A world-wide yearly survey of new data and trends in adverse drug reactions

SIDE EFFECTS OF DRUGS ANNUAL 26

Side Effects of Drugs Annual 26 HONORARY EDITOR Prof. M.N.G. Dukes, Oslo, Norway

ADVISORY EDITORIAL BOARD Prof. F. Bochner, Adelaide, Australia Prof. I.R. Edwards, Uppsala, Sweden Prof. G.P. Velo, Verona, Italy

SIDE EFFECTS OF DRUGS ANNUAL 26 A worldwide yearly survey of new data and trends in adverse drug reactions EDITOR

J. K. ARONSON M.A., D.Phil., M.B.Ch.B., F.R.C.P. Clinical Reader in Clinical Pharmacology University Department of Clinical Pharmacology Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom

2003

ELSEVIER Amsterdam – Boston – Heidelberg – London – New York – Oxford Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo

ELSEVIER SCIENCE B.V. Sara Burgerhartstraat 25 P.O. Box 211, 1000 AE Amsterdam, The Netherlands © 2003 Elsevier Science B.V. All rights reserved. This work is protected under copyright by Elsevier Science, and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone: (+44) 1865 843830, fax: (+44) 1865 853333, e-mail: [email protected]. You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions’. In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (+1) (978) 7508400, fax: (+1) (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London W1P 0LP, UK; phone: (+44) 207 631 5555; fax: (+44) 207 631 5500. Other countries may have a local reprographic rights agency for payments. Derivative Works Tables of contents may be reproduced for internal circulation, but permission of Elsevier Science is required for external resale or distribution of such material. Permission of the Publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the Publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Except as outlined above, no part of this work may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier’s Science & Technology Rights Department, at the phone, fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. First edition 2003 ISBN: 0-444-50999-2 ISSN: 0378-6080 ∞ The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of !

Paper). Printed in The Netherlands.

Contributors M.C. ALLWOOD, B . PHARM ., PH . D . University of Derby, School of Health and Community Studies, Pharmacy Academic Practice Unit, Kingsway House, Derby, DE22 3HL, U.K. E-mail: [email protected] J.K. ARONSON, M . A ., M . B . CH . B ., D . PHIL ., F. R . C . P. University Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, U.K. E-mail: [email protected] S. ARROYO, M . D ., PH . D . Medical College of Wisconsin, Froedtert Hospital, Department of Neurology, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, U.S.A. E-mail: [email protected] I. AURSNES, M . D . University of Oslo, Department of Pharmacotherapeutics, P.O. Box 1065 Blindern, N-0316 Oslo, Norway. E-mail: [email protected] A.M. BALDACCHINO, M . D ., M . R . C . PSYCH ., M . PHIL ., DIP. ADD . BEH . Centre for Addiction Studies, St. George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London, SW17 0RE, U.K. M. BEHREND, M . D ., PH . D . Klinik für Viszeral-, Gefäß-, Thorax- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Str. 41, D-94469 Deggendorf, Germany. E-mail: [email protected] T. BICANIC, M . A ., MB . CH . B ., M . R . C . P. St. George’s Hospital Medical School, Department of Infectious Diseases, Cranmer Terrace, London, SW17 0RE, U.K. C. BOKEMEYER, PH . D ., M . D . Department of Hematology/Oncology/Immunology, Eberhard Karls University Tübingen, UKT - Medical Center II, Department of Hematology, Oncology, Immunology, Rheumatology, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. A. CARVAJAL, M . D ., PH . D . Instituto de Farmacoepidemiologia, Facultad de Medicine, 47005 Valladolid, Spain. E-mail: [email protected] N.H. CHOULIS, M . D ., PH . D . LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania (Attika), Greece. E-mail: [email protected] P. COATES, M . B . B . S ., F. R . A . C . P., F. R . C . P. A . University of Pittsburgh, Department of Endocrinology and Metabolism, 1110 Kaufmann Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, U.S.A. E-mail: [email protected] J. COSTA, M . D . Universitat Autònoma de Barcelona, Hospital Universitari Germans Trias I Pujol, Clinical Pharmacology Department, Ctra de Canyet, 08916 Badalona, Spain. E-mail: [email protected]

v

vi

Contributors

P.J. COWEN, M . D . University Department of Psychiatry, Warenford Hospital, Oxford, OX3 7JX, U.K. E-mail: [email protected] S. CURRAN, B . S . C ., M . B . CH . B ., M . MED . SC ., M . R . C . PSYCH ., PH . D . South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, U.K. E-mail: [email protected] H.J. DE SILVA, M . B . B . S ., M . D ., D . PHIL ., F. R . C . P., F. R . C . P. E ., F. C . C . P. University of Kelaniya, Department of Medicine, Faculty of Medicine, P.O. Box 6, Ragama, Sri Lanka. E-mail: [email protected] F.A. DE WOLFF, M . A ., PH . D ., EUR . CLIN . CHEM ., E . R . T., F. A . T. S . Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Pharmacy and Toxicology, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] A. DEL FAVERO, M . D . Istituto di Medicina Interna e Science Oncologiche, Policlinico Monteluce, 06122 Perugia, Italy. E-mail: [email protected] J. DESCOTES, M . D ., PH . D ., PHARM . D . Hôpital Edouard Herriot, Centre Antipoison – Centre de Pharmacovigilance, 5 Place d’Arsonval, 69347 Lyon cedex 03, France. E-mail: [email protected] S. DITTMANN, M . D ., D . SC . MED . Vice-Chairman, German Advisory Committee on Immunization, 19 Hatzenporter Weg, 12681 Berlin, Germany. E-mail: [email protected] M.N.G. DUKES Trosterudveien 19, 0778 Oslo, Norway. E-mail: [email protected] I.R. EDWARDS, M . B ., F. R . C . P., F. R . A . C . P. Uppsala Monitoring Centre, The WHO Collaborating Centre for International Drug Monitoring, Stora Torget 3, S-753 20 Uppsala, Sweden. E-mail: [email protected] H.W. EIJKHOUT, M . D . Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] E. ERNST, M . D ., PH . D ., F. R . C . P. ( EDIN ) University of Exeter, Peninsula Medical School, Department of Complementary Medicine, 25 Victoria Park Road, Exeter, EX2 4NT, U.K. E-mail: [email protected] M. FARRÉ, M . D . Universitat Autónoma de Barcelona, Institut Municipal d’Investigació Mèdica (IMIM-IMAS), Unitat de Farmacologia, Doctor Aiguader 80, 08003 Barcelona, Spain. E-mail: [email protected] D.J. FINNEY, M . A ,. SC . D . 13 Oswald Court, South Oswald Road, Edinburgh, EG9 2HY, U.K. E-mail: [email protected] J.A. FRANKLYN, M . D ., PH . D ., F. R . C . P., F. MED . SCI . University of Birmingham, Queen Elizabeth Hospital, Department of Medicine, Edgbaston, Birmingham, B15 2TH, U.K. E-mail: [email protected]

Contributors

vii

M.G. FRANZOSI, PH . D . Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] A.H. GHODSE, M . D ., PH . D ., F. R . C . P., F. R . C . PSYCH . Centre for Addiction Studies, St. George’s Hospital Medial School, 6th Floor, Hunter Wing, Cranmer Terrace, London, SW17 0RE, U.K. E-mail: [email protected] G. GILLESPIE, M . B . CH . B . F. R . C . A . Royal Perth Hospital, Department of Anaesthesia and Pain Medicine, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected] A.H. GROLL, M . D . Infectious Disease Research Program, Center for Bone Marrow Transplantation and Division of Hematology/Oncology, Department of Pediatrics, Wilhelms University, Muenster, Germany. E-mail: [email protected] K. HARTMANN, P. SC . PHARM . Swiss Drug Monitoring Center, Neubruchstrasse 37, 7000 Chur, Switzerland. J.T. HARTMANN, PH . D ., M . D . Department of Hematology/Oncology/Immunology, Eberhard Karls University Tübingen, UKT - Medical Center II, Department of Hematology, Oncology, Immunology, Rheumatology, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. E-mail: [email protected] A. IMHOF, M . D . Program in Infectious Disease, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D3-100, Seattle, WA 98109-1024, U.S.A. E-mail: [email protected] PROFESSOR L.L. IVERSEN, M . A ., PH . D . University of Oxford, Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, U.K. E-mail: [email protected] PROFESSOR J.W. JEFFERSON, M . D . University of Wisconsin Medical School, Madison Institute of Medicine, 7617 Mineral Point Road, Madison, WI 53717, U.S.A. E-mail: [email protected] M. JOERGER, M . D . Kantonsspital, Department of Internal Medicine, 9007 St. Gallen, Switzerland. P. JOUBERT, B . SC ., M . B . B . CH ., M . MED . SC ., F. C . P.( SA ), M . D . Honorary Professor of Pharmacology and Therapeutics, Medical University of Southern Africa, Pretoria, South Africa. E-mail: [email protected] H.M.J. KRANS, M . D . Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, Building 1 C4-R, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: [email protected] S. KRISHNA, B . A ., D . PHIL ., F. R . C . P. St. George’s Hospital Medical School, Department of Infectious Diseases, Cranmer Terrace, London, SW17 0RE, U.K. E-mail: [email protected] M. KUHN, M . D . Swiss Drug Monitoring Center, Neubruchstrasse 37, 7000 Chur, Switzerland. E-mail: [email protected]

viii

Contributors

R. LATINI, M . D . Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] M. LEUWER, M . D . The University of Liverpool, University Department of Anaesthesia, The Duncan Building, Daulby Street, Liverpool, L69 3GA, U.K. E-mail: [email protected] H.-P. LIPP, PH . D . Eberhard-Karls-University Tübingen, Department of Clinical Pharmacy, Röntgenweg 9, 72076 Tübingen, Germany. C. LUDWIG, M . D . Abt. Thoraxchirurgie, Universitätsklinikum Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany. P. MAGEE, B . SC ., M . SC ., M . R . PHARM . S . Director of Pharmaceutical Sciences, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, U.K. E-mail: [email protected] A.P. MAGGIONI, M . D . Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] L.H. MARTÍN ARIAS, M . D ., PH . D . Instituto de Farmacoepidemiologia, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected] I.R. MCNICHOLL, PHARM . D ., B . C . P. S . WITH ADDED QUALIFICATIONS IN INFECTIOUS DIS EASES

UCSF Positive Health Program, Building 80, Ward 86, San Francisco General Hospital, 995 Potrero Avenue, San Francisco, CA 94110, U.S.A. E-mail: [email protected] M.M.H.M. MEINARDI, M . D ., PH . D . Academic Medical Centre, Department of Dermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: [email protected] R.H.B. MEYBOOM, M . D ., PH . D . Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands. T. MIDTVEDT, M . D ., PH . D . Karolinska Institutet, Laboratory of Medical Microbial Ecology, Von Eulers v. 5, Box 60 400, S-171 77 Stockholm, Sweden. E-mail: [email protected] S.K. MORCOS, F. R . C . S ., F. F. R . R . C . S . I ., F. R . C . R . Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Sheffield, S5 7AU, U.K. E-mail: [email protected] W.M.C. MULDER, M . D ., PH . D . Academic Medical Center, Department of Dermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. S. MUSA, M . B . CH . B ., M . R . C . PSYCH . South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, U.K.

Contributors

ix

S. OLSSON, M . SCI . PHARM . Uppsala Monitoring Centre, The WHO Collaborating Centre for International Drug Monitoring, Stora Torget 3, S-753 20 Uppsala, Sweden. E-mail: [email protected] J.N. PANDE, M . D ., F. A . M . S . Professor of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. E-mail: [email protected] J.K. PATEL, M . D . University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, U.S.A. E-mail: [email protected] K. PEERLINCK, M . D . University of Leuven, Center for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, B-3000 Leuven, Belgium. E-mail: [email protected] T. PLANCHE, M . R . C . P. St. George’s Hospital Medical School, Department of Infectious Diseases, Cranmer Terrace, London, SW17 0RE, U.K. B.C.P. POLAK, M . D . VU University Medical Center, Department of Ophthalmology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: [email protected] H.D. REUTER, PH . D . Siebengebirgsallee 24, D-50939 Köln, Germany. E-mail: [email protected] M. SCHACHTER, M . D . Department of Clinical Pharmacology, St. Mary’s Hospital, London, W2 1NY, U.K. E-mail: [email protected] S.A. SCHUG, M . D ., F. A . N . Z . C . A ., F. F. P. M . A . N . Z . C . A . University of Western Australia, Anaesthesia, School of Medicine and Pharmacology, MRF Building, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected] G. SCREATON, B . M . B . CH ., D . PHIL ., M . R . C . P. Nuffield Department of Clinical Medicine, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, U.K. E-mail: [email protected] R.P. SEQUEIRA, PH . D . Arabian Gulf University, College of Medicine and Medial Sciences, Department of Pharmacology and Therapeutics, P.O. Box 22979, Manama, Bahrain. E-mail: [email protected] DOMENIC A. SICA, M . D . Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Medical College of Virginia of Virginia Commonwealth University, Box 980160 MCV Station, Richmond, Virginia 23298-0160, U.S.A. E-mail: [email protected] A. STANLEY, PH . D ., M . R . PHARM . S . Birmingham Oncology Centre, St. Chad’s Unit, City Hospital, Dudley Road, Birmingham, B18 7QH, U.K. E-mail: [email protected] K.J.D. STANNARD, B . SC ., M . B . B . S ., F. R . C . A . Royal Perth Hospital, Department of Anaesthesia and Pain Medicine, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected]

x

Contributors

W.G. VAN AKEN, M . D . Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] G.B. VAN DER VOET, PH . D ., E . R . T. Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Pharmacy and Toxicology, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] P.J.J. VAN GENDEREN, M . D ., PH . D . Habour Hospital and Institute of Tropical Diseases, Department of Internal Medicine, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail: [email protected] R. VERHAEGHE, M . D . University of Leuven, Center for Vascular and Molecular Biology, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] J. VERMYLEN, M . D . University of Leuven, Center for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, B-3000 Leuven, Belgium. E-mail: [email protected] T. VIAL, M . D . Hôpital Edouard Herriot, Centre Antipoison – Centre de Pharmacovigilance, 5 Place d’Arsonval, 69347 Lyon cedex 03, France. E-mail: [email protected] P.J.M. VOSSEBELD, PH . D . Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] G.M. WALSH, M . SC ., PH . D . University of Aberdeen, IMS Building, Department of Medicine & Therapeutics, Foresterhill, Aberdeen, AB25 2ZD, U.K. E-mail: [email protected] T.J. WALSH, M . D . Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A. E-mail: [email protected] E.J. WONG, M . D . Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Boston, MA 02115, U.S.A. E-mail: [email protected] Y. YOUNG, M . B . B . S ., M . R . C . P.( UK ), F. R . C . A . Auckland Hospital, Department of Anaesthesia, Private Bag 92024, Auckland, New Zealand. E-mail: [email protected] O. ZUZAN, M . D . Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, U.K. E-mail: [email protected]

Contents Contributors List of special reviews

v xv

Cumulative index of special reviews

xvii

How to use this book

xxiii

Historical Essay: From thalidomide to pharmacovigilance: a personal account D.J. Finney Essay: How safe is cannabis? L. Iversen

xxv xxxiii

1.

Central nervous system stimulants and drugs that suppress appetite R.P. Sequeira

1

2.

Antidepressant drugs P.J. Cowen

11

3.

Lithium J.W. Jefferson

19

4.

Drugs of abuse E. Wong and J.K. Patel

30

5.

Hypnosedatives and anxiolytics S. Curran and S. Musa

46

6.

Antipsychotic drugs A. Carvajal and L.H.M. Arias

53

7.

Antiepileptic drugs S. Arroyo

70

8.

Opioid analgesics and narcotic antagonists A.H. Ghodse and A.M. Baldacchino

89

9.

Anti-inflammatory and antipyretic analgesics and drugs used in gout A. Del Favero

111

10.

General anesthetics and therapeutic gases Y. Young

131

11.

Local anesthetics S.A. Schug, G. Gillespie, and K.J.D. Stannard

140

xi

xii 12.

Contents

Neuromuscular blocking agents and skeletal muscle relaxants

150

O. Zuzan and M. Leuwer 13.

Drugs that affect autonomic functions or the extrapyramidal system M. Schachter

156

14.

Dermatological drugs and topical agents W.M.C. Mulder and M.M.H.M. Meinardi

168

15.

Antihistamines (H1 receptor antagonists) G.M. Walsh

180

16.

Drugs acting on the respiratory tract M. Kuhn, M. Joerger, and K. Hartmann

186

17.

Positive inotropic drugs and drugs used in dysrhythmias J.K. Aronson

198

18.

Beta-adrenoceptor antagonists and antianginal drugs

223

A.P. Maggioni, M.G. Franzosi, and R. Latini 19.

Drugs acting on the cerebral and peripheral circulations R. Verhaeghe

230

20.

Antihypertensive drugs P. Joubert

233

21.

Diuretics D.A. Sica

238

22.

Metals G.B. van der Voet and F.A. de Wolff

243

23.

Metal antagonists

253

R.H.B. Meyboom 24.

Antiseptic drugs and disinfectants P. Magee

258

25.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines T. Midtvedt

262

26.

Miscellaneous antibacterial drugs A. Imhof

271

27.

Antifungal drugs A.H. Groll and T.J. Walsh

302

28.

Antiprotozoal drugs T. Bicanic, T. Planche, and S. Krishna

315

Contents

xiii

29.

328

Antiviral drugs I.R. McNicholl

30.

Drugs used in tuberculosis and leprosy

339

J.N. Pande 31.

Antihelminthic drugs

344

P.J.J. van Genderen 32.

Vaccines

353

S. Dittmann 33.

Blood, blood components, plasma, and plasma products

363

P.J.M. Vossebeld, H.W. Eijkhout, and W.G. van Aken 34.

Intravenous infusions—solutions and emulsions

374

M.C. Allwood 35.

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

379

K. Peerlinck and J. Vermylen 36.

Gastrointestinal drugs

382

H.J. de Silva 37.

Drugs acting on the immune system

393

T. Vial, J. Descotes, G. Screaton, M. Behrend, and C. Ludwig 38.

Vitamins

416

H.D. Reuter 39.

Corticotrophins, corticosteroids, and prostaglandins

427

J. Costa and M. Farré 40.

Sex hormones and related compounds, including hormonal contraceptives

434

M.N.G. Dukes 41.

Thyroid hormones and antithyroid drugs

457

J.A. Franklyn 42.

Insulin, glucagon, and hypoglycemic drugs

461

H.M.J. Krans 43.

Miscellaneous hormones

477

P. Coates 44.

Drugs that affect lipid metabolism I. Aursnes

486

xiv

Contents

45.

Cytostatic drugs H.-P. Lipp, C. Bokemeyer, J.T. Hartmann, and A. Stanley

490

46.

Radiological contrast agents S.K. Morcos

512

47.

Drugs used in ocular treatment B.C.P. Polak

525

48.

Treatments used in complementary and alternative medicine E. Ernst

528

49.

Miscellaneous drugs, materials, and medical devices N.H. Choulis

540

50.

The WHO International Drug Monitoring Programme I.R. Edwards and S. Olsson

548

Address list of national centres that participate in the WHO Drug Monitoring Programme

559

Index of drugs

xxx

Index of adverse effects

xxx

Special reviews The cognitive effects of MDMA Antipsychotic drugs and weight gain Cognitive effects of topiramate Valproate-associated polycystic ovary syndrome Vigabatrin-related visual abnormalities Managing the adverse effects of morphine An update on NSAIDs and chronic renal disease What is safe prescribing and use of selective COX-2 inhibitors? Comparisons with non-selective NSAIDs Propofol-infusion syndrome Allergic reactions to rocuronium The baclofen withdrawal syndrome Midodrine Sleep disorders with dopamine receptor agonists The cardiotoxic effects of antihistamines CNS effects of second-generation antihistamines Inhaled corticosteroids and growth inhibition in children Systemic availability of inhaled corticosteroids Dofetilide The role of endothelin receptor antagonists in hypertension Tetracyclines and metalloproteinases Adverse effects of the chemically modified tetracyclines (CMTs) Hepatotoxicity of antituberculous agents revisited Surveillance of adverse events following immunization (AEFI) Bioterrorism and prevention through immunization Co-medication and multimedication in users of acetylsalicyclic acid and vitamin E in Germany Could fertility treatments cause malignant melanoma? The third-generation oral contraceptives: a judicial assessment and further evidence Modes of administration of insulin Ovarian hyperstimulation syndrome Platinum compounds Delayed reactions to iodinated water-soluble contrast agents

32 56 78 81 82 98 111 116 135 150 152 157 160 180 182 186 187 208 233 266 268 339 353 354 423 434 442 464 477 490 513

xv

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Cumulative index of special reviews, Annuals 16–25 Index of drugs Note: the format 24.115 refers to SEDA-24, p. 115. ACE inhibitors angio-edema, 22.225 cough, 19.211 indications, 24.233 Alcohol, vitamin A, beta-carotene, interaction, 24.442 Aldosterone antagonists, in heart failure, 24.246 Aluminium, in albumin solutions, 23.359 Aminoglycoside antibiotics, 17.304 deafness, 18.268 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 17.305 Amiodarone, dysrhythmias, 25.211 Amphotericin, liposomal, 17.319 Analgesics headache, 21.95 headaches in children, 23.114 nephropathy, 21.98 Androgens, in women, 24.477 Anesthesia, dental, safety of, 16.122 Anesthetics halogenated, renal damage, 20.106 local, combinations, 20.121 local, neurotoxicity, 21.129, 25.152 ocular, 17.542 Anorectic drugs cardiac valvulopathy 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Anthracyclines, 25.533 Antibiotics allergic reactions, 23.251 coagulation disorders, 18.258 colitis, 17.303 male fertility, 16.262 new, with adjuvants, 17.296 the pill and pregnancy, 24, 274 policies and politics, 16.273 preterm infants, 21.258 prudent use, 25.279 resistance, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273 seizures, 18.261 side chains, 16.264

Anticholinergic drugs, 22.507 Anticonvulsants, see Antiepileptic drugs Antidepressants, during and after pregnancy, 21.17 Antidysrhythmic drugs in atrial fibrillation, 24.197 prodysrhythmic effects, 17.218, 23.196 Antiepileptic drugs comparison, 25.78 death, 23..83 overdosage, 22.84 psychiatric effects, 22.82 Antifungal drugs drug interactions (azoles), 24.318 Pneumocystis carinii pneumonia, 18.289 Antihistamines cardiovascular adverse effects, 17.196, 22.176, 25. 183 drowsiness, 23.171 sedation, 21.170 Antihypertensive drugs, 19.209 fixed-dose combinations, 22.224 individualizing therapy, 17.246 Antimalarial drugs, 17.325, 20.257 adjunctive treatments, 24. 330 prophylaxis, 23.304 Antioxidant vitamins, 20.363 Antiprotozoal drugs African trypanosomiasis, 18.293 toxoplasmosis, 20.262 Antipsychotic drugs, comparison 25.53 Antitubercular drugs, 16.341 Liver damage, 25.363 Mycobacterium avium–complex infection, 20.278 Appetite suppressants cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Aspirin, 21.100 gastrointestinal effects, 17.95, 18.90 rhinosinusitis/asthma, 17.94 Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Azoles, see antifungal drugs Bambuterol, cardiac failure, 23.181 Benzodiazepines, depression, 17.43

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Cumulative index of special reviews, Annuals 16–25

Beta2 -adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 Beta-carotene alcohol, vitamin A, interaction, 24.442 carcinogenicity, 25.454 Beta-lactams, pregnancy, 25.280

Fertility drugs, ovarian cancer, 24.474 Flecainide, in supraventricular dysrhythmias, 21.200 Fluoroquinolones, 18.271 Fluorouracil, adverse effects, 23.476 Folic acid, dietary supplementation, 19.369 Formoterol, tolerance, 24.187 Fragrances, contact allergy, 20.149

Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carotenoids, carcinogenicity, 25.454 Charcoal, activated, in digitalis overdose, 24.201 Ciclosporin, urinary system, 19.348 Clozapine, agranulocytosis, 22.1359 Co-trimoxazole, hypersensitivity reactions, 20.264 Cocaine cardiovascular effects, 18.5 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151 Contrast agents adverse effects, 24.525 anaphylactoid and allergic reactions, 20.422 in magnetic resonance imaging, 20.419 Corticosteroids bone, 16.447, 22.182, 25.195 contact allergy, 21.158 effective dose and therapeutic ratio, 23.175 inhaled, systemic availability, 24.185 musculoskeletal adverse effects, 21.417 osteoporosis and osteonecrosis, 19.377, 20.374 preterm infants, 17.445 Cosmetics contact allergy, 16.150, 19.151 ingredient labeling 22.159 COX2 inhibitors, 24.115, 25.126

General anesthetics, see Anesthetics Germanium, 16.545 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501 insulin resistance, 24.504 malignancy, 23.468

Deferoxamine, 16.247 bone dysplasia, 23.241 Diamorphine, progressive spongiform leukoencephalopathy, 24.40 Diclofenac, liver damage, 20.91 Digitalis, in atrial fibrillation, 24.197 Digoxin, heart failure in sinus rhythm, 18.196 Diuretics renal cell carcinoma, 23.225 renal insufficiency, 25.250 Ecstasy, deaths, 24.32 EDTA, pseudothrombocytopenia, 21.250 Erythromycin, versus the new macrolides, 21.269 Erythropoietin, status and safety, 16.400 Euxyl K 400, contact allergy, 16.150 Felbamate aplastic anemia, 19.68, 22.86 risk/benefit ratio, 23.86 Fenfluramine cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Fenoterol, safety in severe asthma, 23.182 Fentanyl, buccal and transdermal administration, 20.77

Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Heroin, see diamorphine HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530 Hormones, sex, tumors, 22.465 Hypnotics, 20.30 avoiding adverse effects, 21.37 Immunization adverse effects, 24.364 bioterrorism, 25.378 surveillance after, 22.333, 23.335, 24.364, 25.376 Indomethacin, fetal and neonatal complications, 18.102 Insulin resistance, and growth hormone, 24. 504 synthetic analogs, 24. 489 Isoniazid, prophylactic, toxicity, 24. 352 Ketorolac, risk of adverse effects, 17.110 Lamotrigine, skin rashes, 20.62, 24.88 Leukotriene receptor antagonists, Churg–Strauss syndrome, 24.183 Lithium adverse effects, prevention and treatment, 17.28 interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 18.25 mortality, 19.14 urinary system, 19.16 Local anesthetics, see Anesthetics Lyme disease vaccine, autoimmune disease, 24.366 Macrolides, intestinal motility, 18.269 Malaria vaccines, 22.306 MAO inhibitors, 17.361 Measles immunization autism, 23.350 Crohn’s disease, 23.350 neurological adverse effects, 23.348 Melatonin, 25.523 Metformin, lactic acidosis, 23.459 Methyldibromoglutaronitrile, contact allergy, 16.150, 19.151

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Cumulative index of special reviews, Annuals 16–25 Mibefradil, drug interactions, 23.210 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387 Crohn’s disease, 23.350, 25.387 Muscle relaxants emergency medicine, 20.133 eyes, 21.145 intensive care, 19.140

Phentermine, cardiac valvulopathies, 24.4 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 PUVA, malignant melanoma, 22.166

Niacin, extended-release, 16.440 NSAIDs blood pressure, 19.92 children, 19.96 current controversies, 17.102 COX2 inhibitors, 24.115, 25.126 gastrointestinal adverse effects, 17.95, 18.90, 18.99, 20.86, 21.96, 22.108, 23.114 gastrointestinal toxicity, prevention, 19.93 inflammatory bowel disease, 25.131 nephrotoxicity, 18.100, 20.89, 24.120 topical, 18.163

Rotashield, intussusception, 23.354

Ocular drugs allergic reactions, 21.486 geriatric patients, 16.542 risk factors for adverse effects, 22.507 Omeprazole, tumors, 16.423 Opioids adverse effects, prevention, 24.100 death, 25.37 obstetric use, 24.102 tolerance in neonates, 23.97 Oral contraceptives antibiotics, and pregnancy, 24.274 formulations, 24.472 third-generation, 25.484 venous thromboembolism, 23.442 Paclitaxel, adverse effects, 21.463 Pancreatic enzyme supplements, fibrosing colonopathy, 20.322 Paracetamol liver damage, 17.98, 18.94 overdose, 23.117 Penicillins, acute desensitization, 23.252 Peritoneal dialysis fluids, effects on peritoneum, 22.381

Salmeterol, tolerance, 24.187 Sex hormones, tumors, 22.465 Specific serotonin reuptake inhibitors, drug interactions, 22.13 Statins, see HMG co-A reductase inhibitors Steroids, see corticosteroids Sumatriptan, 17.171 Suramin, patients with prostate cancer, 20.283 Tetracyclines comparative toxicity, 22.268 in pregnancy, 25.280 in rheumatology, 23.255 therapeutic effects, 24.278 Theophylline, asthma, 17.2, 18.1, 18.2 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 Total parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 Vaccines, poliomyelitis, 22.352 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78, 24.95, 25.98 Vitamin A, 17.436 alcohol, beta-carotene, interaction, 24.442 in pregnancy, 21.405 Vitamin B6 , debate, 23.420 Vitamin K cancer, 23.424 skin reactions, 25.461 Vitamins, in old age, 22.431

Index of adverse effects Cardiovascular atrial fibrillation, antidysrhythmic drugs, 24.197 atrial fibrillation, digitalis, 24.197 cardiac failure, aldosterone antagonists, 24.246 cardiac failure, bambuterol, 23.181 cardiotoxicity, antihistamines, 17.196, 25.183 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 dysrhythmias, antihistamines, 22.176 dysrhythmias, amiodarone, 25.211 hypertension, NSAIDs, 19.92

prodysrhythmic effects, antidysrhythmic drugs, 17.218, 23.196 QT interval prolongation, 24.54 valvulopathies, fenfluramine, 22.3, 23.2, 24.4, 25.5 valvulopathies, phentermine, 24.4, 25.5 venous thromboembolism, oral contraceptives, 23.442 Respiratory asthma, aspirin, 17.94 asthma, fenoterol, 23.182

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Cumulative index of special reviews, Annuals 16–25

asthma deaths, beta2 -adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 Churg–Strauss syndrome, leukotriene receptor antagonists, 24. 183 cough, ACE inhibitors, 19.211 primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2, 25.5 rhinosinusitis, aspirin, 17.94 Nervous system demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness, antihistamines, 23.171 headache, analgesics, 21.95, 23.114 neuroleptic malignant syndrome, 20.41 neurotoxicity, anesthetics, local, 21.129 neurotoxicity, measles immunization, 23.348 overdosage, antiepileptic drugs, 22.84 poliomyelitis, vaccines, 22.352 progressive spongiform leukoencephalopathy, diamorphine, 24.40 sedation, antihistamines, 21.170 seizures, antibiotics, 18.261 tardive dyskinesia, 20.38 tardive syndromes, 17.54 transient symptoms, intrathecal anesthetics, 25.152 Sensory systems deafness, aminoglycosides, 18.268 eye effects, muscle relaxants, 21.145 visual field defects, vigabatrin, 21.78, 24.95, 25.98 Psychiatric antiepileptic drugs, 22.82 autism, MMR/measles immunization, 23.350, 25.387 depression, benzodiazepines, 17.43 psychosis and abnormal behavior, vigabatrin, 18.71 Endocrine insulin resistance, growth hormone, 24.504 insulin resistance, HIV-protease inhibitors, 22.317 Metabolism lactic acidosis, metformin, 23.459 lipodystrophy, HIV-protease inhibitors, 22.317 polyvinylpyrrolidone storage disease, 22.522 Hematologic agranulocytosis, clozapine, 22.59 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 pseudothrombocytopenia, EDTA, 21.250 Gastrointestinal bleeding, aspirin, 17.95, 18.90 bleeding and perforation, NSAIDs , 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114 cholestasis, total parenteral nutrition, 22.376 colitis, antibiotics, 17.303 Crohn’s disease, MMR/measles immunization, 23.350, 25.387 fibrosing colonopathy, pancreatic enzyme supplements, 20.322 inflammatory bowel disease, NSAIDs, 25.131 intestinal motility, macrolides, 18.269 intussusception, Rotashield, 23.354

Liver hepatotoxicity, alcohol/vitamin A/beta-carotene, 24.442 hepatotoxicity, antitubercular drugs, 25.363 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, paracetamol, 17.98, 18.94 Urinary tract cystitis, tiaprofenic acid, 18.106 nephrotoxicity, aminoglycosides, 17.305 nephrotoxicity, analgesics, 21.98 nephrotoxicity, anesthetics, halogenated, 20.106 nephrotoxicity, ciclosporin, 19.348 nephrotoxicity, lithium, 19.16 nephrotoxicity, NSAIDs, 18.100, 20.89, 24.120 renal cell carcinoma, diuretics, 23.225 renal insufficiency, diuretics, 25.250 Skin contact allergy, 23.160 rashes, lamotrigine, 20.62, 24.88 vitamin K1, 25.461 Serosae peritoneum, peritoneal dialysis, 22.381 pleurodesis, 25.189 Musculoskeletal bone, total parenteral nutrition, 22.378 bone dysplasia, deferoxamine, 23.241 bone mineral density, corticosteroids, 25.195 osteoporosis and osteonecrosis, corticosteroids, 16.447, 19.377, 20.374, 21.417, 22,182 Sexual function fertility, male, antibiotics, 16.262 Immunologic allergic reactions, antibiotics, 23.251 angio-edema, ACE inhibitors, 22.225 autoimmune disease, Lyme disease vaccine, 24.366 cocamidopropylbetaine, 19.151 contrast agents, 20.422 corticosteroids, 21.158 cosmetics, 16.150, 19.151 co-trimoxazole, 20.264 desensitization, penicillin, 23.252 Euxyl K 400, 16.150 fragrances, 20.149 methyldibromoglutaronitrile, 16.150, 19.151 ocular drugs, 21.486 propolis, 17.181 red man syndrome, 17.312 Infection risk AIDS, polio vaccine, 23.352 total parenteral nutrition, 22.379 Body temperature malignant hyperthermia, 18.112 Death antiepileptic drugs, 23.83 calcium antagonists, 22.214 ecstasy, 24.32 lithium, 19.14 opiates, 25.37 Drug tolerance antibiotic resistance, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 25.279 opioids in neonates, 23.97 Carcinogenicity alcohol/vitamin A/beta-carotene, 24.442

Cumulative index of special reviews, Annuals 16–25 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474 growth hormone, 23.468 omeprazole, 16.423 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424 Use in pregnancy affective disorders in, 21.17 antibiotics and the pill, 24.274 beta-lactams, 25.280 opioids, 24.102 tetracyclines, 25.280 vitamin A, 21.405 Teratogenicity tretinoin, topical, 18.164 Fetotoxicity cocaine, 20.24 indomethacin, 18.102 Risk factors children, NSAIDs, 19.96 intensive care, muscle relaxants, 19.140 neonatal complications, indomethacin, 18.102 ocular drugs, 22.507

xxi old age, vitamins, 22.431 preterm infants, beta-lactam antibiotics, 21.258 Drug administration dosage regimens, aminoglycosides, 23.264 formulations, oral contraceptives, 24.472 inhaled corticosteroids, systemic availability, 24.185 labeling problems, cosmetics, 22.159 Drug overdose digitalis, charcoal, 24.201 paracetamol, 23.117 Drug interactions alcohol/vitamin A/beta-carotene, 24.442 antibiotics/the pill, 24.274 antifungal azoles, 24.318 grapefruit juice, 23.519 HMG Co-A reductase inhibitors, 25.530 lithium, 16.13 lithium/specific serotonin reuptake inhibitors, 18.30 mibefradil, 23.210 specific serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Methods Post-marketing surveillance, 24.274

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How to use this book

THE SCOPE OF THE ANNUAL The Side Effects of Drugs Annual has been published every year since 1977. It is designed to provide a critical and up-to-date account of new information relating to adverse drug reactions and interactions from the clinician’s point of view. It complements the standard encyclopedic work in this field, Meyler’s Side Effects of Drugs, the 14th edition of which was published in November 2000. PERIOD COVERED The present Annual reviews all reports that presented significant new information on adverse reactions to drugs during 2001. During the production of this Annual, some more recent papers have also been included. SELECTION OF MATERIAL In compiling the Side Effects of Drugs Annual particular attention is devoted to publications that provide essentially new information or throw a new light on problems already recognized. In addition, some authoritative new reviews are listed. Publications that do not meet these criteria are omitted. Readers anxious to trace all references on a particular topic, including those that duplicate earlier work, or to cross-check an electronic search, are advised to consult Adverse Reactions Titles, a monthly bibliography of titles from about 3400 biomedical journals published throughout the world, compiled by the Excerpta Medica International Abstracting Service. SPECIAL REVIEWS The special reviews deal in more detail with selected topics, interpreting conflicting evidence and providing the reader with clear guidance. They are identified by the traditional prescription symbol and are printed in italics. This volume includes a Cumulative Index of Special Reviews (SEDA-16 to SEDA-25) and a list of the titles of the Special Reviews published in the current Annual. CLASSIFICATION OF DRUGS Drugs are classified according to their main field of use or the properties for which they are most generally recognized. In some cases a drug is included in more than one chapter (for example, lidocaine may be mentioned in Chapter 11 as a local anesthetic and in Chapter 17 as an antidysrhythmic drug). Fixed combinations of drugs are dealt with according to their most characteristic component. DRUG NAMES Drugs are usually dealt with under their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a fixed combination has a generic combination name (e.g. co-trimoxazole for trimethoprim + sulfamethoxazole) that has been used; in some cases brand names have been used instead.

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How to use this book

SYSTEM OF REFERENCES References in the text are tagged in an extended version of the tagging system that has been used in previous editions; the new tagging system is as follows: M: E: A: R: r: C: c: S:

A meta-analysis or other form of systematic review; An experimental study (animal or in vitro); An anecdote or set of anecdotes (i.e. case histories); A major review, including non-systematic statistical analyses of published studies; A brief commentary (e.g. an editorial or a letter); A major randomized controlled trial or observational study; A minor randomized controlled trial or observational study or a non-randomized study; Official (e.g. Governmental, WHO) statements.

The various editions of Meyler’s Side Effects of Drugs are cited in the text as SED-13, SED-14, etc.; the Side Effects of Drugs Annuals 1–25 are cited as SEDA-1, SEDA-2, etc. INDEXES Index of drugs: this index provides a complete listing of all references to a drug for which adverse effects and/or drug interactions are described. Index of adverse effects: this index is necessarily selective, since a particular adverse effect may be caused by very large numbers of compounds; the index is therefore mainly directed to adverse effects that are particularly serious or frequent, or are discussed in special detail; before assuming that a given drug does not have a particular adverse effect, consult the relevant chapters. American spelling has been used throughout, e.g. anemia, estrogen rather than anaemia, oestrogen.

SIDE EFFECTS OF DRUGS HISTORICAL ESSAY

From thalidomide to pharmacovigilance: a personal account David J. Finney∗ In the beginning After I had been totally out of contact with matters related to adverse reactions to drugs for several years, a chance meeting in the summer of 2002 with Dr Ralph Edwards, Director of the WHO Uppsala Monitoring Centre, brought me an invitation to speak at the forthcoming Conference of the International Society of Pharmacovigilance. As a biometrician without medical education, I found myself cynically wondering what facts and reasoning had governed medical practice before the currency of the now fashionable term “evidence-based medicine”. The essay that follows has been prepared from the talk that I gave at the Conference. The ancient but now discredited “Doctrine of Signatures”, espoused by Paracelsus as an accepted science, must through the ages have encouraged many a priest or doctor to compound a drug from leaves or flowers that bore some resemblance to an ailing bodily organ. As Nelson has concisely stated (1): “The Doctrine relies on the concept that like affects like. Hence plants designed by the Creator for man may be expected to bear each a sign pointing to their special use”. Were adverse reactions to such drug therapy uncommon? I believe that even in the eighteenth century the great Dutch physician Herman Boerhaave recorded serious harm occasionally resulting from standard well-intentioned medication. Yet not until the thalidomide crisis of ∗ David Finney, MA ScD, is Professor Emeritus of Statistics in the University of Edinburgh, UK.

the mid-twentieth century was there widespread public concern or determination to prevent similar tragedies in the future. I shall try to place the birth of pharmacovigilance in perspective with the history of this period. Ignorance will oblige me to place undue emphasis on my personal involvement: I hope to draw attention to a few of the people who have been important to the growth of this discipline, but inevitably I shall omit many worthy names. Inman has written an excellent account of early days in the UK, with much detail that is outside my own memory (2).

Early ideas An academic statistician with long experience in biometry, in 1962 I began my only period of sabbatic leave from university duties. I had accepted an invitation to spend a year in the Statistics Department of Harvard University. I took with me a need to benefit from Harvard’s superior computing facilities in order to advance my research into a problem related to plant breeding. For reasons that are no longer important, my hosts had arranged that for about half my time I should occupy a room in the Department of Preventive Medicine. In one of my first conversations with David D Rutstein, then Professor of Preventive Medicine, he said that he hoped that I could produce ideas on how statisticians might contribute to the early detection of dangers like the thalidomide problem that was then alarming the medical world. At that time, I had never heard of

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xxvi thalidomide or its effects, but Dave referred me to several publications. I read the reports from McBride in Sydney and Lenz in Hamburg. I was fortunately able to visit Frances Kelsey of FDA, whose suspicions had ensured that thalidomide never became a disaster in the USA. I soon began to embody preliminary suggestions in a short paper (3). Naive though these first notions were, Rutstein saw promise in them; he, Louis Lasagna, and others encouraged me to develop proposals in greater detail and to present them in a more formal memorandum. After some months, Rutstein urged me to distribute this memorandum to a selection of national and international health authorities. I had drafted no blueprint for pharmacovigilance, only a common-sense presentation of logical principles, with an outline of how these might be implemented. At a time when noone else had attempted to take a comprehensive view of the general problem, my ideas proved useful; in addition to my private distribution, early publication followed (4, 5). I saw the need for adoption of a terminology that would give precision to discussion of such data as might be collectable and to the kinds of logical inference that could be supported. A subsequent fuller published version (6) has been quite widely quoted. From the earliest days, I have argued that the problem is international and needs to be handled through internationally coordinated sharing of information (7–9). By the 1960s, the stimulus of Bradford Hill and his colleagues was enabling much clinical research to achieve the standards of experimental design and objective statistical assessment that were then expected in non-medical biological research. It was evident that data collectable on adverse reactions would never have the objectivity, mutual independence, and freedom from bias that, as an experienced biometrician, I expect from the records of good wellplanned experiments. Here the word “bias” has the statistician’s sense of a systematic departure of observations from the intended truth, possibly because of faulty instrumentation or unavoidable subjectivity of judgment, and not as implying any reprehensible wish to deceive. Recognition of this was a step on my road to what has become a firmly held belief (10): when faced with a problem of vital importance

David J. Finney

to public health and welfare, and despite severe imperfections in the only available data, a statistician may have an ethical duty to cooperate in cautiously turning whatever relevant skills he possesses to the extracting and interpretation of any usable information.

British drug safety In 1963, the UK Ministry of Health invited Professor Sir Derrick Dunlop to head a new agency, the Committee on Safety of Drugs (CSD), which would advise on measures for the future protection of the community against adverse reactions to therapeutic drugs. One important need was the introduction of a system for the licensing of new drugs. The CSD was to have only a small central medical and administrative Secretariat, but its operations would depend on suitable academics and others who could make their special skills available. This typically British pattern of the quango (Quasi-Autonomous Non-Governmental Organization) was later to be much criticized by political malcontents, but I believe that in this and many other instances it was a successful method of obtaining enthusiastic but normally unpaid help from diverse experts, who would not have been attracted by offers of full-time government employment. From among medical scientists, Dunlop assembled a complex of subcommittees to support his vision for the CSD. At the time I did not know Dunlop, but presumably he had seen my memorandum and thought that I might be helpful to the Subcommittee on Adverse Reactions, so beginning for me a period of over 30 years of fascinated involvement in this subject. The Ministry of Health had written (11) to every British doctor urging alertness to any suspicion that: “an untoward condition in a patient might be the result of drug treatment”. Dunlop hoped that, whether a drug had been prescribed by a physician or purchased over the counter, spontaneously submitted accounts of suspicions would come to the CSD for study by the Adverse Reactions Subcommittee. Reports soon began to reach us. Our first chairman, Professor Leslie Witts, proved an inspiring leader for a group of enthusiasts who, argumentative and often frustrated by bureaucracy, worked well together at learning how to handle their task. Initially we were much helped by Roy Goulding,

From thalidomide to pharmacovigilance: a personal account

who, as Director of the National Poisons Information Service, had valuable experience in handling anecdotal medical evidence. In 1964, Dunlop appointed Dr WHW Inman as a Senior Medical Officer in the CSD Secretariat. This fortunate choice gave Bill, as he was soon known to all, special responsibilities in respect of adverse reactions. We of the Subcommittee were industrious, enthusiastic, and aware of the need to avoid the fallacy of “post hoc ergo propter hoc”, but lacking any formal procedures that could aid interpretation of the suspicions reported to us. During several years, the papers distributed as agenda for each of our regular meetings included standardized listings of all recent reports. These we would scan in advance, noting apparent anomalies or confirmations of previous indications that would need careful scrutiny when we met; a few days later, physicians and pharmacologists would discuss the inherent plausibility of drug causation for each serious suspicion, while my role was more to search for patterns or to play devil’s advocate, by suggesting how an apparent cluster of cases might have resulted from the subjective judgments of the reporting doctors. One evident need was to have a standardized pattern of reporting, rather than informal letters. Inman saw that all practising physicians ought to be encouraged to act promptly, by having on their desks a supply of standard forms on which they could enter the minimal set of relevant facts. He redesigned prototypes already under trial and developed the yellow card that soon became recognized as the main instrument of reporting. The CSD realized that responsible reporting could prove a burden to general practitioners; the cards were therefore made selfsealing and free of postal charges. Although the subsequent 30 years have seen the yellow card undergo many changes and improvements in order to provide fuller information, I believe it to be still the main form of data input to the UK monitoring system.

WHO involvement From the start, my own belief had been that, because the drug industry was a world-wide force, effective action for safety needed international coordination. Late in 1963, I was able

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to visit Geneva in order to talk with Dr Hans H. Halbach of the WHO, who was then facing a novel and difficult task: “In 1962, as a direct consequence of the thalidomide tragedy, it was requested by the Member States that WHO should initiate an international programme for exchanging information on safety and efficacy of drugs” (12). However, there were no guidelines on how to interpret and comply with this request. Hence, despite its evident weaknesses, my memorandum came at a fortunate moment: Halbach quickly became a strong advocate of studying and trying to use its suggestions. The next year saw the first of a long series of small meetings convened by, or associated with, the WHO for the development of international standardized reporting and dissemination of information. Most were held in Geneva, but others were in Washington and Honolulu. Relevant experts and others with national responsibilities for drug safety met for intensive discussion of ways and means. During long days, we argued vigorously but constructively in the quest for ways of creating a viable international centre. WHO secretaries went far beyond their normal duties by working long hours to keep us supplied with successive revisions of daily documents, and even to ensure immediate delivery of drafts to Geneva hotels. In retrospect, I am amazed at how well the ever-changing small group worked together, without pressing special national interests, and even coping with the emotional stress for a Czech and a Russian colleague on the morning that brought news of the USSR army’s entry into Prague. Disagreements scarcely went beyond friendly joking about Ed Napke’s somewhat extravagant claims for the superiority of his pigeon-hole system (13). Today, I sometimes wonder whether Napke’s ability to make rapid visual survey of his accumulated reports might not sometimes be a more effective safeguard than the statistically sophisticated procedures now sometimes advocated without the assurance that they are appropriate to the type of data available. An early realization was the need for a comprehensive dictionary of possible adverse reactions, a purpose for which the existing International Classification of Diseases was too restricted. In excellent cooperation, Inman and Barbro Westerholm of Sweden worked to produce this dictionary. With the benefit of input

xxviii from many who were now operating a diversity of monitoring programmes in their own countries—notably James Crooks of the UK, Juhana Idänpään-Heikkilä of Finland, Garth McQueen of New Zealand, Ronald Meyboom of the Netherlands, and Arthur Ruskin of the USA—our meetings produced advice for Halbach on the creation of a WHO coordinating centre. Encouraged and helped by the USA Food and Drug Administration, a feasibility trial in Virginia gave this a start. In the 1960s, transatlantic data transmission facilities were far from ideal and effective operation was not easy. In 1970, this centre was moved to a more permanent home in Geneva, where it was first directed by Bruce W Royall with valuable assistance from Margaretha Helling and Jan Venulet. Such a novel operation could not become firmly established without time for growth and evolutionary adaptation to its practicability; during the 1970s, however, the WHO was unable to support this growth with adequate staffing and equipment. In 1978, the WHO gratefully accepted an invitation, first suggested by Professor Åke Liljestrand, with support from the Swedish Government, to move the centre to Uppsala. Thus was created the WHO Uppsala Monitoring Centre.

Adverse events From my time at Harvard, I had sensed the need for language and terminology that would facilitate objective discussion of evidence. It was natural for a statistician to be unhappy with the subjectivity of reports that originated in suspicion, not fact. Clearly there could be no question of imposing on physicians a legal requirement to report adverse reactions. Nothing in an episode of jaundice or agranulocytosis or thrombosis announces itself as having been caused by a drug taken 2 weeks previously. A natural reaction for a statistician was to propose that more informative data would be obtained if a cohort of patients beginning to take a nominated drug could be identified and their subsequent medical history recorded in respect of all events of medical importance (14, 15). I think that this suggestion (6) may have been the first introduction of the term “event” in pharmacovigilance. I also stressed (16, 17)

David J. Finney

the need to keep careful account of how patients who experienced adverse events were detected for inclusion in monitoring files. Special difficulties may arise in respect of adverse reactions, such as carcinogenesis, that are detectable only from events that by their nature may be unobservable until long after their cause; I hope that by now there has been much thought given to this type of problem (18). Hershel Jick and his Boston colleagues thought along lines similar to mine, when they planned studies that defined a cohort as a set of admissions to a chosen hospital, thereafter recording each patient’s subsequent history in respect of drugs received and all events or incidents of medical importance. This facilitated the examination of associations between a drug and objectively recorded patient experience, free from any prejudice involving initial suspicion of drug causation. A new Act of Parliament replaced the CSD by the Committee on Safety of Medicines (CSM); this may have meant little change in purpose and duties, but in our Subcommittee it certainly made bureaucracy more evident. Inman had long struggled for improvements in the data-gathering process, but he could not gain official support. Frustrated by indifference and refusal to think ahead, in 1980 he resigned from his position with the CSM Secretariat. By great determination, he obtained minimal financial backing and fortunately found in the University of Southampton a willingness to help him start what was to become the Drug Safety Research Unit (DSRU). From among his personal contacts, he found a small group to join this enterprise as an advisory committee, and eventually to become trustees of what was constituted as a charity (19, 20). I was one of these from the start until 1997. Despite continuing financial stresses, we firmly maintained a principle that Inman saw as vital, namely a refusal to undertake any study sponsored by the pharmaceutical industry, lest loss of independence should in any way constrain our freedom to investigate and publish. The DSRU adopted my idea of defining a cohort as consisting of all persons for whom a named drug is prescribed and then seeking to record a subsequent event history for each of them. Unknown to me until very recently, as early as 1977 in New Zealand, Garth McQueen had been trying a similar procedure that

From thalidomide to pharmacovigilance: a personal account

would later become known as “PrescriptionEvent Monitoring” (PEM). In implementing its form of PEM, the DSRU was able to use a special feature of the British National Health Service. With cooperation from the national agency responsible for handling individual prescription costs, access is possible to all prescriptions of a named drug during a stated period of time. The prescribing physicians can then be asked to provide, in confidence of course, information on events experienced by each patient. For this purpose (21), an event is defined as: “any new diagnosis, any reason for referral to a consultant or admission to hospital (e.g. operation, accident, or pregnancy), any unexpected deterioration (or improvement) in a concurrent illness, any suspected drug reaction, or any other complaint which was considered of sufficient importance to enter in the patient’s notes”. In 1991, a House of Lords committee, with a membership that included several eminent medical scientists, recommended (22) “that the Commission considers the use of Prescription Event Monitoring throughout the [European] Community. Its method of in-depth analysis of a carefully selected group of new products on the basis of data from a large random sample seems both effective and well adapted for Community policy”. Inman had estimated that PEM would cost about £150 000 per drug, a small expense relative to development costs, but apparently this strongly worded recommendation has been ignored.

Computers Today, any medical scientist faced with an accumulating collection of individual case records immediately thinks of entering each into a computer database designed for easy retrieval or later statistical study. Few scientists still under the age of 50 realize that in the mid 1960s this was not possible. During those years, as a member of the UK Computer Board, and for four years its Chairman, I was closely involved in efforts to ensure that every British university had access to a mainframe computer. The Board’s funding related almost solely to the demands of number-crunching for scientific research, with no provision for holding administrative records or handling the communication

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and text-processing tasks that form so large a part of the life of a computer in AD 2003. My first involvement in drug monitoring led me to think of this new subject as a form of operational research. I saw it as demanding imaginative new software for data retrieval and analysis associated with the then rapidly evolving computer technology. I considered the needs to be similar to those of a detective agency responsible for scanning miscellaneous imperfect records for evidence on previously unsuspected crimes (23, 24). Initially, the CSD had no computer support. Inman would transfer the information on each yellow card to a special type of index card; he classified and sorted packs of these by ingenious manipulation of knitting needles pushed through holes in the card edges. This “advanced technology” sufficed for his early successes in using retrospective case-control techniques to understand adverse reactions to oral contraceptives. The total number of stored records soon necessitated better systematic processing of summaries, which could be debated in subcommittees or possibly become the basis for discussion with a drug manufacturer. After a few years, the CSD secured some rights of use on a computer far from London. Each new access of data had to be transported to it by road; if we were lucky, standard tabulations would return to London in time for regular meetings of our Subcommittee. Improvement was slow. The CSM repeatedly inquired into the possibility of obtaining a small computer dedicated to its varied needs, by that time, scarcely an extravagant proposal. In 1980, at almost the last meeting I attended, a civil servant told me firmly that Subcommittee members had no right to be told anything about progress of negotiations on a request for a computer. Inman and I have always been sceptical about applying formal statistical significance tests to an accumulation of records of suspected adverse reactions. Such tests are incorporated into the clever software now readily available on most standard computers, tempting uncritical use by every medical scientist without questioning whether inherent assumptions are satisfied. Nevertheless, discussion on problems met within the CSD encouraged me to try to specify acceptable uses of standard statistical test procedures (25–28). Independently Inman empirically devised an ingeniously simple test of

xxx whether reports of a specific event are more frequent than a natural background rate. Under plausible assumptions of randomness such as seem appropriate to PEM, Andrew et al. have shown a theoretical basis for this “T1/T2 Test” (29). Once a monitoring system has all its data systematically stored within a computer, the computer can be instructed to maintain a continuous watch on a selected measure of association between a drug and a type of event, and to output a warning signal if that measure goes beyond a critical threshold. Napke advanced ideas on this with reference to his pigeon-hole data store (30), and in an internal WHO report, Patwary described another possibility (31). I reviewed the signalling problem more completely (32), but later years have seen many more developments. A modern computer will have no difficulty in checking the value of the chosen measure after each new case enters the database; output of a signal, however, is not in itself proof of adverse reaction to a drug, only a warning that an association merits closer study.

David J. Finney

the raw data was essential. Individual acknowledgment of every report received was scarcely needed, but I believed that the CSD ought to have done more than it did to interact with doctors and the public (33, 34). If we are to have a flow of therapeutic improvements by the introduction of new drugs, adverse reactions that could not have been predicted by a pharmacologist nor always observed during the routine of clinical trials will inevitably sometimes occur. I have emphasized (35) the importance of regular communication between a national monitoring agency, the drug industry, doctors, and the public, in order to increase understanding of problems that are common to all. From early in the life of the DSRU, Inman distributed to all collaborating doctors successive issues of PEM NEWS, booklets filled with information on the studies planned or in progress. I hope that today other drug monitoring operations have analogous practices of feedback.

Language Feedback to doctors and public Within the CSD, when the Adverse Reactions Subcommittee found strengthening evidence of a causal link between a drug and a potentially dangerous reaction, discussion would intensify, aided by consultation with all relevant levels of expertise and possibly with the manufacturer’s technical experts. If the main Committee became convinced that the link was genuine, much attention was given to drafting and distributing a suitable warning. Because this would go to all doctors and would of course reach the public press, avoidance of unduly alarmist tones was important. Errors of judgment were inevitable, but I think that the CSD managed this responsibility well. Whether for a national monitoring agency, or for the Boston hospital studies, or the type of work undertaken by the DSRU, the quality and completeness of the reports on which all inference depends requires the willing cooperation of busy men and women. From early days, I had thought that systematic feedback of information to the medical professionals who provided

I have emphasized the importance to pharmacovigilance of using unambiguous terminology. Inaccurate use of words is today a disease that afflicts speech and writing about quantitative statements in the news media, in popular journalism, and increasingly even in serious technical writing. It may be primarily an Anglophone phenomenon, but it needs to be noted and avoided by all who write on any topic for an international readership. I shall comment on examples from my large collection of horrors. One cause may lie in educational principles, acceptance of a doctrine that creative use of language is inhibited by any insistence on verbal precision. Among a younger generation, the correct words for simple arithmetical operations have almost disappeared because no longer taught, so that even “divisor”, “numerator”, “product”, and “quotient” are unknown; in speech, one may hear a simple multiplication described by a non-existent verb: “I timesed [sic] 15 by 12”. A similar fate has befallen basic grammatical terms, so that “adverb” and “conjunction” cease to be recognized as elements of sentence construction. Is it mere outdated pedantry to regret these losses and object to the consequential errors?

From thalidomide to pharmacovigilance: a personal account

A more damaging source of scientific confusion, not limited to pharmacovigilant or epidemiological contexts, is the frequent miscalculation of percentages in consequence of failure to distinguish numerator and denominator, or to recognize what either quantity represents. Thus, one can find a biologist summarizing an experiment by stating: “The mean weight of the treated animals was reduced by 122%”, and I have recently read that: “Migraines affect approximately 14% of women and 7% of men; that’s one fifth of the population”. In similar vein, a newspaper reported that: “70% of what we die from is the foods we eat” and even the astounding: “Men commit suicide four times more often than women”. Anyone who cannot think more coherently than those who penned these statements would be wise to write in such a way as to avoid all mention of percentages. On any topic that involves probabilistic inferences, one can find journalists and senior scientists writing as though “chance”, “likelihood”, “odds”, “probability”, and “risk” are synonymous. In a serious report of recent medical research, I have read: “If a woman is on HRT and has one of these clotting factors, her chance of having a DVT is increased 80 times”, and elsewhere I found: “The smoking of cannabis increases by five times the risk of dy-

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ing from heart attack in middle age”. Such statements leave uncertain whether “chance” and “risk” are intended as synonyms for probability (in an unspecified population); if they are, multiplications by 80 or 5 may produce some implausible values! I do not imply that pharmacovigilantes are especially liable to the making of such errors: what is important is that they become alert to the danger that the quality of data they must interpret and the meaning of articles they read may be contaminated by adverse effects from those who report numbers ambiguously or meaninglessly. We live in a world that depends critically on numerical facts. Do we need a campaign to eliminate from science and technology the kind of faults that I have illustrated?

Acknowledgments Without the stimulus of Ralph Edwards, this essay would never have existed, but its content owes far more to Bill Inman for years of enjoyable cooperation and for his recent help in recalling important facts and names. This essay is based on a lecture given to the International Society of Pharmacology in Amsterdam, 2002.

REFERENCES 1. Nelson, A. Medical Botany. Edinburgh: E & S Livingstone Ltd, 1951. 2. Inman WHW. Don’t Tell The Patient. Los Angeles: Highland Park Publications, 1999. 3. Finney DJ. An international drug safety program. J New Drugs 1963; 3: 262–5. 4. Finney DJ. An international drug safeguard plan, J Chron Dis 1964; 17: 565–81. 5. Finney DJ. Le contrôle des medicaments et la securité des medicaments. Biométrie-Praximétrie 1964; 5: 3–19. 6. Finney DJ. The design and logic of a monitor of drug use. J Chron Dis 1965; 18: 77–98. 7. Finney DJ. A gyögyszerek pályafutasá. Gyögyszereink 1971; 21: 337–48. 8. Finney DJ. Adverse reactions to therapeutic drugs [in Japanese]. 1977; 29: 706–12. 9. Finney DJ. Theoretical objectives of international collaboration. In: Gross H, Inman WHW (editors). Drug Monitoring. London: Academic Press, 1977: 207–18.

10. Finney DJ. Problems, data, and inference. J R Stat Soc 1974; A137: 1–23. 11. Ministry of Health. Safety of Drugs: An Invitation to all Medical Practitioners. London: Her Majesty’s Stationery Office, 1964. 12. Dunne JF. The World Health Organization, In: Inman WHW (editor). Monitoring for Drug Safety. Lancaster: MTP Press, 1985: 165–72. 13. Napke R. Canada. In: Inman WHW (editor). Monitoring for Drug Safety. Lancaster: MTP Press, 1985: 59–69. 14. Finney DJ. Statistical logic in the monitoring of reactions to therapeutic drugs. Proceedings of the Fourth Conference on Probability Theory, Brasov, 1973: 91–2. 15. Finney DJ. The detection of causation of adverse events. Proceedings of the 39th Session of the International Statistical Institute, 1973; 1: 387–94. 16. Finney DJ. The vital statistics of a drug. Biomet Z 1966; 8: 15–31.

xxxii 17. Finney DJ. Monitoring adverse reactions to drugs—its logic and its weaknesses. Proc Eur Soc Study Drug Tox 1966; 7: 198–207. 18. Finney DJ. Statistical problems in detecting the late consequences of therapy. Cancer 1976; 37: 1226–32. 19. Finney DJ. Statistical aspects of pharmacoepidemiology. Drug Inf J 1996; 30: 987–90. 20. Finney DJ. Postmarketing studies: the work of the Drug Safety Research Unit. Drug Saf 1999; 21: 337–38. 21. Inman WHW, Hawson HSA, Wilton LV. Prescription event monitoring. In: Inman WHW (editor). Monitoring for Drug Safety. Lancaster: MTP Press, 1985: 213–35. 22. House of Lords Select Committee on the European Community. European Medicines Agency and Future Marketing Authorisation Procedures. London: Her Majesty’s Stationery Office, 1991. 23. Finney DJ. Statistical techniques, medicine, and computers. Trab Estadist Invest Operat 1965; 16: 43–61. 24. Finney DJ. Reporting and interpreting adversities that follow drug administration. In: Ducrot H, Goldberg M, Hoigné H, Middleton P (editors). Computer Aid to Drug Therapy and Drug Monitoring. Amsterdam: North-Holland Publishing Company, 1978: 109–14. 25. Finney DJ. Statistical aspects of monitoring for dangers in drug therapy. Methods Inf Med 1971; 10: 1–8. 26. Finney DJ. Statistical logic in the monitoring of reactions to therapeutic drugs, Methods Inf Med 1971; 10: 237–45.

David J. Finney 27. Finney DJ. Statistical aspects of monitoring systems. In: Gent M, Shigematsu I (editors). Epidemiological Issues in Reported Drug-Induced Illnesses—SMON and Other Examples. Hamilton, Ontario: McMaster University Library Press, 1978: 32–39. 28. Finney DJ. Drugs, adverse reactions, and patients. In: Gent M, Shigematsu I (editors). Epidemiological Issues in Reported Drug-Induced Illnesses—SMON and Other Examples. Hamilton, Ontario: McMaster University Library Press, 1978: 311–18. 29. Andrew JE, Prescott P, Smith TMF, Inman WHW, Kubota K. Testing for adverse reactions using Prescription Event Monitoring. Stat Med 1996; 15: 987–1002. 30. Napke E. Drug Adverse Reaction Alerting Program. Can Pharm J 1968; 29: 251–4. 31. Patwary KW. Report on Statistical Aspects of the Pilot Project for International Drug Monitoring. Geneva: World Health Organization, 1969. 32. Finney DJ. Systematic signalling of adverse reactions to drugs. Methods Inf Med 1974; 13: 1–10. 33. Finney DJ. The detection of adverse reactions to therapeutic drugs. Stat Med 1982; 1: 153–61. 34. Finney DJ. Report–Record–Detect–Interpret– Inform. In: Boström H, Ljungstedt N (editors). Detection and Prevention of Adverse Drug Reactions. Skandia International Symposia. Stockholm: Almqvist & Wiksell International, 1984: 121–32. 35. Finney DJ. Drugs and patients: thoughts on communication. Adv Drug React Bull 1976; 56: 192–5.

