcoholism is a major public health problem in the United States, but little is known of the neurochemical pathways in the human brain that mediate the reinforcing and other properties of ethanol. The brain's endogenous opioid system is known to play an important role in reward mechanisms and recently it has been targeted in treatment efforts using the opiate antagonist naltrexone. The rationale for using opioid blockade in the treatment of alcoholism is well founded in experimental animal models of human alcohol use and abuse, but we know little about the underlying differences in the endogenous opioid system between healthy individuals and alcoholics. Positron emission tomography (PET) is a non-invasive imaging method that can be used to image and quantitate a number of neuromarkers and mu opioid receptors can be imaged in the human brain by PET using the well-validated ligand C11 carfentanil. Our long-term goal is to better understand the function of the endogenous brain opioid system in alcohol use and abuse, and determine if it is involved in increasing the risk of alcoholism. The use of PET to measure regional mu opioid receptors is an approach that could provide new insight into the role of the endogenous opioid system in alcoholism. The specific aims of this study are: l) Measure regional mu opioid receptor binding by PET in non-alcoholic men and women with a positive family history of alcoholism.; 2) Measure regional brain mu opioid receptor binding by PET in FHP and FHN alcoholic men and women and relate regional binding to behavioral measures of alcohol abuse; and 3) Measure the change in regional mu opioid receptor binding during one month controlled abstinence from ethanol in alcoholic men and women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHARMACOGENETIC INVESTIGATION OF NALTREXONE Principal Investigator & Institution: Lerman, Caryn E.; Mary W. Calkins Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Several converging lines of evidence support the role of the endogenous opioid system in the reinforcing effects of nicotine; however, the efficacy of opioid antagonists (e.g., naltrexone, NTX) for the treatment of tobacco dependence remains unresolved. The results of clinical studies of NTX for tobacco dependence are inconsistent, which may reflect individual differences in drug response. Rather than concluding that NTX is an ineffective treatment for tobacco dependence, research is needed to identify those smokers for whom NTX will have the strongest beneficial effects on smoking behavior. Therefore, the specific goal of the proposed research is to test whether genetic variation in the functional mu-opioid receptor gene predicts the effects of NTX on cigarette smoking and nicotine reinforcement. Based on preclinical animal and human research, we hypothesize that smokers with the OPRM1 Asp40 variant will be more likely to respond to NTX compared to placebo (PLA), as reflected in reduced cigarette smoking and lower levels of nicotine reinforcement. This hypothesis will be tested using two within-subject behavioral pharmacology paradigms in which NTX 50mg and PLA will be administered to smokers who have been genotyped for OPRM1. The first experiment will examine the effects of NTX on the risk of relapse following an initial smoking lapse, using the validated experimental model of relapse designed by Stitzer and colleagues. Following 3 days of NTX (or PLA) and verified smoking abstinence, 70 smokers (35 from each genotype group) will be exposed to a "programmed" smoking lapse, and then monitored for three days in their natural environments. Following a 5-day wash-out period, the sequence will be repeated with NTX or PLA (order of medications counterbalanced). The primary outcomes are cigarette smoking and nicotine levels following the lapse episode. While such ad-libitum smoking experiments are more naturalistic, these designs can't disentangle the effects of a medication on the reinforcing value of nicotine from effects on the reinforcing value of smoking (including conditioned reinforcers). Therefore, the second experiment will examine the effects of NTX (vs. PLA) on the reinforcing value of nicotine, using a validated cigarette choice paradigm, developed by Perkins and colleagues. In this experiment 80 smokers genotyped for OPRM1 (40 from each genotype group) will receive acute pre-treatment with NTX 50mg or PLA following overnight abstinence, and before they participate in the cigarette choice procedure. The primary outcome will be the number of puffs taken from a 0.6 mg nicotine cigarette versus a 0.05 (denicotinized) cigarette during a 3-hour period. Following a washout period, the sequence will be repeated (with NTX or PLA). The long-term objective of this research is to discover and develop new pharmacogenetic treatment models that can be readily translated to the clinical setting to individualize pharmacotherapy and maximize effectiveness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHARMACOLOGICAL AND BEHAVIORAL TREATMENTS WITH ALCOHOLIC Principal Investigator & Institution: Donovan, Dennis M.; Professor; Alcohol & Drug Abuse Institute; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: Recent research has suggested that a number of medications hold promise for improving outcomes in alcohol treatment. In particular, naltrexone and acamprosate act
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at different receptor sites and have each demonstrated an impact on alcohol consumption in animal and clinical trials. However, these drugs are typically given as an adjunct to behavioral interventions, despite little research to guide the specific nature of possible interactions between behavioral and pharmacological interventions. The present application proposes both a pilot study and a larger scale study for inclusion in the NIAAA cooperative agreement focusing on combined use of pharmacotherapies and behavioral interventions in the treatment of alcohol problems. A preliminary randomized trial is proposed that would evaluate the acceptability, safety, and clinical outcomes of naltrexone and acamprosate used in combination. The preliminary study will monitor side effects, adverse consequences, medication compliance, treatment retention, and changes in drinking, and craving during a 3-month trial period. The larger study is designed as a double-blind, placebo-controlled clinical efficacy trial of six-month intervention investigating the relative efficacy of two medications, naltrexone and acamprosate, used in combination with two behavioral interventions, one basic Motivation and Compliance Enhancement (MCE) and one where specific relapse preventive skills-training is added, MCE plus Integrated Relapse Prevention (MCE/IRP) across a twelve\month post-intervention follow-up. Subjects will be randomly assigned to one of four conditions combining the medications 1) naltrexone/acamprosate, 2) naltrexone placebo, 3) placebo acamprosate, and 4) placebo/placebo. All subjects will also receive a behavioral intervention to enhance motivation for chance (based on Motivational Enhancement Therapy) and medication compliance. Participants will be randomized to either eight sessions of Motivation and Compliance Enhancement or fifteen sessions of Integrated Relapse Prevention. Aims for the large study include: a) comparing, main and interactive effects of naltrexone, acamprosate, and behavioral interventions on outcome, b) evaluating medication compliance, treatment retention, and therapist effects medication clinical outcomes, and c) identifying patient attributes associated with differential response to the intervention combinations, thus suggesting, possible client-treatment matches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PLACE DETOXIFICATION
OF
LOW-DOSE
NALTREXONE
IN
OPIATE
Principal Investigator & Institution: Mannelli, Paolo; Psychiatry and Human Behavior; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): This study is being submitted for review under the R21 (exploratory grant) mechanism, Its purpose is to explore whether the addition of very low doses of naltrexone to a methadone tapering schedule for opiate detoxification is safe, decreases withdrawal intensity and enhances patient treatment compliance. Although many different techniques for opiate detoxification have been employed, there is a continuing search for more effective approaches to reduce the duration and discomfort of withdrawal. Recent attempts have included the use of opiate antagonists to induce "ultra rapid" detoxification. However, the resulting need for heavy sedation or anesthesia to control withdrawal intensity and the increased possibility of medical complications has discouraged and limited the use of this approach. By contrast, there is experimental evidence that very low doses of naltrexone administered in the presence of opiates has analgesic and dependency reducing properties, suggesting that the use of very low dose naltrexone in the clinical management of opiate detoxification might be a useful strategy. To test this hypothesis, 360 volunteer opiate dependent subjects,
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admitted to the inpatient detoxification program of a community hospital and placed on a 4-day detoxification schedule, will be randomly assigned to receive one of three different low-dose naltrexone schedules or placebo in addition to their routine methadone tapering treatment. The four groups will be compared with respect to behavioral, biological and subjective withdrawal signs and symptoms, detoxification completion rates, acceptance of referral to outpatient treatment, and one and seven day post-detoxification follow-up evaluations. If the administration of low-dose naltrexone (antagonist) at the same time as methadone (agonist) is found to be more effective than placebo in reducing withdrawal discomfort, the findings will have clear treatment implications and raise important questions about the mechanisms of opiate agonist and antagonist interactions at the receptor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: POST TREATMENT EFFECTS OF NALTREXONE Principal Investigator & Institution: Davidson, Dena; Associate Professor; Psychiatry; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 26-SEP-2000; Project End 31-JUL-2005 Summary: APPLICANT'S ABSTRACT: The long-term research goal of the applicant investigators is to maximize the clinical effectiveness of treatment for alcoholism. The specific aims of this protocol are to compare 3 and 6 months of naltrexone (NTX) as an adjunct to two psychotherapies that differ in scope and intensity. The effect of these treatments will be assessed with patients who differ in their psychosocial need and psychosocial resources at their disposal, and in their level of cravings for alcohol. In this randomized clinical trial, 50 mg of NTX daily and either Motivational Enhancement Treatment (MET), or the more comprehensive Broad Spectrum Treatment (BST), will be provided over 12 weeks (Phase I). Following Phase I, half of the group receiving NTX in both psychotherapy conditions will crossover to placebo, in double-blind fashion. Daily medication will continue for an additional 3 months (Phase II). MET will terminate in Phase I, while those patients with greater psychosocial need and fewer psychosocial resources may continue in BST during Phase II. Medication and BST terminate at the end of Phase II, and patients are then followed for 12 months (Phase III). Outcome measures during all treatment phases include: 1) drinking outcomes (time to first drink; % days abstinent; % heavy drinking days); 2) negative drinking consequences; and 3) psychosocial adjustment. Overall, it is anticipated that the optimum treatment package will be one that targets the majority of the unique psychosocial needs of the patient while addressing the biological aspects of alcohol dependence via effective medication management. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROGRAMMATIC RESEARCH ON FAMILIES AND ADDICTION Principal Investigator & Institution: O'farrell, Timothy J.; Professor of Psychology; Psychiatry; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-MAY-2007 Summary: (provided by applicant): The overall aim of the proposed Research Career Award is to free the candidate from clinical and administrative duties so that he may devote nearly full-time to continue and develop further his programmatic research on family treatment and family processes among individuals with alcoholism and other
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drug problems. Family-involved treatments for alcohol and drug problems have substantial evidence for their effectiveness as documented in recent reviews. Family processes affect and are affected by the course and treatment outcome of addictions, and processes within families troubled by addiction are linked to some of our most urgent societal problems. This application has two specific aims: (1) the aims for research on family treatment are to conduct a randomized clinical trial evaluating behavioral family counseling and naltrexone with opioid dependent patients and to complete work currently in progress; and (2) the aims for research on family processes are to describe the natural history and to explore explanations of male-to-female violence among female alcoholics and their male partners and to complete work currently in progress on domestic violence among male alcoholic patients. Career development activities will include (1) consultation from leading experts about adding a focus on the functioning of children to the candidate's couple/family treatment outcome research and to his longitudinal research on domestic violence; and (2) a course on the responsible conduct of research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF WOUND HEALING BY OPIOID GROWTH FACTOR Principal Investigator & Institution: Wilson, Ronald P.; Comparative Medicine; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): The skin is the largest organ of the body and its primary function is to serve as a protective barrier against the external environment. Injury to the skin requires prompt resurfacing in order to re-establish this protective function. Healing of a skin wound is a highly complex, dynamic process involving contraction, cell proliferation, cell migration, production of an extracellular matrix, and remodeling. It is now appreciated that a number of growth substances participate in the healing process to coordinate the interaction between the cells involved. We have discovered that an endogenous opioid system, comprised of [Met5]-enkephalin (termed opioid growth factor, OGF) and its receptor (OGFr), modulates homeostasis and reepithelialization in human and mouse skin. This native opioid peptide is autocrine- and possibley paracrine-produced and interacts with its receptor to tonically inhibit DNA synthesis, and retard cellular proliferation in a non-cytotoxic and reversible fashion. In this grant we propose to test the hypothesis that OGF-OGFr interactions participate in the healing of a full-thickness skin wound and that the repair process can be modulated by pharmacologically manipulating OGFr. Experiments are designed to test this hypothesis by examining the consequences of cellular and molecular perturbation of the peptide, and of the receptor, in order to delineate their individual contributions to skin repair, with a focus on cellular proliferation, migration, and differentiation. The planned studies are part of a long-range program directed towards understanding the mechanisms involved in maintenance and repair of the epidermis. Furthermore, if our hypothesis is proven, manipulation of the endogenous OGF system represents a potential chemotherapeutic modality for the management of wounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SELECTIVE NONPEPTIDE OPIOID LIGANDS Principal Investigator & Institution: Portoghese, Philip S.; Professor; Medicinal Chemistry; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070
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Timing: Fiscal Year 2003; Project Start 01-JUN-1981; Project End 31-MAY-2007 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SERTRALINE FOR ALCOHOL DEPENDENCE AND DEPRESSION Principal Investigator & Institution: Pettinati, Helen M.; Director; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 31-MAR-2004 Summary: This is a competing continuation proposal to extend results from a 5- year NIAAA-funded project on sertraline for depressed alcoholics. Comorbidity in substance abusers traditionally has been associated with a more severe clinical picture and a poorer prognosis for drinking outcome, compared to cases of uncomplicated alcoholism. In clinical populations, one-third to one-half of patients seeking alcohol treatment have a lifetime major depressive disorder. Persistent depression in abstinent alcoholics is both disabling and a risk factor for relapse to drinking, and further clinical deterioration that may result in suicide. Because we have effective, FDA-approved pharmacotherapy for alleviating depressive symptoms, it is important that we are fully informed about the advantages (or disadvantages) of treating primary or secondary depression in alcoholics with antidepressant medications. Results from our initial, project suggested that comorbidly depressed alcoholics appeared to have reduced antidepressant effects from sertraline and sertraline did not reduce their drinking (more than placebo). To address these results, we propose a study that will examine if we can achieve a more optimal outcome in comorbidly depressed alcoholics by directly treating the alcoholism with naltrexone, and combining this pharmacotherapy with the use of sertraline for treating depression. Thus, the primary aim of this proposal is to examine in depressed alcoholic outpatients whether combining naltrexone (an FDA-approved pharmacological intervention to reduce drinking) with sertraline (an FDA-approved pharmacological intervention to treat depression) will result in greater reductions in both drinking and depression over either medication alone or placebo. A secondary aim is to examine whether certain patient features, e.g., extent of pre-treatment drinking or severity of depression, will predict response to sertraline, naltrexone, or the combination. Patients who present to the University of Pennsylvania Treatment Research Center will be recruited for participation in this study over a 5-year period. There will be 160 males and females with a current DSM-IV diagnosis of alcohol dependence and also of major depression (via PRISM) who will be randomized to one of four treatment groups (40 per group): 1) the combination of 100mg/day naltrexone and 200mg/day sertraline, 2) 100mg/day naltrexone, 3) 200mg/day sertraline, or 4) placebo. Subjects will also receive once- weekly sessions of Cognitive Behavioral Therapy that has been adapted to include a medication compliance enhancement component. The treatment phase will last 16 weeks (includes a week of baseline, and a week of single-blind, placebo lead-in, and 14 weeks of double-blind pharmacotherapy). The follow-up phase includes two visits at 6 and 9 months post-treatment entry. Overall, this project will determine if combining pharmacotherapies results in a better response in comorbidly depressed alcoholics than either medication alone or placebo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYNTHESIS & PHARMACOLOGY OF NOVEL OPIATES AND SYSTEMS Principal Investigator & Institution: Pasternak, Gavril W.; Professor of Neuroscience in Pyschiatry; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2003; Project Start 01-JUL-1990; Project End 30-JUN-2008 Summary: (provided by applicant): The primary goal of this project is to develop novel and useful drugs for the control of pain and drug abuse. Recent years have seen a resurgence of opioid abuse, as well as the need for additional analgesics with limited abuse potential. Our objectives are to identify new lead drug candidates for further development and to identify and characterize modulatory systems that influence opioid action. The project contains three major aims. The first aim addresses the role of the antiopioid sigma1 receptor system in the modulation of opioid analgesia. Sigma1 agonists potently reverse the analgesic activity of a variety of classes of opioid analgesics while sigma1 antagonists potentiate opioid analgesia. The sigma1 receptor has recently been cloned and will serve as a basis for examining this system at the molecular level. The cloned receptor also can serve as a screening system for potential new drugs. The second aim involves the role of ATP-binding cassette (ABC) transporters in opioid pharmacology. The most prominent member of this category, P-glycoprotein (i.e. mdr) has been implicated in the blood-brain barrier, as well as providing a system for transporting endogenous neuropeptides/transmitters from the brain to the peripheral circulation. It also plays a major role in morphine tolerance, with chronic morphine upregulating its expression. In addition to Pgp, MRP1 also has been implicated in opioid action. The last aim involves further studies with a series of opioid analogs synthesized in the laboratory during the previous granting period. By understanding how opioids and their modulatory systems interact, we hope to develop better approaches towards the management of pain and the discovery of new agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETED NALTREXONE FOR EARLY PROBLEM DRINKERS Principal Investigator & Institution: Kranzler, Henry R.; Professor of Psychiatry; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2003; Project Start 28-JAN-2003; Project End 30-NOV-2007 Summary: (provided by applicant): This proposal is for a 16-week, placebo-controlled trial of naltrexone (50 mg orally) in 200 early problem drinkers (i.e., hazardous or harmful drinkers without significant alcohol dependence severity). The study will employ a factorial design in which the effects of schedule of medication administration (i.e., daily vs. targeted), as well as the interaction of medication and schedule of administration will be examined. Targeted administration refers to the use of medication to cope with anticipated high-risk drinking situations. The primary outcome measures will be drinking days and heavy drinking days. Secondary outcomes will include alcohol-related problems and biological measures of alcohol consumption (i.e., GGTP and CDT). The study will provide an opportunity to replicate and extend the results of a recently completed 8-week trial of targeted naltrexone in early problem drinkers. That study showed a significant advantage of naltrexone over placebo on heavy drinking days and a trend for an effect of targeted administration on daily drinking. In the proposed study, procedures will be refined, the sample size will be increased and the duration of treatment will be double that of the recently completed study. In addition, the daily monitoring of mood, desire to drink, perceived self-efficacy, and drinking behavior will make it possible to examine in depth the mechanisms by
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which the study variables exert their effects. Follow-up evaluations conducted at 3 and 6 months post-treatment will provide a measure of the durability of treatment effects. Careful evaluation of the study hypotheses will provide important information on the efficacy and mechanism of targeted naltrexone for early problem drinkers, who comprise a substantial proportion of the general population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TEN YEAR FOLLOW-UP OF DUAL DIAGNOSIS TREATMENT Principal Investigator & Institution: Drake, Robert E.; Director; Psychiatry; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 01-DEC-1998; Project End 30-NOV-2003 Summary: Although several long-term studies of alcoholism and drug disorders in the general population exist, the long-term course of substance use disorder in patients with severe mental illness (i.e., dual diagnosis) is largely unknown. We have currently followed 223 adults with dual diagnosis in the New Hampshire Dual Diagnosis Study for 6-7 years with minimal attrition (85 percent with nearly complete data). By extending the study to 10 years of follow-up, the proposed project will yield unique data on the pattern, stability, prediction, timing, and correlates of remissions of substance use disorder in this population. We will also be able to examine treatment costs longitudinally. The 10- year data will allow us to chart the course of abstinence, asymptomatic use, remission, and recovery in dual-diagnosis patients. The study will increase our understanding of the relationships among substance disorder, clinical outcomes, and service costs. Longitudinal data will also allow us to examine several hypotheses from the literature regarding the effects of treatment and non-treatment experiences on the course of substance use disorder in this population. Specifically, we will examine response to new medications (such as olanzapine and naltrexone), prolonged intervals of close supervision (e.g., parole, conditional discharge, or living in a supervised setting), participation in peer support groups (such as dual-diagnosis groups or Alcoholics Anonymous), new sources of hope (like marriage, work, or religion), and medical illnesses related to substance disorder (e.g., gastritis). The results will be of interest to policy makers in many states that are replicating the model of integrated dual-diagnosis services that has been used in New Hampshire since 1988. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSDERMAL BUPRENORPHINE FOR OPIATE ANTAGONIST THERAPY Principal Investigator & Institution: Nichols, L D.; Biotek, Inc. Woburn, Ma 01801 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JAN-2004 Summary: (provided by applicant): Opiate antagonist therapy is an important treatment for recently withdrawn narcotic addicts. Buprenorphine is a drug with mixed agonistantagonist properties, which eliminates physiological reinforcement by preventing any subjective reward from morphine-like drugs. Buprenorphine is very effective and is preferred by subjects to either methadone or naltrexone. BIOTEK proposes to improve buprenorphine therapy by developing a 3-day transdermal delivery system. A buprenorphine patch would avoid the inconvenience of frequent clinical visits, and steady maintenance of the agonist action of buprenorphine should motivate compliance by providing more positive reinforcement. BIOTEK has previously demonstrated high transdermal delivery rates for buprenorphine. Recent results from a study of human subjects using BIOTEK's injectable buprenorphine microcapsules suggest that effective
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opiate blockade can be maintained by a much lower buprenorphine dose rate than previously thought necessary. It is the purpose of the proposed program to develop an effective antagonist patch containing too little buprenorphine to be an attractive target for subversion or abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TREATMENT OF ADULT ADHD IN METHADONE PATIENTS Principal Investigator & Institution: Levin, Frances R.; Q. J. Kennedy Associate Professor of Cli; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 100321098 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-JAN-2004 Summary: In spite of the availability of effective pharmacologic agents for the treatment of opiate dependence, such as methadone and naltrexone, successful treatment remains inadequate for many patients. One factor which may contribute to poor treatment outcome for patients in methadone maintenance programs is the presence of comorbid disorders, of which Attention-Deficit Hyperactivity Disorder (ADHD) has been a neglected one. Based on data we have collected, the prevalence of adult ADHD is substantially higher among substance abusers, both methadone-maintained patients and cocaine abusers seeking treatment, compared to the general population. It is our hypothesis that a comorbid diagnosis of ADHD in methadone-maintained patients may impede treatment efficacy. Medications, such as methylphenidate (MPH) and bupropion (BRP), are currently two of the most effective treatments for ADHD. In fact, we have shown that sustained-release MPH is effective in reducing both ADHD symptoms and cocaine use in cocaine abusers with adult ADHD. By treating methadone maintained patients who have adult ADHD with effective medications, we hypothesize that a reduction in ADHD symptoms will improve treatment efficacy as defined by: retention in the treatment study and in the methadone program, reduction in illicit drug use and drug craving, and improvement in functioning based on the Addiction Severity Index and Clinical Global Impression. Specifically, the effectiveness of sustained-release MPH and sustained-release BPR will be assessed using a three-armed, double-blind, placebo-controlled treatment trial in 120 methadone-maintained patients diagnosed with adult ADHD. Unfortunately, ADHD often goes undiagnosed. The second aim of this proposal is to determine the positive predictive value of several self-report instruments used to evaluate adult ADHD. Specifically, we will determine the utility of these instruments for assessing adult ADHD in substance-abusing populations. Overall, this proposal will provide a better understanding of the relationship between ADHD and substance abuse, better diagnostic evaluation, and improved pharmacologic treatment approaches for this sub-population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TREATMENT OF LATE LIFE DEPRESSION COMPLICATED BY ALCOHOL Principal Investigator & Institution: Oslin, David W.; Assistant Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: The focus of this Mentored Clinical Scientist Development Award (MCSDA) is to enable David Oslin, MD to acquire academic and research expertise for the treatment of late life mental disorders including major depression and comorbid alcoholism. Dr. Oslin is currently an Assistant Professor of Psychiatry at the University of Pennsylvania with appointments in the Section of Geriatric Psychiatry and the Center
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for Studies on Addiction. His career goals include: 1) gaining expertise in study design and methodology for intervention research, 2) establishing independent research projects on the treatment of comorbid mental health disorders, 3) enhancing his clinical expertise in the prevention, recognition and treatment of late life mental illness, and 4) being a resource for the university community on the research and clinical care of older adults, especially those with comorbid mental health problems. The proposal for this application includes both formal and informal instruction in research design and methodology as well as an intervention development project that will have both educational and scientific significance. The research plan for this award includes an intervention development study for older adults with primary major depression complicated by alcohol dependence. The aim of the project is to evaluate the tolerability and efficacy of naltrexone compared to placebo as a treatment for alcoholism in combination with sertraline as a treatment for primary major depression. Focusing on older adults enhances the goal of examining primary depression and comorbid alcoholism as the literature suggests that alcoholism is more often secondary to major depression in older adults compared to younger adults. This research plan is seen as a step toward the design of future studies of comorbidity in late life major depression. A growing awareness of a strong association between depression and alcohol abuse/dependence, the need for safe and effective treatments for comorbidity, and everpresent problem of gaining patient compliance with treatment regimens all appear to be fertile ground for study in an older population. The MCSDA would provide an important vehicle via course work and mentoring to enable Dr. Oslin to advance his knowledge and experience in these areas, which in turn, may advance the field of psychiatry's understanding of these complex issues. Dr. Oslin's training in geriatric psychiatry and addictions also makes him a good candidate to conduct the proposed intervention study. Finally, proposed plans for this MCSDA are well coordinated with the research activities of the Section of Geriatric Psychiatry and the Center for Studies on Addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VERY WITHDRAWAL
LOW
NALTREXONE
TREATMENT
OF
OPIATE
Principal Investigator & Institution: Van Bockstaele, Elisabeth J.; Associate Professor; Pathology, Anat/Cell Biology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2003; Project Start 15-MAR-2003; Project End 31-JAN-2006 Summary: (provided by applicant): It is the intention of this R21 application to gather data regarding the feasibility of a novel opiate detoxification method, with the use of very low-dose naltrexone pretreatment to reduce withdrawal symptoms in morphine dependent rats. Pharmacological withdrawal management is often the first step in the treatment of opiate dependent patients. Although a wide range of detoxification techniques have been employed, there is a continuing search for more effective approaches. Recently, the use of opiate antagonists (i.e. naltrexone, naloxone) in detoxification protocols has been introduced to sharply decrease withdrawal duration, but at the cost of greatly increased symptom intensity requiring heavy sedation and even anesthesia. Resulting serious medical complications has discouraged and limited the use of this approach. On the other hand, experimental evidence on analgesic and dependence-reducing properties of very low doses of opiate antagonists points to an alternative strategy for the use of these antagonist drugs during detoxification. Although the behavioral manifestations of opiate withdrawal have been thoroughly
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described in animal models, the cellular bases underlying these changes have only recently been characterized. Several brain nuclei exhibit immediate early gene expression (e.g. c-fos), which is used as a marker of neuronal activation, in the course of withdrawal. Furthermore, alterations in intracellular messengers, including cyclic adenosine monophosphate (cAMP)-dependent protein kinases (PKA), and cAMPresponse element-binding protein (CREB) have been shown following opiate withdrawal in the central nervous system. Specific purpose of this study is to test the hypothesis that pretreatment of opiate dependent rats with very-low doses of opiate antagonists ameliorates behavioral and biochemical expressions of withdrawal. Experiments in Aim I are proposed to examine whether naltrexone pretreatment reduces the aversive and somatic signs of withdrawal. To this end, behavioral expression of withdrawal will be rated according to a well-described score of behaviors. Aim II will examine the distribution of c-fos protein in brain regions known to be activated following withdrawal to test whether very low-dose naltrexone pretreatment diminishes the expression of c-fos in these brain areas. Finally, Aim Ill will use western blot analysis to examine levels of intracellular messengers known to be increased during withdrawal to determine whether these are altered following pretreatment with lowdoses of naltrexone. The information collected will provide the necessary foundation for designing detoxification trials in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “naltrexone” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for naltrexone in the PubMed Central database: •
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Effects of opioid antagonists naloxone and naltrexone on neuropeptide Y-induced feeding and brown fat thermogenesis in the rat. Neural site of action. by Kotz CM, Grace MK, Briggs J, Levine AS, Billington CJ.; 1995 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185185
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with naltrexone, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “naltrexone” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for naltrexone (hyperlinks lead to article summaries): •
A 6-month controlled naltrexone study: combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence. Author(s): Balldin J, Berglund M, Borg S, Mansson M, Bendtsen P, Franck J, Gustafsson L, Halldin J, Nilsson LH, Stolt G, Willander A. Source: Alcoholism, Clinical and Experimental Research. 2003 July; 27(7): 1142-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878920
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A case of kleptomania and compulsive sexual behavior treated with naltrexone. Author(s): Grant JE, Kim SW. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 2001 December; 13(4): 229-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11958364
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A clinical laboratory paradigm for evaluating medication effects on alcohol consumption: naltrexone and nalmefene. Author(s): Drobes DJ, Anton RF, Thomas SE, Voronin K. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2003 April; 28(4): 755-64. Epub 2002 October 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12655322
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A comparison of antagonist-precipitated withdrawal under anesthesia to standard inpatient withdrawal as a precursor to maintenance naltrexone treatment in heroin users: outcomes at 6 and 12 months. Author(s): McGregor C, Ali R, White JM, Thomas P, Gowing L. Source: Drug and Alcohol Dependence. 2002 September 1; 68(1): 5-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12167548
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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A double-blind, placebo-controlled study of naltrexone in the treatment of alcoholdependence disorder: results from a multicenter clinical trial. Author(s): Guardia J, Caso C, Arias F, Gual A, Sanahuja J, Ramirez M, Mengual I, Gonzalvo B, Segura L, Trujols J, Casas M. Source: Alcoholism, Clinical and Experimental Research. 2002 September; 26(9): 1381-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12351933
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A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Author(s): Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR, O'Brien CP. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2003 August; 28(8): 1546-52. Epub 2003 June 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12813472
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A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Author(s): Mason BJ, Goodman AM, Dixon RM, Hameed MH, Hulot T, Wesnes K, Hunter JA, Boyeson MG. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2002 October; 27(4): 596-606. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12377396
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A pilot double blind placebo controlled trial of sertraline with naltrexone in the treatment of opiate dependence. Author(s): Farren CK, O'Malley S. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2002 Summer; 11(3): 228-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12202015
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A pilot study to assess the impact of naltrexone implant on accidental opiate overdose in 'high-risk' adolescent heroin users. Author(s): Hulse GK, Tait RJ. Source: Addiction Biology. 2003 September; 8(3): 337-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13129836
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A possible role for implantable naltrexone in the management of the high-risk pregnant heroin user. Author(s): Hulse GK, O'Neill G. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2002 February; 42(1): 93-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11926651
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A preliminary report on possible naltrexone and nonsteroidal analgesic interactions. Author(s): Kim SW, Grant JE, Adson DE, Remmel RP. Source: Journal of Clinical Psychopharmacology. 2001 December; 21(6): 632-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11763022
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A systematic review on the efficacy of naltrexone maintenance treatment in opioid dependence. Author(s): Kirchmayer U, Davoli M, Verster AD, Amato L, Ferri A, Perucci CA. Source: Addiction (Abingdon, England). 2002 October; 97(10): 1241-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12359026
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Acamprosate and naltrexone treatment for alcohol dependence: an evidence-based risk-benefits assessment. Author(s): Mason BJ. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 2003 December; 13(6): 469-75. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14636963
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Acute opioid withdrawal on accidental injection of naltrexone. Author(s): Yeo M, Campbell V, Bonomo Y, Sawyer SM. Source: Journal of Paediatrics and Child Health. 2003 May-June; 39(4): 315-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12755943
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Addition of naltrexone to fluoxetine in the treatment of binge eating disorder. Author(s): Neumeister A, Winkler A, Wober-Bingol C. Source: The American Journal of Psychiatry. 1999 May; 156(5): 797. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10327921
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Adolescent kleptomania treated with naltrexone--a case report. Author(s): Grant JE, Kim SW. Source: European Child & Adolescent Psychiatry. 2002 April; 11(2): 92-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12033750
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Advances in the use of naltrexone: an integration of preclinical and clinical findings. Author(s): O'Malley SS, Froehlich JC. Source: Recent Dev Alcohol. 2003; 16: 217-45. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12638640