SIDE EFFECTS OF DRUGS ESSAY

How safe is cannabis? Leslie Iversen∗ Enthusiasm for cannabis in the 1960s and early 1970s was rapidly followed by a wave of reaction in the Western world. Extravagant warnings were issued, suggesting that cannabis was a highly dangerous drug that could cause chromosomal damage, impotence, sterility, respiratory damage, depressed immune system responses, personality changes, psychosis, and permanent brain damage (1R , 2S ). Most of these claims were later proved to be spurious, and balanced reviews (3R –5R ) have shown how effectively many of them have been demolished. Currently cannabis is widely perceived to be relatively safe. Many people believe that there are genuine medical uses for cannabis-based medicines (6R , 7R , 8RS ), and it seems likely that such products will gain official approval in several Western countries. At the same time there is a move towards relaxation of the criminal penalties associated with the recreational use of cannabis, ranging from a proposed downgrading of criminal penalties in the UK to the possibility of full legalization in Canada and Jamaica. In the light of these changes in attitude it is timely to consider again the adverse effects that are associated with the use of cannabis, since no drug can ever be considered completely safe.

Animal toxicology 9 -Tetrahydrocannabinol (THC), the active component in herbal cannabis, is very safe. Laboratory animals (rats, mice, dogs, monkeys) can tolerate doses of up to 1000 mg/kg, equivalent to some 5000 times the human intoxicant dose. Despite the widespread illicit use ∗ Leslie Iversen is Visiting Professor of Pharmacology in the University of Oxford.

of cannabis, there are very few if any instances of deaths from overdose (9R ). Long term toxicology studies with THC were carried out by the National Institute of Mental Health in the late 1960’s (10ER ). These included a 90-day study with a 30-day recovery period in both rats and monkeys and involved not only 9 -THC but also 8 -THC and a crude extract of marijuana. Doses of cannabis or cannabinoids in the range 50–500 mg/kg caused reduced food intake and lower body weight. All three substances initially depressed behavior, but later the animals became more active and were irritable or aggressive. At the end of the study the weights of the ovaries, uterus, prostate, and spleen were reduced and the weight of the adrenal glands was increased. The behavioral and organ changes were similar in monkeys, but less severe than those seen in rats. Further studies were carried out to assess the damage that might be done to the developing fetus by exposure to cannabis or cannabinoids during pregnancy. Treatment of pregnant rabbits with THC at doses up to 5 mg/kg had no effect on birth weight and did not cause any abnormalities in the offspring (10ER ). A similarly detailed toxicology study was carried out with THC by the National Institute of Environmental Health Sciences in the USA, in response to a request from the National Cancer Institute (11E ). Rats and mice were given THC up to 500 mg/kg 5 times a week for 13 weeks; some were followed for a period of recovery over 9 weeks. By the end of the study more than half of the rats treated with the highest dose (500 mg/kg) had died, but all of the remaining animals appeared to be healthy, although in both species the higher doses caused lethargy and increased aggressiveness. The THC-treated animals ate less food and their body weights were consequently significantly lower than those of untreated controls

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xxxiv at the end of the treatment period, but returned to normal during recovery. During this period the animals were sensitive to touch and some had convulsions. There was a trend towards reduced uterine and testicular weights. In further studies rats were treated with doses of THC up to 50 mg/kg and mice with up to 500 mg/kg 5 times a week for 2 years in a standard carcinogenicity test (11E ). After 2 years more treated animals had survived than controls, probably because the treated animals ate less and had lower body weights. The treated animals also had a significantly lower incidence of the various cancers normally seen in aged rodents, in testes, pancreas, pituitary gland, mammary glands, liver, and uterus. Although there was an increased incidence of precancerous changes in the thyroid gland in both species and in the mouse ovary after one dose (125 mg/kg), these changes were not doserelated. The conclusion was that there was “no evidence of carcinogenic activity of THC at doses up to 50 mg/kg”. This was also supported by the failure to detect any genetic toxicity in other tests designed to identify drugs capable of causing chromosomal damage. For example, THC was negative in the so-called “Ames test”, in which bacteria are exposed to very high concentrations of a drug to see whether it causes mutations. In another test, hamster ovary cells were exposed to high concentrations of the drug in tissue culture; there were no effects on cell division that might suggest chromosomal damage. By any standards, THC must be considered to be very safe, both acutely and during longterm exposure. This probably partly reflects the fact that cannabinoid receptors are virtually absent from those regions at the base of the brain that are responsible for such vital functions as breathing and blood pressure control. The available animal data are more than adequate to justify its approval as a human medicine, and indeed it has been approved by the FDA for certain limited therapeutic indications (generic name = dronabinol) (9R ).

Acute adverse effects of cannabis Psychoactive effects Of all the immediate actions of cannabis, its psychoactive effects are

Leslie Iversen

undoubtedly those that give the greatest concern in considering its medical uses (7R , 8RS , 10ER ). All of the CNS effects of THC, both the desired medical actions and the undesired psychological effects, appear to be mediated through a single type of brain receptor, the CB1 cannabinoid receptor. This was illustrated, for example, by a well-controlled study in 63 healthy cannabis users, who received either the CB1 receptor antagonist rimonabant (SR141716A) or placebo and smoked either a THC-containing or a placebo marijuana cigarette (12C ). Rimonabant blocked the acute psychological effects of the active cigarettes, but when given alone (with placebo cigarettes) produced no significant psychological effects. In many of the medical applications that have been assessed to date, unwanted psychological adverse effects have been blamed as the main cause of patients’ rejection of the drug as unacceptable. Patients who have had no prior experience with cannabis often find its intoxicant effects disturbing, and it can cause panic/anxiety attacks in such people. Others may simply not want to be “high” when they go about their daily work. The deleterious effects of cannabis on short-term memory and other aspects of cognition make it especially unacceptable for those whose occupation depends on an ability to remain alert and capable of handling and processing complex information. The medicinal use of cannabis often involves oral administration, but absorption is slow and erratic, leading to the risks of overdosage or underdosage. For this reason smoking is the preferred route of administration, but it carries its own hazards (see below). If improved delivery systems could be devised, it is likely that patients could titrate optimum doses of the drug to avoid some of these unwanted effects, but the therapeutic window between a medically effective dose and an intoxicant one is narrow. A possible acceptable alternative to smoking may be to give cannabis by means of a sublingual spray, and this is currently being tested in clinical trials (13S ). Psychomotor impairment CB1 receptors are expressed in particularly high densities in the basal ganglia and cerebellum, so it is not surprising that cannabinoids have complex effects on psychomotor function (14R ). One of the earliest reports of the effects of cannabis extracts in experimental animals described an awkward

How safe is cannabis?

swaying and rolling gait in dogs, with periods of intense activity provoked by tactile or auditory stimuli, and followed eventually by catalepsy and sleep (15E ). In mice a “popcorn effect” was described: the animals are sedated by THC but will jump in response to auditory or tactile stimuli; as they fall into other animals these in turn jump, resembling popping corn (16R ). These effects of cannabinoids may be due in part to actions at cerebellar or striatal receptors. Tests of specific cerebellar functions have shown that cannabinoids increased gait width and the number of slips on a bar cross test (17E ). Rotorod impairments were also reported in mice after direct injection of synthetic cannabinoids into the cerebellum, but not in animals pretreated with cerebellar injections of an antisense oligonucleotide directed at a sequence in the CB1 receptor (18E ). In humans cannabis caused impaired performance in tests of balance (19E ) or tests that require fine psychomotor control, for example tracking a moving point of light on a screen (20E ). Human cannabis users may also seek isolation and remain immobile for long periods (21R ). Because psychomotor skills are impaired by cannabis intoxication, it is inadvisable for users to drive for some hours after taking the drug, and the ability to carry out any tasks that require manual dexterity is likely to be impaired. Druginduced impairment of balance could also make elderly patients more likely to fall. A comparison of 452 marijuana smokers with a similar number of non-smokers attending the Kaiser Permanente Health Group in California showed that the marijuana smokers had an increased risk of attending out-patient clinics with injuries of various types, perhaps as a result of the acute intoxicant effects of the drug (22C ). Effects on memory One of the well-established effects of acute intoxication with cannabis in man is impairment of short-term memory (21R , 23R –25R ). Many studies have shown significant effects on short-term memory, particularly when tests were used that depend heavily on attention (26E , 27R ). In animals THC, synthetic cannabinoids, and anandamide cause deficits in short-term memory in spatial learning tasks (28ER ). These include delayed matching or non-matching tests in rodents (29E , 30E ), performance in a maze (31E ,

xxxv 32E ), and a fixed-ratio food acquisition task in squirrel monkeys (33E ). The effects of both cannabinoids (32E ) and anandamide (30E ) were reversed by rimonabant, showing that they are mediated by the CB1 receptor. A likely site for these effects is the hippocampus: the effects of cannabinoids on shortterm memory in rats were the same as the effects seen after surgical removal of the hippocampus (29E ). In each case the animals were unable to segregate information between trials in the task because of disruptions to the processing of sensory information in hippocampal circuits. CB1 receptors are expressed in high density in the hippocampus (34E , 35E ) and the mechanisms underlying synaptic plasticity have been studied more intensely in the hippocampus than in any other brain region. In particular the electrophysiological phenomena of longterm potentiation and long-term depression are thought to be involved in memory formation at glutamatergic synapses in the hippocampus. Several studies have shown that cannabinoids inhibit the induction of both long-term potentiation and depression (36R ). Cannabinoids appear to work by reducing glutamate release below the level needed to activate NMDA receptors, a requirement for long-term potentiation and depression (37E , 38E ). Effects on other cognitive functions Like other intoxicant drugs, cannabis causes profound changes in a variety of higher brain functions (9R , 21R , 23R , 25R ). The distribution of CB1 receptors in the neocortex has been described in detail (39E , 40E ). The earlier literature contained several reports of the effects of acute and chronic cannabis use on EEG activity, both in animals (16R ) and man (25R ). Most studies in man have shown EEG changes consistent with a state of drowsiness, with increases in relative and absolute alpha power, particularly in the frontal cortex. In contrast, the CB1 antagonist rimonabant caused EEG changes characteristic of arousal in rats and increased the time spent in wakefulness as opposed to sleep (41E ). There have been many studies of the acute and chronic effects of cannabis on human cognitive function (21R , 23R , 25R ). Performance in a variety of tests is impaired, but by comparison with alcohol the effects of cannabis are subtle. Whereas even moderate doses of alcohol impair

xxxvi reaction time, most studies of cannabis have failed to show consistent effects. Therefore, abnormal cognitive function due to cannabis cannot be due to an inability to respond promptly. Among the types of impairment of cognitive function that have been observed in many, but not all, human studies are: a reduced ability to inhibit responses, impaired vigilance, especially for long and boring tasks, reduced ability to perform complex mental arithmetic, and impairment in tests of complex reaction times. On the other hand, intoxicated subjects can perform simple arithmetic, learn simple lists of words, and recall memories laid down earlier (21R ). Cardiovascular effects Cannabis has profound effects on the cardiovascular system. In inexperienced users it can cause a large increase in heart rate (up to a doubling) and this could be harmful to someone with a previous history of coronary artery disease or heart failure (3R , 4R , 9R ). Such patients should therefore be excluded from clinical trials of cannabis-based medicines. The postural hypotension that can be caused by cannabis could also be distressing or possibly dangerous. These cardiovascular effects usually show rapid tolerance on repeated exposure to cannabis, so for healthy subjects they are not of concern.

Effects of long-term exposure to cannabis Is cannabis neurotoxic? Although there have been claims that chronic cannabis use can permanently damage the brain, there is little scientific evidence to support this (3R , 4R , 5R , 42R ). Some studies have shown modest impairment of the ability to focus attention and filter out irrelevant information in ex-cannabis users (25R ), but other studies have failed to show any long-term impairment in cognitive function (43E ). There is little evidence that cannabis impairs work performance or leads to an “amotivational syndrome” (3R , 42R , 44R ). Nor is there any convincing evidence for neuropathological changes in the brains of cannabis users (3R ). The earlier studies have been complemented by the application of powerful modern neuroimaging methods. For example, in an MRI imaging study 18 current, young adult, frequent

Leslie Iversen

cannabis users were compared with 13 comparable non-users; there was no evidence of cerebral atrophy or regional changes in tissue volumes (45c ). Animal studies have yielded conflicting results. Treatment of rats with high doses of THC given orally for 3 months (46E ) or subcutaneously for 8 months (47E ) produced neural damage in the hippocampal CA3 zone, with shrunken neurons, reduced synaptic density, and loss of cells. But in perhaps the most severe test of all, rats and mice treated on 5 days each week for 2 years had no histopathological changes in the brain, even after 50 mg/kg/day (rats) or 250 mg/kg/day (mice) (11E ). Although claims were made that exposure of a small number of rhesus monkeys to cannabis smoke led to ultrastructural changes in the septum and hippocampus (48E , 49E ), subsequent larger-scale studies failed to show any cannabis-induced histopathology in monkey brain (50E ). Studies of the effects of cannabinoids on neurons in vitro have also yielded inconsistent results. Exposure of rat cortical neurons to THC shortened their survival: twice as many cells were dead after exposure to THC 5 µmol/l for 2 h than in control cultures (51E ). Concentrations of THC as low as 0.1 µmol/l had a significant effect. The effects of THC were accompanied by release of cytochrome c, activation of caspase-3, and DNA fragmentation, suggesting an apoptotic mechanism. All of the effects of THC could be blocked by the antagonist AM-251 or by pertussis toxin, suggesting that they were mediated through CB1 receptors. Toxic effects of THC have also been reported in hippocampal neurons in culture, with 50% cell death after exposure to THC 10 µmol/l for 2 h or 1 µmol/l for 5 days (52E ). The antagonist rimonabant blocked these effects, but pertussis toxin did not. The authors proposed a toxic mechanism involving arachidonic acid release and the formation of free radicals. On the other hand, other authors have failed to observe any damage in rat cortical neurons exposed for up to 15 days to THC 1 µmol/l, although they found that this concentration killed rat C6 glioma cells, human astrocytoma U373MG cells, and mouse neuroblastoma N18TG12 cells (53E ). In a remarkable study, injection of THC into solid tumors of C6 glioma in rodent brain led to increased survival times, and there was complete eradication of the tumors in 20–35% of

How safe is cannabis?

the treated animals (54E ). A stable analogue of anandamide also produced a drastic reduction in the tumor volume of a rat thyroid epithelial cell line transformed by K-ras oncogene, implanted in nude mice (55E ). The antiproliferative effect of cannabinoids has suggested a potential use for such drugs in cancer treatment (56R ). Some authors have reported neuroprotective actions of cannabinoids. WIN55,212-2 reduced cerebral damage in rat hippocampus or cerebral cortex after global ischemia or focal ischemia in vivo (57E ). The endocannabinoid 2AG protected against damage elicited by closed head injury in mouse brain, and the protective effects were blocked by rimonabant (58E ). THC had a similar effect in vivo in protecting against damage elicited by ouabain (59E ). Rat hippocampal neurons in tissue culture were protected against glutamate-mediated damage by low concentrations of WIN55,212-2 or CP-55,940, and these effects were mediated through CB1 receptors (60E ). But not all of these effects seem to require mediation by cannabinoid receptors. The protective effects of WIN55,212-2 did not require either CB1 or CB2 cannabinoid receptors in cortical neurons exposed to hypoxia (57E ), and there were similar findings for the protective actions of anandamide and 2-AG in cortical neuronal cultures (61E ). Both THC and cannabidiol, which is not active at cannabinoid receptors, protected rat cortical neurons against glutamate toxicity (62E ) and these effects were also independent of CB1 receptors. The authors suggested that the protective effects of THC might be due to the antioxidant properties of these polyphenolic molecules, which have redox potentials higher than those of known antioxidants (e.g. ascorbic acid). The mixed reports of neurotoxic and neuroprotective effects of cannabinoids are confusing. While it may be possible to show neurotoxic actions after exposure of neurons to high concentrations of cannabinoids in vitro, there is little evidence for any significant neural damage in vivo after the administration of pharmacologically relevant doses. Cannabis and psychiatric illness There is a long-standing concern that the use of cannabis might precipitate mental illness in some users. There was a lively correspondence in the columns of the British Medical Journal in 1893,

xxxvii for example, as to whether or not the endemic use of hashish in Egypt led to mania and insanity (63r –68r ). There was also concern that the mental asylums in British India were filling with cannabis-induced lunatics, and this was one of the factors that led the British Government to appoint the Indian Hemp Drugs Commission. The Commission undertook a large and painstaking review and concluded that there were virtually no patients in the Indian asylums whose illness could be attributed to cannabis use (69RS ). However, the Commission’s findings were not widely noted, and claims of a relation between cannabis use and insanity continued to be made in India and many other countries. Claims that cannabis causes insanity were used by early advocates of marijuana prohibition in the USA. A temporary form of drug-induced psychosis can occur in some cannabis users. In some of the psychiatric literature this is referred to as “cannabis psychosis” (or “marijuana psychosis”) (21R ). Research psychiatrists, particularly in Britain, have carefully studied this condition (70R –72R ). It nearly always results from taking large doses of the drug, often in food or drink, and may persist for some time, perhaps as the accumulated body load of THC is washed out. The acute toxic psychosis that is sometimes caused by cannabis can be sufficiently serious to lead to hospital admission, and the initial diagnosis can be confused with schizophrenia, with delusions of control, grandiose identity, persecution, thought insertion, auditory hallucinations, changed perception, and blunting of emotions. Not all of these symptoms will occur in every patient, but there can be a considerable similarity to paranoid schizophrenia. This has led some to propose a “cannabinoid hypothesis of schizophrenia”, suggesting that the symptoms of schizophrenic illness might be caused by abnormal overactivity of endogenous cannabinoid mechanisms in the brain (73R ). Several studies have addressed the more contentious question of whether cannabis can precipitate long-term psychiatric illness. The strongest evidence seemed to come from a Swedish study with detailed medical records and information about the social background and drug-taking habits of 45 570 conscripts on entry to the Swedish army at age 18 years and follow-up of their subsequent medical history over 15 years (74C ). A total of 4293 of the

xxxviii conscripts admitted having taken cannabis at least once, but the cannabis users accounted for a disproportionate number of the 246 cases of schizophrenic illness diagnosed in the overall group on follow-up. The relative risk of schizophrenia in those who had used cannabis was 2.4 times greater than in the non-users. And in the small number of heavy users (who had taken the drug on more than 50 occasions) the relative risk of schizophrenia increased to 6.0. The authors concluded that cannabis was an independent risk factor for schizophrenia. There have been other similar reports (71R , 72R , 75R ). Of 232 patients in Germany with first-episode schizophrenia, 13% had a history of cannabis use, a rate twice that of matched healthy controls (76C ). At first sight these findings seem convincing, but they do not prove a cause-and-effect relation with cannabis. It may be that both cannabis use and schizophrenia are related to some common predisposing factor, such as personality. Indeed, some psychologists and psychiatrists believe that they can identify psychological traits that are described as “schizotypy” and may predict an increased risk of clinical psychosis. Some studies in healthy adults have shown that those users of cannabis scored higher on schizotypy scales than non-users (77C , 78C ). Half of the cannabis-users in the original Swedish study (74C ) had used cannabis more than 10 times, and those who subsequently developed schizophrenia had also taken amphetamine, which can cause a schizophreniform psychosis. The cannabis users also came from deprived social backgrounds, another known risk factor for schizophrenia. However, in a more detailed follow-up of some of the original Swedish cohort the authors claimed to have answered some of these criticisms and denied that other drug use or premorbid psychosis could have explained the data (79C , 80C ). In addition, longitudinal studies of large cohorts of young people in New Zealand have added weight to the hypothesis that cannabis dependence is associated with increased rates of psychiatric symptoms, although these were described as “schizophrenia symptoms” or “schizophreniform disorder” rather than schizophrenic illness (81C , 82C ). An Australian study further suggested a relation between heavy cannabis use in adolescents and the subsequent development of symptoms of depression and anxiety, which was particularly marked in adolescent girls (83C ).

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Nevertheless, a causative relation between cannabis use and long-term psychotic illness remains unproven. If cannabis did precipitate schizophrenia one might expect to have seen a large increase in the numbers of sufferers from this illness as cannabis use became more common in the West during the past 30 years. However, a detailed review of the epidemiological evidence up to 1990 has shown that this has not been the case (84R ). But a more recent survey in South-East London showed that there has been a progressive increase in the incidence of schizophrenia (as defined by DSM-III diagnostic criteria) over the period 1965–1997, with more than a doubling over the past three decades, particularly in people under 35 years of age (85C ). Although the question of whether cannabis can cause mental illness remains open, it is clear that it can exacerbate the symptoms of existing psychotic illness. While schizophrenic patients seem to use cannabis and other psychoactive drugs as a form of “self-medication”, cannabis can make the key symptoms of delusions and hallucinations worse, and it tends to counteract the antipsychotic effects of the drugs used to treat the illness (86C , 87C ). On the other hand, in one Swedish study cannabis made schizophrenic patients less withdrawn and more likely to speak (88E ). It would be prudent, nevertheless, to discourage the use of cannabis in patients with existing psychotic illness. Cognitive functions Several studies have addressed the question of whether more severe deficits in cognitive function develop in chronic heavy users of cannabis, or in animals treated for prolonged periods. The human studies are fraught with difficulties (21R ). For example, comparisons have to be made between groups of users and non-users, but it is usually impossible to compare the baseline performances of these groups before cannabis use to see if they are properly matched. Statistical analysis of such data has often been poor, common errors being the use of so many different tests that the likelihood of finding some significant differences is increased, or the use of inadequate sample sizes. Other drug use can also confound the data. Results have been very variable. Some studies in very heavy long-term users of cannabis (10–20 joints/day for more than 10 years) in Jamaica (89C ), and Costa Rica

How safe is cannabis?

(90C ) failed to show any significant difference between users and non-users with a battery of tests of cognitive function, and similar negative results were reported in some studies of US college students (21R ). However, most studies have shown deficits in the performance of complex cognitive tasks in long-term cannabis users, although there is little evidence that these are qualitatively or quantitatively more severe than those seen after acute drug use (21R ). Even more controversial is the question of whether long-term cannabis use can cause irreversible deficits in higher brain function, which persist after drug withdrawal. Many studies have been poorly designed. It is not sufficient to identify a group of cannabis users and test them after withdrawing cannabis. One study, for example, involved 63 current heavy users who had smoked cannabis at least 5000 times in their lives and 72 control subjects (43E ). The subjects underwent a 28-day washout from cannabis use, monitored by urine assays. On days 0, 1, and 7 the heavy users scored significantly less than control subjects on a battery of neuropsychological tests, particularly word recall. However, by day 28 there were virtually no differences between the groups and no significant association between cumulative lifetime cannabis use and test scores. The fact that drug-induced effects on cognitive performance can persist for up to 1 week after withdrawal (perhaps because of the persistence of THC in the body, or because of a subtle withdrawal syndrome) means that many earlier studies that did not allow a sufficiently long washout period may have been invalid. On the other hand, some well-designed studies have shown subtle persistent cognitive deficits in ex-cannabis users. For example, 36 people who had used cannabis regularly for at least 5 years but who had stopped on average 2 years before the experiment were given a very difficult task: they had to listen to a series of tones (some in the right ear some in the left), either long or short (but differing by only 51 ms), and high or low pitch (but differing very little) they had to press a button as fast as possible in response to longer tones of a specified pitch in the correct ear (25R ). Previous research using this paradigm had shown that current regular cannabis users had difficulty in discriminating between tones of this sort. Measurements of event-related potentials also showed small but significant abnormalities in the P300 wave. The

xxxix ex-users continued to make significant errors in the discrimination task, but they had normal P300 waves. The conclusion of these and many other studies in ex-users seems to be that regular cannabis use can cause a small but significant degree of impairment in cognitive function, which may persist after drug withdrawal. Such impairment appears to be associated with longterm heavy use and is unlikely to affect most recreational users. Tolerance and dependence Many animal studies have shown that tolerance develops to most of the behavioral and physiological effects of THC (91R ). Earlier clinical reports also suggested that tolerance occurs after repeated administration of THC in man, although many of these studies were poorly controlled (3R , 23R , 92R ). But for many years cannabis was not considered to be a drug of addiction. Withdrawal did not lead to any obvious physical withdrawal symptoms, either in people or in animals, and animals failed to self-administer the drug, a behavior that is usually associated with drugs of dependence. Attitudes have changed markedly in recent years. The DSM-IV diagnostic manual defines “substance dependence” and “substance abuse” rather than “addiction” (93S ). When the DSMIV criteria are applied to populations of regular cannabis users, surprisingly high proportions appear to be positive by these definitions. In a survey of 10 641 Australians aged 18 years and over almost one-third of regular cannabis users fell within the definitions of “substance abuse” (11%) or “substance dependence” (21%) (94C ). A large-scale survey in the USA showed that some 46% of those interviewed had ever used cannabis and that 9% of such users became dependent (95C ). More carefully controlled studies have shown that a reliable and clinically significant withdrawal syndrome does occur in human cannabis users. The symptoms include craving for cannabis, reduced appetite, difficulty in sleeping, and weight loss; anger, aggression, increased irritability, restlessness, and strange dreams also sometimes occur (96C ). Dependence on cannabinoids in animals is also much more clearly observable, because of the availability of CB1 receptor antagonists, which can be used to precipitate withdrawal. Thus, a behavioral withdrawal syndrome was precipitated by rimonabant in rats treated for

xl only 4 days with THC in doses as low as 0.5–4.0 mg/kg/day (97E ). The syndrome included scratching, face rubbing, licking, wet dog shakes, arched back, and ptosis, many of the signs that are seen in rats undergoing opiate withdrawal. Similar withdrawal signs occurred when rats treated chronically with the synthetic cannabinoid CP-55,940 were given rimonabant (98E ). Rimonabant-induced withdrawal after 2 weeks of treatment of rats with the cannabinoid HU-120 was accompanied by a marked increase in release of the stress-related neuropeptide corticotropin-releasing factor in the amygdala, a result that also occurred in animals undergoing heroin withdrawal (99E ). An electrophysiological study showed that precipitated withdrawal was also associated with reduced firing of dopamine neurons in the ventral tegmental area of rat brain (100E ). These data clearly show that chronic administration of cannabinoids leads to adaptive changes in the brain, some of which are similar to those seen with other drugs of dependence. The ability of THC to cause selective release of dopamine from the nucleus accumbens (101E ) also suggests some similarity between THC and other drugs in this category. Furthermore, although many earlier attempts to obtain reliable self-administration behavior with THC were unsuccessful (91R ), some success has been obtained recently. Squirrel monkeys were trained to self-administer low doses of THC (2 µg/kg per injection), but only after the animals had first been trained to selfadminister cocaine (102E ). THC is difficult to give intravenously, but these authors succeeded, perhaps in part because they used doses comparable to those to which human cannabis users are exposed, and because the potent synthetic cannabinoids are far more water-soluble than THC, which makes intravenous administration easier. Mice could be trained to self-administer intravenous WIN55,212-2, but CB1 receptor knockout animals could not (103E ). Another way of demonstrating the rewarding effects of drugs in animals is the conditioned place preference paradigm, in which an animal learns to approach an environment in which it has previously received a rewarding stimulus. Rats had a positive THC place preference after doses as low as 1 mg/kg (104E ). Some studies have suggested that there may be links between the development of dependence to cannabinoids and to opiates (105E ).

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Some of the behavioral signs of rimonabantinduced withdrawal in THC-treated rats can be mimicked by the opiate antagonist naloxone (106E ). Conversely, the withdrawal syndrome precipitated by naloxone in morphinedependent mice can be partly relieved by THC (107E ) or endocannabinoids (108E ). Rats treated chronically with the cannabinoid WIN55,212-2 became sensitized to the behavioral effects of heroin (109E ). Such interactions can also be demonstrated acutely. Synergy between cannabinoids and opiate analgesics has been described above. THC also facilitated the antinociceptive effects of RB 101, an inhibitor of enkephalin inactivation, and acute administration of THC caused increased release of Met-enkephalin into microdialysis probes placed into the rat nucleus accumbens (110E ). The availability of receptor knockout animals has also helped to illustrate cannabinoid/opioid interactions. CB1 receptor knockout mice had greatly reduced morphine self-administration behavior and less severe naloxone-induced withdrawal signs than wild type animals, although the antinociceptive actions of morphine were unaffected in the knockout animals (103E ). The rimonabantprecipitated withdrawal syndrome in THCtreated mice was significantly attenuated in animals with knockout of the pro-enkephalin gene (111E ). Knockout of the µ-opioid receptor also reduced rimonabant-induced withdrawal signs in THC-treated mice, and there was an attenuated naloxone withdrawal syndrome in morphine-dependent CB1 knockout mice (112E , 113E ). These findings clearly point to interactions between the endogenous cannabinoid and opioid systems in the CNS, although the neuronal circuitry involved is unknown. Whether this is relevant to the so-called “gateway” theory is unclear. In the US National Household survey of Drug Abuse respondents aged 22 years or over who had started to use cannabis before the age of 21 years were 24 times more likely than non-cannabis users to begin using hard drugs (114C ). However, in the same survey the proportion of cannabis users who progressed to heroin or cocaine use was very small (2% or less). Mathematical modelling using the Monte Carlo method suggested that the association between cannabis use and hard drug use need not be causal, but could relate to some common

xli

How safe is cannabis?

predisposing factor, e.g. “drug-use propensity” (115E ). Cannabis in pregnancy In animals THC can cause spontaneous abortion, low birth weight, and physical deformities (5R ). However, these were only seen after treatment with extremely high doses of THC (50–150 times higher than human doses), and only in rodents and not in monkeys. In most studies in which babies born to women who had used marijuana during pregnancy were compared with the babies of women who had not there were no significant differences, but some differences are likely to occur by chance and small differences have been reported in some studies (5R , 21R ). There is a tendency towards a shorter gestation period and smaller birth weight in babies born to mothers who have used marijuana. However, although there was a significantly lower birth weight in the largest such study (involving 12 424 births), when other factors were taken into account (for example, tobacco smoking) there was no relation between marijuana use and low birth weight (116C ). Similarly, there was only a nonsignificant trend towards a higher incidence of birth abnormalities in the marijuana-exposed babies in the same study. If marijuana smoking does cause a reduction in birth weight, this may be to be due to the presence of carbon monoxide in marijuana smoke, as has been suggested for tobacco smoking, although this is speculative. Several studies have examined the development of children born to mothers who were exposed to marijuana during pregnancy, to see whether there were any abnormalities in physical or mental development. While the results of most of these investigations were negative, the few instances in which subtle abnormalities could be detected in subsets of the IQ scale have been used as evidence that marijuana can impair children’s cognitive development. In one of the largest studies of this kind, the Ottowa Prenatal Prospective Study, children whose mothers were exposed to marijuana for the first years of their life were given hundreds of different psychological tests, but there were very few differences between the marijuana-exposed and non-exposed groups (117R ). The investigators, who appeared to be convinced that there must be some abnormalities, tried a new series of cognitive tests when the children were

6 years old, and claimed to have found deficits in frontal lobe “executive” functions. However, the differences in the babies born to mothers who used marijuana were relatively minor by comparison with the consistent cognitive deficits observed in children of all ages born to mothers who had been heavy cigarette smokers during pregnancy.

Special hazards of smoked cannabis Traditionally the use of cannabis both in Oriental and Western medicine involved taking the drug by mouth, but most current use in the West involves the inhalation of cannabis smoke. Unfortunately, although smoking is a remarkably efficient means of delivering an accurately gauged dose of THC it also carries special hazards. Although THC itself appears to be relatively safe, the same cannot be said of marijuana smoke. Cannabis smoke and smoking behavior Although there has been relatively little research on the effects of cannabis smoke, a great deal is known about the toxic components in tobacco smoke and their biological effects. Cannabis smoke is very similar in chemical composition to tobacco smoke, so it is not unreasonable to suggest that our knowledge of the dangers of tobacco can provide useful predictions about the hazards of smoking cannabis. Both cannabis and tobacco smoke contain carbon monoxide and a number of toxic chemicals, several of which are carcinogenic. Two of the most potent carcinogens in tobacco smoke, benzanthracene and benzpyrene, are also present in cannabis smoke (3R , 118R ). The way in which experienced users smoke cannabis tends to enhance the potential dangers of taking the drug by this route. Cannabis smokers usually inhale more deeply than tobacco smokers and tend to hold their breath, in the belief that this increases the absorption of THC by the lungs. The results of these differences in smoking behavior are profound. In a study of the amounts of particulate matter (tar) and carbon monoxide absorbed in 15 volunteers who were regular tobacco and cannabis smokers, smoking cannabis resulted in a fivefold

xlii greater absorption of carbon monoxide than tobacco and 4–5 times more tar was retained in the lungs (119E ). Effects of cannabis smoke on the lungs Since tobacco smoking is known to be the most important cause of chronic obstructive lung disease and lung cancer, it is reasonable to be concerned about the adverse effects of cannabis smoke on the lungs. There have been several attempts to address this question by exposing laboratory animals to cannabis smoke. After such exposure on a daily basis for periods of up to 30 months, extensive damage has been observed in the lungs of rats (120E ), dogs (121E ), and monkeys (122E ), but it is very difficult to extrapolate these findings to man, as it is difficult or impossible to imitate human exposure to cannabis smoke in any animal model. The various studies that have been undertaken in human cannabis smokers seem to be far more relevant, although here the problem is confounded by the fact that many cannabis smokers take the drug with tobacco, making it difficult to disentangle the effects of the two agents. In 144 volunteers who were heavy smokers of cannabis only, 135 who smoked tobacco and cannabis, 70 smokers of tobacco only, and 97 non-smokers, about 20% of both tobacco smokers and cannabis smokers reported the symptoms of chronic bronchitis (chronic cough and phlegm production), even though the cannabis smokers consumed only 3–4 joints a day compared with over 20 cigarettes for the tobacco smokers (123C , 124R ). There were no additive effects in those who smoked both cannabis and tobacco, although additive effects have been reported in other studies of this type. Lung function in the tobacco smokers continued to get worse over 10 years, particularly in the small airways, making them more liable to develop chronic obstructive lung disease later in life (125C ). However, there was no such decline in the cannabis smokers, suggesting that they may be less likely to develop such diseases as emphysema through smoking. At the Kaiser Permanente Health Care Group in California, 452 “daily” cannabis smokers who had never smoked tobacco were compared with 450 non-smokers of either substance; the cannabis smokers had a small increase in the number of out-patient visits for respiratory illness (RR = 1.19; 95% CI = 1.01, 1.41) (22C ).

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In volunteers who were subjected to a saline rinse of their lungs in order to sample the population of white blood cells present, about 2–3 times more macrophages were collected from the lungs of tobacco or cannabis smokers versus non-smokers, suggesting the presence of an inflammatory response (125C , 126C ). The macrophages from both tobacco smokers and cannabis smokers also had significantly impaired ability to kill and engulf yeasts (Candida albicans) or bacteria (Staphylococcus aureus). The macrophages from smokers were also less able to generate some of the chemical toxins (e.g. superoxides) that they normally use to kill invading micro-organisms, or the cytokines that help to activate further inflammatory and immune system responses (126C ). In addition, the macrophages had impaired ability to attack and kill cancer cells (small cell cancers) in vitro. The depressed immune function may be caused by an interaction of THC with the CB2 receptors present on macrophages (126C ). These findings suggest that, like tobacco smokers, cannabis smokers are likely to be more susceptible to respiratory tract infections and possibly less able to defend themselves against the development of lung cancers. An added complication is that some batches of herbal cannabis may be contaminated with fungi (e.g. Aspergillus spp) that could themselves cause lung infections. This could be a particular hazard to patients with AIDS. Cannabis smoking and cancer THC does not appear to be carcinogenic, but there is plenty of evidence that the tar derived from cannabis smoke is. Bacteria exposed to cannabis tar develop mutations in the standard Ames test for carcinogenicity (127E ), and hamster lung cells in tissue culture develop accelerated malignant transformations within 3–6 months of exposure to tobacco or cannabis smoke (128E ). But is there any evidence that this happens in the lungs of cannabis smokers? Bronchoscopic examination of the large airways showed that a large proportion of both cannabis and tobacco smokers had evidence of increased redness and swelling and increased mucus production relative to non-smokers (124R , 125C , 126C ). Biopsies taken from the lining of the airways showed abnormal cell changes in both cannabis and tobacco smokers. These included abnormal proliferation of

How safe is cannabis?

mucus-producing cells and a reduced number of ciliated cells. These changes could explain the chronic cough and overproduction of phlegm reported by tobacco and cannabis smokers. A more sinister observation was the presence of abnormal cells resembling those normally seen in skin (squamous metaplasia) in the lungs of smokers. These changes are thought to represent premalignant precursors. There were even more possible premalignant cells in the lungs of volunteers who smoked both cannabis and tobacco. In lung biopsies from cannabis and tobacco smokers there was evidence of overexpression of genes that control receptors for epidermal growth factor and a nuclear proliferation protein responsible for cell division known as KI-67 in the lungs of smokers (125C , 126C ). Bronchial biopsies from cannabis smokers also showed evidence of overexpression of the enzyme CYP1A1 (125C ), which plays a key role in converting the benz[a]pyrene present in tobacco smoke into a very potent carcinogen. However, the P53 oncogene, which plays a role in 75% of lung cancers, was not activated, except in a single subject who was a combined cannabis and tobacco smoker. These changes may indicate that precancerous changes take place in the lungs of cannabis smokers, similar to those that occur in tobacco smokers, the end result of which may be to increase the likelihood of lung cancer. One of the reasons why we should be seriously concerned about the possible link between cannabis smoking and lung cancer is that it could take a very long time for such a relation to become manifest. Cigarette smoking became common among men in the developed world during the first decades of this century, but it was not until 30–40 years later that the first evidence of a link between tobacco smoking and lung cancer was obtained. Even though cigarette consumption has fallen significantly in many developed countries, deaths from tobacco-related diseases will continue to rise for many years to come, particularly among women, who did not commonly smoke cigarettes until the 1930s or 1940s. The relation between cigarette smoking and lung cancer is very complex. The increased risk of lung cancer depends far more strongly on the duration of cigarette smoking than on the number of cigarettes consumed each day (129CR ). Thus, while smoking three times as many cigarettes a day does increase the lung cancer risk

xliii about threefold, smoking for 30 years as opposed to smoking for 15 years does not simply double the lung cancer risk, it increases it 20fold, and smoking for 45 years as opposed to 15 years increases the risk 100-fold. The reasons underlying the relation between the duration of tobacco smoking and the development of lung cancer are unknown, but they are likely to apply to cannabis smokers as well. Since the widespread use of cannabis as a recreational drug is a fairly recent development in the West, large numbers of people have not yet been exposed to cannabis smoke for long enough for any link to become clear. The following comments on tobacco smoking (129CR ) could well apply also to cannabis: “Among regular cigarette smokers, the excess lung cancer risk depends strongly not only on smoking habits during the past few years, but also on smoking habits during early adult life. Hence, current lung cancer rates in countries where smoking among young adults became widespread less than half a century ago may be serious underestimates of the eventual magnitude of the tobaccoinduced lung cancer hazard.”

One of the few large-scale studies of the health consequences of cannabis smoking was reported in 65 171 men and women undergoing health checks at the Kaiser Permanente Health Care Organization in California between 1979 and 1985 (130C ). The health of these subjects was then followed for an average of a further 10 years. Nearly 27 000 people admitted to being either current or former cannabis users (defined as ever having smoked more than six times). Over the period of the study 182 tobaccorelated cancers were detected, of which 97 were lung malignancies. There were no effects of former or current cannabis use on the risks of any cancers. However, although this study involved large numbers, almost all of the cannabis smokers were young (15–39 years) and the follow-up period was relatively short. Such a study could not have been expected to detect any relation between cannabis and lung cancer if the lag time were comparable to that seen with tobacco. It may not be possible to answer the question of a link between cannabis smoking and lung cancer for another decade or more. Although the added risk of lung cancer that cigarette smoking confers does not go away, the risk becomes much greater with increased duration of exposure, so that those who give

xliv up gain a disproportionate benefit. British doctors who gave up smoking before the age of 35 years had a pattern of survival that did not differ significantly from non-smokers (131C ). Those who gave up at later ages had a survival pattern that was intermediate between continuing smokers and non-smokers. The relevance of this to cannabis smokers is clear. Several surveys have shown that most cannabis smokers are in their teens or twenties and that they tend to give up the habit when they reach their thirties. If the pattern is similar to that seen with tobacco smoking, their risk of developing lung cancer later in life may not be significantly increased. On the other hand, some surveys of current cannabis use have shown that more and more people are continuing to smoke throughout their lives, so the pattern of giving up in mid-life may not hold in the future. Another factor to consider is how much tar cannabis smokers are exposed to compared with cigarette smokers. Although cannabis smokers on average consume no more than 3–4 joints a day, in contrast to the 15–20 cigarettes commonly consumed by tobacco users, each joint is liable to deposit 4–5 times more tar in the lungs than a tobacco cigarette (119E ). Tar exposure is thus similar, except for the large numbers who smoke cannabis with tobacco, for whom the hazards are compounded. When experienced users are given cannabis cigarettes containing different amounts of THC, they adjust their smoking behavior to obtain a similar dose of THC, while depositing less tar in the lungs (132C ). This might paradoxically be an argument in favor of the use of higher THC potency strains of herbal cannabis, which are now increasingly available. At the moment the jury is out on the link between cannabis and cancer, although there has been some concern about reports of an increased number of cancers of the head and neck in young people with a history of heavy cannabis use (63c –68r , 133C ). However, these reports are based on small numbers, and no cause-and-effect relation has been established.

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Conclusions The medical and recreational uses of cannabis are associated with some adverse effects. While the acute toxicity of cannabis is low, longterm use is associated with cognitive impairment and can lead to dependence in a proportion of regular users. The medical uses of cannabis are complicated by the narrow therapeutic window between the desired effects and intoxication. Smoking cannabis involves the additional risks of chronic lung damage and possibly cancer. The adverse effects of cannabis are not sufficient to limit possible medical uses. But the recreational use of cannabis, although less dangerous than heroin or cocaine, carries some risks that should inform public debate on changes to the drug laws. What place, if any, should smoked cannabis have in modern medicine? Because of the potential hazards of chronic respiratory disease and cancer, it is unlikely that smoked cannabis could ever be recommended for the long-term treatment of any illness in which its use might need to be continued on a regular basis for many years. However, the principal groups that currently smoke cannabis consist mainly of patients with life-threatening illnesses. Patients with AIDS, cancer, or multiple sclerosis have a considerably reduced life-expectancy, and it could plausibly be argued that the long-term health risks of smoking cannabis are of little relevance to them. If their illness does not respond to conventional medicine, and their doctor has agreed that smoked cannabis might be beneficial, why should the law stand in their way? The authors of the influential US Institute of Medicine report concluded that although smoked cannabis should generally not be recommended for long-term use, there were certain patients for whom short-term use could be justified (7R ). A similar conclusion was reached by the UK House of Lords enquiry into cannabis (8RS ).

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Reginald P. Sequeira

1

Central nervous system stimulants and drugs that suppress appetite

METHYLXANTHINES

(SED-14, 1; SEDA-23, 1; SEDA-24, 1; SEDA-25, 1)

Caffeine Cardiovascular Guarana is produced from the guarana plant (Paullina cupana), the seeds of which contain 3.6–5.8% caffeine. • A 25-year-old woman, who had pre-existing mitral valve prolapse and a history of having had bouts of palpitation with caffeine, developed intractable ventricular fibrillation after consuming a “natural energy” guarana health drink containing a high concentration of caffeine (1A ). At autopsy, she was found to have sclerosis and myxoid changes in the mitral valve leaflets. The caffeine concentration in her aortic blood was 19 mg/l.

This case highlights the need for more careful regulation of “natural” products, including warning for patients with underlying health problems, and clear labeling to document the presence of any constituents with potentially toxic effects. It also shows the need for medical practitioners to be familiar with the more widely used “natural remedies” and their toxicological profiles. Following the death of this patient, the Western Australian Coroner recommended that Race 2005 Energy Blast should be removed from the local market, and the product was recalled nationally in August 1999. Nervous system Red Bull, a widely consumed “power drink”, a mixture of caffeine, taurine, and inositol, affects mental performance and mood. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

• A 36-year-old man with bipolar I disorder had a second manic episode, after having been in remission for 5 years while taking lithium to maintain a serum lithium concentration of 0.8–1.1 mmol/l (2A ). One week before this episode he drank three cans of Red Bull at night and needed less sleep. Three days later he drank three more cans. After 4 days he was feeling euphoric, hyperactive, and insomniac. He gradually became more hyperactive and had increased libido and irritability. He took no more Red Bull and improved within 7 days.

Based on this report the authors suggested that stimulant beverages containing caffeine might cause cognitive and behavioral changes, especially in vulnerable patients with bipolar illness. Musculoskeletal Caffeine toxicity is an uncommon cause of myopathy, but a history of excessive dietary and pharmaceutical consumption of caffeine should be sought in any patient with unexplained myopathy, particularly if there is concomitant hypokalemia (3A ). • A 21-year-old woman with a 12-month history of progressive muscle weakness, nausea, vomiting, diarrhea, and weight loss had significant worsening of muscle weakness over 2 weeks, associated with exercise-induced muscle stiffness and pain. She had severe hypokalemia and a metabolic acidosis. For the past 1–2 years she had been consuming about 8 liters of cola every day. She stopped drinking the cola and took potassium supplements, after which her hypokalemia and muscle weakness resolved and the serum creatine kinase activity fell. Based on the concentration of caffeine in the cola, it was estimated that she had been consuming at least 1 g/day of caffeine for more than 12 months.

Hypokalemia and myopathy are known effects of caffeine toxicity, and severe hypokalemia and fatigue and hypokalemia with myopathy have been described before (4R ).

1

2 Consumption of methylxanthine-containing products can aggravate the neurological symptoms associated with the glucose transporter type 1 (Glut 1) deficiency syndrome. The human erythrocyte and brain glucose transporters are identical, and the erythrocyte transporter has been used in four patients with individual mutations in the Glut 1 gene to demonstrate that caffeine and theophylline inhibit glucose transport (5E ). The Glut 1 deficiency syndrome represents impaired glucose transport across the blood–brain barrier caused by partial Glut 1 deficiency, which results in hypoglycorrhachia, seizures, and developmental delay. Identifying potential inhibitors of Glut 1 is essential in preventing further impairment of glucose transport in these patients. In addition to phosphodiesterase inhibition and adenosine A1 receptor antagonism by methylxanthines, it is likely that inhibition of glucose transport also contributes to the convulsive effects of methylxanthines in high doses.

Theophylline Risk factors Age Developmental differences in the balance between metabolic and renal elimination pathways determine the unique toxicokinetics of theophylline in neonates. Three premature neonates received inadvertent intravenous doses of theophylline for apnea of prematurity (6A ). All the neonates had sinus tachycardia and agitation. Maximum serum theophylline concentrations were 55–123 mg/l; theophylline-derived caffeine concentrations plateaued at 8.4–13 mg/l and did not fall during the sampling period. The half-life of theophylline was 28–37 hours and the clearance 0.02–0.05 l/kg/h. This study shows that, in contrast to older children, theophylline elimination remains a first-order process during acute intoxication in premature infants, and that large overdoses of theophylline in neonates, while inducing symptoms and signs of overdose, do not uniformly result in life-threatening sequelae and do not necessarily require invasive treatment. Although the literature is rather scanty, the pharmacokinetics of theophylline in premature neonates do not seem to be different from those in full term neonates. Furthermore, toxic

Chapter 1

Reginald P. Sequeira

concentrations in neonates have not been defined. It has been speculated that various factors in neonates, such as low plasma protein binding, metabolic interconversion to caffeine, and limited excretory capacity, make them susceptible to toxicity even at plasma concentrations within the usual adult therapeutic range (SEDA23, 1; SEDA-25, 1). Drug overdose In patients with theophylline overdose, charcoal hemoperfusion is the recommended method for rapid reduction of serum theophylline concentrations. However, access to this technique is limited in most hospitals. Venovenous hemofiltration, which is readily available in many hospitals, appears to be a realistic and practical alternative to charcoal hemoperfusion, in combination with oral activated charcoal, particularly in the hemodynamically unstable patient with severe theophylline toxicity without anticoagulation (7A , 8A ). A higher extraction ratio in neonates than in adults has also been described (8A ). Rhabdomyolysis is a rare complication of theophylline overdose (9A ). • A 73-year-old man took an unknown number of theophylline modified-release tablets and furosemide 40 mg tablets. He developed a tachydysrhythmia, vomiting, and restlessness. His maximum theophylline concentration was 67 mg/l and he had hypokalemia (2.8 mmol/l) and hyponatremia (123 mmol/l). The maximum creatine kinase activity was (32 mol/l [[sic]]) and the serum myoglobin concentration was 3789 µg/l. He was treated with oral activated charcoal, continuous venovenous hemodialysis, intravenous potassium and sodium chloride, forced diuresis, and continuous intravenous metoprolol, and survived without sequelae.

Interference with diagnostic tests Methylxanthines, especially theophylline, in healthy subjects appear to inhibit solute reabsorption in both the proximal nephron and the diluting segment without changing either glomerular filtration rate or renal blood flow appreciably. Accordingly, such a discrepancy between GFR and creatinine clearance has been ascribed to the increase in creatinine clearance in a heavy tea drinker (10A ). Drug interactions Levofloxacin A 59-yearold Japanese man taking theophylline for emphysema had stimulation, insomnia, and tachycardia owing to theophylline toxicity after

Central nervous system stimulants and drugs that suppress appetite

he also took levofloxacin and clarithromycin (11A ). His theophylline clearance returned to normal and his symptoms resolved after withdrawal of levofloxacin, while clarithromycin was continued. Moxifloxacin In a randomized, multiple-dose, period-balanced, three-way, crossover study in healthy non-smoking male volunteers, moxifloxacin did not alter the pharmacokinetics of theophylline (12c ). Tegaserod The effect of tegaserod on the single-dose pharmacokinetics and safety profile of theophylline has been determined in a randomized, open-label, crossover study in 18 subjects (13c ). Tegaserod did not alter the pharmacokinetics of theophylline and the incidence of adverse events was similar after coadministration. However, since in vitro studies have shown that tegaserod inhibits CYP1A2 (14E ), more evidence is needed to claim that no dosage adjustment is required when theophylline is co-administered with tegaserod. Trimethoprim Two episodes of severe hyponatremic symptoms have been described in the same patient, one attributed to theophylline and one to trimethoprim (15A ). The evidence to support an interaction is circumstantial, and the patient was taking multiple medications, making interpretation difficult.

STIMULANT DRUGS

(SED-14, 12; SEDA-23, 2; SEDA-24, 2; SEDA-25, 2)

Amphetamines Cardiovascular The cardiovascular response to an oral dose of d-amphetamine 0.5 mg/kg has been determined in 81 subjects with schizophrenia, eight healthy controls who took amphetamine, and seven subjects with schizophrenia who took a placebo (16c ). Blood pressure increased in both amphetamine groups, whereas placebo had no effect. However, pulse rate did not change in the schizophrenic group and only increased after 3 hours in the controls. Intramuscular haloperidol 5 mg produced a more rapid fall in systolic blood pressure in

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3

six subjects, compared with 12 subjects who did not receive haloperidol. The authors concluded that increased blood pressure due to amphetamine may have a dopaminergic component. They also suggested that haloperidol may be beneficial in the treatment of hypertensive crises caused by high doses of amphetamine or methamphetamine. Vertebral artery dissection has been described in a previously healthy man with a 3-year history of daily oral amphetamine abuse (17A ). • A 40-year-old man had mild hypertension and a chronic history of heavy cigarette smoking. MRI scans showed infarction of both mesial occipital lobes, the left posteromedial thalamus, and the right superior and left superior cerebellum. Magnetic resonance angiography and fat saturation MRI showed changes consistent with dissection and hematoma. He was treated with anticoagulants and made a partial recovery.

Since this patient had no known risk factors for vertebral artery dissection and had abused amphetamine daily for 3 years with escalating amounts, an association between methamphetamine and vertebral artery dissection cannot be excluded. The local and systemic vascular impacts of amphetamine could have contributed to initial changes (along with smoking), resulting in dissection. Nervous system Methamphetamine-induced neurotoxicity in animals, especially involving effects on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascade, has been comprehensively reviewed (18ER ). Although prior work has focussed primarily on the effects of methamphetamine on dopaminergic neurons, there is evidence that other types of neurons are also affected. Regional brain metabolism has been studied using positron emission tomography after administration of [18 F]-fluorodeoxyglucose in 15 detoxified methamphetamine abusers and 21 controls (19c ). The authors concluded that since the parietal cortex is devoid of any significant dopaminergic innervation, the observed changes in cerebral metabolism resulted from the effects of methamphetamine on circuits other than those modulated by dopamine. These results provide evidence that methamphetamine, in doses abused by humans, produces

4 long-lasting metabolic changes in brain regions neuroanatomically connected with dopaminergic pathways, but also in areas that are not innervated by dopamine. Notwithstanding several confounding factors and limitations of this study, it shows the need to explore whether these changes recover and if they predispose to neurodegenerative diseases. Dopamine transporter reductions in methamphetamine abusers are associated with motor and cognitive impairment. There is therefore growing evidence to support the view that the long-term changes that methamphetamine can cause in the brain have implications in understanding methamphetamine neurotoxicity. However, we do not know whether this reduction in dopamine transporter activity reflects dopaminergic neuronal damage or down-regulation of the dopamine transporter (20c ). Teratogenicity The possible neurotoxic effect of prenatal methamphetamine exposure on the developing brain has been studied using 1 H magnetic resonance spectroscopy in 12 methamphetamine-exposed children and 14 age-matched unexposed controls (21c ). There was an increased creatinine concentration in the striatum, with relatively normal concentrations of N-acetyl-containing compounds in children exposed to methamphetamine. These findings suggest that exposure to methamphetamine in utero causes abnormal energy metabolism in the brains of children. However, there were no differences in reported behavioral problems among methamphetamine-exposed children compared with controls. Risk factors Genetic factors A study in 93 unrelated methamphetamine-dependent subjects and 131 controls did not prove any association between methamphetamine dependence in Caucasians of Czech origin and TaqI A polymorphism of the DRD2 gene, I/D polymorphism of the ACE gene, or M235T polymorphism of the AGT gene (22C ). Drug overdose Concentrations of methamphetamine and its metabolite amphetamine were measured in autopsied brain regions of 14 human methamphetamine abusers (23E ). There was no evidence of variation in the regional distribution of amphetamines in the

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brain. Postmortem redistribution of methamphetamine in the heart and lung has been reported before, although peripheral blood concentrations appear to remain constant (24E , 25E ).

Methylphenidate Two reviews have addressed the diagnosis and management of attention-deficit hyperkinetic disorder (ADHD) and have summarized the effects of stimulants, including those of methylphenidate and adderal (a mixture of equal components of d-amphetamine saccharate, d,lamphetamine aspartate, d-amphetamine sulfate, and d,l-amphetamine sulfate, which seems to be gaining popularity in the treatment of ADHD) (26R , 27R ). The results of the National Institute of Mental Health Collaborative Multimodal Treatment Study of children with attention deficit hyperkinetic disorder have been analysed (28C ). This double-blind, placebo-controlled methylphenidate titration trial identified the optimum dose and replicated previously reported methylphenidate response rates and doserelated adverse events. For parent ratings, the severity of the following adverse events increased as the dose was raised: appetite suppression, dull/listless appearance, stomach ache, tearfulness, and trouble sleeping. For teacher ratings, the only significant drug-related adverse event that had a dose-related trend was reduced appetite. Other adverse events reported by teachers were dull/listless appearance, crabbiness, and buccal movement or chewing. However, these teacher-reported adverse events improved with increased methylphenidate dosage. The authors also emphasized that parents report more dose-related adverse events than teachers do, making them better reporters of safety during dosage titration. A modified-release, once-daily formulation has been evaluated in 282 children with ADHD in a double-blind, placebo-controlled trial for 28 days (29C ). For core ADHD symptoms both once-daily modified-release and thrice-daily immediate-release methylphenidate were superior to placebo and not different from each other. A similar percentage of patients reported

Central nervous system stimulants and drugs that suppress appetite

at least one adverse event with both formulations. The most commonly reported adverse events were headache and upper respiratory infections, followed by abdominal pain, cough, pharyngitis, vomiting, and otitis media. Of these, only headache and abdominal pain were considered to be related to the study medication. One patient withdrew because of depression with modified-release methylphenidate and one because of tics with placebo. Headache occurred in 14%, 5.8%, and 10% of patients taking modified-release methylphenidate, immediate-release methylphenidate, or placebo respectively, and abdominal pain in 6.7%, 5.8%, and 1.0%. Other adverse events included appetite suppression (modified-release methylphenidate) and insomnia (all three). The results of this study suggest that once-daily modified-release methylphenidate provides efficacy superior to placebo and not significantly different from thrice-daily immediate-release methylphenidate. Nervous system Episodes of explosive behavior, apparently due to methylphenidate, masquerading as unmanageable ADHD have been reported (30A ). • A 10-year-old boy developed motor and vocal tics and severe obsessive–compulsive symptoms, predominantly about symmetry. These were not evident before he started taking methylphenidate. At 7 years of age he had begun a regimen of methylphenidate 20 mg/day in divided doses. Paradoxically, his impulsive behavior increased and he began to have explosions of aggressive and violent behavior, during which he would lash out at his family or destroy things. After a year of methylphenidate therapy, the tics subsided spontaneously but other symptoms remained. Eventually, because of severe impairment resulting from obsessive–compulsive symptoms, his parents stopped giving him methylphenidate. A few months later there were no further obsessive– compulsive preoccupations and no tics, and he did not have any explosive behavior.

It is well recognized that methylphenidate can induce or aggravate Tourette’s syndrome in vulnerable individuals, most often characterized by motor tics and occasionally vocal tics (31A ). Moreover, obsessive–compulsive symptoms caused by methylphenidate have also been reported (32A , 33A ). However, it is not clear whether explosive episodes associated with Tourette’s syndrome are an integral part

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of the disorder or occur as part of a co-morbid disorder, predominantly ADHD or obsessive– compulsive disorder. In this case the explosive episodes coincided with a period of treatment with methylphenidate. In view of the extreme, sudden, discrete nature of the outbursts and the temporal relation to treatment, it was concluded that the episodes were behavioral problems caused by methylphenidate, rather than a feature of the underlying ADHD. Drug interactions Ciclosporin Potential drug–drug interactions involving methylphenidate with ciclosporin and amfebutamone (bupropion) with ciclosporin have been described (34A ). A 10-year-old boy with a heart transplantation had a potentially lifethreatening reduction in ciclosporin blood concentrations with amfebutamone. He subsequently had an increase in ciclosporin concentrations while taking methylphenidate. These interactions merit further systematic investigation. Citalopram There is growing interest in using stimulants, particularly methylphenidate, in the management of elderly depressed patients, either alone (35c ) or in combination with antidepressants such as citalopram (36A ). In a preliminary trial in 10 elderly patients a combination of methylphenidate and citalopram was well tolerated. Levodopa Methylphenidate increased some of the motor effects of levodopa in selected patients with Parkinson’s disease (37A ). Changes in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ.

Modafinil Once-daily modafinil for an average of 4.6 weeks has been evaluated in an open-label trial in 11 children aged 5–15 years with ADHD (38c ). This pilot study, with non-blinded ratings, a small number of subjects, and a short duration of treatment, showed significant improvement. Adverse events were responsible for drug withdrawal in one child. The most common adverse event was delayed onset of sleep or sleep disruption, which, in two of three

6 cases, responded to a reduction in dosage. No patient taking modafinil lost weight or had a reduced appetite. A larger-scale, double-blind, placebo-controlled study will be needed to further substantiate the efficacy and safety of modafinil.

Strychnine A 33-year-old man attempted suicide by selfinjection of strychnine intramuscularly (39A ). A few seconds after the first injection he developed dizziness and lightheadedness. Ten minutes after the second injection he had seizures, opisthotonos, and tetany. He was rescued with a benzodiazepine and ventilatory support.

DRUGS THAT SUPPRESS APPETITE (SEDA-22, 3; SEDA-23, 2; SEDA-24, 4; SEDA-25, 5)

Fenfluramines Cardiovascular Further evidence that the prevalence of significant valvular regurgitation is low in patients treated with fenfluramine/phentermine has been reported (40C ). Transthoracic echocardiography was performed in 343 obese patients in a 3-year prospective study that began within 4 months from the withdrawal of fenfluramine and dexfenfluramine from the market. There were 281 women and 62 men, mean age 47 years and mean body mass index 40 kg/m2 . Using the FDA’s criteria, only 21 subjects (6.1%) had significant valvular lesions. Aortic regurgitation was detected in 18 subjects, mitral regurgitation in three, and both aortic and mitral regurgitation in one. Significant valvular disease did not correlate with age, sex, initial or final body mass index, drug dose, or the duration of therapy. In another study, 50 patients with fenfluramine-associated valvular heart disease were followed by serial echocardiography for 6–24 months after withdrawal of therapy (41C ). In most cases valvular heart disease did not

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change, or improved at least by one grade. Mitral and aortic regurgitation improved in some patients, and tricuspid and pulmonic regurgitation improved in most patients after withdrawal. When improvement did occur, regression of regurgitation often involved multiple valves on both the left and right sides of the heart, rather than affecting one valve in isolation. Although most of the patients stabilized or improved, a few had worsening of valvular regurgitation despite withdrawal. Comparable results were also reported in a larger series in another study (42C ). Sequential echocardiographic evaluation 1 year after withdrawal of dexfenfluramine showed a significant reduction in aortic regurgitation. There were no significant changes in mitral regurgitation or any other valvular variables. Although these results can be applied only to the population studied (predominantly middleaged, obese, white women who took dexfenfluramine for 2–3 months), the implications are considerable. Because valvular regurgitation remained stable or improved in most of the patients, surgical referral for patients with severe regurgitation may be delayed. Improvement in valvular regurgitation often occurred within months after drug withdrawal. It remains unclear, however, whether further improvement will continue to occur over longer periods. Watchful waiting, with serial echocardiography, prophylaxis against endocarditis, and medical therapy, may be a reasonable management strategy in patients with severe regurgitation, minimal symptoms, and no evidence of left ventricular dysfunction (41c ). It is not known what factors determine outcome after withdrawal of fenfluramine. Hematologic A clotting disorder has been attributed to fenfluramine–phentermine (fen– phen) (43A ). • A 35-year-old woman developed calf-pain while taking fen–phen. It resolved when the medications were stopped, but her pain returned when fenfluramine was restarted. She had slight rises in aspartate aminotransferase and lactate dehydrogenase activities and a remarkably shortened prothrombin time. The clot was composed of very thin fibrin fibers. All laboratory abnormalities, including the abnormal fibrin structure, completely resolved when fen–phen was stopped.

This is the first report of clotting abnormalities associated with fenfluramine. Thin fibrin

Central nervous system stimulants and drugs that suppress appetite

fibers are more resistant to lysis and can result from a variety of factors and increase the risk of thrombosis. Whether abnormal fibrin structure and an increased thrombotic tendency play a role in patients who develop fenfluramineassociated pulmonary hypertension and valvular heart disease is a question that deserves further investigation.

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Alzheimer’s disease (49M , 50R –52R ). However, these drugs are not expected to alter the neurodegenerative disease process, which is variable and unpredictable. Treatment response was not predicted by the Apo E genotype of six patients (53C ).

Donepezil Sibutramine Although serious adverse events have not been reported, there is no evidence of the longterm safety of sibutramine (44M ). Several new randomized clinical trials have assessed longterm weight reduction efficacy, tolerability, and safety of sibutramine. In a 1-year placebocontrolled study in primary care, sibutramine 10 mg/day (n = 122) or 15 mg/day (n = 123) with dietary advice produced and maintained more weight loss than dietary advice alone (45C ). None of the patients taking sibutramine or placebo (n = 114) was withdrawn because of a raised blood pressure. There were comparable results in 44 patients who took sibutramine 10 mg/day for 12 months in a double-blind, placebo-controlled, crossover design (46C ). After sibutramine withdrawal the patients gained weight but did not reach baseline body weight. There were no significant adverse events of sibutramine withdrawal. Early sibutramine administration produced better effects than late post-diet administration. Cardiovascular risk factors associated with obesity, including dyslipidemia, particularly raised triglyceride and lowered high density lipoprotein concentrations, can be improved with weight loss during sibutramine treatment (45C –47C ). In general, improvements in serum lipids are proportional to the degree of body weight loss, whether that weight loss occurs with sibutramine or with placebo (47C , 48c ).

DRUGS USED IN ALZHEIMER’S DISEASE (SED-14, 435; SEDA-23, 8; SEDA-24, 6; SEDA-25, 7) Cholinesterase inhibitors are currently the mainstay of treatment for mild-to-moderate

The beneficial effect of donepezil on global ratings of dementia symptoms cognition and activities of daily living has been confirmed (53C , 54c ). Donepezil was well tolerated for periods up to 1 year and adverse events were usually mild and transient, lasting only an initial few days, and typically resolved without the need for dosage modification. It has been suggested that patients with Alzheimer’s disease do best while taking donepezil 10 mg/day and when the dosage is maintained at that level without interruption. Donepezil treatment effects that are lost after prolonged withdrawal do not fully recover when the drug is restarted (55c ).

Pemoline Liver Limitations in post-marketing surveillance and public reporting in the USA, particularly in the 1980s, largely accounted for delays in ensuring an appropriate response to pemoline hepatotoxicity (56R ). Several authors have urged that voluntary reporting systems need augmentation (57R , 58r , 59R ), including the addition of an active surveillance system to assess the prevalence of adverse drug reactions and the increased use of public health-oriented information sources to disseminate clearly documented drug risk information to physicians and their patients. The case of pemoline is just one example of this.

Piracetam Piracetam has received significant attention in the media for its purported beneficial effect on cognition in children with Down syndrome. Piracetam 80–100 mg/day for 4 months has

8 been evaluated in a randomized, double-blind, placebo-controlled, crossover study in 25 children with Down syndrome (60c ). Piracetam did not enhance cognition or behavior, but was associated with adverse events: 18 children completed the study, four withdrew, and three were excluded at baseline. The adverse events were CNS related, such as aggression (n = 4), agitation/irritability (n = 2), sexual arousal (n = 2), poor sleep (n = 1), and reduced appetite (n = 1).

Rivastigmine

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Reginald P. Sequeira

while taking rivastigmine (61A ). The time course suggested an association with rivastigmine, and each improved after withdrawal.

Tacrine Liver Tacrine-induced hepatotoxicity was reduced by ursodeoxycholic acid (13 mg/kg/d for 105 days) in a pilot study in 14 patients with Alzheimer’s disease (62c ). Serum activity of AlT in 100 patients taking ursodeoxycholic acid was normal in 93% of cases compared with 69% of patients who had taken tacrine alone.

Psychiatric Three patients with dementia, with no prior psychiatric history, deteriorated

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P.J. Cowen

2

Antidepressant drugs

TRICYCLIC ANTIDEPRESSANTS (SED-14, 44; SEDA-23, 16; SEDA-24, 12; SEDA-25, 13) Cardiovascular At therapeutic doses tricyclic antidepressants can cause postural hypotension, but they are regarded as being safe in patients who require general anesthesia. However, hypotension during surgery has been associated with clomipramine (1A ). • A 57-year-old man due to undergo mitral valve surgery took clomipramine (150 mg at night) up to the night before surgery. His blood pressure before induction with thiopental (250 mg) and fentanyl (250 µg) was 105/65 mmHg, with a heart rate of 70 beats/minute. Anesthesia was maintained with isofluorothane, and 45 minutes after induction, his systolic blood pressure fell to 90 mmHg. Neither ephedrine (30 mg total), phenylephrine (500 µg total), nor dopamine (10 µg/kg/minute) increased the blood pressure. After sternotomy, his systolic blood pressure fell to 55 mmHg and his pulse rate to 60 beats/minute and he had third degree atrioventricular block. Further ephedrine, phenylephrine, and adrenaline were without effect. During cardiopulmonary bypass a noradrenaline infusion was started (0.2 µg/kg/minute) and isofluorothane withdrawn. After he had been weaned from bypass the noradrenaline infusion was continued at a dose of 0.2–0.8 µg/kg/minute, sufficient to maintain the systolic blood pressure at 90–100 mmHg. After the operation clomipramine was withheld and the noradrenaline infusion tapered off, and 3 days later the hypotension had resolved.

The hypotension in this case was severe and refractory to noradrenergic stimulation, perhaps because of the alpha1 -adrenoceptor antagonist properties of clomipramine. The fall in systolic blood pressure was accompanied by a paradoxical fall in heart rate, perhaps because the anticholinergic effect of clomipramine removed the effect of vagal tone on the resting heart rate. It seems likely that the hypotensive effect of © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

clomipramine was potentiated by general anesthesia; however, such a reaction is rare and the underlying cardiac problem may have contributed to this severe adverse reaction. This case reinforces current advice that tricyclic antidepressants are best avoided in patients with significant cardiac disease. Drug interactions There is growing interest in the use of herbal medicines to treat depression, and the propensity of St John’s wort to cause drug interactions has been noted previously (SEDA-24, 12). In 12 patients (nine women, three men) the addition of St John’s wort (900 mg/day) to amitriptyline (150 mg/day) led to a 20% reduction in plasma amitriptyline concentrations, while nortriptyline concentrations were almost halved (2c ). The mechanism is likely to be induction either of hepatic CYP enzymes or the drug transporter P glycoprotein, which causes a net efflux of substrates such as amitriptyline from intestinal epithelial cells into the gut lumen. Amitriptyline can be added to the growing list of drugs (including theophylline, ciclosporin, and warfarin) whose clearance is significantly increased by St John’s wort.

SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) (SED-14, 67; SEDA-23, 17; SEDA-24, 14; SEDA-25, 14) Severe adverse reactions to SSRIs that had been reported to Health Canada’s database in 1986– 96 have been reviewed (3R ). There were 295 severe adverse reactions with 87 deaths. Of the fatal cases, 65 were due to intentional overdose. The other 22 deaths were due chiefly to other forms of suicide or were accidental or indeterminate (12 cases). Of the rest there were three cases of neuroleptic malignant syndrome and

11

12 individual cases of cardiac or respiratory disease in which the role of SSRIs was less clear. This report shows that the major causes of death in patients taking SSRIs are related to the risks of depression itself, particularly selfharm. SSRIs themselves appear to be relatively safe. It is possible, however, that the cases of neuroleptic malignant syndrome could have been misdiagnosed forms of the serotonin syndrome, which, like the neuroleptic malignant syndrome, can present with hyperthermia and changes in consciousness. I have previously pointed out the risk of SSRI-induced serotonin toxicity, which is usually produced by pharmacodynamic interaction between SSRIs and other serotonin potentiating compounds (SEDA-25, 24). In general, the risks of SSRIs are increased by co-prescription, and fatal overdose with SSRIs usually involves a mixture of psychotropic drugs and/or alcohol. Cardiovascular Generally SSRIs have a benign cardiovascular profile. However, fluoxetine has reportedly caused prolongation of the QTc interval (4A ). • A 52-year-old man had an abnormally prolonged QTc interval of 560 ms, with broad-based T waves. He had taken fluoxetine (40 mg/day) over the previous 3 months, before which an electrocardiogram had shown a normal QTc interval (380 ms). The fluoxetine was withdrawn, and 10 days later the QTc interval was 380 ms. His only other medication was verapamil, which had been started 3 years before for hypertension.

Systematic studies of fluoxetine as monotherapy have not shown evidence of QTc prolongation. It is possible in this case that fluoxetine interacted with verapamil to produce a conduction disorder. The other SSRI that has been associated with cardiovascular abnormalities is citalopram (SEDA-24, 14). These are most commonly apparent in large overdoses, in which a variety of cardiac abnormalities, including QTc prolongation, have been noted. • A 21-year-old woman developed QTc prolongation (457 ms) after taking a fairly modest overdose (400 mg) of citalopram (usual daily dose 20–60 mg) (5A ). The QTc prolongation resolved uneventfully over the next 30 hours.

This case suggests that even modest overdoses of citalopram can cause QTc prolongation

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and that cardiac monitoring should be considered. Based on the pharmacokinetic profile of citalopram and the temporal pattern of QTc change, the authors suggested that the effect of citalopram on the QTc interval was mediated by one of its metabolites, dimethylcitalopram. Nervous system SSRIs can cause extrapyramidal disorders, including Parkinsonism (SEDA-23, 24). In these cases, withdrawal of SSRIs usually results in remission of symptoms. However, occasionally SSRIs can unmask a vulnerability to Parkinson’s disease. • An 81-year-old woman took sertraline 100 mg/day for depression and 6 months later presented with tremor and difficulty in moving her right arm and leg (6A ). A diagnosis of right hemi-parkinsonism was made and the sertraline was withdrawn. Her extrapyramidal symptoms resolved within 3 months, but 14 months later she developed Parkinsonism and was treated with levodopa and carbidopa. • A 70-year-old man developed Parkinsonian symptoms 1 month after starting to take sertraline 100 mg/day (7A ). Withdrawal of sertraline resulted in amelioration but not complete remission of his symptoms, which then required treatment with carbidopa and levodopa.

In these cases presumably the sertraline prematurely precipitated Parkinson’s disease. Fluvoxamine causes increased plasma melatonin concentrations. In an in vitro preparation melatonin was metabolized to 6-hydroxymelatonin by CYP1A2, which was inhibited by fluvoxamine at therapeutic plasma concentrations (8E ). This effect was not shared by other SSRIs or by tricyclic antidepressants which do not have prominent effects on melatonin secretion. Whether increased concentrations of melatonin and loss of its normal circadian rhythm might cause symptoms is unclear. However, melatonin is believed to play a role in the regulation of circadian rhythms, including entrainment of the sleep-wake cycle. There have been 10 cases of circadian rhythm sleep disorder associated with fluvoxamine (9c ). All the patients had delayed sleep-phase syndrome, which is characterized by delayed sleep onset and late awakening. The delay in falling asleep and waking up in the morning was 2.5–4 hours. In nine of the cases withdrawal of fluvoxamine or a reduced dosage led to resolution of the sleep disorder. When the patients were given alternative serotonin

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potentiating agents, such as clomipramine or fluoxetine, the sleep disorder did not recur. SSRIs can cause insomnia and daytime somnolence; however, the symptoms seem to reflect a sleep-wake cycle disorder. It is conceivable that disruptions in the normal pattern of melatonin secretion, particularly a delay in the normal early morning fall in plasma concentrations could be involved in the pathophysiology of these symptoms. The fact that these sleep disorders were seen only with fluvoxamine would also support a role of melatonin. Endocrine SSRIs can cause modest increases in plasma prolactin concentrations, presumably because serotonin pathways in the hypothalamus facilitate the release of prolactin releasing factor. This is rarely associated with obvious clinical sequelae, but hyperprolactinemia and galactorrhoea have been reported. • A 71-year-old woman who had taken fluoxetine (dose unspecified) for a number of weeks noted unilateral galactorrhea and had a raised prolactin of 37 ng/ml (reference range 1.2–24 ng/ml) (8A ). She was also taking estrogen hormonal replacement therapy, benazapril, and occasional alprazolam. Withdrawal of the fluoxetine led to normalization of the prolactin concentration and resolution of the galactorrhea. • A 32-year-old woman taking paroxetine 40 mg/day had a raised prolactin concentration (46 ng/ml) and galactorrhea, both of which resolved a few days after paroxetine withdrawal (9A ).

Estrogens also facilitate prolactin release, and so hormone replacement therapy may have played a part in the first case. Electrolyte balance Reports of hyponatremia with SSRIs continue to appear (12A , 13R ). Hyponatremia is probably more common with SSRIs than tricyclic antidepressants and predominantly but not exclusively affects older patients. Most reports involve fluoxetine but this might represent greater patient exposure. All SSRIs and venlafaxine can produce this adverse effect (SEDA-23, 21; SEDA-25, 14). According to the published reports the median time to onset of hyponatremia is 13 days (range 3–120) and the presentation is of inappropriate secretion of antidiuretic hormone (12A ). Symptoms, such as lethargy and confusion, can be non-specific, so awareness of the possibility of SSRI-induced hyponatremia, particularly in elderly people, is needed.

13 Skin As with other antidepressants, SSRIs have been associated with skin reactions. • A 20-year-old woman taking paroxetine 10 mg/day for obsessive–compulsive disorder developed multiple purple lesions on the fingers of both hands after 15 weeks (14A ). The lesions disappeared after 1 week but returned 2 days after re-challenge with paroxetine.

The skin reaction here was consistent with a vasculitis, a potentially serious adverse reaction that has been previously reported with fluoxetine but not paroxetine. Sexual function SSRIs are usually associated with reduced sexual function, including loss of interest. However, occasionally they are associated with increased sexual desire and behavior. • A 27-year-old married woman with a borderline personality disorder was admitted to hospital with depression and suicidal ideation (15A ). Over 3 weeks she was treated with fluvoxamine in doses up to 150 mg/day, but because of lack of response the dosage was increased to 200 mg/day; 3 days later she reported that her sex drive was greater than it had ever been before and that she felt she could not control it. There was no evidence of mania. Within a week of withdrawal of fluvoxamine her sexual desire had returned to its previous level.

Patients with borderline personality disorder may behave in a sexually disinhibited manner and have mood swings. In this patient, however, it did not appear as though the hypersexuality was part of a manic syndrome, and she was clear that the sexual feelings were unusually great for her. Support for a role of the SSRI in this adverse effect comes from a series of five patients (four taking citalopram and one paroxetine) who had an unusual increase in sexual interest, with preoccupation with sexual thoughts, promiscuity, and excessive interest in pornography (16A ). In some of the cases symptoms such as diminished need for sleep suggested the possibility of a manic syndrome. These reports suggest that occasionally SSRIs can be associated with increased sexual desire and behavior. This might be associated with mood instability, for example in a manic or mixed affective state, but in some people personality factors are likely to be important. Unlike most other antidepressants, SSRIs can cause ejaculatory delay and even complete anorgasmia in both men and women (SEDA23, 18). This adverse effect has been used

14 with benefit in men with premature ejaculation. However, laboratory studies in such patients have shown that fluvoxamine differs from paroxetine, sertraline, and fluoxetine in not delaying the time to ejaculation. The effect of citalopram to delay ejaculation is also relatively modest (17r ). There are, however, many other ways in which SSRIs can interfere with sexual function, for example by causing loss of sexual interest and erectile difficulties. In an open, prospective study of 1000 Spanish patients taking a variety of antidepressants, there was an overall incidence of sexual dysfunction of 59% (18R ). The highest rates, 60–70%, were found with SSRIs (including fluvoxamine) and venlafaxine. The lowest rates were found with mirtazepine (24%), nefazodone (8%), and moclobemide (4%). Spontaneous resolution of this adverse effect was uncommon—80% of subjects had no improvement in sexual function over 6 months of treatment. This study suggests very high rates of sexual dysfunction in patients taking SSRIs and venlafaxine. However, in investigations of this nature it can be difficult to tease out the effect of the drug from that of the underlying disorder. Nevertheless, while depressive symptoms should improve in most patients over 6 months of treatment, the sexual dysfunction in these subjects tended not to remit, suggesting that the antidepressant was the main culprit. Lactation The benefit : harm ratio of breast feeding during antidepressant treatment is difficult to compute and must be done on an individual basis. In general, breast-feeding with SSRIs is regarded as safe, as the amount of drug ingested by the infant is very low. However, adverse effects in the child are reported occasionally (SEDA-25, 15) and it is difficult to exclude completely the possibility of longterm effects on brain development in the infant. Clearly the lower the concentration of SSRI in the infant the less likely are problems of acute and longer-term toxicity. In two cases treatment of breast-feeding mothers with fluvoxamine (300 mg/day) was associated with undetectable concentrations of fluvoxamine (below 2.5 ng/ml) in the plasma of both infants (19A ). These results are encouraging, but further data will be needed before it can be concluded that fluvoxamine has an advantage over other SSRIs in this respect.

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Drug interactions Olanzapine is an atypical antipsychotic drug, which is increasingly being used in combination with SSRIs in the management of both depression and schizophrenia with secondary depression. It is metabolized by CYP1A2, which is inhibited by fluvoxamine. • A 21-year-old woman with schizophrenia and depression, who had been taking fluvoxamine (150 mg/day) and olanzapine (15 mg/day) for several months, developed an extrapyramidal movement disorder, including rigidity and tremor (20A ). The plasma fluvoxamine concentration was 70 µg/l (usual target range 20–500 µg/l), while that of olanzapine was 120 µg/l (usual target range 9–25 µg/l). The dosage of olanzapine was reduced to 5 mg/day and the plasma olanzapine concentration fell to 38 µg/l, with resolution of the tremor and rigidity. When fluvoxamine was replaced with paroxetine (20 mg/day) the olanzapine concentration fell further to 22 µg/l.

Of the SSRIs, fluvoxamine is the most potent inhibitor of CYP1A2 and is therefore likely to increase plasma olanzapine concentrations. The extrapyramidal effects in this case were presumably due excessive blockade of dopamine D2 receptors by raised olanzapine concentrations. Fluvoxamine also inhibits CYP2C9 and CYP2C19, the enzymes responsible for the metabolism of phenytoin. • A 45-year-old woman taking phenytoin (300 mg/day) had a plasma phenytoin concentration of 66 µmol/l (21A ). When she became depressed fluvoxamine (50 mg/day) was added. A month later her depressive symptoms had improved but she was ataxic and the plasma phenytoin concentration was 196 µmol/l. The fluvoxamine was withdrawn and the phenytoin dose reduced to 150 mg/day. Her plasma phenytoin concentration fell to 99 µmol/l, with resolution of the ataxia.

In vitro studies suggest that fluvoxamine is the most potent SSRI in terms of its ability to inhibit phenytoin metabolism. Inhibition of CYP2C19 or CYP2C9 could be responsible, although in vitro studies suggest that fluvoxamine is a relatively weak inhibitor of CYP2C9. However, in 14 healthy volunteers treatment with fluvoxamine (150–300 mg/day) for 5 days significantly reduced the clearance of tolbutamide (22C ). This suggests that fluvoxamine should be used with caution when it is co-administered with drugs such as tolbutamide, phenytoin, and warfarin, which are substrates for CYP2C9.

Antidepressant drugs

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Chapter 2

Like olanzapine, risperidone is a atypical antipsychotic that is frequently combined with SSRI treatment. Risperidone is metabolized mainly by CYP2D6. As might be expected, the addition of paroxetine (20 mg/day) to risperidone (4–8 mg/day) in 10 patients with schizophrenia produced a 45% increase in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (23C ). An increase in risperidone concentrations of this magnitude is likely to be clinically significant, and one of the patients developed signs of drug-induced Parkinson’s disease following the addition of paroxetine. Another case of severe parkinsonism with urinary retention occurred when fluoxetine (20 mg/day) was added to risperidone treatment (2 mg/day) in a 46-year-old man with schizophrenia. Risperidone had been prescribed at this dose for 1 month without any adverse effects, and the authors considered that a pharmacokinetic interaction between fluoxetine and risperidone was the most likely mechanism (24A ). Co-prescription of citalopram, which does not inhibit CYP2D6, has been reported not to alter plasma risperidone concentrations (SEDA23, 18). In a study treatment with citalopram (40 mg/day) for 4 weeks also failed to alter the pharmacokinetics of digoxin (1 mg orally) (25C ). Digoxin is not a CYP substrate, so an interaction with SSRIs is unlikely, but the authors cited a report that showed that fluoxetine increased plasma digoxin concentrations. Caution has been advocated when SSRIs such as fluoxetine are combined with the triptan drugs used to treat acute episodes of migraine (SEDA-24, 16). Triptans are metabolized mainly by monoamine oxidase, which makes pharmacokinetic interactions with SSRIs unlikely. However, there are case reports of symptoms suggestive of serotonin toxicity when fluoxetine has been combined with sumatriptan, perhaps because the SSRI can potentiate the 5-HT1B/1D agonist effects of the triptan (SEDA22, 14). The effect of fluoxetine 60 mg/day for 8 days on the pharmacokinetics of almotriptan has been studied in 14 healthy volunteers (26C ). Fluoxetine produced a significant increase in the peak concentration of almotriptan, but the AUC was not altered. These results suggest that CYP2D6 plays a minor role in the metabolism of almotriptan. The combined treatment was reported to be well tolerated, but this does not

exclude the possibility of occasional cases of serotonin toxicity in some individuals.

OTHER ANTIDEPRESSANTS Amfebutamone (bupropion) (SED-14, 60; SEDA-23, 20; SEDA-24, 16; SEDA-25, 17) Death The anti-smoking drug amfebutamone has been linked to 41 deaths (27Ar ). From the reports of suspected adverse events received by the Netherlands Pharmacovigilance Foundation, it appears that more than half of these cases concerned patients at risk of developing smoking-related diseases. In 15 cases there had been simultaneous use of amfebutamone with another antidepressant (10 patients), theophylline (one patient), or insulin (four patients). These combinations may lead to an increase in the risk of seizures. Furthermore, two patients reported having taken antiepileptic drugs, despite the fact that amfebutamone is contraindicated in patients with a seizure disorder. These results suggest that the guidelines described in the product information are not being adhered to in some cases. Although amfebutamone is useful new aid for patients who are trying to quit smoking, the contraindications should be carefully evaluated. Drug overdose A major concern about amfebutamone has been the risk of seizures (SEDA-23, 20), although this appears to be low with the modified-release formulation that is licensed in the UK for the treatment of nicotine dependence. However, it appears that seizure is a significant risk in amfebutamone overdose. • An 18-year-old man attempted suicide by taking bupropion 7.5 g (50 × 150 mg tablets) (28A ). On assessment 90 minutes later he was agitated and aggressive, with a resting pulse of 160 beats/minute and a blood pressure of 142/63 mmHg. He quickly developed a persistently low blood pressure (65/40 mmHg), followed by three generalized tonic–clonic seizures, which were controlled by diazepam. He was ventilated and a metabolic acidosis was corrected with sodium bicarbonate. Despite this, his blood pressure remained persistently low (70/40 mmHg) with a sinus tachycardia (150 beats/minute). Dopamine was ineffective and adrenaline was required. After

16 24 hours he was extubated and made a full recovery over the next 3 days. • A 14-year-old boy took 1.5–3.0 g of amfebutamone and had a persistent tachycardia, seizures, and brief agitation and aggression (29A ). He also had visual hallucinations, disorientation, and confusion but recovered about 24 hours after ingestion.

These cases show that overdose of amfebutamone can be serious.

Nefazodone

(SED-14, 64; SEDA-23, 20; SEDA-24, 17; SEDA-25, 17)

Liver There has been previous concern about rare but severe hepatic reactions to nefazodone (SEDA-24, 25). The cumulative incidence of hepatic adverse reactions associated with antidepressant treatment has been estimated through spontaneous reports to the Spanish Pharmacovigilance System (30c ). For classical tricyclic antidepressants and SSRIs the estimated rate of adverse hepatic reactions was 1.28–4.00 per 100 000 patient years. However, the rate with nefazodone was much higher (29 per 100 000 patient years). This report supports concerns that nefazodone may be more hepatotoxic than other antidepressants. Significant hepatic reactions to nefazodone are relatively rare but can be serious. Drug interactions Nefazodone is a potent inhibitor of CYP3A4 and raises plasma concentrations of drugs that are substrates for this enzyme, such as benzodiazepines, carbamazepine, and ciclosporin. A previous report suggested that nefazodone did not increase plasma concentrations of the atypical antipsychotic drug clozapine, suggesting that CYP3A4 may not play a major role in the metabolism of clozapine (SEDA-24, 17). However, in one case the addition of nefazodone appeared to produce clozapine toxicity (31A ). • A 40-year-old man had taken clozapine 450 mg/day and risperidone 6 mg/day for several years. Nefazodone (200 mg/day) was added in an attempt to improve persistent negative symptoms, and after a week the dosage was increased to 300 mg/day. One week later he reported anxiety and dizziness and was hypotensive. The combined concentrations of clozapine and its active metabolite norclozapine had increased from 309 ng/ml

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before nefazodone to 566 ng/ml. The nefazodone dosage was reduced to 200 mg/day and the anxiety, dizziness, and hypotension resolved over the next 7 days. At the same time plasma concentrations of clozapine and norclozapine fell to 370 ng/ml.

These results suggest that in some individuals CYP3A4 plays a significant role in the metabolism of clozapine and that the combination of nefazodone and clozapine should therefore be used with caution. It is possible that in this case concomitant treatment with risperidone may have increased the effect of nefazodone to reduce the clearance of clozapine. Drugs that inhibit CYP3A4 inhibit the clearance of terfenadine, an antihistamine that can prolong the QTc interval. This can cause potentially dangerous interactions. In a doubleblind, placebo-controlled study of the effect of nefazodone (600 mg/day for 1 week) on the pharmacokinetics of terfenadine (120 mg/day for 14 days) and another antihistamine, loratadine (20 mg/day for 14 days), in 67 healthy volunteers, nefazodone significantly reduced the clearance of terfenadine and prolonged the mean QTc interval (32C ). In addition, nefazodone produced a similar but smaller decrease in the clearance of loratadine and combined treatment also significantly increased the QTc interval. This effect of nefazodone on the clearance of terfenadine is expected, as is the increase in QTc interval. Loratadine is also partly metabolized by CYP2D6, which probably explains the lesser effect of nefazodone on loratadine clearance. Loratadine by itself does not increase the QTc interval significantly, but the current data suggest that cardiotoxicity might be a possibility when it is combined with nefazodone.

Venlafaxine

(SED-14, 66; SEDA-23, 20; SEDA-24, 18; SEDA-25, 18)

Hair SSRIs can cause occasional, idiosyncratic hair loss in some patients (SEDA-19, 10), and this has also been attributed to venlafaxine (33A ). • A 50-year-old woman took venlafaxine (75 mg/day) for depression, and the dose was increased to 150 mg/day after 2 weeks. After 4 weeks she noted increased hair loss when brushing or washing her hair. After 3 months she stopped taking

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17

venlafaxine and 1 month later her hair loss stopped completely. However, 10 months later she developed another depressive episode and was again successfully treated with venlafaxine. Once again she noted excessive hair loss. She was subsequently treated with sertraline (50 mg/day), which helped her depression without causing hair loss.

enced after sudden withdrawal of tricyclic antidepressants). The fact that they were relieved by a serotonin but not a noradrenaline re-uptake inhibitor suggests that venlafaxine-induced withdrawal symptoms are indeed mediated by serotonergic mechanisms.

The fact sertraline did not cause hair loss in this patient suggests that the mechanism was not related to serotonin re-uptake blockade.

Drug overdose Venlafaxine has been associated with occasional reports of cardiac conduction disturbances at both therapeutic doses and in overdose (SEDA-24, 19).

Drug withdrawal Both SSRIs and venlafaxine can cause troublesome withdrawal symptoms (SEDA-22, 12, 17). Because venlafaxine blocks the re-uptake of both serotonin and noradrenaline the mechanism of venlafaxineinduced abstinence symptoms is not clear. • A 72-year-old woman taking venlafaxine (150 mg/day) for depression was abruptly switched to the noradrenaline re-uptake inhibitor maprotiline 75 mg/day and 1 day later had agitation, sweating, nausea, vomiting, tinnitus, and insomnia (34A ). These symptoms continued for another week, but were abolished on the second day of sertraline treatment 50 mg/day.

The symptoms experienced by this patient were typical of venlafaxine and SSRI withdrawal (although they could also be experi-

• A 44-year-old woman took an overdose of venlafaxine of 3 g. An electrocardiogram showed sinus rhythm and incomplete right bundle branch block (35A ). She was monitored in an intensive care unit and 10 hours later a further electrocardiogram showed atrial fibrillation with wide QRS complexes. Both of these abnormalities resolved with sodium bicarbonate (100 ml of a 1 M solution). No further conduction disturbances were noted over the following days.

The authors suggested that the effect of venlafaxine on cardiac conduction was mediated by its ability to block the fast inward sodium current in cardiac myocytes. This might promote membrane stabilizing effects in a similar way to tricyclic antidepressants. They recommended that the management of venlafaxine overdose should include cardiac monitoring.

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24. Bozikas V, Petrikis P, Karavatos A. Urinary retention caused after fluoxetine-risperidone combination. J Psychopharmacol 2001; 15: 142–3. 25. Larsen F, Priskorn M, Overø KF. Lack of citalopram effect on oral digoxin pharmacokinetics. J Clin Pharmacol 2001; 41: 340–6. 26. Fleishaker JC, Ryan KK, Carel BJ, Azie NE. Evaluation of the potential pharmacokinetic interaction between almotriptan and fluoxetine in healthy volunteers. J Clin Pharmacol 2001; 41: 217–23. 27. Bhattacharjee C, Smith M, Todd F, Gillespie M. Bupropion overdose: A potential problem with the new ‘miracle’ anti-smoking drug. Int J Clin Pract 2001; 55: 221–2. 28. Ayers S, Tobias JD. Bupropion overdose in an adolescent. Pediatr Emerg Care 2001; 17: 104–6. 29. Carvajal García-Pando A, García del Pozo J, Sánchez AS, Velasco Martín A, Rueda de Castro AM, Lucena MI. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 2002; 63: 135–7. 30. Khan AY, Preskorn SH. Increase in plasma levels of clozapine and norclozapine after administration of nefazodone. J Clin Psychiatry 2001; 62: 375–6. 31. Abernethy DR, Barbey JT, Franc J, Brown KS, Feirrera I, Ford N, Salazar DE. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2001; 69: 96–103. 32. Pitchot W, Ansseau M. Venlafaxine-induced hair loss. Am J Psychiatry 2001; 158: 1159–60. 33. Luckhaus C, Jacob C. Venlafaxine withdrawal syndrome not prevented by maprotiline, but resolved by sertraline. Int J Neuropsychopharmacol 2001; 4: 43–4. 34. Combes A, Peytavin G, Theron D. Conduction disturbances associated with venlafaxine. Ann Intern Med 2001; 134: 166–7. 35. Wagena EJ, De Graaf L, Chavannes NH, Van Groothiest AC, Van Schayck CP. Onrust over de veiligheid van bupropion als middel om te stoppen met roken onterecht. Ned Tijdschr Geneeskd 2001; 145: 1489–92.

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3 A review of the comparative efficacy and tolerability of drug treatments for bipolar disorder included tolerability comparisons of lithium versus carbamazepine, lithium versus valproate semisodium, and lithium versus other medications (1R ). When 60 patients (22 men, 38 women) who had taken lithium for 1 year or more (mean 6.9 years; mean serum concentration 0.74 mmol/l) were interviewed about adverse effects, 60% complained of polyuria–polydipsia syndrome (serum creatinine concentrations were normal) and 27% had hypothyroidism requiring treatment (2c ). Weight gain was more common in women (47% vs. 18%) as were hypothyroidism (37% vs. 9%) and skin problems (16% vs. 9%), while tremor was more common in men (54% vs. 26%). Weight gain of over 5 kg in the first year of treatment was the only independent variable predictive of hypothyroidism. How knowledgeable 123 patients in a lithium clinic (mean treatment duration 12.1 years) were about lithium has been assessed with 63 questions based on the Lithium Knowledge Test. About two-thirds of the questions were answered correctly, and knowledge about lithium was not related to diagnosis, education, or sex. There was a negative association between increasing age and knowledge, and this was independent of the duration of lithium treatment (3C ). Even in a specialized lithium clinic, it seems that patient education could be improved upon, with the hope of a positive outcome on the effectiveness and safety of treatment.

ORGANS AND SYSTEMS Cardiovascular Investigators who used a Bayesian confidence propagation network to © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Lithium mine the World Health Organization International Drug Monitory Database for information on antipsychotic drugs and heart muscle disorders found 17 case reports involving lithium (4R ). There was a significant association with lithium and cardiomyopathy, but not with myocarditis. However, a causal relation could not be established. Two reviews of drug-related congenital malformation briefly mentioned lithium and cardiovascular teratogenesis, but no new information was provided (5r , 6r ). Likewise, two reviews of the cardiac effects of psychotropic drugs briefly mentioned lithium and dysrhythmias, with a focus on sinus node dysfunction (7r , 8r ). Case reports of adverse cardiovascular effects of lithium have included the following: • a 52-year-old man who took an overdose of lithium (serum concentration 4.58 mmol/l) and developed asymptomatic sinus bradycardia with sinus node dysfunction and multiple atrial extra beats, which resolved after hemodialysis (9A ); • a 59-year-old woman with syncope and sick sinus syndrome, which remitted when lithium was withdrawn, recurred when lithium was restarted, and then persisted despite lithium withdrawal; after a pacemaker was implanted she was treated successfully with lithium for 7 years (10A ); • a 66-year-old woman with pre-existing first-degree AV block who, about 2 weeks after beginning lithium therapy, developed sinus bradycardia, a junctional rhythm, a prolonged QT interval, and syncopal episodes (serum lithium concentration 1.4 mmol/l in a 40-hour sample); she was treated successfully with a pacemaker and a lower dose of lithium (11A ); • a 36-year-old man who became hypomanic after lithium was withdrawn because of symptomatic first-degree atrioventricular block (although how first-degree block could have caused symptoms is unclear) (12A ); • a 59-year-old man who was noted to have tachycardia, a shortened QT interval, and non-specific ST-T changes while hospitalized with lithium-associated hypercalcemia (13A ); • a 13-year-old boy in whom lithium induced a “pseudo-myocardial infarct pattern” on the electrocardiogram (this may have been an overinterpretation of non-specific T-wave changes) (14A );

19

20 • a 44-year-old woman with atropine-resistant but isoprenaline-sensitive bradycardia (36 bpm), thought to be due to sinus node dysfunction related to lithium, fentanyl, and propofol (15A ).

Respiratory A 60-year-old woman with bipolar disorder since the age of 29 developed idiopathic pulmonary fibrosis (cryptogenic fibrosing alveolitis) after having taken lithium for 9 years (16A ). Whether lithium played a causal role is at best highly speculative. Nervous system (see also Drug overdose) A case-control study of delirium in 22 psychiatric in-patients showed that lithium was one of the risk factors (adjusted odds ratio of 2.23) (17c ). Four of 17 patients who had paroxetine added to lithium as an adjunctive antidepressant developed symptoms suggestive of emerging serotonin syndrome (e.g. nausea, vomiting, diarrhea, sweating, anxiety, oversleeping) (see also Drug interactions) (18c ). Although the English abstract of a Polish review concluded that there is no evidence of significant cognitive deficits caused by lithium (19r ), others would take issue with this conclusion (20M ). Case reports of adverse nervous system effects of lithium have included the following: • permanent cerebellar sequelae in a 36-year-old man after intoxication at therapeutic lithium concentrations (21A ); • a prolonged seizure after ECT in a 45-year-old man taking lithium, amfebutamone, and venlafaxine (see also Drug interactions) (22A ); • worse stuttering in a 48-year-old man while taking lithium with improvement when he was switched to valproate (23A ); • severe essential tremor, which was at first mistaken for tardive dyskinesia in an 80-year-old woman taking lithium; it resolved almost completely when lithium was withdrawn (24A ).

Neuromuscular Lithium has been implicated in impaired athletic prowess in two cases (25A ). • A 21-year-old man had muscular incoordination while fast bowling (cricket), which improved when he switched to valproate. • A 71-year-old woman was unable to serve properly at tennis until she stopped taking lithium.

Endocrine Thyroid The prevalence of thyroperoxidase antibodies was higher in 226 bipolar patients (28%) than in population control

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and psychiatric control groups (3–18%). While there was no association with lithium exposure, the presence of antibodies increased the risk of lithium-induced hypothyroidism (26C ). When 22 men and 38 women who had taken lithium for at least a year (mean 6.9 years) for bipolar disorder were evaluated for adverse effects, hypothyroidism requiring thyroid supplementation was found in 16 (14 women and two men); nine had a goiter (2C ). The area from which some of the patients came was known to have a high background incidence of thyroid dysfunction. In 1989, 150 patients at different stages of lithium therapy had thyroid function assessed and subsequently, 118 were reassessed at least once and 54 completed a 10-year follow-up (27C ). The annual rates of new thyroid dysfunction were subclinical hypothyroidism 1.7%, goiter 2.1%, and autoimmunity 1.4%. While these figures were little different from those found in the general population, the authors acknowledged that lithium was a potential cause of thyroid dysfunction. Serum TSH concentrations were raised (to 10 mU/l or more) in 13 of 61 children aged 5–17 years taking lithium and valproate for up to 20 weeks (28c ). Of 42 bipolar patients who had taken lithium for 4–156 months, three had subclinical hypothyroidism, three had subclinical hyperthyroidism, and one was overtly hyperthyroid (29C ). Goiter by ultrasonography was present in 38% and mild thyroid dysfunction was suggested in 48% because of an apparent increased conversion of free T4 to free T3 . There was no correlation between the duration of lithium therapy and thyroid abnormalities. A retrospective record review of 300 patients with Graves’ disease and 100 with silent thyroiditis who had undergone thyroid scans showed that the likelihood of lithium exposure was 4.7 times higher in the latter, suggesting a link between lithium and thyrotoxicosis caused by silent thyroiditis (30C ). Case reports of adverse thyroid effects of lithium have included the following: • 56-year-old man taking lithium whose TSH concentration was abnormally high (50 mU/l) (31A ); • a 44-year-old woman who had taken lithium for 10 years and who developed swelling of the right lobe of the thyroid and hypothyroidism (15A );

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• a 63-year-old woman taking long-term lithium who developed subclinical hypothyroidism and primary hyperparathyroidism (32A ); • a 30-year-old man taking long-term ciclosporin and prednisolone following a bone-marrow transplant and long-term lithium for bipolar disorder who developed subacute thyroiditis, but without a clear relation to lithium (33A ); • a 27-year-old man who developed thyrotoxicosis while taking lithium (34A ).

Parathyroid Links between lithium and parathyroid dysfunction abound. Total serum calcium and intact parathyroid hormone concentrations were measured in 15 patients taking long-term lithium and 10 lithium-naïve patients; both were significantly higher in the lithium group (35c ). While the number of lithium patients with abnormally high concentrations was not stated, mean intact parathyroid hormone concentrations were almost twice the upper limit of the reference range (102 vs. 55 pg/ml). Parathyroid tumors from nine patients with lithium-associated hyperparathyroidism (six multiglandular, three uniglandular) have been compared with 13 non-lithium-associated sporadic parathyroid tumors with regard to gross genomic alterations (36c ). Gross chromosomal alterations were absent in most of the lithium group and were more common in the sporadic group. A lithium chloride solution caused changes in gravicurvature, statocyte ultrastructure, and calcium balance in pea root, believed to be due to effects of lithium on the phosphoinositide second messenger system (37E ). The implications with regard to human parathyroid function are obscure. Case reports of adverse parathyroid effects of lithium have included the following: • three cases of hyperparathyroidism among 26 cases of chronic lithium poisoning (see also Drug overdose) (38A ); • a 78-year-old man who had taken lithium for 30 years who presented with dehydration, azotemia, hypernatremia, hypercalcemia, and increased parathyroid hormone concentrations (39A ); • a 63-year-old woman taking long-term lithium therapy who had primary hyperparathyroidism (32A ); • a woman who had taken lithium for 15 years who became hypercalcemic and stopped taking lithium, but 2 years later had two parathyroid adenomas removed surgically (40A );

21 • a 42-year-old man who had taken lithium for 17 years and who had raised serum calcium and parathyroid hormone concentrations, which normalized after removal of a parathyroid adenoma (41A ); • a 59-year-old man with hypercalcemia and increased parathyroid hormone concentrations 3 months after starting lithium, which normalized after lithium was withdrawn (13A ); • three cases of lithium-related hyperparathyroidism from Denmark (42A ) and one from Spain (43A ).

Diabetes insipidus Two of 10 patients taking long-term lithium therapy were thought to have hypothalamic diabetes insipidus, because of a positive response to desmopressin (44c ). Metabolic It has been reported that diabetes mellitus is three times more common in bipolar patients than in the general population (45r ). However, the authors of this review also pointed out that data are conflicting with regard to the effects of lithium on blood glucose concentrations. An increased lithium dosage requirement in a hyperglycemic 40-year-old woman was attributed to the osmotic diuretic effect of glycosuria, increasing lithium excretion (46A ). In two cases of lithium intoxication, type 2 diabetes mellitus was felt to be a contributing factor (47A ). Electrolyte balance Potassium A 25-yearold man had a single episode of generalized flaccid hypokalemic paralysis while taking lithium. He responded to intravenous potassium, lithium was stopped, and 1 year later there were no further episodes (48A ). While the authors believed that lithium had been the cause, without confirmation by rechallenge this remains far from conclusive. Sodium Hypernatremia can occur secondary to dehydration in patients taking lithium and is not uncommon in association with lithium poisoning. Lithium-induced diabetes insipidus is often a contributing factor (see also Urinary tract and Drug overdose). Hematologic The effects of lithium on hemopoiesis have been studied in 100 patients who had developed chronic granulocytopenia after cancer chemotherapy or radiotherapy (49C ). The mean leukocyte count rose by 46%, but there were no changes in platelet or erythrocyte counts. However, there was a significant

22 increase in platelet count in those whose baseline values were below 150 × 109 /l. Lithium was well tolerated (mean serum concentration 0.59 mmol/l). Granulocyte counts and granulocyte colonystimulating factor (G-CSF) concentrations were measured in 18 patients before and after 1 and 4 weeks of lithium treatment, and compared with values in 20 patients taking long-term lithium (50c ). At week 4, the granulocyte count was significantly higher than at baseline or at week 1, or in the long-term group. There was only a non-significant increase in G-CSF concentration at weeks 1 and 4. The granulocyte count in those taking long-term lithium did not differ significantly from the baseline values in the other group. Mouth and teeth The issue has been raised of whether oral lithium therapy was responsible for failure of titanium dental implants in a 62-year-old man (51A ). Pancreas All cases of drug-induced pancreatitis (n = 47) reported to the Danish Committee on Adverse Drug Reactions between 1968 and 1999 have been analysed; one involved lithium (plus a neuroleptic drug) (52C ). Whether lithium was causally involved is not known. Urinary tract In a retrospective study, 114 patients who had taken lithium for 4–30 years were compared with 94 unmedicated age- and sex-matched controls with regard to changes in creatinine concentrations (53C ). Of the patients taking lithium 21% had blood creatinine concentrations that had increased gradually and were now over the top of the reference range. This finding was associated with episodes of lithium intoxication and with diseases and other medications that could also affect glomerular function. Sex, psychiatric diagnosis, duration of treatment, cumulative dose, and serum lithium concentrations did not predict an abnormal creatinine concentration. Renal function has been assessed in 10 patients taking long-term lithium (over 3 years, mean 80 months), 10 taking short-term lithium (3 years or less, mean 16 months), and 10 lithium-naïve patients (44C ). Serum BUN and creatinine concentrations were within the reference ranges and did not differ among the

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groups, but 24-hour creatinine clearance was significantly lower in those taking long-term lithium (73 vs. 125 and 150 ml/min). There were no significant differences among the groups in urine osmolality after 8-hour water deprivation and desmopressin, but partial nephrogenic diabetes insipidus was diagnosed in four long-term and two short-term patients and hypothalamic diabetes insipidus in two long-term patients. The authors concluded that long-term lithium therapy is a risk factor for renal impairment. There have been several case reports of lithium-related nephrogenic diabetes insipidus, sometimes associated with dehydration and lithium intoxication (39A , 54A –57A ). For example, a 77-year-old woman who had taken lithium for 10 years developed delirium, hypernatremia, prerenal azotemia, and a serum lithium concentration of 1.4 mmol/l; her condition was attributed to dehydration related to partial nephrogenic diabetes insipidus (54A ). An 83-year-old man developed nephrotic syndrome while taking lithium (58A ). Two studies in rats have potential implications for humans. In rats with mild to severe lithium-induced nephropathy, urine N-acetyl-bD-glucosaminidase (NAG) was an early indicator of renal insufficiency (59E ). Both 6 Li and 7 Li caused reduced urine concentrating ability and increased urine volume and renal tubular lesions, but 6 Li was more nephrotoxic (60E ). The authors suggested that eliminating 6 Li from pharmaceutical products might reduce nephrotoxicity (although 6 Li accounts for only about 7% of the lithium in such products). Skin Six months after beginning lithium, a man in his late twenties developed severe truncal acne, which worsened over 5 years, at which time lithium was withdrawn (61A ). Nevertheless, the lesions were still present 4 years later, leading to the conclusion that lithium had caused irreversible acne. Of course, the association could have been coincidental. Skin and hair A 55-year-old man (erroneously reported by me in SEDA-25 to be a woman), who had taken lithium and haloperidol for 11 years, developed hyperkeratotic follicular papules on his scalp, extremities, and trunk, which on biopsy were suggestive of follicular mycoses fungoides (62A ). He also had a

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1-year history of scalp, axillary, and pubic hair loss. Following replacement of lithium with valproate, his hair regrew and the papules cleared almost completely in 3 months. Hair When a split hair sample from a healthy volunteer was sent to six commercial laboratories in the USA for trace mineral analysis, marked variations in results were found (including lithium concentrations), leading to the conclusion that such analyses were unreliable (63c ). Sexual function A 17-year-old man had taken risperidone for 2 years without adverse effects, but 12 weeks after lithium was added he reported prolonged erections (lasting 1–3 hours) 2–5 times daily; risperidone was tapered and withdrawn and the problem resolved (64A ). Reproductive system In an in vitro study, LY294002, a phosphatidylinositol-3-kinase inhibitor, overcame impaired human sperm motility induced by lithium chloride (65E ). At blood concentrations within the human target range, oral lithium caused degenerative changes in testicular morphology in spotted munia (Lonchura punctulata), a seasonally breeding sub-tropical finch (66E ). How this might relate to effects in men is open to question. Immunologic Lithium has complex effects on immune function, as suggested by a study of 10 healthy volunteers who had increases in interleukin-4 and interleukin-10 concentrations, and falls in interleukin-2 and interferon concentrations (67c ). The clinical implications of these findings are unclear. Death Evidence continues to accrue that long-term lithium therapy reduces suicidal behavior. A retrospective study divided high-risk patients into excellent, moderate, and poor responders to lithium and showed that no further suicide attempts occurred in 93%, 83%, and 49% respectively (68C ). The substantial reduction in suicidal tendency in the poor responder group suggested an antisuicidal effect of lithium beyond its mood stabilizing properties, although the psychosocial benefits of lithium clinic treatment could have been contributing factors. For deaths related to lithium toxicity, see Drug overdose.

LONG-TERM EFFECTS Withdrawal Of 30 patients with major depressive disorder who had responded to lithium augmentation for antidepressant-resistant depression, 15 were switched to placebo over 1–7 days (69c ). Two became manic, and it was suggested that lithium withdrawal may have uncovered latent bipolar disorder (70r ). When 21 elderly patients with a major depressive episode who had responded to lithium augmentation had lithium withdrawn gradually (over 2–12 weeks), nine relapsed but none became manic (71c ). Whether gradual withdrawal protected against withdrawal mania or whether there were no latent bipolar patients in the study is unknown.

SECOND-GENERATION EFFECTS Pregnancy and lactation The treatment of bipolar disorder during pregnancy and lactation has been reviewed, with reference to lithiumrelated maternal, fetal, and neonatal toxicity, morphological and behavioral teratogenicity, carcinogenicity and mutagenicity, and miscellaneous effects (72R ). Elsewhere the effects of lithium, valproic acid, and carbamazepine during pregnancy (73R ), and drug-induced congenital defects (with only a brief mention of lithium) (6r ) have been reviewed. A more specific review dealing with the use of drugs during pregnancy in women with renal disease mentioned the need for lithium dosage reduction in such cases (74r ). A 37-year-old woman with severe bipolar disorder, who continued to take lithium throughout pregnancy, had a normal delivery but was not allowed to breast-feed (75A ). In a review of the use of psychotropic drugs during breast-feeding it was briefly mentioned that lithium was not advisable but was justified under certain circumstances (76r ). Lithium was also briefly discussed in a review of xenobiotics and breast-feeding (77r ).

RISK FACTORS Age In a cross-sectional study of 12 octogenarians (average age 84 years) who had

24 taken lithium for an average of 54 months (mean serum concentration 0.42 mmol/l), none became toxic and none had to stop treatment because of adverse effects. Transient renal function abnormalities were noted, one patient developed nephrogenic diabetes insipidus, and one became hypothyroid (78c ). For lithium therapy in very old people the authors advised close monitoring in a specialized setting.

DRUG ADMINISTRATION Drug formulations Brain lithium concentrations (measured by magnetic resonance spectroscopy) after the use of a modified-release formulation (Lithobid SR) or an immediaterelease formulation have been compared in a crossover design (79c ). There were higher brain concentrations with the modified-release formulation, but whether this has clinical implications requires further study. Formulations of lithium carbonate tablets with various binding substances have been discussed (80c ). Drug additives Gelatin is derived from natural pork and beef products and is present in some lithium formulations. Since certain religions forbid the consumption of gelatin, knowing that it is present in Eskalith capsules and Eskalith CR and absent in Eskalith tablets (not available in the USA) and Lithobid SR might influence prescribing practices under certain circumstances (81r ). The same would apply to other lithium products. Drug dosage regimens In an open-label pilot study of rapid administration of slow-release lithium (20 mg/kg/day in two divided doses) for acute mania, five of 15 patients completed 10 days of treatment, seven improved sooner and were discharged, and two withdrew because of adverse effects (bradycardia in one and tremor, fatigue, and diarrhea in the other; one patient appears not to have been accounted for); two other patients also had asymptomatic bradycardia (82c ). A review of loading strategies in acute mania included a section on lithium (83r ). A small study of brain lithium concentrations measured by magnetic resonance spectroscopy showed higher brain:serum lithium

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concentration ratios in subjects taking a single daily dose (n = 5) than in those taking a twicedaily regimen (n = 3) (84c ). Even to speculate about the possible clinical implications of this finding would be premature. Drug administration route To determine the safety of using lithium chloride dilution to measure cardiac output, the pharmacokinetic and toxic effects of intravenous lithium chloride have been studied in six conscious healthy Standardbred horses (85E ). The mean peak serum concentration was 0.56 mmol/l. There were no toxic effects nor significant changes in laboratories studies, electrocardiograms, or gastrointestinal motility. Three horses had increased urine output. A similar study was performed in patients undergoing cardiac surgery and healthy volunteers; the highest dose of LiCl was 0.6 mmol given intravenously five times at 2-minute intervals (86c ). Unfortunately, no mention was made of tolerability or adverse effects. Drug overdose There are three forms of lithium overdose: • acute (abrupt overdose in a drug-naïve person); • chronic (gradual accumulation, reaching toxic concentrations); • acute-on-chronic (abrupt overdose by a person already taking lithium). Overdose secondary to drug interactions is discussed in that section. The 2000 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System listed six lithium-related deaths (four cases of intentional suicide and two of therapeutic error) and two other deaths in which lithium was not listed as the primary cause (87R ). A total of 4663 lithium-related exposures were reported, in which death was the outcome in 13 and a major life-threatening event or cause of significant disability in 267. A retrospective study of 97 cases of lithium poisoning treated at a regional center in Australia over 13 years found severe neurotoxicity in 28 (26 were cases of chronic poisoning and two were acute-on-chronic) (38C ). Risk factors were nephrogenic diabetes insipidus, older age,

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abnormal thyroid function, and impaired renal function. In a retrospective study of 114 patients admitted to a toxicological ICU with suspected lithium intoxication, 81 had definite intoxication; 78% were deliberate overdoses and 22% were accidental (due, for example, to renal insufficiency, dehydration, drug interactions, poor compliance, drunkenness). Most were treated conservatively with gastric lavage and forced diuresis; hemodialysis was used only in 3–6%. Two of those who took a deliberate overdose and one of those who took an accidental overdose died (88C ). Cases of lithium toxicity in a municipal hospital over a 10-year period involved eight women (mean age 66 years); neurological symptoms were the most common presentations (89c ). Two were acute overdoses and the rest were chronic intoxications. There was one death (group not specified). A 64-year-old woman had a two-week history of daily bilateral holocranial headache as the presenting complaint of lithium toxicity (serum concentration 2.5 mmol/l); dosage reduction resolved the headache and the extrapyramidal and cerebellar findings (90A ). Another toxic patient presented with nonconvulsive status epilepticus and a serum lithium concentration of 1.9 mmol/l (91A ). Non-reversible lithium neurotoxicity continues to be reported (92A , 93A ), including a case of lithium overdose (serum lithium concentration 3.9 mmol/l) with persistent severe ataxia for 9 months that improved markedly when inadvertently treated with high-dose buspirone (120–160 mg/day) (94A ). Hemodialysis (56A , 95A , 96A ), sometimes with additional continuous venovenous hemofiltration dialysis (97A , 98A ), continues to be described as a successful intervention for lithium poisoning. Peritoneal dialysis is a far less efficient way to clear lithium from the body. One patient treated in this way had permanent neurological abnormalities and another died; a third toxic patient who also had diabetic ketoacidosis died after treatment with hydration and insulin (99A ). On the other hand, a 51-yearold woman who took fifty 450 mg slow-release lithium carbonate tablets had a serum lithium concentration of 10.6 mmol/l 13 hours later, but no evidence of neurotoxicity or nephrotoxicity. She was treated conservatively with intravenous

fluids and recovered fully (100A ). Acute lithium overdose is often tolerated better than chronic intoxication. An 85-year-old woman became gradually toxic (serum lithium 2.9 mmol/l) in a nursing home (101A ). Despite only conservative management, there was slow but complete resolution of severe neurological symptoms, including coma, fixed pupils, and Cheyne–Stokes respiration.

DRUG INTERACTIONS In a review of the pharmacokinetics of mood stabilizers and new anticonvulsants, lithium drug interactions were only briefly mentioned (102r ). Anesthetics Sinus bradycardia (36 bpm) developed in a 44-year-old woman taking lithium, fentanyl, and propofol (15A ) (see also Cardiovascular). Antibiotics A 40-year-old woman developed nausea, malaise, impaired concentration, trembling, unsteadiness, diarrhea, and muscle spasm in association with a serum lithium concentration of 2.1 mmol/l while taking trimethoprim 300 mg/day (103A ). The interaction was attributed to the amiloride-like diuretic effect of the latter, causing lithium retention. Anticonvulsants In a review of pharmacokinetic interactions between antiepileptic drugs and psychotropic drugs, there were no clinically significant interactions of lithium with gabapentin, lamotrigine, valproate, or topiramate, although serum lithium concentrations were reduced slightly by topiramate (104r ). Lithium intoxication in a 33-year-old man was attributed to carbamazepine-induced renal insufficiency (105A ). Antidepressants Of 17 patients who took paroxetine as an adjunct to lithium therapy, retrospectively evaluated, four developed symptoms suggestive of an evolving serotonin syndrome that remitted when either drug was withdrawn (see also Nervous system) (18c ). A 45-year-old man taking lithium, amfebutamone, and venlafaxine developed a prolonged

26 seizure after ECT, thought to have been caused by a lowering of the seizure threshold due to amfebutamone (although a role of the other two drugs could not be excluded) (22A ). Antipsychotic drugs A 59-year-old man taking lithium, haloperidol, and carbamazepine had impaired memory, impaired attention, and an encephalopathy-like pattern on EEG that normalized when haloperidol was withdrawn (106A ). Olanzapine 5 mg/day was added, and 3 weeks later he became disoriented. Surprisingly, the olanzapine was continued and he remained disoriented. A 13-year-old boy with rhabdomyolysis ascribed to olanzapine was also taking lithium, so that a drug interaction could not be excluded (14A ). Diuretics A 26-year-old woman had been stable on lithium (serum concentration 1.1 mmol/l), but after taking herbal diuretics for 2–3 weeks

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developed manifestations of lithium toxicity (serum concentration 4.5 mmol/l) (107A ). NSAIDs A man of unspecified age developed cognitive impairment and a serum lithium concentration of 2.4 mmol/l after taking ibuprofen for shoulder pain (108A ). In a review of celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor, increased serum lithium concentration was mentioned as a possibility, but no specifics were provided (109r ). A 44-year-old woman taking nimesulide, a COX-2 inhibitor, and ciprofloxacin developed lithium intoxication (serum concentration 3.23 mmol/l) complicated by renal insufficiency; the interaction was attributed to nimesulide (110A ). Xanthines There have been case reports of caffeine withdrawal leading to increased serum lithium concentrations, assumed to be due to reduced renal lithium clearance (111r ).

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9. Newland KD, Mycyk MB. Hemodialysis reversal of lithium overdose cardiotoxicity. Am J Emerg Med 2002; 20: 67–8. 10. Terao T. Lithium therapy with pacemaker. Pharmacopsychiatry 2002; 35: 35. 11. Delva NJ, Hawken ER. Preventing lithium intoxication. Guide for physicians. Can Fam Phys 2001; 47: 1595–600. 12. Montes JM, Ferrando L. Gabapentin-induced anorgasmia as a cause of noncompliance in a bipolar patient. Bipolar Disord 2001; 3: 52. 13. Rifai MA, Moles JK, Harrington DP. Lithiuminduced hypercalcemia and parathyroid dysfunction. Psychosomatics 2001; 42: 359–61. 14. Rosebraugh CJ, Flockhart DA, Yasuda SU, Woosley RL. Olanzapine-induced rhabdomyolysis. Ann Pharmacother 2001; 35: 1020–3. 15. Uchiyama Y, Nakao S, Asai T, Shingu K. A case of atropine-resistant bradycardia in a patient on long-term lithium medication [Japanese]. Jpn J Anesthesiol 2001; 50 1229–31. 16. Bhandari S, Samellas D. Bipolar affective disorder and idiopathic pulmonary fibrosis. J Clin Psychiatry 2001; 62: 574–5. 17. Patten SB, Williams JVA, Petcu R, Oldfield R. Delirium in psychiatric inpatients: a case–control study. Can J Psychiatry 2001; 46: 162–6. 18. Fagiolini A, Buysse DJ, Frank E, Houck PR, Luther JF, Kupfer DJ. Tolerability of combined treatment with lithium and paroxetine in patients

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with bipolar disorder and depression. J Clin Psychopharmacol 2001; 21: 474–8. 19. Suwalska A, Lojko D, Rybakowski J. Wplyw lekow normotymicznych na czynnosci poznawcze. Psychiatr Pol 2001; 35: 245–56. 20. Arts BMG, Honig A, Riedel WJ, Ponds RWHM. Cognitive effects of lithium; a metaanalysis and proposal for screening. Tijdschr Psychiatr 1998; 40: 466–8. 21. Van der Steenstraten IM, Achilles RA. Irreversibele neurologische schade na een lithiumintoxicatie bij therapeutische concentraties. Tijdschr Psychiatr 2001; 43: 271–5. 22. Conway CR, Nelson LA. The combined use of bupropion, lithium, and venlafaxine during ECT: a case of prolonged seizure activity. J ECT 2001; 17: 216–18. 23. Netski AL, Piasecki M. Lithium-induced exacerbation of stutter. Ann Pharmacother 2001; 35: 961. 24. Davis JM. Lithium intoxication and pontine haemorrhage. Acta Psychiatr Scand 2001; 103: 401. 25. Grounds D. Connection between lithium and muscular incoordination. Aust NZ J Psychiatry 2002; 36: 142–3. 26. Kupka RW, Nolen WA, Post RM, McElroy SL, Altshuler LL, Denicoff KD, Frye MA, Keck PE, Leverich GS, Rush AJ, Suppes T, Pollio C, Drexhage HA. High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Biol Psychiatry 2002; 51: 305–11. 27. Bocchetta A, Mossa P, Velluzzi F, Mariotti S, Del Zompo M, Loviselli A. Ten-year follow-up of thyroid function in lithium patients. J Clin Psychopharmacol 2001; 21: 594–8. 28. Gracious BL. Elevated TSH in bipolar youth prescribed both lithium and divalproex sodium. Int Drug Ther Newslett 2001; 36: 94–5. 29. Çayköylü A, Çapoglu I, Ünüvar N, Erdem F, Çetinkaya R. Thyroid abnormalities in lithiumtreated patients with bipolar affective disorder. J Int Med Res 2002; 30: 80–4. 30. Miller KK, Daniels GH. Association between lithium use and thyrotoxicosis caused by silent thyroiditis. Clin Endocrinol (Oxf) 2001; 55: 501–8. 31. Bermudes RA. Psychiatric illness or thyroid disease? Don’t be misled by false lab tests. Curr Psychiatry 2002; 1: 51–2, 57–61. 32. Mira SA, Gimeno EJ, Díaz-Guerra GM, Carranza YFH. Alteraciones tiroideas y paratiroideas asociadas al tratamiento crónico con litio. A propósito de un caso. Rev Esp Enferm Metab Oseas 2001; 10: 153–6. 33. Obuobie K, Al-Sabah A, Lazarus JH. Subacute thyroiditis in an immunosuppressed patient. J Endocrinol Invest 2002; 25: 169–71. 34. Scanelli G. Tireotossicosi da litio. Descrizione di un caso e revisione della letteratura. Recenti Prog Med 2002; 93: 100–3. 35. Turan MT, Esel E, Tutus A, Sofuoglu S, Gönük AS. Lithium-induced alterations in parathormone function in patients with bipolar disorder. Bull Clin Psychopharmacol 2001; 11: 96–100. 36. Dwight T, Kytölä S, Teh BT, Theodosopoulos G, Richardson AL, Philips J, Twigg S, Delbridge L.