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Alcohol urge and plasma beta-endorphin change after alcohol challenge with naltrexone pretreatment in social drinkers. Author(s): Na C, Lee YS. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2002 May; 26(4): 663-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12188097
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An open-label study of naltrexone in the treatment of kleptomania. Author(s): Grant JE, Kim SW. Source: The Journal of Clinical Psychiatry. 2002 April; 63(4): 349-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12000210
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Antagonist-precipitated heroin withdrawal under anaesthetic prior to maintenance naltrexone treatment: determinants of withdrawal severity. Author(s): Ali R, Thomas P, White J, McGregor C, Danz C, Gowing L, Stegink A, Athanasos P. Source: Drug and Alcohol Review. 2003 December; 22(4): 425-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14660132
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Anxiolytics, adrenergic agents, and naltrexone. Author(s): Riddle MA, Bernstein GA, Cook EH, Leonard HL, March JS, Swanson JM. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1999 May; 38(5): 546-56. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10230186
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Behavioral family counseling and naltrexone for male opioid-dependent patients. Author(s): Fals-Stewart W, O'Farrell TJ. Source: Journal of Consulting and Clinical Psychology. 2003 June; 71(3): 432-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12795568
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Behavioral naltrexone therapy: an integrated treatment for opiate dependence. Author(s): Rothenberg JL, Sullivan MA, Church SH, Seracini A, Collins E, Kleber HD, Nunes EV. Source: Journal of Substance Abuse Treatment. 2002 December; 23(4): 351-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12495797
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Behavioral responses to ethanol in light and moderate social drinkers following naltrexone pretreatment. Author(s): Doty P, Kirk JM, Cramblett MJ, de Wit H. Source: Drug and Alcohol Dependence. 1997 August 25; 47(2): 109-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9298332
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Behavioural and endocrine effects of naltrexone in male talapoin monkeys. Author(s): Meller RE, Keverne EB, Herbert J. Source: Pharmacology, Biochemistry, and Behavior. 1980 November; 13(5): 663-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7192404
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Beta-endorphin levels in peripheral blood mononuclear cells and long-term naltrexone treatment in autistic children. Author(s): Cazzullo AG, Musetti MC, Musetti L, Bajo S, Sacerdote P, Panerai A. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 1999 June; 9(4): 361-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10422898
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Binge eating disorder: response to naltrexone. Author(s): Marrazzi MA, Markham KM, Kinzie J, Luby ED. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 1995 February; 19(2): 143-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7735342
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Bioequivalence, dose-proportionality, and pharmacokinetics of naltrexone after oral administration. Author(s): Meyer MC, Straughn AB, Lo MW, Schary WL, Whitney CC. Source: The Journal of Clinical Psychiatry. 1984 September; 45(9 Pt 2): 15-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6469932
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Blockade of morphine dependence-related enhancement of secretory protein synthesis in the pons-medulla and striatum-septum by naltrexone. Author(s): Retz KC, Steele WJ. Source: Neuropharmacology. 1983 February; 22(2): 183-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6300721
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Blood morphine levels in naltrexone-exposed compared to non-naltrexone-exposed fatal heroin overdoses. Author(s): Arnold-Reed DE, Hulse GK, Hansson RC, Murray SD, O'Neil G, Basso MR, Holman CD. Source: Addiction Biology. 2003 September; 8(3): 343-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13129837
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Blood pressure monitoring at home for rapid opioid withdrawal with clonidine and naltrexone. Author(s): Brewer C. Source: Lancet. 1987 March 14; 1(8533): 621. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2881149
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Borderline personality, opioids, and naltrexone. Author(s): Saper JR. Source: Headache. 2000 October; 40(9): 765. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11091301
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Brief report: case reports on naltrexone use in children with autism: controlled observations regarding benefits and practical issues of medication management. Author(s): Williams PG, Allard A, Sears L, Dalrymple N, Bloom AS. Source: Journal of Autism and Developmental Disorders. 2001 February; 31(1): 103-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11439748
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Brief report: six months continuation treatment in naltrexone-responsive children with autism: an open-label case-control design. Author(s): Willemsen-Swinkels SH, Buitelaar JK, van Berckelaer-Onnes IA, van Engeland H. Source: Journal of Autism and Developmental Disorders. 1999 April; 29(2): 167-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10382138
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Case study: paradoxical response to naltrexone treatment of self-injurious behavior. Author(s): Benjamin S, Seek A, Tresise L, Price E, Gagnon M. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1995 February; 34(2): 238-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7896657
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Cessation of self-mutilation in a patient with borderline personality disorder treated with naltrexone. Author(s): McGee MD. Source: The Journal of Clinical Psychiatry. 1997 January; 58(1): 32-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9055839
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Chronic naltrexone treatment induces desensitization of the luteinizing hormone pulse generator for opioid blockade in hyperprolactinemic patients. Author(s): de Wit W, Schoute E, Schoemaker J. Source: The Journal of Clinical Endocrinology and Metabolism. 1995 May; 80(5): 1739-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7745028
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Clinical effects of naltrexone on autistic behavior. Author(s): Zingarelli G, Ellman G, Hom A, Wymore M, Heidorn S, Chicz-DeMet A. Source: Am J Ment Retard. 1992 July; 97(1): 57-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1497864
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Clinical efficacy of naltrexone: a one year follow up. Author(s): Resnick R, Aronoff M, Lonborg G, Kestenbaum R, Kauders F, Washton A, Hough G. Source: Nida Res Monogr. 1976 September; (9): 114-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1088899
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Combined use of trazodone-naltrexone versus clonidine-naltrexone in rapid withdrawal from methadone treatment. A comparative inpatient study. Author(s): Pozzi G, Conte G, De Risio S. Source: Drug and Alcohol Dependence. 2000 June 1; 59(3): 287-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10812288
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Combining ondansetron and naltrexone effectively treats biologically predisposed alcoholics: from hypotheses to preliminary clinical evidence. Author(s): Johnson BA, Ait-Daoud N, Prihoda TJ. Source: Alcoholism, Clinical and Experimental Research. 2000 May; 24(5): 737-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10832917
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Combining ondansetron and naltrexone reduces craving among biologically predisposed alcoholics: preliminary clinical evidence. Author(s): Ait-Daoud N, Johnson BA, Prihoda TJ, Hargita ID. Source: Psychopharmacology. 2001 February; 154(1): 23-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11292002
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Combining ondansetron and naltrexone treats biological alcoholics: corroboration of self-reported drinking by serum carbohydrate deficient transferrin, a biomarker. Author(s): Ait-Daoud N, Johnson BA, Javors M, Roache JD, Zanca NA. Source: Alcoholism, Clinical and Experimental Research. 2001 June; 25(6): 847-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11410720
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Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Author(s): Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R, Kampf P, Stracke R, Baehr M, Naber D, Wiedemann K. Source: Archives of General Psychiatry. 2003 January; 60(1): 92-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12511176
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Compliance to naltrexone treatment after ultra-rapid opiate detoxification: an open label naturalistic study. Author(s): Rabinowitz J, Cohen H, Tarrasch R, Kotler M. Source: Drug and Alcohol Dependence. 1997 August 25; 47(2): 77-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9298329
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Concurrent substance use and outcome in combined behavioral and naltrexone therapy for opiate dependence. Author(s): Church SH, Rothenberg JL, Sullivan MA, Bornstein G, Nunes EV. Source: The American Journal of Drug and Alcohol Abuse. 2001 August; 27(3): 441-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11506261
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Conservative management with naltrexone of an iatrogenic methadone overdose in an opiate-naive patient. Author(s): Dhopesh V, Yu E, Fudala PJ. Source: Journal of Clinical Psychopharmacology. 2002 April; 22(2): 231-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11910276
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Contingency management to enhance naltrexone treatment of opioid dependence: a randomized clinical trial of reinforcement magnitude. Author(s): Carroll KM, Sinha R, Nich C, Babuscio T, Rounsaville BJ. Source: Experimental and Clinical Psychopharmacology. 2002 February; 10(1): 54-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11866252
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Controlled, randomized trial in maintenance treatment of intravenous buprenorphine dependence with naltrexone, methadone or buprenorphine: a novel study. Author(s): Ahmadi J, Ahmadi K, Ohaeri J. Source: European Journal of Clinical Investigation. 2003 September; 33(9): 824-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12925043
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d-Amphetamine raises cortisol levels in schizophrenic patients with and without chronic naltrexone pretreatment. Author(s): van Kammen DP, Schulz SC. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 1985; 64(1): 35-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4067601
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Detection of alkylating agents by the analysis of amino acid residues in hemoglobin and urine. 1. The in vivo and in vitro effects of ethyl methanesulfonate, methyl methanesulfonate, hycanthone methanesulfonate, and naltrexone. Author(s): Truong L, Ward JB Jr, Legator MS. Source: Mutation Research. 1978 December; 54(3): 271-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=740012
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Determination of naltrexone and 6 beta-naltrexol in plasma by high-performance liquid chromatography with coulometric detection. Author(s): Zuccaro P, Altieri I, Betto P, Pacifici R, Ricciarello G, Pini LA, Sternieri E, Pichini S. Source: Journal of Chromatography. 1991 July 5; 567(2): 485-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1939481
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Determination of naltrexone and 6-beta-naltrexol in plasma by solid-phase extraction and gas chromatography-negative ion chemical ionization-mass spectrometry. Author(s): Huang W, Moody DE, Foltz RL, Walsh SL. Source: Journal of Analytical Toxicology. 1997 July-August; 21(4): 252-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9248940
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Development of rhabdomyolysis after rapid opioid detoxification with subcutaneous naltrexone maintenance therapy. Author(s): Chanmugam AS, Hengeller M, Ezenkwele U. Source: Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2000 March; 7(3): 303-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10730843
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Diazepam inhibits retroactive interference of memory in humans: pretreatment with naltrexone does not alter this effect. Author(s): Chaves ML, Pezzin S, Jardim CP, Izquierdo I. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 1990; 23(5): 417-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2095291
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Differential naltrexone antagonism of hydromorphone and pentazocine effects in human volunteers. Author(s): Preston KL, Bigelow GE. Source: The Journal of Pharmacology and Experimental Therapeutics. 1993 February; 264(2): 813-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7679737
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Discriminative stimulus effects of naltrexone in narcotic-naive and morphine-treated pigeons. Author(s): Valentino RJ, Herling S, Woods JH. Source: The Journal of Pharmacology and Experimental Therapeutics. 1983 February; 224(2): 307-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6681632
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Discriminative stimulus effects of naltrexone in the morphine-dependent rat. Author(s): Gellert VF, Holtzman SG. Source: The Journal of Pharmacology and Experimental Therapeutics. 1979 December; 211(3): 596-605. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=574545
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Dose-ranging kinetics and behavioral pharmacology of naltrexone and acamprosate, both alone and combined, in alcohol-dependent subjects. Author(s): Johnson BA, O'Malley SS, Ciraulo DA, Roache JD, Chambers RA, Sarid-Segal O, Couper D. Source: Journal of Clinical Psychopharmacology. 2003 June; 23(3): 281-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826990
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Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling. Author(s): Kim SW, Grant JE, Adson DE, Shin YC. Source: Biological Psychiatry. 2001 June 1; 49(11): 914-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11377409
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Duration of occupancy of opiate receptors by naltrexone. Author(s): Lee MC, Wagner HN Jr, Tanada S, Frost JJ, Bice AN, Dannals RF. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1988 July; 29(7): 1207-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2839637
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Effect of long-term naltrexone treatment on endocrine profile, clinical features, and insulin sensitivity in obese women with polycystic ovary syndrome. Author(s): Fruzzetti F, Bersi C, Parrini D, Ricci C, Genazzani AR. Source: Fertility and Sterility. 2002 May; 77(5): 936-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12009347
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Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence. Author(s): King AC, Volpicelli JR, Frazer A, O'Brien CP. Source: Psychopharmacology. 1997 January; 129(1): 15-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9122358
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Effect of naltrexone on weight gain and food craving induced by tricyclic antidepressants and lithium: an open study. Author(s): Zimmermann U, Rechlin T, Plaskacewicz GJ, Barocka A, Wildt L, Kaschka WP. Source: Biological Psychiatry. 1997 March 15; 41(6): 747-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9067000
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Effect of naltrexone upon self-injurious behavior, learning and activity: a case study. Author(s): Taylor DV, Hetrick WP, Neri CL, Touchette P, Barron JL, Sandman CA. Source: Pharmacology, Biochemistry, and Behavior. 1991 September; 40(1): 79-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1780350
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Effective treatment of pruritus with naltrexone, an orally active opiate antagonist. Author(s): Metze D, Reimann S, Luger TA. Source: Annals of the New York Academy of Sciences. 1999 October 20; 885: 430-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10816681
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Effects of chronic treatment with methadone and naltrexone on sleep in addicts. Author(s): Staedt J, Wassmuth F, Stoppe G, Hajak G, Rodenbeck A, Poser W, Ruther E. Source: European Archives of Psychiatry and Clinical Neuroscience. 1996; 246(6): 305-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8908412
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Effects of dexamethasone and dexamethasone plus naltrexone on pituitary response to GnRH and TRH in normal women. Author(s): la Marca A, Torricelli M, Morgante G, Lanzetta D, De Leo V. Source: Hormone Research. 1999; 51(2): 85-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10352398
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Effects of naltrexone and isradipine, alone or in combination, on cocaine responses in humans. Author(s): Sofuoglu M, Singha A, Kosten TR, McCance-Katz FE, Petrakis I, Oliveto A. Source: Pharmacology, Biochemistry, and Behavior. 2003 July; 75(4): 801-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957222
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Effects of naltrexone on food intake and changes in subjective appetite during eating: evidence for opioid involvement in the appetizer effect. Author(s): Yeomans MR, Gray RW. Source: Physiology & Behavior. 1997 July; 62(1): 15-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9226337
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Effects of naltrexone on mannerisms and water imbalance in polydipsic schizophrenics: a pilot study. Author(s): Becker JA, Goldman MB, Alam MY, Luchins DJ. Source: Schizophrenia Research. 1995 November; 17(3): 279-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8664207
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Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans. Author(s): Walsh SL, Sullivan JT, Preston KL, Garner JE, Bigelow GE. Source: The Journal of Pharmacology and Experimental Therapeutics. 1996 November; 279(2): 524-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8930154
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Effects of opioid antagonism with naltrexone on pulsatile luteinizing hormone secretion in women with hypothalamic amenorrhea in basal conditions and after discontinuation of treatment with pulsatile LHRH. Author(s): Armeanu MC, Lambalk CB, Berkhout GM, Schoemaker J. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 1992 March; 6(1): 3-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1580165
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Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. Author(s): Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Source: Journal of Hepatology. 2002 December; 37(6): 717-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12445410
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Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis. Author(s): Kranzler HR, Van Kirk J. Source: Alcoholism, Clinical and Experimental Research. 2001 September; 25(9): 1335-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11584154
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Efficacy of naltrexone on acetylcholine-induced alloknesis in atopic eczema. Author(s): Heyer G, Groene D, Martus P. Source: Experimental Dermatology. 2002 October; 11(5): 448-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12366698
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Emergency department presentations of naltrexone-accelerated detoxification. Author(s): Armstrong J, Little M, Murray L. Source: Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2003 August; 10(8): 860-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12896887
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Even after priming with ovarian steroids or pulsatile gonadotropin-releasing hormone administration, naltrexone is unable to induce ovulation in women with functional hypothalamic amenorrhea. Author(s): Couzinet B, Young J, Brailly S, Chanson P, Schaison G. Source: The Journal of Clinical Endocrinology and Metabolism. 1995 July; 80(7): 2102-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7608262
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Evidence about the use of naltrexone and for different ways of using it in the treatment of alcoholism. Author(s): Sinclair JD. Source: Alcohol and Alcoholism (Oxford, Oxfordshire). 2001 January-February; 36(1): 210. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11139409
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Experience of a "slip" among alcoholics treated with naltrexone or placebo. Author(s): O'Malley SS, Jaffe AJ, Rode S, Rounsaville BJ. Source: The American Journal of Psychiatry. 1996 February; 153(2): 281-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8561215
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Experiences with an outpatient relapse program (community reinforcement approach) combined with naltrexone in the treatment of opioid-dependence: effect on addictive behaviors and the predictive value of psychiatric comorbidity. Author(s): Roozen HG, Kerkhof AJ, van den Brink W. Source: European Addiction Research. 2003 April; 9(2): 53-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644730
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Failure of naltrexone hydrochloride to reduce self-injurious and autistic behavior in mentally retarded adults. Double-blind placebo-controlled studies. Author(s): Willemsen-Swinkels SH, Buitelaar JK, Nijhof GJ, van England H. Source: Archives of General Psychiatry. 1995 September; 52(9): 766-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7654128
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Failure of naltrexone to affect the pleasantness or intake of food. Author(s): Hetherington MM, Vervaet N, Blass E, Rolls BJ. Source: Pharmacology, Biochemistry, and Behavior. 1991 September; 40(1): 185-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1780340
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First, do no harm: naltrexone-accelerated detoxification. Author(s): Gaughwin MD. Source: The Medical Journal of Australia. 1999 November 1; 171(9): 499. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10615346
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Five-year follow-up of opiate addicts with naltrexone and behavior therapy. Author(s): Rawson RA, Tennant FS Jr. Source: Nida Res Monogr. 1984 March; 49: 289-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6434974
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Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis. Author(s): Jones EA, Dekker LR. Source: Gastroenterology. 2000 February; 118(2): 431-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10648471
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Formulation and stability of naltrexone oral liquid for rapid withdrawal from methadone. Author(s): Fawcett JP, Morgan NC, Woods DJ. Source: The Annals of Pharmacotherapy. 1997 November; 31(11): 1291-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9391680
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Gas chromatography/tandem mass spectrometry measurement of delta 9tetrahydrocannabinol, naltrexone, and their active metabolites in plasma. Author(s): Nelson CC, Fraser MD, Wilfahrt JK, Foltz RL. Source: Therapeutic Drug Monitoring. 1993 December; 15(6): 557-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8122294
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Heroin addiction and naltrexone. Author(s): Byrne A. Source: Aust Fam Physician. 1998 May; 27(5): 344. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9612997
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Heroin and naltrexone effects on pituitary-gonadal hormones in man: interaction of steroid feedback effects, tolerance and supersensitivity. Author(s): Mendelson JH, Ellingboe J, Kuehnle JC, Mello NK. Source: The Journal of Pharmacology and Experimental Therapeutics. 1980 September; 214(3): 503-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7400959
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Heroin and naltrexone effects on pituitary-gonadal hormones in man: tolerance and supersensitivity. Author(s): Mendelson JH, Ellingboe J, Kuehnle J, Mello NK. Source: Nida Res Monogr. 1979; 27: 302-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=121347
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High dose naltrexone for dyskinesias induced by levodopa. Author(s): Manson AJ, Katzenschlager R, Hobart J, Lees AJ. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2001 April; 70(4): 554-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11254789
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High-dose naltrexone and liver function safety. Author(s): Marrazzi MA, Wroblewski JM, Kinzie J, Luby ED. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 1997 Winter; 6(1): 21-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9097868
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High-dose naltrexone therapy and dietary counseling for obesity. Author(s): Mitchell JE, Morley JE, Levine AS, Hatsukami D, Gannon M, Pfohl D. Source: Biological Psychiatry. 1987 January; 22(1): 35-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3790639
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High-performance liquid chromatographic determination of naltrexone in plasma of hemodialysis patients. Author(s): Kambia K, Bah S, Dine T, Azar R, Odou P, Gressier B, Luyckx M, Brunet C, Ballester L, Cazin M, Cazin JC. Source: Biomedical Chromatography : Bmc. 2000 May; 14(3): 151-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10850617
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Hormonal and other effects of naltrexone in normal men. Author(s): Volavka J, Mallya A, Bauman J, Pevnick J, Cho D, Reker D, James B, Dornbush R. Source: Advances in Experimental Medicine and Biology. 1979; 116: 291-305. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=224675
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Hostility in heroin abusers subtypes: fluoxetine and naltrexone treatment. Author(s): Gerra G, Fertonani G, Zaimovic A, Rota-Graziosi I, Avanzini P, Caccavari R, Delsignore R, Lucchini A. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1995 December; 19(8): 1225-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8868205
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How is naltrexone used in the treatment of alcoholism? Author(s): Osser DN. Source: The Harvard Mental Health Letter / from Harvard Medical School. 1998 December; 15(6): 8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9833574
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Hyperthermia in the rat from handling stress blocked by naltrexone injected into the preoptic-anterior hypothalamus. Author(s): Pae YS, Lai H, Horita A. Source: Pharmacology, Biochemistry, and Behavior. 1985 February; 22(2): 337-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4039067
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Hypothalamic-pituitary-adrenocortical (HPA) axis response and biotransformation of oral naltrexone: preliminary examination of relationship to family history of alcoholism. Author(s): King AC, Schluger J, Gunduz M, Borg L, Perret G, Ho A, Kreek MJ. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2002 June; 26(6): 778-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12007748
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Idiosyncratic reaction to naltrexone augmented by thioridazine. Author(s): Malcolm R, Gabel T, Morton A. Source: The American Journal of Psychiatry. 1988 June; 145(6): 773-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3369583
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Impact of long-term naltrexone treatment on growth hormone and insulin secretion in hyperandrogenic and normal obese patients. Author(s): Villa P, Fulghesu AM, De Marinis L, Valle D, Mancini A, Pavone V, Caruso A, Lanzone A. Source: Metabolism: Clinical and Experimental. 1997 May; 46(5): 538-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9160821
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Improvement in naltrexone treatment compliance with contingency management. Author(s): Preston KL, Silverman K, Umbricht A, DeJesus A, Montoya ID, Schuster CR. Source: Drug and Alcohol Dependence. 1999 April 1; 54(2): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10217552
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Improvement of the oral bioavailability of naltrexone in dogs: a prodrug approach. Author(s): Hussain MA, Koval CA, Myers MJ, Shami EG, Shefter E. Source: Journal of Pharmaceutical Sciences. 1987 May; 76(5): 356-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3656096
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Improving naltrexone response: an intervention for medical practitioners to enhance medication compliance in alcohol dependent patients. Author(s): Pettinati HM, Volpicelli JR, Pierce JD Jr, O'Brien CP. Source: Journal of Addictive Diseases : the Official Journal of the Asam, American Society of Addiction Medicine. 2000; 19(1): 71-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10772604
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Increase in plasma melatonin, beta-endorphin, and cortisol after a 28.5-mile mountain race: relationship to performance and lack of effect of naltrexone. Author(s): Strassman RJ, Appenzeller O, Lewy AJ, Qualls CR, Peake GT. Source: The Journal of Clinical Endocrinology and Metabolism. 1989 September; 69(3): 540-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2527243
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Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhea. Author(s): Wildt L, Leyendecker G. Source: The Journal of Clinical Endocrinology and Metabolism. 1987 June; 64(6): 1334-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3571432
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Influence of chronic naltrexone treatment on growth hormone secretion in normal subjects. Author(s): Villa P, Valle D, De Marinis L, Mancini A, Bianchi A, Fulghesu AM, Caruso A, Mancuso S, Lanzone A. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 1997 December; 137(6): 631-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9437228
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Influence of naltrexone on cue-elicited craving among hazardous drinkers: the moderational role of positive outcome expectancies. Author(s): Palfai T, Davidson D, Swift R. Source: Experimental and Clinical Psychopharmacology. 1999 August; 7(3): 266-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10472515
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Inhibition of human colon cancer by intermittent opioid receptor blockade with naltrexone. Author(s): Hytrek SD, McLaughlin PJ, Lang CM, Zagon IS. Source: Cancer Letters. 1996 March 29; 101(2): 159-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8620464
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Initial aggravation of self-injurious behavior in autistic patients receiving naltrexone treatment. Author(s): Knabe R, Schulz P, Richard J. Source: Journal of Autism and Developmental Disorders. 1990 December; 20(4): 591-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2279977
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Initial and maintenance naltrexone treatment for alcohol dependence using primary care vs specialty care: a nested sequence of 3 randomized trials. Author(s): O'Malley SS, Rounsaville BJ, Farren C, Namkoong K, Wu R, Robinson J, O'Connor PG. Source: Archives of Internal Medicine. 2003 July 28; 163(14): 1695-704. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12885685
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Interaction between naltrexone and oral THC in heavy marijuana smokers. Author(s): Haney M, Bisaga A, Foltin RW. Source: Psychopharmacology. 2003 February; 166(1): 77-85. Epub 2002 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12491025
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Interaction between thioridazine and naltrexone. Author(s): Maany I, O'Brien CP, Woody G. Source: The American Journal of Psychiatry. 1987 July; 144(7): 966. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3605414
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Intraoperative high-dose remifentanil in a patient on naltrexone therapy. Author(s): Schwab CA, Wright DA. Source: Anaesthesia and Intensive Care. 2000 December; 28(6): 701-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11153302
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Intravenous cocaine challenges during naltrexone maintenance: a preliminary study. Author(s): Kosten T, Silverman DG, Fleming J, Kosten TA, Gawin FH, Compton M, Jatlow P, Byck R. Source: Biological Psychiatry. 1992 September 15; 32(6): 543-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1445971
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Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the "address" recognition locus. Author(s): Metzger TG, Paterlini MG, Ferguson DM, Portoghese PS. Source: Journal of Medicinal Chemistry. 2001 March 15; 44(6): 857-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11300867
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Is naltrexone a cure for heroin dependence? Author(s): Hall WD, Wodak A. Source: The Medical Journal of Australia. 1999 July 5; 171(1): 9-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10451663
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Isolation and identification of a new metabolite of naltrexone in human blood and urine. Author(s): Verebely K, Chedekel MA, Mule SJ, Rosenthal D. Source: Res Commun Chem Pathol Pharmacol. 1975 September; 12(1): 67-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1188187
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Isolation and stereochemical identification of a metabolite of naltrexone from human urine. Author(s): Chatterjie N, Fujimoto JM, Inturrisi CE, Roerig S, Wang RI, Bowen DV, Field FH, Clarke DD. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 1974 September-October; 2(5): 401-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4156301
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Kinetics and inhibition of the formation of 6beta-naltrexol from naltrexone in human liver cytosol. Author(s): Porter SJ, Somogyi AA, White JM. Source: British Journal of Clinical Pharmacology. 2000 November; 50(5): 465-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11069441
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Kinetics of a naltrexone sustained-release preparation. Author(s): Chiang CN, Hollister LE, Kishimoto A, Barnett G. Source: Clinical Pharmacology and Therapeutics. 1984 November; 36(5): 704-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6488691
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Lack of efficacy of naltrexone in the prevention of alcohol relapse: results from a German multicenter study. Author(s): Gastpar M, Bonnet U, Boning J, Mann K, Schmidt LG, Soyka M, Wetterling T, Kielstein V, Labriola D, Croop R. Source: Journal of Clinical Psychopharmacology. 2002 December; 22(6): 592-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454559
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Lack of hepatotoxicity with naltrexone treatment. Author(s): Sax DS, Kornetsky C, Kim A. Source: Journal of Clinical Pharmacology. 1994 September; 34(9): 898-901. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7983232
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Learning the language of abstinence in addiction treatment: some similarities between relapse-prevention with disulfiram, naltrexone, and other pharmacological antagonists and intensive "immersion" methods of foreign language teaching. Author(s): Brewer C, Streel E. Source: Substance Abuse : Official Publication of the Association for Medical Education and Research in Substance Abuse. 2003 September; 24(3): 157-73. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12913365
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Letter: Treatment of accidental naltrexone-induced withdrawal. Author(s): Volavka J, Resnick RB. Source: The American Journal of Psychiatry. 1976 February; 133(2): 233. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=56139
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Long-term effects of naltrexone on self-injurious behavior. Author(s): Sandman CA, Hetrick W, Taylor DV, Marion SD, Touchette P, Barron JL, Martinezzi V, Steinberg RM, Crinella FM. Source: Am J Ment Retard. 2000 March; 105(2): 103-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10755174
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Long-term naltrexone treatment normalizes the pituitary response to gonadotropinreleasing hormone in polycystic ovarian syndrome. Author(s): Lanzone A, Apa R, Fulghesu AM, Cutillo G, Caruso A, Mancuso S. Source: Fertility and Sterility. 1993 April; 59(4): 734-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8458488
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Long-term naltrexone treatment reduces the exaggerated insulin secretion in patients with polycystic ovary disease. Author(s): Fulghesu AM, Lanzone A, Cucinelli F, Caruso A, Mancuso S. Source: Obstetrics and Gynecology. 1993 August; 82(2): 191-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8336863
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Long-term response to naltrexone in polycystic ovary syndrome? Author(s): Cagnacci A, Paoletti AM. Source: Fertility and Sterility. 2003 March; 79(3): 659; Author Reply 659-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12620465
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Loss of the cortisol response to naltrexone in Alzheimer's disease. Author(s): Pomara N, Stanley M, Rhiew HB, Bagne CA, Deptula D, Galloway MP, Tanimoto K, Verebey K, Tamminga CA. Source: Biological Psychiatry. 1988 April 1; 23(7): 726-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3285899
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Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Author(s): Bouvard MP, Leboyer M, Launay JM, Recasens C, Plumet MH, WallerPerotte D, Tabuteau F, Bondoux D, Dugas M, Lensing P, et al. Source: Psychiatry Research. 1995 October 16; 58(3): 191-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8570775
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Measurement of compliance with naltrexone in the treatment of alcohol dependence: research and clinical implications. Author(s): Namkoong K, Farren CK, O'Connor PG, O'Malley SS. Source: The Journal of Clinical Psychiatry. 1999 July; 60(7): 449-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10453799
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Medical management of alcohol dependence: clinical use and limitations of naltrexone treatment. Author(s): Volpicelli JR, Volpicelli LA, O'Brien CP. Source: Alcohol and Alcoholism (Oxford, Oxfordshire). 1995 November; 30(6): 789-98. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8679021
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Metabolic reduction of naltrexone. I. Synthesis, separation and characterization of naloxone and naltrexone reduction products and qualitative assay of urine and bile following administration of naltrexone, alpha-naltrexol, or beta-naltrexol. Author(s): Malspeis L, Bathala MS, Ludden TM, Bhat HB, Frank SG, Sokoloski TD, Morrison BE, Reuning RH. Source: Res Commun Chem Pathol Pharmacol. 1975 September; 12(1): 43-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=810832
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Metabolism and disposition of naltrexone in man after oral and intravenous administration. Author(s): Wall ME, Brine DR, Perez-Reyes M. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 1981 JulyAugust; 9(4): 369-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6114837
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Methadone and naltrexone in the treatment of heroin dependence. Author(s): Greenstein RA, Resnick RB, Resnick E. Source: The Psychiatric Clinics of North America. 1984 December; 7(4): 671-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6522309
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Methadone vs naltrexone. Author(s): Blansfield HN. Source: Conn Med. 1997 January; 61(1): 53-4. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9040159
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Misuse of naltrexone. Author(s): Measom MO. Source: The Journal of Clinical Psychiatry. 1996 October; 57(10): 488-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8909339
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More on idiosyncratic reaction to naltrexone. Author(s): Malcolm R, Gabel T, Morton A. Source: The American Journal of Psychiatry. 1989 January; 146(1): 124-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2912237
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Multiple family therapy and naltrexone in the treatment of opiate dependence. Author(s): Anton RF, Hogan I, Jalali B, Riordan CE, Kleber HD. Source: Drug and Alcohol Dependence. 1981 September; 8(2): 157-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7318681
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Multiple, single-dose naltrexone administrations fail to effect overall cognitive functioning and plasma cortisol in individuals with probable Alzheimer's disease. Author(s): Pomara N, Roberts R, Rhiew HB, Stanley M, Gershon S. Source: Neurobiology of Aging. 1985 Fall; 6(3): 233-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3903533
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Naltrexone and communication skills in young children with autism. Author(s): Feldman HM, Kolmen BK, Gonzaga AM. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1999 May; 38(5): 587-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10230191
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Naltrexone and dysphoria: fact or myth? Author(s): Miotto K, McCann M, Basch J, Rawson R, Ling W. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2002 Spring; 11(2): 151-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12028745
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Naltrexone and nicotine patch smoking cessation: a preliminary study. Author(s): Krishnan-Sarin S, Meandzija B, O'Malley S. Source: Nicotine & Tobacco Research : Official Journal of the Society for Research on Nicotine and Tobacco. 2003 December; 5(6): 851-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14750508
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Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia. Author(s): Petrakis IL, O'Malley S, Rounsaville B, Poling J, McHugh-Strong C, Krystal JH; VA Naltrexone Study Collaboration Group. Source: Psychopharmacology. 2004 March; 172(3): 291-7. Epub 2003 November 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14634716
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Naltrexone blockade of nicotine effects in cigarette smokers. Author(s): Brauer LH, Behm FM, Westman EC, Patel P, Rose JE. Source: Psychopharmacology. 1999 April; 143(4): 339-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10367550
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Naltrexone effects on alcohol consumption in a clinical laboratory paradigm: temporal effects of drinking. Author(s): Anton RF, Drobes DJ, Voronin K, Durazo-Avizu R, Moak D. Source: Psychopharmacology. 2004 April; 173(1-2): 32-40. Epub 2004 January 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722705
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Naltrexone effects on short-term and long-term smoking cessation. Author(s): Covey LS, Glassman AH, Stetner F. Source: Journal of Addictive Diseases : the Official Journal of the Asam, American Society of Addiction Medicine. 1999; 18(1): 31-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10234561
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Naltrexone improves outcome of a controlled drinking program. Author(s): Rubio G, Manzanares J, Lopez-Munoz F, Alamo C, Ponce G, Jimenez-Arriero MA, Palomo T. Source: Journal of Substance Abuse Treatment. 2002 December; 23(4): 361-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12495798
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Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting. Author(s): Cochrane Database Syst Rev. 2003;(2):CD001333 Source: The Medical Journal of Australia. 2002 June 3; 176(11): 530-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804405
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Naltrexone in the treatment of alcohol dependence: a Canadian trial. Author(s): Romach MK, Sellers EM, Somer GR, Landry M, Cunningham GM, Jovey RD, McKay C, Boislard J, Mercier C, Pepin JM, Perreault J, Lemire E, Baker RP, Campbell W, Ryan D. Source: Can J Clin Pharmacol. 2002 Fall; 9(3): 130-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12422250
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Naltrexone treatment for alcoholics: effect on cigarette smoking rates. Author(s): Rohsenow DJ, Monti PM, Colby SM, Gulliver SB, Swift RM, Abrams DB. Source: Nicotine & Tobacco Research : Official Journal of the Society for Research on Nicotine and Tobacco. 2003 April; 5(2): 231-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12745496
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Naltrexone-bupropion combination therapy for protracted abstinence dysphoria. Author(s): Williams J, Ziedonis DM. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2003 May-June; 12(3): 270-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851023
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Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous lowdose interleukin-2, melatonin and naltrexone: modulation of interleukin-2-induced antitumor immunity by blocking the opioid system. Author(s): Lissoni P, Malugani F, Malysheva O, Kozlov V, Laudon M, Conti A, Maestroni G. Source: Neuro Endocrinol Lett. 2002 August; 23(4): 341-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12195238
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Occurrence and management of depression in the context of naltrexone treatment of alcoholism. Author(s): Farren CK, O'Malley SS. Source: The American Journal of Psychiatry. 1999 August; 156(8): 1258-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10450269
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Operant analysis of human heroin self-administration and the effects of naltrexone. Author(s): Mello NK, Mendelson JH, Kuehnle JC, Sellers MS. Source: The Journal of Pharmacology and Experimental Therapeutics. 1981 January; 216(1): 45-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7452507
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Opiate addiction and plasma beta-endorphin-like immunoreactivity: methadone maintained, recently detoxified and early naltrexone treated ex-addicts. Author(s): Cushman P, Morris D, Adams M, Dewey W. Source: Alcohol Drug Res. 1987; 7(5-6): 533-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2956960
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Opiate addiction and the locus coeruleus. The clinical utility of clonidine, naltrexone, methadone, and buprenorphine. Author(s): Gold MS. Source: The Psychiatric Clinics of North America. 1993 March; 16(1): 61-73. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8456048
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Opiate antagonists in erectile dysfunction: a possible new treatment option? Results of a pilot study with naltrexone. Author(s): van Ahlen H, Piechota HJ, Kias HJ, Brennemann W, Klingmuller D. Source: European Urology. 1995; 28(3): 246-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8536780
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Opioid antagonist (naltrexone) stimulation of cell proliferation in human and animal neuroblastoma and human fibrosarcoma cells in culture. Author(s): Zagon IS, McLaughlin PJ. Source: Neuroscience. 1990; 37(1): 223-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2243594
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Opioid withdrawal and naltrexone induction in 48-72 hours with minimal drop-out, using a modification of the naltrexone-clonidine technique. Author(s): Brewer C, Rezae H, Bailey C. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1988 September; 153: 340-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3250670
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Opioid-immune interactions in autism: behavioural and immunological assessment during a double-blind treatment with naltrexone. Author(s): Scifo R, Cioni M, Nicolosi A, Batticane N, Tirolo C, Testa N, Quattropani MC, Morale MC, Gallo F, Marchetti B. Source: Ann Ist Super Sanita. 1996; 32(3): 351-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9028057
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Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Author(s): Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Source: Gastroenterology. 1997 October; 113(4): 1264-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9322521
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Outcomes of naltrexone maintenance following ultra rapid opiate detoxification versus intensive inpatient detoxification. Author(s): Rabinowitz J, Cohen H, Atias S. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2002 Winter; 11(1): 52-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11876583
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Outcomes of ultrarapid opiate detoxification combined with naltrexone maintenance and counseling. Author(s): Rabinowitz J, Cohen H, Kotler M. Source: Psychiatric Services (Washington, D.C.). 1998 June; 49(6): 831-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9634168
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Outpatient cognitive behavioural therapy programme for alcohol dependence: impact of naltrexone use on outcome. Author(s): Feeney GF, Young RM, Connor JP, Tucker J, McPherson A. Source: The Australian and New Zealand Journal of Psychiatry. 2001 August; 35(4): 4438. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11531723
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Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts. Author(s): Miotto K, McCann MJ, Rawson RA, Frosch D, Ling W. Source: Drug and Alcohol Dependence. 1997 April 14; 45(1-2): 131-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9179515
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Ovulation induction with a single-blind treatment regimen comparing naltrexone, placebo and clomiphene citrate in women with secondary amenorrhea. Author(s): Armeanu MC, Moss RJ, Schoemaker J. Source: Acta Endocrinol (Copenh). 1992 May; 126(5): 410-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1621484
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Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naive healthy male volunteers under a naltrexone block. Author(s): McAleer SD, Mills RJ, Polack T, Hussain T, Rolan PE, Gibbs AD, Mullins FG, Hussein Z. Source: Drug and Alcohol Dependence. 2003 October 24; 72(1): 75-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14563545
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Phase II clinical trials of buprenorphine: detoxification and induction onto naltrexone. Author(s): Kosten TR, Morgan C, Kleber HD. Source: Nida Res Monogr. 1992; 121: 101-19. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1406906
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Pilot study of the use of naltrexone to treat the severe pruritus of cholestatic liver disease. Author(s): Carson KL, Tran TT, Cotton P, Sharara AI, Hunt CM. Source: The American Journal of Gastroenterology. 1996 May; 91(5): 1022-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8633543
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Placebo-controlled acute dosage naltrexone study in young autistic children. Author(s): Willemsen-Swinkels SH, Buitelaar JK, Weijnen FG, van Engeland H. Source: Psychiatry Research. 1995 October 16; 58(3): 203-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8570776
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Plasma beta-endorphin levels, naltrexone, and haloperidol in autistic children. Author(s): Ernst M, Devi L, Silva RR, Gonzalez NM, Small AM, Malone RP, Campbell M. Source: Psychopharmacology Bulletin. 1993; 29(2): 221-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8290669
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Posttreatment results of combining naltrexone with cognitive-behavior therapy for the treatment of alcoholism. Author(s): Anton RF, Moak DH, Latham PK, Waid LR, Malcolm RJ, Dias JK, Roberts JS. Source: Journal of Clinical Psychopharmacology. 2001 February; 21(1): 72-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11199951
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Preclinical evaluation of the effects of buprenorphine, naltrexone and desipramine on cocaine self-administration. Author(s): Mello NK. Source: Nida Res Monogr. 1991; 105: 189-95. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1875998
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Predictors of compliance with naltrexone among alcoholics. Author(s): Rohsenow DJ, Colby SM, Monti PM, Swift RM, Martin RA, Mueller TI, Gordon A, Eaton CA. Source: Alcoholism, Clinical and Experimental Research. 2000 October; 24(10): 1542-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11045863
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Preparation of oral naltrexone solution. Author(s): Abboud TK. Source: Anesthesiology. 1990 July; 73(1): 190-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2360733
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Prevention of suicide by naltrexone in a recently detoxified heroin addict. Author(s): Krupitsky EM, Masalov DV, Didenko TY, Burakov AM, Romanova TN, Zvartau EE, Woody G. Source: European Addiction Research. 2001 July; 7(2): 87-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11455175
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Prolonged opioid blockade with naltrexone and luteinizing hormone modifications in women with polycystic ovarian syndrome. Author(s): Cagnacci A, Soldani R, Paoletti AM, Falqui A, Melis GB. Source: Fertility and Sterility. 1994 August; 62(2): 269-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8034071
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Prophylactic oral naltrexone with intrathecal morphine for cesarean section: effects on adverse reactions and analgesia. Author(s): Abboud TK, Lee K, Zhu J, Reyes A, Afrasiabi A, Mantilla M, Steffens Z, Chai M. Source: Anesthesia and Analgesia. 1990 October; 71(4): 367-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2205128
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Pulsatile administration of gonadotrophin releasing hormone and oral administration of naltrexone in hypothalamic amenorrhoea. Author(s): Leyendecker G, Waibel-Treber S, Wildt L. Source: Human Reproduction (Oxford, England). 1993 November; 8 Suppl 2: 184-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8276957
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Pulsatile luteinizing hormone secretion in hypothalamic amenorrhea, anorexia nervosa, and polycystic ovarian disease during naltrexone treatment. Author(s): Armeanu MC, Berkhout GM, Schoemaker J. Source: Fertility and Sterility. 1992 April; 57(4): 762-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1555686
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Pulsatile secretion of luteinizing hormone and prolactin in lactating and nonlactating women and the response to naltrexone. Author(s): Kremer JA, Borm G, Schellekens LA, Thomas CM, Rolland R. Source: The Journal of Clinical Endocrinology and Metabolism. 1991 February; 72(2): 294-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1899421
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Quantification of naltrexone and 6,beta-naltrexol in plasma and milk using gas chromatography-mass spectrometry. Application to studies in the lactating sheep. Author(s): Chan CF, Chiswell GM, Bencini R, Hackett LP, Dusci LJ, Ilett KF. Source: J Chromatogr B Biomed Sci Appl. 2001 September 15; 761(1): 85-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11585135
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Quantitative determination of 2-hydroxy-3-methoxy-6 beta-naltrexol (HMN), naltrexone, and 6 beta-naltrexol in human plasma, red blood cells, saliva, and urine by gas liquid chromatography. Author(s): Verebey K, De Pace A, Jukofsky D, Volavka JV, Mule SJ. Source: Journal of Analytical Toxicology. 1980 January-February; 4(1): 33-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6927049
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Quantitative determination of naltrexone and beta-naltrexol in human plasma using electron detection. Author(s): Verebey K, Kogan MJ, DePace A, Mule SJ. Source: Journal of Chromatography. 1976 April 7; 118(3): 331-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1254668
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Quantitative determination of naltrexone, 6 beta-naltrexol and 2-hydroxy-3-methoxy-6 beta-naltrexol (HMN) in human plasma, red blood cells, saliva and urine by gas liquid chromatography. Author(s): Verebey K. Source: Nida Res Monogr. 1981; 28: 36-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6791012
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Radioendocrine therapy of brain tumors with the long acting opioid antagonist naltrexone in association with radiotherapy. Author(s): Lissoni P, Meregalli S, Fossati V, Barni S, Tancini G, Barigozzi P, Frigerio F. Source: Tumori. 1993 June 30; 79(3): 198-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8236504
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Randomised crossover trial of naltrexone in uraemic pruritus. Author(s): Peer G, Kivity S, Agami O, Fireman E, Silverberg D, Blum M, laina A. Source: Lancet. 1996 December 7; 348(9041): 1552-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8950882
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Rapid opiate detoxication in outpatient treatment: relationship with naltrexone compliance. Author(s): Gerra G, Zaimovic A, Rustichelli P, Fontanesi B, Zambelli U, Timpano M, Bocchi C, Delsignore R. Source: Journal of Substance Abuse Treatment. 2000 March; 18(2): 185-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10716102
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Rapid transition from methadone maintenance to naltrexone. Author(s): Loimer N, Lenz K, Presslich O, Schmid R. Source: Lancet. 1990 January 13; 335(8681): 111. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1967391
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Regional cerebral blood flow changes in chronic alcoholic patients induced by naltrexone challenge during detoxification. Author(s): Catafau AM, Etcheberrigaray A, Perez de los Cobos J, Estorch M, Guardia J, Flotats A, Berna L, Mari C, Casas M, Carrio I. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1999 January; 40(1): 19-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9935051
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Relative bioavailability of controlled-release oral morphine sulfate during naltrexone blockade. Author(s): Bashaw ED, Kaiko RF, Grandy RP, Reder RF, Goldenheim PD. Source: Int J Clin Pharmacol Ther. 1995 September; 33(9): 524-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8520812
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Repeated administration of naltrexone and diprenorphine decreases food intake and body weight in squirrel monkeys. Author(s): Herman BH, Holtzman SG. Source: Life Sciences. 1984 January 2; 34(1): 1-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6319931
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Reproductive toxicity and teratology evaluations of naltrexone. Author(s): Christian MS. Source: The Journal of Clinical Psychiatry. 1984 September; 45(9 Pt 2): 7-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6469938
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Research to practice: adoption of naltrexone in alcoholism treatment. Author(s): Thomas CP, Wallack SS, Lee S, McCarty D, Swift R. Source: Journal of Substance Abuse Treatment. 2003 January; 24(1): 1-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12646325
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Resolution of treatment-refractory depression with naltrexone augmentation of paroxetine--a case report. Author(s): Amiaz R, Stein O, Dannon PN, Grunhaus L, Schreiber S. Source: Psychopharmacology. 1999 April; 143(4): 433-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10367562
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Resolved: autistic children should have a trial of naltrexone. Author(s): Campbell M, Harris JC. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1996 February; 35(2): 246-9; Discussion 249-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8720635
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Rett syndrome: controlled study of an oral opiate antagonist, naltrexone. Author(s): Percy AK, Glaze DG, Schultz RJ, Zoghbi HY, Williamson D, Frost JD Jr, Jankovic JJ, del Junco D, Skender M, Waring S, et al. Source: Annals of Neurology. 1994 April; 35(4): 464-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8154874
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Reversal of self-abusive behavior with naltrexone. Author(s): Lienemann J, Walker FD. Source: Journal of Clinical Psychopharmacology. 1989 December; 9(6): 448-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2592592
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Review of naltrexone, a long-acting opiate antagonist. Author(s): Crabtree BL. Source: Clin Pharm. 1984 May-June; 3(3): 273-80. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6329589
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Rhabdomyolysis associated with naltrexone. Author(s): Zaim S, Wiley DB, Albano SA. Source: The Annals of Pharmacotherapy. 1999 March; 33(3): 312-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10200856
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Risks associated with the inappropriate use of naltrexone in the treatment of opioid dependence. Author(s): Latt NC. Source: The Medical Journal of Australia. 1999 November 1; 171(9): 500-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10615348
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Role of endogenous opiates in pubertal maturation: opposing actions of naltrexone in prepubertal and late pubertal boys. Author(s): Mauras N, Veldhuis JD, Rogol AD. Source: The Journal of Clinical Endocrinology and Metabolism. 1986 June; 62(6): 1256-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3517031
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Role of naltrexone in initial smoking cessation: preliminary findings. Author(s): King AC. Source: Alcoholism, Clinical and Experimental Research. 2002 December; 26(12): 1942-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12500129
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Selective effects of naltrexone on food pleasantness and intake. Author(s): Yeomans MR, Gray RW. Source: Physiology & Behavior. 1996 August; 60(2): 439-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8840904
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Selective naltrexone-derived opioid receptor antagonists. Author(s): Takemori AE, Portoghese PS. Source: Annual Review of Pharmacology and Toxicology. 1992; 32: 239-69. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1318671
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Sequential analysis of the effects of naltrexone on the environmental mediation of self-injurious behavior. Author(s): Symons FJ, Tapp J, Wulfsberg A, Sutton KA, Heeth WL, Bodfish JW. Source: Experimental and Clinical Psychopharmacology. 2001 August; 9(3): 269-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11534537
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Sequential use of naltrexone in the treatment of relapsing alcoholism. Author(s): Farren CK, O'Malley S. Source: The American Journal of Psychiatry. 1997 May; 154(5): 714. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9137139
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Serum naltrexone and 6-beta-naltrexol levels from naltrexone implants can block very large amounts of heroin: a report of two cases. Author(s): Brewer C. Source: Addiction Biology. 2002 July; 7(3): 321-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12126492
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Serum time course of naltrexone and 6 beta-naltrexol levels during long-term treatment in drug addicts. Author(s): Ferrari A, Bertolotti M, Dell'Utri A, Avico U, Sternieri E. Source: Drug and Alcohol Dependence. 1998 November 1; 52(3): 211-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9839147
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Short-term effects of naltrexone in 155 heroin ex-addicts. Author(s): Volavka J, Resnick RB, Kestenbaum RS, Freedman AM. Source: Biological Psychiatry. 1976 December; 11(6): 679-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=999987
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Short-term treatment of post-traumatic stress disorder with naltrexone: an open-label preliminary study. Author(s): Lubin G, Weizman A, Shmushkevitz M, Valevski A. Source: Human Psychopharmacology. 2002 June; 17(4): 181-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12404685
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Six-month follow-up of naltrexone and psychotherapy for alcohol dependence. Author(s): O'Malley SS, Jaffe AJ, Chang G, Rode S, Schottenfeld R, Meyer RE, Rounsaville B. Source: Archives of General Psychiatry. 1996 March; 53(3): 217-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8611058
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SPECT regional cerebral blood flow alterations in naltrexone-precipitated withdrawal from buprenorphine. Author(s): van Dyck CH, Rosen MI, Thomas HM, McMahon TJ, Wallace EA, O'Connor PG, Sullivan M, Krystal JH, Hoffer PB, Woods SW, et al. Source: Psychiatry Research. 1994 December; 55(4): 181-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7701033
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Stereospecific accumulation of dihydromorphine and naltrexone by corpus striatal slices of morphine-dependent mice. Author(s): Oishi R, Takemori AE. Source: Neuropharmacology. 1982 January; 21(1): 57-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6278352
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Straight-chain naltrexone ester prodrugs: diffusion and concurrent esterase biotransformation in human skin. Author(s): Stinchcomb AL, Swaan PW, Ekabo O, Harris KK, Browe J, Hammell DC, Cooperman TA, Pearsall M. Source: Journal of Pharmaceutical Sciences. 2002 December; 91(12): 2571-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12434400
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Strategies to maximize the efficacy of naltrexone for alcohol dependence. Author(s): O'Malley SS. Source: Nida Res Monogr. 1995; 150: 53-64. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8742772
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Studies of EN-1639A (naltrexone): a new narcotic antagonist. Author(s): Resnick RB, Volavka J, Freedman AM, Thomas M. Source: The American Journal of Psychiatry. 1974 June; 131(6): 646-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4827793
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Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment. Author(s): Roozenburg BJ, van Dessel HJ, Evers JL, Bots RS. Source: Human Reproduction (Oxford, England). 1997 August; 12(8): 1720-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9308800
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Successful use of naltrexone in addicted physicians and business executives. Author(s): Washton AM, Gold MS, Pottash AC. Source: Adv Alcohol Subst Abuse. 1984 Winter; 4(2): 89-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6524509
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Supersensitivity of brain opiate receptor subtypes after chronic naltrexone treatment. Author(s): Tempel A, Zukin RS, Gardner EL. Source: Life Sciences. 1982 September 20-27; 31(12-13): 1401-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6292636
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Sustained-release naltrexone for alcoholism treatment: a preliminary study. Author(s): Kranzler HR, Modesto-Lowe V, Nuwayser ES. Source: Alcoholism, Clinical and Experimental Research. 1998 August; 22(5): 1074-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9726277
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Symptom complaints of patients maintained on methadone, LAAM (methadyl acetate), and naltrexone at different times in their addiction careers. Author(s): Judson BA, Goldstein A. Source: Drug and Alcohol Dependence. 1982 October-November; 10(2-3): 269-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7166139
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Synthesis and pharmacologic characterization of an alkylating analogue (chlornaltrexamine) of naltrexone with ultralong-lasting narcotic antagonist properties. Author(s): Portoghese PS, Larson DL, Jiang JB, Caruso TP, Takemori AE. Source: Journal of Medicinal Chemistry. 1979 February; 22(2): 168-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=218009
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Targeted naltrexone for early problem drinkers. Author(s): Kranzler HR, Armeli S, Tennen H, Blomqvist O, Oncken C, Petry N, Feinn R. Source: Journal of Clinical Psychopharmacology. 2003 June; 23(3): 294-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826991
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Targeted naltrexone treatment moderates the relations between mood and drinking behavior among problem drinkers. Author(s): Kranzler HR, Armeli S, Feinn R, Tennen H. Source: Journal of Consulting and Clinical Psychology. 2004 April; 72(2): 317-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15065964
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Targeted naltrexone treatment of early problem drinkers. Author(s): Kranzler HR, Tennen H, Penta C, Bohn MJ. Source: Addictive Behaviors. 1997 May-June; 22(3): 431-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9183513
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Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. Author(s): Heinala P, Alho H, Kiianmaa K, Lonnqvist J, Kuoppasalmi K, Sinclair JD. Source: Journal of Clinical Psychopharmacology. 2001 June; 21(3): 287-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11386491
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Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence: efficacy of contingency management and significant other involvement. Author(s): Carroll KM, Ball SA, Nich C, O'Connor PG, Eagan DA, Frankforter TL, Triffleman EG, Shi J, Rounsaville BJ. Source: Archives of General Psychiatry. 2001 August; 58(8): 755-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11483141
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The clinical usefulness of narcotic antagonists: preliminary findings on the use of naltrexone. Author(s): Lewis DC. Source: The American Journal of Drug and Alcohol Abuse. 1975; 2(3-4): 403-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1227300
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The effects of chronic naltrexone treatment in young autistic children: a double-blind placebo-controlled crossover study. Author(s): Willemsen-Swinkels SH, Buitelaar JK, van Engeland H. Source: Biological Psychiatry. 1996 June 15; 39(12): 1023-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8780837
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The effects of naltrexone in autistic children: report of two cases. Author(s): Akkok F. Source: Turk J Pediatr. 1995 January-March; 37(1): 19-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7732604
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The effects of naltrexone maintenance on the response to yohimbine in healthy volunteers. Author(s): Rosen MI, Kosten TR, Kreek MJ. Source: Biological Psychiatry. 1999 June 15; 45(12): 1636-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10376126
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The efficacy of naltrexone in preventing reabuse of heroin after detoxification. Author(s): Shufman EN, Porat S, Witztum E, Gandacu D, Bar-Hamburger R, Ginath Y. Source: Biological Psychiatry. 1994 June 15; 35(12): 935-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8080893
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The opioid agonist codeine and antagonist naltrexone do not affect voluntary suppression of capsaicin induced cough in healthy subjects. Author(s): Hutchings HA, Eccles R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1994 April; 7(4): 715-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8005254
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The rationale for naltrexone therapy as an alternative to methadone treatment for opiate addiction. Author(s): Simon DL. Source: Conn Med. 1996 November; 60(11): 683-5. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8979434
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The therapeutic role of naltrexone in negative symptom schizophrenia. Author(s): Marchesi GF, Santone G, Cotani P, Giordano A, Chelli F. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1995 December; 19(8): 1239-49. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8868206
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The urinary excretion profiles of naltrexone in man, monkey, rabbit, and rat. Author(s): Dayton HE, Inturrisi CE. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 1976 September-October; 4(5): 474-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10147
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Thyroid function of former opioid addicts on naltrexone treatment. Author(s): Ilias I, Kakoulas I, Christakopoulou I, Katsadoros K. Source: Acta Medica (Hradec Kralove). 2001; 44(1): 33-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11367890
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Tolerability of naltrexone in treating older, alcohol-dependent patients. Author(s): Oslin D, Liberto JG, O'Brien J, Krois S. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 1997 Summer; 6(3): 266-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9256993
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Treatment of compulsive sexual behaviour with naltrexone and serotonin reuptake inhibitors: two case studies. Author(s): Raymond NC, Grant JE, Kim SW, Coleman E. Source: International Clinical Psychopharmacology. 2002 July; 17(4): 201-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131605
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Treatment of neurotoxic side effects of interferon-alpha with naltrexone. Author(s): Valentine AD, Meyers CA, Talpaz M. Source: Cancer Investigation. 1995; 13(6): 561-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7583704
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Tritiated naltrexone binding in plasma from several species and tissue distribution in mice. Author(s): Ludden TM, Malspeis L, Baggot JD, Sokoloski TD, Frank SG, Reuning RH. Source: Journal of Pharmaceutical Sciences. 1976 May; 65(5): 712-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=819644
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Twenty-four week maintenance treatment of cigarette smoking with nicotine gum, clonidine and naltrexone. Author(s): Ahmadi J, Ashkani H, Ahmadi M, Ahmadi N. Source: Journal of Substance Abuse Treatment. 2003 April; 24(3): 251-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810146
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Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone. Author(s): Cruciani RA, Lussier D, Miller-Saultz D, Arbuck DM. Source: Journal of Pain and Symptom Management. 2003 June; 25(6): 491-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12782427
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Understanding US addiction physicians' low rate of naltrexone prescription. Author(s): Mark TL, Kranzler HR, Song X. Source: Drug and Alcohol Dependence. 2003 September 10; 71(3): 219-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957340
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Update of naltrexone treatment. Author(s): O'Brien CP, Greenstein R, Woody GE. Source: Nida Res Monogr. 1978; (19): 315-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=218107
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Use of naltrexone as a provocative test for hypothalamic-pituitary hormone function. Author(s): Mendelson JH, Mello NK, Cristofaro P, Skupny A, Ellingboe J. Source: Pharmacology, Biochemistry, and Behavior. 1986 February; 24(2): 309-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3006087
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Use of naltrexone for the diagnosis and treatment of reproductive hormone disorders in women. Author(s): Mendelson JH, Mello NK, Teoh SK, Ellingboe J. Source: Nida Res Monogr. 1991; 105: 161-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1875996
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Use of naltrexone in postmenopausal women with exaggerated insulin secretion: a pilot study. Author(s): Cucinelli F, Soranna L, Perri C, Barini A, Cento RM, Mancuso S, Lanzone A. Source: Fertility and Sterility. 2004 April; 81(4): 1047-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15066462
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Use of naltrexone in the treatment of alcohol use disorders in patients with concomitant major mental illness. Author(s): Maxwell S, Shinderman MS. Source: Journal of Addictive Diseases : the Official Journal of the Asam, American Society of Addiction Medicine. 2000; 19(3): 61-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11076120
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Use of naltrexone in the treatment of alcoholism nationally in the Department of Veterans Affairs. Author(s): Petrakis IL, Leslie D, Rosenheck R. Source: Alcoholism, Clinical and Experimental Research. 2003 November; 27(11): 1780-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14634494
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Use of narcotic antagonists (naltrexone) in an addiction treatment program. Author(s): Lewis D, Hersch R, Black R, Mayer J. Source: Nida Res Monogr. 1976 September; (9): 99-105. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=794728
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Use of oral and implantable naltrexone in the management of the opioid impaired physician. Author(s): Hulse GK, O'Neil G, Hatton M, Paech MJ. Source: Anaesthesia and Intensive Care. 2003 April; 31(2): 196-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712786
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Use of very low-dose naltrexone during opiate detoxification. Author(s): Mannelli P, Gottheil E, Buonanno A, De Risio S. Source: Journal of Addictive Diseases : the Official Journal of the Asam, American Society of Addiction Medicine. 2003; 22(2): 63-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12703669
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Using analog baselines to assess the effects of naltrexone on self-injurious behavior. Author(s): Garcia D, Smith RG. Source: Research in Developmental Disabilities. 1999 January-February; 20(1): 1-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9987807
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Using naltrexone implants in the management of the pregnant heroin user. Author(s): Hulse G, O'Neil G. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2002 November; 42(5): 569-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12495120
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Using naltrexone in inpatient alcoholism treatment. Author(s): Knox PC, Donovan DM. Source: J Psychoactive Drugs. 1999 October-December; 31(4): 373-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10681104
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Variable dose naltrexone-induced hypothalamic-pituitary-adrenal stimulation in abstinent alcoholics: a preliminary study. Author(s): Farren CK, O'Malley S, Grebski G, Maniar S, Porter M, Kreek MJ. Source: Alcoholism, Clinical and Experimental Research. 1999 March; 23(3): 502-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10195825
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Varying clinical contexts for administering naltrexone. Author(s): Hurzeler M, Gerwirtz D, Kleber H. Source: Nida Res Monogr. 1976 September; (9): 48-66. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=794721
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What place does naltrexone have in the treatment of alcoholism? Author(s): Rohsenow DJ. Source: Cns Drugs. 2004; 18(9): 547-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15222772
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What you need to know: addiction--prescribing naltrexone. Author(s): Yeo BK. Source: Singapore Med J. 1997 February; 38(2): 92-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9269372
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CHAPTER 2. NUTRITION AND NALTREXONE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and naltrexone.
Finding Nutrition Studies on Naltrexone The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “naltrexone” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7 Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “naltrexone” (or a synonym): •
A randomized trial of adding fluoxetine to a naltrexone treatment programme for heroin addicts. Author(s): Centro de Drogodependencias de Barakaldo, Vizcaya, Spain. Source: Landabaso, M A Iraurgi, I Jimenez Lerma, J M Sanz, J Fernadez de Corres, B Araluce, K Calle, R Gutierrez Fraile, M Addiction. 1998 May; 93(5): 739-44 0965-2140
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An open naltrexone treatment study in pathological gambling disorder. Author(s): Department of Psychiatry, University of Minnesota Medical School, Minneapolis 55454-1495, USA.
[email protected] Source: Kim, S W Grant, J E Int-Clin-Psychopharmacol. 2001 September; 16(5): 285-9 0268-1315
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Effectiveness of repeated administration of a new oral naltrexone controlled-release system on morphine analgesia. Author(s): Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Spain.
[email protected] Source: Alvarez Fuentes, J Rojas Corrales, M O Holgado, M A Sanchez Lafuente, C Mico, J A Fernandez Arevalo, M J-Pharm-Pharmacol. 2001 September; 53(9): 1201-5 0022-3573
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Influence of oral buprenorphine, oral naltrexone or morphine on the effects of laparotomy in the rat. Author(s): Comparative Biology Centre, Medical School, University of Newcastle upon Tyne, UK. Source: Liles, J H Flecknell, P A Roughan, J Cruz Madorran, I Lab-Anim. 1998 April; 32(2): 149-61 0023-6772
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Interaction of morphine and naltrexone on oral ethanol self-administration in rhesus monkeys. Author(s): Department of Pharmacology, University of Michigan, Ann Arbor 481090632, USA.