27 Marsh DJ, Nelson AE, Larsson C, Robinson BG. Genetic analysis of lithium-associated parathyroid tumors. Eur J Endocrinol 2002; 146: 619–27. 37. Belyavskaya NA. Lithium-induced changes in gravicurvature, statocyte ultrastructure and calcium balance of pea roots. Adv Space Res 2001; 27: 961– 6. 38. Oakley PW, Whyte IM, Carter GL. Lithium toxicity: an iatrogenic problem in susceptible individuals. Aust NZ J Psychiatry 2001; 35: 833–40. 39. Krastins MG, Phelps KR. Nephrogenic diabetes insipidus and hyperparathyroidism in a patient receiving chronic lithium therapy. J Am Geriatr Soc 2002; 50: S140. 40. Dieserud F, Brun AC, Låhne PE, Normann E. Litiumbehandling og hyperparatyreoidisme. Tidsskr Nor Laegeforen 2001; 121: 2602–3. 41. Pieri-Balandraud N, Hugueny P, Henry JF, Tournebise H, Dupont C. Hyperparathyroïdie induite par le lithium. Un nouveau cas. Rev Med Interne 2001; 22: 460–4. 42. Valeur N, Andersen RS. Lithium-induced dysfunction of the parathyroid hormone. Ugeskr Laeg 2002; 164: 639–40. 43. Catalá JC, Rubio AB, Fernández CC, Ballester YAH. Hiperparatiroidismo asociada al tratamiento con litio. Rev Esp Enferm Metab Oseas 2001; 10: 157–8. 44. Turan T, Esel E, Tokgöz B, Aslan S, Sofuoglu S, Utas C, Kelestimur F. Effects of short- and long-term lithium treatment on kidney functioning in patients with bipolar mood disorder. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 651–5. 45. Cassidy F. Diabetes mellitus in manicdepressive patients. Essent Psychopharmacol 2001; 4: 49–57. 46. Cyr M, Guia MAC, Laizure SC. Increased lithium dose requirement in a hyperglycemic patient. Ann Pharmacother 2002; 36: 427–9. 47. Uzu T, Ichida K, Ko M, Tsukurimichi S, Yamato M, Takahara K, Ohashi M, Yamauchi A, Nomura M. Two cases of lithium intoxication complicated by type 2 diabetes mellitus [Japanese]. J Jpn Diabetes Soc 2001; 44: 767–70. 48. Chémali KR, Suarez JI, Katirji B. Acute hypokalemic paralysis associated with long-term lithium therapy. Muscle Nerve 2001; 24: 297–8. 49. Hager ED, Dziambor H, Höhmann D, Winkler P, Strama H. Effects of lithium on thrombopoiesis in patients with low platelet cell counts following chemotherapy or radiotherapy. Biol Trace Elem Res 2001; 83: 139–48. 50. Esel E, Özdemir MA, Turan MT, Bastürk M, Kiliç H, Köse K, Gönül AS, Sofuoglu S. Effects of lithium treatment on granulocytes and granulocyte colony-stimulating factor in patients with bipolar affective disorder. Bull Clin Psychopharmacol 2001; 11: 28–32. 51. Corica M, Borcese R, Savoldi E. Can the lithium therapy cause titanium implant failure? J Dent Res 2001; 80: 1246. 52. Andersen V, Sonne J, Andersen M. Spontaneous reports on drug-induced pancreatitis in Den-

28 mark from 1968 to 1999. Eur J Clin Pharmacol 2001; 57: 517–21. 53. Lepkifker E, Sverdlik A, Iancu I, Ziv R. Renal failure in long-term lithium treatment. Bipolar Disord 2001; 3 Suppl 1: 45. 54. Mukhopadhyay D, Gokulkrishnan L, Mohanaruban K. Lithium-induced nephrogenic diabetes insipidus in older people. Age Ageing 2001; 30: 347–50. 55. Eustatia-Rutten CFA, Tamsma JT, Meinders AE. Lithium-induced nephrogenic diabetes insipidus. Neth J Med 2001; 58: 137–42. 56. Laßnig E, Berent R, Wallner M, Jagsch C, Auer J, Eber B. Manisch-depressive Patientin mit Polyurie unter Lithiumtherapie. Intensivmedizin 2001; 38: 26–30. 57. Waise A, Fisken RA. Unsuspected nephrogenic diabetes insipidus. Br Med J 2001; 323: 96–7. 58. Herrero-Mendoza MD, Caramelo C, BellverÁlvarez TM, Lopez-Cubero L. Sindrome nefrotico y tratamiento con litio. Med Clin (Barc) 2001; 116: 758–9. 59. Ida S, Yokota M, Ueoka M, Kiyoi K, Takiguchi Y. Mild to severe lithium-induced nephropathy models and urine N-acetyl-b-D-glucosaminidase in rats. Methods Find Exp Clin Pharmacol 2001; 23: 445–8. 60. Stoll PM, Stokes PE, Okamoto M. Lithium isotopes: differential effects on renal function and histology. Bipolar Disord 2001; 3: 174–80. 61. Öztas P, Aksakal AB, Öztas MO. Severe acne with lithium. Ann Pharmacother 2001; 35: 961–2. 62. Francis GJ, Silverman AR, Saleh O, Lee GJ. Follicular mycosis fungoides associated with lithium. J Am Acad Dermatol 2001; 44: 308–9. 63. Seidel S, Kreutzer R, Smith D, McNeel S, Gilliss D. Assessment of commercial laboratories performing hair mineral analysis. J Am Med Assoc 2001; 285: 67–72. 64. Owley T, Leventhal B, Cook EH. Risperidoneinduced prolonged erections following the addition of lithium. J Child Adolesc Psychopharmacol 2001; 11: 441–2. 65. Luconi M, Marra F, Gandini L, Filimberti E, Lenzi A, Forti G, Baldi E. Phosphatidylinositol 3kinase inhibition enhances human sperm motility. Hum Reprod 2001; 16: 1931–7. 66. Banerji TK, Maitra SK, Dey M, Hawkins HK. Gametogenic responses of the testis in spotted munia (Lonchura punctulata; aves) to oral administration of lithium chloride. Endocr Res 2001; 27: 345–56. 67. Rapaport MH, Manji HK. The effects of lithium on ex vivo cytokine production. Biol Psychiatry 2001; 50: 217–24. 68. Ahrens B, Müller-Oerlinghausen B. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry 2001; 34: 132–6. 69. Bauer M, Bschor T, Kunz D, Berghöfer A, Ströhle A, Müller-Oerlinghausen B. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry 2000; 157: 1429–35.

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70. Faedda GL, Tondo L, Baldessarini RJ. Lithium discontinuation: uncovering latent bipolar disorder? Am J Psychiatry 2001; 158: 1337–8. 71. Fahy S, Lawlor BA. Discontinuation of lithium augmentation in an elderly cohort. Int J Geriatr Psychiatry 2001; 16: 1004–9. 72. Davis LL, Shannon S, Drake RG, Petty F. The treatment of bipolar disorder during pregnancy. In: Yonkers KA, Little BB, editors. Management of Psychiatric Disorders in Pregnancy. London: Arnold, 2001: 122–33. 73. Iqbal MM, Sohhan T, Mahmud SZ. The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. Clin Toxicol 2001; 39: 381–92. 74. Keller F, Griesshammer M, Häussler U, Paulus W, Schwarz A. Pregnancy and renal failure. The case for application of dosage guidelines. Drugs 2001; 61: 1901–20. 75. Retamal PC, Cantillano VA. Tratamiento de la enfermedad bipolar durante el embarazo y puerperio. Caso clinico. Rev Med Chil 2001; 129: 556–60. 76. Burt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E. The use of psychotropic medications during breast-feeding. Am J Psychiatry 2001; 158: 1001–9. 77. Howard CR, Lawrence RA. Xenobiotics and breastfeeding. Pediatr Clin North Am 2001; 48: 485–504. 78. Fahy S, Lawlor BA. Lithium use in octogenarians. Int J Geriatr Psychiatry 2001; 16: 1000–3. 79. Henry ME, Moore CM, Demopolas C, Cote J, Renshaw PF. A comparison of brain lithium levels attained with immediate and sustained release lithium. Biol Psychiatry 2001; 49 Suppl 8: 119S. 80. Gazikolovic E, Obrenovic D, Nicovic Z. Formulation of lithium carbonate tablets with various binding substances [Serbo-Croatian]. Vojnosanit Pregl 2001; 58: 641–4. 81. Sattar SP, Pinals DA. When taking medications is a sin. Psychiatr Serv 2002; 53: 213–14. 82. Keck PE, Strakowski SM, Hawkins JM, Dunayevich E, Tugrul KC, Bennett JA, McElroy SL. A pilot study of rapid lithium administration in the treatment of acute mania. Bipolar Disord 2001; 3: 68–72. 83. Carroll BT, Thalassinos A, Fawver JD. Loading strategies in acute mania. CNS Spectrums 2001; 6: 919–22, 30. 84. Soares JC, Boada F, Spencer S, Mallinger AG, Dippold CS, Wells KF, Frank E, Keshavan MS, Gershon S, Kupfer DJ. Brain lithium concentrations in bipolar disorder patients: preliminary 7 Li magnetic resonance studies at 3T. Biol Psychiatry 2001; 49: 437–43. 85. Hatfield CL, McDonell WN, Lemke KA, Black WD. Pharmacokinetics and toxic effects of lithium chloride after intravenous administration in conscious horses. Am J Vet Res 2001; 62: 1387–92. 86. Jonas MM, Linton RAF, O’Brien TK, Band DM, Linton NWF, Kelly F, Burden TJ, Chevalier SFA, Thompson RPH, Birch NJ, Powell JJ. The pharmacokinetics of intravenous lithium chloride in patients and normal volunteers. J Trace Microprobe Techn 2001; 19: 313–20.

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87. Litovitz TL, Klein-Schwartz W, White S, Cobaugh DJ, Youniss J, Omslaer JC, Drab A, Benson BE. 2000 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001; 19: 337–95. 88. Montagnon F, Saïd S, Lepine JP. Lithium: poisonings and suicide prevention. Eur Psychiatry 2002; 17: 92–5. 89. Meltzer E, Steinlauf S. The clinical manifestations of lithium intoxication. Isr Med Assoc J 2002; 4: 265–7. 90. Bigal ME, Bordini CA, Speciali JG. Daily headache as a manifestation of lithium intoxication. Neurology 2001; 57: 1733–4. 91. Kuruvilla PK, Alexander J. Lithium toxicity presenting as non-convulsive status epilepticus (NCSE). Aust NZ J Psychiatry 2001; 35: 852. 92. García-Resa E, Blasco-Fontecilla H, ValbuenaBriones A. Sindrome de neurotoxicidad irreversible por litio. Med Clin (Barc) 2001; 116: 357. 93. Roy M, Fond L, Ratrema M, Convers Ph, Lutz MF, Cathébras P. Intoxication au lithium: complications neurologiques sevères. Presse Med 2001; 30: 900–1. 94. Megna J, O’Dell M. Ataxia from lithium toxicity successfully treated with high-dose buspirone: a single-case experimental design. Arch Phys Med Rehabil 2001; 82: 1145–8. 95. Peces R, Pobes A. Effectiveness of haemodialysis with high-flux membranes in the extracorporeal therapy of life-threatening acute lithium intoxication. Nephrol Dial Transplant 2001; 16: 1301–3. 96. Danel V, Rhodes AS, Saviuc P, Hanna J. Intoxication grave par le lithium: à propos de deux cas. JEUR 2001; 14: 134–6. 97. Meyer RJ, Flynn JT, Brophy PD, Smoyer WE, Kershaw DB, Custer JR, Bunchman TE. Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Am J Kidney Dis 2001; 37: 1044–7. 98. Beckmann U, Oakley PW, Dawson AH, Byth PL. Efficacy of continuous venovenous hemodialy-

29 sis in the treatment of severe lithium toxicity. Clin Toxicol 2001; 39: 393–7. 99. Suraya Y, Yoong KY. Lithium neurotoxicity. Med J Malaysia 2001; 56: 378–81. 100. Nagappan R, Parkin WG, Holdsworth SR. Acute lithium intoxication. Anaesth Intensive Care 2002; 30: 90–2. 101. Dolamore MJ. Case report: lithium toxicity in a nursing home patient. Ann Long-Term Care 2001; 9: 56–61. 102. Wang PW, Ketter TA. Pharmacokinetics of mood stabilizers and new anticonvulsants. Psychopharmacol Bull 2002; 36: 44–66. 103. De Vries PL. Lithiumintoxicatie bij gelijktijdig gebruik van trimethoprim. Ned Tijdschr Geneeskd 2001; 145: 539–40. 104. Spina E, Perucca E. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs. Epilepsia 2002; 43 Suppl 2: 37–44. 105. Mayan H, Golubev N, Dinour D, Farfel Z. Lithium intoxication due to carbamazepineinduced renal failure. Ann Pharmacother 2001; 35: 560–2. 106. Swartz CM. Olanzapine–lithium encephalopathy. Psychosomatics 2001; 42: 370. 107. Pyevich D, Bogenschutz MP. Herbal diuretics and lithium toxicity. Am J Psychiatry 2001; 158: 1329. 108. Joseph DiGiacomo. Interview with F Flach. Risk management issues associated with psychopharmacological treatment. Essent Psychopharmacol 2001; 4: 137–50. 109. Davies NM, Gudde TW, De Leeuw AWC. Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis. Expert Opin Pharmacother 2001; 2: 139–52. 110. Bocchia M, Bertola G, Morganti D, Toscano M, Colombo E. Intossicazione da litio e uso di nimesulide. Recenti Prog Med 2001; 92: 462. 111. Donovan JL, DeVane CL. A primer on caffeine pharmacology and its drug interactions in clinical psychopharmacology. Psychopharmacology Bull 2001; 35: 30–48.

Eileen Wong and Jayendra K. Patel

4 AMPHETAMINES

(SED-14, 100; SEDA-23, 34; SEDA-24, 32; SEDA-25, 34)

Amphetamine Cardiovascular Two new cases of myocardial infarction following use of amphetamine have been reported (1Ar , 2Ar ). • A 34-year-old man who smoked a pack of cigarettes a day took amphetamine for mild obesity. He developed an acute myocardial infarction 1 week later. Echocardiography showed inferior left ventricular hypokinesia and a left ventricular ejection fraction of 50%. Coronary cineangiography showed normal coronary arteries, but confirmed the inferior left ventricular hypokinesia. Blood and urine toxicology were positive only for amphetamine. • A 31-year-old man developed generalized discomfort after injecting four doses of amphetamine and methamphetamine over 48 hours, but no chest pain or tightness or shortness of breath. Electrocardiograms showed inverted T waves and left bundle branch block. Echocardiography showed reduced anterior wall motion.

The authors reviewed other reported cases of myocardial infarction associated with amphetamine. The patients were in their mid-thirties and most were men. The interval from the use of amphetamines to the onset of symptoms varied from a few minutes to years. No specific myocardial site was implicated. Coronary angiography in most cases showed non-occlusion. The cause of myocardial ischemia in these cases was uncertain, even though coronary artery spasm followed by thrombus formation was considered the most likely underlying mechanism. Some have suggested that electrocardiographic and biochemical cardiac marker testing should be considered in every patient, with or without symptoms suggesting acute coronary syndrome, after the use of amphetamines. Others © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

30

Drugs of abuse have suggested that calcium channel blockers may play an important role in the treatment of myocardial infarction due to amphetamine use or abuse. In one patient, administration of betablockers caused anginal pain, suggesting that they should be avoided. All the patients except one had a good outcome. Nervous system Vertebral artery dissection has been reported in a patient taking amphetamine and methamphetamine (3Ar ). • A healthy 40-year-old right-handed man presented with a 3-day history of an occipital headache and imbalance. He had a 3-year history of daily oral amphetamine abuse with escalating quantities, the last occasion being 12 hours before the onset of the symptoms. He had a history of “speed” abuse and a 20-pack-year history of tobacco use. He had mild right arm dysmetria without ataxia. His brain CT scan without contrast was normal. He then developed nausea, vomiting, visual loss, and progressive obtundation. He had hypertension (160/90 mmHg), bilateral complete visual loss, right lower facial weakness, mild dysarthria without tongue deviation, divergent gaze attenuated by arousal, bilateral truncal and appendicular dysmetria with inability to stand and walk, and generalized symmetrical hyper-reflexia with extensor plantar reflexes. His urine screen was positive for methamphetamine. A brain MRI scan showed infarction of both medial temporal lobes, the left posteromedial thalamus, and the right superior and left inferior cerebellum. Magnetic resonance angiography and fat saturation MRI showed reduced flow in the left vertebral artery and a ring of increased signal within its lumen, consistent with hematoma and dissection.

The authors suggested that there was a possible association between the use of amphetamines and vertebral artery dissection.

Methamphetamine Psychiatric Methamphetamine is difficult to control legally, as it is easily manufactured

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in a small laboratory. Chronic methamphetamine use is associated with psychiatric symptoms, such as psychosis and anxiety. Methamphetamine increases the activity of dopamine, mainly by inhibiting the dopamine transporter. However, this does not explain why psychosis persists even when the methamphetamine is no longer present in the body (4R ). Chronic methamphetamine use has been reported to reduce dopamine transporter density in the caudate/putamen and nucleus accumbens. However, previous studies have been criticized for not controlling for other drug use. Dopamine transporter density in the brain has been investigated during a period of abstinence in 11 methamphetamine monodrug users and nine healthy subjects, all men (5C ). The dopamine transporter density of methamphetamine users was significantly lower in the caudate/putamen, nucleus accumbens, and prefrontal cortex than in the controls. The severity of psychiatric symptoms correlated with the duration of methamphetamine use. The reduction in dopamine transporter density in the caudate/putamen and nucleus accumbens was significantly associated with the duration of methamphetamine use and closely related to the severity of persistent psychiatric symptoms. The reduction in dopamine transporters may be long lasting, even if methamphetamine is withdrawn. Only some methamphetamine users develop psychosis, not all (4R ). In laboratory animals, methamphetamine is toxic to dopamine terminals. In 15 subjects (six men and nine women, mean age 32 years), who met the criteria for methamphetamine abuse, and 18 healthy volunteers (12 men and six women), there was a significant reduction in the number of dopamine transporters in detoxified methamphetamine abusers compared with controls (mean values of 28% in the caudate and 21% in the putamen) (6C ). This was associated with poor motor and memory performance. The reductions in dopamine transporters in the methamphetamine abusers were smaller than those found in patients with Parkinson’s disease and occurred in subjects who had been abstinent for 11 months. Since significant reductions in dopamine transporters occur with both age and methamphetamine use, it is possible that methamphetamine will be associated with a higher risk of parkinsonian symptoms in abusers later in life.

31 Glucose metabolism in the brain has been studied using positron emission tomography, to look for evidence of functional changes in regions other than those innervated by dopamine neurons in 15 detoxified methamphetamine abusers and 21 controls (7C ). Whole-brain metabolism in the methamphetamine abusers was 14% higher than in the controls. The difference was largest in the parietal cortex (20%), but there was significantly lower metabolism in the thalamus (17%) and striatum (12% caudate and 6% putamen). The authors suggested that methamphetamine, in doses abused by humans, causes long-lasting metabolic changes in brain regions connected with dopamine pathways, but also in areas that are not innervated by dopamine. The effects of protracted abstinence on loss of dopamine transporters in the striatum in 5 methamphetamine abusers has been evaluated during short-term abstinence and then retested during protracted abstinence (12–17 months) (8C ). The dopamine transporters increased in number, providing hope for effective treatment; however, this regeneration was not sufficient to provide complete functional recovery, as measured by neuropsychological tests. Drug dependence The role of dopamine in the addictive process has been explored (9C ). The authors raised the possibility that the orbitoprefrontal cortex is linked to compulsive drug abuse. They recruited 15 methamphetamine users and 20 non-drug user controls. The methamphetamine abusers had significantly fewer dopamine D2 receptors than the controls. There was an association between lower numbers of dopamine D2 receptors and metabolism in the orbitofrontal cortex in the methamphetamine users. These findings are similar to those observed in cocaine, alcohol, and heroin users. The authors suggested that D2 receptormediated dysregulation of the orbitofrontal cortex could be a common mechanism underlying loss of control and compulsive abuse of drugs.

Methylenedioxymethamphetamine (ecstasy, MDMA) Concern has been raised about the increasing use of ecstasy in Europe in the last 10

32 years (10Cr ), particularly the UK and the Netherlands. MDMA and drugs such as its Ndemethylated derivative (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), N-methylbenzodioxazolylbutamine (MBDB), and 4bromo-2,5-dimethoxyphenylethylamine (2-CB or Nexus) are often grouped together as “ecstasy”. Some have used the term “enactogen”, meaning “touching within”, to describe MDMA. The patterns and trends of substance use among college students have been evaluated over a 30-year period (11C ). Alcohol use remained stable, but illicit drug use peaked in 1978 and fell sharply over the next 20 years. MDMA was the exception: its use rose from 4.1% in 1989 to 10% in 1999. MDMA was the second most frequently tried illicit drug after marijuana.

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Respiratory Pneumomediastinum after MDMA has been reported (13c ). • A 16-year-old boy took six ecstasy tablets over 2 hours. A period of vomiting ensued and he developed chest pain and swelling in the neck. A chest X-ray showed pneumomediastinum. He was managed conservatively and his emphysema settled uneventfully within 2 days.

The authors reported that five such cases have been reported in the past 4 years in the British literature; the respiratory complications were thought to be due to severe physical exercise or secondary to vomiting. It is therefore possible that this complication may not be due to a direct effect of MDMA, but rather a consequence of repeated Valsalva maneuvers associated with the dance habits of ecstasy users or vomiting induced by the drug.

Cardiovascular Cardiotoxicity following ecstasy use has been reported (12Ar ). • A 16-year-old boy took three tablets of ecstasy and amphetamine 0.3 g and several hours later had convulsions and a temperature of 40.9◦ C. His heart rate was 210 and his blood pressure 100/75 mmHg. His creatine kinase activity was raised and he had myoglobinuria, renal impairment, hyperkalemia, and hypocalcemia. An electrocardiogram showed ventricular and supraventricular tachycardias but no myocardial ischemia. A diagnosis of serotonin syndrome due to ecstasy ingestion with associated hyperpyrexia and rhabdomyolysis was made. Following active treatment, his condition stabilized, with restoration of sinus rhythm and normal urine output. However, 12 hours later he developed jaundice, raised liver enzymes, and coagulopathy, suggesting acute liver failure due to ecstasy. With supportive treatment, his liver function improved. However, another 12 hours later, he developed shortness of breath associated with right-sided chest signs and X-ray changes compatible with aspiration pneumonia, and required emergency intubation 4 days later. He developed pulmonary edema, his pulmonary artery was occluded, and an echocardiogram showed globally impaired left ventricular function with an ejection fraction of 30–35%; there was electrocardiographic T wave inversion. Primary myocardial damage causing cardiac dysfunction was investigated using serial creatine kinase and troponin measurements. He recovered completely with treatment and an echocardiogram showed an ejection fraction of 60%.

The authors reported that this was the first case report of clinical, radiological, biochemical, and echocardiographic evidence of myocardial damage and cardiac dysfunction following ecstasy and amphetamine use.

The cognitive effects of MDMA Recently, several studies have focused on the cognitive effects of MDMA, and a review of the adverse effects of MDMA in animals has raised concerns about potential toxicity in humans (14R ). MDMA can selectively damage brain serotonin (5-HT) neurons in animal brains, even at doses within the range of those typically used recreationally. In many studies lasting reductions in various brain 5-HT markers have been reported in MDMA-treated animals. Axons of 5-HT neurons were damaged in MDMA-treated animals, including monkeys, and neurotoxic effects of MDMA have been observed in every animal species studied so far. In non-human primates, the toxic dose of MDMA closely approaches the dose used by humans. In 30 regular ecstasy users (drug use ten or more times per month) and 31 ecstasy-free controls, prospective memory—the process of remembering to do things at some future time— was assessed using a self-report questionnaire (15C ). Ecstasy users reported global impairment in prospective memory, even after controlling for the use of other drugs. The authors observed that their finding of impairment of cognitive functions, especially memory, in regular ecstasy users is similar to findings in other recent studies. They postulated that serotonergic toxicity secondary to chronic MDMA exposure

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can cause cognitive impairment, as serotonergic pathways are involved in memory function. More support for a relation between memory impairment, serotonin neurotoxicity, and chronic MDMA use has come from a study of cognitive performance and serotonin function in two groups of 21 men with moderate or heavy MDMA use and a control group of 20 men who had not used MDMA (16R ). Ecstasy users had a broad spectrum of statistically significant but clinically subtle impairment of memory and prolonged reaction times. Heavy users had larger effects than moderate users. Serotonergic function was assessed in a double-blind crossover challenge with dexfenfluramine 30 mg or placebo. Release of cortisol, but not prolactin, after dexfenfluramine was significantly reduced in both groups of ecstasy users compared with controls. According to the authors, these neuroendocrine findings are similar to those observed in animals and humans. Recent exposure to ecstasy, psychosocial profiles, and the use of other drugs did not explain the differences. As mentioned above, animal studies have shown reductions in various serotonin markers in the brain. The density of serotonin transporters (SERTs) in humans can be measured by neuroimaging techniques, such as SPECT and PET. Two groups of ecstasy users (22 recent but abstinent and 16 ex-users) were compared with ecstasy-naïve controls (17C ). In subjects who had stopped using MDMA more than 1 year before the study, cortical densities of SERTs did not differ from those of controls. However, recent MDMA users had global reductions in SERTs. In addition, individuals who had stopped using MDMA had a deficit in verbal memory similar to that in current MDMA users. Higher lifetime doses of MDMA were associated with greater impairment of immediate verbal memory. The authors suggested that the absence of reductions in SERT densities in exMDMA users suggested reversibility of MDMAinduced changes in brain SERTs. Thus, MDMA use can lead to neurotoxic changes in human cortical 5-HT brain neurons, but these changes may be reversible. However, functional consequences of MDMA on cortical brain 5-HT neurons may not be reversible, as seen by impaired memory function in this group, similar to that in current MDMA users. The amino acid N-acetylaspartate is a robust, non-specific marker of neuronal loss or

33 brain dysfunction. It is detectable by proton magnetic resonance spectroscopy (MRS). The ratio of creatine to phosphocreatine, another marker that remains stable in many brain diseases, can also be assessed using MRS. In a recent study, the ratio of N-acetylaspartate to creatine/phosphocreatine was used to determine whether there are memory deficits in MDMA users and whether there are changes in specific brain regions (18C ). Eight men with a history of MDMA use and seven MDMA-naïve male controls took part. The findings included a significant difference in delayed recall between MDMA users and MDMA-naïve controls. There was a strong association between impaired memory function in MDMA users and neuronal pathology, specific to the prefrontal cortex. Poorer performance on verbal memory testing was associated with greater neuronal loss or dysfunction in MDMA users. These findings implicate MDMA as a cause of serotonergic neuronal damage and memory impairment. Another group has assessed cognitive function in 80 subjects who were non-users, novice users, regular users, or currently abstinent users of MDMA (19C ). Compared with the nonusers, all three groups of MDMA users had significantly poorer verbal fluency and immediate and delayed prose recall. Days since last use and total lifetime consumption of MDMA made separate contributions to the variance in recall scores. Novice and currently abstinent users likewise had significantly poorer immediate recall than non-users. The novice users had milder impairment than the regular users, while those who were currently abstinent performed at a similar level to regular users. These deficits were not attributable either to differences in general reasoning ability or to impairment of working memory. The authors expressed concern that increased use of MDMA in large numbers of young people and its enduring effects on memory are under-appreciated consequences. However, cognitive impairment and MDMA use is a complex association to study, with difficult confounding variables. For example, MDMA users may consume cannabis to relieve the negative experience that occurs when MDMA-related euphoria diminishes. In a recent study the concurrent use of cannabis was controlled by the recruitment of 31 drug-naïve controls, 11 MDMA/cannabis users, and 18 cannabis users (20C ). Users were instructed

34 to abstain from drug use for 48 hours before testing. The MDMA/cannabis user group had deficits in learning, memory, verbal word fluency, speed of processing, and manual dexterity compared with the healthy controls. The authors suggested that the deficits in the drug group were not related to MDMA. They observed that the study group did not perform poorly compared with those who used cannabis only. Moreover, the finding that the MDMA/cannabis group was no different from the cannabis group suggested that MDMA does not cause significant cognitive deficits. The poorer performance of the MDMA/cannabis users was very little affected by the frequency of use or total MDMA consumption. However, co-varying for indices of cannabis consumption removed most of the significant differences between the groups. On the other hand, MDMA did affect the measures of working memory, such as forward and backward digit span. The authors raised the question of whether previous evaluations of the effects of MDMA on cognition had been confounded by the concomitant use of cannabis. Risk factors Sex differences in subjective experiences of MDMA use have been reported. Three previously published controlled studies of the acute effects of MDMA in healthy subjects with no or single previous MDMA experience have been summarized (21M ). There were 74 subjects (54 men and 20 women), aged 20– 49 (mean 27) years, of whom 69 were ecstasynaïve and five had used it on one or two occasions before. All had been screened using a semi-structured interview, and anyone with a personal or family history of mood disorders, schizophrenia, or other psychiatric disorders was excluded. The analysis included psychological and physiological effects of MDMA in controlled settings. Generally, subjective effects of MDMA were more intense in women then men. Women had especially higher scores for MDMA-induced perceptual changes, anxiety, and adverse effects. In contrast, men were slightly activated by MDMA compared with women and had significantly higher increases in systolic blood pressure. The authors suggested that women may be more sensitive to the effects of MDMA. Many previous studies have suggested sex differences in markers for serotonergic activity in ecstasy users, with sugges-

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tions that serotonergic function is relatively impaired in women compared with men. The authors, based on their findings coupled with data from previous reports, raised the question of whether women might be more susceptible to MDMA-induced depletion of serotonin. Psychiatric Psychosis, both acute and chronic, has been reported following the use of ecstasy. A 26-year-old man without previous psychopathology (except social phobia) unknowingly consumed ecstasy with alcohol and developed an acute psychosis 12 hours later. The authors reported that 12 cases of acute psychosis have previously been reported after the use of ecstasy once or twice. Based on a previously suggested hypothesis, they proposed that the psychosis was probably due to the indirect effects of MDMA on the dopaminergic system, secondary to serotonergic deregulation. Most patients who went on to develop a chronic psychosis were either chronic ecstasy users or multiple substance users. However, in the case mentioned here, after 6 months the patient still had symptoms of psychosis. The authors further suggested that genetically slow metabolizers of ecstasy are probably more vulnerable to this adverse effect, even with a single exposure. Past reports have suggested that MDMA use is associated with increased scores on selfreport measures of depression. The long-term effects of MDMA consumption on depression have been examined in 29 individuals who had consumed large quantities of the drug in the past, but were now leading relatively drug-free lives (22C ). They had taken an average of 1.5 ecstasy tablets in the last month, 8.4 in the last 6 months, and 23.3 in the last 12 months. None had taken it in the last 14 days. The former chronic ecstasy users had not taken ecstasy for an average of 26 weeks. The female former users had taken ecstasy more recently than the men (15 versus 31 weeks respectively). The levels of depression, as measured by Beck’s depression inventory (BDI), were significantly increased compared with a matched non-drug using control group. The depression scores were independent of alcohol and cannabis use. Peak usage (maximum ecstasy usage in 12 hours) and current levels of perceived stress together significantly predicted depression scores. Thus, former chronic ecstasy users may be at a high risk of developing more severe depression.

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Liver A case of MDMA-associated hepatotoxicity has been reported (23Ar ). • A 17-year-old girl developed progressive jaundice and weight loss. Four months before, she had had malaise, anorexia, a sore throat, and tender cervical lymph nodes. Two months later she reported eating “hallucinogenic mushrooms”. Five weeks before admission she observed blood clots in her stool. Three weeks later, she ate more mushrooms. She then developed progressive jaundice, with vomiting, dark urine, light colored stools, and raised aminotransferases. She drank alcohol in binges and reported marijuana use since the age of 15. She had used MDMA on several occasions during the previous 2 months. She had a minimally tender enlarged liver. Her viral hepatitis screen was negative. Genetic, metabolic, and autoimmune disorders were also ruled out. A urine screen for drugs was positive only for cannabinoids. Abdominal ultrasound showed periportal edema and contraction of the gall bladder, but no gallstones or dilated bile ducts. A CT scan showed moderate amounts of free fluid in the abdomen and pelvis and periportal hepatic edema. Percutaneous liver biopsy showed acute cholestatic hepatitis with cholangitis, eosinophils, and histiocytes, strongly suggesting a hypersensitivity reaction. There was no evidence of chronic liver disease. Within 24 hours after the liver biopsy, her liver enzymes and coagulopathy had begun to improve.

Two cases of successful liver transplantation after ecstasy-induced hepatotoxicity have been reported (24Ar , 25Ar ). • A 19-year-old man with no significant past history of medical problems took 1½ tablets of ecstasy and some alcohol. Within 2–4 days he developed tiredness, nausea, malaise, and vomiting and on the fifth day weakness and anorexia; 12 days later he was admitted to hospital with marked jaundice and weight loss. He deteriorated and developed hepatomegaly and an abnormal prothrombin time; his total bilirubin was 571 (reference range 5–17) µmol/l, AsT 213 (14–50) U/l, and AlT 336 (11– 60) U/l. By day 20, his condition had deteriorated, with increased jaundice, somnolence, mild disorientation, and altered glucose metabolism. His total bilirubin was 654 µmol/l, AsT 1290 U/l, and AlT 1932 U/l. A liver biopsy showed swollen hepatocytes, patches of necrosis, and patchy cholestasis. Two days later, he developed a grade III encephalopathy and further disturbances of coagulation. Abdominal ultrasonography showed hepatic atrophy and a liver biopsy showed massive necrosis. Serological tests for viral infections were negative. The probable diagnosis was toxic hepatitis secondary to MDMA. On day 31, he had a right auxiliary liver transplantation, but there was no clinical and laboratory improvement during the next 48 hours. Histopathology of the transplanted liver showed massive liver necrosis consistent with

35 a “diagnosis of primary non-function”. A second liver transplant on day 33 was successful. • A 17-year-old woman with no history of drug abuse took two tablets of ecstasy at a disco 10 days apart, and reported malaise, constipation, and icterus 6 days after taking the second. She had severe acute hepatic failure. Viral hepatitis was ruled out. Following rapid clinical and neurological deterioration (encephalopathy grade I–II), she had an urgent liver transplant and made a good recovery. In the affected liver there was submassive centrilobular hemorrhagic necrosis (75–80%) with massive periportal and lobular lymphocytic infiltration (CD 8+) and moderate fatty changes.

Many cases of hepatotoxicity and some deaths have occurred in drug-naïve subjects after the ingestion of relatively small amounts of MDMA. The authors reported that more than 70 deaths have been reported world wide between 1990 and 1998 after the onset of severe hepatic damage from ecstasy. Although many patients died after liver transplantation, a significant number recovered. The authors suggested that in emergency care the use of ecstasy should be suspected in young people who present with unexplained jaundice, hepatomegaly, or altered liver function, in the absence of other known substance exposure. Early referral for liver transplantation may be significantly beneficial. The prognosis may be better with grade I–II encephalopathy than grade III–IV, which is usually associated with rapid deterioration and a poor prognosis. Pregnancy Workers in Canada have tried to characterize women who reported gestational exposure to ecstasy (26C ). The Motherisk Program is a large Teratogen Information Service based in Toronto and receives over 150 calls daily about exposure to various agents during pregnancy. The authors reviewed the data from 1998 to 2000. The study group consisted of all pregnant women who had been exposed to MDMA. The control group was randomly selected pregnant women who visited the Motherisk Clinic during the same week as the subject who called about MDMA. The 132 MDMAexposed women were significantly younger, earlier in gestational age, and weighed less than the non-exposed controls. The MDMA users had had significantly fewer pregnancies and live births and had a higher rate of therapeutic abortions but not spontaneous abortions. Significantly more MDMA users reported unplanned

36 pregnancies and were more likely to be single and white. The MDMA users were more likely than controls to have had alcohol exposure in pregnancy, and significantly more drank heavily. The MDMA-exposed women were more likely to binge drink and smoke cigarettes during pregnancy, and more were significantly heavy smokers. MDMA users also had a greater tendency to use marijuana, cocaine, amphetamines, ketamine, gamma-hydroxybutyrate, and psilocybin. Of the 132 women who reported MDMA use, 129 had used it during pregnancy, of whom 101 reported previous use of MDMA before their pregnancy, but had discontinued it. The mean gestational age of last MDMA exposure was 5.0 weeks (range 1–24 weeks). All but three used tablets: two snorted and one used a liquid formulation. The mean dose taken on one occasion was 1.24 tablets. Of the 122 patients whose data were included in the analysis, most (57%) had only one exposure to MDMA during pregnancy; 10 women had more than five exposures. One 15-year-old girl did not realize she was pregnant until 24 weeks gestation and had used two tablets of MDMA four times a day. Only seven of the MDA group reported exposure to MDMA alone. MDMA associated adverse events were reported by 33 of 77 respondents. The physical adverse effect most commonly reported was vomiting (23%). The authors raised significant concerns about the potential teratogenic effects in these women, due to clustering of risk factors. Drug contamination It is not uncommon for people to be deceived into consuming other substances, believing them to be MDMA. At dance parties and “raves” for young adults compounds passed as ecstasy may be more lethal than MDMA, either because they contain more potent amphetamines than MDMA or because of adulteration with other substances. In three fatal cases reported in the USA the victims (two men aged 19 and 24 and a woman aged 18) believed that they were using MDMA but had in fact taken paramethoxyamphetamine (PMA), a more potent central stimulant with structural and pharmacological similarities to MDMA (27c ). They became agitated and developed bruxism, severe hyperthermia, convulsions, and hemorrhages. The presence of PMA was confirmed by enzyme immunoassay, and

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MDMA was not detected. PMA is not a contaminant of MDMA.

CANNABINOIDS

(SED-14, 95; SEDA-23, 41; SEDA-24, 36; SEDA-25, 43) The adverse effects of cannabis are discussed in detail in the Side Effects of Drugs Essay in this volume (pp. xxxiii–xlviii), in the context of the question of whether cannabis should be made available for medical use. The essay contains many references to experimental data in animals, not usually a feature of these volumes. Cardiovascular Marijuana has several effects on the cardiovascular system, and can increase resting heart rate and supine blood pressure and cause postural hypotension. It is associated with an increase in myocardial oxygen demand and a decrease in oxygen supply. Marijuana use is most popular among young adults (18–25 years old). However, with a generation of post-1960s smokers growing older, the use of marijuana in the age group that is prone to coronary artery disease has increased. Nevertheless, it is not known whether marijuana can precipitate myocardial infarction. Investigators in the Determinants of Myocardial Infarction Onset Study recently reported that smoking marijuana is a rare trigger of acute myocardial infarction (28C ). Interviews of 3882 patients (1258 women) were conducted an average of 4 days after infarction. Reported use of marijuana in the hour preceding the first symptoms of myocardial infarction was compared with use in matched controls. Among the patients, 124 reported smoking marijuana in the previous year, 37 within 24 hours, and nine within 1 hour of cardiac symptoms. The risk of myocardial infarction was increased 4.8 times over baseline in the 60 minutes after marijuana use and then fell rapidly. The authors emphasized that in a majority of cases, the mechanism that triggered the onset of myocardial infarction involved a ruptured atherosclerotic plaque secondary to hemodynamic stress. It was not clear whether marijuana has direct or indirect hemodynamic effects sufficient to cause plaque rupture.

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Paroxysmal atrial fibrillation has been reported in two cases after marijuana use (29A ). • A healthy 32-year-old doctor, who smoked marijuana 1–2 times a month, had paroxysmal tachycardia for several months. An electrocardiogram was normal and a Holter recording showed sinus rhythm with isolated supraventricular extra beats. He was treated with propranolol. He later secretly smoked marijuana while undergoing another Holter recording, which showed numerous episodes of paroxysmal atrial tachycardia and atrial fibrillation lasting up to 2 minutes. He abstained from marijuana for 12 months and maintained stable sinus rhythm. • A 24-year-old woman briefly lost consciousness and had nausea and vomiting several minutes after smoking marijuana. She had hyporeflexia, atrial fibrillation (maximum 140 beats/min with a pulse deficit), and a blood pressure of 130/80 mmHg. Echocardiography was unremarkable. Within 12 hours, after metoprolol, propafenone, and intravenous hydration with electrolytes, sinus rhythm was restored.

The authors discussed the possibility that delta-9-tetrahydrocannabinol, the active ingredient of marijuana, can cause intra-atrial reentry by several mechanisms and thereby precipitate atrial fibrillation. Nervous system Marijuana can interact with the neurotransmitter dopamine, and the effects of marijuana on the brain in schizophrenia have been studied by single photon emission computerized tomography (SPECT) (30A ). • A 38-year-old man with schizophrenia secretively smoked marijuana during a neuroimaging study. A comparison of two sets of images, before and after marijuana inhalation, showed a 20% reduction in the striatal dopamine D2 receptor binding ratio, suggestive of increased synaptic dopaminergic activity.

On the basis of this in vivo SPECT study, the authors speculated that marijuana may interact with dopaminergic systems in brain reward pathways.

COCAINE

(SED-14, 106; SEDA-23, 37; SEDA-24, 37; SEDA-25, 40) Cardiovascular Chest pain is a frequent emergency presenting complaint of cocaine

37 users. Myocardial infarction is the most serious cause, but other causes for pain must be considered, including aortic rupture and dissection (SEDA-18, 36; SEDA-19, 26; SEDA-21, 29; SEDA-22, 31). A first case of intramural hematoma of the ascending aorta has been reported in a cocaine user (31A ). • A healthy 39-year-old man developed retrosternal chest pain radiating to the back with nausea and sweating. About 10–15 minutes before he had inhaled cocaine for 2 hours and then smoked crack cocaine. He had an aortic dissection, which was repaired surgically.

The authors identified hypertension secondary to the use of cocaine as the risk factor for this complication. Coronary artery dissection associated with cocaine is rare. The first case was reported in 1994 (32A ), and two new cases have been reported (33A , 34A ). • A healthy 33-year-old man with prior cocaine use had a small myocardial infarction, and 36 hours later, having inhaled cocaine, developed a dissection of the left main coronary artery, extending distally to the left anterior descending and circumflex arteries. There was marked anterolateral and apical hypokinesis. • A 23-year-old man with a history of intravenous drug abuse and hepatitis C was found unconscious, hypoxic, and hypotensive. A urine drug screen was positive for cocaine metabolites, benzodiazepines, and opiates. An electrocardiogram suggested a myocardial infarction, verified by raised troponin I and the MB fraction of creatine kinase. He had severe hypokinesia with a left ventricular ejection fraction of 10%, falling to less than 5%. He became septic, developed multiorgan system failure, and died. The post-mortem findings included dissection of the left anterior descending artery with complete occlusion of the true lumen and thrombosis of the false lumen. The left ventricle showed extensive transmural myocardial necrosis with adjacent contraction band necrosis. He also had deep vein thromboses in veins in the neck and abdomen and multiple pulmonary infarctions.

Cocaine is associated with vascular complications, including pulmonary, musculoskeletal, intestinal, and placental. Cocaine-induced ischemic finger necrosis has been reported (35A ). • A healthy 36-year-old man, who had used intranasal crack cocaine daily in increasing doses for 2 weeks, developed pain, numbness, swelling, and cyanosis of the fingers and toes aggravated by cold and an ulcer on one finger. Ultrasound Doppler of

38 the hand confirmed ischemic finger necrosis. He was treated unsuccessfully with aspirin, diltiazem, and heparin, but responded to intravenous infusions of iloprost for 5 days.

Respiratory Pulmonary complications associated with cocaine use include exacerbation of asthma, lung infiltrates, pulmonary infarction, pneumothorax, and end-stage lung disease (SEDA-20, 21; SEDA-21, 25; SEDA-22, 31; SEDA-23, 37; SEDA-25, 41). A case of severe bullous emphysema in a cocaine smoker has been described (36A ). • A 40-year-old man with cough, shortness of breath, and fever progressed to respiratory failure. He had smoked cocaine for the past 17 years. His tobacco history was not known. His medical history included recurrent respiratory tract infections. A chest X-ray and CT scan showed findings consistent with bilateral bullous emphysema with a right lung abscess. He was ventilated and given antibiotics but died from respiratory failure secondary to pneumonia. Sputum cultures were positive for Enterobacter cloacae and Streptococcus species. Alpha-1 antitrypsin deficiency was ruled out.

Spontaneous pneumomediastinum has been reported (37R ). • A 20-year-old obese Hispanic man awoke with severe, continuous retrosternal chest pain radiating to the neck and back. The pain was aggravated by deep breathing and local chest pressure. He denied substance abuse and gave a history of a flu-like illness 2 months before. His respiratory rate was 19/minute. He had a two-component pericardial rub. Laboratory blood testing ruled out myocardial infarction. His arterial blood gases and pH, electrocardiogram, chest X-ray, and echocardiogram were unremarkable. A later chest X-ray showed air in the mediastinum and chest CT confirmed the diagnosis of pneumomediastinum. Urine toxicology was positive for cocaine and cannabinoids. On further questioning, he admitted to substance use and performing a Valsalva maneuver during inhalation.

Ear, nose, throat Intranasal cocaine can damage the sinonasal tract, causing acute and chronic inflammation, necrosis, and osteocartilaginous erosion (SEDA-17, 36). These conditions occur secondary to the combined effects of direct trauma from instrumentation, vasoconstriction of small blood vessels with resultant ischemic necrosis, and chemical irritation from adulterants. Intranasal cocaine users can develop septal perforation, saddle-nose deformities, and sinonasal structural damage (38A ).

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• A 43-year-old woman with a past history of chronic heavy cocaine use and osteomyelitis of the hard palate and nasal cavity 10 years before had required continuous follow-up for recurrent ethmoid and sphenoid sinusitis. Endoscopy showed an absent nasal septum, middle turbinates, anterior twothirds of the inferior turbinates, and lateral nasal wall.

In another case there was progression of septal perforation to secondary bone infection in a chronic cocaine user (39A ). • A 56-year-old chronic intranasal cocaine abuser with a visible nasal defect presented with a hole in the roof of his mouth. He had been reportedly drug free for 2 weeks. He had an oronasal fistula with adjacent black necrotic areas and erosive destruction of the nasal septum, turbinates, and antrum, with mucoperiosteal thickening of the sphenoid and maxillary sinuses. Treatment included antibiotics and a prosthesis plate construction to cover the defect. Two years later, having continued to inhale cocaine, he had progressive destruction of his sinonasal tract, a fistula between his oral and nasal cavity, a saddle-nose deformity with total cartilage loss, and a complete palatal defect. Biopsy of the nasal septum showed acute osteomyelitis and extensive bacterial overgrowth (including anerobic Actinomyces-like organisms). He was given intravenous antibiotics for 6 weeks followed by longterm oral antibiotics.

Nervous system Cocaine has been associated with movement disorders, such as acute dystonias, choreoathetosis, and akathisia. Chronic pancerebellar dysfunction occurred in a cocaine user with schizophrenia treated with risperidone (40A ). • A 38-year-old man was found comatose in a crack house. The ambient temperature was 13◦ C. He had earlier abused cocaine. His temperature was 43◦ C, heart rate 115, blood pressure 144/89 mmHg, and oxygen saturation 97% on air. His general muscle tone was flaccid. He had a mild leukocytosis and hypophosphatemia. Urine toxicology was positive for benzoylecgonine, a cocaine metabolite. He was mechanically ventilated, cooled, and given intravenous fluids. His temperature fell to 38◦ C, but he later developed acute disseminated intravascular coagulation and rhabdomyolysis. After 5 days he developed nystagmus, intention tremor, truncal ataxia, dysarthria, ocular dysmetria, and dysmetria of the arms and legs. There were no sensory or motor deficits. Finger-to-nose and heelto-knee tests were slowed and uncoordinated. He could not stand. Brain imaging studies (CT and MRI scans) were unremarkable. He was given thiamine, propranolol, clonazepam, primidone, and baclofen every 8 hours without improvement. After 1 year he still had nystagmus, intention tremor,

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ataxic gait, and dysmetria were. He could walk short distances slowly.

Cocaine and neuroleptic drugs can both cause hyperthermia and the authors proposed that the combination of cocaine and risperidone may have caused this problem. Cocaine-induced delirium with severe acidosis has been reported (41A ). • A 25-year-old man with agitation and paranoia who had consumed a lot of alcohol with cocaine the night before had a clonic seizure lasting 1 minute. In the emergency room, he responded to pain and made incomprehensible sounds. His pulse rate was 116, blood pressure 100/40 mmHg, respiratory rate 28, and temperature 38.3◦ C. He was acidotic (pH 6.53), with a PaCO2 of 13.1 kPa, a base deficit of 36 mmol/l, a serum potassium concentration of 7 mmol/l, and sodium 153 mmol/l. He was hyperventilated and given sodium bicarbonate, dantrolene, and passive cooling. His acidosis quickly corrected and his temperature fell to 37.6◦ C within 1 hour.

The association between cocaine use and aneurysmal subarachnoid hemorrhage has previously been reported (SEDA-18, 36; SEDA21, 26). New research has identified cocaine as a risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage (42M ). In a retrospective analysis of the medical records of 440 patients who presented to a neurosurgery unit between 1992 and 1999 with aneurysmal subarachnoid hemorrhage, 27 patients (6.1%) had either a positive urine screen for cocaine metabolites (n = 20) or a history of cocaine use within 72 hours of subarachnoid hemorrhage (n = 7). Cocaine users were more likely to have cerebral vasospasm from 3 to 16 days after subarachnoid hemorrhage than non-exposed patients (63% versus 30%). They were also more likely to be younger and to have aneurysms of the anterior circulation than the control group (97% versus 84%). Cocaine use has been associated with a reduced inhibitory response of the P50 auditory evoked response, attributed to catecholaminergic neurotransmission secondary to cocaine (43A ). In a double-blind, placebo-controlled study, 11 cocaine users in the first and third weeks of detoxification had electrophysiological testing 10 minutes before and 30 minutes after taking nicotine gum 6 mg. Nicotine briefly reversed the inhibitory deficit.

39 Psychological Chronic substance use has been associated with long-lasting changes in brain function (44c ). Five brain regions that may be affected (the orbitofrontal gyrus, rectal gyrus, anterior cingulate gyrus, basal ganglia, and thalamus) were selected for analyses of cerebral glucose metabolism by positron emission scanning in controls, cocaine users, and alcoholics (17 in each group), who performed the Stroop test, which assesses cognitive interference and response inhibition. In controls, higher brain glucose metabolism in the orbitofrontal gyrus correlated with poorer performance. In contrast, in substance users, higher brain glucose metabolism was associated with better performance. Chronic abuse appears to be associated with altered function of the orbitofrontal gyrus. Urinary tract Cocaine can cause acute renal insufficiency (SEDA-21, 19, SEDA-24, 38). A recent study has suggested that it can also cause chronic renal insufficiency (45C ). Of hemodialysis patients from an urban center in California, 55 who reported a history of significant cocaine use were compared with 138 non-users. A diagnosis of hypertension-related end-stage renal disease was reported in 49 of the 55 cocaine users (89%) and 64 of the 138 non-users (46%). Of 113 patients with endstage renal disease, 49 had a history of cocaine use. The patients who had used cocaine had hypertension for a shorter duration (5.3 vs. 12.7 years). They were also younger (41 vs. 54 years). The authors proposed that this outcome had been caused by several mechanisms: renal vasoconstriction or stenosis, resulting in ischemic nephropathy and secondary hypertension, direct renal damage with progressive renal insufficiency, and recurrent episodes of accelerated hypertension, vasculitis, acute tubular necrosis, and rhabdomyolysis. Renal infarction is an uncommon adverse effect of cocaine (46A ). • After using intranasal cocaine, a 25-year-old African man developed fever and progressive right flank pain over 4 days. He had a temperature of 38.3◦ C, a blood pressure of 106/54 mmHg, and severe tenderness in the right flank and right lower quadrant of the abdomen. His urine contained cocaine. A CT scan showed reduced uptake in the lower pole of the kidney, confirming renal infarction. Other causes were ruled out.

40 Sexual function Priapism has been reported in men who have used cocaine by inhalation or applied it topically to the glans penis or intraurethrally (SEDA-19, 26; SEDA-23, 24, SEDA24, 38). Priapism associated with intracavernosal injection of cocaine has now also been reported (47A ). • A 43-year-old man developed persistent painful erection after intracavernosal injection of cocaine. He had previously administered cocaine in this way to prolong erections. Cavernosal aspiration resulted in partial detumescence, but the condition recurred. Urine screen was positive for cocaine. Aspiration and irrigation fully alleviated the condition.

During penile erection, nitric oxide is released from the endothelium of the cavernous spaces and from nerve endings (non-adrenergic and non-cholinergic). Nitric oxide stimulates guanylate cyclase, which is involved in the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP); the latter relaxes the smooth muscle in the corpora cavernosa, allowing influx of blood for erection. The authors suggested that cocaine directly applied to the cavernosal endothelium can cause nitric oxide production. Drug abuse A rare case of polysubstance abuse, which unmasked myasthenia and caused complete external ophthalmoplegia, has been reported (48A ). • A 29-year-old woman, who used cocaine 2 g/day, heroin 1 g/day, and methadone 40 mg/day, developed abscesses caused by drug injection. She had had generalized weakness, difficulty in swallowing, and lagging eyelids for 1 week. There was bilateral ptosis, and a diagnosis of myasthenia was made. Edrophonium 10 mg relieved the ptosis and improved ocular movements.

Fetotoxicity The prevalence rate of cocaine use during pregnancy is 10–45% in some centers in North America. As cocaine use is increasing and widespread, information on the possible adverse effects secondary to fetal cocaine exposure continue to amass in case reports and studies. Fetal microcephaly has been attributed to cocaine abuse during pregnancy (49A ). Urine toxicology confirmed the presence of morphine, benzoylecgonine, barbiturates, paracetamol, and propoxyphene. Analyses of amniotic fluid, placenta, and fetal serum and urine

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were also positive for these substances. The authors suggested that vascular disruption was the likely major mechanism of anomalies, both behavioral and malformative, due to prolonged exposure to cocaine in utero. However, in a prospective, large-scale, longitudinal study there was no association between prenatal cocaine exposure and congenital anomalies in 272 offspring of 154 cocaineusing mothers and 154 non-using matched controls (50C ). The cocaine-exposed group had significantly more premature infants, who were significantly smaller in birth weight, length, and head circumference than the control infants. However, there were no differences in the type or number of abnormalities. The impact of prenatal exposure to cocaine on fetal growth and fetal head circumference has been studied in 476 African–American neonates, including 253 full term infants prenatally exposed to cocaine (with or without alcohol, tobacco, or marijuana) and 223 noncocaine exposed infants (147 drug-free, 76 exposed to alcohol, tobacco, or marijuana) (51C ). The cocaine-associated deficit in fetal growth was 0.63 standard deviations and for gestational age 0.33 standard deviations. There were also cocaine-associated deficits in birth weight and length, but no evidence of a disproportionate effect on head circumference. There have been two studies of the adverse effect of prenatal cocaine on behavior of the offspring. In the first, 31 cocaine-exposed, very low birth weight infants and matched very low birth weight controls followed longitudinally were assessed at 3 years (52C ). The cocaineexposed children had delayed cognitive, motor, and language development compared with the controls. Of the exposed children 45% scored in the range of mental retardation compared with 16% of the controls. Infants in the exposed group during the neonatal period were less responsive in their interactions and their mothers were less nurturing and less emotionally available. In contrast, in a second study there were few differences in interactive behaviors between prenatally cocaine-exposed and non-exposed 12-month-old infants and their mothers (53c ). Videotapes recorded African–American infants and their mothers engaged in interactions (49 cocaine-exposed, 63 non-exposed). Children

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who were prenatally exposed to cocaine ignored their mother’s departure during separation significantly more often than controls. Mothers who abused cocaine used more verbal behavior with their children than non-abusers. The effects of prenatal cocaine exposure on later learning abilities, including language, have been further investigated in 265 infants aged 1 year (134 cocaine-exposed and 131 matched non-exposed), who were tested using the Preschool Language Scale-3 (PLS-3) by blinded examiners (54C ). The infants were assigned to three cocaine exposure groups: (as defined by maternal self-report and infant meconium assay): non-exposure (n = 131), heavier exposure (n = 66), and lighter exposure (n = 68). Fetal cocaine exposure was associated with deficits in developmental precursors of speech/language skills. At 1 year of age, more heavily exposed infants had poorer auditory comprehension than the non-exposed infants and worse total language performance than lighter and non-exposed infants. The more heavily exposed infants were also more likely to be classified as mildly delayed than nonexposed infants. Moreover, the degree of cocaine exposure had an inverse relation to auditory comprehension. Prenatal cocaine exposure has been associated with subependymal hemorrhage and subependymal cyst formation in term neonates and more recently in preterm neonates (25% increase) in 14% of patients taking levetiracetam and 26% of patients taking placebo. There were nine sudden unexplained deaths; the overall mortality rates and standardized mortality rates were higher in the placebo group (1.8 levetiracetam vs. 2.5 placebo). Behavioral problems occurred in 5.2–14% of those taking levetiracetam and 4.1–6.0% in those taking placebo. There were higher incidences of adverse effects, particularly behavioral effects, among patients with epilepsy than in elderly patients with cognitive disorders or in patients with anxiety disorders. The long-term retention rate, efficacy, and safety of levetiracetam have been evaluated in all patients with epilepsy exposed to the drug during its developmental program (n = 1422) (38C ). The retention rate was 60% after 1 year and 32% after 5 years. Seizures were reduced by over 50% in 39% of the patients, and 13% became seizure free for at least 6 months. The commonest treatment-emergent adverse events requiring withdrawal were convulsions (3.4%), somnolence (2.0%), weakness (0.6%), depression (0.6%), dizziness (0.5%), and headache (0.5%). There was no evidence of idiosyncratic adverse effects or any serious hematological or biochemical abnormalities during exposure to levetiracetam. Eight patients died suddenly and unexpectedly, about one death per 300 patients years, which is within the expected range in patients with refractory epilepsy. Psychiatric Psychiatric adverse events, most often hostility and irritability, have been reported in children taking levetiracetam. Four cases of acute psychosis have also been reported (39A ).

76 • A 5-year-old girl with refractory epilepsy treated with a ketogenic diet was given levetiracetam 250 mg bd (25 mg/kg/day). She had a history of mild mental retardation and was receiving special education. Two weeks later she started to have visual hallucinations, became agitated, bit relatives, and could not sleep. Levetiracetam was withdrawn and her symptoms resolved within 24 hours and did not recur.

Drug interactions Two placebo-controlled studies in healthy subjects have shown no interactions of levetiracetam with digoxin (40C ) or warfarin (41C ).

Oxcarbazepine

(SED-14, 190; SEDA-23, 88; SEDA-24, 90; SEDA-25, 90)

Two doses of oxcarbazepine have been compared in a double-blind, parallel-group, randomized trial in patients with uncontrolled partial-onset epilepsy who had previously taken carbamazepine monotherapy (42A ). After two open phases in 143 patients, 96 were randomized to oxcarbazepine 300 or 2400 mg/day for 126 days. The time to meet an exit criterion was significantly in favor of oxcarbazepine 2400 mg/day. In all, 24 of the 47 non-randomized patients withdrew because of an adverse event, most commonly dizziness, ataxia, headache, nausea, vomiting, or fatigue. Three withdrew because of laboratory abnormalities, one each with leukopenia, hyponatremia, and hyperglycemia. Headache, dizziness, and nausea were the only adverse events that occurred in more than 10% in either group. Similar adverse events were reported in the randomized patients, but none withdrew. Electrolyte balance Hyponatremia is a frequent, but usually not severe, adverse effect of oxcarbazepine (43R ). Changes in serum electrolyte balance and underlying regulatory mechanisms have been evaluated in ten men with epilepsy 2 and 6 months after long-term carbamazepine monotherapy had been replaced with oxcarbazepine (44C ). Serum sodium concentrations fell in four patients (in two below the reference range) and remained unaltered in six. Serum aldosterone rose in the six patients whose serum sodium concentrations did not fall, but not in those with low sodium concentrations during oxcarbazepine. The serum

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concentration of the N-terminal fragment of pro-atrial natriuretic peptide fell in all patients, reflecting the reduced serum sodium concentrations. Thus, compensatory aldosterone release may prevent hyponatremia in some patients taking oxcarbazepine. Drug interactions A possible interaction of oxcarbazepine with ciclosporin has been reported after renal transplantation in a 32-yearold man (45A ). The ciclosporin trough serum concentration and serum sodium concentration fell after oxcarbazepine was added.

Phenytoin and fosphenytoin (SED-14, 180; SEDA-23, 89; SEDA-24, 90; SEDA-25, 90) Immunologic Hypersensitivity to phenytoin (which had been previously well tolerated) after a hypersensitivity reaction to carbamazepine has been reported (46A ). • A 19-year-old man with partial epilepsy took phenytoin 300 mg/day for over 6 months. Carbamazepine was introduced and after about 6 weeks (while taking phenytoin 300 mg/day and carbamazepine 600 mg/day), he developed fever, anorexia, a sore throat, bloody diarrhea, a diffuse, erythematous, maculopapular rash and palatal petechiae, tender cervical lymphadenopathy, and mild splenomegaly. His liver enzymes were raised and he had a leukocytosis with eosinophilia. Phenytoin and carbamazepine were withdrawn, and he was given prednisone and sodium valproate 1000 mg/day. The rash resolved, as did other manifestations of what was thought to be a hypersensitivity reaction. About a year later phenytoin was reintroduced starting at 100 mg/day. He developed a sore throat after taking the first dose and a widespread rash after the second dose. There was no evidence of hepatic or hematological dysfunction. Phenytoin was withdrawn and the rash resolved in 1 week.

Cross-sensitivity among aromatic antiepileptic drugs occurs in about 50% of patients with a hypersensitivity reaction. It has previously been described on first exposure to each of the offending drugs (47R ). However, this patient developed an allergic rash on his second exposure to phenytoin, having previously tolerated it for 6 months. This suggests that carbamazepine altered his response to phenytoin.

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Skin The incidence of purple glove syndrome associated with intravenous phenytoin has been assessed in a prospective review of 179 consecutive exposures (48C ). There were only three mild cases (1.7%). Drug administration route The extent of absorption and tolerability of intramuscular fosphenytoin has been assessed in an double-blind study in which patients received 10 mg/kg dose of intramuscular fosphenytoin in one gluteus and intramuscular saline in the other (49C ). More than half the patients had serum concentrations in the target range at 30 minutes. There was no pain at either the fosphenytoin or saline injection sites in 46% of patients and no difference in pain at 60 minutes and thereafter.

Remacemide

(SEDA-25, 91)

The efficacy of adjunctive therapy with remacemide has been evaluated in 11 children (50C ). Remacemide was well tolerated in doses up to 13.5 mg/kg/day. The most common adverse events were dizziness, ataxia, and gastrointestinal events. One patient died after a suspected seizure, which was unlikely to have been related to remacemide.

Tiagabine

(SED-14, 190; SEDA-23, 89; SEDA-24, 91; SEDA-25, 92) The efficacy and safety of tiagabine have been assessed in a study with an open screening phase (in which patients were titrated to the optimal tiagabine dose) followed by a double-blind, placebo-controlled, crossover phase (51C ). Of the 88 patients who entered the double-blind phase, seizure frequency was significantly reduced in 44, and there was an over 50% reduction of partial seizures in 33%. There were adverse events in 77% of the patients during the screening phase and 22% during the double-blind phase. The most frequent adverse events were dizziness (32%), somnolence (30%), and weakness (19%). Two patients taking tiagabine withdrew during the double-blind phase because of adverse events.

77 Nervous system Three patients had transient dystonic reactions while taking tiagabine 20– 30 mg/day in addition to carbamazepine (52A ). The dystonic reactions occurred during the first few weeks of treatment. The patients each had a different type of dystonia: focal limb dystonia, oromandibular dystonia, and writer’s cramp. In each case the dystonia resolved spontaneously without withdrawal of tiagabine and without any other treatment. Although paroxysmal dystonic movements have been well described with carbamazepine, these patients had been taking carbamazepine for years without this adverse effect. There have previously been reports of tiagabine-related non-convulsive status epilepticus (53A ). Now the frequency of status during tiagabine trials has been compared with the occurrence of status epilepticus in four large epidemiological cohorts from Rochester (Minnesota), Turku (Finland), New York, and New Haven (Connecticut) (54R ). Review of 13 cases with non-convulsive status showed that most of them had had generalized discharges on prior electroencephalography. Only three had encephalographic evidence of status during tiagabine treatment. In the placebo-controlled trials, there was no difference in the frequency of status or complex partial status between patients taking tiagabine or placebo (0.8–1.0% vs. 1.5%). In long-term safety studies, which included 2248 patients, there was a 5% frequency of status and a 3% frequency of complex partial status in the tiagabine-treated patients, which was similar to the rates of occurrence in the four external cohorts. Thus, tiagabine does not appear to increase the risk of status or nonconvulsive status. Drug dosage regimens Two different dosage regimens (twice or three times a day) of addon tiagabine have been compared in a multicenter, open, randomized, parallel-group study in 347 patients (55C ). The tiagabine dosage was titrated over 12 weeks to a target of 40 mg/day. The patients were followed for a further 12 weeks. Significantly more patients in the thrice-daily group completed the titration period (81% versus 73%). The proportion of responders during the last 8 weeks of the flexible phase was similar in the two groups (42% for twice-daily and 47% for thrice-daily administration). Thus, although both regimens

78 appear to offer similar efficacy, significantly more patients completed the study in the thricedaily group, probably because tolerability is less when high doses are given undivided.