[email protected] Source: Williams, K L Kane, E C Woods, J H Behav-Pharmacol. 2001 September; 12(5): 325-33 0955-8810
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Investigation of phenolic bioisosterism in opiates: 3-sulfonamido analogues of naltrexone and oxymorphone. Author(s): Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA. Source: McCurdy, C R Jones, R M Portoghese, P S Org-Lett. 2000 March 23; 2(6): 819-21 1523-7060
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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CHAPTER 3. ALTERNATIVE MEDICINE AND NALTREXONE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to naltrexone. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to naltrexone and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “naltrexone” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to naltrexone: •
A new neuroimmunotherapeutic strategy of subcutaneous low-dose interleukin-2 plus the long-acting opioid antagonist naltrexone in metastatic cancer patients progressing on interleukin-2 alone. Author(s): Lissoni P, Malugani F, Bordin V, Conti A, Maestroni G, Tancini G. Source: Neuro Endocrinol Lett. 2002 June; 23(3): 255-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12080288
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Abolition of conditioned heart-rate responses in rabbits following central administration of [N-MePhe3, D-Pro4] morphiceptin. Author(s): Lavond DG, Mauk MD, Madden J 4th, Barchas JD, Thompson RF. Source: Pharmacology, Biochemistry, and Behavior. 1983 August; 19(2): 379-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6634886
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Acoustic startle and open-field behavior in mice bred for magnitude of swim analgesia. Author(s): Blaszczyk JW, Tajchert K, Lapo I, Sadowski B. Source: Physiology & Behavior. 2000 September 15; 70(5): 471-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11111000
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Acupuncture analgesia in a new rat model of ankle sprain pain. Author(s): Koo ST, Park YI, Lim KS, Chung K, Chung JM. Source: Pain. 2002 October; 99(3): 423-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12406517
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Addiction and anesthesiology. Author(s): Spiegelman WG, Saunders L, Mazze RI. Source: Anesthesiology. 1984 April; 60(4): 335-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6703387
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Addiction medicine for the primary care physician. Author(s): Yarborough WH. Source: J Okla State Med Assoc. 2001 November; 94(11): 499-506. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11729596
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Alcoholics Anonymous and the use of medications to prevent relapse: an anonymous survey of member attitudes. Author(s): Rychtarik RG, Connors GJ, Dermen KH, Stasiewicz PR. Source: J Stud Alcohol. 2000 January; 61(1): 134-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10627107
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Alcoholism treatment in the United States. An overview. Author(s): Fuller RK, Hiller-Sturmhofel S. Source: Alcohol Research & Health : the Journal of the National Institute on Alcohol Abuse and Alcoholism. 1999; 23(2): 69-77. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10890799
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Alterations of evoked potentials link research in attention dysfunction to peptide response symptoms of schizophrenia. Author(s): Davis GC, Buchsbaum MS, Bunney WE Jr. Source: Adv Biochem Psychopharmacol. 1980; 22: 473-87. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7395603
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Analgesia-producing mechanism of processed Aconiti tuber: role of dynorphin, an endogenous kappa-opioid ligand, in the rodent spinal cord. Author(s): Omiya Y, Goto K, Suzuki Y, Ishige A, Komatsu Y.
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Source: Japanese Journal of Pharmacology. 1999 March; 79(3): 295-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10230857 •
Antagonism of the acute pharmacological actions of morphine by panax ginseng extract. Author(s): Ramarao P, Bhargava HN. Source: General Pharmacology. 1990; 21(6): 877-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2279687
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Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c, C57BL/6, and DBA/2 mice. Author(s): Kiianmaa K, Hoffman PL, Tabakoff B. Source: Psychopharmacology. 1983; 79(4): 291-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6407041
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Antinociceptive effects of (+)-matrine in mice. Author(s): Kamei J, Xiao P, Ohsawa M, Kubo H, Higashiyama K, Takahashi H, Li J, Nagase H, Ohmiya S. Source: European Journal of Pharmacology. 1997 October 22; 337(2-3): 223-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9430418
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Antinociceptive effects of Nigella sativa oil and its major component, thymoquinone, in mice. Author(s): Abdel-Fattah AM, Matsumoto K, Watanabe H. Source: European Journal of Pharmacology. 2000 July 14; 400(1): 89-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10913589
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Antinociceptive profiles of platycodin D in the mouse. Author(s): Choi SS, Han EJ, Lee TH, Han KJ, Lee HK, Suh HW. Source: The American Journal of Chinese Medicine. 2004; 32(2): 257-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15315263
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Barriers to the use of medications to treat alcoholism. Author(s): Mark TL, Kranzler HR, Poole VH, Hagen CA, McLeod C, Crosse S. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2003 July-September; 12(4): 281-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504021
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Behavioral therapies for substance abuse. Author(s): Childress AR, McLellan AT, O'Brien CP.
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Source: Int J Addict. 1985 June-July; 20(6-7): 947-69. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2867051 •
Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS). Author(s): Kalra A, Urban MO, Sluka KA. Source: The Journal of Pharmacology and Experimental Therapeutics. 2001 July; 298(1): 257-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11408550
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Blockade of opioid receptors with naltrexone inhibits thyrotropin increase after noise stress but does not prevent the decrease caused by immobilization. Author(s): Armario A, Marti O, Gavalda A, Jolin T. Source: Brain Research Bulletin. 1990 August; 25(2): 347-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2171723
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Brain opioids and mother-infant social motivation. Author(s): Panksepp J, Nelson E, Siviy S. Source: Acta Paediatrica (Oslo, Norway : 1992). Supplement. 1994 June; 397: 40-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7981473
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Changes in urination/defecation, auditory startle response, and startle-induced ultrasonic vocalizations in rats undergoing morphine withdrawal: similarities and differences between acute and chronic dependence. Author(s): Kalinichev M, Holtzman SG. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 February; 304(2): 603-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538812
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Characterization and opioid modulation of inflammatory temporomandibular joint pain in the rat. Author(s): Hartwig AC, Mathias SI, Law AS, Gebhart GF. Source: Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2003 November; 61(11): 1302-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14613087
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Cholecystokinin antagonists selectively potentiate analgesia induced by endogenous opiates. Author(s): Watkins LR, Kinscheck IB, Kaufman EF, Miller J, Frenk H, Mayer DJ. Source: Brain Research. 1985 February 18; 327(1-2): 181-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3838691
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Clinical trials and treatment prospects. Author(s): Percy AK. Source: Mental Retardation and Developmental Disabilities Research Reviews. 2002; 8(2): 106-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12112736
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Comorbid alcoholism and depression: treatment issues. Author(s): Thase ME, Salloum IM, Cornelius JD. Source: The Journal of Clinical Psychiatry. 2001; 62 Suppl 20: 32-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11584873
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Current strategies for the treatment of alcohol dependence in the United States. Author(s): O'Malley SS. Source: Drug and Alcohol Dependence. 1995 September; 39 Suppl 1: S3-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8565795
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Effect of current density on pharmacokinetics following continuous or intermittent input from a fentanyl electrotransport system. Author(s): Gupta SK, Southam M, Sathyan G, Klausner M. Source: Journal of Pharmaceutical Sciences. 1998 August; 87(8): 976-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9687342
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Effect of naltrexone on relaxation induced by flank pressure in pigs. Author(s): Grandin T, Dodman N, Shuster L. Source: Pharmacology, Biochemistry, and Behavior. 1989 August; 33(4): 839-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2616603
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Effect of protein kinases on lactate dehydrogenase activity in cortical neurons during hypoxia. Author(s): Hong SS, Gibney GT, Esquilin M, Yu J, Xia Y. Source: Brain Research. 2004 May 29; 1009(1-2): 195-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15120597
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Effects of endorphin blocking on conditioned SCR in humans. Author(s): Merckelbach H, Arntz A, de Jong P, Schouten E. Source: Behaviour Research and Therapy. 1993 November; 31(8): 775-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8257409
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Effects of noise on high-affinity choline uptake in the frontal cortex and hippocampus of the rat are blocked by intracerebroventricular injection of corticotropin-releasing factor antagonist. Author(s): Lai H, Carino MA.
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Source: Brain Research. 1990 September 17; 527(2): 354-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2253041 •
Electrical stimulation at traditional acupuncture sites in periphery produces brain opioid-receptor-mediated antinociception in rats. Author(s): Chen XH, Geller EB, Adler MW. Source: The Journal of Pharmacology and Experimental Therapeutics. 1996 May; 277(2): 654-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8627542
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Electroacupuncture analgesia in naive rats: effects of brainstem and spinal cord lesions, and role of pituitary-adrenal axis. Author(s): Bossut DF, Mayer DJ. Source: Brain Research. 1991 May 17; 549(1): 52-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1893253
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Electroacupuncture analgesia in rats: naltrexone antagonism is dependent on previous exposure. Author(s): Bossut DF, Mayer DJ. Source: Brain Research. 1991 May 17; 549(1): 47-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1893252
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Electroacupuncture in rats: evidence for naloxone and naltrexone potentiation of analgesia. Author(s): Bossut DF, Huang ZS, Sun SL, Mayer DJ. Source: Brain Research. 1991 May 17; 549(1): 36-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1893251
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Electroacupuncture suppresses a nociceptive reflex: naltrexone prevents but does not reverse this effect. Author(s): Pomeranz B, Bibic L. Source: Brain Research. 1988 June 14; 452(1-2): 227-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3401730
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Naltrexone in alcohol dependence. Author(s): Hartmann PM. Source: American Family Physician. 1997 April; 55(5): 1877-9, 1883-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9105212
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Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting. Author(s): Latt NC, Jurd S, Houseman J, Wutzke SE.
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Source: The Medical Journal of Australia. 2002 June 3; 176(11): 530-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12064984 •
Naltrexone in the treatment of alcohol dependence. Author(s): Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck RA; Veterans Affairs Naltrexone Cooperative Study 425 Group. Source: The New England Journal of Medicine. 2001 December 13; 345(24): 1734-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11742047
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Naltrexone: a controversial therapy for alcohol dependence. Author(s): Freed PE, York LN. Source: Journal of Psychosocial Nursing and Mental Health Services. 1997 July; 35(7): 248. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9243420
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Naltrexone's effects on reactivity to alcohol cues among alcoholic men. Author(s): Rohsenow DJ, Monti PM, Hutchison KE, Swift RM, Colby SM, Kaplan GB. Source: Journal of Abnormal Psychology. 2000 November; 109(4): 738-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11195999
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Predicting treatment response to naltrexone: the influence of craving and family history. Author(s): Monterosso JR, Flannery BA, Pettinati HM, Oslin DW, Rukstalis M, O'Brien CP, Volpicelli JR. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2001 Summer; 10(3): 258-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11579624
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Reducing naltrexone-resistant hyperphagia using laser acupuncture to increase endogenous opiates. Author(s): Read A, Beaty P, Corner J, Sommerville Ville C. Source: Brain Injury : [bi]. 1996 December; 10(12): 911-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8939309
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Use of naltrexone to extinguish opioid-conditioned responses. Author(s): O'Brien CP, Childress AR, McLellan AT, Ternes J, Ehrman RN. Source: The Journal of Clinical Psychiatry. 1984 September; 45(9 Pt 2): 53-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6381473
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to naltrexone; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Alcoholism Source: Integrative Medicine Communications; www.drkoop.com Mumps Source: Integrative Medicine Communications; www.drkoop.com Sexually Transmitted Diseases Source: Integrative Medicine Communications; www.drkoop.com STDs Source: Integrative Medicine Communications; www.drkoop.com Tension Headache Source: Healthnotes, Inc.; www.healthnotes.com
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•
Alternative Therapy Shiatsu Alternative names: acupressure schiatsu shiatsu massage therapy shiatsu therapy shiatzu Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/s.html
•
Chinese Medicine Cuitang Wan Alternative names: Cuitang Pills Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China
•
Herbs and Supplements PABA Source: Healthnotes, Inc.; www.healthnotes.com PABA Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10049,00.html SAMe (S-Adenosylmethionine) Source: Prima Communications, Inc.www.personalhealthzone.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON NALTREXONE Overview In this chapter, we will give you a bibliography on recent dissertations relating to naltrexone. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “naltrexone” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on naltrexone, we have not necessarily excluded nonmedical dissertations in this bibliography.
Dissertations on Naltrexone ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to naltrexone. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
The client's perspective of naltrexone pharmacotherapy: A qualitative study by Ernst, Anthony Joseph, PhD from THE UNIVERSITY OF TEXAS AT AUSTIN, 2002, 169 pages http://wwwlib.umi.com/dissertations/fullcit/3077636
•
The effects of naltrexone on repressive coping and disclosure of emotional material: A test of the opioid-peptide theory of repression/hypertension by Younger, Jarred Wayne, PhD from THE UNIVERSITY OF TENNESSEE, 2003, 83 pages http://wwwlib.umi.com/dissertations/fullcit/3104497
Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON NALTREXONE Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “naltrexone” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on naltrexone, we have not necessarily excluded nonmedical patents in this bibliography.
Patents on Naltrexone By performing a patent search focusing on naltrexone, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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example of the type of information that you can expect to obtain from a patent search on naltrexone: •
Abusable substance dosage form having reduced abuse potential Inventor(s): Goetz; Victor (Philadelphia, PA), Lee; Eun S. (Redwood City, CA) Assignee(s): Alza Corporation (Palo Alto, CA) Patent Number: 5,236,714 Date filed: November 1, 1988 Abstract: Compositions and dosage forms for administering abusable substances are disclosed which have a reduced potential for abuse without diminishing the therapeutic or beneficial effects of the abusable substance. Topical compositions for application to the skin or mucosa contain the abusable substance in a form which is permeable to the skin or mucosa to which it is to be applied and an antagonist for the abusable substance is present in the composition in an abuse negating amount and in a form that is impermeable to the skin or mucosa to which the composition is to be applied. Controlled release dosage forms which release the abusable substance from a drug reservoir composition confined behind a release rate controlling barrier have the abusable substance and its antagonist in the drug reservoir. The abusable substance is present in a form that is releasable from the dosage form and the antagonist is present in an abuse negating amount in a form that is not releasable from the dosage form. Thus the compositions and dosage forms of this invention permit the therapeutic use, at substantially full potency, of an abusable substance when use as prescribed but reduce the abuse potential of the compositions and dosage forms by other routes of administration. Preferred embodiments of the invention utilize fentanyl as the abusable substance and naltrexone as the antagonist in a transdermal dosage form. Excerpt(s): This invention relates to dosage forms of abusable substances having reduced potential for abuse. In particular, the dosage forms of this invention are intended to administer the abusable substance to the body by topical application to the skin or mucosa or to release the abusable substance to the body through a membrane on the dosage form. The potential for abuse by either oral or parenteral routes of narcotic and other psychoactive drugs is well known. For example, the potential for abuse of the synthetic narcotic drug fentanyl is so high that it has become a major cause of death for anesthesiologists and other hospital workers having access to the drug. In order to prevent abuse of these substances, it has been proposed to provide dosage forms which combine the abusable substance with an amount of an antagonist for the abusable substance sufficient to eliminate the "high" associated with abuse of the substance without eliminating the other therapeutic benefits for which the drugs are intended to be administered. See, for example, U.S. Pat. Nos. 4,457,933, 3,493,657 and 3,773,955 which are incorporated herein by reference. Many abusable substances are capable of being administered to the body by direct application of the drug to the skin or mucosa, i.e., nasal, vaginal, oral, or rectal mucosa. They can also be delivered to the body from advanced dosage forms such as those described in U.S. Pat. Nos. 4,655,766, 4,588,580, 3,993,073, and 3,845,770 which are incorporated herein by reference. Compositions suitable for topical application to the skin or for forming reservoir compositions in the advanced dosage forms described above could be subject to abuse, and it would clearly be desirable to have such compositions or dosage forms available in a condition in which the abuse potential of the composition or dosage form is reduced without diminishing the therapeutic efficacy of the abusable substance to be administered.
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Web site: http://www.delphion.com/details?pn=US05236714__ •
Analgesic compositions Inventor(s): Lewis; John W. (North Ferriby, GB2), Lloyd-Jones; John G. (Cottingham, GB2) Assignee(s): Reckitt & Colman Products Limited (GB) Patent Number: 4,661,492 Date filed: November 21, 1985 Abstract: An analgesic composition in parenteral or sublingual unit dosage form comprising an active dose of buprenorphine and an amount of naltrexone sufficient to prove aversive to a narcotic addict by parenteral administration but insufficient to compromise the analgesic action of the buprenorphine. Excerpt(s): This invention relates to analgesic compositions and more particularly to compositions containing buprenorphine. Buprenorphine (International Non-proprietary Name for N-cyclopropylmethyl-7.alpha.-[1-(S)-hydroxy-1,2,2-trimethylpropyl]6,14-end oethano-6,7,8,14-tetrahydronororipavine) has been shown in clinical trials to be a potent antagonist analgesic lacking the psychotomimetic effects found with other antagonist analgesics. Buprenorphine effectively relieves moderate to severe pain in doses of 0.1 mg or more administered either parenterally or sublingually. The optimum therapeutic range for single doses is 0.3 mg-0.6 mg by injection and 0.1 mg-0.4 mg for sublingual tablets. In animal tests and in man buprenorphine has been shown to have both agonist (morphine-like) and (morphine) antagonist properties. However from direct dependence studies in animals and in man it has been concluded that buprenorphine does not produce significant physical dependence and the potential to produce psychological dependence is low as indicated by animal self administration studies and by the measurement of euphorigenic effects in human post addicts. Web site: http://www.delphion.com/details?pn=US04661492__
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Combination for the treatment of alcohol and drug dependence containing an opioid antagonist and a NMDA receptor complex modulator Inventor(s): Bonhomme; Yves (Charbonnieres les Bains, FR), Daoust; Martine (Notre Dame de Bondevile, FR), Durbin; Philippe (Villeurbanne, FR) Assignee(s): Lipha (Lyons, FR) Patent Number: 6,512,009 Date filed: January 12, 2001 Abstract: A pharmaceutical composition for the treatment of alcohol and drug dependence, comprising a therapeutically effective amount of a combination of: (i) an opioid antagonist; and (ii) a NMDA receptor complex modulator. A pharmaceutical kit is also provided, comprising these two substances. The opioid antagonist can, for example, be naltrexone and the NMDA receptor complex modulator can be a spermidine site modulator such as acamprosate. Excerpt(s): The present invention relates to a method for the treatment of alcohol and drug dependence. More specifically the present invention relates to a method for the treatment of the alcohol dependence. It relates also to a method for the treatment of a
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dependence to drugs such as opioid derivatives, cannabinoides, nicotin derivatives, amphetamines and tranquilizers. Web site: http://www.delphion.com/details?pn=US06512009__ •
Composition and method of treating depression using naloxone or naltrexone in combination with a serotonin reuptake inhibitor Inventor(s): Dante; Lee G. (Merion Station, PA) Assignee(s): Nagle; John S. (Thousand Oaks, CA) Patent Number: 5,817,665 Date filed: November 20, 1995 Abstract: This invention relates to a composition and method for treating depression by administering to a patient a pharmacologically effective dose of an opioid antagonist having a pentacyclic nucleus structurally analogous to naltrexone, and a pharmacologically effective dose of a nontricyclic antidepressant Excerpt(s): The present invention relates to the use of an opioid antagonist such as naltrexone in combination with one or more serotonin (5-hydroxytryptamine or 5-HT) or norepinephrine reuptake inhibitor(s) and/or lithium to treat mental or emotional disorders characterized by depression, obsessiveness, depression with anxiety, mania, manic depression, depression with manic episodes, and depression concomitant with an illness causing seizures which are inhibited by carbamazepine, or a combination of any of these mental or emotional illnesses, or mental or emotional illnesses with seizures. The inventor has discovered that naltrexone is useful in combination with lithium and/or one or more serotonin (5-HT) uptake inhibitor and/or norepinephrine (N.E.) uptake inhibitor drug compounds in treating patients whose depression and/or associated mental illnesses or conditions were refractory to drug treatment using one or more known antidepressant agents or agents for manic and manic depressive disorders such as lithium, and tricyclic and a-typical antidepressants including, but not limited to clomipramine, amitriptyline, imipramine, sertraline and nortriptyline that inhibit 5-HT and/or N.E. reuptake. The inventor has further discovered that such treatment using naltrexone in combination with lithium and/or 5-HT or N.E. reuptake inhibitors is effective even where benzodiazepines are concurrently administered to treat anxiety. Additionally, the inventor has discovered that lithium in combination with naltrexone in some cases reduces manic and manic depressive bipolar symptoms. A general discussion of the effectiveness of tricyclic antidepressants and non-tricyclic a-typical antidepressants in inhibiting 5-HT and/or N.E. neuronal synaptic reuptake and in treating depression, along with the pharmacology of these compounds is found in Goodman and Gillman, The Pharmacological Basis of Therapeutics, 7th and 8th Eds. (MacMillan Publ. Co.) Chapt. 19, Section 11 "Drugs Used in the Treatment of Disorders of Mood", incorporated by reference herein. According to the present invention, tricyclic antidepressants include, but are not limited to, imipramine, amitriptyline, trimipramine, doxepin, desipramine, nortriptyline, protriptyline, amoxapine, clomipramine, maprotriline, and carbamazepine, and their pharmaceutically effective salts and esters, such as, but not limited to their hydrochlorides, maleates, tartrates and lactates. Although carbamazepine is approved in the U.S. as antiepileptic, it is chemically related to tricyclic antidepressants, its actions on human brain neurons are not completely known, and for the present invention it is classified as a tricyclic antidepressant. See, Goodman and Gillman, The Pharmacological Basis of Therapeutics, referenced above, 7th Ed., page 457 et seq.
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Web site: http://www.delphion.com/details?pn=US05817665__ •
Growth regulation and related applications of opioid antagonists Inventor(s): McLaughlin; Patricia J. (Harrisburg, PA), Zagon; Ian S. (Hershey, PA) Assignee(s): Research Corporation (New York, NY) Patent Number: 4,689,332 Date filed: April 9, 1984 Abstract: A method for regulating the growth processes in a myriad of cells, tissues, organ systems and unicellular and multicellular organisms including plants, animals and man by the administration of effective amounts of the opioid antagonists naloxone, naltrexone, their analogs metabolites derivatives, and/or mixtures thereof. At the cellular level, the growth processes entail all mitotic events and related processes including cell proliferation, as well as cell migration and cell differentiation, and at the somatic or organismal level, anatomical, behavioral and neurological development, metamorphisis and maturation. Growth regulation can be effected in vivo and/or in vitro. Excerpt(s): The present invention relates to a method for regulating the growth processes in a myriad of cells, tissues, organ systems and unicellular and multicellular organisms. More specifically, in accordance with the present invention, the fundamental growth processes in a multitude of biological systems can be modulated by the administration of the opioid antagonists naloxone, naltrexone, their analogs, metabolites, and/or derivatives. In the past, naloxone and naltrexone have been employed predominantly for the treatment of narcotic addiction. Specifically, these compounds reverse the narcotic effects of exogenous opiates and opiate-like substances such as heroin and morphine, acting antagonistically thereto on a biochemical level. Naloxone, the first of these compounds to be synthesized in 1960, was shortly thereafter discovered to have "pure" antagonist character, i.e., exhibiting virtually no agonist activity. Thus, naloxone became the preferred regime for the treatment of acute narcoticism. Web site: http://www.delphion.com/details?pn=US04689332__
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Immunosuppressive agent and process of producing the same Inventor(s): Arakawa; Kohei (Kyoto, JP), Endoh; Takashi (Chigasaki, JP), Katsura; Yoshiaki (Otsu, JP), Kawai; Koji (Kamakura, JP), Matsumoto; Shu (Kamakura, JP), Nagase; Hiroshi (Kamakura, JP) Assignee(s): Toray Industries, Inc. (JP) Patent Number: 5,332,818 Date filed: March 22, 1993 Abstract: An immunosuppressive agent which has low toxicity and which exhibits excellent effectiveness even if it is orally administered is presented. The immunosuppressive agent of the present invention is characterized in that it contains.delta.-opioid antagonist having high selectivity to.delta.-opioid receptor. The present invention also provides a process of producing a naltrindole derivative
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characterized by reacting naltrexone or a salt thereof with a phenylhydrazine derivative in a solvent in the presence of methanesulfonic acid. Excerpt(s): The present invention relates to an immunosuppressive agent and to a process of producing the same. Immunosuppressive agents are indispensable to inhibit rejection reaction mainly encountered in organ transplantations. Before 1980, no agent was known which can be called a real immunosuppressive agent. Therefore, even in the transplantation of pancreas which is thought to be the easiest one, the rate of success was only 7%. In 1980, cyclosporine A was discovered and the rate of success of organ transplantations was drastically promoted and the era of real organ transplantations initiated. However, cyclosporine A has a very strong toxicity to kidney, so that it is now tried to reduce the amount of cyclosporine A to be used as small as possible by coemploying other drugs. In 1984, FK-506 was discovered from a ray fungus. It was said that this compound has an immunosuppressive effect as high as 10 to 100 times higher than that of cyclosporine A, and at first, side effects such as toxicity to kidney are small (Science, January, 62, 1989). Recently, however, it was confirmed that FK-506 has stronger toxicity to kidney than cyclosporine A and also has a strong toxicity to liver. Thus, an effective immunosuppressive agent with low toxicity, which replaces these compounds is demanded. In general, among the administration routes of drugs, oral administration is best preferred because it can be carried out in the absence of a doctor and patients can take the drug at their homes. However, the effectiveness of cyclosporine A when orally administered is insufficient. Web site: http://www.delphion.com/details?pn=US05332818__ •
Injectable naltrexone microsphere compositions and their use in reducing consumption of heroin and alcohol Inventor(s): Ferrell; Teresa M. (Vestavia Hills, AL), Staas; Jay K. (Alabaster, AL), Tice; Thomas R. (Birmingham, AL) Assignee(s): Southern Research Institute (Birmingham, AL) Patent Number: 6,306,425 Date filed: April 7, 2000 Abstract: An injectable slow-release naltrexone formulation is provided comprising naltrexone in a poly(D,L-lactide) matrix with a small amount of residual ethyl acetate. Upon intramuscular injection of the composition, naltrexone is released in a controlled manner over an extended period of time. The composition finds use in the treatment of heroin addicts and alcoholics to reduce consumption of the abused substances. Excerpt(s): The disease of substance abuse remains a scourge on society. As it becomes more evident that there is a substantial genetic contribution to becoming addicted, helping addicted individuals to terminate their dependency or at least achieve a level of becoming a functional member of society, rather than treating substance abuse as a moral issue, has become increasingly accepted policy. Various programs have been put in place in the public and private sectors. In the private sectors, there are such organizations as Alcoholics Anonymous and Narcotics Anonymous, which play an important role in psycho-social support. In addition there are many private clinics which serve to provide both psycho-social support and medicinal support, using the somewhat limited repertoire of drugs which are available. In the public arena, there are the extensive programs to bring to the attention of young people and parents the hazards of substance abuse and discourage the young people from embarking on drug
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use. Also, there are the methadone programs, which are primarily public supported. The number of substance abusing subjects in the United States is quite staggering. There are estimated to be about 15 million people who abuse alcohol, about 1.3 million who abuse cocaine in its many manifestations, about 0.8 million who abuse amphetamines and about 0.5-0.8 million who abuse heroin, in addition to the use of other drugs, such as the psychedelic drugs. Efforts to reduce the numbers of scheduled substances and alcohol users have been continuous and relatively unavailing. Those subjects who have entered programs have had a dismal record of relapse, so that only a small proportion of the people who do enter programs and are retained in the programs remain clean long after the completion of the program. One significant factor in lack of retention and relapse is compliance. A repetitive act, such as taking a pill daily, is not a simple matter, even where the subject has no qualms about taking the pill. With the substance abuser, who may have physiological and emotional needs for the abused substance, the sustaining of the therapeutic routine is substantially more difficult. Therapeutic techniques, which require perseverance on the part of the subject, decrease the likelihood of success of the treatment. It is therefore of great importance to be able to reduce the level of involvement of the subject where medicinal treatments are involved, particularly treatments, which may involve frequent scheduling, monitoring of compliance, and sustaining a particular regimen. Web site: http://www.delphion.com/details?pn=US06306425__ •
Method for inducing anorexia Inventor(s): Smith, Jr.; Dewey H. (Wilmington, DE) Assignee(s): E. I. Du Pont de Nemours and Company (Wilmington, DE) Patent Number: 4,217,353 Date filed: April 6, 1979 Abstract: Naltrexone is administered orally so as to effect appetite suppression in mammals. Excerpt(s): This invention relates to inducing anorexia in warm-blooded animals by administering naltrexone orally thereto. Naltrexone, otherwise known as (-)-17(cyclopropylmethyl)-4,5.alpha.-epoxy-3,14-dihydroxymorphinan-6-one, is known to be a potent narcotic antagonist which shows considerable promise for the treatment of opiate dependence in man. It can be prepared in accordance with the teachings of Blumberg et al. in U.S. Pat. No. 3,322,950, as well as those of Pachter et al. in Canadian Pat. No. 913,077. Obesity is a serious problem, leading to, among other things, an increased risk of cardiovascular disease. None of the appetite supressants currently available is completely satisfactory. Web site: http://www.delphion.com/details?pn=US04217353__
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Method of treating cancer of the prostate Inventor(s): Bihari; Bernard (29 W. 15th St., New York, NY 10011) Assignee(s): none reported Patent Number: 6,384,044 Date filed: November 20, 2000
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Abstract: Cancer of the prostate in human male patients even at an advanced state with metastasis to other organs, is treated by the administration, preferably at bedtime, to the patient by a pharmacologically effective mode of an essentially pure opiate receptor antagonist, typified by Naltrexone and Naloxone, exerting substantially higher blocking action for Mu opiate receptor sites than against Delta opiate receptor sites at a low dose concentration which produces therapeutic results corresponding to those obtained by the administration of Naltrexone at a low dosage level in the range of 1.0 mg. to 10 mg. per day and at which Delta receptor blocking activity is at most small and Mu receptor blocking activity is substantial. Naltrexone is suitable for oral administration and is preferred. Excerpt(s): This invention relates to the treatment of cancer and is concerned more especially with treatment of cancer of the prostate gland in human males by administration of an essentially pure opiate receptor antagonist such as Naltrexone and Naloxone at a low level dosage. The use of an essentially pure opiate receptor antagonist in the treatment of several diseases has already been disclosed in patents in which I am named as an inventor. In U.S. Pat. No. 4,888,346, issued Dec. 19, 1989, the treatment was for the acquired immune deficiency syndrome (or AIDS) in any of its known states, including AIDS-related complex. In U.S. Pat. No. 5,013,739, issued May 7, 1991, the disease treated was chronic fatigue syndrome while in U.S. Pat. No. 5,346,900, issued Oct. 18, 1994, the disease was chronic herpes virus infections. In the latter patent, examples of treatment of multiple sclerosis and chronic inflammation of the connective tissue, such as arthritis and lupus, was also disclosed. For the treatment of all these diseases, the amount of the essentially pure opiate receptor antagonist to be administered was required to be at a quite low level corresponding in results achieved thereby to those obtained by the administration of Naltrexone at a dosage level of from 1.0 mg. to 10 mg per day., preferably at a dosage level of 1.0 mg. to about 5 mg., and most preferably at about 3.0 mg per day. At dosage levels above about 10 mg per day, not only were the desired therapeutic results not obtained but the effect of the treatment appeared to be negative in exacerbating the disease. Web site: http://www.delphion.com/details?pn=US06384044__ •
Method of treating chronic fatigue syndrome using an opiate receptor antagonist Inventor(s): Bihari; Bernard (29 W. 15th St., New York, NY 10011), Drury; Finvola (25 Colby St., Rochester, NY 14610) Assignee(s): none reported Patent Number: 5,013,739 Date filed: November 8, 1989 Abstract: Chronic herpes viral infections, including chronic genital herpes caused by the herpes simplex virus, Type 2, and chronic infections due to the Epstein-Barr virus, chronic fatigue syndrome, chronic inflammatory connective tissue disease, including rheumatoid arthritis and systemic lupus erythematous and related diseases, and multiple sclerosis are treated by the administration via a pharmacologically effective route of an essentially pure opiate receptor antagonist, preferably an essentially pure opiate receptor antagonist exhibiting a substantially higher blocking effectiveness against Mu opiate receptor sites than against Delta receptor sites, exemplified by naltrexone and naloxone, at a low dose concentration, corresponding to about 1-10 mg per day for naltrexone, at which concentration Delta blocking activity is small, while Mu blocking activity is significant.
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Excerpt(s): The diseases with which the invention is particularly concerned are listed below, together with a summary description of their pertinent medical features. The important herpes virus infections are chronic genital herpes and chronic infections due to the Epstein-Barr virus (EPV). Genital herpes is a highly prevalent disease caused by the herpes simplex virus (HSV) type No. 2, transmitted from person to person by direct contact. The disease typically begins with a genital rash and mild itching which develops into vesicular lesions appearing mainly on the genitalia and adjacent body regions, which leasions can expand to an ulcerated condition, which can be accompanied by a general malaise, fever and anorexia. Neurological complications are possible but rare. The disease is often self-limiting and may disappear after a single episode or, more typically, can reoccur in milder and less frequent episodes; but for some, it can be become chronic with severe and painful episodes at weekly or monthly intervals. Such episodes can be precipitated by stress, trauma, menstrual hormone changes, etc. The chronic disease is usually associated with high levels of serum antibodies against HSV. There is presently no cure for genital herpes. Treatment with the anti-viral drug, acylovir, administered in topical form appears to limit episodic duration but does not effect a cure, prevent transmission or protect against subsequent reoccurrence. Otherwise, treatment is generally palliative. Substantial risk exists for infants delivered by normal birth from infected mothers; neonatal herpes can cause brain damage and possible death. The most important inflammatory connective tissue diseases are rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Web site: http://www.delphion.com/details?pn=US05013739__ •
Method of treating multiple sclerosis Inventor(s): Bihari; Bernard (29 W. 15th St., New York, NY 10011), Drury; Finvola (25 Colby St., Rochester, NY 14610) Assignee(s): none reported Patent Number: 6,586,443 Date filed: September 27, 1994 Abstract: Multiple sclerosis in a human patient is treated by the administration via a pharmacologically effective route of an essentially pure opiate receptor antagonist, preferably an essentially pure opiate receptor antagonist exhibiting a substantially higher blocking effectiveness against Mu opiate receptor sites than against Delta receptor sites, exempliefied by Naltrexone and Naloxone, at a low dose concentration which produces therapeutic results corresponding to those produced by Naltrexone when administered in the range of about 1 mg to about 10 mg and at a lelel at which Delta blocking activity is small while Mu blocking activity is significant and most preferably substantially exclusive. Excerpt(s): This invention relates to the treatment of certain chronic diseases; namely, chronic infections caused by herpes virus, both herpes simplex virus and Epstein-Barr virus, chronic long-term inflammatory disease of the connective tissue, chronic fatigue syndrome and multiple sclerosis, by, the low dose administration of an essentially pure opiate receptor antagonist, such as naltrexone and naloxone. In our application Ser. No. 129,862, and now U.S. Pat. No. 4,888,346, we disclosed and claimed the treatment of humans infected with HTLV-III (AIDS) virus, including clinically diagnosed AIDS and AIDS-related complex (ARC), by the administration at low dosage levels of an essentially pure opiate receptor antagonist, preferably such antagonist having preferential blocking activity for Mu over Delta opiate receptor sites and exhibiting at
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the contemplated low dosage level a substantially selective blocking activity for Mu over Delta receptor sites, exemplified by naltrexone and naloxone. The patent literature relating to the medical utility proposed at the time for these and related drugs is summarized in the introductory discussion of the earlier application, the complete contents of which are hereby incorporated by reference, and include the treatment of narcotic addiction and narcotic overdose, the relief of severe itching in conjunction with Hodgkins Disease, mycosis funoides, severe jaundice, and various types of pruritis, the treatment of anorexia, the treatment of medical shock; i.e., anaphylactic, burn, cardiac, and the like shock, and the treatment of alcoholism or alcoholic intoxication. As explained in the prior applications, essentially pure opiate receptor antagonists, exemplified by naltrexone and naloxone, appear to be effective in potentiating the natural human immune system against the HTLV-III (AIDS) virus, apparently by upregulation of the endorphinergic system to thereby enhance hemostatic regulation of the natural immune function or the human body in ways by no means adequately understood. It has now been discovered that surprisingly these drugs are likewise effective for the treatment of certain chronic long-term diseases for which a specific medical treatment has been largely unavailable up to now, and even their etiology is, in a majority of instances, unknown. Web site: http://www.delphion.com/details?pn=US06586443__ •
Method of treatment for autoimmune diseases Inventor(s): Atkinson; David C. (Pembroke Pines, FL), Sherman; Fred P. (Hollywood, FL) Assignee(s): Baker Cummins Pharmaceuticals, Inc. (Miami, FL) Patent Number: 4,857,533 Date filed: December 15, 1988 Abstract: A method of treating a human or animal patient suffering from an autoimmune disease comprises daily administration to such patient of from about 1 to about 100 mg of the narcotic antagonists nalmefene or naltrexone. The nalmefene or naltrexone may be administered in equally divided doses from one to four times daily, preferably by the oral route. Parenteral administration may be utilized where suitable. Excerpt(s): The invention relates to methods of treating autoimmune diseases, e.g., systemic lupus erythematosus and rheumatoid arthritis. Autoimmunity develops when an organism mounts an anti-self response, usually as a result of abnormalities of the afferent parts of the immune system which are involved in antigen-specific responses. Autoimmunity is a primary cause or secondary contributor in many diseases, usually as a result of the formation of autoantibodies by the immune system of the organism which attack its own cells. Such diseases include, for example, systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hemolytic anemia, and certain forms of progressive liver disease. Systemic lupus erythematosus produces disturbances in more than one organ system with abnormalities in the immune system. Deposition of antigen-autoantibody complexes in tissues with resultant damage produces many of the clinical manifestations seen in lupus. These include arthritis with pain and swelling in both small and large joints, which may be confused with rheumatoid arthritis. Arthritis or arthralgia is seen in 55 percent of lupus patients. The classic "butterfly rash" which is an erythematous rash over the face and bridge of the nose is seen in 42 percent of lupus patients. Renal involvement secondary to deposition of antigen-antibody complexes producing glomerulonephritis is a major cause of
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morbidity and mortality in lupus patients. Cardiac involvement is seen in about half the lupus patients and also accounts for significant morbidity and mortality. Systemic lupus erythematosus may involve almost any organ system and confuse the physician as to the primary diagnosis. Web site: http://www.delphion.com/details?pn=US04857533__ •
Method of treatment for interestitial cystitis Inventor(s): Sherman; Fred P. (Hollywood, FL) Assignee(s): Baker Cummins Pharmaceuticals, Inc. (Miami, FL) Patent Number: 4,877,791 Date filed: November 1, 1988 Abstract: A method of treating patients suffering from interstitial cystitis comprises daily administration to such patients of from about 1 to about 50 mg of the narcotic antagonists nalmefene or naltrexone. The nalmefene or naltrexone may be administered in equally divided doses from one to four times daily, preferably by the oral route. Parenteral administration may be utilized where suitable. Excerpt(s): Histopathalogic examination of bladder biopsy specimens in patients with suspected interstitial cystitis is often used to rule out other diseases (e.g., carcinoma). Typical histopathalogic findings in interstitial cystitis include a non-specific inflammatory reaction, edema and vasodilatation in the submucosa, with or without detrusor fibrosis depending on the stage of the disease. A significant increase in the number of mast cells in the bladder lining, mainly in the detrusor muscle layer, is evident, and the histamine content of the bladder wall is significantly increased. See, e.g., E. M. Meares, Urology (Supplement), vol. 29, pp. 46-48 (1987 ); W. L. Lynes et al., J. Urology, vol. 138pp. 746-52 (1987); and J. Kastrup et al., Brit. J. Urology, vol. 55, pp. 495500 (1983). Recent studies indicate that the type of mast cells present in inflammatory bladder conditions such as interstitial cystitis may be of a special type know as mucosal mast cells, which are differentiated morphologically and histochemically from mast cells found, for example, in connective tissue. See J. Cornish et al., Int. Archs. Allergy Appl. Immun., vol. 81 , pp. 337-42 (1986). The progressive effects of interstitial cystitis on patients are severe and debilitating. Urinary frequency, urgency and pain, among other classic symptoms, impact dramatically and adversely on the patients' quality of life and drive them to seek any possible treatment to alleviate this disorder. Web site: http://www.delphion.com/details?pn=US04877791__
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Preparation of naltrexone from codeine and 3-benzylmorphine Inventor(s): Christodoulou; Aris P (New York, NY), Huang; Bao-Shan (Edison, NJ), Ji; Ben-Yi (Edison, NJ), Lu; Yansong (Edison, NJ) Assignee(s): Penick Corporation (Newark, NJ) Patent Number: 6,013,796 Date filed: July 16, 1998 Abstract: For the synthesis of 3-methylnaltrexone from codeine in this invention, codeine is converted to 6-acetylcodeine, which is N-demethylated to 6-acetylcodeine hydrochloride, followed by alkylating the nitrogen to form 17-
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cyclopropylmethylnorcodeine. The latter is oxidized to 17cyclopropylmethylnorcodeinone. For the synthesis of naltrexone from morphine in this invention, morphine is converted to 3-benzylnormorphine as described above in the synthesis of noroxymorphone. 3-Benzylnormorphine is reacted with cyclopropylmethyl halide to produce 3-benzyl-17cyclopropylmethylnormorphine, a novel compound, which is oxidized to 3-benzyl-17-cyclopropylmethyl-normorphinone, a novel compound, by Swern oxidation. Excerpt(s): This invention relates in general to process for the conversion of normorphinone and its derivatives, which can be synthesized from morphine, to the corresponding 14-hydroxynormorphinone and its derivatives including oxycodone, oxymorphone, noroxymorphone, and naltrexone. Noroxymorphone is a key intermediate for the production of important narcotic analgesics and antagonists. In another aspect, the invention is directed to certain novel intermediates. 14-Hydroxysubstituted morphine derivatives are important narcotic analgesics and/or antagonists. These drugs include oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, and nalmefene. They are readily synthesized from thebaine, which is a minor component of gum opium. As the supply of thebaine is limited and the demand is increasing, therefore, the price of thebaine is high. As a result, many alternative approaches have been made for the preparation of 14-hydroxymorphine derivatives. The reported efforts for preparing these narcotics bearing a 14-hydroxy group from readily abundant starting materials morphine or codeine (a minor component of gum opium, which may also be synthesized by methylation of morphine) are summarized as the following: (1) the conversion of codeine to thebaine through dihydrocodeinone (5.4% yield, H. Rapoport, et al., J. Am. Chem Soc., vol. 89, 1967, p. 1942 and H. Rapoport, et al., J. Org. Chem., vol. 15, 1950, p. 1103), codeinone (20% yield, I. Seki, Chem. Pharm. Bull., vol. 18, 1970, p. 671 and H. Rapoport, et al., J. Am. Chem. Soc., vol. 77, 1955, p. 490) or 6-methyl ether of codeine (using manganese dioxide, 67% yield, R. B. Barber, et al., J. Med. Chem., vol. 18, 1975, p. 1074); (2) the oxidation of codeinone pyrrolidinyl di-enamine to 14hydroxycodeinone (30-40% yield, I. Seki, Chem. Pharm. Bull., vol. 18, 1970, p. 671); (3) the direct allylic oxidation of codeine to the corresponding 14-hydroxy derivatives with, manganese dioxide (I. Brown, et al., J. Chem. Soc., 1960, p. 4139), and selenium dioxide plus t-butyl hydrogen peroxide (M. A. Schwartz, et al., J. Med. Chem., vol. 24, 1981, p. 1525); and (4) the six-step transformation of codeine to noroxycodone (52% yield) and noroxymorphone (43% yield) using photochemically generated singlet oxygen (M. A. Schwartz, et al., J. Med. Chem. vol. 24, 1981, p. 1525); and (5) the preparation of noroxymorphone from morphine through an intermediate with carbamate protection on the nitrogen atom (17-position) or a carbonate protecton at the 3 position and the carbamate protection at the 17 position of normorphinone dienol acetate with MCPBA in the substantial absence of water (37% yield, Wallace, U.S. Pat. No. 5,112,975). These processes suffer from either low yields, long steps, not amenable to scale-up, or involve the use of environmentally unfriendly heavy metals. Web site: http://www.delphion.com/details?pn=US06013796__
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•
Process for making methylenenaltrexone
6-desoxy-6-methylenenaloxone
and
6-desoxy-6-
Inventor(s): Coe; Jotham W. (Belmont, MA), Meltzer; Peter C. (Lexington, MA) Assignee(s): Key Pharmaceuticals, Inc. (Miami, FL) Patent Number: 4,535,157 Date filed: November 1, 1983 Abstract: An improved Wittig reaction for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone from naloxone and naltrexone utilizing an alkoxide base in an ethereal solvent. Excerpt(s): The present invention relates to an improved Wittig reaction for making 6desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone (also called nalmefene) from naloxone and naltrexone, respectively. Narcotic agonists such as morphine are commonly used to provide analgesia in cases of severe pain. As is well known, narcotic addiction and drug abuse are commonly associated with their use. Much effort has been directed to the development of satisfactory narcotic antagonists, drugs with the capacity to reverse or block the agonist effects of narcotics. Narcotic antagonists are presently used to reverse respiratory depression, a side effect when narcotics are administered, and are being tested as prophylactic agents in combating narcotic drug abuse. For the later purpose, a narcotic antagonist is required which exhibits little or no agonist properties, has an extended duration of action, and is preferably orally effective. Most narcotic antagonists synthesized thus far exhibit at least some degree of agonist activity. The best known and currently utilized antagonists are naloxone and naltrexone; the later exhibits somewhat greater agonist activity but is of greater potency and has a longer duration of action. It has been discovered that the 6desoxy derivatives of these compounds are even more useful as narcotic antagonists. Hahn and Fishman, J. Med. Chem., Vol. 18, No. 3, pp. 259-262 (1975) describe the preparation and properties of 6-desoxy-6-methylenenaloxone and 6-desoxy-6methylenenaltrexone. The compounds were prepared on a small scale from naloxone and naltrexone, respectively, using preformed methylenetriphenylphosphorane, prepared in situ from methyltriphenylphosphonium bromide, sodium hydride and dimethyl sulfoxide, as the reagent, according to the method of Corey and Chaykovsky, J. Amer. Chem. Soc., 87, 1345, (1965). Web site: http://www.delphion.com/details?pn=US04535157__ •
Smoking cessation treatments using naltrexone and related compounds Inventor(s): Krishnan-Sarin; Suchitra (Durham, CT), Meandzija; Boris (Hamden, CT), O'Connor; Patrick G. (Woodbridge, CT), O'Malley; Stephanie (New Haven, CT) Assignee(s): Yale University (New Haven, CT) Patent Number: 6,004,970 Date filed: November 12, 1997 Abstract: Nicotine dependency is treated by administration of an opioid antagonist. In some embodiments, rapid or ultra rapid detoxification techniques include using a combination of an effective amount of an opioid antagonist such as nalmefene, naloxone or naltrexone or a mixture of any one of these, and either clonidine or related compounds either while awake, or while under sedation or anesthesia, followed by
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continued administration of an effective amount of an opioid antagonist with or without agents that enhance nicotine dependency treatment. Persons are also treated for nicotine dependency with more gradual detoxification methods using administration of a combination of an effective amount of an opioid antagonist such as nalmefene, naloxone, naltrexone, or a mixture of any of these, and an effective amount of agents used to treat nicotine withdrawal including nicotine, such as that delivered by a nicotine patch, nicotine chewing gum, nicotine inhaler or other methods for delivering nicotine, antidepressants and antianxiety agents, and/or clonidine and related compounds. Administration of an effective amount of an opioid antagonist to prevent relapse, attenuate craving, and reduce weight gain during and after treatment for nicotine dependency is continued in some embodiments. Excerpt(s): This invention relates to the use of opioid antagonists such as naltrexone, naloxone or nalmephene alone or with either nicotine replacement therapy or with other withdrawal attenuating agents, to increase smoking abstinence rates, to decrease craving for cigarettes, reduce relapse to heavy smoking during detoxification or once smoking abstinence has been achieved, and to reduce weight gain associated with smoking cessation. Tobacco dependence continues to be a major health hazard for millions of Americans, and because smoking may pose a health risk for non-smokers as well, smoking cessation treatments are of great public interest. Dependence is an adaptive biological state induced by chronic drug exposure which manifests itself in various behavioral and physiological responses when drug exposure ceases. Withdrawal from nicotine following chronic use of tobacco products results in the emergence of an abstinence syndrome which reaches its peak intensity within the first day. Cessation of smoking has been shown to result in a number of signs and symptoms of withdrawal such as increases in irritability, anxiety, restlessness, impatience, somatic complaints, cigarette craving, hunger, insomnia, tremulousness and heart rate as well as difficulty concentrating, all of which are collectively called the tobacco withdrawal syndrome. Web site: http://www.delphion.com/details?pn=US06004970__ •
Synthesis and utilization of 17-methyl and 17-cyclopropylmethyl-3,14-dihydroxy4,5.alpha.-epoxy 6.beta.-fluoromorphinans (foxy and cyclofoxy) as (18F)-labeled opioid ligands for position emission transaxial tomography (PETT) Inventor(s): Burke, Jr.; Terrence R. (West Bethesda, MD), Channing; Michael A. (Annapolis, MD), Eckelman; William C. (Rockville, MD), Larson; Steven M. (Cabin John, MD), Pert; Candace B. (Bethesda, MD), Rice; Kenner C. (Rockville, MD) Assignee(s): The United States of America as represented by the Department of Health (Washington, DC) Patent Number: 4,775,759 Date filed: November 27, 1984 Abstract: Fluorinated derivatives 3,14-dihydroxy-4,5.alpha.-epoxy-6.beta.-fluoro-17methylmorphinan ("fluorooxymorphone"; FOXY, compound 10) and 17cyclopropylmethyl-3,14-dihydroxy-4,5.alpha.-epoxy-6.beta.-fluoromorphin an (CYCLOFOXY, compound 18) are prepared based upon the structures of the potent opioid agonist oxymorphone 4 and the antagonist naltrexone 11, respectively. Fluorine was introduced in the final stages of synthesis by a facile nucleophilic displacement with fluoride ion of the 6.alpha.-triflate functions in 8 and 16. The synthetic procedures were suitable for the production of the corresponding positron emitting.sup.18 F-labeled
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analogs.sup.18 F-FOXY and.sup.18 F-CYCLOFOXY, which are useful for in vivo studies of the opioid receptor system using positron emission transaxial tomography. In addition, the tritiation of FOXY (10) to high specific activity is noted. Excerpt(s): The structure and function of the opioid receptor system is set out in the synthesis of a variety of opioid ligands designed as pharmacological probes of the system. One shortcoming of these lines of investigation is that they are not suitable for in vivo visualization of opioid receptors in the living human brain. With the development of positron emission transaxial tomography (PETT), in vivo investigation of the opioid receptor system in humans is possible if an appropriate positron emitting opioid ligand is used (see Phelps et al, Annals of Internal Medicine, 98:339-359, 1983). To be useful, such a ligand must have high binding affinity and specificity for the opioid receptor system and must be synthetically accessible by introduction of the positron emitting isotope in rapid, high yield reaction immediately prior to use. Use of.sup.18 F, a positron emitting isotope with a half life of 110 min, has proven to be successful for PETT scanning in other systems. PETT as here used is a non-invasive method for counting or scanning opiate receptors. Described herein is the synthesis of four new fluorinated opioids 9, 10, 17 and 18 by routes which involve facile introduction of fluorine in the final stages in a manner suitable for incorporation of.sup.18 F. Synthesis of the.sup.18 F-labeled 17 (a prodrug of Cyclofoxy 18) and utilization of this material for visualization of opiate receptors in the brain of a living baboon is also included. Also included in this invention is the tritiation of 10 to high specific activity. Morphinan 10 ("fluorooxymorphone," FOXY), whose structure is based on the potent opioid agonist oxymorphone (4), was obtained in a clean, rapid (20 min) reaction of triflate 8 with KF/18-crown-6 in refluxing acetonitrile. The choice of triflate (trifluoromethanesulfonate) as the leaving group in this nucleophilic displacement is based upon its proven value in similar reactions and the observation that methyl triflates are 10.sup.4.3 times more reactive to solvolysis than tosylates. In the reaction of 8 with fluoride the 3-OAc group was retained, giving 9, which upon treatment with aqueous NH.sub.3 yielded the title compound FOXY (10). However, for experiments utilizing.sup.18 F where shorter reaction times are critical, the 3-OAc derivative 9 can be taken directly for in vivo studies, eliminating the hydrolysis step. By analogy to other 3OAc 4,5-epoxymorphinans such as heroin, the presence of the 3-OAc group in 9' and 17' is believed to facilitate uptake in the brain where rapid enzymatic deacetylation yields the free [.sup.18 F]3,14-dihydroxy-4,5.alpha.-epoxy-6.beta.-fluoro-17-methylmorphinan, or.sup.18 F-FOXY (10') and [.sup.18 F] 17-cyclopropylmethyl-3,14-dihydroxy-4,5.alpha.epoxy-6.beta.-fluoromorphin an, or.sup.18 F-CYCLOFOXY (18'). Triflate 8 was prepared by reaction of 6 --OH compound 7 with a molar excess of trifluoromethanesulfonic anhydride in pyridine/CHC.sub.13. The excess anhydride did not acylate the 14-OH group under these conditions. The 3-acetyl-14-hydroxy-dihydromorphine 7 was obtained as a crystalline solid, mp 125.degree.-126.degree. C. (previously reported as a gum) by treatment of the corresponding 3-OH compund 5 with acetic anhydride in aqueous NaHCO.sub.3. The 3-OH compound 5 can be obtained directly from 14hydroxydihydromorphinone (4) by reduction with NaBH.sub.4. However, in contrast to previous reports, substantial formation of epimeric 6.beta.-OH product 6 was observed, necessitating tedious purification by silica gel chromatography to obtain the pure 6 --OH epimer 5. Alternately, pure 6.beta.-OH compound 2 was obtained by NaBH.sub.4 reduction of the didehydro compound 1 which followed by hydrogenation to 3 and Odemethylation (BBr.sub.3 in CHCl.sub.3) yield 5. Web site: http://www.delphion.com/details?pn=US04775759__
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Transdermal therapeutic systems for the administration of naloxone, naltrexone and nalbuphine Inventor(s): Chen; Yu-Ling (Cupertino, CA), Chun; Leslie L. (Palo Alto, CA), Enscore; David J. (Sunnyvale, CA) Assignee(s): ALZA Corporation (Palo Alto, CA) Patent Number: 4,573,995 Date filed: October 9, 1984 Abstract: A method for transdermal delivery of naloxone, naltrexone and nalbuphine base through intact skin is described. Preferred embodiments of transdermal therapeutic systems for delivering these drugs and polyethylene glycol monolaurate employ an ethylene vinylacetate matrix containing drug base at a concentration above saturation and polyethylene glycol monolaurate below unit activity. Polyethylene glycol manolaurate is disclosed as a permeation enhancer for the base form of these drugs and is preferably delivered simultaneously with the drug. Excerpt(s): This invention relates to transdermal therapeutic system for the parenteral administration of naloxone, naltrexone and nalbuphine through intact skin. This application is related to the copending coassigned patent application Ser. No. 06/659,121 of like date herewith of Taskovich et al. for Skin Permeation Enhancer Compositions. Naloxone, naltrexone and nalbuphine are known, chemically similar drugs and are described in the 1984 USAN and the USP Dictionary of Drug Names, United States Pharmacopiea Convention, Inc., Rockville, MD pp. 327 and 378 (1983). The therapeutic administration of naloxone and nalbuphine is currently limited to injection or infusion typically from solution of the hydrochloride and naltrexone is under investigation for similar administration. Although various types of transdermal therapeutic systems for delivering a wide variety of drugs are known to the art, such as described in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454, 4,286,592, and 4,317,557, (which are all incorporated herein by reference) for example, none of these patents are directed specifically to systems for the transdermal delivery of either naloxone, naltrexone or nalbuphine. We found that the permeability through skin of these drugs is too low to produce any therapeutic effect from a reasonably sized therapeutic system. When we attempted to increase their permeation through skin by the contemporaneous administration of conventional permeation enhancers we were either unsuccessful in increasing the flux or we observed unacceptable levels of irritation to the skin. Web site: http://www.delphion.com/details?pn=US04573995__
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Treating opiate dependence Inventor(s): Lewis; John W. (North Humberside, GB) Assignee(s): Reckitt & Colman Products Limited (London, GB2) Patent Number: 4,935,428 Date filed: November 25, 1988 Abstract: A pharmaceutical composition in sublingual unit dosage form for maintenance treatment of opiate addicts comprising from 2 to 8 mg buprenorphine and an amount of naltrexone sufficient to substantially attenuate the euphorigenic effect of the buprenorphine when injected and to provide greater opiate blocking effect than that of naltrexone alone.
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Excerpt(s): This invention relates to compositions useful for the treatment of opiate dependence and more particularly to compositions containing naltrexone and buprenorphine. Naltrexone (INN for 1-N-cyclopropylmethyl-14hydroxynordihydromorphinone) is a pure opiate antagonist which, when administered orally (50 mg/day) as a maintenance drug for opiate addicts, blocks the effects of selfadministered opiates and this contributes to the extinction of drug craving. Unfortunately, only about 10 percent of addicts inducted on to a naltrexone treatment regime remain in treatment since naltrexone has no positive reinforcing effect to satisfy the needs of the addict. It also has the disadvantage that it precipitates abstinence in opiate abusers including those with only a low level of physical dependence. Thus an addict must be detoxified and be drug free for at least ten days before starting naltrexone treatment. Buprenorphine (INN for N-cyclopropylmethyl-7&-[1-(S)hydroxy-1,2,2-trimethylpropyl]6,14-endoethan o-6,7,8,14-tetrahydronororipavine) has been shown in man to be a potent antagonist analgesic lacking the psychotomimetic effects found with other antagonist analgesics. Buprenorphine effectively relieves moderate to severe pain in doses of 0.1 mg or more administered either parenterally or sublingually. The optimum therapeutic range for single doses is 0.3 mg-0.6 mg by injection and 0.1 mg-0.4 mg for sublingual tablets. In animal tests and in man buprenorphine has been shown to have both agonist (morphine-like) and (morphine) antagonist properties. However from direct dependence studies in animals and in man it has been concluded that buprenorphine does not produce significant physical dependence and the potential to produce psychological dependence is low as indicated by animal self administration studies and by the measurement of euphorigenic effects in human post addicts. In man the agonist and narcotic antagonist characteristics of buprenorphine have been demonstrated in opiate addicts. Thus oral buprenorphine in the dose range 6-16 mg has been shown to precipitate abstinence in highly dependent opiate addicts presenting for detoxification. On the other hand in a study involving subjects stabilised on a relatively low daily dose of oral methadone, sublingual buprenorphine could be substituted for methadone with only a low level of discomfort. In this situation buprenorphine was behaving as an opiate agonist of low intrinsic activity. Web site: http://www.delphion.com/details?pn=US04935428__
Patent Applications on Naltrexone As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to naltrexone:
9
This has been a common practice outside the United States prior to December 2000.