Topiramate

(SED-14; 191; SEDA-23, 90; SEDA-24, 92; SEDA-25, 93)

Topiramate has been used for the treatment of psychiatric disorders, especially bipolar disease. The adverse events profile is similar to that in patients with epilepsy. In a retrospective assessment of 76 patients taking topiramate for bipolar spectrum disorders there was mild improvement in 47% and moderate-to-marked improvement in 13% (56C ). Responders took a significantly higher mean dose (180 mg/day) than non-responders (83 mg/day). There was weight loss (mean 6.4 kg) in 50% of the patients; the dose was significantly higher in patients who lost weight. Other adverse events were reported by 82% of patients: cognitive effects, sedation, paresthesia, nausea, insomnia, headache, and dizziness. Adverse effects led to withdrawal in 36% of the total patient population. Similar anecdotal experiences in the treatment of bipolar disorders have been reported by others (57A , 58C ).

Cognitive effects of topiramate All antiepileptic drugs have been associated with adverse cognitive events, and many, sometimes contradictory, studies of classical antiepileptic drugs have been published (59R ). Cognitive adverse effects are large for phenobarbital, and possibly larger for phenytoin than for carbamazepine or valproic acid (59R ). Most often cognitive adverse events result in mild general psychomotor slowing. Although the severity of cognitive adverse effects is considered mild to moderate for most antiepileptic drugs, their impact may be substantial in some patients, especially in those with pre-existing impaired cognitive function. There is relatively little reliable information on cognitive adverse events of new antiepileptic drugs. Most of the published studies are on polytherapy and there

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is little information about healthy volunteers (60C ). Topiramate has been specifically associated with cognitive complaints. Two patients had neuropsychological deficits during topiramate treatment and cognitive improvement after withdrawal (61A ). One patient was assessed during and after topiramate withdrawal and the other before, during, and after. The cognitive adverse effects of gabapentin, lamotrigine, and topiramate in healthy volunteers have been compared in a randomized, single-blind, parallel-group study (60C ). Neurobehavioral testing was conducted at baseline, during the acute oral dosing period 3 hours after medication administration, and at 2 and 4 weeks during chronic dosing. Acutely, those who took topiramate (2.8 mg/kg) performed significantly worse than those who took gabapentin (17 mg/kg) or lamotrigine (3.5 mg/kg) on tasks of letter and category word fluency and visual attention; cognitive effects were not different between those who took gabapentin or lamotrigine. The doses were then increased to topiramate 5.7 mg/kg/day, lamotrigine 7.1 mg/kg/day, and gabapentin 35 mg/kg/day. At 2 and 4 weeks, those taking topiramate had significant verbal memory deficit and slow psychomotor speed compared with baseline; those taking gabapentin and lamotrigine did not. However, the clinical impact of the trial was limited, owing to the small sample size (17 patients) and the very rapid topiramate titration, much faster than is currently recommended (62C ). There has been a retrospective analysis of neuropsychological scores before and after the use of topiramate 125–600 mg/day for at least 3 months in 18 patients (63C ). Topiramate was associated with significant deterioration in verbal IQ, learning, and fluency. Withdrawal or dosage reduction was associated with significant improvement. There was no correlation between individual topiramate dose and the change in test score. This study was retrospective and the patients were selected because they had cognitive problems; the resultant bias makes it difficult to generalize these results to wider populations. A group of 14 US epilepsy centers has published the results of a post-marketing surveillance study of 701 patients taking topiramate (64C ). Although 41% of the patients reported

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cognitive adverse events at any time during treatment, only 5.8% of them discontinued for that reason. Cognitive effects were the most frequent reason for withdrawal because of adverse events (41/170 or 24% of those who discontinued). The central nervous system-related adverse effects profile in these patients included psychomotor slowing, fatigue, slurred speech, irritability, behavioral changes, confusion, inappropriate laughter, and hallucinations. Only 2.4% of the patients were taking monotherapy, and the mean dose of topiramate at 6 months was 385 mg/day, with a mean weekly dose during titration of 35.5 mg/day. Risk factors for discontinuation were evaluated. A slow titration rate (slower than 25 mg/week), but not the total dose at discontinuation, was significantly associated with a lower discontinuation rate. There was no specific population, dose titration, or concomitant antiepileptic drug that increased the risk of treatment discontinuation because of cognitive complaints. Psychomotor slowing was the most common complaint, but most patients elected to continue treatment because of improved seizure control. The effects of topiramate and valproate, when added to carbamazepine, on cognitive status in adults have been compared in a randomized, observer-blinded, parallel-group study (65C ). Topiramate was introduced slowly at a starting dose of 25 mg/day and increased weekly by 25 mg/day increments over 8 weeks to a minimum dosage of 200 mg/day. The target dosages were 200–400 mg/day for topiramate and 1800 mg/day for valproate. There were significant differences between topiramate and valproate in short-term verbal memory— worsening with topiramate and improvement with valproate—but the differences were small. There were no effects on mood disorders, psychiatric symptoms, or motor and mental speed and language tests. These results suggest that if the dose of topiramate is slowly titrated cognitive adverse events can be minimized. However, although most patients tolerated topiramate if properly titrated and dosed, a subset of patients had clinically significant deficits, possibly as an idiosyncratic reaction. In another multicenter, parallel-group, randomized study there were similar results when topiramate or valproate was added to carbamazepine (66C , 67C ). In conclusion, topiramate can cause cognitive adverse effects in some patients. Those

79 affected often have impaired verbal learning and fluency. Slow titration reduces the likelihood of cognitive adverse events. Sensory systems On 26 September, 2001 OrthoMacneil/Jansen-Cilag issued a “Dear Doctor” letter about an ocular syndrome in patients taking topiramate. The syndrome is characterized by acute myopia and secondary angle closure glaucoma. Several case reports have been published (68A –70A ). As of 17 August, 2001 there have been 23 reported cases (22 adults and one child) out of 825 000 patients. Symptoms typically occur within the first month of therapy, and the patients report acutely reduced visual acuity and/or ocular pain. There is myopia, redness, swelling of the anterior chamber, and raised ocular pressure, with or without pupil dilatation. Supraciliary effusion can displace the lens and iris anteriorly, secondarily causing angle closure glaucoma. The symptoms are reversible if topiramate is withdrawn. Acute myopia has been described as a rare idiosyncratic reaction to other sulfonamides. It has been postulated that the pathogenic mechanism is related to partial inhibition of carbonic anhydrase and to ciliary body swelling. Psychiatric Three patients treated with topiramate for bipolar disorder developed substantial depression (71A ). The symptoms began or increased within 1 week of topiramate treatment (25 mg/day) or with an increase in dosage to 50 mg/day. All had significant relief from depression 1–2 weeks after withdrawal of topiramate. The close association with the onset of the most severe depression these patients had ever experienced suggests an adverse effect of topiramate. However, all these patients had bipolar disorder, so the onset of depression could have been coincidental. Moreover, their depression might also have been due to a synergistic interaction between topiramate and their other medications. A single case report of new-onset panic attacks in a 24 year-old woman with a history of bipolar disorder and binge eating has been described (72A ). She had a history of “isolated” panic attacks 8 years before and the attacks subsided 14 days after topiramate withdrawal. Because she had a history of psychiatric diseases and panic attacks, the relation of these symptoms to topiramate was doubtful.

80 Acid-base balance Two children developed symptomatic metabolic acidosis while taking topiramate (73A ). • An 11-year-old boy with refractory partial epilepsy who had been taking topiramate 300 mg/day for 13 months developed hyperventilation. He had a hyperchloremic metabolic acidosis with partial respiratory compensation. The hyperventilation and acidosis resolved after the administration of sodium bicarbonate and reduction of the dose of topiramate. • A 16-month-old girl developed increasing irritability associated with topiramate; it resolved promptly on withdrawal. Venous blood showed a metabolic acidosis.

The authors postulated that the mechanism of topiramate-induced acidosis is inhibition of carbonic anhydrase in the proximal renal tubule, resulting in impaired proximal bicarbonate reabsorption. Blood gases should be obtained in patients taking topiramate who develop hyperventilation and changes in mental status. Body temperature Reduced sweating, heat and exercise intolerance, and fever have been associated with topiramate. Three patients (aged 17 months, 9 years, and 16 years) developed hyperthermia because of reduced sweating capacity during the summer and/or during exercise 2–3 months after reaching the target dose of topiramate (74A ). A reduction in the dosage of topiramate did not correct the symptoms, which disappeared on topiramate withdrawal. This adverse effect may be related to carbonic anhydrase inhibition by topiramate, as it has been described with zonisamide (another carbonic anhydrase inhibitor). • A 9-year-old boy with partial epilepsy taking topiramate (4 mg/kg/day) developed hyperthermia, reduced sweating, and tiredness after exercise 4 months after the start of treatment (74A ). Sudomotor function showed 180 sweat glands/cm2 (normal 286, fifth percentile 221). After topiramate withdrawal he became asymptomatic and 5 weeks later he had 392 sweat glands/cm2 .

Drug administration Slow dosage titration of topiramate has been advocated by clinicians for improving tolerability. In a multicenter, double-blind trial in adults with refractory partial epilepsy 188 patients were randomized to add-on topiramate by either “slow” titration (initial dose 50 mg/day increased

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weekly by 50 mg/day) or “fast” titration (initial dose 100 mg/day increased weekly by 100– 200 mg/day) (62C ). The maximum dosage of 400 mg/day in both groups was achieved by 3 weeks or 8 weeks. Efficacy was comparable, but slow titration was significantly associated with a lower frequency of adverse events or withdrawals because of adverse events.

Valproate sodium

(SED-14, 182; SEDA-23, 90; SEDA-24, 93; SEDA-25, 95) Nervous system Valproate can occasionally cause aggravation of absence seizures in children (75A ). Eight patients with typical and myoclonic absence epilepsy and electroencephalography that showed generalized 3-Hz spike-and-wave had an increase in the frequency of absence seizures within days of valproate introduction. Dosage increments resulted in further aggravation. Serum concentrations of valproate were within the target range in all cases. All the children improved on valproate withdrawal; in five valproate was reintroduced, resulting in further seizure aggravation. Metabolism A randomized, double-blind study was conducted for 32 weeks to analyse weight change in patients taking lamotrigine (n = 65; mean age 35 years; target dosage 200 mg/day) and valproate (n = 68; mean age 30 years; target dosage 20 mg/kg/day) (76C ). Weight remained stable in the patients taking lamotrigine. However, there was significant weight gain in the patients taking valproate by the 10th week of treatment, and weight continued to increase throughout the study. After 32 weeks, mean weight gain was significantly higher in those taking valproate (5.8 kg) compared with lamotrigine (0.6 kg). Similar proportions of patients taking lamotrigine (29%) or valproate (26%) were seizure-free. The frequencies of adverse events were similar in the two groups. Liver Valproate is often associated with mild asymptomatic rises in liver enzymes. The association between valproate and raised transaminases has been studied in a retrospective review of the medical records of patients positive for

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hepatitis C virus (77C ). Of 214 patients 28 were taking valproate and 186 were not. The controls and those who had been hepatitis-positive for longer were significantly more likely to have worse hepatotoxicity. Valproate, either alone or in the presence of other potential hepatotoxins, was not associated with raised transaminases. Skin Cutaneous pseudolymphoma has been attributed to valproate (78A ). • A 41-year-old man presented with an erythematous papule, histologically mimicking a nonepidermotropic T cell lymphoma. Polymerase chain reaction in the skin biopsy showed monoclonal rearrangement of the T cell receptor gamma gene. Withdrawal of valproate was followed by regression of the lesion, but 5 months after substitution by carbamazepine, two further papules appeared, with similar histological features. Carbamazepine was withdrawn and the lesions disappeared without relapse over 4 years.

Valproate-associated polycystic ovary syndrome There is evidence that polycystic ovary syndrome (polycystic ovaries, hyperandrogenism, obesity, hirsutism, anovulatory cycles, and menstrual disorders) is more common in women with epilepsy. Valproate has been associated with alterations in reproductive hormonal function beginning in the first month of treatment. Serum androgen concentrations increase in patients taking valproate but the profile of hormonal changes is different in women and men (5C ). Animal studies have corroborated the adverse ovarian and endocrine effects of valproate (79E ). Four review articles have recently been published dealing with this reported adverse event, highlighting controversial views (80R , 81R –83R ). The estimated prevalence of polycystic ovary syndrome in patients with epilepsy is 13–25%, compared with 4–6% in the general population (80R ). Polycystic ovary syndrome has been described in women with epilepsy taking valproate, especially those who start treatment before 20 years of age (84C , 85C ), and the frequency is high: in a cross-sectional study of 22 women taking valproate monotherapy, 59% were obese and 64% had polycystic ovaries, hyperandrogenism, or both (85C ).

81 In a prospective study of polycystic ovary syndrome in 52 controls and 72 women with epilepsy (37 taking valproate monotherapy and 35 carbamazepine monotherapy), the frequency of polycystic ovaries, hyperandrogenism, or both was significantly higher in those taking valproate than in the controls (70% vs. 19%) (86C ). They occurred in 20% of the patients taking carbamazepine. The obese women taking valproate who had polycystic ovaries or hyperandrogenism or both had hyperinsulinemia and associated unfavorable changes in serum lipid concentrations consistent with insulin resistance. In both obese and lean women, polycystic ovaries and related hyperandrogenism were similarly found. Most of the abnormalities were reversed when valproate was withdrawn (87C ). Although the association between polycystic ovary syndrome and valproate treatment appears to be established, current published studies are limited owing to small sample sizes and diverse definitions of polycystic ovary syndrome. Thus, the true clinical relevance and frequency of the association needs further investigation in large, multicenter, prospective studies. Women taking valproate should be asked about menstrual disorders. The presence of a menstrual disorder, hirsutism, or weight gain should trigger thorough evaluation and, if necessary, valproate withdrawal. Infection risk In vitro tests have shown that valproate can increase the viral burden in HIVinfected individuals by potentiating replication of the virus (88E ). In a retrospective review of 11 HIV-positive patients with behavioral disturbances taking valproate HIV-1 viral load did not increase in six of the nine patients who had measurements between the first week and 3.5 months after the start of valproate treatment; no follow-up was available for the other three (89C ). These data suggest that, contrary to in vitro data, HIV-1 viral load is not adversely affected by valproate in the presence of effective antiretroviral therapy. Body temperature Hypothermia related to valproate has been reported in a child (90A ). There have been five previously described cases in adults or elderly patients (91A ). • A 2-year-old boy was admitted after a prolonged febrile seizure that stopped only after he was given

82 several doses of benzodiazepines plus phenobarbital. A CT scan showed a right arachnoid cyst. He was given valproate 13 mg/kg/day and 2 days later developed hypothermia (33.8–34.5◦ C). He was lethargic and irritable. Valproate was withdrawn. His lethargy improved within 48 hours and the temperature slowly returned to normal over the course of 1 week.

Fetotoxicity Fetal valproate syndrome comprises a number of typical dysmorphic features and major organ system anomalies (92R ). In a case file review of 2220 children with craniosynostosis, detailed maternal health information was obtained in 1676 cases (93C ). Of these, 17 mothers had taken valproate monotherapy during pregnancy. All 17 children had trigonocephaly (caused by premature fusion of the metopic suture). Their IQs were 45–100 (mean 75). IQs were significantly higher in patients who underwent surgery before 6 months of age. This is the first study to have reported trigonocephaly associated with fetal valproate syndrome. Five patients with fetal valproate syndrome and autism have been described (94A ).

Vigabatrin

(SED-14, 192; SEDA-23, 92; SEDA-24, 94; SEDA-25, 98)

In a single-blind, randomized trial of vigabatrin for 2 weeks in children with newly diagnosed infantile spasms the children were randomly assigned to low-dose vigabatrin (18– 36 mg/kg/day) or high-dose vigabatrin (100– 148 mg/kg/day) (95C ). The time to response was evaluated during the first 3 months, and safety was evaluated during the entire study. Eight of 75 children who took low-dose vigabatrin and 24 of 67 who took high-dose vigabatrin responded. The time to response was significantly shorter in those who took high-dose vigabatrin and in those with tuberous sclerosis. The most common treatment-related adverse events were sedation (42/167), insomnia (15/167), and irritability (15/167). There were no dose-related adverse events, and adverse event rates were similar in the low-dose and high-dose groups. Only nine patients withdrew because of adverse events. Vigabatrin efficacy and tolerability have been evaluated for a mean of 16 months in

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children in a retrospective study of 73 patients (mean age 87 months) (96C ). In 16% of the children vigabatrin was given as monotherapy and patients with both partial or generalized seizures were included. Vigabatrin was highly effective in 30 children (over 90% seizure reduction) and partially effective in four (50– 90% seizure frequency reduction). There were adverse effects in 24%, the commonest being irritability, aggression, opposition/defiance, self-injurious behaviors, and deterioration in behavioral control. There was seizure deterioration in 7% of the children; worsening of myoclonic seizures was most common. Visual field testing by perimetry was possible in only 12 of the children; two had visual field constriction.

Vigabatrin-related visual abnormalities Visual field defects Visual field constriction associated with vigabatrin has continued to be the focus of attention in many reports (SEDA24, 95; SEDA-25, 98; 97R , 98R ). Prevalence and risk factors The prevalence of visual field defects has been analysed in several studies and has varied from study to study: 60% (99C ), 40% (100C ), or 19% (101C ). These different rates have probably been related to the diverse methods of patient inclusion and visual field testing. The longer the duration of vigabatrin treatment and the higher the dose the greater the probability of field defects (99C , 101C , 102C ). In a cohort study of 99 patients taking vigabatrin, the prevalence of visual field defects increased significantly with increasing total vigabatrin dose. The prevalence ranged from four of 51 patients who had been exposed to 1 g/day or less to six of eight patients taking a total dose of 3–5 g/day (101C ). Reversibility Several studies have suggested that vigabatrin-associated visual field defects are irreversible (101C , 102C ). In one study, 12 vigabatrin-treated patients with visual field defects were re-examined 2–10 years after vigabatrin withdrawal, and all still had visual field defects (101C ). In five cases there was apparent worsening. Exceptional cases of reversible visual field defects have been reported in children (103A ). However, perimetry assessment in children is burdened with multiple methodological problems that usually preclude reliable results.

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83

Pathophysiology The pathophysiology of vigabatrin-related visual field defects is not known. Recent evidence suggests that they might be related to accumulation of GABA in the retina. In rats treated either with vigabatrin or tiagabine, vigabatrin reduced the activity of GABA transaminase and increased GABA concentrations in the brain, but these effects were more pronounced in the retina, in which vigabatrin concentrations are as much as fivefold higher than in the brain (104E ). On the other hand, tiagabine concentrations are considerably lower in the retina than in the brain. Tiagabine has not been associated with visual field defects. The pathological features of visual field constriction have been described in a patient taking vigabatrin (105A ).

some cases to assess the reliability of the apparent worsening or improvement experienced by some patients. In a study in 60 adults with partial epilepsy, progression or reversibility of vigabatrin-associated visual field defects were examined (102C ). The patients had taken vigabatrin for 7 months to 14 years as monotherapy or addon therapy and were examined with repeated kinetic Goldmann perimetry. A follow-up examination was performed after 4–38 months in 55 patients. There was vigabatrin-associated visual field constriction in 40%, and in 13% the defect was severe. During follow-up after withdrawal of vigabatrin, there was no significant recovery of visual fields in any patient. Conversely, there was no progression in those who continued therapy.

• A 41-year-old man who had taken vigabatrin for 2 years in doses of 3–6 g/day developed bilateral concentric visual field defects, with greater loss in the nasal fields, and vigabatrin was withdrawn. Later he had a cardiopulmonary arrest and died. At post-mortem there was peripheral retinal atrophy with loss of ganglion cells, severe in the peripheral retina and less severe in the maculae. There was loss of nerve fibers in the optic nerves, chiasm, and tracts. There was no evidence of intramyelin edema.

Assessment The value of electroretinography and electro-oculography in the early diagnosis of vigabatrin-associated visual field defects has been assessed in 30 patients with temporal lobe epilepsy (107C ). The patients were stratified into three groups: (A) concentric contraction of the visual field associated with vigabatrin (n = 15), (B) normal visual field with vigabatrin use (n = 11), and (C) normal visual field without vigabatrin (n = 4). There were abnormal electrophysiological results in 50% of the patients in group A. The electro-oculographic Arden ratio was lowered in 57%. The amount of visual field loss and the total dose of vigabatrin used correlated only weakly with the results of electroretinography and electro-oculography. These results suggest that ocular electrophysiology is not a good method for detecting patients at risk of vigabatrin-related visual field defects. Regular visual field examination remains the cornerstone in screening. This has been confirmed by a retrospective, comparative case series in which the degree of electroretinal dysfunction was analysed using electroretinography in 40 patients taking vigabatrin, 24 as monotherapy (108C ). There was no statistically significant relation between the frequency of electrodiagnostic abnormalities and the duration of use or the total cumulative dosage of vigabatrin. In conclusion, the relatively high prevalence and the irreversibility of the vigabatrin-related visual field constriction suggest that vigabatrin

These findings suggest that vigabatrin may be directly associated with direct retinal injury (to the ganglion cells). The degree of cell loss suggested that the visual field loss was irreversible. Long-term safety The safety of continuing vigabatrin therapy in adults who have taken prolonged treatment (over 2 years) has been assessed by serially monitoring changes in visual function over 1 year of continued therapy (106C ). Fifteen patients who continued to take vigabatrin had visual function testing (visual acuity, color vision, and kinetic and static perimetry) every 3 months for 1 year. Nine had normal visual fields and six had visual field constriction. During follow-up, they showed no worsening of visual acuity, color vision, or visual field constriction, beyond that measured in the initial test. This study showed that mild changes in visual function after long-term vigabatrin generally remain stable with continued treatment. However, patient consistency was variable and repeated testing was necessary in

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should be used only as a last resort in most patients with epilepsy. In Europe, vigabatrin is being used mostly in children, especially those with infantile spasms. For this indication, vigabatrin has high efficacy and causes fewer severe adverse effects than ACTH (95C , 109C , 110R ). However, the long-term retinal effects of vigabatrin in children are unknown, and visual field testing is usually impossible. Recent evidence has suggested that a short course of vigabatrin (6 months) in children with infantile spasms may be sufficient (111C ) and minimizes the potential for visual adverse effects. Retinal dysfuntion Retinal dysfunction has been retrospectively assessed in 29 children taking vigabatrin 25–114 mg/kg/day for 6.5 years (112C ). Ophthalmic examination was performed before treatment and every 6 months thereafter. Four children developed eye changes (retinal pigmentation, hypopigmented retinal spots, vascular sheathing, and optic atrophy). Visual evoked potentials were abnormal in 16. Electroretinography and electro-oculography were not performed. Color vision changes Changes in color vision have been investigated in healthy volunteers who took a single oral dose of either vigabatrin or carbamazepine in a single-blind, placebocontrolled, randomized trial (113C ). All underwent color visual-evoked potential testing and color perimetry at baseline and after taking placebo, vigabatrin (2000 mg), or carbamazepine (400 mg). Carbamazepine caused mild overall impairment of the chromatic and achromatic systems. Vigabatrin caused selective blue impairment, consistent with GABAergic inhibition in the retina. The relation of this change in color perception to visual field defects, if any, is unknown.

Zonisamide

(SED-14, 193; SEDA-25,

100) In a double-blind, placebo-controlled, add-on, randomized trial of zonisamide 400 mg/day in 203 patients over 14 years of age with refractory partial-onset seizures, the response

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rate was 42% (114C ). The most common treatment-emergent adverse events were somnolence, anorexia, rhinitis, dizziness, nausea or vomiting, ataxia, fatigue, and headache. With zonisamide, 22% of the patients lost over 2.3 kg compared with 10% on placebo. In a Cochrane Collaboration meta-analysis of trials of zonisamide, levetiracetam, oxcarbazepine, and remacemide, there were no significant differences in efficacy among the four drugs (115M ). The relative risks for treatment withdrawal were also not significantly different. Immunologic Zonisamide-induced lupus erythematosus has been reported in a 5-year-old child taking zonisamide and ethosuximide (116A ). He had raised titers of antinuclear antibodies and anti-DNA antibodies and presented with fever, pericarditis, pleurisy, and arthralgia. Clinical recovery and a reduction in the anti-DNA-antibody titer promptly followed withdrawal. A lymphocyte transformation test against zonisamide was positive. Body temperature Children have a higher risk of zonisamide-associated oligohidrosis and hyperthermia (117R ). Elan Pharma have recently issued a “Dear Doctor” letter reporting this adverse event (June 2002). During the zonisamide development program in Japan one case of oligohidrosis was reported among 403 children (an incidence of 1/285 patient-years of exposure). There were no cases reported in the US or European development programs, although under 100 children were included in those programs. In the first 11 years of marketing in Japan, 38 cases have been reported (about 1 per 10 000 patient-years). In the first year in the USA, two cases were reported (an estimated reporting rate of 12/10 000 patient-years). This rate might be an underestimate, owing to underreporting. There has been one report of heat stroke in an 18-year-old patient in the USA. Children treated with zonisamide should be monitored closely for evidence of reduced sweating and increased body temperature, especially in warm or hot weather and when taking other drugs that predispose to this (carbonic anhydrase inhibitors, anticholinergic drugs, topiramate).

Antiepileptic drugs

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48. Burneo JG, Anandan JV, Barkley GL. A prospective study of the incidence of the purple glove syndrome. Epilepsia 2001; 42: 1156–9. 49. Pryor FM, Gidal B, Ramsay RE, DeToledo J, Morgan RO. Fosphenytoin: pharmacokinetics and tolerance of intramuscular loading doses. Epilepsia 2001; 42: 245–50. 50. Besag FM, Newton RE, Blakey GE, Dean AD. Safety, tolerability, and pharmacokinetics of remacemide in children. Pediatr Neurol 2001; 24: 352–6. 51. Crawford P, Meinardi H, Brown S, Rentmeester TW, Pedersen B, Pedersen PC, Lassen LC. Tiagabine: efficacy and safety in adjunctive treatment of partial seizures. Epilepsia 2001; 42: 531–8. 52. Wolanczyk T, Grabowska-Grzyb A. Transient dystonias in three patients treated with tiagabine. Epilepsia 2001; 42: 944–6. 53. Fitzek S, Hegemann S, Sauner D, Bonsch D, Fitzek C. Drug-induced nonconvulsive status epilepticus with low dose of tiagabine. Epileptic Disord 2001; 3: 147–50. 54. Shinnar S, Berg AT, Treiman DM, Hauser WA, Hesdorffer DC, Sackellares JC, Leppik I, Sillanpaa M, Sommerville KW. Status epilepticus and tiagabine therapy: review of safety data and epidemiologic comparisons. Epilepsia 2001; 42: 372– 9. 55. Biraben A, Beaussart M, Josien E, Pestre M, Savet JF, Schaff JL, Tourniaire D, Sevestre M, Renault-Djouadi J. Comparison of twice- and three times daily tiagabine for the adjunctive treatment of partial seizures in refractory patients with epilepsy: an open label, randomised, parallel-group study. Epileptic Disord 2001; 3: 91–100. 56. Ghaemi SN, Manwani SG, Katzow JJ, Ko JY, Goodwin FK. Topiramate treatment of bipolar spectrum disorders: a retrospective chart review. Ann Clin Psychiatry 2001; 13: 185–9. 57. Davanzo P, Cantwell E, Kleiner J, Baltaxe C, Najera B, Crecelius G, McCracken J. Cognitive changes during topiramate therapy. J Am Acad Child Adolesc Psychiatry 2001; 40: 262–3. 58. Chengappa KN, Gershon S, Levine J. The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder. Bipolar Disord 2001; 3: 215–32. 59. Aldenkamp AP. Effects of antiepileptic drugs on cognition. Epilepsia 2001; 42 Suppl 1: 46–9. 60. Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J, Sinclair K, Gilliam F, Faught E. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999; 52: 321– 7. 61. Rorsman I, Kallen K. Recovery of cognitive and emotional functioning following withdrawal of topiramate maintenance therapy. Seizure 2001; 10: 592–5. 62. Biton V, Edwards KR, Montouris GD, Sackellares JC, Harden CL, Kamin M. Topiramate titration and tolerability. Ann Pharmacother 2001; 35: 173–9. 63. Thompson PJ, Baxendale SA, Duncan JS, Sander JW. Effects of topiramate on cognitive func-

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88 96. Prasad AN, Penney S, Buckley DJ. The role of vigabatrin in childhood seizure disorders: results from a clinical audit. Epilepsia 2001; 42: 54–61. 97. Spence SJ, Sankar R. Visual field defects and other ophthalmological disturbances associated with vigabatrin. Drug Saf 2001; 24: 385–404. 98. Kalviainen R, Nousiainen I. Visual field defects with vigabatrin: epidemiology and therapeutic implications. CNS Drugs 2001; 15: 217–30. 99. Toggweiler S, Wieser HG. Concentric visual field restriction under vigabatrin therapy: extent depends on the duration of drug intake. Seizure 2001; 10: 420–3. 100. Nousiainen I, Mantyjarvi M, Kalviainen R. No reversion in vigabatrin-associated visual field defects. Neurology 2001; 57: 1916–17. 101. Malmgren K, Ben Menachem E, Frisen L. Vigabatrin visual toxicity: evolution and dose dependence. Epilepsia 2001; 42: 609–15. 102. Hardus P, Verduin WM, Engelsman M, Edelbroek PM, Segers JP, Berendschot TT, Stilma JS. Visual field loss associated with vigabatrin: quantification and relation to dosage. Epilepsia 2001; 42: 262–7. 103. Vanhatalo S, Alen R, Riikonen R, Rantala H, Aine MR, Mustonen K, Nousiainen I. Reversed visual field constrictions in children after vigabatrin withdrawal – true retinal recovery or improved test performance only? Seizure 2001; 10: 508–11. 104. Sills GJ, Patsalos PN, Butler E, Forrest G, Ratnaraj N, Brodie MJ. Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina. Neurology 2001; 57: 196–200. 105. Ravindran J, Blumbergs P, Crompton J, Pietris G, Waddy H. Visual field loss associated with vigabatrin: pathological correlations. J Neurol Neurosurg Psychiatry 2001; 70: 787–9. 106. Paul SR, Krauss GL, Miller NR, Medura MT, Miller TA, Johnson MA. Visual function is stable in patients who continue long-term vigabatrin therapy: implications for clinical decision making. Epilepsia 2001; 42: 525–30.

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107. Hardus P, Verduin WM, Berendschot TT, Kamermans M, Postma G, Stilma JS, Van Veelen CW. The value of electrophysiology results in patients with epilepsy and vigabatrin associated visual field loss. Acta Ophthalmol Scand 2001; 79: 169– 74. 108. Coupland SG, Zackon DH, Leonard BC, Ross TM. Vigabatrin effect on inner retinal function. Ophthalmology 2001; 108: 1493–6. 109. Curatolo P, Verdecchia M, Bombardieri R. Vigabatrin for tuberous sclerosis complex. Brain Dev 2001; 23: 649–53. 110. Nabbout R. A risk-benefit assessment of treatments for infantile spasms. Drug Saf 2001; 24: 813–28. 111. Nabbout R, Melki I, Gerbaka B, Dulac O, Akatcherian C. Infantile spasms in Down syndrome: good response to a short course of vigabatrin. Epilepsia 2001; 42: 1580–3. 112. Koul R, Chacko A, Ganesh A, Bulusu S, Al Riyami K. Vigabatrin associated retinal dysfunction in children with epilepsy. Arch Dis Child 2001; 85: 469–73. 113. Mecarelli O, Rinalduzzi S, Accornero N. Changes in color vision after a single dose of vigabatrin or carbamazepine in healthy volunteers. Clin Neuropharmacol 2001; 24: 23–6. 114. Faught E, Ayala R, Montouris GG, Leppik IE. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology 2001; 57: 1774–9. 115. Marson AG, Hutton JL, Leach JP, Castillo S, Schmidt D, White S, Chaisewikul R, Privitera M, Chadwick DW. Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 2001; 46: 259–70. 116. Mutoh K, Hidaka Y, Hirose Y, Kimura M. Possible induction of systemic lupus erythematosus by zonisamide. Pediatr Neurol 2001; 25: 340–3. 117. Glauser TA, Pellock JM. Zonisamide in pediatric epilepsy: review of the Japanese experience. J Child Neurol 2002; 17: 87–96.

A.H. Ghodse and A.M. Baldacchino

8

Opioid analgesics and narcotic antagonists

OPIOID RECEPTOR AGONISTS Alfentanil

(SED-14, 211; SEDA 23, 98; SEDA-24, 104; SEDA 25, 110) Alfentanil is a potent short-acting opioid with a rapid onset and short duration of action. It is therefore the ideal analgesic for focused and ambulatory interventions. In a prospective, uncontrolled study in three consecutive groups of out-patients undergoing shock-wave lithotripsy, group 1 (152 patients) had an induction dose of a combination of propofol 0.8 mg/kg and alfentanil 8 µg/kg; in group 2 (78 patients) and group 3 (250 patients), the induction dose was reduced by 20% (1C ). For all three groups the maintenance dose was a mixture of propofol 0.25 mg/kg and alfentanil 5 µg/kg given via a PCA device with a lock-out time of 5 minutes. In groups 1 and 2 the lithotripter was equipped with a standard electromagnetic shock-wave emitter (the EMSE 200), while in group 3 an upgraded EMSE F150 was used. Analgesic consumption was lower in the patients treated with the EMSE 150; groups 2 and 3, with a 20% reduction in induction dose, did not compensate by using more PCA. Groups 2 and 3 also had a significant reduction in the incidence of oxygen desaturation. The intravenous administration of a mixture of alfentanil and propofol, using the updated EMSE F150 device as in group 3, was therefore considered to be safe and reliable, with good patient tolerance and rapid recovery. Nervous system Simultaneous scalp and depth electrode recordings were performed on five patients with complex partial epilepsy who © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

underwent alfentanil anesthesia induction before depth electrode removal (2c ). Five equal bolus doses of alfentanil 100 µg were given to each patient at 60-second intervals (total 500 µg alfentanil). Epileptiform activity was increased in three of the five, but without clinical evidence of seizure activity. Gastrointestinal A 30-year-old woman with multiple body injuries required five general anesthetics in under 7 days for reconstructive surgery and dressing changes. In order to avoid further general anesthesia she was given a target-controlled infusion of alfentanil 10 mg in 50 ml of 0.9% sodium chloride (a total dose of 5.04 mg alfentanil over 35 minutes). There was one self-limiting episode of nausea with no vomiting. Oxygen saturation was 93–98% on air. There were no episodes of hypotension, cardiac dysrhythmias, or sedation (3A ).

Codeine

(SED-14, 212; SEDA-23, 98; SEDA-25, 110) Nervous system Patients with migraine who use daily codeine or other opioids may be more susceptible to chronic daily headaches; this is evident in opiate overuse. In a pilot questionnaire study of 32 patients who used codeine or other opioids for control of their bowel motility after colectomy, chronic daily headaches occurred in those who were misusing opioids, but only if they had pre-existing migraine (4c ). The study had significant limitations, including the small sample size, diagnosis by means of a mailed questionnaire, a short duration of overuse of opioids, and the fact that it was uncontrolled.

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90 Skin Rashes have been attributed to codeine. • A 72-year-old man developed a generalized maculopapular rash 12 hours after taking co-codamol (codeine 10 mg plus paracetamol 500 mg) (5A ). The lesions persisted for 7 days, became scaly, and disappeared. He later reported a similar skin condition after having taken a combination of acetylsalicylic acid, codeine, and caffeine. Patch tests gave a positive result for codeine, suggesting a type IV allergic reaction. • A 58-year-old man developed a maculopapular rash on the dorsal aspects of the hand and upper body 6 days after taking codeine as an analgesic for hemoptysis secondary to tuberculosis; on withdrawal of codeine, the rash subsided after 48 hours (6A ).

Drug abuse Recreational use and abuse of codeine cough syrup is becoming more frequent. In a literature search of scientific journals and news media, complemented with in-depth interviews of 12 professionals working in the law enforcement or treatment aspects of drug abuse and 25 adults who reported using codeine syrup in the 30 days before their interview, the information provided useful insights into the different types of cough formulations, the reported reasons for their use, and the various types of administration (7MC ). The effects of cough syrup, including their adverse effects, were reported. The most frequently mentioned negative effects included taste disturbance, prolonged sedation beyond the desired effect, loss of co-ordination, lethargy, constipation, and urinary retention. This qualitative study cannot be described as authoritative or representative, because of its limited nature, involving as it did only a small number of individuals living in the Houston area.

Dextromethorphan

(SED-14, 212; SEDA-23, 99; SEDA-24, 104; SEDA-25, 111) The effect of dextromethorphan premedication on postoperative analgesic requirements, pain scores, and adverse effects has been examined in two double-blind, randomized studies (8C , 9C ). In the first study, 60 adults scheduled for elective upper abdominal surgery were randomly allocated to three equal groups (8C ). One group received intramuscular dextromethorphan 120 mg 30 minutes before

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skin incision (pre-incisional group); the second group received placebo (intramuscular saline) 30 minutes before skin incision and intramuscular dextromethorphan 120 mg 30 minutes before the end of surgery (post-incisional group); the third group received placebo 30 minutes before skin incision and 30 minutes before the end of surgery (control group). Pre-incisional intramuscular dextromethorphan 120 mg provided pre-emptive analgesia, reduced the need for postoperative analgesic supplements, and had a minimal and non-significant adverse effects profile. In the second study oral dextromethorphan 90 mg was compared with placebo given 90 minutes preoperatively to patients undergoing laparoscopic cholecystectomy or inguinal hernioplasty under general anesthesia (9C ). Pain intensity and sedation were significantly reduced in the experimental group, with sparing of postoperative analgesics for up to 24 hours. Dextromethorphan 90 mg also abolished postoperative thermal-induced hyperalgesia and hyperpathia. No adverse effects were recorded in either group. A randomized, double-blind, placebo-controlled study of oral dextromethorphan and PCA morphine has been performed in 66 patients undergoing knee surgery (10C ). The study was in two parts. The first was a dose escalation study in 25 postoperative patients to determine the maximum tolerated oral dose of dextromethorphan. The second involved giving less than the maximum tolerated dose divided into three increments at 8-hour intervals. The maximum tolerated dose of dextromethorphan was 750 mg. One patient, who was given 800 mg of dextromethorphan, had adverse effects, including severe slurred speech and lightheadedness followed by deep sedation. In the second part of the study 66 patients were intended to receive dextromethorphan 800 mg in three doses of 400, 200, and 200 mg. The treatment group was subsequently reduced to 22 patients, compared with 34 in the placebo group, because of unexpected nausea and vomiting in five patients given dextromethorphan 400 mg. Dextromethorphan 200 mg 8-hourly caused a significant increase in nausea 2–24 hours after the first dose. One patient given dextromethorphan had mild hallucinations on one occasion only. There was an associated modest reduction in postoperative morphine consumption (29%),

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with no other benefits. The study failed to provide evidence that the maximum tolerated dose of dextromethorphan 200 mg 8-hourly is useful in the treatment of postoperative pain after knee surgery. Three double-blind, crossover, randomized, placebo-controlled studies of the role of dextromethorphan in neurological pain conditions in 40 adults with diabetic neuropathy, postherpetic neuralgia, and non-specific neuropathic pain syndromes have been reviewed (11M ). Dextromethorphan dosages varied from 13.5 mg tds on alternate days to 120 mg qds. High-dose dextromethorphan significantly reduced pain in diabetic neuropathy with no effect in post-herpetic neuralgia. Sedation (58%) and dizziness (25%) were the most commonly reported adverse effects. Neuromuscular Dextromethorphan has been implicated in a case of movement disorder (12A ). • An 8-year-old boy complained of abnormal facial movements and hallucinations. One day before these symptoms, he had been given his sister’s Cordec DM droplets (carbinoxamine maleate 2 mg, pseudoephedrine hydrochloride 25 mg, and dextromethorphan 4 mg) for a cold. He had facial dyskinesia, dilated pupils, pyrexia, tachycardia, and reduced bowel sounds and responded to a benzodiazepine.

Pregnancy In 184 pregnancies exposed to dextromethorphan (128 exposures in the first trimester) there were 172 live births, 10 spontaneous abortions, one therapeutic abortion, and one stillbirth (13C ). There were three major malformations and seven minor malformations in the children of women who had used dextromethorphan in the first trimester. In the control group there were 174 live births, eight spontaneous abortions, and two therapeutic abortions; there were five major and l8 minor malformations. This small study did not show that dextromethorphan used during pregnancy increases the rates of major malformations above the expected baseline rate of 1–3%.

Diamorphine (heroin)

(SED-14, 214;

SEDA-24, 105; SEDA-25, 112) Combined spinal–epidural anesthesia for mobile analgesia in labor is now widely used. It

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offers the advantage of rapid onset of analgesia with the flexibility of epidural top-ups later in labor. In 62 women who asked for regional analgesia in labor and who were randomized to an intrathecal injection of either bupivacaine 2.5 mg with fentanyl 25 µg or bupivacaine 2.5 mg with diamorphine 250 µg, the diamorphine provided longer analgesia (14C ). There were significant differences in adverse effects between the groups. There were no instances of nausea or vomiting, but pruritus was more common in those who received fentanyl. The dose of diamorphine was deliberately low, and more studies are needed to confirm these findings. High-dose intrathecal diamorphine for analgesia after elective cesarean section has been studied in 40 women who were randomized to diamorphine 0.5 mg or 1 mg (15C ). All also received diclofenac 100 mg at the end of the cesarean section and morphine via a patient-controlled analgesia system. Postoperative analgesia was more prolonged and reliable in those who were given diamorphine 1 mg, who needed significantly less morphine. There was postoperative nausea in just under half of the patients in each group, and most of the patients (93%) had mild to moderate pruritus. There were no cases of excessive sedation or oxygen desaturation. High-dose diamorphine has been compared with morphine in a double-blind, crossover, randomized study in 39 intravenous opioid users who were allocated to either morphine 3% solution or diamorphine 2% solution, gradually increased up to an individual maintenance dose adjusted to meet the patient’s subjective needs (16C ). Those who started with diamorphine and subsequently switched to morphine terminated prematurely owing to excessive histamine reactions, all of which occurred during crossover to morphine. Symptoms included severe pruritus, flushing, swelling, urticaria, severe headaches, nausea, general malaise, hypotension, and tachycardia. Only 44% of the original cohort finished the 6-week study (14 getting diamorphine at the end and three getting morphine). Average daily doses were 491 mg for diamorphine and 597 mg for morphine. These results suggest that diamorphine produces fewer adverse effects than morphine and may be preferable for high-dose maintenance prescription. However, the study was very small and subject selection was biased,

92 as were the variables used to determine a successful outcome. The result was contrary to all the well established pharmacological facts, and the authors did not mention the risks associated with high doses of short-acting opioids. Nasal diamorphine is as effective as intramuscular morphine and is much better tolerated by children, with no apparent increased risk of adverse effects (17M , 18C ). In a multicenter, randomized, controlled study, 404 children aged 3–16 years with a fracture of an arm or leg were given either nasal diamorphine 0.1 mg/kg or intramuscular morphine 0.2 mg/kg. The onset of pain relief was faster with nasal diamorphine, and there were no serious adverse effects. The frequencies of mild opioid-related adverse effects were similar in the two groups. Nervous system Demyelination has been attributed to diamorphine (19A ). • A 41-year-old chronic diamorphine user developed an unsteady gait and dysarthria over 2 weeks, followed by severe cerebellar ataxia and moderate dysmetria of the arms and legs. An MRI scan suggested myelin damage, with symmetrical involvement of the cerebellar hemispheres and decussation of the superior cerebellar peduncles, the corticospinal tracts, and the centrum semiovale, suggesting spongiform leukoencephalopathy. Two years later having taken no more diamorphine he was improved, with minor regression of the MRI lesions, especially the white matter lesions.

Sensory systems Profound reversible deafness with vestibular dysfunction has been described in a 47-year-old intravenous opiate user 24 hours after he had injected illicit diamorphine (20A ). He developed bilateral symmetrical sensorineural hearing loss, ear fullness, and loud tinnitus 20 minutes after injecting about 0.25 g of diamorphine after a period of abstinence. His symptoms gradually subsided with no sequelae after 3 weeks.

Dihydrocodeine Dihydrocodeine is an opioid analgesic related to codeine, in which the double bond in the 7th position is saturated. It has an analgesic potency 2–3 times that of codeine. A modified-release formulation extends the duration of action from 2–4 hours to 12 hours. In 12 volunteers who

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took modified-release dihydrocodeine 60 mg or 120 mg and 120 minutes later lactulose 40 mg diluted in 100 mg of water the orocecal transit time was significantly prolonged by dihydrocodeine compared with placebo (21c ). Dihydrocodeine also significant suppressed the pupillary light reflex. Both dosages caused similar adverse effects. Tiredness and dry mouth were reported in 80%, vertigo in 5%, and headache in 1%.

Fentanyl

(SED-14, 213; SEDA-23, 100; SEDA-24, 105; SEDA-25, 113) Fentanyl can be used transdermally because of its high solubility in both fat and water, low molecular weight, high analgesic potency, and fewer adverse effects, especially gastrointestinal symptoms (22C ). It is easy to administer and can be given at 3-day intervals. Transdermal fentanyl in chronic cancer pain control has been extensively reviewed (23M ). Data from non-blinded, randomized trials suggest that it is as effective as modified-release oral morphine and that the most common adverse effects include nausea, vomiting, and constipation. The most serious adverse effect reported was hypoventilation, which occurred in about 2% of patients. Skin reactions occurred in 1–3%. A number of non-comparative trials have described the use of transdermal fentanyl for periods of at least a year without serious adverse effects. In a follow-up study of 78 patients with cancer who participated in a cross-over, randomized study of transdermal fentanyl (mean final dose 100 µg/hour) and oral morphine for 4 weeks, the incidences of skin reactions and gastrointestinal symptoms were low (24C ). Other adverse effects reported were breakthrough pain, light-headedness, and diarrhea. In the original randomized study, which lasted 15 days, there was significantly less constipation with fentanyl than with morphine (25C ). These results suggest that many patients have stable analgesic requirements with transdermal fentanyl up to the time of death with no need for additional medication. In a questionnaire survey of 1005 patients only 11 had chronic pain from nonmalignant disease while taking transdermal

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fentanyl (26C ). Their physicians were asked to provide information about their reasons for switching to transdermal fentanyl and the patients were then surveyed until withdrawal of fentanyl because of death, change in analgesic regimen, or serious adverse effects. Modifiedrelease morphine (median dose 90 mg/day) was used in 72% of patients before switching to fentanyl. More than 20% of the cohort had received no continuous opioid medication before the start of transdermal therapy. Most of the patients were switched to fentanyl because of inadequate analgesia or opioid-induced gastrointestinal symptoms. The simplicity of administration and patients’ wishes were also contributory factors. Transdermal fentanyl was discontinued primarily because patients died (46%); other reasons included inadequate pain relief (10%), pain relief with another analgesic regimen (10%), adverse effects (5%), rejection of transdermal therapy by the patient (6%), and other unspecified causes, such as pathological fractures and anemia (16%). There were opioidrelated adverse effects in 26% of the patients. Serious neurotoxic effects, such as hallucinations (0.2%), withdrawal symptoms (0.1%), or convulsions (0.1%), were rare. Under controlled conditions transdermal fentanyl is a useful option for direct conversion from mild to strong opioids in cancer patients. In addition, 25 µg/hour daily incremental steps of transdermal fentanyl can be made by palliative care specialists, if it is required for cancer pain management (27C ). Transdermal fentanyl for chronic non-cancer pain control has been studied in two open trials (28C , 29C ). In a multicenter, open, randomized study of 256 patients with a history of chronic non-cancer pain, 65% preferred transdermal fentanyl, whereas 28% preferred modified-release oral morphine. Subjective pain control and quality of life were significantly better in the patients who used transdermal fentanyl. Despite a preference for transdermal fentanyl, more patients withdrew because of adverse effects in the first fentanyl period (16%) than in the first morphine period (9%). The difference could have been related to patients’ previous experience of morphine, with enhanced tolerance of its adverse effects. In the second study, 35 patients with severe AIDS-related chronic pain were recruited

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in a prospective, open, before/after comparison of the analgesic efficacy and adverse effects profile of a stable dose of transdermal fentanyl (25–300 µg/h) or oral morphine (less than 45 mg/day) for 15 consecutive days (29C ). Transdermal fentanyl alleviated chronic pain and those who were already dependent on an opioid needed less fentanyl for the same analgesic result. The addition of fentanyl 1 µg/ml to ropivacaine 7.5 mg/ml did not improve nerve blockade by axillary brachial plexus anesthesia in a double-blind, randomized study in 30 patients undergoing orthopedic procedures (30C ). In another double-blind, randomized study, 60 patients receiving axillary brachial plexus blockade were given 0.25% bupivacaine 40 mg, 0.25% bupivacaine 40 mg plus fentanyl 2.5 µg/ml, or 0.125% bupivacaine 40 mg plus fentanyl 2.5 µg/ml (31C ). The addition of fentanyl 2.5 µg/ml prolonged sensory and motor blockade without any improvement in the onset of anesthesia and no significant increase in adverse effects. These two studies have reaffirmed the current position of conflicting results in studies of the benefits of adding fentanyl to local anesthetics for peripheral nerve blockade. In 100 patients undergoing arthroscopic outpatient surgery minidose spinal lidocaine plus fentanyl (0.5% lidocaine 20 mg plus fentanyl 20 µg) has been compared with traditional spinal anesthesia (1% lidocaine 30 ml with titrated intravenous propofol infusion) (32C ). The study was randomized and prospective but unblinded. Whereas those given local anesthesia were more likely to have pain requiring analgesic medication before discharge (44% vs. 20%), those given spinal anesthesia group were more likely to have nausea (8% vs. 22%) or pruritus (8% vs. 68%). Both techniques provided a high degree of patient satisfaction, with comparable efficacy both intraoperatively and postoperatively. Fentanyl 2 µg/ml has been used in combination with another local anesthetic, ropivacaine 2 mg/ml, to determine its impact on the quality of postoperative analgesia and the incidence of adverse effects after colonic surgery in 155 patients scheduled for elective colonic surgery in a multicenter, double-blind, randomized study (33C ). The incidences of hypotension and pruritus in those given fentanyl were significantly increased, although they had better analgesic

94 control. They also had an increased incidence of serious adverse effects affecting the respiratory, cardiovascular, and genitourinary systems. Further studies are required to evaluate the role of adding epidural opioids to local anesthetic infusions in major abdominal surgery. The relations between fentanyl and local anesthetics and their adverse effects profiles in epidural analgesia (34MC ) further demonstrate the need for well-controlled, double-blind studies (35C , 36C ). Respiratory Cough has been attributed to fentanyl (37A ). • A 7-year-old boy with trisomy 21 (Down syndrome) had explosive coughing 30 seconds after fentanyl 50 µg (2 µg/kg) had been injected and flushed through an intravenous cannula. The cough was unproductive and persisted in spasmodic bursts for a further 2–3 minutes until anesthesia was induced with propofol 60 mg and atracurium 15 mg intravenously. The coughing immediately ceased. A petechial rash in the conjunctivae and periorbital regions was subsequently noted and disappeared by the end of the first postoperative day.

Urinary tract There have been two cases of urinary retention leading to renal pelvocalyceal dilatation as a result of continuous infusion of fentanyl (3 µg/kg/h) in premature neonates (38A ). In both cases the problem was resolved by inserting an indwelling catheter. Skin A rash has been attributed to fentanyl (39A ). • A 70-year-old man with metastatic cancer of the colon was given transdermal fentanyl 50 mg for analgesia. After 10 days he developed an itchy pustular eruption on the trunk and limbs. The lesions subsided on withdrawal of fentanyl. When he restarted transdermal fentanyl 2 months later the skin lesions reappeared and became more generalized. The pustules were scattered, sparse, and superficial, and included the tongue and buccal mucosa, but not the conjunctivae or genitalia. A history of eosinophilia suggested an immunoallergic origin.

Drug formulations A woman suffered sedation, localized erythematous lesions on the hands, and reduced appetite with weight loss after removing transdermal fentanyl patches from her daughter’s skin and replacing them without wearing protective gloves (40A ). She had severe headaches, night sweats, irritability, nausea,

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and insomnia. When she used gloves her weight gradually increased and the sedation abated. A 57-year-old woman using transdermal fentanyl (75 µg/h) developed a reduced respiratory rate and bilateral pinpoint pupils when an upper body warming blanket was used as a normal postoperative procedure (41A ). The resultant increase in skin temperature significantly enhanced skin perfusion, and increased the systemic absorption of fentanyl from the intracutaneous fentanyl depot, leading to symptoms of opioid overdose. She recovered after removal of the fentanyl patch and the intravenous administration of naloxone 60 µg.

Hydromorphone

(SEDA-24, 106)

Intolerable adverse effects or inadequate analgesia occur in 10–15% of patients with chronic pain given continuous intrathecal morphine. Hydromorphone is a semisynthetic derivative of morphine used extensively in the management of cancer pain. It is more soluble than morphine, has a slightly shorter duration of action, and is about five times more potent when given systemically. In a retrospective review of 37 patients with chronic non-malignant pain (mostly from failed lumbosacral spine surgery) treated with intrathecal hydromorphone there was an analgesic response in six of the 16 patients who were switched from morphine to hydromorphone because of poor pain relief (42C ). Opioid-related adverse effects, such as nausea, vomiting, pruritus, and sedation, were also reduced by hydromorphone in the 21 patients who were switched to hydromorphone because of morphine-related adverse effects, especially 1 month after use. These results should be treated cautiously, because of the limitations of a retrospective study that lacks strict inclusion criteria, with obvious population bias and under-reporting, and without standardized procedures for rotation to hydromorphone.

Methadone

(SED-14, 214; SEDA-23, 103; SEDA-24, 106; SEDA-25, 115) Methadone is increasingly being used as an analgesic for chronic pain. It is an attractive

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alternative mu opioid analgesic because of its lack of neuroactive metabolites, a clearance that is independent of renal function, good oral systemic availability, a longer half-life with fewer doses needed per day, and extremely low cost. In a prospective, open, uncontrolled study 50 patients with a history of cancer taking daily oral morphine (90–800 mg) but with uncontrolled pain with or without severe opioid adverse effects, were switched to oral 8-hourly methadone in a dose ratio of 1 : 4 for patients receiving less than 90 mg of morphine daily, 1 : 8 for patients receiving 90–300 mg daily, and 1 : 12 for patients receiving more than 300 mg daily (43C ). Methadone was effective in 80% of the patients when comparing analgesic response with opioid-related adverse effects. Ten patients were switched because of uncontrolled pain, eight because of moderate or severe adverse effects in the presence of acceptable pain control, and 32 because of uncontrolled pain with morphine-related adverse effects. In the last 32 there were significant improvements in pain intensity, nausea and vomiting, constipation, and drowsiness, with a 20% increase in methadone dose over and above the recommended starting dose. A similar effect was shown in a prospective uncontrolled study of intrathecal methadone in 24 patients with a history of intractable chronic non-malignant pain (44C ). Methadone was a better analgesic than morphine, with improved quality of life and no adverse effects in 13 patients. The final rates of methadone infusion were 20% higher than the preceding morphine rates. Several methadone studies have focused on opioid-dependent or opioid-abusing subjects. For example, six opioid-dependent individuals maintained on methadone subsequently developed cancer and continued to use methadone, but in a higher dose as an analgesic (45c ). The first five were partly refractory to the analgesic effects of opioids other than methadone, but all six achieved adequate analgesia without sedation or respiratory depression from aggressive upward intravenous methadone titration using an infusion of 100 mg/hour. Methadone was given in divided doses every 6–12 hours rather than once daily, as is customary in maintenance therapy for opioid dependence. The reasons for increasing the methadone dosage and frequency of administration are cross-tolerance to

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other opioids and the presence in methadonemaintained individuals of hyperalgesia to pain (a low pain tolerance to pain detection ratio) (46C ). These issues are also relevant to determining whether other drugs are more effective than morphine in managing acute pain in these patients. Cardiovascular The use of methadone/dihydrocodeine has been linked to an acute myocardial infarction (47A ). • A 22-year-old man with a 6-year history of intravenous heroin use was maintained on methadone 60 mg/day and dihydrocodeine 0.5 g/day. He had an extensive anterior myocardial infarction as a result of occlusion of the left anterior descending coronary artery, which was reopened by percutaneous transluminal coronary angioplasty.

This case presents circumstantial evidence only, and the association was probably not a true one. There has been a report of five cases of episodes of syncope and an electrocardiogram showing ventricular tachydysrhythmias with prolonged QT intervals and episodes of torsade de pointes; all the patients were taking high doses of methadone (270–660 mg/day) with no previous history of cardiac disease (48A ). Torsade de pointes also occurred when high doses (3 mg/kg) of the long-acting methadone derivative, levomethadyl acetate HCl (LAAM), were given to a 41-year-old woman with a history of heroin dependence (49A ). She was also taking fluoxetine and intravenous cocaine, which can prolong the QT interval, and fluoxetine and marijuana, which inhibit the activity of CYP3A4, which is responsible for the metabolism of LAAM and its active metabolite. Respiratory In ten stable methadone-maintained patients (50–120 mg/day) and nine healthy subjects assessed using polysomnography, the methadone-maintained patients had more abnormalities of sleep architecture, with a higher prevalence of central sleep apnea (50C ). Methadone depresses respiration, probably by acting on the mu receptors in the ventral surface of the medulla and possibly on other receptor sites in the lung and spinal cord. All patients taking methadone also used benzodiazepines and cannabis, which may have influenced the above findings.

96 Nervous system Spastic paraparesis has been attributed to methadone (51A ). • A 43-year-old patient taking methadone for pain secondary to a squamous cell carcinoma of the larynx, which progressed despite surgery and radiation therapy, developed reversible spastic paraparesis with prominent extensor spasms in the legs while receiving an infusion of high-dose intravenous methadone 100 mg/h. On the second day, after 5 hours on 100 mg/h, he noted weakness in both legs, uncontrollable trembling, bilateral tinnitus, and generalized anxiety. Dexamethasone 6 mg intravenously every 6 hours was started and the methadone was reduced to 60 mg/h. Dexamethasone was withdrawn when an MRI scan confirmed the absence of metastases in the thoracic and cervical spinal cord. Because of persistent spastic paraparesis, methadone was switched to levorphenol 40 mg/h intravenously, and there was complete resolution of symptoms 24 hours later.

Neuromuscular Methadone can cause movement disorders characterized by tremor, choreiform movements, and a gait abnormality (52A ). • A 41-year-old woman with a 15-year history of chronic neuropathic pain was given methadone 5 mg tds and then qds. One month after the final increase she had bilateral tremor spreading from her arm up to her neck, followed by choreiform movements of the torso, a broad-based gait, and staccato-like speech. She was switched from methadone to modified-release oxycodone 60 mg/day, with complete resolution after 3 weeks.

Psychological In a randomized, double-blind, crossover study of 20 patients on a stable methadone regimen, a single dose of methadone caused episodic memory deficits (53C ). This was significant in patients with a history of diamorphine use averaging more than 10 years duration. Such deficits can be avoided by giving methadone in divided doses. Risk factors From a literature search and subsequent analysis of data on the relation between methadone prescribing and mortality, it was concluded that (54M ): • 69% of deaths attributed to methadone occurred in subjects who had not previously received methadone; • 51% of deaths attributed to methadone occurred during the dose-stabilizing period of methadone maintenance treatment;

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• the dose of illicit methadone exceeded that prescribed for methadone maintenance therapy; • deaths were attributed to discharge from prison and immediate intravenous injection of methadone in people who had lost their tolerance to high doses of methadone when incarcerated. Subsequent advice related to the above identifiable risk factors included: • restriction of take-home prescriptions with daily supervised consumption of methadone in pharmacy premises; • meticulous evaluation of substance abuse history; • slowing down of increases and tolerance testing during the stabilization period of methadone maintenance; • enhanced psychosocial assistance during the first months out of prison; • use of naloxone as an adjunct to methadone syrup. Drug interactions Methadone is predominantly metabolized by CYP3A4. Antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (e.g. efavirenz, abacavir, and nevirapine) and/or a protease inhibitor (e.g. amprenavir) will induce the metabolism of methadone. This therapeutic combination is becoming increasingly common in HIV-positive substance misusers. Two studies have explicitly shown a significant reduction of methadone concentration in 28–87%. In the first study, 11 patients taking methadone maintenance therapy were given efavirenz and had a mean increase in methadone dosage requirement of 22% (55c ). In the second study five methadonemaintained opioid-dependent individuals were given a combination of abacavir and amprenavir; the methadone concentration fell to 35% of the original concentration within 14 days (56c ). In a prospective study of 54 patients taking antiretroviral drugs who also took methadone and a further 154 patients who did not take methadone there were similar clinical, virological, and immunological outcomes after 12 months (57C ). These results support the usefulness of methadone in the management of intravenous drug users with HIV infection.

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Morphine

(SED-14, 215; SEDA-23, 103; SEDA-24, 107; SEDA-25, 115) Morphine is the benchmark “step 3” opioid analgesic based on the WHO’s concept of an analgesic ladder (58S ). Revised recommendations for the use of morphine in cancer pain have been published by the European Association for Palliative Care’s Expert Working Group on Opioid Analgesics (59M ). In summary, oral morphine is still the opioid of first choice for moderate to severe cancer pain, every 4 hours for normal-release morphine and 12- or 24-hourly for modified-release morphine. If patients are not able to take morphine orally the preferred alternative is subcutaneous infusion, especially in patients who require continuous parenteral morphine. A small proportion of patients develop intolerable adverse effects with oral morphine, and a change to an alternative opioid (e.g. hydromorphone, oxycodone, methadone, transdermal fentanyl) or a change in the rate of administration should be considered. If despite optimal use of systemic opioids and non-opioids a patient still has intolerable adverse effects or inadequate analgesia, spinal (epidural or intrathecal) administration of an opioid analgesic in combination with a local anesthetic or clonidine should be considered. In a 7-year, retrospective, multicenter, observational study, 95 children aged 1–19 years with cancer pain and treated with long-acting morphine were investigated for adverse effects and age-dependent analgesic effects (60C ). The adverse effects most frequently reported were constipation (10 patients at the beginning of treatment, 20 patients during the course of therapy, and three patients at the end of data collection), followed by vomiting (five, eight, and two patients) and nausea (two, six, and three patients), especially in children aged 7 years or more. Some of the children repeatedly complained of pruritus (five, eleven, and two patients). There were no cases of respiratory depression. Oral long-acting morphine proved to be safe and effective, even in very young patients with a history of malignancy. There have been another two studies of the analgesic effect of intrathecal morphine in children (61C , 62C ). In a prospective, double-blind study, 30 children (aged 9–19 years) scheduled for spinal fusion were randomly allocated

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to a single dose of saline or intrathecal morphine 2 or 5 µg/kg; after surgery, a PCA device provided access to additional intravenous morphine (61C ). The doses of 2 µg/kg and 5 µg/kg had similar analgesic effectiveness and adverse effects profiles (nausea, vomiting, pruritus). There were no episodes of severe respiratory depression. Low-dose intrathecal morphine supplemented with PCA morphine provides better analgesia than PCA morphine alone. In a smaller prospective, open, uncontrolled study, 12 children (3–6 years of age) were given either intermittent intrathecal morphine 5 µg/kg qds or a continuous infusion of a mixture of bupivacaine (40 µg/kg/h) and morphine (0.6 µg/kg/h) for intense postoperative pain after selective dorsal rhizotomy (62C ). The bupivacaine/morphine mixture provided better analgesia with fewer adverse effects. The incidence of pruritus was 83% with morphine compared with 33% with bupivacaine/morphine. Otherwise the adverse effects were similar. Two retrospective reviews looked at the effect of using intrathecal morphine (63C ) or intrathecal hydromorphone (42C ) in the management of chronic non-malignant pain. Eightyeight patients were originally evaluated followed by 67 patients 6 months later (63C ). At the time of follow-up mean pain relief was 60%, and 74% of respondents reporting increased activity. There were frequent reports of opioid adverse effects, including sexual dysfunction and menstrual disturbances. The reported adverse effects in descending order of frequency were: excessive sweating (62%), weight gain (52%), difficulty in concentrating, thinking, and memory (48%), nausea and vomiting (42%), arthralgia (25%), peripheral edema (25%), and pruritus (21%). Despite these adverse effects, most of the patients expressed satisfaction with intrathecal opioid therapy. The results were limited owing to the retrospective nature of the study, differing rates of response to specific questions, and the lack of objective measures. Pregnancy In a double blind, randomized, controlled study of analgesia in labor, the addition of morphine 150 µg to an intrathecal combination of fentanyl (25 µg) and bupivacaine (2.5 mg) significantly prolonged analgesia to more than 4 hours without increasing opioidrelated adverse effects (64C ).