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Analgesic compositions containing buprenorphine Inventor(s): Chapleo, Christopher Bourne; (Gainsborough, GB), McCormack, Keith; (Kilburn, GB), Varey, Nicolas Calvert; (Goole, GB) Correspondence: Frederick H. Rabin; Fish & Richardson P.C.; Suite 2800; 45 Rockefeller Plaza; New York; NY; 10111; US Patent Application Number: 20030004178 Date filed: May 14, 2002 Abstract: An analgesic composition in parenteral unit dosage form or in a unit dosage form suitable for delivery via the mucosa comprising an amount of buprenorphine which is less than the clinical dose required to achieve pain relief and an amount of naloxone such that the ratio by weight of buprenorphine to naloxone is in the range of from 12.5:1 to 27.5:1, or an amount of naltrexone or nalmefene such that the ratio by weight of buprenorphine to naltrexone or nalmefene is in the range of from 12.5:1 to 22.5:1. The analgesic action of the buprenorphine is potentiated by the low dose of naloxone, naltrexone or nalmefene. Excerpt(s): This is a continuation-in-part of application No. PCT/GB00/04372 filed on Nov. 17, 2000, which is a continuation-in-part of U.S. Provisional Application No. 60/176,208 filed on Jan. 14, 2000. The present invention relates to analgesic compositions, containing buprenorphine and, in particular, to compositions which contain buprenorphine at a sub-clinical analgesic dose level in combination with naloxone, naltrexone or nalmefene. Buprenorphine (International Non-proprietary Name for N-cyclopropylmethyl-7.alpha.-[1-(S)-hydroxy-1,2,2-trimethylpropyl]6,14-endoethano-6,7,8,14-tetrahydronororipavine) has been shown in clinical trials to be a potent opiate partial agonist analgesic lacking the psychotomimetic effects found with other opiate analgesics. Buprenorphine effectively relieves moderate to severe pain in doses of 0.1 mg or more administered either parenterally or sublingually. The optimum therapeutic range for single doses is 0.3 mg-0.6 mg by injection and 0.2 mg-0.8 mg for sublingual tablets. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compositions and methods for enhancing analgesic potency of tramadol and attenuating its adverse side effects Inventor(s): Barbier, Remi; (San Francisco, CA), Crain, Stanley M.; (State College, PA), Friedmann, Nadav; (Lafayette, CA), Remien, Mary; (San Francisco, CA), Shen, Ke-Fei; (Flushing, NY), Sherman, Barry; (Hillsborough, CA) Correspondence: Mcandrews Held & Malloy, Ltd; 500 West Madison Street; Suite 3400; Chicago; IL; 60661 Patent Application Number: 20030148941 Date filed: March 12, 2002 Abstract: The invention generally relates to compositions and methods with tramadol and an opioid antagonist to enhance analgesic potency and/or attenuate one or more adverse effects of tramadol, including adverse side effect(s) in humans such as nausea, vomiting, dizziness, headache, sedation (somnolence) or pruritis. This invention relates to compositions and methods for selectively enhancing the analgesic potency of tramadol and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability,
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physical dependence and/or tolerance effects associated with the administration of tramadol. The methods of the present invention comprise administering to a subject an analgesic or subanalgesic amount of tramadol and an amount of excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of tramadol and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of tramadol. Excerpt(s): This is a continuation-in-part of co-pending application Ser. No. 09/306,164 filed May 6, 1999, the content of which is hereby incorporated by reference in its entirety. Morphine or other bimodally-acting opioid agonists are administered to relieve severe pain due to the fact that they have analgesic effects mediated by their activation of inhibitory opioid receptors on nociceptive neurons (see North, Trends Neurosci., Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends Pharmacol. Sci., Vol. 11, pp. 77-81 (1990)). However, morphine and other bimodally-acting opioid agonists also activate opioid excitatory receptors on nociceptive neurons, which attenuate the analgesic potency of the opioids and result in the development of physical dependence and increased tolerance (see Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992)), as well as hyperexcitability, hyperalgesia and other undesirable (excitatory) side effects. As a result, a long-standing need has existed to develop a method of both enhancing the analgesic (inhibitory) effects of bimodally-acting opioid agonists and blocking or preventing undesirable (excitatory) side effects caused by such opioid agonists. Tramadol is an orally active, clinically effective, centrally acting analgene compound with opioid and non-opioid activity. This synthetic analgesic has a novel mechanism of action involving a complementary and synergistic interaction between inhibition of neuronal monamine uptake and weak affinity for opioid receptors (Raffa et al., Rev. Contemp. Pharmacother. 6:485-497 (1995)). Tramadol is generally well tolerated, with dizziness, nausea, constipation, headache, somnolence (sedation), vomiting, pruritis, CNS stimulation, sezures, asthenia, dyspepsia, diarrhea, dry mouth and/or sweating as adverse side effects. Respiratory depression is uncommon (Lee et al., Drugs 46: 313-340 (1993); Vickers et al., Anaesthesia 47: 291-296 (1992)). Tramadol is marketed in the United States as ULTRAM.RTM. Data from a double-blind, crossover study suggest that oral tramadol 120 mg is equipotent to oral morphine 30 mg (Wilder et al., Ann. Oncol. 5: 141-146 (1994)). A need thus exists for compositions and methods that could enhance the analgesic potency of tramadol and/or block or prevent its adverse side effects, particularly its principal adverse effects in humans. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for curbing dietary cravings Inventor(s): Bernstein, Richard K.; (Mamaroneck, NY) Correspondence: Kirkpatrick & Lockhart Llp; 535 Smithfield Street; Pittsburgh; PA; 15222; US Patent Application Number: 20020198227 Date filed: July 2, 2002 Abstract: Provided is a method for curbing dietary cravings in a patient, typically a diabetic or obese patient, by administration of a low dose of naltrexone to the patient. Excerpt(s): A method for curbing carbohydrate craving and, in general, overeating through long-term use of low dose naltrexone. The described method finds particular use in treatment of diabetes and obesity. Obesity and diabetes both have reached
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epidemic proportions. Many obese people are able to effectively reduce their weight by combinations of exercise and/or diet. However, some are not able to reduce their weight on their own and undergo medically supervised diets and/or therapies. Diabetics also can improve their condition by minimizing carbohydrate intake. A number of lowcarbohydrate diet plans make it possible for many diabetics to achieve normal blood sugars. There are, however, three exceptions. The first is gastroparesis, or the partial paralysis of the stomach, and other ailments that can impair stomach emptying. These ailments may include hiatal hernia, stomach or duodenal ulcers, a "tonic" (tight) stomach, gastritis, duodenitis and scleroderma. The second exception is infection. The third exception is the inability to control food intake, especially carbohydrate intake. Because of the "thrifty genotype" or "thrifty phenotype," this condition is expected in many type 2 diabetics. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of preventing lipodystrophy syndrome or reversing a pre-existing syndrome in HIV-infected patients being treated with antiretroviral agents Inventor(s): Bihari, Bernard; (New York, NY) Correspondence: William J. Daniel; 6100 Woodland Terrace; Mclean; VA; 22101; US Patent Application Number: 20030105121 Date filed: January 14, 2003 Abstract: An improvement in a method of treating an HIV/AIDS infection in human patients in which the patient receives antiretroviral therapy and is consequently subjected to significant risk of developing the lipodystrophy syndrome in one or more of its characteristics. This risk is reduced, and pre-existing signs of such syndrome from past therapy can be substantially reversed, by the concurrent administration by a therapeutically effective mode of an essentially pure opiate receptor antagonist such as Naltrexone and Naloxone at a low level dosage. Excerpt(s): This application is a continuation-in-part of my prior application Ser. No. 09/613,251, filed Jul. 10, 2000, as a complete application of PROV. S. No. 60/145,843, filed Jul. 27, 1999. This invention relates to the treatment of HIV-infected patients who are already undergoing or about to undergo treatment by an antiretroviral therapy employing at least one antiretroviral agent, especially a protease inhibitor and optionally at least one reverse transcriptase inhibitor, selected from either or both of the nucleoside and non-nucleoside categories, and are consequently at significant risk of developing lipodystrophy syndrome or have already developed such syndrome from past therapy, by the concurrent administration with such antiretrovireal agent(s) of an essentially pure opiate receptor antagonist such as Naltrexone and Naloxone by a therapeutically effective mode at a low level dosage which produces substantially the therapeutic results corresponding to those obtained by the administration of Naltrexone at a low dosage level in the range of 1.0 mg. to 10 mg. and preferably 1.0 to 4.5 mg., generally during the night hours, e.g. bedtime. Since emerging about 1977, acquired immunodeficiency syndrome (AIDS) and its underlying HIV infection has become a major medical problem in the United States and even more so elsewhere in the world. According to "The Merck Manual of Medical Information", Home Edition, Copyright 1997 by Merck and Co., Inc., through roughly the end of 1995, more than one-half million cases had been reported in the U.S. with about 300,000 deaths attributable to this syndrome. The number of persons infected with its causative virus, human immunodeficiency virus (HIV), is currently believed to be about double the number of
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active cases. The virus is transmitted via contact with the bodily fluids of an infected persons, particularly with mucous membranes or sera, and its attack was initially concentrated in the homosexual and injecting drug-using population. More recently, however, the rate of infection in heterosexuals is rapidly increasing with women making up 10% of the cases and increasing at a more rapid rate than men. There is, therefore, as compelling need for improved modalities for treating AIDS and/or achieving control over the spread of HIV systemically in a given individual. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
METHOD OF SIMULTANEOUSLY ENHANCING ANALGESIC POTENCY AND ATTENUATING ADVERSE SIDE EFFECTS CAUSED BY TRAMADOL AND OTHER BIMODALLY-ACTING OPIOID AGONISTS Inventor(s): CRAIN, STANLEY M.; (LEONIA, NJ), SHEN, KE-FEI; (FLUSHING, NY) Correspondence: Craig J Arnold Esq; Amster Rothstein & Ebenstein; 90 Park Avenue; New York; NY; 10016 Patent Application Number: 20010006967 Date filed: May 6, 1999 Abstract: This invention relates to a method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist such as tramadol and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the bimodally-acting opioid agonist. The method of the present invention comprises administering to a subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist such as tramadol and an amount of an excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist. Excerpt(s): This is a continuation-in-part of copending application Ser. No. 09/094,977, filed Jun. 16, 1998, which is a continuation of application Ser. No. 08/759,590, filed Dec. 3, 1996, now U.S. Pat. No. 5,767,125, which is a continuation-in-part of application Ser. No. 08/276,966, filed Jul. 19, 1994, now U.S. Pat. No. 5,512,578, which is a continuationin-part of application Ser. No. 08/097,460, filed Jul. 27, 1993, now U.S. Pat. No. 5,472,943, which is a continuation-in-part of application Ser. No. 07/947,690, filed Sep. 19, 1992, now abandoned, the contents of which are hereby incorporated by reference in their entirety. This invention relates to a method of enhancing the analgesic (inhibitory) effects of bimodally-acting opioid agonists, including morphine, codeine and other clinically used opioid analgesics, while at the same time attenuating anti-analgesia, physical dependence, tolerance, hyperexcitability, hyperalgesia, and other undesirable (excitatory) side effects typically caused by chronic use of bimodally-acting opioid agonists. "Bimodally-acting opioid agonists" are opioid agonists that bind to and activate both inhibitory and excitatory opioid receptors on nociceptive neurons which mediate pain. Opioid analgesia results from activation by opioid agonists of inhibitory opioid receptors on neurons in the nociceptive (pain) pathways of the peripheral and central nervous systems. The undesirable side effects, including anti-analgesic actions, hyperexcitability and hyperalgesia, the development of physical dependence, and some types of tolerance result from sustained activation by bimodally-acting opioid agonists of excitatory opioid receptors on neurons in the nociceptive (pain) pathways of the peripheral and central nervous systems. In the instant invention, a very low dose of a
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selective excitatory opioid receptor antagonist, an opioid which binds to and acts as an antagonist to excitatory but not inhibitory opioid receptors on nociceptive neurons which mediate pain, is combined with a dose of a bimodally-acting opioid agonist so as to enhance the degree of analgesia (inhibitory effects) and attenuate the undesired side effects (excitatory effects). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of treating pain using nalbuphine and opioid antagonists Inventor(s): Levine, Jon D.; (San Francisco, CA) Correspondence: Townsend And Townsend And Crew; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20020016331 Date filed: June 8, 2001 Abstract: Inflammatory or neuropathic pain in both men and women patients is treated by administering, sequentially or simultaneously, (a) nalbuphine and (b) an opioid antagonist selected from naloxone, naltrexone and nalmefene, or a salt or prodrug of nalbuphine and/or the opioid antagonist. Preferably, administration is made of (a) an amount of from about 3 to about 8 mg nalbuphine and (b) from about 0.2 to about 0.8 mg of an opioid antagonist selected from naloxone, naltrexone and nalmefene, or a salt and/or prodrug of either (in an amount that produces in a patient the same blood concentration of the compound in question as would administration of said amount of the nalbuphine or opioid antagonist itself).Treatment of both inflammatory and neuropathic pain can be achieved; side effects common with.mu.-opioids such as morphine were not observed. Excerpt(s): This invention relates to methods and compositions for treating pain in humans using a combination of the kappa-opioid nalbuphine, in a relatively low dosage, with a low dosage of an opioid antagonist selected from naloxone, naltrexone, and nalmefene. Nalbuphine is a kappa-opioid, a member of the larger opioid group of agonists that includes many well-known agents used to relieve pain. The most well known member of this class is the mu-opioid morphine. Morphine, of course, is a widely known compound, administered for various purposes, including analgesia. Morphine, in fact, is the compound most often used to treat moderate to severe pain. However, it has known limitations. With time, patients can develop tolerance to it and/or become dependent on it or addicted to it. In addition, morphine can cause severe constipation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Naltrexone hydrochloride compositions Inventor(s): Goliber, Philip; (Brookfield, CT), Huang, Hua-Pin; (Englewood Cliffs, NJ), Mannion, Richard; (Carmel, NY), Oshlack, Benjamin; (New York, NY) Correspondence: Davidson, Davidson & Kappel, Llc; 14th Floor; 485 Seventh Avenue; New York; NY; 10018; US Patent Application Number: 20030229111 Date filed: March 14, 2003
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Abstract: The present invention relates to compositions and methods of stabilizing naltrexone hydrochloride. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application No. 60/364,521, filed on Mar. 14, 2002, which is hereby incorporated by reference. The present invention relates to pharmaceutical compositions comprising naltrexone hydrochloride and a stabilizer, and methods of making and using the same. Naltrexone is an opioid antagonist. The compound and methods for the synthesis of naltrexone are described in U.S. Pat. No. 3,332,950. When coadministered with morphine, heroin or other opioids on a chronic basis in a sufficient amount, naltrexone may reduce the incidence of physical dependence to opioids. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Neutral antagonists and use thereof in treating drug abuse Inventor(s): Sadee, Wolfgang; (Ross, CA), Wang, Danxin; (San Francisco, CA) Correspondence: Caroly S. Elmore; Hamilton, Brook, Smith & Reynolds, P.C.; Two Militia Drive; Lexington; MA; 02421-4799; US Patent Application Number: 20010049375 Date filed: March 15, 2001 Abstract: The invention relates to the use of naltrexone and naloxone analogs, which are neutral antagonists at the.mu. opioid receptor, for the treatment of drug dependency in a drug-dependent individual. Surprisingly, it has been found that administration of a therapeutically effect amount of the naloxone or naltrexone analogs described herein for the treatment of a drug dependency, can result in reduction of undesirable side effects resulting from current treatments using naloxone and naltrexone. For example, the treatment described herein can result in a reduction in the withdrawal symptoms and aversion encountered in the use of naloxone and naltrexone in the treatment of drug dependency. In addition, the naltrexone and naloxone analogs of the invention can be used for the treatment of pain in an individual in need thereof by modulating opoid pain treatment using neutral antagonists, for example, reversing respiratory depression withough causing other adverse effects. In addition, during chronic use of opioid drugs for pain therapy, neutral antagonists can be used to diminish constipation peripherally without effecting the central analgesic effects. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/189,372 filed on Mar. 15, 2000. The entire teachings of the above application are incorporated herein by reference. Endogenous opiate receptors were discovered in the 1970s, and have been intensely studied in seeking the mechanisms by which particular drugs lead to addiction. However, such mechanisms have remained elusive. See, for example, J. Neurosci., 12(7): 2349-2450 (1992). A number of different opioid receptor types have been identified. Known receptor types include, for example, the mu.mu. (MOR), delta.delta. (DOR), and.kappa. kappa receptors. Narcotic analgesics act at the opioid.mu. receptor to produce analgesia. The.mu. receptor mediates analgesia, respiratory depression, and inhibition of gastrointestinal transit. As such, narcotic analgesics act at the.mu. receptor to produce analgesia. However, continued use of narcotic analgesics typically leads to habit or addiction, and use of one leads to crosstolerance/dependence for the others. Despite their therapeutic uses, undesirable side effects such as physical dependence and drug craving can develop. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Opioid growth factor modulates angiogenesis Inventor(s): Blebea, John; (Hummelstown, PA), McLaughlin, Patricia J.; (Harrisburg, PA), Zagon, Ian S.; (Hummelstown, PA) Correspondence: Leopold Presser; Scully, Scott, Murphy & Presser; 400 Garden City Plaza; Garden City; NY; 11530; US Patent Application Number: 20010046968 Date filed: March 22, 2001 Abstract: The present invention provides that an endogenous opioid peptide, OGF, inhibits angiogenesis in vivo via acting on OGF receptor. The present inventions also provides that opioid antagonist naltrexone and naltrexone stimulated blood vessel development. Therapeutic compositions and methods for modulating angiogenesis are provided. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/191,522, filed on Mar. 23, 2000. The present invention relates to the use of opioid growth factor ("OGF") and OGF antagonists in the modulation of angiogenesis. Atherosclerosis affects more than 20 million people in the United States (Thorn T. J. et al., Hurst's The Heart, Arteries, and Veins, 9.sup.th Ed. McGraw-Hill; 3-17 (1998)). Approximately one million patients undergo either coronary artery bypass or balloon angioplasty/stenting each year, while more than 100,000 individuals have lower extremity arterial revascularization (Stanley J. C. et al., J. Vasc. Surg., 23: 172-181 (1996)). Additionally, more than 100,000 people require leg amputations each year because of infection or advanced atherosclerotic disease not amenable to present revascularization modalities. Recent studies have suggested that exogenous angiogenic growth factors can stimulate the peripheral development of collateral arteries in patients with critical limb ischemia, thus inducing therapeutic angiogenesis and avoiding amputations in selected patients (Baumgartner I. et al., Circulation, 97: 1114-1123 (1998); Isner J. M. et al., Lancet, 348: 370-347 (1996); Tsurumi Y. et al., Circulation, 96: II382-11388 (1997)). Conversely, inhibition of angiogenesis has been studied in patients with life threatening hemangiomas, ocular neovascularization, and cancer (Folkman J., NEJM, 333: 1757-1763 (1995); Folkman J. et al., J. Biol,. Chem., 16: 10931-10934 (1992)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with naltrexone, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “naltrexone” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on naltrexone. You can also use this procedure to view pending patent applications concerning naltrexone. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 6. BOOKS ON NALTREXONE Overview This chapter provides bibliographic book references relating to naltrexone. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on naltrexone include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “naltrexone” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “naltrexone” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “naltrexone” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Best-Case Series for the Use of Immuno-Augmentation Therapy and Naltrexone for the Treatment of Canc (Evidence Report/Technology Assessment) by Ian D. Coulter (Other Contributor); ISBN: 1587630826; http://www.amazon.com/exec/obidos/ASIN/1587630826/icongroupinterna
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The Cost-Effectiveness of the Use of Naltrexone in Alcoholism Treatment by Minghao Her, Jurgen Rehm; ISBN: 0888683111; http://www.amazon.com/exec/obidos/ASIN/0888683111/icongroupinterna
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CHAPTER 7. PERIODICALS AND NEWS ON NALTREXONE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover naltrexone.
News Services and Press Releases One of the simplest ways of tracking press releases on naltrexone is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “naltrexone” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to naltrexone. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “naltrexone” (or synonyms). The following was recently listed in this archive for naltrexone: •
Long-acting naltrexone cuts drinking in alcoholic men, but not women Source: Reuters Medical News Date: December 08, 2003
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Ultra-low-dose naltrexone can prevent opioid tolerance and dependence Source: Reuters Industry Breifing Date: June 06, 2002
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Ultrarapid opioid detox with naltrexone pellet implantation risky Source: Reuters Industry Breifing Date: February 07, 2002
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Rapid opiate detox and naltrexone gets thumbs up Source: Reuters Industry Breifing Date: July 09, 2001
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Depot formulation of naltrexone shows sustained opiate blockade Source: Reuters Industry Breifing Date: February 08, 2001
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Ultra-low-dose naltrexone allows low-dose morphine to exert analgesic effect Source: Reuters Medical News Date: January 12, 2001
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Alkermes extended-release naltrexone successful in phase I trial Source: Reuters Industry Breifing Date: December 11, 2000
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Nociceptin effects may surpass naltrexone in treating alcohol dependence Source: Reuters Medical News Date: July 14, 2000 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “naltrexone” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests.
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Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “naltrexone” (or synonyms). If you know the name of a company that is relevant to naltrexone, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “naltrexone” (or synonyms).
Academic Periodicals covering Naltrexone Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to naltrexone. In addition to these sources, you can search for articles covering naltrexone that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for naltrexone. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with naltrexone. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to naltrexone: Naltrexone •
Systemic - U.S. Brands: ReVia http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202388.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
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These publications are typically written by one or more of the various NIH Institutes.
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
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Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
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Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “naltrexone” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 5563 21 138 16 28 5766
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “naltrexone” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
18 Adapted 19
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on naltrexone can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to naltrexone. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to naltrexone. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “naltrexone”:
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Alcohol and Youth http://www.nlm.nih.gov/medlineplus/alcoholandyouth.html Alcoholism http://www.nlm.nih.gov/medlineplus/alcoholism.html Pregnancy and Substance Abuse http://www.nlm.nih.gov/medlineplus/pregnancyandsubstanceabuse.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on naltrexone. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •
Naltrexone (Trexan) Contact: Project Inform, HIV Treatment Hotline, 205 13th St Ste 2001, San Francisco, CA, 94103, (415) 558-8669, http://www.projectinform.org. Summary: This fact sheet describes naltrexone (trexan) as a pharmaceutical product with potential for treating Human immunodeficiency virus (HIV) infection by stimulating production of natural endorphins (important links between the immune system and the central nervous system). Some researchers believe that its use in small amounts may help re-establish normal regulation of certain immune functions which have been eroded by Acquired immunodeficiency syndrome (AIDS). Pros and cons of naltrexone are covered, as are procedures for its use. The NIH Search Utility
The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to naltrexone. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html.
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Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
•
Family Village: http://www.familyvillage.wisc.edu/specific.htm
•
Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
•
Med Help International: http://www.medhelp.org/HealthTopics/A.html
•
Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
•
Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
•
WebMDHealth: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to naltrexone. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with naltrexone. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about naltrexone. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “naltrexone” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given
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the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “naltrexone”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “naltrexone” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “naltrexone” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
21
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
•
Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
•
Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
•
California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
•
California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
•
California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
•
California: Gateway Health Library (Sutter Gould Medical Foundation)
•
California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
•
California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
•
California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
•
California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
•
California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
•
California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
•
California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
•
California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
•
Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
•
Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
•
Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
22
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
•
Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
•
Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
•
Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
•
Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
•
Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
•
Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
•
Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
•
Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
•
Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
•
Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
•
Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
•
Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
•
Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
•
Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
•
Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
•
Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
•
Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
•
Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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•
Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
•
Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
•
Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
•
Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
•
Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
•
Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
•
Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
•
Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
•
Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
•
Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
•
Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
•
Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
•
Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
•
Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
•
Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
•
Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
•
National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
•
National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
•
National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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•
Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
•
New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
•
New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
•
New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
•
New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
•
New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
•
New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
•
New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
•
New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
•
Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
•
Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
•
Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
•
Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
•
Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
•
Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
•
Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
•
Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
•
Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
•
Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
•
Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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•
South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
•
Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
•
Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
•
Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
•
Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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NALTREXONE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Monophosphate: Adenylic acid. Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases
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catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenergic Agents: Drugs that act on adrenergic receptors or affect the life cycle of adrenergic transmitters. Included here are adrenergic agonists and antagonists and agents that affect the synthesis, storage, uptake, metabolism, or release of adrenergic transmitters. [NIH]
Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Aggravation: An increasing in seriousness or severity; an act or circumstance that intensifies, or makes worse. [EU] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Agoraphobia: Obsessive, persistent, intense fear of open places. [NIH] Alcohol Drinking: Behaviors associated with the ingesting of alcoholic beverages, including social drinking. [NIH] Alcoholic Intoxication: An acute brain syndrome which results from the excessive ingestion of ethanol or alcoholic beverages. [NIH] Aldehyde Dehydrogenase: An enzyme that oxidizes an aldehyde in the presence of NAD+ and water to an acid and NADH. EC 1.2.1.3. Before 1978, it was classified as EC 1.1.1.70. [NIH]
Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH]
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Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amitriptyline: Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antaganize cholinergic and alpha-1 adrenergic responses to bioactive amines. [NIH] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH] Amoxapine: The N-demethylated derivative of the antipsychotic agent loxapine that works by blocking the reuptake of norepinephrine, serotonin, or both. It also blocks dopamine receptors. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral
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ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]
Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anaesthetic: 1. Pertaining to, characterized by, or producing anaesthesia. 2. A drug or agent that is used to abolish the sensation of pain. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthesiology: A specialty concerned with the study of anesthetics and anesthesia. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Ankle: That part of the lower limb directly above the foot. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea.
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[NIH]
Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antiepileptic: An agent that combats epilepsy. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the
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movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antispasmodic: An agent that relieves spasm. [EU] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Apathy: Lack of feeling or emotion; indifference. [EU] Approximate: Approximal [EU] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthralgia: Pain in the joint. [NIH] Aspartate: A synthetic amino acid. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asthenia: Clinical sign or symptom manifested as debility, or lack or loss of strength and energy. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Atopic Eczema: Generic term for acute or chronic inflammatory conditions of the skin, typically erythematous, edematous, papular, vesicular, and crusting; often accompanied by sensations of itching and burning. [NIH] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH]
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Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Behavior Therapy: The application of modern theories of learning and conditioning in the treatment of behavior disorders. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a
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diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Beta-Endorphin: A peptide consisting of amino acid sequence 61-91 of the endogenous pituitary hormone beta-lipotropin. The first four amino acids show a common tetrapeptide sequence with methionine- and leucine enkephalin. The compound shows opiate-like activity. Injection of beta-endorphin induces a profound analgesia of the whole body for several hours. This action is reversed after administration of naloxone. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH]
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Bladder: The organ that stores urine. [NIH] Blister: Visible accumulations of fluid within or beneath the epidermis. [NIH] Blister pack: A package consisting of a clear plastic overlay affixed to a cardboard backing for protecting and displaying a product. [EU] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Regions: Anatomical areas of the body. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Brown Fat: A thermogenic form of adipose tissue found in newborns of many species, including humans, and in hibernating mammals. The tissue is capable of rapid liberation of energy and seems to be important in the maintenance of body temperature immediately after birth and upon waking from hibernation. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Buprenorphine: A derivative of the opioid alkaloid thebaine that is a more potent and longer lasting analgesic than morphine. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist
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activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use. [NIH] Bupropion: A unicyclic, aminoketone antidepressant. The mechanism of its therapeutic actions is not well understood, but it does appear to block dopamine uptake. The hydrochloride is available as an aid to smoking cessation treatment. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Capsaicin: Cytotoxic alkaloid from various species of Capsicum (pepper, paprika), of the Solanaceae. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH]
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Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Catalyse: To speed up a chemical reaction. [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cesarean Section: Extraction of the fetus by means of abdominal hysterotomy. [NIH]
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Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]
Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clomiphene: A stilbene derivative that functions both as a partial estrogen agonist and complete estrogen antagonist depending on the target tissue. It antagonizes the estrogen receptor thereby initiating or augmenting ovulation in anovulatory women. [NIH]
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Clomipramine: A tricyclic antidepressant similar to imipramine that selectively inhibits the uptake of serotonin in the brain. It is readily absorbed from the gastrointestinal tract and demethylated in the liver to form its primary active metabolite, desmethylclomipramine. [NIH]
Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaethylene: Hard drug formed by cocaine and alcohol. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin
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system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concomitant: Accompanying; accessory; joined with another. [EU] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective
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tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]
Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or
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clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticotropin-Releasing Hormone: A neuropeptide released by the hypothalamus that stimulates the release of corticotropin by the anterior pituitary gland. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Criterion: A standard by which something may be judged. [EU] Cryopreservation: Preservation of cells, tissues, organs, or embryos by freezing. In histological preparations, cryopreservation or cryofixation is used to maintain the existing form, structure, and chemical composition of all the constituent elements of the specimens. [NIH]
Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclazocine: An analgesic with mixed narcotic agonist-antagonist properties. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystitis: Inflammation of the urinary bladder. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxic chemotherapy: Anticancer drugs that kill cells, especially cancer cells. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide,
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from a chemical compound. [NIH] Defecation: The normal process of elimination of fecal material from the rectum. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Delavirdine: A potent, non-nucleoside reverse transcriptase inhibitor with activity specific for HIV-1. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delusions: A false belief regarding the self or persons or objects outside the self that persists despite the facts, and is not considered tenable by one's associates. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [NIH]
Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]
Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Desipramine: A tricyclic dibenzazepine compound that potentiates neurotransmission. Desipramine selectively blocks reuptake of norepinephrine from the neural synapse, and also appears to impair serotonin transport. This compound also possesses minor anticholingeric activity, through its affinity to muscarinic receptors. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton
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in the nucleus. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Diffusion of Innovation: The broad dissemination of new ideas, procedures, techniques, materials, and devices and the degree to which these are accepted and used. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dihydromorphine: A semisynthetic analgesic used in the study of narcotic receptors. It has abuse potential. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Dimethyl Sulfoxide: A highly polar organic liquid, that is used widely as a chemical solvent. Because of its ability to penetrate biological membranes, it is used as a vehicle for topical application of pharmaceuticals. It is also used to protect tissue during cryopreservation. Dimethyl sulfoxide shows a range of pharmacological activity including analgesia and anti-inflammation. [NIH] Diploid: Having two sets of chromosomes. [NIH] Diprenorphine: A narcotic antagonist similar in action to naloxone. It is used to remobilize animals after etorphine neuroleptanalgesia and is considered a specific antagonist to etorphine. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU]
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Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Disulfiram: A carbamate derivative used as an alcohol deterrent. It is a relatively nontoxic substance when administered alone, but markedly alters the intermediary metabolism of alcohol. When alcohol is ingested after administration of disulfiram, blood acetaldehyde concentrations are increased, followed by flushing, systemic vasodilation, respiratory difficulties, nausea, hypotension, and other symptoms (acetaldehyde syndrome). It acts by inhibiting aldehyde dehydrogenase. [NIH] Diuresis: Increased excretion of urine. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dopa: The racemic or DL form of DOPA, an amino acid found in various legumes. The dextro form has little physiologic activity but the levo form (levodopa) is a very important physiologic mediator and precursor and pharmacological agent. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a
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delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Doxepin: A dibenzoxepin tricyclic compound. It displays a range of pharmacological actions including maintaining adrenergic innervation. Its mechanism of action is not fully understood, but it appears to block reuptake of monoaminergic neurotransmitters into presynaptic terminals. It also possesses anticholinergic activity and modulates antagonism of histamine H(1)- and H(2)-receptors. [NIH] Drinking Behavior: Behaviors associated with the ingesting of water and other liquids; includes rhythmic patterns of drinking (time intervals - onset and duration), frequency and satiety. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Combinations: Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. It is differentiated from combination drug therapy in which two or more drugs are administered separately for a combined effect. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duodenal Ulcer: An ulcer in the lining of the first part of the small intestine (duodenum). [NIH]
Duodenitis: An irritation of the first part of the small intestine (duodenum). [NIH] Duodenum: The first part of the small intestine. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyspepsia: Impaired digestion, especially after eating. [NIH] Dysphoria: Disquiet; restlessness; malaise. [EU] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Echolalia: The pathological repetition by imitation of the speech of another. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH]
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Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrochemistry: The study of chemical changes resulting from electrical action and electrical activity resulting from chemical changes. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emetic: An agent that causes vomiting. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endorphin: Opioid peptides derived from beta-lipotropin. Endorphin is the most potent naturally occurring analgesic agent. It is present in pituitary, brain, and peripheral tissues. [NIH]
Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH]
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Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]
Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethyl Methanesulfonate: An antineoplastic agent with alkylating properties. It also acts as a mutagen by damaging DNA and is used experimentally for that effect. [NIH] Ethylketocyclazocine: A kappa opioid receptor agonist. The compound has analgesic action
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and shows positive inotropic effects on the electrically stimulated left atrium. It also affects various types of behavior in mammals such as locomotion, rearing, and grooming. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Euphoria: An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Evoked Potentials: The electric response evoked in the central nervous system by stimulation of sensory receptors or some point on the sensory pathway leading from the receptor to the cortex. The evoked stimulus can be auditory, somatosensory, or visual, although other modalities have been reported. Event-related potentials is sometimes used synonymously with evoked potentials but is often associated with the execution of a motor, cognitive, or psychophysiological task, as well as with the response to a stimulus. [NIH] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Family Therapy: A form of group psychotherapy. It involves treatment of more than one
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member of the family simultaneously in the same session. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fentanyl: A narcotic opioid drug that is used in the treatment of pain. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Finasteride: An orally active testosterone 5-alpha-reductase inhibitor. It is used as a surgical alternative for treatment of benign prostatic hyperplasia. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Fluorine: A nonmetallic, diatomic gas that is a trace element and member of the halogen family. It is used in dentistry as flouride to prevent dental caries. [NIH] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH] Flushing: A transient reddening of the face that may be due to fever, certain drugs, exertion, stress, or a disease process. [NIH] Fluvoxamine: A selective serotonin reuptake inhibitor. It is effective in the treatment of depression, obsessive-compulsive disorders, anxiety, panic disorders, and alcohol amnestic disorders. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Follow-Up Studies: Studies in which individuals or populations are followed to assess the outcome of exposures, procedures, or effects of a characteristic, e.g., occurrence of disease. [NIH]
Forearm: The part between the elbow and the wrist. [NIH]
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Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above, and through its lateral and median apertures it communicates with the subarachnoid space. [NIH]
Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]
Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Galanin: A neurotransmitter. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastritis: Inflammation of the stomach. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastrointestinal Transit: Passage of food (sometimes in the form of a test meal) through the gastrointestinal tract as measured in minutes or hours. The rate of passage through the intestine is an indicator of small bowel function. [NIH] Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
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Gene Dosage: The number of copies of a given gene present in a cell or nucleus. An increase in gene dosage can result in the formation of higher levels of gene product, provided that the gene is not subject to autogenous regulation. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used in a radiopharmaceutical. [NIH] Genital: Pertaining to the genitalia. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Geriatric Psychiatry: A subspecialty of psychiatry concerned with the mental health of the aged. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]
Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU]
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Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]
Grafting: The operation of transfer of tissue from one site to another. [NIH] Gravidity: Pregnancy; the condition of being pregnant, without regard to the outcome. [EU] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]
Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haloperidol: Butyrophenone derivative. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heartburn: Substernal pain or burning sensation, usually associated with regurgitation of gastric juice into the esophagus. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to
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hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heroin Dependence: Strong dependence, both physiological and emotional, upon heroin. [NIH]
Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Hiatal Hernia: A small opening in the diaphragm that allows the upper part of the stomach to move up into the chest. Causes heartburn from stomach acid flowing back up through the opening. [NIH] Hibernation: The dormant state in which some animal species pass the winter. It is characterized by narcosis and by sharp reduction in body temperature and metabolic activity and by a depression of vital signs. It is a natural physiological process in many warm-blooded animals. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum,
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and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hycanthone: Potentially toxic, but effective antischistosomal agent, it is a metabolite of lucanthone. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrogenation: Specific method of reduction in which hydrogen is added to a substance by the direct use of gaseous hydrogen. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydromorphone: An opioid analgesic made from morphine and used mainly as an analgesic. It has a shorter duration of action than morphine. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperalgesia: Excessive sensitiveness or sensibility to pain. [EU] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hyperphagia: Ingestion of a greater than optimal quantity of food. [NIH]
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Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothyroidism: Deficiency of thyroid activity. In adults, it is most common in women and is characterized by decrease in basal metabolic rate, tiredness and lethargy, sensitivity to cold, and menstrual disturbances. If untreated, it progresses to full-blown myxoedema. In infants, severe hypothyroidism leads to cretinism. In juveniles, the manifestations are intermediate, with less severe mental and developmental retardation and only mild symptoms of the adult form. When due to pituitary deficiency of thyrotropin secretion it is called secondary hypothyroidism. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hysterotomy: An incision in the uterus, performed through either the abdomen or the vagina. [NIH] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Imipramine: The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group. [NIH]
Immersion: The placing of a body or a part thereof into a liquid. [NIH] Immune Complex Diseases: Group of diseases mediated by the deposition of large soluble complexes of antigen and antibody with resultant damage to tissue. Besides serum sickness and the arthus reaction, evidence supports a pathogenic role for immune complexes in many other systemic immunologic diseases including glomerulonephritis, systemic lupus erythematosus and polyarteritis nodosa. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH]
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Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]
Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] Impulse Control Disorders: Disorders whose essential features are the failure to resist an impulse, drive, or temptation to perform an act that is harmful to the individual or to others. Individuals experience an increased sense of tension prior to the act and pleasure, gratification, or release of tension at the time of committing the act. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus,
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or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the
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laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Interneurons: Most generally any neurons which are not motor or sensory. Interneurons may also refer to neurons whose axons remain within a particular brain region as contrasted with projection neurons which have axons projecting to other brain regions. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isradipine: 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methyl ethyl ester. A potent calcium channel antagonist that is highly selective for vascular smooth muscle. It is effective in the treatment of chronic stable angina pectoris, hypertension, and congestive cardiac failure. [NIH]
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Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]
Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Ketamine: A cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (receptors, NMethyl-D-Aspartate) and may interact with sigma receptors. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactate Dehydrogenase: A tetrameric enzyme that, along with the coenzyme NAD+, catalyzes the interconversion of lactate and pyruvate. In vertebrates, genes for three different subunits (LDH-A, LDH-B and LDH-C) exist. [NIH] Lactates: Salts or esters of lactic acid containing the general formula CH3CHOHCOOR. [NIH] Lactation: The period of the secretion of milk. [EU] Laparotomy: A surgical incision made in the wall of the abdomen. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined
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functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkages: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipodystrophy: A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat. They include total, congenital or acquired, partial, abdominal infantile, and localized lipodystrophy. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]
Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locus Coeruleus: Bluish region in the superior angle of the fourth ventricle floor, corresponding to melanin-like pigmented nerve cells which lie lateral to the pontomesencephalic central gray (griseum centrale). It is also known as nucleus pigmentosus pontis. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Lorazepam: An anti-anxiety agent with few side effects. It also has hypnotic, anticonvulsant, and considerable sedative properties and has been proposed as a preanesthetic agent. [NIH] Loxapine: An antipsychotic agent used in schizophrenia. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH]
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Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Malaise: A vague feeling of bodily discomfort. [EU] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU] Manic: Affected with mania. [EU] Mannans: Polysaccharides consisting of mannose units. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Memantine: Amantadine derivative that has some dopaminergic effects. It has been proposed as an antiparkinson agent. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH]
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Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mesencephalic: Ipsilateral oculomotor paralysis and contralateral tremor, spasm. or choreic movements of the face and limbs. [NIH] Mesolimbic: Inner brain region governing emotion and drives. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Methadyl Acetate: A narcotic analgesic with a long onset and duration of action. It is used mainly in the treatment of narcotic dependence. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methyl Methanesulfonate: An alkylating agent in cancer therapy that may also act as a mutagen by interfering with and causing damage to DNA. [NIH] Methylphenidate: A central nervous system stimulant used most commonly in the treatment of attention-deficit disorders in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms
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include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphine Dependence: Strong dependence, both physiological and emotional, upon morphine. [NIH] Morphine Derivatives: Analogs or derivatives of morphine. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]
Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH]
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Mutagen: Any agent, such as X-rays, gamma rays, mustard gas, TCDD, that can cause abnormal mutation in living cells; having the power to cause mutations. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutilation: Injuries to the body. [NIH] Mycosis: Any disease caused by a fungus. [EU] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Nadir: The lowest point; point of greatest adversity or despair. [EU] Nalbuphine: A narcotic used as a pain medication. It appears to be an agonist at kappa opioid receptors and an antagonist or partial agonist at mu opioid receptors. [NIH] Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Narcotic Antagonists: Agents inhibiting the effect of narcotics on the central nervous system. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Endings: Specialized terminations of peripheral neurons. Nerve endings include neuroeffector junction(s) by which neurons activate target organs and sensory receptors which transduce information from the various sensory modalities and send it centrally in the nervous system. Presynaptic nerve endings are presynaptic terminals. [NIH] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Nervousness: Excessive excitability and irritability, with mental and physical unrest. [EU]
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Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroleptanalgesia: A form of analgesia accompanied by general quiescence and psychic indifference to environmental stimuli, without loss of consciousness, and produced by the combined administration of a major tranquilizer (neuroleptic) and a narcotic. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuronal Plasticity: The capacity of the nervous system to change its reactivity as the result of successive activations. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Nevirapine: A potent, non-nucleoside reverse transcriptase inhibitor used in combination with nucleoside analogues for treatment of HIV infection and AIDS. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide
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activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nociceptors: Peripheral receptors for pain. Nociceptors include receptors which are sensitive to painful mechanical stimuli, extreme heat or cold, and chemical stimuli. All nociceptors are free nerve endings. [NIH] Nonblinded: Describes a clinical trial or other experiment in which the researchers know what treatments are being given to each study subject or experimental group. If human subjects are involved, they know what treatments they are receiving. [NIH] Non-nucleoside: A member of a class of compounds, including delavirdine, loviride and nevirapine, that acts to directly combine with and block the action of HIV's reverse transcriptase. [NIH] Nonverbal Communication: Transmission of emotions, ideas, and attitudes between individuals in ways other than the spoken language. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nortriptyline: A metabolite of amitryptyline that is also used as an antidepressive agent. Nortriptyline is used in major depression, dysthymia, and atypical depressions. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Medicine: A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds in a pharmaceutical form. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleus Accumbens: Collection of pleomorphic cells in the caudal part of the anterior horn of the lateral ventricle, in the region of the olfactory tubercle, lying between the head of the caudate nucleus and the anterior perforated substance. It is part of the so-called ventral striatum, a composite structure considered part of the basal ganglia. [NIH] Obsessive-Compulsive Disorder: An anxiety disorder characterized by recurrent, persistent obsessions or compulsions. Obsessions are the intrusive ideas, thoughts, or images that are experienced as senseless or repugnant. Compulsions are repetitive and seemingly purposeful behavior which the individual generally recognizes as senseless and from which the individual does not derive pleasure although it may provide a release from tension. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Ointments: Semisolid preparations used topically for protective emollient effects or as a
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vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Ondansetron: A competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin, and it has reported anxiolytic and neuroleptic properties. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opioid Peptides: The endogenous peptides with opiate-like activity. The three major classes currently recognized are the enkephalins, the dynorphins, and the endorphins. Each of these families derives from different precursors, proenkephalin, prodynorphin, and proopiomelanocortin, respectively. There are also at least three classes of opioid receptors, but the peptide families do not map to the receptors in a simple way. [NIH] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]
Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH]
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Oxycodone: Semisynthetic derivative of codeine that acts as a narcotic analgesic more potent and addicting than codeine. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Panax ginseng: A Chinese herb (Panax schinseng) having 5-foliolate leaves and umbels of small greenish flowers succeeded by scarlet berries. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [NIH] Papaverine: An alkaloid found in opium but not closely related to the other opium alkaloids in its structure or pharmacological actions. It is a direct-acting smooth muscle relaxant used in the treatment of impotence and as a vasodilator, especially for cerebral vasodilation. The mechanism of its pharmacological actions is not clear, but it apparently can inhibit phosphodiesterases and it may have direct actions on calcium channels. [NIH] Paradoxical: Occurring at variance with the normal rule. [EU] Paralysis: Loss of ability to move all or part of the body. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parity: The number of offspring a female has borne. It is contrasted with gravidity, which refers to the number of pregnancies, regardless of outcome. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Paroxetine: A serotonin uptake inhibitor that is effective in the treatment of depression. [NIH]
Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural
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and functional changes in tissues and organs of the body caused by the disease). [EU] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pergolide: A long-acting dopamine agonist which is effective in the treatment of Parkinson's disease and hyperprolactinemia. It has also been observed to have antihypertensive effects. [NIH]
Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an antiarrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch.
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Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [NIH] Pheromone: A substance secreted externally by certain animal species, especially insects, to affect the behavior or development of other members of the species. [NIH] Phototransduction: The transducing of light energy to afferent nerve impulses, such as takes place in the retinal rods and cones. After light photons are absorbed by the photopigments, the signal is transmitted to the outer segment membrane by the cyclic GMP second messenger system, where it closes the sodium channels. This channel gating ultimately generates an action potential in the inner retina. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physicochemical: Pertaining to physics and chemistry. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placebos: Any dummy medication or treatment. Although placebos originally were medicinal preparations having no specific pharmacological activity against a targeted condition, the concept has been extended to include treatments or procedures, especially those administered to control groups in clinical trials in order to provide baseline measurements for the experimental protocol. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH]
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Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Post-traumatic stress disorder: A psychological disorder that develops in some individuals after a major traumatic experience such as war, rape, domestic violence, or accident. [NIH] Postural: Pertaining to posture or position. [EU] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU]
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Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Preferred Provider Organizations: Arrangements negotiated between a third-party payer (often a self-insured company or union trust fund) and a group of health-care providers (hospitals and physicians) who furnish services at lower than usual fees, and, in return, receive prompt payment and an expectation of an increased volume of patients. [NIH] Preload: The tension in the heart muscle at the end of diastole (before the contraction). [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Presynaptic Terminals: The distal terminations of axons which are specialized for the release of neurotransmitters. Also included are varicosities along the course of axons which have similar specializations and also release transmitters. Presynaptic terminals in both the central and peripheral nervous systems are included. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Private Sector: That distinct portion of the institutional, industrial, or economic structure of a country that is controlled or owned by non-governmental, private interests. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Prone: Having the front portion of the body downwards. [NIH] Pro-Opiomelanocortin: A precursor protein, MW 30,000, synthesized mainly in the anterior pituitary gland but also found in the hypothalamus, brain, and several peripheral tissues. It incorporates the amino acid sequences of ACTH and beta-lipotropin. These two hormones, in turn, contain the biologically active peptides MSH, corticotropin-like intermediate lobe peptide, alpha-lipotropin, endorphins, and methionine enkephalin. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all
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free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostate gland: A gland in the male reproductive system just below the bladder. It surrounds part of the urethra, the canal that empties the bladder, and produces a fluid that forms part of semen. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protriptyline: Tricyclic antidepressant similar in action and side effects to imipramine. It may produce excitation. [NIH] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH]
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Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychomotor Performance: The coordination of a sensory or ideational (cognitive) process and a motor activity. [NIH] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Psychopharmacology: The study of the effects of drugs on mental and behavioral activity. [NIH]
Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH] Psychotomimetic: Psychosis miming. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Putrescine: A toxic diamine formed by putrefaction from the decarboxylation of arginine and ornithine. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH]
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Radioactive: Giving off radiation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reaction Time: The time from the onset of a stimulus until the organism responds. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH]
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Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflective: Capable of throwing back light, images, sound waves : reflecting. [EU] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Research Support: Financial support of research activities. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Rhabdomyolysis: Necrosis or disintegration of skeletal muscle often followed by myoglobinuria. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and
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leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU]
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Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Self Administration: Administration of a drug or chemical by the individual under the direction of a physician. It includes administration clinically or experimentally, by human or animal. [NIH] Self-Help Groups: Organizations which provide an environment encouraging social interactions through group activities or individual relationships especially for the purpose of rehabilitating or supporting patients, individuals with common health problems, or the elderly. They include therapeutic social clubs. [NIH] Self-Injurious Behavior: Behavior in which persons hurt or harm themselves without the motive of suicide or of sexual deviation. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensibility: The ability to receive, feel and appreciate sensations and impressions; the quality of being sensitive; the extend to which a method gives results that are free from false negatives. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septum: A dividing wall or partition; a general term for such a structure. The term is often used alone to refer to the septal area or to the septum pellucidum. [EU] Septum Pellucidum: A triangular double membrane separating the anterior horns of the lateral ventricles of the brain. It is situated in the median plane and bounded by the corpus callosum and the body and columns of the fornix. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequential treatment: One treatment after the other. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Sertraline: A selective serotonin uptake inhibitor that is used in the treatment of depression. [NIH]
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Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shivering: Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Sibutramine: A drug used for the management of obesity that helps reduce food intake and is indicated for weight loss and maintenance of weight loss when used in conjunction with a reduced-calorie diet. It works to suppress the appetite primarily by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin. Side effects include dry mouth, headache, constipation, insomnia, and a slight increase in average blood pressure. In some patients it causes a higher blood pressure increase. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Sociability: The tendency of organisms to grow together with others of the same kind. [NIH] Social Behavior: Any behavior caused by or affecting another individual, usually of the same species. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH]
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Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Soft tissue sarcoma: A sarcoma that begins in the muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somnolence: Sleepiness; also unnatural drowsiness. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Spermidine: A polyamine formed from putrescine. It is found in almost all tissues in association with nucleic acids. It is found as a cation at all pH values, and is thought to help stabilize some membranes and nucleic acid structures. It is a precursor of spermine. [NIH] Spermine: A biogenic polyamine formed from spermidine. It is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at all pH values. Spermine is associated with nucleic acids, particularly in viruses, and is thought to stabilize the helical structure. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Stabilization: The creation of a stable state. [EU] Stabilizer: A device for maintaining constant X-ray tube voltage or current. [NIH]
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Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steady state: Dynamic equilibrium. [EU] Stereotyped Behavior: Relatively invariant mode of behavior elicited or determined by a particular situation; may be verbal, postural, or expressive. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Sublingual: Located beneath the tongue. [EU] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH]
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Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetrahydrocannabinol: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Dronabinol is a synthetic form of delta-9-THC. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU]
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Thermogenesis: The generation of heat in order to maintain body temperature. The uncoupled oxidation of fatty acids contained within brown adipose tissue and shivering are examples of thermogenesis in mammals. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyroiditis: Inflammation of the thyroid gland. [NIH] Thyroiditis, Autoimmune: Progressive enlargement of the thyroid gland, often associated with hypothyroidism. [NIH] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU]
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Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tramadol: A narcotic analgesic proposed for severe pain. It may be habituating. [NIH] Transaminase: Aminotransferase (= a subclass of enzymes of the transferase class that catalyse the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2-keto acid). Most of these enzymes are pyridoxal-phosphate-proteins. [EU]
Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcutaneous: Transdermal. [EU] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH]
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Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]
Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Trimipramine: Tricyclic antidepressant similar to imipramine, but with more antihistaminic and sedative properties. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]
Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]
Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH]
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Venous: Of or pertaining to the veins. [EU] Venter: Belly. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventral Tegmental Area: A region in the mesencephalon which is dorsomedial to the substantia nigra and ventral to the red nucleus. The mesocortical and mesolimbic dopaminergic systems originate here, including an important projection to the nucleus accumbens. Overactivity of the cells in this area has been suspected to contribute to the positive symptoms of schizophrenia. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] War: Hostile conflict between organized groups of people. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to
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treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yohimbine: A plant alkaloid with alpha-2-adrenergic blocking activity. Yohimbine has been used as a mydriatic and in the treatment of impotence. It is also alleged to be an aphrodisiac. [NIH]
Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
239
INDEX A Abdomen, 177, 185, 198, 206, 209, 210, 211, 231, 232, 237 Abdominal, 177, 187, 194, 211, 219 Acceptor, 177, 218, 235 Acetylcholine, 78, 177, 188, 216 Acquired Immunodeficiency Syndrome, 144, 177 Acute renal, 177, 204 Acyl, 177, 198 Adenine, 177 Adenosine, 64, 177, 186 Adenosine Monophosphate, 64, 177 Adipocytes, 177, 191, 210 Adipose Tissue, 177, 185, 234 Adjustment, 5, 57, 177 Adolescence, 14, 177 Adrenal Cortex, 177, 192, 223 Adrenal Medulla, 177, 187, 198, 217 Adrenergic, 37, 68, 178, 179, 182, 195, 196, 198, 233, 238 Adrenergic Agents, 68, 178 Adsorption, 74, 178 Adsorptive, 178 Adverse Effect, 46, 142, 143, 147, 178, 221, 230 Afferent, 50, 134, 178, 210, 221 Affinity, 8, 117, 139, 143, 178, 193, 211, 230 Aggravation, 84, 178 Agoraphobia, 178, 206, 219 Alcohol Drinking, 35, 44, 178 Alcoholic Intoxication, 134, 178 Aldehyde Dehydrogenase, 178, 195 Alertness, 178, 186 Algorithms, 178, 184 Alimentary, 178, 219 Alkaloid, 178, 185, 186, 189, 214, 216, 219, 238 Alkylating Agents, 74, 179 Allergen, 179, 193, 229 Alpha-1, 179 Alternative medicine, 152, 179 Amenorrhea, 78, 83, 94, 97, 179, 180, 222 Amine, 179, 205 Amino Acid Sequence, 179, 181, 184, 223 Amitriptyline, 128, 179 Amnestic, 179, 200 Amoxapine, 128, 179
Amphetamine, 44, 73, 179, 194 Ampulla, 179, 188 Amygdala, 43, 179, 183, 211 Anaesthesia, 85, 90, 107, 143, 180, 207 Anaesthetic, 68, 180 Anal, 180, 200, 211 Analog, 43, 108, 180 Analogous, 46, 128, 180, 235 Anaphylatoxins, 180, 190 Anatomical, 29, 129, 180, 182, 185, 188, 207, 228 Anemia, 134, 180 Anesthesia, 37, 56, 63, 65, 96, 137, 180, 210 Anesthesiology, 96, 114, 180 Anesthetics, 180, 198 Angina, 180, 209 Angina Pectoris, 180, 209 Angiogenesis, 148, 180 Animal model, 11, 14, 18, 27, 30, 39, 53, 54, 64, 180 Ankle, 114, 180 Anorexia, 97, 131, 133, 134, 180 Anorexia Nervosa, 97, 180 Anovulation, 181, 222 Antagonism, 10, 12, 16, 44, 74, 75, 78, 115, 118, 181, 186, 196 Antibacterial, 181, 231 Antibiotic, 181, 220, 231 Antibodies, 133, 181, 183, 203, 206, 212, 221, 226 Antibody, 36, 178, 181, 189, 203, 205, 206, 207, 208, 212, 226, 229, 231 Anticholinergic, 179, 181, 196 Anticoagulant, 181, 224 Anticonvulsant, 181, 186, 211, 220 Antiepileptic, 128, 181 Antigen, 36, 134, 178, 181, 190, 205, 206, 207, 208, 212, 229 Antigen-Antibody Complex, 134, 181, 190 Antihypertensive, 181, 220 Anti-infective, 181, 205 Anti-inflammatory, 181, 194, 202 Antineoplastic, 179, 181, 198 Antineoplastic Agents, 179, 181 Antipsychotic, 179, 181, 211, 216 Antispasmodic, 182, 218 Antitussive, 182, 218 Antiviral, 182, 209, 220
240
Naltrexone
Anus, 180, 182, 189, 226 Anxiety, 33, 36, 128, 138, 182, 200, 211, 217, 219 Anxiolytic, 182, 218 Apathy, 182, 216 Approximate, 27, 182 Aqueous, 139, 182, 192, 205 Arginine, 180, 182, 216, 225 Arterial, 31, 148, 182, 191, 206, 224, 233 Arteries, 148, 182, 185, 191, 213, 225 Arterioles, 182, 185, 213 Artery, 148, 182, 192, 225 Arthralgia, 134, 182 Aspartate, 26, 43, 182, 210 Assay, 9, 37, 88, 182 Asthenia, 143, 182 Asymptomatic, 61, 182 Atopic, 78, 182 Atopic Eczema, 78, 182 Atrial, 182, 191, 236 Atrioventricular, 182, 191 Atrium, 182, 191, 199, 236, 237 Atrophy, 182, 211 Attenuated, 35, 183, 236 Attenuation, 26, 183 Atypical, 183, 217 Auditory, 116, 183, 199 Autoantibodies, 134, 183 Autoantigens, 183 Autoimmune disease, 134, 183, 214 Autonomic, 177, 182, 183, 217, 220 Autosuggestion, 183, 206 Axons, 183, 193, 209, 215, 223 B Bacteria, 177, 178, 181, 183, 184, 190, 193, 200, 213, 214, 231, 235, 236 Bactericidal, 183, 198 Bacteriophage, 183, 235 Bacterium, 183, 190, 204 Basal Ganglia, 182, 183, 211, 217 Basal Ganglia Diseases, 183 Basement Membrane, 183, 199 Behavior Therapy, 15, 51, 79, 95, 183 Benign, 183, 200, 203, 215, 226 Benzene, 183 Benzodiazepines, 128, 183 Beta-Endorphin, 68, 83, 92, 95, 184 Bilateral, 184, 222 Bile, 88, 184, 205, 210, 211, 232 Bile Acids, 184, 232 Bile Acids and Salts, 184 Bile Pigments, 184, 210
Biliary, 184, 188 Bioavailability, 46, 83, 98, 184 Biochemical, 8, 17, 64, 129, 184, 229 Biological therapy, 184, 203 Biological Transport, 184, 194 Biopsy, 135, 184 Biopsy specimen, 135, 184 Biotechnology, 64, 65, 152, 161, 184 Biotransformation, 82, 102, 184 Bladder, 135, 185, 190, 192, 214, 224, 236 Blister, 12, 185 Blister pack, 12, 185 Bloating, 185, 201 Blood Glucose, 185, 204, 208 Blood Platelets, 185, 229 Blood pressure, 28, 69, 181, 185, 186, 206, 214, 225, 230 Blood-Brain Barrier, 60, 185, 210 Blot, 64, 185 Body Composition, 37, 185 Body Fluids, 185, 186, 230 Body Regions, 133, 185 Bone Marrow, 183, 185, 192, 207, 212, 231 Bowel, 180, 185, 201, 209, 232 Bradykinin, 185, 216 Bronchial, 185, 205 Brown Fat, 64, 185 Buccal, 185, 211 Buprenorphine, 6, 11, 15, 35, 37, 61, 73, 92, 94, 95, 96, 102, 110, 127, 140, 141, 142, 185 Bupropion, 16, 51, 62, 91, 186 Bypass, 148, 186 C Caffeine, 20, 186 Calcium, 186, 189, 209, 219 Capsaicin, 10, 105, 186 Capsules, 186, 196 Carbamazepine, 128, 186 Carbohydrate, 72, 143, 186, 222 Carbon Dioxide, 186, 192, 193, 200, 227 Carcinogenic, 179, 183, 186, 208, 232 Carcinoma, 135, 186 Cardiac, 134, 135, 186, 191, 197, 198, 199, 209, 215, 232 Cardiovascular, 24, 131, 179, 186, 229 Cardiovascular disease, 131, 186 Case report, 47, 67, 70, 99, 186, 187, 188 Case series, 187, 188 Catalyse, 187, 235 Catecholamine, 187, 195, 220 Caudal, 187, 194, 206, 217, 222
241
Caudate Nucleus, 183, 187, 217 Cause of Death, 126, 187 Cell Differentiation, 40, 129, 187 Cell Division, 183, 187, 203, 212, 214, 221, 223 Cell proliferation, 58, 93, 129, 187 Cell Respiration, 187, 227 Cell Survival, 187, 203 Cellulose, 187, 201, 221 Central Nervous System Infections, 187, 203 Cerebellum, 187, 201, 222, 227 Cerebral, 31, 98, 102, 183, 185, 187, 198, 199, 201, 219, 225, 233 Cerebrovascular, 183, 186, 187 Cerebrum, 187 Cesarean Section, 96, 187 Character, 129, 180, 188, 193 Chemotactic Factors, 188, 190 Chin, 188, 213 Chlorophyll, 188, 201 Cholestasis, 78, 79, 188 Cholesterol, 184, 188, 192, 232 Choline, 117, 188 Cholinergic, 179, 182, 188, 216 Chromatin, 188 Chronic Disease, 133, 188 Chronic Fatigue Syndrome, 132, 133, 188 Chronic renal, 188, 221 Cisplatin, 188, 218 Clinical Medicine, 188, 222 Clinical study, 37, 188, 191 Clinical trial, 4, 8, 13, 16, 21, 22, 23, 25, 27, 32, 35, 39, 44, 45, 49, 56, 66, 95, 117, 127, 142, 161, 188, 191, 192, 196, 214, 217, 221, 224, 226 Clomiphene, 94, 102, 188 Clomipramine, 128, 189 Cloning, 184, 189 Coca, 189 Cocaethylene, 19, 189 Cocaine, 8, 19, 20, 23, 34, 37, 62, 77, 85, 96, 131, 189 Codeine, 26, 105, 135, 136, 145, 189, 218, 219 Coenzyme, 189, 210 Cofactor, 189, 224, 234 Cognition, 189, 216 Collagen, 179, 183, 189, 191, 221 Colon, 84, 189, 210 Comorbidity, 35, 42, 47, 59, 63, 79, 189 Complement, 31, 180, 189, 190, 229
Complementary and alternative medicine, 113, 121, 190 Complementary medicine, 113, 190 Compliance, 5, 12, 22, 23, 24, 42, 45, 48, 52, 56, 59, 61, 72, 83, 87, 96, 98, 131, 190 Computational Biology, 161, 190 Concomitant, 17, 19, 107, 128, 190 Confusion, 190, 216 Conjugation, 184, 190 Connective Tissue, 132, 133, 135, 185, 189, 190, 191, 193, 200, 201, 227, 233 Connective Tissue Cells, 190, 191 Connective Tissue Diseases, 133, 191 Consciousness, 180, 191, 193, 195, 216, 224 Constipation, 143, 146, 147, 182, 191, 230 Constriction, 191, 209 Consultation, 58, 191 Continuum, 6, 191 Contraindications, ii, 191 Control group, 191, 221, 226 Controlled clinical trial, 6, 31, 191 Controlled study, 15, 28, 37, 42, 66, 72, 78, 87, 93, 99, 191 Coordination, 187, 191, 214, 225 Cor, 53, 117, 191, 192, 223 Corneum, 191, 198 Coronary, 148, 180, 186, 191, 192, 213 Coronary heart disease, 186, 191 Coronary Thrombosis, 192, 213 Corpus, 102, 192, 211, 223, 229 Cortex, 117, 192, 198, 199, 227 Cortical, 117, 192, 199, 229 Corticotropin-Releasing Hormone, 53, 192 Cortisol, 36, 44, 73, 83, 87, 89, 192 Cortisone, 192, 194 Cranial, 187, 192, 203, 220 Craniocerebral Trauma, 183, 192, 203 Criterion, 43, 192 Cryopreservation, 192, 194 Cues, 28, 31, 36, 49, 51, 119, 192 Curative, 192, 233 Cutaneous, 192, 211 Cyclazocine, 8, 192 Cyclic, 64, 186, 192, 203, 217, 221, 228 Cyclosporine, 130, 192 Cystitis, 135, 192 Cytokine, 36, 40, 192 Cytoplasm, 192, 197 Cytotoxic, 58, 186, 192, 218, 226 Cytotoxic chemotherapy, 192, 218 D Decarboxylation, 192, 205, 225
242
Naltrexone
Defecation, 116, 193 Degenerative, 193, 204 Delavirdine, 193, 217 Deletion, 41, 193 Delusions, 193, 225 Dementia, 177, 181, 193 Demethylation, 139, 193 Dendrites, 193, 216 Density, 117, 193, 218, 222, 231 Dental Caries, 193, 200 Dentate Gyrus, 193, 205 Depressive Disorder, 59, 128, 193, 211 Dermis, 193, 235 Desensitization, 71, 193 Desipramine, 96, 128, 193 Deuterium, 19, 193, 205 Dexamethasone, 77, 194 Dextroamphetamine, 179, 194, 213 Diabetes Mellitus, 194, 204 Diagnostic procedure, 125, 152, 194 Dialyzer, 194, 203 Diaphragm, 194, 204 Diarrhea, 143, 194 Diastole, 194, 223 Diastolic, 194, 206 Diencephalon, 194, 206 Diffusion, 5, 6, 102, 184, 194, 208 Diffusion of Innovation, 5, 194 Digestion, 178, 184, 185, 194, 196, 201, 209, 211, 232 Dihydromorphine, 102, 139, 194 Dihydroxy, 138, 139, 194 Dimethyl, 137, 194, 209 Dimethyl Sulfoxide, 137, 194 Diploid, 194, 221 Diprenorphine, 99, 194 Direct, iii, 18, 35, 37, 126, 127, 133, 136, 141, 155, 188, 194, 195, 205, 219, 227, 233 Discrete, 5, 195 Discrimination, 11, 12, 26, 195 Disinfectant, 195, 198 Disposition, 85, 88, 105, 195 Dissociation, 178, 195, 209 Distal, 195, 197, 223 Disulfiram, 19, 86, 195 Diuresis, 186, 195 Dizziness, 142, 143, 195, 219 Domesticated, 195, 203 Dopa, 195, 210 Dopamine, 8, 19, 29, 33, 35, 38, 41, 51, 179, 182, 186, 189, 194, 195, 210, 214, 216, 220 Dorsal, 50, 195, 222
Dorsum, 195 Dosage Forms, 126, 195 Doxepin, 128, 196 Drinking Behavior, 14, 29, 30, 41, 49, 60, 103, 196 Drive, ii, vi, 10, 15, 20, 21, 29, 57, 58, 109, 135, 196, 207 Drug Combinations, 38, 196 Drug Interactions, 26, 156, 196 Drug Tolerance, 196, 234 Duodenal Ulcer, 144, 196 Duodenitis, 144, 196 Duodenum, 184, 196, 201, 232 Dyskinesia, 182, 196 Dyspepsia, 143, 196 Dysphoria, 19, 89, 91, 196 Dysphoric, 52, 193, 196 E Echolalia, 4, 196 Edema, 135, 196 Effector, 36, 40, 177, 189, 196 Effector cell, 40, 196 Elastin, 189, 191, 197 Elective, 100, 197 Electrocardiogram, 16, 197 Electrochemistry, 29, 197 Electrode, 29, 197 Electrolyte, 197, 230 Electrons, 197, 209, 218, 225, 226 Electrophysiological, 29, 41, 197 Emaciation, 177, 197 Embryo, 187, 197, 207 Emetic, 22, 197 Endocrine System, 197, 216 Endorphin, 53, 69, 117, 184, 197 Endothelial cell, 185, 197, 234 Endothelium, 197, 216 Endothelium-derived, 197, 216 Endotoxins, 190, 197, 210 End-stage renal, 188, 197, 221 Energy balance, 197, 210 Enhancer, 140, 198 Enkephalin, 58, 184, 198, 223 Entorhinal Cortex, 198, 205 Environmental Health, 160, 162, 198 Enzymatic, 139, 179, 186, 190, 193, 198, 205 Enzyme, 10, 178, 189, 196, 198, 202, 203, 210, 214, 224, 227, 234, 235, 237, 238 Epidemic, 4, 14, 34, 144, 198 Epidermis, 58, 185, 191, 193, 198 Epigastric, 198, 219 Epinephrine, 178, 195, 198, 216, 217, 236