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Managing the adverse effects of morphine The strategies used in managing the adverse effects of oral morphine have been reassessed in another special article compiled by the Expert Working Group of the European Association of Palliative Care Network (65M ). Factors that predict opioid adverse effects include: • Drug-related factors: there is little evidence suggesting that any one opioid agonist has a substantially better adverse effects profile than any other. • Route-related factors: there is limited evidence to suggest differences in adverse effects associated with specific routes of systemic administration. • Patient-related factors: there is evidence to suggest that there is inter-individual variability in sensitivity to opioid-related adverse effects; the variables include genetic susceptibility, the presence of co-morbidity, and age. • Dose-related factors: a dose-response relation is most evident with the CNS adverse effects of sedation, cognitive impairment, hallucinations, myoclonus, and respiratory depression, although there is still inter-individual variability in dose responsiveness to these effects; nausea and vomiting are common at the start of therapy but are then unpredictable. • Starting doses and escalation: the adverse effects of morphine, especially cognitive impairment, occur transiently and abate spontaneously; there are no reports of a relation between the starting dose of morphine or dose escalation and the occurrence of nausea, vomiting, or delirium. • Drug interactions: adverse effects of concurrent medications may be synergistic or cumulative with those associated with opioids. The reviewers also stressed the importance of differentiating opioid-related adverse effects from other causes of co-morbidity that might mimic opioid-induced adverse effects. Examples include cerebral metastases, stroke, metabolic changes, septicemia, bowel obstruction, and iatrogenic factors (other drugs or radiotherapy).

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Four different approaches to the management of opioid adverse effects were described in the review: 1. Dosage reduction. A reduction in the dosage of the systemic opioid is usually enough to relieve adverse effects. If dosage reduction is accompanied by loss of pain control, a non-opioid analgesic (e.g. an NSAID) can be added. Specific therapy, such as radiotherapy, chemotherapy, or surgery, that targets the cause of the pain can be helpful, as can a regional anesthetic or neuroablative intervention (e.g. celiac plexus blockade in patients with pancreatic cancer). 2. Symptomatic management of the adverse effects. 3. Opioid rotation. 4. Switching the route of administration. The reviewers also examined the symptomatic management of specific adverse effects and commented that most approaches are based on cumulative anecdotal evidence and that there have been few prospective evaluations of the efficacy and toxicity of these approaches over a long period of use. Polypharmacy adds to the burden of adverse effects and drug interactions. The authors of two related double-blind, randomized, placebo-controlled studies of the use of dexamethasone prophylaxis for nausea and vomiting after epidural morphine for post-cesarean or post-hysterectomy analgesia concluded that 5 mg of dexamethasone is an effective dose (66C , 67C ). Meanwhile, ADL 8-2698, a trans-3,4-dimethyl-4-piperidine that is a novel opioid antagonist, produced improved gastrointestinal transit time (peripherally mediated opioid activity) without affecting centrally mediated opioid analgesia (68C ). This contrasts with naloxone or nalmefene, which tend to antagonize central opioid effects, resulting in withdrawal symptoms in up to 50% of patients when used to treat constipation. Gabapentin has been used to treat morphineinduced myoclonus in a 54-year-old patient with gall bladder cancer (69A ). Effective pain control was maintained with morphine 300 mg, but after 24 hours the patient developed generalized muscular movements while asleep. Gabapentin 300 mg bd produced complete resolution of symptoms after 12 hours. In another

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case gabapentin 600 mg/day was used to treat a 1-month history of spontaneous jerking of both wrists after an increase in the dose of morphine to 120 mg/day; the myoclonus disappeared over the next 24 hours (69A ).

Oxycodone

(SED-14, 216; SEDA-23, 104; SEDA-24, 107; SEDA-25, 116) A double-blind, randomized, crossover comparison of modified-release or immediate-release oxycodone has been carried out in 30 patients with cancer pain (70C ). There were no significant differences between the two groups with respect to pain intensity or acceptability of therapy. More than 80% of the patients did not require rescue medication. Adverse effects were similar with the two formulations and occurred in relatively low numbers compared with previous morphine studies. The greatest difference in adverse effects was in the incidence of vomiting, which occurred in 6% of those given immediate-release morphine, and none of those given modified-release morphine. The modified-release formulation provided equal analgesia with the benefit of less frequent dosing.

Pethidine (meperidine)

(SED-14, 217; SEDA-24, 107; SEDA-25, 117) In a double-blind, randomized, controlled study, 17 patients undergoing gastrectomy were given epidural PCA pethidine (10 mg bolus and a 4-hourly maximum dose of 3 mg/kg) and were compared with 20 post-gastrectomy patients who were given the same regimen intravenously (71C ). The mean pethidine consumption in the first 24 hours was 33% less in the epidural group than in the intravenous group. Pain scores, adverse effects profiles, patient satisfaction, and patient outcome were similar. However, the sample size was small, and even though the study was intended to be double-blind, the route of pethidine administration and the patient’s perception of an intravenous and epidural injection might have caused bias.

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Drug abuse The interaction between the drug-dependent patient and health professional has been investigated in a retrospective study of the medical records of 20 patients with chronic organic pain and perceived as being dependent on pethidine (72C ). The fact that the patients were perceived as being addicted may have influenced the adequate management of their chronic intractable pain, precipitated poor staff–patient relationships, created a lower pain threshold or tolerance due to anxiety and depression, and led to overuse of placebo, leading to inadequate analgesia. All of these factors may then have led to craving-like behavior and demands for more analgesics, further fuelling the negative stereotyped perception of the addicted personality. The authors suggested that people with dependence-related problems should be evaluated for suicidal intent; concurrent psychiatric illnesses should be treated; and precipitating factors that make pain worse should be identified. Medical and other staff should be educated about the use of opiate analgesics and concepts of dependence, in order to reduce negative judgmental attitudes and misconceptions. Drug overdose Cardiac arrest occurred after pethidine overdose (73A ). • Cardiac arrest occurred in a 2-month-old boy when he was given a combination of pethidine, promethazine, and chlorpromazine in 10 times the recommended dose by the wrong route (intravenously rather than intramuscularly). Within seconds he became apneic and stiff. Cardiopulmonary resuscitation was instituted, including two intravenous doses of adrenaline 0.06 mg and naloxone 0.6 mg, with recovery 7 minutes after the incident and complete resolution 24 hours later.

Remifentanil

(SED-14, 217; SEDA-23, 105; SEDA-24, 108; SEDA-25, 118) Remifentanil is a relatively pure mu receptor opioid agonist with conventional pharmacodynamic properties. Seven randomized controlled trials and one descriptive trial using infused remifentanil as part of an anesthetic technique in children between 1997 and 2000 have been reviewed (74M ). The general consensus is that a bolus dose of remifentanil 0.5–1 µg/kg appears to be well tolerated when it is given over

100 at least 60 seconds. However, a loading dose is not required if the infusion can be started at least 10 minutes before the skin incision is made. Infusion rates of 0.25–0.5 µg/kg/min provide hemodynamic stability when propofol or a volatile agent is also given. The authors advised that infants who receive remifentanil should be paralysed and mechanically ventilated, because of the possible risk of respiratory depression due to chest wall rigidity in non-paralysed patients. Remifentanil is liable to cause respiratory depression in children (74M , 75c ), as well as muscle rigidity, hypotension and bradycardia, without increasing the incidence of gastrointestinal symptoms (76c ). The adverse effects profiles of remifentanil in neonates and infants undergoing pyloromyotomy have been investigated (77C , 78C ). The hemodynamic responses, recovery profiles, and perioperative and postoperative respiratory patterns in 38 children given remifentanil plus nitrous oxide and 22 given halothane plus nitrous oxide have been studied in a multicenter, open, randomized comparison. There were no cases of bradycardia or dysrhythmias. There were hypertensive responses at the time of incision in 24% of those given remifentanil and 18% of those given halothane and vomiting in 34% and 45% respectively. None of those who were given remifentanil developed newonset postoperative apnea compared with three of those who were given halothane. All other adverse effects had similar incidences in the two groups. Remifentanil 0.1 µg/kg/min by infusion was safe and efficacious in 55 patients (aged 2 months to 12 years) undergoing cardiac catheterization (79C ). In a double-blind, randomized, placebocontrolled study in 28 adults undergoing carotid endarterectomy, remifentanil provided adequate analgesia, and supplementary local anesthetics were not needed (80C ). The remifentanil infusion rate was as low as 0.04 µg/kg/min and there were no episodes of respiratory depression or hemodynamic instability. Intravenous remifentanil 0.3 µg/kg with propofol 2 µg/ml has been compared with propofol 2 µg/ml alone in a double-blind, randomized study in 86 day-case adults undergoing elective orthopedic surgery (81C ). The study was designed to assess whether remifentanil improves conditions for laryngeal mask

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airway insertion. Those given remifentanil had a better quality of airway patency, with minimal cardiorespiratory changes. Remifentanil by infusion (n = 49) has been compared with titrated boluses of pethidine (n = 51) in a randomized, double-blind study in 100 patients undergoing out-patient colonoscopy (82C ). The incidences of tachycardia, hypotension, and nausea were significantly less with remifentanil than with pethidine, but there were higher anxiety and pain scores with remifentanil. However, the study was a comparison of two opioids with different pharmacokinetic profiles, which makes it very difficult to achieve equipotent doses for the purpose of comparison. Remifentanil by infusion has been compared with another opioid, fentanyl, in two studies (83C , 84C ). In a prospective multicenter, double-blind, randomized study in 297 patients undergoing elective coronary artery bypass surgery, remifentanil infusion 1 µg/kg/min was compared with a loading dose of fentanyl 15 µg/kg. The most common adverse effects were nausea and vomiting, which occurred equally often in the two groups. Hypertension and shivering were significantly more common with remifentanil (83C ). In a smaller randomized study, remifentanil 0.5 µg/kg/min was compared with fentanyl 2 µg/kg in 22 patients undergoing rigid bronchoscopy (84C ). The results suggested that remifentanil attenuated the hemodynamic response to bronchoscopy without significantly increasing the incidences of hypotension or bradycardia. Four patients given remifentanil developed ST segment depression compared with eight patients given fentanyl. Mixtures of remifentanil and sevoflurane have been used in two prospective, open, randomized studies (85C , 86C ), which showed that adding remifentanil results in a reduced requirement for sevoflurane for maintenance of anesthesia, leading to faster and easier recovery. Remifentanil has been successfully combined with general anesthetics, as shown in the above studies, but there are few experimental demonstrations of its analgesic properties. Three studies have now focused on the analgesic use of remifentanil (87C –89C ). In a double-blind, crossover, randomized study 20 healthy volunteers received an infusion of either remifentanil or saline (87C ). Thermal sensory

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testing of the heat pain threshold was performed every 5 minutes and the dose of remifentanil was increased by 0.01 µg/kg/minute every 5 minutes. Remifentanil produced a dosedependent increase in the heat pain threshold, and a dose of 0.05 µg/kg/min was suggested as an effective and safe increment in healthy volunteers. The rate of adverse effects (nausea, vomiting, and pruritus) was comparable with previous reports; there were no cardiovascular adverse effects. The postoperative analgesic efficacy and safety of two continuous constant-dose intravenous remifentanil infusions have been investigated in a double-blind, randomized study in 30 patients scheduled to undergo elective abdominal or thoracic surgery (89C ). The patients were randomly assigned to intravenous remifentanil 0.05 µg/kg/min or 0.1 µg/kg/min. There were no cases of respiratory depression, and nausea and vomiting occurred in one patient in each group. There was adequate analgesia in 75% and 78% of the patients in the low-dose and high-dose groups respectively and pethidine rescue analgesia was required in 26% and 6% respectively. Remifentanil 0.1 µg/kg/min was therefore effective and safe for postoperative pain. Further studies are needed to determine the role of remifentanil infusion for severe postoperative pain. Cardiovascular Asystole has been attributed to remifentanil (90A ). • A 78-year-old man with laryngeal cancer developed asystole 1 minute after an intravenous bolus of remifentanil 0.5 µg/kg followed by a continuous infusion of 0.5 µg/kg/h. The asystole was unresponsive to intravenous atropine 1 mg. The remifentanil infusion was stopped and cardiac sinus rhythm resumed after two precordial thumps.

The authors postulated that rapid-sequence induction of anesthesia with sevoflurane had blunted sympathetic tone and allowed uncompensated parasympathetic activation by remifentanil. Nervous system Seizures have been attributed to remifentanil (91A ). • A 42-year-old woman asked for an intravenous opioid as analgesia during paracervical block and was given an intravenous infusion of remifentanil

1.0 µg/kg/min. After 3 minutes she became unresponsive, with upward deviation of gaze and tonic– clonic contractions of the arms. The infusion was discontinued and after another 3 minutes of generalized seizure activity she was given intravenous propofol 80 mg and intravenous succinylcholine 60 mg; she recovered completely 15 minutes later.

Pregnancy Six patients admitted at 36 weeks pregnancy with pre-eclampsia received patientcontrolled intravenous analgesia with remifentanil for labor (88C ). Remifentanil was delivered as continuous background infusion of 0.05 µg/kg/min and 25 µg boluses with a 5-minute lockout period. The procedure did not cause maternal or neonatal adverse effects and this small uncontrolled study suggests that patient-controlled intravenous analgesia with remifentanil might be an effective alternative when epidural analgesia is contraindicated.

Sufentanil

(SED-14, 217; SEDA-23, 105; SEDA-24, 109; SEDA-25, 118)

Sufentanil 1 µg/ml plus 0.1% ropivacaine by epidural infusion has been compared with intravenous patient-controlled analgesia with piritramide in a double-blind, randomized study in 24 patients undergoing elective total hip replacement (92C ). The PCA group had significantly more adverse effects than the epidural group, including hypotension, nausea, and vomiting. There were no cases of respiratory depression, pruritus, hypertension, or dysrhythmias in either group. Epidural sufentanil was a better analgesic. The analgesic efficacy of intrathecal sufentanil with or without lidocaine has been examined in two groups of out-patients undergoing lithotripsy or gynecological laparoscopy in order to determine optimal analgesia with rapid recovery and discharge (93C , 94C ). In a retrospective case-record study of 62 shock-wave lithotripsy procedures, the 25 cases performed using intrathecal sufentanil alone had better outcomes, significantly shorter post-anesthesia care unit time, and time for ambulation compared with 37 procedures performed with intrathecal lidocaine; pruritus was significantly more common with sufentanil (93C ).

102 A double-blind, randomized study in 13 patients undergoing gynecological laparoscopy, who received either lidocaine 10 mg with sufentanil 10 µg or intrathecal sufentanil 20 µg, was terminated early owing to unacceptably frequent adverse effects and inferior analgesia in those given intrathecal sufentanil (94C ). In a double-blind, randomized, placebocontrolled study in 80 patients of the analgesic efficacy of different subarachnoid applications of sufentanil and/or bupivacaine using a microcatheter for easy postoperative pain relief, sufentanil 10 µg, bupivacaine 5 mg, or a combination of sufentanil 2.5 µg and bupivacaine 2.5 mg provided immediate and adequate postoperative analgesia for 2–3 hours (95C ). The group who received only sufentanil had the highest incidence of pruritus and respiratory depression. The limitations of this study were highlighted in a letter, which questioned the value of the above procedure when other tried and tested perioperative pain management methods are available (96r ). Pregnancy In a double-blind, randomized study the analgesic efficacy of sufentanil 0.25 µg/ml with 0.125% bupivacaine was compared with fentanyl 2 µg/ml with 0.125% bupivacaine in 226 patients in labor with a patient-controlled epidural analgesic device (97C ). Overall analgesia was good, with no observed difference between the two groups. There was a significant difference in the occurrence of mild pruritus, with 10 cases in the fentanyl group (n = 105) and only two in the sufentanil group (n = 101). There were no gastrointestinal adverse effects. Sufentanil was deemed preferable owing to a lower incidence of adverse effects for equal analgesic potency. An epidural mixture of sufentanil with ropivacaine has been used in a double-blind, randomized study in 100 women in the first stage of labor (98C ). They were randomized to receive 0.2% ropivacaine 12 mg either alone or with sufentanil 5 µg, 10 µg, or 15 µg. With combined sufentanil plus ropivacaine the duration of analgesia was about 40 minutes longer than with ropivacaine alone. There were no differences in analgesic efficacy or the incidence of opioid-related adverse effects in the three sufentanil groups. Sufentanil 5 µg plus ropivacaine 0.2% was therefore recommended.

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Tramadol

(SED-14, 218; SEDA-23, 107; SEDA-24, 109; SEDA-25, 119)

The postoperative analgesic efficacy of tramadol 2 mg/kg has been studied in 80 children (aged 1–3 years) undergoing day-case adenoidectomy without premedication in a doubleblind, randomized, placebo-controlled study (99C ). General anesthesia was induced with intravenous alfentanil 10 µg/kg plus lidocaine followed by propofol and mivacurium. The children received intravenous tramadol 2 mg/kg or placebo immediately after induction of anesthesia. Those given tramadol required fewer pethidine rescue medication doses than those given placebo. In fact, 45% of the children who were given tramadol did not require postoperative analgesia at all, compared with 15% of the children who were given placebo. The incidences of adverse effects were similar in the two groups. The use or addition of tramadol in children undergoing lower abdominal surgery has been examined in three studies (100C –102C ). In a double-blind, randomized, controlled study, 125 children undergoing inguinal herniorrhaphy were allocated to receive tramadol 2 mg/kg or morphine sulfate 0.03 mg/kg before surgery; the control group received morphine sulfate 0.03 mg/kg at the end of surgery (100C ). Caudal tramadol 2 mg/kg provided reliable postoperative analgesia and there were no inter-group differences in postoperative adverse effects or quality and duration of pain relief. In a randomized, controlled study in 60 boys (aged 1–7 years) undergoing unilateral herniorrhaphy, caudal 0.25% bupivacaine 1 mg/kg plus tramadol 1.5 mg/kg resulted in superior analgesia (quality and duration) with no significant increase in opioid-related adverse effects compared with children who received 0.25% bupivacaine 1 mg/kg alone or caudal tramadol 1.5 mg/kg in 0.9% saline alone (101C ). Thirty children (1–5 years old) in an open, controlled study were randomly given caudal block with 0.25% bupivacaine 0.8 mg/kg or tramadol 0.8 or 2 mg/kg (102C ). The duration of analgesia was longer (9.1 hours) in those given tramadol but the incidences of opioidrelated adverse effects (gastrointestinal effects and sweating) were significantly higher. In a double-blind, randomized study in 120 patients scheduled to undergo out-patient hand

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surgery with intravenous regional anesthesia, tramadol 100 mg was compared with either metamizol 1 g or paracetamol 1 g, all 6-hourly (103C ). Seven patients given tramadol withdrew because of severe nausea and dizziness. Tramadol was the most effective analgesic, but none of the drugs alone provided effective analgesia in all patients and 40% needed rescue analgesia. In another double-blind study 150 patients with post-traumatic musculoskeletal pain were allocated to either tramadol 100 mg, with possible increases to a total of 200 mg, or morphine 5 mg or 10 mg with a total increase to 20 mg (104C ). Analgesic efficacy and adverse effect profiles were similar in the two groups. Tramadol has been compared with a paracetamol derivative in a double-blind, randomized, controlled study in 80 patients undergoing elective thyroidectomy (105C ). They were randomly assigned to propacetamol (an injectable prodrug of paracetamol) 2 g or intravenous tramadol 1.5 mg/kg. A single dose of tramadol provided better analgesia than propacetamol during the first 6 hours after surgery, but failed to ensure optimal analgesia subsequently. The incidences of nausea, vomiting, and sedation were comparable in the two groups. Tramadol and non-steroidal anti-inflammatory drugs have been compared in two studies of patients with joint pain associated with osteoarthritis (106C , 107C ). In an open, randomized study 60 patients with osteoarthritis taking NSAIDs were given either modified-release tramadol 100 mg 8-hourly or modified-release dihydrocodeine 60 mg 8-hourly for 4 days; the controls were 30 patients who took an NSAID alone (106C ). Both opioids provided adequate analgesic adjuncts to NSAIDs, but tramadol caused significantly more minor initial adverse effects. In a similar study of 129 patients with severe joint pain associated with osteoarthritis tramadol was significantly more effective than placebo, but 26 patients taking tramadol and 43 taking placebo withdrew because of ineffectiveness or adverse effects; the main adverse effects of tramadol were nausea and constipation (107C ). In a 4-week, double-blind, multicenter, randomized study tramadol plus paracetamol (37.5 mg/325 mg) was as effective as codeine plus paracetamol (co-codamol 30 mg/300 mg)

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in chronic non-malignant low back pain and osteoarthritis pain, with acceptable tolerability (108C ). The use of modified-release tramadol in chronic malignant pain has been examined in an open, prospective study in 146 patients with moderate to severe cancer pain; 90 patients completed the 6-week trial (109C ). Drop outs were due to opioid adverse effects (20%), inadequate pain relief (9%), or both (2.5%). There was at least one adverse effect in 86%. Overall, 433 adverse effect events were reported but some reduced in frequency over the 6 weeks. Modified-release tramadol (400 mg/day) provided fast and efficient pain relief in almost 60% of patients both during initial dosing and long-term treatment. Drug dependence Seizures followed by opioid withdrawal symptoms have been reported in a patient taking tramadol (110A ). • A 29-year-old woman took tramadol 50 mg 6-hourly for pain associated with the carpal tunnel syndrome. She slowly increased the dose of tramadol and obtained it from several physicians and different hospitals, so that after 3 years she was taking 30 tramadol 50 mg tablets daily. She had two generalized seizures and stopped taking tramadol; 1 day later she developed severe opioid withdrawal symptoms, including diarrhea, headache, insomnia, and blurred vision. She was detoxified with tapering doses of tramadol and discharged after 6 days.

Drug overdose A 26-year-old male nurse died of tramadol intoxication (111A ). The peripheral blood concentration of tramadol was 9.6 mg/l (target concentration 0.1–0.3 mg/l). There was no objective evidence at post mortem of any pre-existing disease or use/overuse of ethanol or other drugs that could have contributed to or caused death. Drug interactions Tramadol dosage requirements for patient-controlled analgesia increased when ondansetron was given as a prophylactic antiemetic in 40 patients undergoing lumbar laminectomy in an open, controlled study (112C ). During the first 4 hours postoperatively tramadol consumption increased by about 30% in those given ondansetron and remained 22–25% higher thereafter. A single dose of ondansetron 4 mg given during induction did not reduce the 24-hour incidence of nausea or vomiting.

104 Serotonin syndrome and mania occurred in a 72-year-old woman taking fluoxetine 20 mg/day and tramadol 150 mg/day 18 days after she started to take the combination (113A ). Inhibition of CYP2D6 may have played a part (114M ).

PARTIAL OPIOID AGONISTS Buprenorphine

(SED-14, 220; SEDA-23, 108; SEDA-24, 110; SEDA-25, 120)

The use of buprenorphine to treat opioiddependent individuals has been the subject of several studies. In a double-blind randomized comparison of sublingual buprenorphine tablets with oral methadone in a 6-week trial in 58 patients using a flexible dosing procedure the retention rate was significantly better in those using methadone (90 vs. 50%) (115C ). Those who completed the study had a similar number of opioid-positive urine samples, with a mean stabilization dose of 11 mg/day of buprenorphine and 70 mg/day of methadone. This study had several limitations: 6 weeks is too short a period to determine any intermediate or long-term treatment outcomes, the sample size was too small, and the comparison of nonequivalent doses makes interpretation difficult. In another study two doses (8 mg and 16 mg) of sublingual buprenorphine were compared in a 6-week double-blind, placebo-controlled in-patient study of the reinforcing effects of intravenous diamorphine (116C ). Only eight diamorphine-dependent men were recruited and the authors could only postulate that doses over 16 mg might be more effective in blocking the reinforcing effects of diamorphine. Liver Intravenous buprenorphine abuse precipitated acute on chronic hepatitis in a 25-yearold woman who was hepatitis C positive with a history of chronic diamorphine dependence (117A ). Four former opiate-dependent individuals with confirmed hepatitis C virus were given substitution therapy with sublingual buprenorphine. After injecting buprenorphine together with their sublingual doses, they had a marked increase in serum AsT activity (13–50 times

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the upper limit of the reference range), resulting in jaundice (118A ). Another patient who was hepatitis C and HIV positive developed jaundice with panlobular liver necrosis and microvesicular steatosis after using sublingual buprenorphine and small doses of paracetamol and aspirin (118A ). Death Two series of 39 and 78 deaths attributed to buprenorphine have been reported in Strasbourg and 13 other French forensic centers respectively between 1996 and 2000 (119M ). The risks incurred by the misuse of buprenorphine seem to arise through a combination of (a) the concomitant use of other psychotropic drugs (especially benzodiazepines and neuroleptic drugs) and (b) the improper use of tablets for intravenous administration and/or massive oral doses. The total recorded number of buprenorphine-related deaths is largely underestimated, because the very low concentrations require sensitive immunoassay techniques, making them difficult to detect; furthermore different cut-off points are used by different forensic pathology laboratories in diagnosing drug-related deaths.

Nalbuphine

(SED-14, 222; SEDA-24, 100; SEDA-25, 120) Intravenous nalbuphine 3 mg (n = 101) has been compared with intravenous propofol 20 mg (n = 90) in a double-blind, randomized study, to determine efficacy in the treatment of intrathecal morphine-induced pruritus after cesarean delivery 10 minutes after the drug was administered (120C ). Nalbuphine was significantly more effective, especially in cases of moderate but not severe pruritus. Adverse effects such as reduced analgesia and increased nausea, vomiting, sedation, and dizziness were not significantly different between the two groups. Drug abuse A 53-year-old man with no past psychiatric history was found by the police walking aimlessly, unclothed, and responding to auditory hallucinations (121A ). He had slurred speech and generalized tremors. Lumbar puncture, a CT head scan, and urine drug

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screen were all normal. He responded to risperidone 1 mg bd with dramatic improvement after 2 days. He reported chronic use of nalbuphine, with recent increased use.

OPIATE ANTAGONISTS Nalmefene

(SED-14, 219; SEDA-23, 109; SEDA-24, 110; SEDA-25, 121) The efficacy and safety of intravenous nalmefene 0.1 mg/ml has been studied in an open trial in 115 children given fentanyl (122C ). An initial dose of 0.25 µg/kg (maximum 10 µg) was infused over 15 seconds, and another dose of 0.25 µg/kg (maximum 10 µg) was given if there was no response after 1.75 minutes. Further doses were given every 2 minutes until a response occurred or a maximum dose of 1 µg/kg (maximum 40 µg) was reached. Nalmefene was effective and safe, especially in a mean dose of 0.55 µg/kg; the median number of doses was two. The limitations of this study included the small study sample and the use of a short-acting opioid, fentanyl, so that re-sedation was unlikely even without the use of an antagonist.

Naloxone

(SED-13, 179; SEDA-18, 86;

SEDA-21, 92) The use of naloxone has been studied in an open study in 43 patients having combined thoracic epidural and general anesthesia for subtotal gastrectomy, who were randomly assigned to receive a bolus dose of epidural morphine 3 mg followed by a continuous infusion of 3 mg in 0.125% bupivacaine 100 mg with either no naloxone (n = 18) or naloxone 0.208 µg/kg/hour (n = 25) for 48 hours (123C ). The time to the first postoperative passage of flatus and feces (indicating restoration of bowel function) and pain intensity (using a visual analogue scale) were assessed. The results suggested that naloxone 0.208 µg/kg/hour adequately reverses hypomotility induced by epidural morphine. The preliminary results of two pilot schemes to provide take-home naloxone to opiate users have suggested that this provision may save

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lives (124C ). This observation needs corroboration by a prospective case-control study of adequate sample size and response rate, with the ability to collate objective data robust enough for analysis (125r ).

Naltrexone

(SED-14, 200; SEDA-23, 100; SEDA-24, 111; SEDA-25, 121) A systematic review and meta-analysis of seven double-blind, randomized, placebo-controlled out-patient studies of naltrexone used in the treatment of alcohol dependence between 1976 and 2001 has shown that naltrexone was no more toxic than placebo and was not associated with a significantly greater number of withdrawals because of adverse effects (126M ). Naltrexone was more effective than placebo in reducing relapses to heavy drinking and improving alcohol abstinence in the short term, considering that the studies lasted for only 12 weeks. Additional long-term follow-up studies, with the possibility of studying outcomes of naltrexone treatment programs after stopping the drug and with suitable comparison groups, are necessary. Similar results with similar conclusions were seen in a 12-week randomized controlled trial in 55 alcohol-dependent men treated with naltrexone 50 mg or placebo (127C ). In an open, single-blind randomized study naltrexone (50 mg/day) and acamprosate (1665– 1998 mg/day) were used for 1 year by 157 recently detoxified alcohol-dependent men with moderate dependence (128C ). The time to first relapse was 63 days (naltrexone) and 42 days (acamprosate); after 1 year 41% of those given naltrexone and 17% of those given acamprosate had not relapsed. Adverse effects were more common with naltrexone and were worse during the first 2 weeks of treatment. They included nausea (25% vs. 4%), abdominal pain (23% vs. 4%), drowsiness (35% vs. 2%), headache (13% vs. 6%), and nasal congestion (23% vs. 7%). To examine the relation between adverse effects profiles, study retention, and treatment outcomes in alcohol-dependent individuals receiving naltrexone for relapse prevention, 92 subjects had their adverse effects monitored weekly and categorized as either neuropsychiatric or gastrointestinal (129C ). The neuropsychiatric adverse effects had little effect on

106 medication compliance but reduced the length of study retention. In contrast, the gastrointestinal adverse effects significantly affected medication compliance but not study retention. Drug abuse Three opiate-dependent individuals abused intravenous naltrexone, believing it to be diamorphine, and developed acute opiate withdrawal symptoms; they were managed with a combined regimen of diazepam, prochlorperazine, and hyoscine (130A , 131A ).

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postoperative intravenous patient-controlled analgesia with morphine either alone or in combination with nefopam (20 mg 4-hourly) or propacetamol (2 g 6-hourly) (132C ). Nefopam plus morphine was the most effective treatment. Adverse effects, especially sedation, were comparable in the three groups, but there was significantly more nausea in the morphine group and more sweating in the nefopam group (requiring early drug withdrawal in three cases). Tachycardia was seen more often in the nefopam group but did not reach significance.

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119. Kintz P. Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int 2001; 121: 65–9. 120. Charuluxananan S, Kyokong O, Somboonviboon W, Lertmaharit S, Ngamprasertwong P, Nimcharoendee K. Nalbuphine versus propofol for treatment of intrathecal morphine-induced pruritus after caesarian delivery. Anesth Analg 2001; 93: 162–5. 121. Camacho A, Matthews SC, Dimsdale JE. “Invisible” synthetic opiates and acute psychosis. New Engl J Med. 2001; 345: 469. 122. Chumpa A, Kaplan RL, Burns MM, Shannon MW. Nalmefene for elective reversal of procedural sedation in children. Am J Emerg Med 2001; 19: 545–8. 123. Lee J, Shim JY, Choi JH, Kim ES, Kwow OW, Moon DE, Choi JH, Bishop MJ. Epidural naloxone reduces intestinal hypomotility but not analgesia of epidural morphine. Can J Anaesth 2001; 48: 54–8. 124. Dettmer K, Saunders B, Strang J. Take home naloxone and the prevention of deaths from opiate overdose: two pilot schemes. Br Med J 2001; 322: 895–6. 125. Mountain D. Big conclusions are drawn from little evidence. Br Med J 2001; 323: 934–5. 126. Streeton C, Whelan G. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomised controlled trials. Alcohol Alcohol 2001; 36: 544–52. 127. Morris PLP, Hopwood M, Whelan G, Gardiner J, Drummond E. Naltrexone for alcohol dependence: a randomised controlled trial. Addiction 2001; 96: 1565–73. 128. Rubio G, Jimenez-Arriero MA, Ponce G, Palamo T. Naltrexone versus acamprosate: one year follow-up of alcohol dependence treatment. Alcohol Alcohol 2001; 36: 419–25. 129. Oncken C, Van Kirk J, Kranzler HR. Adverse effects of oral naltrexone: analysis of data from two clinical trials. Psychopharmacology 2001; 154: 397–402. 130. Bristow K, Meek R, Clark N. Acute opioid withdrawal in the emergency department: Inadvertent naltrexone abuse? Emerg Med 2001; 13: 359–63. 131. Quigley MA, Boyce SH. Unintentional rapid opioid detoxification. Emerg Med J 2001; 18: 494–5. 132. Mimoz O, Incagnoli P, Josse C, Gillon MC, Kuhlman L, Mirand A, Soilleux H, Fletcher D. Analgesic efficacy and safety of nefopam vs propacetamol following hepatic resection. Anaesthesia 2001; 56: 520–5.

A. Del Favero

9

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An update on NSAIDs and chronic renal disease The relation between long-term heavy exposure to analgesics and the risk of chronic renal disease has been the object of intensive toxicological and epidemiological research for many years (SEDA-24, 120; 1R ). Most of the earlier reports suggested that phenacetincontaining analgesics probably cause renal papillary necrosis and interstitial nephritis. In contrast, there is no convincing epidemiological evidence that non-phenacetin-containing analgesics (including paracetamol, aspirin, mixtures of the two, and NSAIDs) cause chronic renal disease. Moreover, findings from epidemiological studies should be interpreted with caution, because of a number of inherent limitations and potential biases in study design (2R ). Two recent methodologically sound studies have provided more information on this topic. The first was the largest cohort study conducted thus far to assess the risk of renal dysfunction associated with analgesic use (3C ). Details of analgesic use were obtained from 11 032 men without previous renal dysfunction participating in the Physicians’ Health Study (PHS), which lasted 14 years. The main outcome measure was a raised creatinine concentration defined as 1.5 mg/dl (133 μmol/l) or higher and a reduced creatinine clearance of 55 ml/min or less. In all, 460 men (4.2%) had a raised creatinine concentration and 1258 (11%) had a reduced creatinine clearance. Mean creatinine concentrations and creatinine © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

clearances were similar among men who did not use analgesics and those who did. This was true for all categories of analgesics (paracetamol and paracetamol-containing mixtures, aspirin and aspirin-containing mixtures, and other NSAIDs) and for higher risk groups, such as those aged 60 years or over or those with hypertension or diabetes. These data are convincing, as the large size of the PHS cohort should made it possible to examine and detect even modest associations between analgesic use and a risk of renal disease. Furthermore, this study included more individuals who reported extensive use of analgesics than any prior case-control study. However, the study had some limitations, the most important being the fact that the cohort was composed of relatively healthy men, most of whom were white. These results cannot therefore be generalized to the entire population. However, the study clearly showed that there is not a strong association between chronic analgesic use and chronic renal dysfunction among a large cohort of men without a history of renal impairment. The second study was a Swedish nationwide, population-based, case-control study of early-stage chronic renal insufficiency in men whose serum creatinine concentration exceeded 3.4 mg/dl (300 μmol/l) or women whose serum creatinine exceeded 2.8 mg/dl (250 μmol/l) (4C ). In all, 918 patients with newly diagnosed renal insufficiency and 980 controls were interviewed and completed questionnaires about their lifetime consumption of analgesics. Compared with controls, more patients with chronic renal insufficiency were regular users of aspirin (37% vs 19%) or paracetamol (25% vs 12%). Among subjects who did not use aspirin regularly, the regular use of paracetamol was associated with a risk of chronic renal insufficiency

111

112 that was 2.5 times as high as that for non-users of paracetamol. The risk increased with increasing cumulative lifetime dose. Patients who took 500 g or more over a year (1.4 g/day) during periods of regular use had an odds ratio (OR) for chronic renal insufficiency of 5.3 (95% CI = 1.8, 15). Among subjects who did not use paracetamol regularly, the regular use of aspirin was associated with a risk of chronic renal insufficiency that was 2.5 times as high as that for non-users of aspirin. The risk increased significantly with an increasing cumulative lifetime dose of aspirin. Among the patients with an average intake of 500 g or more of aspirin per year during periods of regular use, the OR for chronic renal insufficiency was 3.3 (1.4, 8.0). Among patients who used paracetamol in addition to aspirin, the OR for chronic renal insufficiency was 2.2 (1.4, 3.5) when regular aspirin users served as the reference group, and 1.6 (0.9, 2.7) when regular paracetamol users were used as controls. There was no relation between the use of other analgesics (propoxyphene, NSAIDs, codeine, and pyrazolones) and the risk of chronic renal insufficiency. Thus, the regular use of paracetamol, or aspirin, or both was associated dose-dependently with an increased risk of chronic renal insufficiency. The OR among regular users exceeded 1.0 for all types of chronic renal insufficiency, albeit not always significantly. These results are consistent with exacerbating effects of paracetamol and aspirin on chronic renal insufficiency, regardless of accompanying disease. How can we explain the contrasting results of these two studies? A possible explanation lies in the different populations studied. In PHS relatively healthy individuals were enrolled while in the Swedish study all the patients had preexisting severe renal or systemic disease, suggesting that such disease has an important role in causing analgesic-associated chronic renal insufficiency. People without pre-existing disease who use analgesics may have only a small risk of end-stage renal disease. Pregnancy and teratogenicity NSAIDs are among the commonest drugs prescribed for pregnant woman (5C ). However, the risk of adverse birth outcomes in women who take NSAIDs other than aspirin during pregnancy is largely unknown. Now a Danish study has provided important information (6C ).

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The study was conducted in a Danish county (population about 490 000) and included data on all women who between 1991 and 1998 had a live birth or a stillbirth after the 28th week of gestation, or who had a miscarriage (including missed abortions). The researchers performed a cohort study and a case-control study using data from the Danish birth registry, the county hospital discharge registry, and the county’s prescriptions database. The risk of an adverse birth outcome (congenital abnormality, low birth weight, and preterm birth) was examined in the cohort study and the risks of miscarriage were examined in the case-control study. The cohort study included 1462 women who gave birth after 28 weeks and who had filled a prescription for an NSAID, a total of 1742 prescriptions. The control group consisted of 17 259 pregnant women who did not take any drugs during pregnancy. The case-control study involved 4268 women who had had their first miscarriage, 63 of whom had filled a prescription for an NSAID in the 12 weeks before being discharged from hospital after the miscarriage, and 29 750 primiparous controls who had live births. There was no significant association between the uptake of prescriptions for NSAIDs during pregnancy and the risks of congenital abnormalities, low birth weight, or preterm births. However, there was a significant association with miscarriage in the case-control study. The OR for miscarriage was 7.0 (2.8, 17) when the prescription for the NSAID was filled during the week before the miscarriage and 2.6 (1.8, 4.0) when it was filled at 7–9 weeks before the miscarriage. The validity of these findings has been challenged on the grounds of possible bias and other methodological problems (7r , 8r ). However, according to a statement issued by the UK Royal College of Obstetricians and Gynaecologists (RCOG) NSAIDs should be avoided by women who know that they are pregnant. According to the RCOG, although the study did not establish a causative link between NSAID use and miscarriage, pregnant women should avoid NSAIDs and in the mean time prefer to use effective alternative drugs, such as paracetamol (9c ). As NSAIDs are widely used, even a small increase in the risk of adverse effects can have major implications for public health. Further

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studies therefore need to be conducted on the association between NSAIDs and miscarriage before definitive conclusions can be drawn.

INDIVIDUAL DRUGS AND CLASSES Acetylsalicylic acid (aspirin) and related compounds (SED-14, 233; SEDA-23, 116; SEDA-24, 121; SEDA-25, 132) Gastrointestinal The question of whether the risk of gastrointestinal complications with the long-term use of aspirin is dose-related is controversial (SEDA-21, 100; SEDA-25, 132). A systematic review of 17 epidemiological studies conducted between 1990 and 2001 has provided further data on this topic (10M ). The effect of aspirin dosage was investigated in five studies. There was a greater risk of gastrointestinal complications with aspirin in dosages over 300 mg/day than in dosages of 300 mg/day or less. However, users of low-dose aspirin still had a two-fold increased risk of such complications compared with non-users, with no clear evidence of a dose-response relation at dosages under 300 mg/day, confirming previous findings (11M ). The study also addressed the question of whether the aspirin formulation affects gastrotoxicity. The pooled relative risks of gastrointestinal complications in four studies were 2.4 (95%; CI = 1.9, 2.9) for enteric-coated aspirin, 5.3 (3.0, 9.2) for buffered formulations, and 2.6 (2.3, 2.9) for plain aspirin, compared with non-use. These data confirm those from previous studies (SEDA-21, 100; 11M ), which negate any protective effect of the most frequently used aspirin formulations. Furthermore, there were higher relative risks, compared with non-use, for gastrointestinal complications in patients who used aspirin regularly (RR = 3.2; CI = 2.6, 5.9) than in patients who used it occasionally (2.1; 1.7, 2.6), and during the first month of use (4.4; 3.2, 6.1) compared with subsequent months (2.6; 2.1, 3.1). Liver The use of aspirin in children has been associated with Reye’s syndrome. Its cause is not known and it occurs in children and young

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adults up to 20 years of age. Diagnosis is particularly difficult, and so the estimated frequency varies from country to country. During 1980 initiatives were taken in the UK and USA to warn parents not to give aspirin to their children (under 12 years of age). Over the last 20 years in the USA the incidence of Reye’s syndrome has fallen significantly—since this advice was introduced there have been 25 reported cases, but 15 were in adolescents aged 12–17 years, and 8% of cases occurred in patients aged 15 years or over (12C ). In the UK, in view of these findings, the Commission on Safety of Medicines (CSM) has now amended its original statement and has advised that aspirin should be avoided in febrile illnesses or viral infections in patients aged up to 15 years. However, the appropriateness of this decision has been challenged (13r ). This is because the incidence of Reye’s syndrome is already low and is falling; furthermore, restricting the use of aspirin leaves paracetamol and ibuprofen as the only available therapeutic alternatives, and their safety is not absolutely guaranteed and might be even worse than that of aspirin.

ANILINE DERIVATIVES

(SED-14, 240; SEDA-23, 116; SEDA-24, 122; SEDA-25, 132)

Paracetamol Hematological Two patients developed immune thrombocytopenia attributed to metabolites of paracetamol (14A ). • A 30-year-old man and a 66-year-old woman had taken paracetamol 1 g intermittently for headaches and other non-specific indications. Routine blood testing showed thrombocytopenia (50 × 109 and 45 × 109 /l respectively). They both stopped taking paracetamol, and their platelet counts rose to normal within 7–10 days. Their sera contained antibodies (IgG or IgA) that recognized normal platelets in the presence of the metabolite paracetamol sulfate.

This suggests that in patients with druginduced immune thrombocytopenia, tests for metabolite-dependent antibodies can be helpful in identifying the responsible agent.

114 Drug overdose On 16 September 1998 legislation was introduced in the UK limiting the pack size of paracetamol; at the same time nearly all formulations became available only in blister packs. The justification for this legislation was that analgesic self-poisoning is highly impulsive and is associated with both low suicidal intent and limited knowledge of the possible consequences; it was expected that the number of cases of paracetamol overdose might be reduced by limiting its availability. The impact of this legislation on mortality from paracetamol overdose has been assessed in a prospective study of mortality from paracetamol overdose before and after the new legislation (15C ). The evaluation included the number of patients referred to liver units or listed for liver transplantation, the number of episodes of overdose and tablets taken, the plasma concentration of paracetamol, and sales of paracetamol to pharmacies. In the years after the legislation the number of tablets of paracetamol formulations per packet fell markedly, as did the number of deaths from self-poisoning with paracetamol, the number of liver transplants and admissions to liver units with hepatic damage after paracetamol poisoning, and the number of episodes of overdose in which a large number of tablets was taken. On the basis of these results it seems that the legislation was relatively successful. The results suggested that the main factor was the reduction in the number of tablets per pack available for impulsive self-poisoning. However, the study had some limitations. The period assessed may have been too short for a full assessment of the impact of the legislation (16r ) and the effect of legislation on self-poisoning with other drugs was not examined (17r ). It may be that limiting access to one type of drug simply increases the incidence of overdose with other potentially more dangerous medicines. Because restricting the packet size cannot completely resolve the problem of paracetamol overdose, alternative measures have been proposed (SEDA-22, 114). Acetylcysteine, which provides the thiol groups necessary to replenish glutathione depleted by paracetamol, is used to treat paracetamol overdose. It has therefore been suggested that toxicity caused by paracetamol overdoses, whether intentional or not, could be prevented by formulating paracetamol with added acetylcysteine. It has been estimated

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that including 200 mg acetylcysteine for every 500 mg of paracetamol would prevent toxicity (18r , 19r ). Methionine has previously been added to oral paracetamol formulations for the same reason. For example, Paradote, contains paracetamol 500 mg and methionine 100 mg and the combination is called co-methiamol. However, adding methionine to every paracetamol tablet prompted contrasting opinions (SEDA-22, 114; 20r , 21r ). Pameton (500 mg paracetamol, 250 mg methionine) was voluntarily withdrawn in the UK because of safety concerns, before any evaluation of its impact on overdose had been carried out (20r ). Paradote remains available in the UK, but similar formulations are not currently available in the rest of Europe or the USA. Drug interactions Alcohol Alcohol abuse can aggravate hepatotoxicity, not only in individuals who take excessive doses of paracetamol, but also in moderate social drinkers who take regular paracetamol (SEDA-20, 96; SEDA-24, 122). The theory behind this interaction involves induction by alcohol of CYP2E1, which metabolizes about 5% of a typical dose of paracetamol, producing the reactive hepatotoxic metabolite named N-acetylparabenzoquinone-imine (NAPQI). The rest of a therapeutic dose of paracetamol is conjugated to non-toxic forms of glucuronide and sulfate. Ingestion of alcohol induces the activity of CYP2E1 and therefore predisposes the alcoholic patient to injury even at therapeutic doses of paracetamol (22C ). Despite this theory, the evidence that therapeutic doses of paracetamol can produce liver injury in alcoholics is scanty (23M , 24r ). There has been only one study of the hepatotoxicity of paracetamol in therapeutic doses in alcoholic patients, a double-blind, randomized, placebo-controlled study in which 200 long-term alcoholic patients took placebo or paracetamol 1 g qds on 2 consecutive days (25C ). Paracetamol was not given until alcohol had been eliminated from the body. Liver injury, documented by increased serum transaminases, was not detected. Mean (SD) AsT activity on day 4 was 38 (27) u/l with paracetamol and 38 (28) u/l with placebo. Only five patients who took placebo and four who took paracetamol had an increase in serum AsT to greater than 120 u/l, and the AsT did not exceed 200 u/l in any patient. Thus, repeated administration

Anti-inflammatory and antipyretic analgesics and drugs used in gout

of the maximum recommended daily doses of paracetamol to alcoholic patients was not associated with liver damage. An older report also provided evidence that alcoholic patients are not at risk from therapeutic doses of paracetamol (26C ). The researchers concluded that the usual recommendations that alcoholic patients should use reduced doses of paracetamol or avoid it entirely are not based on firm evidence. However, the study had some limitations, as paracetamol was given for only 2 days in doses that did not exceed the maximum therapeutic daily dose. Moreover, the alcoholic patients enrolled in the study may not have been representative of those who would be at increased risk of paracetamol toxicity (27r –29r ). It therefore seems wise to suggest that caution is still warranted with paracetamol in alcoholic patients. Rifampicin The addition of rifampicin in patients taking paracetamol can reportedly cause liver failure and encephalopathy, and this has been reported again (30A ). • A 32-year-old woman, who had been taking paracetamol 2–4 g/day for several weeks, took rifampicin (600 mg bd), and 2 days later developed agitation, confusion, and laboratory abnormalities indicative of severe liver injury. Both rifampicin and paracetamol were withdrawn and she was given acetylcysteine. Her liver dysfunction resolved.

The severe hepatotoxicity in this case was probably due to induction of CYP3A4 by rifampicin, but rifampicin-induced liver damage could not be excluded.

ARYLALKANOIC ACID DERIVATIVES (SED-14, 268; SEDA-23, 119; SEDA-24, 122; SEDA-25, 133)

Aceclofenac Skin After starting twice-daily topical application of a cream containing aceclofenac, a woman developed acute eczema affecting the sun-exposed areas of her legs (31A ). Aceclofenac can therefore be added to the long list of NSAIDs that cause photosensitivity.

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Diclofenac Electrolyte balance NSAIDs can cause hyperkalemic acidosis and should be used with caution in the presence of renal impairment (32A ). • A 76-year-old woman developed quadriparesis associated with hyperkalemia after taking diclofenac 100 mg/day for 10 months for gouty arthritis. She had a metabolic acidosis with a normal anion gap and mild renal impairment. Her weakness resolved after withdrawal of diclofenac and correction of the hyperkalemia.

Ibuprofen Drug interactions Aspirin Patients with arthritis and vascular disease sometimes take both low-dose aspirin and other NSAIDs. However, concomitant treatment with ibuprofen may limit the cardioprotective effects of aspirin, according to the results of a study of the effects of ibuprofen, diclofenac, coxibs, and paracetamol on the antiplatelet activity of aspirin (33C ). The following combinations of drugs were used: aspirin (81 mg every morning) 2 hours before ibuprofen (400 mg every morning) or in the reverse order; aspirin 2 hours before rofecoxib (25 mg every morning or in the reverse order); enteric-coated aspirin 2 hours before ibuprofen (400 mg tds); and enteric-coated aspirin 2 hours before modified-release diclofenac (75 mg bd). Inhibition of the formation of serum thromboxane B2 (an index of COX-1 activity in platelets) and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. Diclofenac, paracetamol, and rofecoxib did not affect the pharmacodynamics of aspirin. These results suggest that ibuprofen, but not diclofenac, paracetamol, or rofecoxib, antagonizes the irreversible inhibition of platelet COX-1 by aspirin and can therefore limit the cardioprotective effects of aspirin. Sulfonylureas Ibuprofen (150 mg, 3 doses) for arthralgias was associated with hypoglycemia in a 72-year-old man who was taking glibenclamide 2.5 mg/day for type 2 diabetes mellitus; after the last dose he lost consciousness and his blood glucose concentration was under 2.2 mmol/l (34A ).

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Ketoprofen Respiratory Even topical formulation of NSAIDs should be avoided in patients with a history of analgesic-induced asthma (35A ). • A 74-year-old woman with a history of sinusitis, nasal polyps, and analgesic-induced asthma had a sudden life-threatening attack of asthma 2 hours after the application of a 2% ketoprofen adhesive tape. Asthma had not previously occurred when she had used a 0.3% ketoprofen adhesive patch.

Loxoprofen Gastrointestinal In a retrospective study of NSAID-induced colonic ulceration related to NSAID therapy, five of 14 patients were taking loxoprofen (36c ). However, this finding does not prove that loxoprofen is more ulcerogenic than other NSAIDs.

• Ischemic colitis occurred in a 49-year-old woman 10 days after she started to take meloxicam 15 mg/day for osteoarthritis; meloxicam was withdrawn and her symptoms completely resolved within 1 week (37A ).

Although meloxicam is considered to be a preferential COX-2 inhibitor, its safety profile is not much different from other traditional NSAIDs, especially in high doses (38R ). Immunologic Meloxicam may be relatively safe when given to patients with NSAIDinduced urticaria/angio-edema (39C , 40C ). Of 148 NSAID-sensitive subjects with an unequivocal history of urticaria with or without angio-edema, who were challenged with increasing oral doses of meloxicam (1–7 mg/day) in a single-blind placebo-controlled trial, only two had a positive test (urticaria in one and urticaria/angio-edema in the other); both had chronic idiopathic urticaria (41C ).

SELECTIVE COX-2 INHIBITORS

Naproxen

(SEDA-25, 122)

Hematologic Three men, aged 56, 57, and 71 years developed extensive purpuric hemorrhages involving their legs (3), arms (2), and abdomen (1) 10–20 days after having taken naproxen 250 mg tds for musculoskeletal disorders (14A ). One patient also had gastrointestinal bleeding. They all had severe thrombocytopenia (platelet counts below 3 × 109 /l). Naproxen was withdrawn and prednisone started. The platelet counts normalized within a week. The prednisone was withdrawn and the thrombocytopenia did not recur during follow up. Analysis of their sera showed the presence of IgG antibodies that recognized normal platelets in the presence of the metabolite naproxen glucuronide.

OXICAM DERIVATIVES

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(SED-14,

286; SEDA-24, 122)

Meloxicam Gastrointestinal Colitis has been described as an adverse effect of meloxicam (SEDA-20, 94).

At least 11 selective COX-2 inhibitors have been launched or are under development (42r ), but published information is to date available only for celecoxib, parecoxib, and rofecoxib.

What is safe prescribing and use of selective COX-2 inhibitors? Comparisons with non-selective NSAIDs Although the scientific literature has been flooded by articles and reviews on the use of selective COX-2 inhibitors (coxibs) in the last 2 years, the safe prescribing and use of these compounds is controversial (43r , 44R , 45M , 46r ). This topic was considered in previous Annuals (SEDA-24, 115; SEDA-25, 126), but further comments are warranted. Much information on celecoxib and rofecoxib has come from two large pivotal randomized clinical trials, the CLASS and VIGOR studies, in which the efficacy and safety of the two coxibs and various non-selective NSAIDs were compared (47 C , 48C ).

Anti-inflammatory and antipyretic analgesics and drugs used in gout

Cardiovascular In VIGOR rofecoxib 50 mg/day was associated with a higher rate of non-fatal myocardial infarction (0.4%) than the non-selective COX-2 inhibitor naproxen 500 mg bd (0.1%) (RR = 0.2; CI = 0.1, 0.7) (48C ). In CLASS there was no difference in the rates of myocardial infarction in patients taking celecoxib (0.5%) and those taking ibuprofen or diclofenac (0.4%). However, the protocols of the two studies differed substantially with respect to the use of aspirin. In VIGOR the patients were not allowed to take aspirin or any other antiplatelet drug, while in CLASS onefifth of the patients took aspirin. A re-analysis of CLASS for cardiovascular thromboembolic events, including myocardial infarction, stroke, cardiovascular deaths, and peripheral events, showed no significant increase with celecoxib versus NSAIDs (49R ). However a different conclusion was reached in an analysis of FDA data, which suggested an increase in serious cardiac events with celecoxib (45M ). The incidence of serious cardiac adverse events (myocardial infarction, combined anginal events, and atrial dysrhythmias) was 0.6% higher with celecoxib than with other NSAIDs (RR = 1.55; CI = 1.04, 2.30). The reasons for these inconsistencies are not clear and would require an independent meta-analysis using individual patient data. The cardiovascular results in VIGOR may have occurred simply by chance, given the low number of events, or because naproxen may have a cardioprotective effect similar to that of aspirin, or because rofecoxib 50 mg/day could have prothrombotic effects, especially in the absence of concomitant COX-1 inhibition in patients at increased risk of cardiovascular thromboembolic events. Because there was no untreated group in VIGOR, we do not know whether this finding suggests a protective effect of naproxen or a harmful effect of rofecoxib. All three explanations are plausible, and they are not mutually exclusive. It has been suggested that the increase in thrombotic cardiovascular events in rofecoxibtreated patients probably represents the antiplatelet effect of naproxen (50M , 51R , 52r ). Naproxen has a long pharmacodynamic halflife and inhibits platelet aggregation by 88% for up to 8 h (53C ). In VIGOR (45M , 48C ) the incidence of confirmed thrombotic cardiovascular events was

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0.6% higher with rofecoxib than with naproxen (RR = 2.4; 95% CI = 3.9, 4.0). Some recently published data may help to answer the important question of whether the relative difference in the incidence of myocardial infarction in VIGOR was due to a harmful effect of rofecoxib or a beneficial effect of naproxen. Although contrasting data have been published (54R ), the hypothesis that naproxen has a cardioprotective effect has gained wider support (55r ). Only one of the four most recently published studies negated a potential cardioprotective effect of naproxen. In an 11-year observational study in a new users of non-selective, non-aspirin NSAIDs (n = 181 441) and an equal number of nonusers there was no evidence of a protective effect of naproxen (56C ). During 532 634 personyears of follow-up there were 6382 cases of serious coronary heart disease (11.9 per 1000 person-years). Multivariate-adjusted rate ratios for current and former use of non-aspirin NSAIDs, were 1.05 (95% CI = 0.97, 1.14) and 1.02 (0.97, 1.08) respectively. Rate ratios for ibuprofen, naproxen, and other NSAIDs were 1.15 (1.02, 1.28), 0.95 (0.82, 1.09), and 1.03 (0.92, 1.16) respectively. There was no protection in long-term users with uninterrupted use; the rate ratio among current users with more than 60 days of continuous use was 1.05 (0.91, 1.21). When naproxen was directly compared with ibuprofen, the rate ratio in current users was 0.83 (0.69, 0.98). This study therefore seems to have shown no cardioprotective effect of naproxen. However, the study had a number of important limitations, including: lack of information about some important confounders (smoking, obesity), possible exposure misclassification, and lack of information about over-the-counter use of aspirin. Opposite evidence has emerged from three recent case-control studies from the USA, Canada, and the UK, which showed that the rates of myocardial infarction in patients taking naproxen were lower than in patients not taking any NSAIDs (57C , 58C ) and those taking other NSAIDs (59C ). In the first study 4425 patients hospitalized with acute myocardial infarction who used NSAIDs were compared with 17 700 controls in a large health-care database in the USA (57C ). Multivariate models were constructed to control for potential confounders. A quarter of the

118 cases and controls had also filled a prescription for an NSAID in the 6 months before the study. Overall, the NSAID users had the same risk of acute myocardial infarction as non-users, but naproxen users had a significantly lower risk of acute myocardial infarction compared with those who were not taking NSAIDs (adjusted OR = 0.84; 95% CI = 0.72, 0.98). The cardioprotective effect of naproxen was very modest compared with aspirin (a 44% reduction in the risk of acute myocardial infarction in the Physician Health Study (60C )). The second study was a case-control study sponsored by Merck & Co (the manufacturers of celecoxib), in which the risk of acute thromboembolic cardiovascular events among 16 937 patients aged 40–75 years with rheumatoid arthritis using naproxen was examined using the British General Practice Research Database (58C ). Each patient with a first thromboembolic event (n = 809: 435 myocardial infarctions, 347 strokes, 27 sudden deaths) was matched with four controls. The results suggested that patients with rheumatoid arthritis who currently use naproxen have a significantly lower risk of thromboembolic events relative to those who have not used naproxen in the past year (RR = 0.61; 0.39, 0.94). However, the risk was not lower with previous use of naproxen, suggesting that any effect of naproxen is likely to be short-lived. Moreover, the significantly lower risk of myocardial infarction with current naproxen was not found when myocardial infractions were analysed separately (RR = 0.57; 0.3, 1.06). There was no protective effect for thromboembolic events with current use of nonnaproxen NSAIDs. The third study was also sponsored by Merck & Co and was designed to examine the association between the use of naproxen and other non-selective NSAIDs and hospitalization for acute myocardial infarction (59C ). In a database of 14 163 patients aged 65 years or older who were hospitalized for acute myocardial infarction and an equal number of age-matched controls, concurrent exposure to naproxen had a protective effect against myocardial infarction compared with the other non-selective non-aspirin NSAIDs (RR = 0.79; 0.63, 0.99). This effect was present only with concurrent naproxen exposure and was stronger in longterm users. However, this study also had several limitations: some important risk factors, such

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as smoking and obesity, could not be assessed, patients who died of myocardial infarction before reaching the hospital were not included, and there was uncertainty about concurrent use of over-the-counter drugs, especially aspirin. In conclusion, although these three studies suggest that patients who take naproxen have a lower incidence of myocardial infarction than those who take other NSAIDs or who do not take NSAIDs, the data do not provide definitive evidence that naproxen is cardioprotective. The data therefore raise a cautionary flag about the risk of severe cardiovascular events with COX2 inhibitors and again call for more studies. As many users of NSAIDs or COX-2 inhibitors are at risk of coronary artery disease, it has been suggested that a COX-2 inhibitor be used together with low-dose aspirin in order to avoid severe cardiovascular events. However, this might cause more gastrointestinal toxicity and loss of the benefit offered by COX-2 inhibition. This has already been shown with celecoxib, and the benefit of using a combination of rofecoxib with aspirin requires further study. COX-2 selectivity may be a double-edged sword. Because the cardiovascular risk outweighs the gastrointestinal risk in adults with rheumatoid arthritis or osteoarthritis, the harm would outweigh the benefits in most clinical settings. This means that the total number of serious adverse events would be increased by COX-2 selective NSAIDs compared with nonselective NSAIDs. COX-2 selectivity, which is an appealing theoretical concept, might be a clinical failure (45M ). Respiratory Most people tolerate aspirin well, but not patients with asthma, of whom there is a subgroup in whom aspirin precipitates asthmatic attacks (61R , 62C ). This is a distinct clinical syndrome, called aspirin-induced asthma, which affects about 10% of adults with asthma (63R ). Aspirin-induced asthma is usually accompanied by naso-ocular symptoms and can by triggered not only by aspirin, but by several NSAIDs, a fact that makes immunological cross-reactivity most unlikely. The propensity of an NSAID to precipitate an attack of asthma is probably related to inhibition of cyclo-oxygenase (63R ). There is evidence that potent inhibitors of COX-1 (such as ibuprofen, indomethacin, and naproxen) are

Anti-inflammatory and antipyretic analgesics and drugs used in gout

more likely to precipitate bronchoconstriction than NSAIDs that inhibit COX-2 preferentially (such as meloxicam and nimesulide) (39C , 64C ). A widely accepted hypothesis is that in patients with asthma and aspirin intolerance, NSAID-induced COX inhibition results in increased products from the 5-lipoxygenase pathway, the leukotrienes, which are both potent bronchoconstrictors and also inducers of mucous hypersecretion and airway edema. The leukotrienes implicated in aspirin intolerance are cysteinyl leukotrienes (61R , 63R ), but leukotriene release is probably not the only pathogenic mechanism. The hypothesis that in aspirin-induced asthma the attacks are triggered by inhibition of COX-1 and not COX-2 has been tested in three small studies, two of which were double-blind and placebo-controlled (65C –67 C ). In the first study (65C ) 12 patients with aspirin-induced asthma were challenged with increasing doses of rofecoxib (1.25–25 mg/day for 5 days); no patients had any adverse symptoms, and biochemical markers that reflect intolerance to aspirin in asthma (urinary leukotriene E4 and 9a-11b-PGF2 ) were unchanged. In the second study, 60 aspirin-sensitive asthmatics were challenged with oral rofecoxib (12.5 and 25 mg/day for 2 days) (66C ). There were no signs or symptoms of asthma in any patient and no reductions in FEV1 . In the third study, 27 patients with stable chronic asthma in whom inhalation of lysine aspirin caused a 20% fall in FEV1 were challenged with increasing doses of oral celecoxib (from 10 to 200 mg/day); they did not develop bronchoconstriction or other extrapulmonary reactions (67 C ). So is the safety of COX-2 inhibitors in patients with aspirin-induced asthma sufficiently well documented? Avoidance of NSAIDs is crucial in patients with asthma who have aspirin sensitivity, and hitherto two alternative analgesic options have been available: paracetamol and non-acetylated salicylates. Paracetamol is a generally safe substitute; however, it is a weak COX inhibitor and, albeit very rarely, patients who are sensitive to aspirin have an adverse reaction to high-dose paracetamol (68C ). Choline magnesium salicylate and salicylic acid are also weak COX inhibitors and should therefore be used with care in these patients. The results of the above-mentioned studies suggest that rofecoxib and celecoxib can be taken safely by

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patients with aspirin-induced asthma. However, this conclusion must be treated with caution, as only a few patients were studied and this does not exclude COX-2 inhibitors from participating in other types of reactions, including immune recognition after prior treatment. Gastrointestinal The results of CLASS and VIGOR showed, according to the investigators, similar efficacy with less risk of upper gastrointestinal complications. Unfortunately, when the FDA analysed the data from the entire study period, not just the first 6 months (as had been presented in the published article), CLASS did not show that celecoxib was associated with a significantly lower incidence of upper gastrointestinal complications than ibuprofen or diclofenac. Serious criticism was aimed at the authors on the grounds of design, data analysis, and misleading presentation of the results. They were charged with having published and circulated overoptimistic short-term pooled data from different protocols, and of omitting disappointing long-term data. They replied to these criticisms, but their explanations were not considered to be convincing (69r –71r ). Furthermore, Pharmacia, the manufacturers of celecoxib, continue to present inappropriately pooled short-term results from different protocols performed in different continents with different comparator drugs for the SUCCESS 1 trial, the successor to CLASS (69r –71r ). Problems have also occurred in interpreting the results of VIGOR (48C ). There were significantly fewer upper gastrointestinal adverse events with rofecoxib compared with naproxen, but an unexpected substantial excess of serious cardiovascular events, making the overall safety of rofecoxib uncertain. When the complete data from VIGOR were presented and all serious adverse events were included (not just gastrointestinal events) the patients who took naproxen had fewer overall serious events: 9.3% of the patients who took rofecoxib had a serious adverse event compared with 7.8% of those who took naproxen (RR = 0.81; 95% CI = 0.62, 0.97). The reasons for the discrepancy between celecoxib and rofecoxib in the frequency of upper gastrointestinal complications are not clear, but some hypotheses have been proposed. First, aspirin was used concomitantly with celecoxib

120 (20% of patients) in CLASS but not in VIGOR, increasing the risk of gastrointestinal damage. Secondly, diclofenac (which has greater COX2 selectivity than naproxen) was used as a comparator in CLASS. Thirdly, the dosages of celecoxib were too high and at the doses studied in CLASS celecoxib might not have had true selectivity for COX-2. Finally, the selectivity of celecoxib for COX-2 is probably lower than that of rofecoxib. Therefore, given major differences in study design and data analysis between the two trials, a valid comparison of the two coxibs is not possible from these data alone; a headto-head comparison in a large outcome study is needed (72r ). Two recently published articles have helped to clarify this point: a systematic review of randomized clinical trials on the upper gastrointestinal safety of celecoxib (73M ) and a population-based retrospective cohort comparison of the rate of upper gastrointestinal hemorrhages in over 40 000 NSAID-naïve elderly users of non-selective NSAIDs, celecoxib, or rofecoxib with the rate in 100 000 patients who had not been exposed to NSAIDs (74C ). In the systematic review all published and unpublished randomized clinical trials that compared at least 12 weeks of celecoxib treatment with placebo or a traditional NSAID (diclofenac, ibuprofen, naproxen) were analysed. Nine of 17 trials fulfilled the inclusion criteria (a total of 15 187 patients). Withdrawals because of drug-related gastrointestinal adverse effects, ulcers detected at endoscopy, and complicated ulcers were used as measures of gastrointestinal tolerability. Compared with those taking non-selective NSAIDs, the patients who took celecoxib had a lower rate of withdrawals because of adverse gastrointestinal effects at 12 weeks (3.2% vs 6.2%), but there was no significant difference between celecoxib and NSAIDs in the incidence of withdrawals for all adverse events. The incidence of ulcers detected at routine endoscopy at 12 weeks was also lower in patients who took celecoxib compared with those who took non-selective NSAIDs (6.2% vs 23%). In four trials that provided information on the incidence of ulcers detected by endoscopy according to whether or not patients were taking concomitant aspirin up to 325 mg/day, the benefit provided by celecoxib was greater in patients not taking aspirin. The incidences of ulcers were as follows:

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celecoxib alone 6.2%; celecoxib + aspirin 12%; non-selective NSAID alone 25%; non-selective NSAID + aspirin 26%.

However, these results must be treated with great caution, as the total number of patients who took prophylactic aspirin was small (150 taking celecoxib and 140 taking non-selective NSAIDs) and the largest number of patients came from a single trial (CLASS). The same warning applies to evaluation of the incidence of complicated ulcers (bleeds, perforation, and obstructions). The incidence of these serious events with celecoxib was 2.7% (11 events) versus 5% (20 events) in patients taking diclofenac or ibuprofen, a nonsignificant difference. This meta-analysis has provided further evidence that celecoxib has better upper gastrointestinal tolerability that some traditional NSAIDs when withdrawal from trials due to drug-related adverse effects or ulceration detected during routine endoscopy are used as measures of tolerability. However, not all ulcers detected by endoscopy progress to a serious event, and many probably heal spontaneously; the clinical relevance of this measure is therefore controversial. On the other hand, there is a consensus that ulcer complications, the prime cause of concern with NSAIDs, should be the primary end-point of outcome studies aimed at evaluating the gastrointestinal toxicity of NSAIDs. Unfortunately, this consensus is counterbalanced by the problems of doing such studies, as they need to be very large to achieve even marginal power and there are also problems in evaluating the clinical outcomes (72r ). Another recent study that deserves attention was an observational study of upper gastrointestinal hemorrhage in over 40 000 elderly patients taking COX-2 selective drugs (rofecoxib, celecoxib) or non-selective NSAIDs with and without misoprostol, compared with 100 000 non-NSAID users (74C ). Of about 1.3 million potential subjects aged 65 years and over, 364 686 (28%) were given an NSAID during the study period (about 1 year). From the total elderly population, the authors identified 5391 users of non-selective NSAIDs, 5087 users of diclofenac plus misoprostol, 14 583 users of rofecoxib, 18 908 users of celecoxib, and 100 000 controls. Most of the users of non-selective

Anti-inflammatory and antipyretic analgesics and drugs used in gout

NSAIDs were taking naproxen (32%), ibuprofen (23%), or diclofenac (20%). During over 55 000 person-years of follow-up, there were 187 hospitalizations for upper gastrointestinal hemorrhage. Relative to the non-users, there was a significantly greater risk of upper gastrointestinal hemorrhage in the patients who took non-selective NSAIDs (adjusted risk ratio 4.0; 95% CI = 2.3, 6.9), diclofenac plus misoprostol (3.0; 1.7, 5.6), or rofecoxib (1.9; 1.3, 2.6), but not celecoxib (1.0; 0.7, 1.6). There were also significant differences in the risks of upper gastrointestinal hemorrhage. Relative to celecoxib users, there was a higher risk of hospitalization for upper gastrointestinal hemorrhage, not only among users of non-selective NSAIDs and diclofenac plus misoprostol but also among users of rofecoxib. This study has provided further evidence that the risk of upper gastrointestinal hemorrhage with COX-2 inhibitors is significantly lower than with conventional NSAIDs, whether or not they are taken with misoprostol. The apparently greater risk of gastrointestinal hemorrhage with rofecoxib than with celecoxib needs confirmation, as the study had some limitations, of which the most important were the low absolute number of events in the study group and the retrospective design. What are the implications of these data on the use of the coxibs? Overall they suggest that COX-2 selective inhibitors are less likely to cause upper gastrointestinal damage than some traditional NSAIDs. This advantage is measured by a lower number of events that represent a composite end-point of gastrointestinal toxicity, such as endoscopically detected symptomatic ulcers and serious ulcer complications (perforation, obstruction, bleeding). However, this may not be true in all patients, especially in those who simultaneously take aspirin. This question is of major clinical importance, as many patients with osteoarthritis or rheumatoid arthritis use low-dose aspirin for cardiovascular prophylaxis. We do not know whether gastrointestinal safety is preserved with the use of such combinations, nor whether a proton pump inhibitor should be added in this situation. Furthermore, the data on which of the coxibs has better gastrointestinal tolerability are inconclusive. Large outcome studies will be necessary to solve these questions. A final consideration is worth while. To focus attention only on gastrointestinal events

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may provide an incomplete picture of the benefit/harm profile of the COX-2 inhibitors. Metaanalysis of mortality and morbidity outcomes from CLASS and VIGOR has suggested that total mortality was higher with coxibs than with non-selective NSAIDs, although the difference was not statistically significant (45M ). Moreover, if one takes into account the incidence of serious adverse events (including death, admission to hospital, and any life-threatening event or events leading to serious disability) as a combined measure of harm, the incidence was significantly higher with COX-2 selective compounds than with other NSAIDs, and complicated gastrointestinal ulcers accounted for only a small proportion of total serious adverse events. Non-gastrointestinal serious adverse events call for more attention. Immunologic There is considerable difficulty and controversy in identifying and classifying these allergic reactions to NSAIDs, for many reasons (75R ). First, the difficulty in making a definite diagnosis in patients who have these reactions without provocative challenge with the suspected drug and other NSAIDs. Secondly, reactions are characterized by a large spectrum of target organ responses to NSAIDs, and the same drug may cause different types of reactions in different organs in the same or different individuals. Thirdly, a patient can have a similar reaction to a structurally different NSAID. Finally, reports of these reactions include different, often imprecise, terms, making interpretation difficult. It is worth evaluating the safety of new coxibs in patients who cannot tolerate non-selective NSAIDs. Although the celecoxib and rofecoxib package inserts warn about their use in patients who cannot tolerate aspirin and NSAIDs, there is little information about whether or not they cross-react. Some recent information on this topic may be of interest. Anaphylaxis Among the anaphylactic reactions to NSAIDs that result in different types of reaction (urticaria, angio-edema, asthma, or hypotension), there have been very few reports of anaphylactic shock. However, this life-threatening reaction has been described in patients taking celecoxib (76 A , 77 A ) or rofecoxib (78A ). Rofecoxib caused this reaction in a patient who had had a similar reaction to diclofenac, suggesting that COX-2 inhibitors may

122 be not safe in all individuals who have adverse reactions to non-selective COX inhibitors. It also suggests that different mechanisms may be involved in patients with asthma and in those with anaphylactoid reactions to NSAIDs. Sulfonamide-like allergic adverse reactions Concerns that COX-2 inhibitors may be associated with an increased risk of allergic reactions in patients with a history of sulfonamide hypersensitivity arise from the molecular structures of these compounds (SEDA-24, 119; 79R ). A sulfur component is necessary for the receptor binding of both celecoxib and rofecoxib, but their structures differ and they have different potentials for causing allergic reactions. Consequently, celecoxib is thought to be contraindicated in patients with a history of allergy to sulfonamides. The available data on the immunological tolerability profile of celecoxib and rofecoxib are scanty but merit attention. Sulfonamide-like adverse drug reactions seem to occur more frequently with celecoxib than with rofecoxib, according to a recent report from Sweden (80C ). The investigators identified a profile of 19 typical sulfonamide-like adverse reactions from published papers and the WHO Adverse Drug Reactions database from 1968 to 2000, and compared this profile with reported adverse drug reactions associated with celecoxib and rofecoxib. The WHO database contained 11 514 reports about celecoxib describing 21 292 suspected adverse drug reactions and 10 200 reports about rofecoxib describing 18 585 suspected drug reactions. The relative reporting rate of sulfonamide-like adverse drug reactions was almost twice as high for celecoxib as for rofecoxib (1.8; 95% CI = 1.6, 1.9) for all reports and for reports that listed a COX-2 inhibitor as the only suspected drug. The reporting rate for 15 of the 19 sulfonamide-like adverse drug reactions was higher for celecoxib than for rofecoxib, with significant differences for rash (relative reporting rate 2.3; 2.0, 2.6), urticaria (2.0; 1.6, 24), Stevens–Johnson syndrome (3.6; 1.4, 12), and photosensitivity (2.4; 1.5, 4.0). Fatal adverse drug reactions fitting the typical sulfonamide profile also occurred more often with celecoxib than with rofecoxib (1.8; 0.9, 4.0). Even though serious sulfonamide reactions are rare, their clinical impact warrants close monitoring as more data become available,

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and physicians should be aware of possible sulfonamide allergy when prescribing COX-2 inhibitors, in particular celecoxib. There have been single case reports of sulfonamide-like allergic reactions in patients taking celecoxib (see below), and in two cases sulfonamide allergy was ignored and was discovered only after an adverse reaction to celecoxib (81A ) or rofecoxib (82A ). Urticaria and angio-edema Of 110 patients with a history of urticaria and angio-edema triggered by one or more non-selective NSAIDs, who were submitted to 184 single-blind placebocontrolled oral challenges with the suspected NSAID, patients with a positive challenge underwent further oral challenge with various COX-2 inhibitors (celecoxib and rofecoxib, but also nimesulide and meloxicam, which are relatively selective COX-2 inhibitors) (83C ). The maximal challenge doses were celecoxib 200 mg, rofecoxib 25 mg, meloxicam 15 mg, and nimesulide 100 mg. Reactions (expressed as a percentage of tested patients with a positive test) varied among the COX-2 inhibitors: 33% (10/30) for celecoxib, 21% (16/75) for nimesulide, 17% (8/46) for meloxicam, and 3% (1/33) for rofecoxib. This suggests that the degree of cross-reactivity of COX-2 inhibitors was related to the degree of in vitro COX1 inhibition since meloxicam, nimesulide, and celecoxib inhibit COX-1 to a similar extent (84R ). The results also suggested that the most selective COX-2 inhibitor (rofecoxib) might be relatively safe in a patient with NSAID-induced urticaria/angio-edema. In another study, 34 patients with a history of urticaria and/or angio-edema after ingestion of at least two chemically unrelated non-selective NSAIDs, 22 of whom also had chronic urticaria, all underwent a single-blind, placebo-controlled oral tolerance test with rofecoxib (12 and 25 mg 1 h apart) (85C ). Rofecoxib caused urticaria and/or angio-edema in 6/34 patients (18%), with no difference between patients with or without a history of chronic urticaria. There was even better tolerability of rofecoxib in another study in 33 patients with documented urticaria/angio-edema after ingestion of two different NSAIDs (86C ). The patients underwent provocative tests with increasing doses of rofecoxib (from 6.25 mg to 25 mg); at the end of the challenge all tolerated rofecoxib 25 mg.

Anti-inflammatory and antipyretic analgesics and drugs used in gout

Other single case reports have supported the evidence of better tolerability of COX-2 selective inhibitors (in particular rofecoxib) in patients with a history of urticaria/angio-edema (39C , 87 C ). However, contrasting data have shown cross-reactivity of celecoxib with other NSAIDs and between celecoxib and rofecoxib (88c ). Why are COX-2 selective drugs better tolerated? The mechanisms underlying intolerance to chemically unrelated NSAIDs are unknown, but it has been hypothesized that intolerant patients may have exaggerated sensitivity to the effects of leukotrienes, which are more active than histamine in inducing wheal and flare reactions. Blockade of both COX-1 and COX-2 by non-selective NSAIDs increases the production of leukotrienes by the lipoxygenase pathway, whereas COX-2 selective agents do not increase the production of LTB4 or cysteinyl LTS . However, this may not be the only pathogenic mechanism, as some drugs probably trigger histamine release from mast cells and basophils non-specifically, and others may trigger immunological cross-reactivity. Overall, the above-mentioned studies and clinical experience suggest that urticaria and angioedema can occur with COX-2 inhibitors, albeit with a lower frequency than with non-selective NSAIDs. When prescribing COX-2 inhibitors one must be aware of possible cross-reactivity with non-selective NSAIDs or between celecoxib and rofecoxib. Reproductive system Many reproductive processes (ovulation, fertilization, implantation, decidualization, and parturition) depend on prostaglandin ligand–receptor interactions. It is therefore not surprising that selective COX2 inhibition has a negative local effect on ovulation, resulting in delayed follicular rupture and infertility, without affecting peripheral hormonal cyclicity (89R , 90C ). There have been several case reports that non-selective NSAIDs (diclofenac, naproxen, piroxicam) can cause infertility, attributed to “luteinized unruptured ovarian follicles” syndrome (91c –93c ). Now the syndrome has been documented in a double-blind, randomized, placebo-controlled study, in which women were assessed over two menstrual cycles while taking rofecoxib (90C ). Women who are trying

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to become pregnant should avoid taking any NSAIDs if possible, and those who need one for a chronic rheumatic disorder should be aware of possible infertility; in such cases further investigation is not required, as withdrawal of the drug restores fertility. Other effects on human reproduction by COX-2 inhibitors are uncertain and need further attention.

Celecoxib Psychiatric There have been two reports of visual hallucinations in patients taking celecoxib. • A 79-year-old woman presented to her optometrist with a 2-day history of seeing orange spots in both visual fields 2 months after starting to take celecoxib 100 mg/day (94A ). Physical examination and a CT scan were normal. Celecoxib was withdrawn and her symptoms resolved within 3 days. • An 81-year-old woman took celecoxib 100 mg/day, and over the next 2 weeks developed delirium and auditory and visual hallucinations (95A ). Celecoxib was withdrawn and her symptoms resolved over several days. She took a few doses of rofecoxib 12.5 mg/day 6 months later without any problem. She began to take rofecoxib regularly again 2 months later, and after 1 month developed agitation, confusion, and hallucinations. Physical examination suggested no cause of the delirium other than rofecoxib. A CT scan was negative. The rofecoxib was withdrawn, and over the next 2 days her symptoms resolved.

Auditory hallucinations have been previously reported in a patient taking celecoxib (SEDA-25, 134) but are probably uncommon. Gastrointestinal Celecoxib reportedly exacerbated inflammatory bowel disease in two patients (96A ). • An 80-year-old woman with ulcerative colitis started taking celecoxib for arthritic pain, and 3 days later developed abdominal pain and diarrhea. Celecoxib was withdrawn and her symptoms improved. • A 35-year-old woman with ileal and perianal Crohn’s disease took four doses of celecoxib for an orthopedic injury, and had rectal bleeding, severe abdominal pain, and worse diarrhea. Celecoxib was withdrawn and her symptoms returned to baseline within 5 days.

The possible association of NSAIDs with inflammatory bowel disease is a matter of controversy (SEDA-25, 131), and there is little

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clinical experience with the selective COX-2 inhibitors. Coxibs should not be prescribed for patients with chronic inflammatory bowel disease until more experience has accumulated.

the non-selective NSAIDs. Most of these renal adverse reactions occur in patients with risk factors associated with prostaglandin-dependent renal function (100A –102A ).

Liver There have been three case reports of acute cholestatic hepatitis in patients taking celecoxib.

Skin Stevens–Johnson syndrome occurred in a 58-year-old man taking celecoxib (103A ). He recovered promptly after withdrawal. The reaction recurred 1 month later, after one dose of celecoxib. Sweet’s syndrome can be associated with several drugs. A case involving celecoxib has now been reported (104A ).

• A 55-year-old non-alcoholic obese woman, who was allergic to sulfa drugs, presented with a 5day history of jaundice, malaise, and a pruritic rash that began 3 weeks after she started to take celecoxib 200 mg/day for radicular pain (97A ). There were marked increases in liver enzymes and bilirubin and a peripheral eosinophilia. Liver biopsy showed marked intrahepatocyte cholestasis with eosinophil-rich inflammation, consistent with a drug reaction. Her symptoms and laboratory abnormalities completely resolved after withdrawal of celecoxib but took a long time (4 months) to normalize. • A 54-year-old woman took celecoxib 200 mg/day for sacroiliac pain (98A ). After 4 days her pain resolved, but she developed generalized pruritus, which resolved when celecoxib was withdrawn. A week later the pain recurred and celecoxib was restarted; 2 days later she again developed pruritus associated with dark urine and 5 days later jaundice and raised bilirubin and liver enzymes. Her eosinophil count was raised. On withdrawal of celecoxib her liver function tests improved and her symptoms resolved. • A 49-year-old man with alcoholic cirrhosis developed jaundice, fatigue, and choluria after he started to take celecoxib 200 mg/day for musculoskeletal pain (99A ). There were increases in transaminases, alkaline phosphatase, and bilirubin (to 547 µmol/l). Liver biopsy showed cirrhosis and marked hepatocellular cholestasis. On withdrawal of celecoxib the bilirubin began to fall very slowly; 1 year later he was well, with a total bilirubin concentration of 44 µmol/l.

• A 57-year-old man developed the typical cutaneous erosions and plaques of Sweet’s syndrome after taking celecoxib 100 mg bd for 1 week for bursitis. Celecoxib was withdrawn and the mucocutaneous lesions began to clear. However the bursitis recurred and he restarted celecoxib. The cutaneous lesions worsened dramatically. After withdrawal of celecoxib for the second time the lesions cleared completely.

Drug interactions Co-administration of celecoxib and clopidogrel can increase the hemorrhagic potential of clopidogrel, possibly by a pharmacokinetic interaction involving CYP2C9 (105A ). However this possibility requires confirmation, as serious, sometimes fatal, hemorrhage has been reported during the postmarketing use of clopidogrel alone (106A ).

Parecoxib Parecoxib sodium is an injectable COX-2 inhibitor developed for the treatment of acute pain. It is a pro-drug of a sulfonamidebased COX-2 inhibitor, valdecoxib, a potent anti-inflammatory and analgesic drug. The published information on this compound is inadequate to draw any conclusion about its tolerability. Single-dose and multiple-dose studies have not shown any safety problems compared with placebo (42r , 107c –109c ). In small shortterm endoscopic studies parecoxib was much better tolerated than the non-selective NSAID ketorolac (110c , 111c ).

The histories, clinical findings, and laboratory tests in these cases all suggested celecoxibinduced acute cholestatic hepatitis. The first case suggested that a sulfonamide-like allergic reaction was the pathogenic mechanism, and the same mechanism cannot be excluded in the other two patients, as sulfonamide allergy is often ignored and is discovered only when an adverse reaction occurs (see also the special review above). Celecoxib should not be given to patients who are allergic to sulfa drugs.

Rofecoxib

Urinary tract As more experience accumulates it appears clear that COX-2 inhibitors have a nephrotoxic potential similar to that of

Nervous system Aseptic meningitis is a rare adverse effect of non-selective NSAIDs in patients with or without connective tissue disease

Anti-inflammatory and antipyretic analgesics and drugs used in gout

or rheumatological disease. Rofecoxib has been implicated in five patients (four women and one man), in each case occurring within 12 days of the start of rofecoxib therapy (112A ). The clinical presentations and cerebrospinal fluid findings were typical of aseptic meningitis. One patient had rheumatoid arthritis. After drug withdrawal and recovery, two consecutive rechallenges in one patient led to relapses. Urinary tract Acute renal insufficiency has been reported after the use of rofecoxib in patients with predisposing conditions, such as chronic renal insufficiency, renal transplantation, heart disease, liver cirrhosis, and dehydration (113A –116A ). COX-2 inhibitors should be used with great caution, if at all, in patients with medical problems that are associated with prostaglandin-dependent renal function. From this point of view they do not differ from traditional NSAIDs (117A ). Rofecoxib 12.5 mg bd for arthritic pain was associated with biopsy-proven acute tubulointerstitial nephritis in a 67-year-old woman; another 16 cases of possible tubulointerstitial nephritis have been reported to the manufacturers of celecoxib between its launching in 1999 and July 2001, but the diagnosis was not confirmed in 12 of these cases (118Ar ). Drug interactions Methotrexate Methotrexate is often prescribed for the management of rheumatoid arthritis, and some NSAIDs have been reported to interact, causing increased plasma concentrations associated with impaired renal function. The safety of concurrent rofecoxib and oral methotrexate has been studied for 3 weeks in 25 patients with rheumatoid arthritis (119c ). Rofecoxib 12.5–50 mg/day had no effect on the plasma concentrations or renal clearance of methotrexate, but supratherapeutic doses of rofecoxib (75 and 250 mg) caused a significant increase in the plasma methotrexate AUC and reduced renal clearance. Warfarin Significant increases in International Normalized Ratio (INR) have been reported in patients who took rofecoxib and warfarin; in some, the increase in INR was accompanied by a bleeding event (120A , 121A ). Careful monitoring of the INR in patients taking warfarin and concomitant rofecoxib is mandatory.

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MISCELLANEOUS COMPOUNDS Nimesulide Liver Further reports of the potential hepatotoxicity of nimesulide continue to appear (SEDA-25, 135; 122A –124A ). A wide range of types of liver damage have been documented (125A ). Some patients have required liver transplantation (126A ) and deaths have occurred (127A ). The pathogenic mechanism of these unpredictable, sometimes severe, reactions is uncertain (128r , 129r ). In recent months in some countries nimesulide has been withdrawn from the market or its use has been restricted.

DRUGS USED-IN THE TREATMENT OF GOUT

(SED-14, 310; SEDA-23, 122; SEDA-25, 135)

Allopurinol Nervous system A 60-year-old man developed aseptic meningitis after taking allopurinol on two separate occasions (130A ). Immunologic Hypersensitivity may preclude the use of allopurinol. One way to overcome this problem is desensitization (SEDA-25, 135). A protocol for selected patients who have skin reactions has been described (131C ). The standard desensitization protocol consisted of an initial allopurinol dosage of 50 µg/day, increasing every 3 days to a target of 50–100 mg/day. The interval between dosage increases was extended to 5 days or more in elderly patients with multiple co-morbidity. Desensitization was successful in 25/32 patients (78%); 28 patients completed the desensitization protocol and 21 did so without requiring deviation from the standard dosage schedule and without adverse effects. During follow-up for 902 patient-months, seven of the 28 patients had recurrent skin eruptions after completing the desensitization protocol and after rechallenge with allopurinol. Desensitization to allopurinol is not recommended for all patients, but it can be useful

126 in selected patients who have had a pruritic maculopapular eruption during treatment with

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allopurinol and who cannot be treated with other drugs.

REFERENCES 1. Delzell E, Shapiro S. A review of epidemiologic studies of nonnarcotic analgesic and chronic renal disease. Medicine 1998; 77: 102–21. 2. McLaughlin JK, Lipworth L, Chow WH, Blot WJ. Analgesic use and chronic renal failure: a critical review of the epidemiologic literature. Kidney Int 1998; 54: 679–86. 3. Rexrode K, Buring J, Glynn RJ, Stampfer MJ, Youngman L, Gaziano GM. Analgesic use and renal function in men. J Am Med Assoc 2001; 286: 315–21. 4. Fored CM, Ejerblad E, Lindblad P, Fryzek JP, Dickman PW, Signorello LB, Lipworth L, Elinder CG, Blot WJ, McLaughlin JK, Zack MM, Nyrén O. Acetaminophen, aspirin, and chronic renal failure. New Engl J Med 2001; 345: 1801–8. 5. Bonati M, Bortolus R, Marchetti F, Romero M, Tognoni G. Drug use in pregnancy: an overview of epidemiological (drug utilization) studies. Eur J Clin Pharmacol 1990; 38: 325–8. 6. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. Br Med J 2001; 322: 266–70. 7. Chan LY, Yuen PM, Kristensen P, Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of miscarriage in pregnant users of NSAIDs. Br Med J 2001; 322: 1365. 8. Kristensen P. Risk of miscarriage in pregnant users of NSAIDs. Miscarriages also occur in women intending to have induced abortions. Br Med J 2001; 322: 1366. 9. Anonymous. Pregnant woman should avoid NSAIDs, says RCOG. Pharm J 2001; 266: 178. 10. Garcia Rodriguez LA, Hernandez-Diaz S, DeAbajo FJ. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiological studies. Br J Clin Pharmacol 2001; 52: 563–71. 11. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: metaanalysis. Br Med J 2000; 321: 1183–7. 12. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye’s syndrome in the United States from 1981 through 1997. New Engl J Med 1999; 340: 1377–82. 13. Langford NJ. Aspirin and Reye’s syndrome: is the response appropriate? J Clin Pharmacol Ther 2002; 27: 157–60. 14. Bougie D, Aster R. Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen. Blood 2001; 97: 3846–50.

15. Hawton K, Townsend E, Deeks J, Appleby L, Gunnell D, Bennewith O, Cooper J. Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study. Br Med J 2001; 322: 1203–7. 16. Dargan P, Jones A. Effects of legislation restricting pack sizes of paracetamol on self poisoning. It’s too early to tell yet. Br Med J 2001; 323: 633. 17. Isbister G, Balit C. Effects of legislation restricting pack sizes of paracetamol on self poisoning. Authors did not look at effects on all deliberate and accidental self poisoning. Br Med J 2001; 323: 633. 18. Andrus JP, Herzenberg LA, Herzenberg LA. Effects of legislation restricting pack sizes of paracetamol on self poisoning. Paracetamol should be packaged with its antidote. Br Med J 2001; 323: 633. 19. Law R. Severity of overdose after restriction of paracetamol availability. Br Med J 2001; 322: 554. 20. Jones AL, Hayes PC, Proudfoot T, Vale JA, Prescott LF. Controversies in management: should methionine be added to every paracetamol tablet? (No: the risks are not well enough known.) Br Med J 1997; 315; 301–3. 21. Krenzelok EP. Controversies in management: should methionine be added to every paracetamol tablet? (Yes: but perhaps only in developing countries.) Br Med J 1997; 315: 303–4. 22. Thummel KE, Slattery JT, Ro H, Chien JY, Nelson SD, Lown KE, Watkins PB. Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults. Clin Pharmacol Ther 2000; 67: 591–9. 23. Dart RC, Kuffner EK, Rumack BH. Treatment of pain or fever with paracetamol (acetaminophen) in the alcoholic patient: a systematic review. Am J Ther 2000; 7: 123–34. 24. Dart RC. The use and effect of analgesics in patients who regularly drink alcohol. Am J Managed Care 2001; 7: S597–601. 25. Kuffner EK, Dart RC, Bogdan GM, Hill RE, Casper E, Darton L. Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind placebocontrolled trial. Arch Intern Med 2001; 161: 2247– 52. 26. Benson GD. Acetaminophen in chronic liver disease. Clin Pharmacol Ther 1983; 33: 95–101. 27. Holtzman JL. The effect of alcohol on acetaminophen hepatotoxicity. Arch Intern Med 2002; 162: 1193.

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45. Wright JM. The double-edged sword of COX2 selective NSAIDs. Can Med Assoc J 2002; 167: 1131–7. 46. McCormack JP, Rangno R. Digging for data from the COX-2 trials. Can Med Assoc J 2002; 166: 1649–50. 47. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomised controlled trial. J Am Med Assoc 2000; 284: 1247–55. 48. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Bosi Ferraz M, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. New Engl J Med 2000; 343: 1520–8. 49. White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM, Geis GS, Lefkowith JB. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002; 89: 425–30. 50. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. J Am Med Assoc 2001; 286: 954–9. 51. FitzGerald GA, Cheng Y, Austin S. COX-2 inhibitors and the cardiovascular system. Clin Exp Rheumatol 2001; 19: S31–6. 52. Wooltorton E. What’s all the fuss? Safety concerns about COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex). Can Med Assoc J 2002; 166: 1692–3. 53. Van Hecken A, Schwartz JI, Depre M, De Lepeleire I, Dallob A, Tanaka W, Wynants K, Buntinx A, Arnout J, Wong PH, Ebel DL, Gertz BJ, De Schepper PJ. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000; 40: 1109–20. 54. Cleland JGF. No reduction in cardiovascular risk with NSAIDs – including aspirin? Lancet 2002; 359: 92–3. 55. Dalen JE. Selective COX-2 inhibitors, NSAIDs, aspirin, and myocardial infarction. Arch Intern Med 2002; 162: 1091–2. 56. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002; 350: 118–23. 57. Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002; 162: 1099–104. 58. Watson DJ, Rhodes T, Bing Cai MS, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002; 162: 1105–10. 59. Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute

128 myocardial infarction. Arch Intern Med 2002; 162: 1111–15. 60. Anonymous. Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. New Engl J Med 1989; 321: 129–35. 61. Levy S, Volans G. The use of analgesics in patients with asthma. Drug Saf 2001; 24: 829–41. 62. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. Eur Respir J 2000; 16: 432–6. 63. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol 1999; 104: 5–13. 64. Bianco S, Robuschi M, Petrigni G, Scuri M, Pieroni MG, Refini RM, Vaghi A, Sestini PS. Efficacy and tolerability of nimesulide in asthmatic patients intolerant to aspirin. Drugs 1993; 46 Suppl 1: 115–20. 65. Szczeklik A, Nizankowska E, Bochenek G, Nagraba K, Mejza F, Swierczynska M. Safety of a specific COX-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy 2001; 31: 219–25. 66. Stevenson DD, Simon RA. Lack of crossreactivity between rofecoxib and aspirin in aspirinsensitive patients with asthma. J Allergy Clin Immunol 2001; 108: 47–51. 67. Dahlén B, Szczeklik A, Murray JJ. Celecoxib in patients with asthma and aspirin intolerance. New Engl J Med 2001; 344: 142–3. 68. Settipane RA, Stevenson DD. Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma. J Allergy Clin Immunol 1989; 84: 26– 33. 69. Geis GS. CLASS clarification: reaffirms the medical importance of the analyses and results. Br Med J USA 2002; 2: 522–3. 70. Juni P, Rutjes AWS, Dieppe P. Pharmacia addresses June 1 editorial regarding CLASS study: authors’ response. Br Med J 2002; 324: 1287–8. 71. Budenholzer BR, Geis GS, Mamdani M, Juurlink DN, Anderson GM, Stover RR, Juni P, Rutjes AWS, Dieppe P. Are selective COX 2 inhibitors superior to traditional NSAIDs? Br Med J 2002; 325: 161. 72. Hawkey CJ. Outcomes studies of drug induced ulcer complications: do we need them and how should they be done? Br Med J 2000; 321: 291–3. 73. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Br Med J 2002; 325: 619–28. 74. Mamdani M, Rochon PA, Juurlink DN, Kopp A, Andersons GM, Naglie G, Austin PC, Laupacis A. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional nonsteroidal anti-inflammatory drugs. Br Med J 2002; 325: 624–7. 75. Stevenson DD, Sanchez-Borges M, Szczeklik A. Classification of allergic and pseudoallergic reactions to drugs that inhibit cyclooxygenase en-

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zymes. Ann Allergy Asthma Immunol 2001; 87: 177–80. 76. Levy MB, Fink JN. Anaphylaxis to celecoxib. Ann Allergy Asthma Immunol 2001; 87: 72–3. 77. Habki R, Vermeulen C, Bachmeyer C, Charoud A, Mofredj A. Anaphylactic shock induced by celecoxib. Ann Med Interne 2001; 152: 355. 78. Schellenberg RR, Isserow SH. Anaphylactoid reaction to a cyclooxygenase-2 inhibitor in a patient who had a reaction to a cyclooxygenase-1 inhibitor. New Engl J Med 2001; 345: 1856–7. 79. Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of ‘sulfa’ allergy. Drug Saf 2001; 24: 239–47. 80. Wiholm BE. Identification of sulfonamide-like adverse drug reactions to celecoxib in the World Health Organization database. Curr Med Res Opin 2001; 17: 210–16. 81. Anonymous. COX-2 inhibitor-induced rash. Consultant 2001; 41: 1338. 82. Kaur C, Sarkar R, Kanwar AJ. Fixed drug eruption to rofecoxib with cross-reactivity to sulfonamides. Dermatology 2001; 203: 351. 83. Borges MS, Capriles-Hulett A, CaballeroFonseca F, Perez CR. Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions. Ann Allergy Asthma Immunol 2001; 87: 201–4. 84. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA 1999; 96: 7563–8. 85. Asero R. Tolerability of rofecoxib. Allergy Eur J Allergy Clin Immunol 2001; 56: 916–17. 86. Berges-Gimeno MP, Camacho-Garrido E, Garcia-Rodriguez RM, Alfaya T, Martin Garcia C, Hinojosa M. Rofecoxib safe in NSAID hypersensitivity. Eur J Allergy Clin Immunol 2001; 56: 1017–18. 87. Enrique E, Cistero-Bahima A, San MiguelMoncin MM, Alonso R. Rofecoxib should be tried in NSAID hypersensitivity. Allergy Eur J Allergy Clin Immunol 2000; 55: 1090. 88. Kelkar PS, Butterfield JH, Teaford HG. Urticaria and angioedema from cyclooxygenase-2 inhibitors. J Rheumatol 2001; 28: 2553–4. 89. Norman RJ. Reproductive consequences of COX-2 inhibition. Lancet 2001; 358: 1287–8. 90. Pall MS, Friden BE, Brannstrom M. Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study. Hum Reprod 2001; 16: 1323–8. 91. Smith G, Roberts R, Hall C, Nuki G. Reversible ovulatory failure associated with the development luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs. Br J Rheumatol 1996; 35: 458–62. 92. Akil M, Amos RS, Stewart P. Infertility may sometimes be associated with NSAID consumption. Br J Rheumatol 1996; 35: 76–8.

Anti-inflammatory and antipyretic analgesics and drugs used in gout 93. Mendonca LL, Khamashta MA, Nelson-Piercy C, Hunt BJ, Hughes GR. Non-steroidal antiinflammatory drugs as a possible cause for reversible infertility. Rheumatology 2000; 39: 880–2. 94. Lund BC, Neiman RF. Visual disturbance associated with celecoxib. Pharmacotherapy 2001; 21: 114–15. 95. MacKnight C, Rojas-Fernandez CH. Celecoxib- and rofecoxib-induced delirium. J Neuropsychiatry Clin Neurosci 2001; 13: 305–6. 96. Bonner GF. Exacerbation of inflammatory bowel disease associated with use of celecoxib. Am J Gastroenterol 2001; 96: 1306–8. 97. Galan MV, Gordon SC, Silverman AL. Celecoxib-induced cholestatic hepatitis. Ann Intern Med 201: 134: 254. 98. O’Beirne JP, Cairns SR. Drug Points: cholestatic hepatitis in association with celecoxib. Br Med J 2001; 323: 23. 99. Alegria P, Lebre L, Chagas C. Celecoxibinduced cholestatic hepatotoxicity in a patient with cirrhosis. Ann Intern Med 2002: 137: E75. 100. Graham MG. Acute renal failure related to high-dose celecoxib. Ann Intern Med 2001; 135: 69–70. 101. Pfister AK, Crisalli RJ, Carter WH. Cyclooxygenase-2 inhibition and renal function. Ann Intern Med 2001; 134: 1077. 102. Alkhuja S, Menkel RA, Alwarshetty M, Ibrahimbacha AM. Celecoxib-induced nonoliguric acute renal failure. Ann Pharmacother 2002; 36: 52–4. 103. Gill S, Hermolin RH. Case report of a Stevens–Johnson type reaction to celecoxib. Can J Hosp Pharm 2001; 54: 146. 104. Fye KH, Crowley E, Berger TG, LeBoit PE, Connolly MK. Celecoxib-induced Sweet’s syndrome. J Am Acad Dermatol 2001; 45: 300–2. 105. Fisher AA, Le Couteur DG. Intracerebral hemorrhage following possible interaction between celecoxib and clopidogrel. Ann Pharmacother 2001; 35: 1567–9. 106. Irish Medicines Board. Clopidogrel (Plavix). Newsletter National Pharmacovigilance Center 2001; Sep: 2–3. 107. Cheer SM, Goa KL. Parecoxib (parecoxib sodium). Drugs 2001; 61: 1133–41. 108. Karim A, Laurent A, Slater ME, Kuss ME, Qian J, Crosby-Sessoms BA, Hubbard RC. A pharmacokinetic study of intramuscular (IM) parecoxib sodium in normal subjects. J Clin Pharmacol 2001; 41: 1111–19. 109. Daniels SE, Grossman EH, Kuss ME, Talwalker S, Hubbard RC. A double-blind, randomised comparison of intramuscularly and intravenously administered parecoxib sodium versus ketorolac and placebo in a post-oral surgery pain model. Clin Ther 2001; 23: 1018–31. 110. Stoltz RR, Harris SI, Kuss ME, LeCompte D, Talwalker S, Dhadda S, Hubbard RC. Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects. Am J Gastroenterol 2002; 97: 65–71. 111. Harris SI, Kuss M, Hubbard RC, Goldstein JL. Upper gastrointestinal safety evaluation of pare-

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coxib sodium, a new parenteral cyclooxygenase2-specific inhibitor, compared with ketorolac, naproxen, and placebo. Clin Ther 2001; 23: 1422–8. 112. Barclay L. Aseptic meningitis cases linked to rofecoxib. Arch Intern Med 2002; 162: 713–15. 113. Woywodt A, Schwarz A, Mengel M, Haller H, Zeidler H, Kohler L. Nephrotoxicity of selective COX-2 inhibitors. J Rheumatol 2001; 28: 2133–5. 114. Ofran Y, Bursztyn M, Ackerman Z. Rofecoxib-induced renal dysfunction in a patient with compensated cirrhosis and heart failure. Am J Gastroenterol 2001; 96: 1941. 115. Wahba AL, Soper C. Acute, anuric renal failure associated with two doses of a cyclooxygenase 2-inhibitor. Nephron 2001; 89: 239. 116. Meador R, Kolasinski S. Acute renal failure can occur with inappropriate use of a coxib. J Clin Rheumatol 2001; 7: 413–14. 117. Rocha JL, Fernandez-Alonso J. Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 2001; 357: 1946–7. 118. Demke D, Zhao S, Arellano RM. Interstitial nephritis associated with celecoxib. Lancet 2001; 358: 1726–7. 119. Schwartz JI, Agrawal NGB, Wong PH, Bachmann KA, Porras AG, Miller JL, Ebel DL, Sack MR, Holmes GB, Redfern JS, Gertz BJ. Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients. J Clin Pharmacol 2001; 41: 1120–30. 120. Anonymous. Interaction of rofecoxib with warfarin. Aust Adv Drug React Bull 2002; 21 (Feb): 3. 121. Stading JA, Skrabal MZ, Faulkner MA. Seven cases of interaction between warfarin and cyclooxygenase-2 inhibitors. Am J Health-Syst Pharm 2001; 58: 2076–80. 122. Sbeit W, Krivoy N, Shiller M, Farah R, Cohen HI, Struminger L, Reshe R. Nimesulide-induced acute hepatitis. Ann Pharmacother 2001; 35: 1049– 52. 123. Dumortier J, Borel I, Delafosse B, Vial T, Scoazed JY, Boillot O. Subfulminant hepatitis associated with nimesulide treatment requiring liver transplantation. Gastroenterol Clin Biol 2002; 26: 415–16. 124. Ferreiro C, Vivas S, Jorquera F, Dominguez AB, Espinel J, Munoz F, Herrera A, Fernandez MJ, Olcoz JL, Ortiz de Urbina J. Toxic hepatitis caused by nimesulide, presentation of a new case and review of the literature. Gastroenterol Hepatol 2000; 23: 428–30. 125. Macia MA, Carvajal A, Del Pozo JG, Vera E, Del Pino A. Hepatotoxicity associated with nimesulide: data from the Spanish Pharmacovigilance System. Clin Pharmacol Ther 2002; 72: 596–7. 126. Rodrigo L, de Francisco R, Perez-Pariente JM, Cadahia V, Tojo R, Rodriguez M, Lucena MI, Andrade RJ. Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation. Scand J Gastroenterol 2002; 37: 1341–3.

130 127. Merlani G, Fox M, Oehen HP, Cathomas G, Renner EL, Fattinger K, Schneemann M, KullakUblick GA. Fatal hepatotoxicity secondary to nimesulide. Eur J Clin Pharmacol 2001; 57: 321–6. 128. Boelsterli UA. Mechanisms of NSAIDinduced hepatotoxicity: focus on nimesulide. Drug Saf 2002; 25: 633–48. 129. Rainsford KD. Relationship of nimesulide safety to its pharmacokinetics: assessment of ad-

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verse reactions. Rheumatology (Oxford) 1999; 38: 4–10. 130. Greenberg LE, Nguyen T, Miller SM. Suspected allopurinol-induced aseptic meningitis. Pharmacotherapy 2001; 21: 1007–9. 131. Fam AG, Dunne SM, Iazzetta J, Paton TW. Efficacy and safety of desensitisation to allopurinol following cutaneous reactions. Arthritis Rheum 2001; 44: 231–8.

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10

General anesthetics and therapeutic gases

GENERAL TOPICS In a Canadian multicenter, open, randomized trial in 156 patients to determine whether sedation with propofol would lead to shorter times to tracheal extubation and length of stay in ICU than sedation with midazolam, the patients who received propofol spent longer at the target sedation level than those who received midazolam (60% vs 44% respectively) (1C ). Propofol allowed clinically significantly earlier tracheal extubation than midazolam (6.7 vs 24.7 hours). However, this did not result in earlier discharge from the ICU. Nervous system Hypertension and tachycardia during coronary angiography can cause significant problems. In a double-blind, randomized, placebo-controlled study during coronary angiography in 90 patients, midazolam with or without fentanyl under local anesthesia provided better hemodynamic stability than placebo (2C ). Clinical electrophysiological procedures can be very complex and prolonged, requiring safe and effective conscious sedation. A study in 700 patients has shown that intermittent midazolam plus fentanyl in electrophysiological procedures is safe and efficacious (3C ). All the staff were ACLS certified and had successfully completed conscious sedation training courses, but none was an anesthetist; one team member was dedicated to monitoring conscious sedation and providing rescue defibrillation if required. Gastrointestinal Several small clinical trials have suggested that total intravenous anesthesia with propofol reduces the incidence of postoperative nausea and vomiting and results in © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

shorter emergence times. However, a systematic review (4M ) and a meta-analysis (5M ) have shown that most studies were small, did not have follow-up for more than 6 hours postoperatively, and were sponsored by industry. The results were difficult to combine owing to heterogeneous definitions of postoperative nausea and vomiting. The risk of postoperative nausea and vomiting has been studied in a randomized, controlled trial of total intravenous anesthesia with propofol versus inhalational anesthesia with isoflurane and nitrous oxide in 2010 patients (6C ). It was accompanied by an economic analysis. Propofol total intravenous anesthesia reduced the absolute risk of postoperative nausea and vomiting up to 72 hours postoperatively from 61% to 46%, in in-patients (NNT = 6) and from 46% to 28%, in out-patients (NNT = 5). Both anesthetic techniques were otherwise similar. Anesthesia drug costs were more than three times higher for propofol total intravenous anesthesia (as propofol is substantially more expensive than isoflurane–nitrous oxide). However, the patients preferred propofol. Middle ear surgery is associated with high rates of postoperative nausea and vomiting. Propofol in subhypnotic doses is a potent antiemetic. In a double-blind, randomized study a small dose of propofol (0.5 mg/kg) was compared with droperidol (20 µg/kg) or metoclopramide (0.2 mg/kg) given at the completion of surgery performed in 90 patients under standard anesthesia with thiopental, fentanyl, and sevoflurane (7C ). Follow up was to 24 hours. The incidence of emesis at 24 hours was significantly lower in those who received propofol (10% vs 33% and 40% for droperidol and metoclopramide respectively). Because population measures of anesthetic dosages do not consider the individual’s anesthetic needs, anesthetists often err on the side

131

132 of relative overdosage during balanced anesthesia, in order to prevent the devastating consequences of unintentional awareness during surgery. This excessive depth of anesthesia contributes to delayed recovery and more adverse effects, which is particularly important in ambulatory surgery. Monitoring of the bispectral index-processed electroencephalogram has enabled anesthetists to monitor the depth of anesthesia and has brought greater precision to the administration of intravenous and inhaled anesthetics and opioids. The hypothesis that titration of the maintenance dose of sevoflurane during out-patient gynecological surgery using bispectral index monitoring reduces postoperative vomiting and improves recovery has been tested in a randomized, controlled study in 22 patients (8C ). The monitored patients had significantly less vomiting than the controls (16% versus 40%).

ANESTHETIC VAPORS

(SED-14, 318; SEDA-23, 126; SEDA-24, 128; SEDA-25, 139)

Halothane Nervous system The effect of increasing and decreasing concentrations of halothane on the cerebral circulation in 11 young children (aged 4 months to 3.5 years) undergoing minor urological surgery under general relaxant and caudal anesthesia has been studied (9c ). Cerebral blood flow velocity was measured in the middle cerebral artery using transcranial Doppler ultrasound. There was significantly increased cerebral blood flow velocity when the dose was increased from 0.5 to 1.0 minimum alveolar concentration (MAC) and from 0.5 to 1.5 MAC, but not when it was increased from 1.0 to 1.5 MAC. When the halothane concentration was reduced from 1.5 to 1.0 MAC cerebral blood flow velocity fell significantly, whereas there was no effect when the concentration was reduced from 1.0 to 0.5 MAC. These results suggest that there is cerebrovascular hysteresis in response to increasing and decreasing concentrations of halothane. Further comparative studies with sevoflurane are recommended.

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Sevoflurane Cardiovascular Congenital or acquired forms of the long QT syndrome can result in ventricular tachycardia (torsade de pointes). Many drugs, including inhalational anesthetics, alter the QT interval, and sevoflurane prolongs the rate-corrected QT interval (QTc ). In a randomized study of whether sevoflurane-associated QTc prolongation was rapidly reversed when propofol was used instead, 32 patients were randomly allocated to one of two groups (10c ). All received sevoflurane induction and maintenance for the first 15 minutes. In one group, sevoflurane was then withdrawn, and anesthesia was maintained with propofol for another 15 minutes; the other group continued to receive sevoflurane for 30 minutes. Sevofluraneassociated QTc prolongation was fully reversed within 15 minutes when propofol was substituted. Respiratory Inhalational induction of anesthesia is common in children. Sevoflurane is pleasant to breathe and has a rapid onset and offset of action and is challenging the tradition of halothane induction in children. Deep anesthesia with sevoflurane can be obtained rapidly, and recovery is also faster than with halothane. In a randomized study of the respiratory effects of high concentrations of halothane and sevoflurane in 21 healthy boys undergoing inguinal or penile surgery, there was similar respiratory depression with each agent (11C ). Minute ventilation fell by about 50% as a result of a reduction in tidal volume, despite an increase in respiratory rate. Nervous system Convulsions during anesthesia are of concern, because they can be masked by muscle relaxants. They can also cause postoperative delirium. Sevoflurane can cause epileptiform activity on the electroencephalogram, especially during emergence from anesthesia. It has also been associated with epileptiform discharges in volunteer studies, but convulsions appear to be very rare. Epileptiform activity has been reported during sevoflurane anesthesia, but not with propofol in the same individual (12A ). • A 62-year-old woman with no personal or family history of seizures had general relaxant anesthesia for plastic surgery using a total intravenous

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anesthetic technique with propofol, remifentanil, and cisatracurium, after benzodiazepine premedication. Routine EEG monitoring showed continuous slowing followed by burst suppression (consistent with very deep anesthesia), but no epileptiform activity. At a second procedure, and following identical benzodiazepine premedication and induction with propofol, anesthesia was maintained with sevoflurane (plus remifentanil for analgesia and cisatracurium for neuromuscular blockade). During the procedure, sevoflurane was increased from 2 to 8%. After 5 minutes, at an end-tidal concentration of 5.9%, there was epileptiform activity on the EEG. There were no hemodynamic changes.

Epileptiform activity on the electroencephalogram in association with sevoflurane induction has also been reported in a prospective study of 20 non-premedicated healthy children in whom EEG monitoring was started before sevoflurane induction (13c ). At 2 MAC there was epileptiform activity in two boys, with spontaneously resolving myoclonic movements. These cases show that clinicians need to be aware of the possibility of generalized seizures, especially in patients who are predisposed to seizures. Psychiatric Sevoflurane often causes postoperative delirium and agitation in children, and this may be severe. The effect of intravenous clonidine 2 µg/kg on the incidence and severity of postoperative agitation has been assessed in a double-blind, randomized, placebo-controlled trial in 40 boys who had anesthetic induction with sevoflurane after oral midazolam premedication (14C ). There was agitation in 16 of those who received placebo and two of those who received clonidine; the agitation was severe in six of those given placebo and none of those given clonidine. The effect of a single bolus dose of midazolam before the end of sevoflurane anesthesia has been investigated in a double-blind, randomized, placebo-controlled trial in 40 children aged 2–7 years (15C ). Midazolam significantly reduced the incidence of delirium after anesthesia. However, when it was used for severe agitation midazolam only reduced the severity without abolishing agitation. The authors concluded that midazolam attenuates, but does not abolish agitation after sevoflurane anesthesia. Liver and urinary tract Debate still surrounds the effect of sevoflurane on perioperative renal and liver function. Renal impairment

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often follows cardiac surgery, but in a randomized trial in elective coronary artery surgery in 354 patients sevoflurane did not produce greater increases in serum creatinine concentrations than isoflurane or propofol (16C ). It has been suggested that prolonged lowflow closed-circuit anesthesia with sevoflurane may maximize exposure to the haloalkene degradation product Compound A, which causes nephrotoxicity and hepatotoxicity in rats, particularly if barium hydroxide lime is used. In a randomized study of the renal and hepatic effects of prolonged low-flow anesthesia with sevoflurane or isoflurane in patients undergoing prolonged operations (over 8 h), using a technique that maximized Compound A production, there were no significant differences between the groups in serum creatinine or urea concentrations, creatinine clearance, or urinary protein or glucose excretion at 24 or 72 h (17C ). Proteinuria and glycosuria were common in both groups. There was no correlation between exposure to Compound A and any measure of renal function. There were no differences in markers of hepatocellular injury. There was no evidence of nephrotoxicity of sevoflurane even at high degrees of exposure to Compound A for as long as 17 h. The effect on renal function of minimalflow (as opposed to low-flow) anesthesia with sevoflurane and isoflurane has been examined in another randomized trial in 76 patients (18C ). There were no significant differences between the groups in blood chemistry markers of renal or hepatic function or in urinary markers of tubular injury, despite high exposure to Compound A in the patients who received sevoflurane. Plasma alpha-glutathione S-transferase activity (α-GT) is a more sensitive and specific marker of hepatocellular injury than aminotransferase activity and it correlates better with hepatic histology. Anesthesia with halothane leads to transiently raised α-GT activity, but propofol and isoflurane do not. In a randomized study of plasma α-GT activity during and after low-flow anesthesia with sevoflurane or isoflurane there were no significant differences in α-GT activities between the two groups during or after anesthesia (19C ). Thus, the evidence suggests that sevoflurane is as safe as isoflurane in low-flow anesthesia with respect to renal and liver dysfunction.

134 Urinary tract Sevoflurane may contribute to the development of renal insufficiency, perhaps due to toxicity from either the haloalkene degradation product Compound A or inorganic fluoride ions. Compound A is produced in carbon dioxide absorbers (soda lime and barium hydroxide lime in particular) and is nephrotoxic in rats but not humans. Fluoride ions are produced through metabolism of sevoflurane and can reach high concentrations after prolonged anesthesia. • Transient renal tubular dysfunction has been reported in a patient with asthma requiring mechanical ventilation who received sevoflurane for 9 days (20A ). Soda lime was not used, and the cumulative dose was 298 MAC-hours. Serum and urinary inorganic fluoride concentrations reached maximum concentrations of 71 and 2047 µmol/l respectively. Markers of renal tubular injury were also greatly raised (urinary N-acetyl-b-D-glucosaminidase and b2 -microglobulin). However, urine volume, creatinine clearance, and serum creatinine and urea concentrations were unaffected.

Musculoskeletal Malignant hyperthermia triggered by sevoflurane has been reported in two cases (21A , 22A ). The second case was remarkable, in that the specific treatment dantrolene was not available, and yet the patient survived with aggressive active cooling and general supportive measures, including sodium bicarbonate. Drug interactions Ketorolac, which can cause renal vasoconstriction by inhibiting cyclo-oxygenase, is often given to patients anesthetized with sevoflurane, which is also potentially nephrotoxic. The effect of ketorolac has been assessed in a placebo-controlled randomized study in 30 women undergoing breast surgery with sevoflurane anesthesia (23C ). There were no differences in several markers of renal injury in those who did or did not receive ketorolac. The effect of the uricosuric agent probenecid in prolonged sevoflurane anesthesia has been examined in 64 patients randomized to receive high-flow or low-flow anesthesia with sevoflurane with or without preoperative oral probenecid (24C ). There were no differences in urea, creatinine, or creatinine clearance among the treatments. However, patients who received low-flow sevoflurane had some evidence of renal tubular injury (raised urinary markers) compared with those who received either high-flow anesthesia or probenecid.

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Trichloroethylene Carcinogenicity The incidence of cancer among 803 Danish workers exposed to trichloroethylene has been evaluated (25c ). There was no overall increase. However, the standardized incidence ratio was significantly higher in men with non-Hodgkin’s lymphoma or esophageal cancer and in women with cervical cancer. The carcinogenic association was not dose related.

NITROUS OXIDE

(SED-14, 325; SEDA-23, 129; SEDA-24, 132; SEDA-25, 142) Cardiovascular Nitrous oxide inhibits methionine synthase, thereby preventing the conversion of homocysteine to methionine. A high homocysteine concentration has been identified as an independent risk factor for coronary artery, cerebrovascular, peripheral vascular, and venous thromboembolic disease. The effect of nitrous oxide on homocysteine concentrations and perioperative myocardial ischemia/infarction has been extensively reviewed (26R ). Nitrous oxide causes acute rises in postoperative homocysteine concentrations temporally associated with postoperative myocardial ischemia. Preoperative oral folate and vitamins B6 and B12 blunt nitrous oxideinduced postoperative increases in plasma homocysteine (27c ). Nervous system Two cases of polyneuropathy and myelopathy associated with chronic nitrous oxide abuse have been reported (28A , 29A ). Teratogenicity The teratogenicity of nitrous oxide has been extensively reviewed (30R ). Nitrous oxide is the only inhalational anesthetic that has definitely been shown to be teratogenic in experimental animals, but epidemiological studies have suggested that it is not teratogenic in humans.

XENON Xenon anesthesia has been reviewed (31R ). Xenon is receiving renewed interest, because it

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has many characteristics of the ideal anesthetic. In addition to its lack of effects on the cardiovascular system, it has low solubility, enabling faster induction of and emergence from anesthesia. Although its high cost limits its use, the development of closed rebreathing systems has led to further interest. A European multicenter trial is under way.

INTRAVENOUS AGENTS MISCELLANEOUS NON-BARBITURATE ANESTHETICS Ketamine (SED-14, 329; SEDA-23, 130; SEDA-24, 134; SEDA-25, 143) Nervous system There have been several attempts to understand the pathophysiology of schizophrenia using subanesthetic doses of ketamine to probe glutaminergic function in healthy and schizophrenic volunteers; no longterm adverse consequences were attributable to ketamine (32C ). Endocrine In a double-blind, randomized, placebo-controlled comparison of the effects of ketamine and memantine in 15 male volunteers in a three-way crossover trial ketamine increased serum prolactin and cortisol concentrations, whereas memantine and placebo did not (33C ).

Etomidate

(SED-14, 329; SEDA-23, 130)

Endocrine Adrenocortical function has been assessed in a randomized trial after intravenous etomidate in 30 patients who required rapid-sequence induction and tracheal intubation (34C ). The controls received midazolam. Etomidate caused adrenocortical dysfunction, which resolved after 12 hours. Hematologic Platelet hyperaggregablity after general anesthesia has been reported in patients undergoing vascular surgery. The effect of etomidate and thiopental on platelet function has now been examined in 46 patients undergoing

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infrainguinal vascular surgery (35C ). Etomidate caused significant platelet inhibitory effects, whereas the effects of thiopental were minor. This may affect the choice of anesthetic in patients with compromised hemostasis. Immunologic Two cases of anaphylactoid reactions to etomidate have been reported (36A ). The first patient also had a myocardial infarction. Both incidents were successfully managed with intravenous adrenaline and fluids.

Propofol

(SED-14, 330; SEDA-23, 132; SEDA-24, 135; SEDA-25, 144) Cardiovascular The cardiovascular effects of propofol 2.5 mg/kg have been examined a randomized study in 40 healthy subjects using transthoracic echocardiography (37C ). In both groups, global and segmental ventricular function was unchanged, but there was markedly reduced end-systolic quotients, presumably related to reduced afterload. With the higher infusion rate there was a significant reduction in fractional shortening, thought to be related principally to reduced preload. Respiratory Two cases of propofol induced bronchconstriction have been reported (38A ). Both patients had allergic rhinitis and had taken antihistamines during the spring, but were otherwise healthy.

Nervous system A generalized tonic–clonic seizure has been attributed to propofol in a patient with tonic–clonic seizures after surgery for subarachnoid hemorrhage (39A ).

Propofol-infusion syndrome The propofol-infusion syndrome consists of a metabolic acidosis, rhabdomyolysis, and cardiovascular collapse. It occurs after prolonged infusion of propofol (over 48 hours) and has generally been reported in children but also occasionally in adults. Propofol-infusion syndrome mimics the mitochondrial myopathies, in which there are

136 specific defects in the mitochondrial respiratory chain. The clinical features of mitochondrial myopathy result from a disturbance in lipid metabolism in cardiac and skeletal muscle. These patients generally remain well until stressed by infection or starvation, although subclinical biochemical abnormalities of mitochondrial transport can be demonstrated. It has been suggested that early management of critically ill children may not include adequate calorific intake to balance the increase in metabolic demands, and that in susceptible children the diversion of metabolism to fat substrates may cause the propofol-infusion syndrome. It is unclear if the dose or duration of propofol infusion alters this effect. As adults have larger carbohydrate stores and require lower doses of propofol for sedation, this may account for the relative rarity of the syndrome in adults. The authors suggested that adequate early carbohydrate intake may prevent the propofol-infusion syndrome (40AR ). Five adults with head injuries inexplicably had fatal cardiac arrests in a neurosurgical intensive care unit after the introduction of a sedation formulation containing an increased concentration of propofol (41A ). There were striking similarities with the previously reported syndrome of myocardial failure, metabolic acidosis, and rhabdomyolysis in children who received high-dose propofol infusions for more than 48 hours. In a subsequent retrospective cohort analysis the odds ratio for the propofol-infusion syndrome was 1.93 (95% CI = 1.12, 3.32) for every 1 mg/kg/h increase in mean propofol dose above 5 mg/kg/h. The authors suggested that propofol infusion at rates over 5 mg/kg/h should be discouraged for longterm sedation. Reports of the propofol-infusion syndrome in children have continued to appear. • A 13-year-old girl with a head injury who received a high-dose infusion of propofol for 4 days developed the propofol-infusion syndrome (42A ). In an accompanying editorial aspects of the propofolinfusion syndrome were reviewed and the author suggested that prolonged high-dose propofol infusions (over 4.8–6.0 mg/kg/hr for over 48–72 hours) should be avoided and that if high-dose metabolic suppression is required for more than 3 days in head injury, the alternative of a barbiturate should be considered (43r ). However, these long-acting agents have well known potent myocardial depressant effects of their own, which are difficult to manage.

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• A 2-year-old boy with a gunshot head injury developed the propofol-infusion syndrome after receiving propofol in an average dosage of 5.2 mg/kg/h for 72 hours (40AR ). On the fourth day he became oliguric, with raised potassium, urea, and creatinine concentrations, and then developed a nodal bradycardia (28 beats/min). Propofol was withdrawn and an isoprenaline infusion was started, but only emergency transvenous pacing restored his heart rate. Hemofiltration was begun on the basis of another case report, and the acidosis cleared and cardiovascular function was restored. In a blood sample taken before hemofiltration malonylcarnitine, C5-acylcarnitine, creatine kinase, troponin T, and myoglobinemia were raised. The child made a complete recovery and 9 months later all markers of fatty-acid oxidation were normal.

These findings are consistent with impaired fatty-acid oxidation: reduced mitochondrial entry of long-chain acylcarnitine esters due to inhibition of the transport protein (carnitine palmityl transferase 1) and failure of the respiratory chain at complex II. Another previously reported abnormality of the respiratory chain in propofol-infusion syndrome is a reduction in cytochrome C oxidase activity, with reduced complex IV activity and a reduced cytochrome oxidase ratio of 0.004. Propofol can also impair the mitochondrial electron transport system in isolated heart preparations. Liver Hepatocellular injury has been reported after the sole use of propofol for outpatient anesthesia (44A ). • A young woman with multiple allergies underwent femoral hernia repair and the next day developed acute hepatitis, with severe nausea and vomiting and diffuse abdominal tenderness. She had very high transaminase activities and the prothrombin time was slightly raised. No viral cause could be demonstrated. Antinuclear antibody and smooth muscle antibody titers were not raised and the ceruloplasmin concentration was normal. Abdominal ultrasound did not show gallstones or any other abnormality. The urine was normal and there was no evidence of porphyrins or porphobilinogen. She recovered spontaneously and refused liver biopsy.