243
Erectile, 92, 198 Erection, 198 Erythrocytes, 180, 185, 198, 227, 229 Esophagus, 198, 203, 232 Esterification, 19, 198 Estrogen, 188, 198, 223 Estrogen receptor, 188, 198 Ethanol, 14, 18, 19, 22, 27, 29, 34, 38, 41, 43, 53, 54, 68, 110, 115, 178, 198 Ether, 136, 198 Ethyl Methanesulfonate, 74, 198 Ethylketocyclazocine, 8, 198 Eukaryotic Cells, 199, 207 Euphoria, 19, 199 Evacuation, 191, 199, 201 Evoke, 199, 232 Evoked Potentials, 114, 199 Excitability, 14, 199, 215 Excitation, 17, 199, 216, 224 Excitatory, 17, 54, 143, 145, 199, 202 Exhaustion, 181, 199 Exocrine, 199, 219 Exogenous, 15, 129, 148, 178, 184, 197, 199, 224 Expiration, 199, 227 Extracellular, 11, 58, 190, 191, 199, 213, 230 Extracellular Matrix, 58, 190, 191, 199 Extracellular Space, 199, 213 Extraction, 74, 187, 199 Extrapyramidal, 182, 195, 199 Extremity, 148, 199 Exudate, 199, 218 F Family Planning, 161, 199 Family Therapy, 88, 199 Fat, 177, 184, 185, 191, 192, 200, 210, 211, 214, 227, 231 Fatigue, 188, 200 Feces, 191, 200, 232 Fentanyl, 26, 117, 126, 200 Fetus, 187, 200, 236 Fibrosarcoma, 93, 200 Fibrosis, 135, 200, 228 Finasteride, 30, 200 Fixation, 200, 229 Flatus, 200, 201 Fluorine, 138, 139, 200 Fluoxetine, 5, 67, 82, 110, 200 Flushing, 142, 195, 200 Fluvoxamine, 17, 200 Fold, 5, 15, 200 Follow-Up Studies, 36, 200
Forearm, 185, 200 Fourth Ventricle, 201, 211 Functional magnetic resonance imaging, 31, 201 Fungi, 190, 201, 213, 214, 236, 238 Fungus, 130, 201, 215 G Galanin, 33, 201 Gamma Rays, 201, 215, 226 Ganglia, 177, 183, 201, 215, 220 Gap Junctions, 201, 233 Gas, 74, 80, 97, 98, 186, 194, 200, 201, 205, 215, 216, 217 Gastric, 195, 201, 203, 205 Gastric Emptying, 201 Gastrin, 201, 205 Gastritis, 61, 144, 201 Gastrointestinal, 24, 38, 147, 185, 189, 198, 201, 229, 232 Gastrointestinal tract, 189, 198, 201, 229 Gastrointestinal Transit, 147, 201 Gastroparesis, 144, 201 Gene, 37, 55, 64, 66, 184, 201, 202 Gene Dosage, 37, 202 Gene Expression, 37, 64, 202 Generator, 71, 202 Genital, 132, 133, 202 Genotype, 55, 144, 202, 220 Geriatric, 62, 202 Geriatric Psychiatry, 62, 202 Germ Cells, 202, 212, 218, 231 Ginseng, 202 Gland, 177, 192, 202, 219, 221, 224, 228, 232, 234 Glomerular, 202 Glomeruli, 202 Glomerulonephritis, 134, 202, 206 Glucocorticoid, 194, 202 Glucose, 185, 187, 194, 202, 203, 208, 228 Glutamate, 32, 43, 202 Glutamic Acid, 202, 216 Glutathione Peroxidase, 202, 229 Glycine, 179, 184, 202, 216 Glycoprotein, 60, 202, 203, 234 Gonad, 202 Gonadal, 80, 202, 232 Gonadotropin, 78, 86, 203 Governing Board, 203, 222 Gp120, 203, 220 Grafting, 203, 207 Gravidity, 203, 219 Growth factors, 148, 203
244
Naltrexone
Guanylate Cyclase, 203, 217 Guinea Pigs, 45, 203 H Habitual, 16, 188, 203 Half-Life, 19, 203 Haloperidol, 44, 95, 203 Haploid, 203, 221 Haptens, 178, 203 Headache, 70, 120, 142, 143, 186, 203, 230 Headache Disorders, 203 Heart attack, 186, 203 Heartburn, 203, 204 Hemodialysis, 81, 194, 203 Hemoglobin, 74, 180, 198, 203, 204, 210 Hemoglobin A, 74, 204 Hemolytic, 134, 204 Hemorrhage, 192, 203, 204, 232 Hemostasis, 204, 229 Hepatic, 46, 204, 211 Hepatitis, 20, 204 Hepatocyte, 188, 204 Hepatotoxicity, 86, 204 Hereditary, 191, 204 Heredity, 201, 204 Heroin Dependence, 34, 85, 88, 204 Herpes, 132, 133, 204 Herpes virus, 132, 133, 204 Herpes Zoster, 204 Heterogeneity, 178, 204 Hiatal Hernia, 144, 204 Hibernation, 185, 204 Hippocampus, 117, 193, 204, 211, 232 Histamine, 135, 180, 182, 196, 205 Histidine, 205 Homeostasis, 17, 38, 58, 205 Homogeneous, 191, 205, 220 Homologous, 14, 205, 229, 233 Humoral, 53, 205 Humour, 205 Hycanthone, 74, 205 Hydrogen, 45, 136, 177, 179, 186, 193, 202, 205, 214, 218, 224 Hydrogen Peroxide, 136, 202, 205 Hydrogenation, 139, 184, 205 Hydrolysis, 139, 184, 188, 205, 222, 224 Hydromorphone, 75, 77, 205 Hydrophobic, 8, 205 Hydroxyproline, 179, 189, 205 Hyperalgesia, 54, 142, 143, 145, 205 Hyperbilirubinemia, 205, 210 Hyperphagia, 119, 205 Hyperplasia, 200, 206
Hypersensitivity, 179, 193, 206, 227, 229 Hypertension, 28, 123, 186, 203, 206, 209 Hypertrophy, 191, 206, 236 Hypnotic, 206, 211 Hypotension, 182, 195, 206 Hypothalamic, 35, 37, 53, 78, 82, 83, 97, 106, 108, 206 Hypothalamus, 37, 53, 82, 192, 194, 198, 206, 211, 221, 223 Hypothyroidism, 206, 234 Hypoxia, 117, 206 Hysterotomy, 187, 206 I Iatrogenic, 73, 206 Imipramine, 128, 189, 206, 224, 236 Immersion, 86, 206 Immune Complex Diseases, 181, 206 Immune function, 36, 134, 166, 206 Immune response, 10, 36, 41, 181, 183, 192, 203, 206, 207, 229, 232, 237 Immune Sera, 206, 207 Immune system, 11, 36, 134, 166, 184, 196, 206, 207, 212, 214, 237 Immunization, 36, 207, 229 Immunodeficiency, 144, 166, 177, 207 Immunodeficiency syndrome, 166, 207 Immunologic, 24, 188, 206, 207, 226 Immunology, 178, 207 Immunosuppressant, 179, 207 Immunosuppressive, 129, 130, 202, 207 Immunotherapy, 184, 193, 207 Impairment, 20, 188, 196, 207, 213, 225 Implantation, 152, 207 Impotence, 198, 207, 219, 238 Impulse Control Disorders, 46, 207 In situ, 33, 137, 207 In Situ Hybridization, 33, 207 In vitro, 24, 40, 45, 50, 53, 74, 129, 207 In vivo, 10, 11, 17, 45, 50, 74, 129, 139, 148, 207, 213 Incision, 206, 207, 209, 210 Induction, 10, 39, 46, 83, 93, 94, 95, 102, 181, 207, 210, 223 Infancy, 207 Infantile, 70, 207, 211 Infarction, 192, 207, 213 Infiltration, 202, 208 Inflammation, 132, 181, 192, 194, 199, 200, 201, 204, 208, 221, 227, 233, 234 Informed Consent, 5, 208 Infusion, 140, 208 Ingestion, 51, 178, 205, 208, 221
245
Inhalation, 27, 208, 221 Initiation, 13, 14, 21, 24, 40, 208 Innervation, 196, 208 Inositol, 208, 228 Inotropic, 195, 199, 208 Insight, 28, 44, 54, 208 Insomnia, 138, 208, 230 Insulator, 208, 214 Insulin, 76, 83, 87, 107, 208 Insulin-dependent diabetes mellitus, 208 Interferon, 106, 208, 209 Interferon-alpha, 106, 208, 209 Interleukin-2, 91, 113, 209 Intermittent, 84, 117, 209, 211 Interneurons, 41, 209 Interstitial, 135, 199, 209 Intestine, 184, 185, 201, 209, 210 Intoxication, 15, 38, 209, 237 Intracellular, 18, 64, 186, 208, 209, 217, 226, 228, 229 Intramuscular, 130, 209, 219 Intrathecal, 10, 17, 96, 209 Intravenous, 38, 73, 77, 85, 88, 208, 209, 219 Intrinsic, 8, 12, 141, 178, 183, 209 Invasive, 54, 139, 209, 212 Involuntary, 183, 209, 215, 227, 230 Ion Channels, 209, 220, 233 Ionization, 74, 209 Ionizing, 209, 226 Ions, 195, 197, 205, 209, 214 Ischemia, 148, 180, 182, 209 Isradipine, 77, 209 J Jaundice, 134, 205, 210 K Kb, 160, 210 Ketamine, 43, 210 Keto, 210, 235 Kinetics, 76, 85, 86, 210 L Labile, 35, 189, 210 Lactate Dehydrogenase, 117, 210 Lactates, 128, 210 Lactation, 210, 223 Laparotomy, 110, 210 Large Intestine, 209, 210, 226, 230 Latency, 49, 210 Latent, 10, 210, 223 Leptin, 37, 210 Leucine, 184, 210 Leukocytes, 185, 188, 209, 210
Levodopa, 81, 195, 210 Life cycle, 178, 201, 210 Ligament, 210, 224 Ligands, 18, 27, 85, 138, 139, 210 Limbic, 29, 180, 210 Limbic System, 180, 210 Linkages, 203, 211 Lipid, 188, 208, 210, 211, 214 Lipodystrophy, 144, 211 Lipophilic, 45, 211 Lithium, 76, 128, 181, 211 Liver, 10, 20, 23, 24, 49, 81, 85, 95, 130, 134, 177, 184, 189, 193, 200, 204, 211, 227 Liver Cirrhosis, 20, 211 Localized, 43, 50, 193, 200, 208, 211, 221, 228, 236 Locomotion, 199, 211, 221 Locus Coeruleus, 33, 92, 211 Longitudinal study, 30, 211 Long-Term Care, 31, 211 Lorazepam, 44, 211 Loxapine, 179, 211 Lupus, 132, 134, 211, 233 Lutein Cells, 211, 223 Lymphatic, 197, 208, 212, 231, 234 Lymphatic system, 212, 231, 234 Lymphocyte, 177, 181, 212 Lymphocyte Count, 177, 212 Lymphoid, 181, 212 M Magnetic Resonance Imaging, 212 Maintenance therapy, 75, 212 Malaise, 133, 196, 212 Malignant, 177, 181, 212, 215, 226 Mania, 128, 212 Manic, 128, 181, 211, 212, 225 Mannans, 201, 212 Mediate, 14, 32, 49, 50, 54, 145, 195, 212 Mediator, 195, 209, 212, 229 MEDLINE, 161, 212 Meiosis, 212, 233 Melanin, 211, 212, 236 Memantine, 30, 212 Membrane, 50, 126, 190, 194, 199, 203, 209, 212, 213, 214, 220, 221, 227, 229, 235 Memory, 29, 75, 180, 193, 212 Meninges, 187, 192, 212 Menopause, 212, 222 Menstruation, 179, 212, 213, 218 Mental Disorders, 62, 213, 224, 225 Mental Health, iv, 4, 42, 63, 82, 119, 160, 162, 202, 213, 225
246
Naltrexone
Mental Processes, 195, 213, 224 Mesencephalic, 211, 213, 227 Mesolimbic, 33, 35, 41, 182, 213, 237 Meta-Analysis, 78, 213 Metabolite, 19, 45, 74, 85, 184, 189, 194, 205, 213, 217, 223 Metastasis, 53, 132, 213, 215 Metastatic, 91, 113, 213, 228 Metastatic cancer, 113, 213 Methadyl Acetate, 103, 213 Methionine, 184, 194, 213, 223 Methyl Methanesulfonate, 74, 213 Methylphenidate, 62, 213 MI, 102, 104, 175, 213 Microbe, 213, 235 Microcirculation, 211, 213 Microdialysis, 11, 213 Microorganism, 189, 213, 237 Migration, 58, 129, 214 Mitosis, 214 Mitotic, 129, 214 Modification, 7, 93, 179, 214, 225 Modulator, 127, 214 Molecular, 38, 45, 58, 60, 161, 163, 184, 190, 193, 214, 223, 226, 235, 236 Molecular Structure, 214, 236 Molecule, 17, 181, 189, 190, 195, 196, 197, 199, 203, 205, 214, 218, 226, 235, 236 Monitor, 56, 214, 217 Monoamine, 179, 194, 214 Mononuclear, 69, 214 Monotherapy, 13, 42, 214 Morphine Dependence, 12, 69, 214 Morphine Derivatives, 136, 214 Morphological, 197, 201, 214 Motility, 214, 229 Motion Sickness, 214, 215 Motor Activity, 214, 225 Mucins, 214, 228 Mucosa, 126, 142, 211, 214, 223 Multicenter study, 12, 43, 86, 214 Multiple sclerosis, 132, 133, 214 Mutagen, 198, 213, 215 Mutagenesis, 85, 215 Mutagenic, 179, 215 Mutilation, 71, 215 Mycosis, 134, 215 Mydriatic, 215, 238 Myelin, 214, 215 Myocardium, 180, 213, 215 N Nadir, 46, 215
Nalbuphine, 136, 140, 146, 215 Narcolepsy, 194, 213, 215 Narcosis, 204, 215 Narcotic Antagonists, 104, 107, 134, 135, 137, 215 Nausea, 22, 142, 143, 182, 195, 201, 215, 218, 219 Necrosis, 207, 213, 215, 227 Neonatal, 92, 133, 215 Neoplasms, 177, 181, 215, 226 Nerve Endings, 215, 217 Nerve Fibers, 50, 215 Nervous System, 18, 64, 145, 166, 177, 178, 179, 183, 186, 187, 189, 194, 199, 201, 202, 210, 212, 213, 214, 215, 216, 220, 222, 229, 233 Nervousness, 32, 215 Networks, 31, 50, 216 Neural, 9, 17, 29, 64, 73, 178, 193, 205, 216 Neuroblastoma, 93, 216 Neuroendocrine, 28, 36, 37, 53, 216 Neuroleptanalgesia, 194, 216 Neuroleptic, 89, 181, 216, 218 Neuromuscular, 177, 216 Neuromuscular Junction, 177, 216 Neuronal, 11, 18, 29, 64, 128, 143, 215, 216 Neuronal Plasticity, 11, 216 Neuropeptide, 33, 37, 64, 192, 216 Neurotoxic, 106, 216 Neurotransmitter, 22, 177, 179, 185, 195, 201, 202, 205, 209, 216, 217, 228, 232, 233 Nevirapine, 216, 217 Nicotine, 44, 51, 55, 89, 91, 106, 137, 138, 216 Nitric Oxide, 10, 26, 216 Nitrogen, 135, 136, 178, 179, 200, 217, 236 Nociceptors, 50, 217 Nonblinded, 25, 217 Non-nucleoside, 144, 193, 216, 217 Nonverbal Communication, 217, 225 Norepinephrine, 38, 53, 128, 178, 179, 193, 195, 216, 217, 230 Nortriptyline, 128, 217 Nuclear, 31, 76, 98, 183, 190, 197, 199, 201, 211, 215, 217 Nuclear Medicine, 31, 76, 98, 217 Nuclei, 64, 179, 190, 197, 211, 212, 214, 217, 221, 224 Nucleic acid, 207, 217, 231 Nucleus, 8, 18, 29, 33, 43, 128, 188, 192, 194, 199, 201, 202, 211, 212, 214, 217, 223, 224, 237
247
Nucleus Accumbens, 18, 29, 33, 43, 217, 237 O Obsessive-Compulsive Disorder, 200, 217 Ocular, 148, 217 Ointments, 196, 217 Oligomenorrhea, 218, 222 Ondansetron, 22, 28, 34, 50, 72, 218 Opacity, 193, 218 Opioid Peptides, 50, 218 Opium, 136, 214, 218, 219 Opportunistic Infections, 177, 218 Optic Chiasm, 206, 218 Organ Transplantation, 130, 218 Outpatient, 4, 12, 15, 22, 37, 46, 48, 52, 57, 65, 79, 94, 98, 218 Ovaries, 218, 222, 227, 230 Ovary, 87, 202, 218 Overdose, 66, 73, 94, 134, 218 Ovulation, 78, 83, 94, 102, 181, 188, 218 Ovum, 210, 218, 223 Oxidation, 136, 177, 184, 202, 218, 234 Oxidation-Reduction, 184, 218 Oxycodone, 26, 136, 219 Oxygen Consumption, 219, 227 P Palliative, 133, 219, 233 Panax ginseng, 115, 219 Pancreas, 130, 177, 208, 219 Panic, 200, 206, 219 Panic Disorder, 200, 206, 219 Papaverine, 218, 219 Paradoxical, 54, 70, 219 Paralysis, 144, 213, 219 Parenteral, 52, 126, 127, 134, 135, 140, 142, 219 Parity, 8, 219 Parkinsonism, 182, 210, 219 Paroxetine, 99, 219 Partial remission, 219, 227 Particle, 219, 231, 235 Parturition, 219, 223 Patch, 50, 61, 89, 138, 219, 235 Pathologic, 184, 191, 205, 206, 219, 236 Patient Compliance, 63, 220 Patient Education, 166, 170, 172, 175, 220 Pelvic, 220, 224 Penicillin, 181, 220 Peptide, 17, 28, 37, 53, 58, 114, 123, 148, 179, 184, 210, 218, 220, 222, 223, 224, 234 Peptide T, 123, 220 Perfusion, 31, 206, 220, 234
Pergolide, 38, 220 Peripheral blood, 69, 209, 220 Peripheral Nervous System, 216, 220, 223, 232 Pharmaceutical Solutions, 196, 220 Pharmacodynamic, 66, 220 Pharmacokinetic, 8, 19, 66, 220 Pharmacologic, 9, 12, 18, 19, 27, 30, 62, 103, 180, 203, 220, 234, 235 Phenotype, 144, 220 Phenytoin, 186, 220 Pheromone, 36, 221 Phototransduction, 221, 228 Physical Examination, 16, 221 Physicochemical, 45, 221 Physiologic, 5, 28, 30, 178, 195, 203, 213, 221, 226, 230 Physiology, 29, 77, 100, 105, 114, 197, 221 Pilot study, 14, 19, 32, 47, 56, 66, 77, 90, 92, 95, 107, 221 Pituitary Gland, 192, 221, 223 Placebos, 9, 221 Plants, 129, 178, 186, 188, 189, 202, 217, 221, 228, 235 Plasma, 10, 12, 25, 32, 53, 68, 74, 80, 81, 83, 87, 89, 92, 95, 97, 98, 106, 181, 204, 221, 229, 234 Plasma cells, 181, 221 Platelet Aggregation, 180, 216, 221 Platelets, 216, 221 Pleomorphic, 217, 221 Pneumonia, 191, 221 Poisoning, 20, 209, 215, 221 Polycystic, 76, 86, 87, 96, 97, 221, 222 Polycystic Ovary Syndrome, 76, 87, 222 Polyethylene, 140, 222 Polymorphism, 66, 222 Polypeptide, 179, 189, 222, 223, 238 Polysaccharide, 181, 187, 222 Pons, 69, 201, 222 Posterior, 180, 187, 195, 219, 222 Postmenopausal, 107, 222 Postsynaptic, 222, 233 Post-synaptic, 50 Post-synaptic, 222 Post-traumatic, 101, 203, 222 Post-traumatic stress disorder, 101, 222 Postural, 222, 232 Potentiate, 60, 116, 222 Potentiating, 33, 134, 179, 222 Potentiation, 118, 222 Practicability, 222, 236
248
Naltrexone
Practice Guidelines, 162, 222 Preclinical, 11, 17, 34, 42, 43, 45, 55, 67, 96, 222 Precursor, 65, 188, 195, 196, 198, 210, 217, 222, 223, 231, 236 Predisposition, 22, 223 Preferred Provider Organizations, 7, 223 Preload, 20, 223 Presynaptic, 50, 196, 215, 216, 223, 233 Presynaptic Terminals, 196, 215, 223 Prevalence, 30, 35, 62, 223 Private Sector, 130, 223 Probe, 8, 19, 213, 223 Prodrug, 45, 83, 139, 146, 223 Progesterone, 223, 232 Progression, 47, 180, 223 Progressive, 134, 135, 187, 188, 193, 196, 215, 223, 234 Projection, 209, 217, 223, 227, 237 Prolactin, 97, 223 Prone, 40, 43, 223 Pro-Opiomelanocortin, 218, 223 Prophase, 223, 233 Prospective study, 211, 223 Prostate, 131, 132, 224, 227 Prostate gland, 132, 224 Protease, 144, 224 Protein Binding, 224, 234 Protein C, 26, 179, 183, 224 Protein Kinases, 64, 117, 224 Protein S, 54, 69, 184, 224 Proteins, 18, 179, 181, 185, 188, 189, 201, 214, 217, 220, 221, 224, 226, 230, 234, 235, 236 Proteolytic, 179, 190, 224 Protocol, 13, 15, 16, 21, 22, 24, 25, 40, 46, 57, 221, 224 Protons, 205, 209, 224, 225 Protriptyline, 128, 224 Pruritus, 10, 77, 78, 93, 95, 98, 224 Psychiatric, 5, 24, 30, 35, 46, 48, 51, 52, 62, 73, 79, 88, 92, 93, 213, 224 Psychic, 213, 216, 224, 225, 229 Psychoactive, 108, 126, 224, 233, 237 Psychology, 10, 11, 13, 19, 28, 31, 57, 68, 103, 119, 195, 224 Psychomotor, 9, 186, 216, 225 Psychomotor Performance, 9, 225 Psychopathology, 26, 225 Psychosis, 51, 181, 225 Psychotherapy, 22, 23, 25, 31, 36, 51, 57, 70, 101, 199, 225
Psychotomimetic, 127, 141, 142, 179, 194, 225 Public Health, 26, 40, 47, 54, 162, 225 Public Policy, 14, 161, 225 Publishing, 64, 225 Pulmonary, 185, 191, 225, 237 Pulmonary Artery, 185, 225, 237 Pulmonary hypertension, 191, 225 Pulse, 71, 214, 225 Putrescine, 225, 231 Pyridoxal, 225, 235 Q Quality of Life, 135, 225 R Race, 83, 195, 214, 225 Radiation, 180, 201, 209, 225, 226, 237 Radioactive, 50, 203, 205, 207, 209, 217, 226 Radioimmunotherapy, 226 Radiology, 54, 217, 226 Radiopharmaceutical, 202, 226 Radiotherapy, 98, 226 Random Allocation, 226 Randomization, 13, 19, 226 Randomized clinical trial, 57, 58, 73, 226 Reaction Time, 139, 226 Reagent, 137, 226 Reality Testing, 225, 226 Receptors, Serotonin, 226, 229 Rectal, 126, 226 Rectum, 182, 189, 193, 200, 201, 210, 224, 226 Red blood cells, 97, 98, 198, 204, 227, 228 Red Nucleus, 227, 237 Reductase, 200, 227 Refer, 1, 185, 189, 195, 200, 201, 204, 209, 211, 216, 225, 226, 227, 229, 235 Reflective, 34, 227 Reflex, 118, 227 Refraction, 227, 231 Refractory, 44, 99, 128, 227 Regimen, 12, 52, 94, 131, 196, 220, 227 Remission, 61, 212, 227 Reproductive system, 224, 227 Research Support, 29, 227 Respiration, 9, 186, 214, 227 Response rate, 8, 227 Retina, 218, 221, 227, 228 Rhabdomyolysis, 75, 100, 227 Rheumatism, 227 Rheumatoid, 132, 133, 134, 227 Rheumatoid arthritis, 132, 133, 134, 227
249
Riboflavin, 23, 49, 227 Ribose, 177, 228 Risk factor, 20, 36, 59, 224, 228 S Saliva, 97, 98, 228 Salivary, 228 Salivary glands, 228 Saponins, 228, 232 Schizoid, 228, 237 Schizophrenia, 47, 77, 89, 105, 114, 211, 228, 237 Schizotypal Personality Disorder, 228, 237 Scleroderma, 144, 228 Sclerosis, 214, 228 Screening, 16, 60, 188, 228 Second Messenger Systems, 18, 228 Secondary tumor, 213, 228 Secretion, 53, 78, 83, 84, 87, 97, 107, 205, 206, 208, 210, 214, 228, 229 Secretory, 69, 228, 233 Sedative, 179, 189, 206, 211, 228, 236 Seizures, 128, 186, 220, 229 Selenium, 136, 229 Self Administration, 127, 141, 229 Self-Help Groups, 7, 229 Self-Injurious Behavior, 70, 76, 84, 86, 101, 108, 229 Semen, 224, 229 Semisynthetic, 194, 219, 229 Sensibility, 180, 205, 229 Sensitization, 11, 35, 229 Septal, 211, 229 Septum, 69, 229 Septum Pellucidum, 229 Sequence Homology, 220, 229 Sequencing, 15, 229 Sequential treatment, 15, 229 Serotonin, 19, 38, 42, 105, 128, 179, 182, 189, 193, 200, 216, 218, 219, 220, 226, 229, 230, 236 Sertraline, 42, 59, 63, 66, 128, 229 Serum, 23, 45, 49, 72, 101, 133, 180, 189, 203, 206, 230 Sex Characteristics, 177, 230, 233 Shivering, 230, 234 Shock, 134, 230, 235 Sibutramine, 38, 230 Signs and Symptoms, 57, 138, 227, 230 Skeletal, 227, 230 Skull, 192, 230, 233 Small intestine, 196, 205, 209, 230
Smoking Cessation, 44, 89, 90, 100, 138, 186, 230 Smooth muscle, 180, 186, 191, 205, 209, 214, 219, 230, 232 Sociability, 14, 230 Social Behavior, 14, 230 Social Environment, 225, 230 Social Support, 130, 230 Sodium, 137, 221, 230 Soft tissue, 185, 200, 231 Soft tissue sarcoma, 200, 231 Solid tumor, 91, 180, 231 Solvent, 130, 137, 183, 194, 198, 220, 231 Soma, 231 Somatic, 53, 64, 129, 138, 177, 205, 211, 212, 214, 220, 231 Somnolence, 142, 143, 231 Sound wave, 227, 231 Spatial disorientation, 195, 231 Specialist, 12, 167, 231 Specificity, 32, 139, 178, 231, 234 Spectrum, 41, 57, 231 Spermidine, 127, 231 Spermine, 231 Spinal cord, 33, 50, 54, 114, 118, 187, 188, 209, 212, 215, 220, 227, 231 Spinous, 198, 231 Spleen, 10, 212, 231 Stabilization, 53, 220, 231 Stabilizer, 147, 231 Statistically significant, 46, 232 Steady state, 19, 232 Stereotyped Behavior, 3, 232 Steroid, 80, 184, 192, 228, 232 Stimulant, 179, 186, 194, 205, 213, 232 Stimulus, 12, 26, 50, 75, 196, 197, 199, 208, 209, 210, 226, 227, 232, 234 Stomach, 144, 177, 198, 201, 204, 205, 215, 230, 231, 232 Stool, 189, 210, 232 Stress, 28, 35, 36, 42, 82, 116, 133, 187, 192, 200, 215, 223, 227, 232 Striatum, 41, 69, 217, 232 Stroke, 160, 186, 232 Stupor, 215, 232 Subacute, 208, 232 Subarachnoid, 201, 203, 232 Subclinical, 208, 229, 232 Subcutaneous, 73, 75, 91, 113, 177, 196, 211, 219, 232 Subiculum, 204, 232 Sublingual, 94, 127, 140, 141, 142, 232
250
Naltrexone
Subspecies, 231, 232 Substance P, 213, 228, 232 Support group, 61, 232 Suppression, 20, 40, 105, 131, 233 Sympathomimetic, 179, 194, 195, 198, 217, 233 Symphysis, 188, 224, 233 Symptomatic, 17, 233 Symptomatology, 17, 233 Synapse, 178, 193, 216, 223, 233, 235 Synaptic, 41, 50, 128, 216, 233 Synaptic Transmission, 50, 216, 233 Synergistic, 22, 143, 223, 233 Systemic, 33, 132, 133, 134, 156, 185, 195, 198, 206, 208, 228, 233, 235, 236 Systemic lupus erythematosus, 133, 134, 206, 233 Systolic, 206, 233 T Temporal, 89, 180, 203, 204, 233 Temporal Lobe, 180, 233 Teratogenic, 179, 233 Testosterone, 200, 227, 233 Tetrahydrocannabinol, 80, 233 Therapeutics, 53, 75, 77, 80, 86, 92, 116, 118, 128, 156, 233 Thermal, 10, 54, 195, 233 Thermogenesis, 64, 234 Threonine, 220, 234 Threshold, 11, 199, 206, 234 Thrombin, 221, 224, 234 Thrombomodulin, 224, 234 Thrombosis, 224, 232, 234 Thymus, 207, 212, 234 Thyroid, 105, 206, 234, 236 Thyroid Gland, 234 Thyroid Hormones, 234, 236 Thyroiditis, 134, 234 Thyroiditis, Autoimmune, 134, 234 Thyrotropin, 116, 206, 234 Thyroxine, 234 Tissue, 10, 106, 177, 180, 181, 182, 183, 184, 185, 188, 190, 191, 194, 196, 197, 198, 199, 200, 201, 203, 206, 207, 208, 209, 210, 212, 215, 216, 220, 221, 227, 230, 231, 232, 233, 234, 235 Tissue Distribution, 106, 234 Tolerance, 12, 17, 26, 53, 60, 80, 143, 145, 146, 147, 151, 186, 234 Tomography, 46, 54, 138, 139, 234 Tone, 234, 235 Tonic, 144, 235
Topical, 126, 133, 194, 198, 205, 235 Toxic, iv, 9, 179, 183, 190, 199, 205, 216, 225, 229, 235 Toxicity, 99, 129, 130, 196, 235 Toxicology, 15, 35, 74, 97, 100, 162, 235 Toxin, 234, 235 Trace element, 200, 235 Tramadol, 142, 143, 145, 235 Transaminase, 34, 46, 235 Transcriptase, 144, 193, 216, 217, 235 Transcutaneous, 116, 235 Transdermal, 45, 61, 126, 140, 235 Transduction, 40, 50, 208, 235 Transfection, 184, 235 Transfer Factor, 207, 235 Translation, 179, 235 Translational, 27, 31, 235 Transmitter, 177, 195, 209, 212, 217, 235 Transplantation, 130, 188, 207, 235 Trauma, 42, 133, 215, 235 Treatment Outcome, 9, 15, 20, 46, 50, 58, 62, 236 Tricuspid Atresia, 191, 236 Tricyclic, 76, 128, 179, 189, 193, 196, 206, 224, 236 Trimipramine, 128, 236 Tryptophan, 189, 229, 236 Tubercle, 217, 236 Tuberculosis, 211, 236 Tunica, 214, 236 Tyrosine, 195, 236 U Ulcer, 196, 236 Urethra, 224, 236 Urinary, 105, 135, 192, 236 Urine, 15, 16, 23, 26, 35, 49, 74, 85, 88, 97, 98, 185, 195, 228, 236 Uterus, 192, 206, 213, 218, 223, 227, 236 V Vaccines, 236, 237 Vagina, 206, 213, 227, 236 Vaginal, 126, 236 Vascular, 193, 197, 203, 208, 209, 211, 213, 216, 234, 236 Vasodilatation, 135, 236 Vasodilation, 195, 219, 236 Vasodilator, 185, 195, 205, 219, 236 Vector, 235, 236 Vein, 209, 217, 236 Venous, 224, 236, 237 Venter, 237
251
Ventral, 18, 32, 33, 41, 116, 206, 217, 222, 237 Ventral Tegmental Area, 18, 32, 33, 41, 237 Ventricle, 180, 182, 187, 191, 204, 206, 217, 225, 233, 236, 237 Ventricular, 191, 236, 237 Venules, 185, 213, 237 Vertebrae, 231, 237 Vesicular, 133, 182, 204, 237 Veterinary Medicine, 161, 237 Viral, 40, 132, 133, 235, 237 Virulence, 183, 235, 237 Virus, 132, 133, 144, 166, 177, 183, 187, 198, 203, 209, 235, 237
Viscera, 231, 237 Vitro, 40, 45, 237 Vivo, 10, 17, 40, 45, 139, 237 W War, 222, 237 White blood cell, 181, 210, 212, 221, 237 X Xenograft, 180, 237 X-ray, 201, 215, 217, 226, 231, 237 Y Yeasts, 201, 220, 238 Yohimbine, 104, 238 Z Zymogen, 224, 238
252
Naltrexone