Pancreas Acute pancreatitis has been attributed to propofol (45A ). • A healthy 35-year-old man developed acute pancreatitis a few hours after receiving a 15-minute propofol anesthetic for laser treatment of a urethral stricture. He spent 3 weeks in an intensive care unit, requiring both respiratory and renal support. There was no evidence of gallstones on abdominal imaging. There was no defect of lipid metabolism.

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BENZODIAZEPINES

(SED-14, 327; SEDA-23, 131; SEDA-24, 133; SEDA-25, 145; see also Chapter 5)

Diazepam Nervous system Severe and prolonged sedation has been reported in five neonates in a neonatal ICU, due to persistence of diazepam metabolites (46A ). The persistence of the very long acting metabolite of diazepam, Ndesmethyldiazepam, in full-term and preterm neonates, due to reduced capacity of the hepatic microsomal enzyme uridine diphosphate glucuronyl transferase, appears to have been responsible for the severe prolonged sedation.

Midazolam Cardiovascular The incidence of hypotension with the use of midazolam for pre-hospital rapid-sequence intubation of the trachea has been assessed in a retrospective chart review (47c ). The rapid-sequence protocols for the two aeromedical crews who serviced the authors’ region were identical, except for the dose of midazolam. The northern crews used 0.1 mg/kg for all patients without a maximum dose and the southern crews used 0.1 mg/kg up to a maximum dose of 5 mg. This meant that of patients over 50 kg, those from the north received higher doses of midazolam; they also had a higher incidence of hypotension. This relation was also present in patients with traumatic brain injury,

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thus potentially compromising cerebral perfusion at a critical time. Nervous system Midazolam can cause paradoxical reactions, including increased agitation, poor co-operation, and aggressive or violent behavior. Often other drugs are required to continue the procedure successfully. Reversal by flumazenil, a benzodiazepine antagonist, has been reported in a cohort study of 58 patients undergoing surgery under spinal or epidural anesthesia (48c ). Flumazenil 0.1 mg over 10 s abolished the agitation without reversing sedation (total dose range 0.1–0.5 mg). Adverse effects of flumazenil were not reported. Care must be taken when considering flumazenil for reversal of midazolam-induced agitation, as these data are anecdotal and no controlled trials have been published. Myoclonic-like movements associated with midazolam in three full-term newborns were reversed by flumazenil (49A ). Further studies are recommended to provide guidelines. Temperature regulation Midazolam premedication caused exaggerated perioperative hypothermia in 15 elderly surgical patients compared with 15 young patients (50c ). The same group also showed that atropine prevents midazolam-induced core hypothermia in 40 elderly patients (51c ). The thermoregulatory effects of benzodiazepine agonists and cholinergic inhibitors oppose each other, and the combination leaves core temperature unchanged.

REFERENCES 1. Hall RI, Sandham D, Cardinal P, Tweedale M, Moher D, Wang X. Propofol vs midazolam for ICU sedation: a Canadian multicenter randomised trial. Chest 2001; 119: 1151–9. 2. Baris S, Karakaya D, Aykent R, Kirdar K, Sagkan O, Tur A. Comparison of midazolam with or without fentanyl for conscious sedation and haemodynamics in coronary angiography. Can J Cardiol 2001; 17: 277–81. 3. Pachulski RT, Adkins DC, Mirza H. Conscious sedation with intermittent midazolam and fentanyl in electrophysiology procedures. J Intervent Cardiol 2001; 14: 143–6.

4. Tramer M, Moore A, McQuay H. Propofol anaesthesia and postoperative nausea and vomiting: Quantitative systematic review of randomised controlled trials. Br J Anaesth 1997; 78: 247–55. 5. Sneyd JR, Carr A, Byrom WD, Bilski AJ. A meta-analysis of nausea and vomiting following maintenance of anaesthesia with propofol or inhalational agents. Eur J Anaesth 1998; 15: 433–45. 6. Visser K, Hassink EA, Bonsel GJ, Moen J, Kalkman CJ. Randomized controlled trial of total intravenous anesthesia with propofol versus inhalational anesthesia with isoflurane–nitrous oxide. Anesthesiology 2001; 95: 616–26.

138 7. Fujii Y, Tanaka H, Kobayashi N. Prevention of postoperative nausea and vomiting with antiemetics in patients undergoing middle ear surgery: comparison of a small dose of propofol with droperidol or metoclopramide. Arch Otolaryngol Head Neck Surg 2001; 127: 25–8. 8. Nelskyla KA, Yli-Hankala AM, Puro PH, Kortilla KT. Sevoflurane titration using bispectral index decreases postoperative vomiting in phase II recovery after ambulatory surgery. Anesth Analg 2001; 93: 1165–9. 9. Paut O, Bissonnett B. Effect of halothane on the cerebral circulation in young children: a hysteresis phenomenon. Anaesthesia 2001; 56: 360–5. 10. Kleinsasser A, Loekinger A, Lidner KH, Keller C, Boehler M, Puehringer F. Reversing sevofluraneassociated Q-Tc prolongation by changing to propofol. Anaesthesia 2001; 56: 248–50. 11. Walpole R, Olday J, Haetzman M, Drummond GB, Doyle E. A comparison of the respiratory effects of high concentrations of halothane and sevoflurane. Paediatr Anaesth 2001; 11: 157–60. 12. Schultz B, Schultz A, Grouven U, Korsch G. Epileptiform EEG activity: occurrence under sevoflurane and not during propofol application. Anaesthetist 2001; 50: 43–5. 13. Conreux F, Best O, Preckel MP, Lhopitault C, Beydon L, Pouplard F, Granry JC. Electroencephalographic effects of sevoflurane in paediatric anaesthesia: a prospective study of 20 cases. Ann Fr Anesth Réanim 2001; 20: 438–45. 14. Kulka PJ, Bressem M, Tryba M. Clonidine prevents sevoflurane-induced agitation in children. Anesth Analg 2001; 93: 335–8. 15. Kulka PJ, Bressem M, Wiebalck A, Tryba M. Midazolam prophylaxis for post-sevoflurane agitation. Anaesthetist 2001; 50: 401–5. 16. Story DA, Poustie S, Liu G, McNicol PL. Changes in plasma creatinine concentration after cardiac anesthesia with isoflurane, propofol, or sevoflurane: a randomised clinical trial. Anesthesiology 2001; 95: 842–8. 17. Kharasch ED, Frink EJ Jr, Artru A, Michalowski P, Rooke AG, Nogami W. Longduration low-flow sevoflurane and isoflurane effects on postoperative renal and hepatic function. Anesth Analg 2001; 93: 1511–20. 18. Goeters C, Reinhardt C, Gronau E, Wusten R, Prien T, Baum Jvrana S, Van Aken H. Minimal flow sevoflurane and isoflurane anaesthesia and impact on renal function. Eur J Anaesthesiol 2001; 18: 43–50. 19. Higuchi H, Adachi Y, Wada H, Kanno M, Satoh T. Comparison of plasma alpha glutathione transferase concentrations during and after low-flow sevoflurane or isoflurane anaesthesia. Acta Anaesthesiol Scand 2001; 45: 1226–9. 20. Ishikawa M, Miyazaki M, Ohta Y. Transient renal tubular dysfunction in a patient with severe asthmatic attack treated with sevoflurane. J Anesth 2001; 15: 49–52. 21. Massaro F, De Klerk DYJ, Snoeck MMJ. A case of malignant hyperthermia during use of sevoflurane. Ned Tijdschr Anesthesiol 2001; 14: 71–3.

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22. Baris S, Karakaya D, Guldogus F, Sarihasan B, Tekat A. A case of malignant hyperthermia during sevoflurane anesthesia. Turk J Med Sci 2001; 31: 171–3. 23. Laisalmi M, Eriksson H, Koivusalo A-M, Pere P, Rosenberg P, Lindgren L. Ketorolac is not nephrotoxic in connection with sevoflurane anesthesia in patients undergoing breast surgery. Anesth Analg 2001; 92: 1058–63. 24. Higuchi H, Wada H, Usui Y, Goto K, Kanno M, Satoh T. Effects of probenecid on renal function in surgical patients anesthetized with sevoflurane. Anesthesiology 2001; 94: 21–31. 25. Hansen J, Raaschou-Nielsen O, Christensen JM, Johansen I, McLaughlin JK, Lipworth L, Blot WJ, Olsen JH. Cancer incidence among Danish workers exposed to trichloroethylene. J Occup Environ Med 2001; 43: 133–9. 26. Badner NH, Spence JD. Homocyst(e)ine, nitrous oxide and atherosclerosis. Ballière’s Best Pract Res Clin Anesthesiol 2001; 15: 185–93. 27. Badner NH, Freeman D, Spence JD. Preoperative oral B vitamins prevent nitrous oxideinduced postoperative plasma homocysteine increases. Anesth Analg 2001; 93: 1507–10. 28. Iwata K, O’Keefe GB, Karanas A. Neurologic problems associated with chronic nitrous oxide abuse in a non-healthcare worker. Am J Med Sci 2001; 322: 173–4. 29. Eichorn M, Watson M, Wurst F. Polyneuropathy and myelopathy after nitrous oxide abuse. Psychiatr Prax 2001; 28: 204–5. 30. Fujinaga M. Teratogenicity of nitrous oxide. Ballière’s Best Pract Res Clin Anesthesiol 2001; 15: 363–75. 31. Leclerc J, Nieuviarts R, Tavernier B, Vallet B, Schpereel P. Xenon anaesthesia: from myth to reality. Ann Fr Anesth Réanim 2001; 20: 70–6. 32. Lahti AC, Warfel D, Michaelidis T, Weiler MA, Frey K, Tamminga C. Long term outcome of patients who receive ketamine in research. Biol Psychiatry 2001; 49: 869–75. 33. Hergovich N, Singer E, Agneter E, Eichler HG, Graselli U, Simhandl C, Jilma B. Comparison of the effects of ketamine and memantine on prolactine and cortisol release in men: a randomised doubleblind placebo-controlled trial. Neuropsychopharmacology 2001; 24: 590–3. 34. Schenarts CL, Burton JH, Riker RR. Adrenocortical dysfunction following etomidate induction in emergency department patients. Acad Emerg Med 2001; 8: 1–7. 35. Gries A, Weis S, Herr A, Graf BM, Seelos R, Martin E, Bohrer H. Etomidate and thiopental inhibit platelet function in patients undergoing infrainguinal vascular surgery. Acta Anaesthesiol Scand 2001; 45: 449–57. 36. Moorthy SS, Laurent B, Pandya P, Fry V. Anaphylactoid reaction to etomidate: report of a case. J Clin Anesth 2001; 13: 582–4. 37. Bilotta F, Fiorani L, La Rosa I, Spinelli F, Rosa G. Cardiovascular effects of propofol administered at two infusion rates: a transthoracic echocardiographic study. Anaesthesia 2001; 56: 266–71.

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38. Nishiyama T, Hanaoka K. Propofol induced bronchconstriction: two case reports. Anesth Analg 2001; 93: 645–6. 39. Iwasaki F, Mimura M, Yamazaki Y, Hazama K, Sato Y, Namiki A. Generalized tonic–clonic seizure induced by propofol in a patient with epilepsy. Jpn J Anesthesiol 2001; 50: 168–70. 40. Wolf A, Weir P, Segar P, Stone J, Shield J. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet 2001; 357: 606–7. 41. Cremer OL, Moons KGM, Bouman EAC, Kruijswijk JE, De Smet AMGA, Kalkman C. Long-term propofol infusion and cardiac failure in adult headinjured patients. Lancet 2001; 357: 117–18. 42. Cannon ML, Glazier SS, Bauman LA. Metabolic acidosis, rhabdomyolysis and cardiovascular collapse after prolonged propofol infusion. J Neurosurg 2001; 95: 1053–6. 43. Kelly DF. Propofol-infusion syndrome. J Neurosurg 2001; 95: 925–6. 44. Anand K, Ramsay MA, Crippin JS. Hepatocellular injury following the administration of propofol. Anesthesiology 2001; 95: 1523–4. 45. Betrosian AP, Balla M, Papanikolaou M, Kofinas G, Georgiadis G. Postoperative pancreatitis after propofol administration. Acta Anaesthesiol Scand 2001; 45: 1052.

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46. Peinemann F, Daldrup T. Severe and prolonged sedation in five neonates due to persistence of diazepam metabolites. Eur J Pediatr 2001; 160: 378– 81. 47. Davis DP, Kimbro TA, Vilke GM. The use of midazolam for pre-hospital rapid-sequence intubation may be associated with a dose-related increase in hypotension. Prehosp Emerg Care 2001; 5: 163–8. 48. Weinbroum AA, Szold O, Ogorek D, Flaisshon R. The midazolam-induced paradox phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the literature. Eur J Anaesthesiol 2001; 18: 789–97. 49. Zaw W, Knoppert DC, Da Silva O. Flumazenil’s reversal of myoclonic-like movements associated with midazolam in term newborns. Pharmacotherapy 2001; 21: 642–6. 50. Matsukawa T, Ozaki M, Nishiyama T, Imamura M, Kumazawa T. Exaggerated perioperative hypothermia in elderly surgical patients. Anesth Resusc 2001; 37: 53–7. 51. Matsukawa T, Ozaki M, Nishiyama T, Imamura M, Iwamoto R, Iijima T, Kumazawa T. Atropine prevents midazolam-induced core hypothermia in elderly patients. J Clin Anesth 2001; 13: 504–8.

Stephan A. Schug, Gail Gillespie, and Kathryn J.D. Stannard

11

Local anesthetics

EFFECTS RELATED TO MODES OF USE

they often have concomitant coronary artery disease, hypertension, and diabetes. Brachial plexus block is often used: as well as avoiding systemic effects it enhances regional blood flow. However, high doses of local anesthetic are required, and this block carries one of the highest rates of seizures. In this study, following axillary block with mepivacaine 650 mg, plasma concentrations were greater than the threshold of 6 µg/ml, above which signs of CNS toxicity reportedly occur. The authors suggested that the absence of CNS signs may have been due to slow systemic absorption of the local anesthetic. Peak concentrations occurred after 60–90 min, but were still high at 150 min, raising the question of more prolonged monitoring after these blocks. Horner’s syndrome is a well-recognized complication of interscalene brachial plexus block, stellate ganglion block, and occasionally epidural blockade. It occurs when the local anesthetic reaches the cervical sympathetic trunk and is usually transient. However, persistent Horner’s syndrome is a rare complication, and may represent traumatic interruption of the cervical sympathetic chain. Two cases of prolonged Horner’s syndrome related to prevertebral hematoma formation at the site of continuous interscalene blockade have been described (3A ).

Brachial plexus anesthesia Respiratory Brachial plexus blockade is often used in patients with cardiorespiratory disease undergoing upper limb surgery. However, the procedure carries certain significant risks, one being blockade of the phrenic nerve, resulting in paralysis of the ipsilateral hemidiaphragm. This can rarely cause severe respiratory compromise, depending on pre-existing lung dysfunction. In unpremedicated patients who underwent supraclavicular brachial plexus block for upper limb surgery, blocks were performed using a peripheral nerve stimulator and 0.5 ml/kg of bupivacaine 0.375% (1c ). Spirometric and ultrasonographic assessments of diaphragmatic function were made at intervals. Of 30 patients, 15 had complete paralysis of the hemidiaphragm, five had reduced diaphragmatic movement, and 10 had no change. Those with complete paralysis all had significant reductions in pulmonary function and those with reduced or normal movement had minimal changes. Only one of the patients had respiratory symptoms and the oxygen saturation remained unchanged. This may not be the case, however, in patients with significant pre-existing respiratory disease or in obese people; the authors therefore suggested caution in choosing this approach as a safer alternative to general anesthesia in such individuals. Nervous system Mepivacaine toxicity has been studied in 10 patients with end-stage chronic renal insufficiency undergoing vascular access surgery (2c ). These patients represent a high-risk group for general anesthesia, as © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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• A 48-year-old obese woman had a 22G interscalene catheter inserted under local anesthesia via a short-bevel stimulating needle. Anesthesia was achieved using 0.6% ropivacaine 40 ml followed by an infusion of ropivacaine 0.2% for effective analgesia. On day 3 she reported blurred vision and a painful neck swelling. She had developed a hematoma around the catheter insertion site (confirmed by ultrasound) and had an ipsilateral Horner’s syndrome, including myosis, ptosis, enophthalmos, ipsilateral anhidrosis, and conjunctival hyperemia. • An interscalene catheter was inserted in an awake 20-year-old woman for analgesia after shoulder surgery. Analgesia was achieved with ropivacaine 0.2% as a 30 ml bolus followed by an infusion of the same solution. One day later she had visual

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disturbance and neck swelling, due to a hematoma between the prevertebral and scalene muscles.

Neither patient was taking NSAIDs, aspirin, or anticoagulants. Catheters were removed immediately on diagnosis of hematoma formation. There was no neurological or sympathetic fiber damage to the upper limb in either patient, as tested by electroneuromyography and sympathetic skin response. Remission in both cases occurred within 1 year. There has been one previous report of prolonged Horner’s syndrome in the absence of any obvious technical complication (4A ). Further studies into the use of interscalene catheters are needed to assess their propensity to cause this rare complication. In 60 patients receiving patient-controlled interscalene analgesia with either ropivacaine 0.2% or bupivacaine 0.15%, there was a significant reduction in hand motor function and an increased incidence of paresthesia in the bupivacaine group, with no difference in pain scores (5C ). This finding contrasts with that in a comparison of epidural bupivacaine or ropivacaine, in which there was no difference in motor function between the two groups (6C ).

Caudal, epidural, and spinal anesthesia

(8C ). They randomly received 0.25% bupivacaine 0.5 ml/kg or the same dose of bupivacaine plus midazolam 50 µg/kg. There were no untoward events in either group. Fewer required additional analgesia in the first 6 hours postoperatively in the bupivacaine plus midazolam group than with bupivacaine alone: 27% compared with 60%. Midazolam prolonged analgesia with no increase in adverse effects. Cardiovascular There has been a report of T wave changes on the electrocardiogram during caudal administration of local anesthetics (9A ). • A 4.2 kg 2-month-old baby was given a caudal injection under general anesthesia for an inguinal hernia repair. A mixture of 1% lidocaine 2 ml and 0.25% bupivacaine 2 ml was injected. Every 1 ml was preceded by an aspiration test and followed by 20 s observation for electrocardiographic changes. On administration of the third 1 ml dose, there was a significant increase in T wave amplitude. The aspiration test was repeated and was positive for blood. The caudal injection was stopped and the electrocardiogram returned to normal after 35 s. The patient remained cardiovascularly stable with no postoperative sequelae.

Previous reports have suggested that an increase in T wave amplitude could result from inadvertent intravascular administration of adrenaline-containing local anesthetics. This is the first case report of local anesthetics alone causing a significant T wave changes.

Caudal anesthesia Caudal block with bupivacaine in children provides adequate analgesia in the early postoperative period, but additional analgesia is often required as the block wears off. Two studies have looked at adjuvants to prolong the analgesic effect. The first was a randomized, controlled trial in 60 boys undergoing unilateral herniorrhaphy (7C ). They received 0.25% bupivacaine 1 ml/kg or the same dose of bupivacaine plus 1.5 mg/kg tramadol, or tramadol 1.5 mg/kg alone made up to the same volume. Caudal administration of bupivacaine plus tramadol resulted in more effective analgesia, with a longer period without demand for additional analgesia postoperatively without increases in any adverse effects. The second was a study of the addition of midazolam to caudal bupivacaine in 30 children undergoing genitourinary surgery

Epidural anesthesia Patient-controlled epidural analgesia is increasingly being used, as it reduces the need for adjustment of epidural infusion rates by anesthetic personnel. In a retrospective survey of 1057 patients who received postoperative patientcontrolled epidural analgesia using bupivacaine 0.1% plus fentanyl 5 micrograms/ml, on the first postoperative day 93% of the patients had adequate analgesia and 96% reported no nausea; two patients had an episode of respiratory depression and one patient was unrousable (10C ). Hypotension occurred in 4.3%, but there were no cases of epidural hematoma or abscess. Despite these adverse events, the authors concluded that patient-controlled epidural analgesia was effective and safe on surgical wards.

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The large amount of fentanyl in the solution they used is most probably the reason for the rare, potentially life-threatening adverse effects. The amount of bupivacaine with fentanyl used in patient-controlled epidural analgesia was significantly less than with a continuous infusion of the same mixture in a group of 54 patients (mean age 71 years) after total knee arthroplasty (11C ). However, 10% of the patients were too confused to use the PCEA device. Despite the advantages of analgesic dosage reductions, a constant infusion may prove more appropriate in this age group. Epidural infusions of bupivacaine are often used in children. However, there are concerns about the increased incidence of adverse effects in infants, owing to reduced hepatic clearance and serum protein binding. In 22 infants aged 1–7 months who received a continuous infusion of bupivacaine 0.375 mg/kg/hour for 2 days during and after surgery, the unbound and total serum concentrations of bupivacaine were measured, along with presurgical and postsurgical concentrations of alpha1 acid glycoprotein (12c ). The concentrations of alpha1 acid glycoprotein increased markedly after surgery. However, because of reduced clearance unbound concentrations of bupivacaine increased to over 0.2 µg/ml in two infants younger than 2 months. The authors propose a maximum dosage rate of 0.25 mg/kg/h in infants younger than 4 months and 0.3 mg/kg/h in older infants.

Intrathecal (spinal) anesthesia Nervous system Transient radicular irritation, often also incorrectly named transient neurological syndrome, has been previously reported as varying transient pain or dysesthesia following intrathecal administration of local anesthetics. While lidocaine is generally implicated in its causation, a randomized study with isobaric mepivacaine 2% administered intrathecally to patients undergoing surgery in the supine position recently showed an incidence of 7.5% compared with 2.5% with isobaric lidocaine 2% (13C ). Even bupivacaine and tetracaine have been shown to have toxic effects on chick neuron cultures in vitro (14E ).

Early ambulation has previously been implicated in transient radicular irritation. However, in a randomized trial there was no difference between early and late mobilization in patients who received spinal lidocaine 2% for inguinal hernia repair; the incidence was 23% in both groups (15C ). Procaine has been suggested as an alternative to lidocaine for spinal use in ambulatory surgery, as it also has a short duration of action. In a randomized, double-blind comparison of procaine 10% or lidocaine 5% in glucose 7.5% for spinal anesthesia transient radicular irritation occurred in 27% of the lidocaine group compared with none of the patients in the procaine group (16C ). However, the failure rate in the procaine group was 14%. This was perhaps a reflection of the fact that the procaine was glucose-free, but further studies are required with procaine to evaluate its use in this context. Intrathecal hyperbaric lidocaine 1.5% has been compared with hyperbaric bupivacaine 0.75% for outpatient transvaginal oocyte retrieval (17C ). The time to voiding of urine and the time to discharge were significantly longer in the bupivacaine group, despite the fact that there were no differences in the time to recovery of sensory and motor function. The incidence of transient radicular irritation in the lidocaine group was 5%, compared with none of the women in the bupivacaine group. The authors concluded that bupivacaine was a useful alternative to lidocaine in outpatient spinal anesthesia. There have been two recent studies of transient radicular irritation in the obstetric population. One was a randomized, double-blind comparison of intrathecal hyperbaric lidocaine 5% or bupivacaine 0.75% for postpartum tubal ligation (18C ). All the patients were supine for surgery. The incidence of transient radicular irritation was 3% with lidocaine and 7% with bupivacaine. The other was a prospective follow-up study of patients who had cesarean sections under spinal anesthesia using hyperbaric 0.5% bupivacaine; the incidence of transient radicular irritation was 8.8% (19c ). The addition of vasoconstrictors, such as phenylephrine and adrenaline, has previously been implicated in the causation of transient radicular irritation. However, a randomized study in 64 patients undergoing urological, gynecological, or lower limb surgery showed

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no significant difference in the incidence of transient neurological symptoms between hyperbaric tetracaine 0.5% with and without phenylephrine 0.025% (8C ). In fact, the neurological symptoms that were described (in 6.7% of the patients) occurred in the group without phenylephrine and could possibly have been explained by the patient’s position or by the effects of plaster-cast compression postoperatively. Recent animal studies have highlighted the potential toxic effects of adding adrenaline to local anesthetics for intrathecal injection. In one study the effects of adding 0.01% adrenaline to intrathecal tetracaine 1% and 2% was investigated in rabbits (20E ). Although adrenaline had no neurotoxic effects when given alone, there was worsening of neurotoxicity when it was given in combination with tetracaine. The same group had previously shown an increase in glutamate concentrations in the CSF and dose-dependent neurotoxicity with tetracaine injected intrathecally in rabbits (21E ). In another study they looked at the effects of intrathecal lidocaine 5% with and without adrenaline 0.02% on the spinal cord and nerve roots of rats (21E ). They showed that lidocaine 5% caused persistent sensory impairment and histological damage that was significantly exacerbated by the addition of adrenaline. Several explanations for the increased neurotoxicity of vasoconstrictors in combination with local anesthetics have been offered: • Adrenaline may reduce the absorption of local anesthetics and thereby increase anesthetic exposure intrathecally. • A reduction in blood flow caused by adrenaline may cause ischemia in the spinal cord. • Bisulfite, used as a preservative in adrenaline formulations, has previously been implicated in neurological deficits. It may have a role in the toxicity seen, but that would not explain the lack of toxicity seen with adrenaline alone. Further studies are required to attempt to clarify the cause of transient radicular irritation, in particular as it remains unclear if it is an expression of true neurotoxicity, as observed in these animal experiments. The reasons for these doubts are the temporary nature of the symptoms and the lack of any neurological deficits in patients with transient radicular irritation.

Cauda equina syndrome has previously been described in patients receiving intrathecal hyperbaric lidocaine 5% (SEDA-24, 146). • Cauda equina syndrome occurred in a 55-yearold woman who underwent spinal anesthesia with a 22 g needle in the L4–5 interspace (22A ). On needle insertion, she felt radiating pain in her right leg. The needle was immediately withdrawn and repositioned. Pain-free intrathecal injection of 2.0 ml of hyperbaric dibucaine 0.24% with adrenaline 66 micrograms resulted in block to L1. Surgery was carried out in the supine position. Three days postoperatively, she had enuresis and reduced perineal sensation, without bowel dysfunction or lower limb symptoms. There was sensory loss at S2–S5. The symptoms persisted, required self-catheterization and systemic steroids, and disappeared on the 19th postoperative day.

The cause of this transient neurological deficit was unclear, but the authors suggested that the following factors may have contributed: • direct nerve damage; • local anesthetic toxicity; • adrenaline effects.

Infiltration anesthesia Nervous system Two cases of medullary injury after injections of local anesthetics intraoperatively have been reported (23A ). • A 4-year-old child received injections of lidocaine plus adrenaline into the anterior tonsillar pillars and nasopharynx during adenotonsillectomy. After the procedure he became agitated and dysarthric, vomited, and had abnormal eye movements. He was unable to stand and walk, owing to ataxia. An MRI scan showed a cavity in the right paramedian medulla. • A 7-year-old boy underwent tonsillectomy, with an injection of lidocaine plus adrenaline into the operative field. After surgery he was lethargic, and during the next 24 hours he developed respiratory distress requiring mechanical ventilation. He was pyrexial (41.8◦ C) and had cardiomegaly and a left hemiparesis. A cranial MRI scan showed a hemorrhagic lesion in the right paramedian medulla.

Both patients had lesions in the medial medulla supplied by branches of the anterior spinal and vertebral arteries, and although such cases are rare it seems wise, in the light of these reports, to avoid the routine use of adrenaline as an adjunct to local anesthesia for adenotonsillectomy.

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Intravenous regional anesthesia It has previously been suggested that ropivacaine is a good choice for intravenous regional anesthesia because of its longer duration of action and lower risk of toxicity. In 20 patients scheduled for upper limb surgery who received 40 ml of either ropivacaine 0.2% or lidocaine 0.5% for intravenous regional anesthesia, both agents provided same onset and quality of surgical anesthesia, but ropivacaine gave longerlasting analgesia in the immediate postoperative period (24c ). Additionally, one patient in the lidocaine group had tinnitus on release of the tourniquet, while there were no adverse effects in the ropivacaine group.

Topical anesthesia A recent meta-analysis of the use of EMLA cream in the elderly (over 65) showed that the technique is generally safe, with only mild transient effects (pallor, redness, and edema) at the application site; there were no systemic effects (25M ). Hematologic High doses of EMLA cream can cause neonatal methemoglobinemia as a result of prilocaine toxicity (SEDA-22, 141). • A 3-year-old girl with multiple lesions of molluscum contagiosum had EMLA applied to the lesions before curettage (26A ). She became lethargic and hypoactive 2 hours later, with periorbital discoloration and cyanosed lips. Her SaO2 was 85%, systolic blood pressure 185 mmHg, pulse 144 beats/minute, and her methemoglobin concentration was 21%. Her caregiver had applied about 25 g of cream to her entire torso, a massive dose of prilocaine (about 625 mg).

This report reinforces previously described problems arising from carers’ lack of understanding of instructions when using EMLA in children or babies. Skin The first report of hyperpigmentation following the use of EMLA cream has appeared (27A ), although hypopigmentation has previously been reported. • A 12-year-old black child developed a patch of hyperpigmentation on his forehead where EMLA

cream had been used for cutaneous anesthesia before local infiltration with lidocaine for removal of a nevus. This persisted, although fading, for at least 4 months. No other cause could be found.

The authors concluded that the constituents of EMLA had been responsible.

INDIVIDUAL COMPOUNDS Articaine

(SED-14, 350)

Articaine is an amide local anesthetic. It was synthesized in 1969 but only registered in the USA in 2000. It is 4-methyl-3[2-(propylamino)propionamido]-2-thiophenecarboxylic acid, methyl ester hydrochloride. The thiophene group increases its lipid solubility while the ester group enables it to undergo plasma esterase hydrolysis as well as hepatic enzyme metabolism. It is formulated as a 4% solution with adrenaline. The safety of articaine has been studied in a series of three randomized trials (28C ). The adverse effects deemed to be related to articaine were headache, paresthesia/hyperesthesia after injection, infection, and rash. There was one case of mouth ulceration. The overall incidence of adverse effects was comparable to that of lidocaine.

Benzocaine

(SED-14, 351; SEDA-23, 143; SEDA-24, 151; SEDA-25, 155) Hematologic Four cases of methemoglobinemia have again been described after the use of benzocaine spray for topical anesthesia of the airways. • A 42-year-old woman received superior laryngeal nerve block with lidocaine, topical anesthesia with benzocaine spray, and intravenous midazolam for awake fiberoptic intubation (29A ). Her SpO2 fell from about 85% to about 30%, and despite highfrequency jet ventilation with 100% oxygen she had persistent SpO2 readings in the low 80s. Her arterial blood was chocolate-brown in color, with a PaO2 of 330 mmHg and an oxyhemoglobin saturation (SaO2 ) of 51%. This discrepancy between PaO2 and SaO2 suggested methemoglobinemia, and co-oximetry showed a concentration of 51%.

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Methylene blue 140 mg produced an immediate improvement in her color, and her SaO2 improved over the next 10 minutes. • An elderly man received benzocaine 20% spray to the throat in preparation for transesophageal echocardiography. He became unwell 1 hour later, with lethargy, central cyanosis, hypoxia, dyspnea, tachypnea, and tachycardia (30A ). His arterial blood was burgundy-colored and the methemoglobin concentration was 41%. He was treated with two doses of methylene blue 2 mg/kg and was weaned from oxygen within 10 h. • Significant methemoglobinemia occurred in a 65-year-old man on re-exposure to topical 20% benzocaine spray for anesthesia of the airways in preparation for awake fiberoptic intubation (31A ). This occurred despite exposure 3 days before to 14% benzocaine for the same procedure. During attempted intubation, he suddenly desaturated to 80% and had significant hypotension and bradycardia, necessitating external cardiac massage and cricothyroid puncture. His SaO2 did not improve significantly, despite seemingly adequate resuscitation with 100% oxygen and intravenous adrenaline. His arterial methemoglobin concentration was 55%. Methylene blue 100 mg intravenously led to rapid improvement in the SaO2 , allowing surgery to continue. • A 57-year-old man developed severe methemoglobinemia after receiving topical benzocaine spray and lidocaine jelly during awake fiberoptic intubation (32A ). After intubation, his oxygen saturation fell to 65% on 100% oxygen. He was cyanosed and had dark arterial blood sample with normal gas tensions. His methemoglobin concentration was 60% and treatment with methylene blue was successful.

These cases illustrate the importance of co-oximetry on grounds of clinical suspicion. Methemoglobin concentrations of 10–15% can cause dark-colored blood and cyanosis. Concentrations of 20–45% can cause lethargy, dizziness, headache, and collapse. Higher concentrations (50–70%) can cause seizures, dysrhythmias, coma, and death. Skin Allergic contact dermatitis has been attributed to local benzocaine (33A ). • A 72-year-old woman was treated for thoracic Herpes zoster with oral aciclovir and topical benzocaine 20% ointment. She subsequently developed painful pruritic erythematous dermatitis in the area of the lesions, spreading to her arm. The dermatitis was initially misdiagnosed as aciclovir resistance, but on patch testing she had a positive reaction to benzocaine.

The authors highlighted the problem in diagnosing allergic contact dermatitis in patients

who have other skin lesions in that area. They emphasized the importance of patch testing to identify the causative agent.

Chlorprocaine Nervous system Prolonged neuromuscular blockade has been reported after epidural 2chlorprocaine (34A ). • A 29-year-old woman in labor was given an epidural infusion of bupivacaine 0.04% plus fentanyl 1.66 micrograms/ml running at 15 ml/h for 7 h. She then required an urgent cesarean section and 15 ml of chlorprocaine 3% was given, followed 20 min later by 12 ml of 2% lidocaine. Half an hour later she showed signs of high epidural blockade with dyspnea followed by unresponsiveness, and required immediate intubation with succinylcholine. She then developed prolonged neuromuscular blockade with a first-twitch response occurring after 1.75 hours. It took 3.75 hours before she could be extubated. Her plasma cholinesterase activity was low immediately post-partum, with a concentration of 1.3 units/ml (reference range 2.8– 11), returning to normal within 7 weeks.

The authors believed that the high epidural blockade and the prolonged neuromuscular block had resulted from reduced pseudocholinesterase activity. Reduced pseudocholinesterase activity has been described both in pregnancy and with magnesium therapy. As most ester local anesthetics (with the exception of cocaine) are metabolized by this enzyme, caution should be exercised when using ester local anesthetics in pregnancy, especially with the increasing use of magnesium sulfate in this field.

Cinchocaine

(SED-14, 352)

Skin Two cases of allergic contact dermatitis have been described after the use of cinchocaine formulations. • A 71-year-old Japanese man, who was using an over-the-counter formulation, Makiron, for minor wounds, developed an itchy rash with seropapules and erosions on his right leg at the site of application (35A ). Makiron contains 0.1% cinchocaine hydrochloride and chlorpheniramine maleate as well as naphazoline hydrochloride and benzethonium chloride. On patch testing, he was positive to both chlorpheniramine and cinchocaine.

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• A 79-year-old man presented with a 10-day history of weeping dermatitis affecting the perianal skin, buttocks, and proximal thighs (36A ). He had used Proctosedyl ointment topically for the preceding 3 weeks. Proctosedyl is an over-the-counter topical formulation for use as an antihemorrhoidal agent. It contains cinchocaine 5%, hydrocortisone, and lanolin. Patch testing was strongly positive to cinchocaine.

The authors highlighted the potential limitations of the International Contact Dermatitis Research Group (ICDRG) standard series for topical anesthetics. Benzocaine is the only topical anesthetic in the series and it will not detect contact allergy to amide agents; crosssensitivity can also exist. They suggested that patch testing should include agents from both groups. DoloPosterine N is an ointment for topical application in the treatment of hemorrhoids. Its active ingredient is cinchocaine. Although cinchocaine is a known contact sensitizer, as described above, systemic contact dermatitis is rare. • A 62-year-old woman, who had applied DoloPosterine N ointment topically to the perianal skin and rectal mucosa for several days, developed erythematous vesicular lesions in the perianal area and an erythematous edematous rash of the face, axillae, elbow flexures, and inner thighs (37A ). This abated on withdrawal of the drug and the administration of oral prednisolone for 10 days. Patch testing was positive to cinchocaine.

Levobupivacaine Hematologic The effects of the low molecular weight heparin enoxaparin in combination with levobupivacaine on coagulation have been studied in vitro (38E ). Whole blood from 10 patients treated with enoxaparin was mixed with levobupivacaine to concentrations of 2.5 µg/ml and 2.5 mg/ml, followed by thromboelastography. Levobupivacaine produced a dosedependent reduction in clotting. The clinical implications of these findings are yet to be acknowledged; larger, in vivo studies are required.

Lidocaine

(SED-14, 349; SEDA-23, 144;

SEDA-24, 152) Cardiovascular In 23 patients there was a significant dose-dependent reduction in blood pressure following submucosal infiltration of lidocaine plus adrenaline compared with saline plus adrenaline for orthognathic surgery (39c ). The study was randomized but small; larger studies are needed to confirm effects that could easily have been due to multifactorial causes in patients undergoing general anesthesia. Hematologic Although methemoglobinema has previously been described in patients exposed to benzocaine and prilocaine, the association with lidocaine is not well defined. Three cases of lidocaine-induced methemoglobinemia have been reported in patients undergoing topical anesthesia of the airway and oropharynx (40A ). • A 26-year-old woman undergoing bronchoscopy received lidocaine jelly 2% to each nostril, lidocaine solution 2% sprayed on the throat, and 10 ml of lidocaine solution 2% into the trachea. She was also given intravenous diazepam 5 mg and pethidine 75 mg and intramuscular atropine 0.6 mg. She developed dyspnea and cyanosis after the procedure and despite 100% oxygen her SpO2 was 85%. Her methemoglobin concentration was 14%. • A 61-year-old woman was given 15 ml of lidocaine solution 2% and lidocaine spray 4% for topical anesthesia of the throat and oropharynx before upper gastrointestinal endoscopy. She was also sedated with intravenous midazolam 2 mg and pethidine 75 mg. She became cyanosed and desaturated (SpO2 78%) immediately after the procedure. Her SpO2 did not recover, despite 100% oxygen. Her methemoglobin concentration was 37%. • In preparation for transesophageal echocardiogram, a 73-year-old woman was given 15 ml of lidocaine solution 2% and lidocaine spray 4% to anesthetize the oropharynx, plus intravenous midazolam 1 mg and pethidine 12.5 mg. She very rapidly became cyanosed, but remained symptomatic, with an SpO2 of 85% on oxygen 2 l/minute. Her methemoglobin concentration was 25%.

Skin Dermatitis has been attributed to lidocaine (41A ). • A 60-year-old woman was given infiltration anesthesia with lidocaine hydrochloride for removal of a melanoma. She developed an itchy dermatitis over the area 36 h later. Conventional patch testing was negative at 48 and 72 h to lidocaine

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and mepivacaine (both amides), as was intracutaneous testing with lidocaine 2%, mepivacaine 2%, and bupivacaine 0.5%. However, intradermal testing at 1/100 dilutions was positive, with itching and erythema at 48 h with lidocaine and mepivacaine, suggesting delayed hypersensitivity to these drugs, but not with bupivacaine.

It has previously been reported that lidocaine and mepivacaine have a high degree of crossreactivity not seen with bupivacaine. In a phase IV trial 66% patients with postherpetic neuralgia gained relief from a 5% lidocaine patch applied to the most painful area of the body (42C ). The lidocaine patch was well tolerated, a rash being the most common adverse effect, in 14% of patients. Drug interactions A potentially beneficial effect of lidocaine has been studied in a randomized, double-blind, placebo-controlled study of the effects of pre-instillation of lidocaine on tropicamide-induced mydriasis (43c ). Pupillary diameter was significantly increased by the instillation of lidocaine before tropicamide. It was thought that lidocaine may enhance intraocular penetration and hence potentiate the effect of tropicamide.

Oxybuprocaine Skin There have been two reports of patients scheduled for tonometry who developed periorbital dermatitis following the topical instillation of local anesthetic eye drops (44A ). The first patient reacted strongly positive on patch testing to Thilorbin AT (oxybuprocaine, fluorescein, phenylmercuric borate, polysorbate 20, mannitol) and also to oxybuprocaine alone. The second reacted to Conjucain EDO (oxybuprocaine, sorbitol, sodium hydroxide) and to oxybuprocaine alone. The authors believed these to be the only described cases of a delayed hypersensitivity reaction to oxybuprocaine, an ester local anesthetic commonly used for topical anesthesia in the eye.

ing procaine, lidocaine, or bupivacaine in combination with fentanyl for spinal anesthesia for a variety of different surgical procedures (45C ). Procaine plus fentanyl and bupivacaine plus fentanyl produced a higher incidence of pruritus than lidocaine plus fentanyl. The severity of pruritus was also greater in those given procaine plus fentanyl. The incidence and severity of pruritus was not related to the dose of fentanyl. Although this may represent an interaction between fentanyl and ester local anesthetics that differs from the synergy occurring between fentanyl and amide local anesthetics, this was an observational study and was neither randomized nor blinded. Furthermore, the doses of local anesthetic or fentanyl were not standardized. Further prospective randomized studies are therefore required to confirm or refute these claims.

Proparacaine

(SEDA-24, 152)

Skin Allergic contact dermatitis of the ophthalmic mucous membranes has previously been reported. Now sensitization to proparacaine via the cutaneous route has also been described (46C ). • An ophthalmologist developed chronic finger pad dermatitis with fissuring and scaling, which mainly affected his thumbs for 3 years. Patch testing confirmed that “ophthetic solution” (proparacaine hydrochloride 0.5%, glycerine, and benzalkonium chloride 0.01%) was the sensitizing agent. He was instructed to change to tetracaine, to which he had had a negative patch test. However, 2 years later his symptoms recurred and a repeat patch testing was carried out. This was now positive to both tetracaine 1% and proparacaine 0.5%.

Cross-sensitization between proparacaine and tetracaine is thought to be rare. Moreover, the chemical structure of proparacaine is sufficiently different from tetracaine to make crossreactivity unlikely. These cases suggest, however, that some degree of cross-sensitization can occur.

Ropivacaine Procaine

(SED-14, 353)

Skin The incidence of pruritus has been evaluated in a retrospective study of patients receiv-

(SED-14, 353; SEDA-23, 145; SEDA-25, 156) Nervous system A single seizure after epidural ropivacaine has been reported (47A ).

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• A 26-year-old primigravid woman in labor had epidural anesthetic with ropivacaine (a background infusion of 18 mg/h and three bolus doses totalling 44 mg, followed by an infusion of 24 mg/hour). She failed to progress and another three boluses totaling 150 mg were given. She received a total of 279 mg of ropivacaine over 5 hours. Immediately after the final bolus she developed oculogyric movements and slurred speech and then twitching of her face and arms. The seizure ceased with thiopental and the operation was carried out uneventfully under general anesthesia. Her serum ropivacaine concentration 1 hour later was 3.5 mg/l; in previous studies, symptoms of toxicity during intravenous infusions occurred at plasma concentrations of 1–2 mg/l.

This shows that CNS toxicity is a potential problem with ropivacaine; it is important to leave adequate time between bolus doses to detect adverse effects. It also confirms that with ropivacaine CNS adverse effects occur before or without severe cardiovascular toxicity, as there have now been several similar reports of CNS toxicity, but not yet one with severe or fatal cardiotoxicity. This reinforces the claim of increased safety from cardiovascular toxicity with this enantiomeric local anesthetic compared with racemic bupivacaine.

REFERENCES 1. Mak PH, Irwin MG, Ooi CG, Chow BF. Incidence of diaphragmatic paralysis following supraclavicular brachial plexus block and its effect on pulmonary function. Anaesthesia 2001; 56: 352–6. 2. Rodriguez J, Quintelat O, Lopez-Rivadulla M, Barcena M, Diz C, Alvarez J. High doses of mepivacaine for brachial plexus block in patients with end-stage chronic renal failure. A pilot study. Eur J Anaesthesiol 2001; 18: 171–6. 3. Ekatodramis G, Macaire P, Borgeat A. Prolonged Horner syndrome due to neck hematoma after continuous interscalene block. Anesthesiology 2001; 95: 801–3. 4. Sukhani R, Barclay J, Aasen M. Prolonged Horner’s syndrome after interscalene block: a management dilemma. Anesth Analg 1194; 79: 601–3. 5. Borgeat A, Kalberer F, Jacob H, Ruetsch YA, Gerber C. Patient-controlled interscalene analgesia with ropivacaine 0.2% versus bupivacaine 0.15% after major open shoulder surgery: the effects on hand motor function. Anesth Analg 2001; 92: 218–23. 6. Rodriguez Lopez JM, Sanchez-Conde P, Nicolas J, Garcia-Castano M, Del Barrio E, Muriel C. Estudio comparativo entre ropivacaina y bupivacaina en analgesia epidural del parto. Rev Esp Anestesiol Reanim 2001; 48: 199–203. 7. Senel AC, Akyol A, Dohmann D, Solak M. Caudal bupivacaine-tramadol combination for postoperative analgesia in pediatric herniorrhaphy. Acta Anaesthesiol Scand 2001; 45: 786–9. 8. Mahajan R, Batra YK, Grover VK, Kajal J. A comparative study of caudal bupivacaine and midazolam-bupivacaine mixture for post-operative analgesia in children undergoing genitourinary surgery. Int J Clin Pharmacol Ther 2001; 39: 116–20. 9. Tanaka M, Nitta R, Nishikawa T. Increased T-wave amplitude after accidental intravascular injection of lidocaine plus bupivacaine with-

out epinephrine in sevoflurane-anesthetized child. Anesth Analg 2001; 92: 915–17. 10. Wigfull J, Welchew E. Survey of 1057 patients receiving postoperative patient-controlled epidural analgesia. Anaesthesia 2001; 56: 70–5. 11. Silvasti M, Pitkanen M. Patient-controlled epidural analgesia versus continuous epidural analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 2001; 45: 471–6. 12. Meunier J-F, Goujard E, Dubousset AM, Samii K, Mazoit JX. Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with and without biliary atresia. Anesthesiology 2001; 95: 87–95. 13. Salazar F, Bogdanovich A, Adalia R, Chabas E, Gomar C. Transient neurologic symptoms after spinal anaesthesia using isobaric 2% mepivacaine and isobaric 2% lidocaine. Acta Anaesthesiol Scand 2001; 45: 240–5. 14. Saito S, Radwan I, Obata H, Takahashi K, Goto F. Direct neurotoxicity of tetracaine on growth cones and neurites of growing neurons in vitro. Anesthesiology 2001; 95: 726–33. 15. Lindh A, Andersson AS, Westman L. Is transient lumbar pain after spinal anaesthesia with lidocaine influenced by early mobilisation? Acta Anaesthesiol Scand 2001; 45: 290–3. 16. Le Truong HH, Girard M, Drolet P, Grenier Y, Boucher C, Bergeron L. Spinal anesthesia: a comparison of procaine and lidocaine. Can J Anaesth 2001; 48: 470–3. 17. Tsen LC, Schultz R, Martin R, Datta S, Bader AM. Intrathecal low-dose bupivacaine versus lidocaine for in vitro fertilization procedures. Reg Anesth Pain Med 2001; 26: 52–6. 18. Philip J, Sharma SK, Gottumukkala VNR, Perez BJ, Slaymaker EA, Wiley J. Transient neurologic symptoms after spinal anesthesia with lidocaine in obstetric patients. Anesth Analg 2001; 92: 405–9.

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19. Rorarius M, Suominen P, Haanpaa M, Puura A, Baer G, Pajunen P, Tuimala R. Neurologic sequelae after caesarean section. Acta Anaesthesiol Scand 2001; 45: 34–41. 20. Oka S, Matsumoto M, Ohtake K, Kiyoshima T, Nakakimura K, Sakabe T. The addition of epinephrine to tetracaine injected intrathecally sustains an increase in glutamate concentrations in the cerebrospinal fluid and worsens neuronal injury. Anesth Analg 2001; 93: 1050–7. 21. Ohtake K, Matsumoto M, Wakamatsu H, Kawai K, Nakakimura K, Sakabe T. Glutamate release and neuronal injury after intrathecal injection of local anesthetics. Neuroreport 2000; 11: 1105–9. 22. Akioka K-L, Torigoe K, Maruta H, Shimizu N, Kobayashi Y, Kaneko Y, Shiratori R. A case of cauda equina syndrome following spinal anesthesia with hyperbaric dibucaine. J Anesth 2001; 15: 106–7. 23. Kang PB, Phuah HK, Zimmerman RA, Handler SD, Dure LS, Ryan SG. Medial medullary injury during adenoidectomy. J Pediatr 2001; 138: 772–4. 24. Atanassoff PG, Ocampo CA, Bande MC, Hartmannsgruber MWB, Halaszynski TM. Ropivacaine 0.2% and lidocaine 0.5% for intravenous regional anesthesia in outpatient surgery. Anesthesiology 2001; 95: 627–31. 25. Wahlgren C-F, Lillieborg S. Split-skin grafting with lidocaine–prilocaine cream: a meta-analysis of efficacy and safety in geriatric versus nongeriatric patients. Plast Reconstr Surg 2001; 107: 750–6. 26. Touma S, Jackson JB. Lidocaine and prilocaine toxicity in a patient receiving treatment for mollusca contagiosa. J Am Acad Dermatol 2001; 44 Suppl: 399–400. 27. Godwin Y, Brotherston M. Hyperpigmentation following the use of Emla cream. Br J Plast Surg 2001; 54: 82–3. 28. Malamed SF, Gagnon S, Leblanc D. Articaine hydrochloride: a study of the safety of a new amide local anesthetic. J Am Dent Assoc 2001; 132: 177– 85. 29. Singh RK, Kambe JC, Andrews LK, Russell JC. Benzocaine-induced methemoglobinemia accompanying adult respiratory distress syndrome and sepsis syndrome: case report. J Trauma 2001; 50: 1153–7. 30. Ramsakal A, Lezama JL, Adelman HM. A potentially fatal effect of topical anesthesia. Hosp Pract 2001; 36: 13–14. 31. Udeh C, Bittikofer J, Sum-Ping STJ. Severe methemoglobinemia on reexposure to benzocaine. J Clin Anesth 2001; 13: 128–30. 32. Lorelli DR, Morris DE, Lewis JW Jr. Druginduced methemoglobinemia during thoracoscopic lung biopsy. Ann Thorac Surg 2001; 71: 703–5. 33. Roos TC, Merk HF. Allergic contact dermatitis from benzocaine ointment during treatment of Herpes zoster. Contact Dermatitis 2001; 44: 104.

149 34. Monedero P, Hess P. High epidural block with chloroprocaine in a parturient with low pseudocholinesterase activity. Can J Anaesth 2001; 48: 318–19. 35. Hayashi K, Kawachi S, Saida T. Allergic contact dermatitis due to both chlorpheniramine maleate and dibucaine hydrochloride in an overthe-counter medicament. Contact Dermatitis 2001; 44: 38–9. 36. Kearney CR, Fewings J. Allergic contact dermatitis to cinchocaine. Australas J Dermatol 2001; 42: 118–19. 37. Eredmann SM, Sachs B, Merk HF. Systemic contact dermatitis from cinchocaine. Contact Dermatitis 2001; 44: 260–1. 38. Leonard SA, Lydon A, Walsh M, Fleming C, Boylan J, Shorten GD. Does prior administration of enoxaparin influence the effects of levobupivacaine on blood clotting? Assessment using the Thrombelastograph. Br J Anaesth 2001; 86: 808–13. 39. Enlund M, Mentell O, Krekmanov L. Unintentional hypotension from lidocaine infiltration during orthognathic surgery and general anaesthesia. Acta Anaesthesiol Scand 2001; 45: 294–7. 40. Karim A, Ahmed S, Siddiqui R, Mattana J. Methemoglobinemia complicating topical lidocaine used during endoscopic procedures. Am J Med 2001; 111: 150–3. 41. Scala E, Giani M, Pirrotta L, Guerra EC, Girardelli CR, De Pita O, Puddu P. Simultaneous [correction of Spontaneous] allergy to ampicillin and local anesthetics. Allergy Eur J Allergy Clin Immunol 2001; 56: 454–5. 42. Anonymous. Lidocaine patch shown to relieve postherpetic neuralgia. J Pharm Technol 2001; 17: 154. 43. Ghose S, Garodia VK, Sachdev MS, Kumar H, Biswas NR, Pandey RM. Evaluation of potentiating effect of a drop of lignocaine on tropicamideinduced mydriasis. Invest Ophthalmol Vis Sci 2001; 42: 1581–5. 44. Blaschke V, Fuchs T. Periorbital allergic contact dermatitis from oxybuprocaine. Contact Dermatitis 2001; 44: 198. 45. Mulroy MF, Larkin KL, Siddiqui A. Intrathecal fentanyl-induced pruritus is more severe in combination with procaine than with lidocaine or bupivacaine. Reg Anesth Pain Med 2001; 26: 252–6. 46. Dannaker CJ, Maibach HI, Austin E. Allergic contact dermatitis to proparacaine with subsequent cross-sensitization to tetracaine from ophthalmic preparations. Am J Contact Dermatitis 2001; 12: 177–9. 47. Bisschop DY, Alardo JP, Razgallah B, Just BY, Germain M-LY, Millart HG, Trenque TC. Seizure induced by ropivacaine. Ann Pharmacother 2001; 35: 311–13.

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Neuromuscular blocking agents and skeletal muscle relaxants

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14, 371; SEDA-23, 150; SEDA-24, 159; SEDA-25, 160)

Rapacuronium In the aftermath of the withdrawal of rapacuronium from the market, a paper addressing its effects on respiratory function has been published. In their study, which was performed while rapacuronium was still on the market in the USA, the authors observed statistically significant reductions in peak inspiratory flow rate, peak expiratory flow rate, and dynamic compliance and increases in peak inflating pressure when rapacuronium 1.5 mg/kg was given under steady-state conditions to patients who were already anesthetized, intubated, and ventilated (1C ). In five of the 10 patients these changes amounted to more than 25% from baseline and were considered clinically relevant. As rapacuronium is no longer available this has no direct clinical impact. However, while discussing the mechanisms of rapacuroniuminduced bronchospasm the authors speculated that differential effects of the drug on several subtypes of muscarinic acetylcholine receptors might be responsible. As raised histamine concentrations were not found in seven patients with rapacuronium-induced bronchospasm in another study (2C ), they reckoned that histamine release was an unlikely explanation. Referring to the observation that pipecuronium, another non-steroidal muscle relaxant, blocked © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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pilocarpine-stimulated prejunctional M2 receptors in vitro (3E ), they suggested that a similar effect might result in rapacuronium-induced bronchospasm. Prejunctional M2 receptors are thought to have a role in negative feedback and inhibition of further acetylcholine release, thereby reducing smooth muscle relaxation. These aspects will need to be taken into account when new substances are considered for clinical use.

Allergic reactions to rocuronium During the last few years several allergic reactions to rocuronium have been reported. Based on data from the UK, Australia, and France, it had been suggested that the incidence of such reactions after rocuronium administration paralleled its frequency of use, as assessed by its market share, implying that rocuronium did not have unusual allergenic properties (4C –6C ). Also, the incidence of hypotension, tachycardia, or reduced oxygen saturation (which might suggest an anaphylactoid reaction) was relatively low after rocuronium administration compared with other muscle relaxants in a computerized analysis of 47 295 anesthetic records in one hospital (7c ). Recently, however, the French Group on the Study of Perianesthetic Anaphylactoid Reactions (GERAP) has reported that the proportion of anaphylactoid reactions to rocuronium was similar to succinylcholine in relation to the individual market shares of these agents (8C ). This would make rocuronium look unfavorable, taking into account the fact that succinylcholine is believed to trigger anaphylactoid reactions

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more often than any non-depolarizing neuromuscular blocker. The authors assumed that their figures might have been partly due to anesthetists’ paying more attention to the effects of drugs that had become available more recently, especially in cases of mild reactions. Reporting bias has also been offered as one possible explanation of 29 reports of anaphylaxis to rocuronium among 150 000 patients in Norway, in contrast to eight cases among 800 000 patients in the other Scandinavian countries (9Cr ). This observation has prompted the Norwegian Medicines Agency to recommend that rocuronium be temporarily withdrawn from routine practice and that it be used for rapid-sequence induction only. It is difficult to understand why such an increase in the number of reported cases should only be observed in France and Norway and not in other countries in which rocuronium is widely used. For the time being, it is not possible to decide whether anaphylactoid reactions are more common with rocuronium than with other non-depolarizing muscle relaxants. To get a clearer picture, a large longitudinal survey would be needed (10R ), which is unlikely to be performed, owing to the large number of cases that would be required. We shall probably have to rely on national surveys, like the French one cited above. International networking and pooling of data might be the way forward. All of this will depend on clinicians chasing every case of a suspected anaphylactoid reaction by immunological testing and reporting all confirmed cases to appropriate bodies. For reasons of completeness it should be mentioned that reports of anaphylactoid reactions to newer muscle relaxants other than rocuronium also continue to be published (11c – 13c ).

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14, 361; SEDA-23, 150; SEDA-24, 158; SEDA-25, 161) Nervous system Patients with severe head injuries require endotracheal intubation and controlled ventilation. Rapid sequence intubation using an intravenous anesthetic plus succinylcholine is the standard technique for this, as

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the patient may have a full stomach. For a couple of years, however, succinylcholine has been suggested by some to have a negative effect by causing increased intracranial pressure. The literature on this has been reviewed (14R ). The authors found only two studies that specifically addressed the effects of succinylcholine on intracranial pressure in patients with head injuries (15C , 16C ). In both studies succinylcholine was given to patients who were already being ventilated in the intensive care unit. There were no adverse effects of succinylcholine on intracranial pressure or cerebral perfusion pressure. However, when succinylcholine was given to lightly anesthetized patients undergoing resection of intracranial tumors there were significant increases in intracranial pressure (17C , 18C ). These could be prevented by pretreatment with a small dose of a non-depolarizing muscle relaxant (18C ). The importance of an adequate level of anesthesia for intubating patients at risk of intracranial hypertension should be stressed. A lightly anesthetized patient will have large increases in intracranial pressure during intubation, no matter which muscle relaxant is used, because of a stress response that includes venous vasoconstriction and a massive increase in central venous pressure, resulting in impaired venous outflow from the cranium and thereby increased intracranial blood volume. Electrolyte balance The underlying mechanisms of and mortality from succinylcholineassociated hyperkalemic cardiac arrest have been reviewed (19R ). The author concluded that hyperkalemia during rapid acute rhabdomyolysis is more likely to result in unsuccessful resuscitation than is the potassium efflux that results from up-regulation of acetylcholine receptors. It should be stressed that almost all reported cases of hyperkalemic cardiac arrest considered to result from rhabdomyolysis occurred in children and adolescents with underlying muscular dystrophies. The use of succinylcholine in intensive care units has been critically reviewed (20r ). The author concluded that its use is obsolete in this setting, referring to the increased risk of succinylcholine adverse effects in intensive care patients. Of particular concern is the growing number of cases of hyperkalemic cardiac arrest that occurred when succinylcholine was given to critically ill patients after a period of immobilization. As stated in last year’s edition

152 (SEDA-25, 161), we think that succinylcholine should be regarded as being contraindicated in critically ill patients who have been immobilized in an intensive care unit for more than 48 hours. Having said that, we still regard succinylcholine as the muscle relaxant of first choice for rapid sequence intubation in emergencies, if risk factors such as prolonged immobilization, pre-existing hyperkalemia, or neuromuscular disorders, are absent. Recently, the authors of yet another report of succinylcholine-induced fatal hyperkalemic cardiac arrest in an intensive care unit assumed that severe mucositis after cancer chemotherapy might have contributed to the hyperkalemic response (21c ). • A 37-year-old woman with acute myelogenous leukemia was admitted to an intensive care unit (ICU) with mental status changes and progressive dyspnea due to pneumonia. Intubation was performed before ICU admission using a sedative without neuromuscular blockade. She had received chemotherapy with cytarabine, daunorubicin, and intrathecal methotrexate for CNS metastases. After chemotherapy and before ICU admission her course was complicated by continuous neutropenic fevers and by painful mucositis causing dysphagia and bleeding. After 10 days of ventilator treatment in the ICU and treatment with ceftazidime, gentamicin, metronidazole, vancomycin, G-cerebrospinal fluid, amphotericin, and aciclovir, her condition improved, allowing withdrawal of ventilator support and extubation. A few hours later, however, she gradually developed severe respiratory distress and required re-intubation. The serum potassium concentration before intubation was 4.3 mmol/l. For endotracheal intubation she received intravenous etomidate 14 mg and succinylcholine 100 mg. Immediately after intubation she developed a broad-complex tachycardia and her blood pressure could not be measured. Chest compression and advanced cardiac life support were started. Her serum potassium concentration was 13.1 mmol/l. Intravenous calcium chloride, sodium bicarbonate, and insulin/glucose were therefore given. The serum potassium fell to 6.5 mmol/l but rose to 7.4 mmol/l 15 minutes later, despite additional antihyperkalemic treatment. She finally died.

Despite this having been a case of succinylcholine-induced hyperkalemic cardiac arrest after several days of ventilator treatment on the intensive care unit, the authors did not believe that upregulation and extrajunctional spread of acetylcholine receptors were the underlying mechanisms. They implied that mobilization and daily physiotherapy would have both prevented these typical denervation-like changes

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and ruled out a neuromuscular disorder. Rather they suggested that severe generalized mucositis had resulted in a state that they compared to an “internal burns injury”. However, these speculations were not substantiated by additional data. In particular, they gave no information on the pre-succinylcholine neuromuscular state of the patient. Some form of polyneuropathy and/or myopathy could have been present, and this was not ruled out by the fact that the patient could breathe spontaneously and sit in a chair. While it is true that severe mucositis represents a state of widespread cellular damage similar to severe burn injuries, it is not clear why this itself should result in hyperkalemia after succinylcholine. To our knowledge succinylcholine only has effects on excitable cells. Even in patients with severe thermal injuries, no case of hyperkalemia after succinylcholine has been reported within the first 48 hours after the accident, and succinylcholine-induced hyperkalemia in burned patients is believed to result from upregulation of acetylcholine receptors, owing to thermal damage of nerve fibres (structural denervation) and immobilization (functional denervation) (22R ). Apart from immobilization due to the severity of the illness it is very unlikely that mucositis should have similar effects. Mucositis itself should therefore not be regarded as a risk factor for succinylcholine-associated hyperkalemia.

SKELETAL MUSCLE RELAXANTS (SED-14, 390; SEDA-23, 152; SEDA-24, 159; SEDA-25, 163)

The baclofen withdrawal syndrome Long-term administration of baclofen is widely used in patients with muscle spasticity resulting from a variety of cerebral and spinal chord lesions. As with other GABA receptor agonists, withdrawal reactions will occur if it is stopped abruptly. Patients can present with different symptoms, not all of which would be considered classical of drug withdrawal. Some interesting aspects of withdrawal symptoms after baclofen administration have been highlighted in three recent reports.

Neuromuscular blocking agents and skeletal muscle relaxants

Clinical presentation There is a proposed similarity between baclofen withdrawal and the neuroleptic malignant syndrome. • A 36-year-old man with paraplegia after a spinal cord injury became disoriented (23A ). He had been taking baclofen 10 mg at night for several years. He had marked rigidity in both arms and legs, he was sweating and pyrexial (38◦ C), and his heart rate was 112 beats/min. His serum creatine kinase was raised at 2668 U/l and rose to 2982 U/l on day 3. At that time, baclofen was restarted. Within 3 days he was fully oriented. Over 2 weeks his creatine kinase activity gradually fell to normal and his temperature settled. It turned out that he had neglected to take any medication for several days before admission.

The authors believed that symptoms in this case resembled the neuroleptic malignant syndrome, based on the combination of muscle rigidity, pyrexia, signs of autonomic disturbance, and altered consciousness. They did not think that the raised serum creatine kinase activity was associated with rhabdomyolysis, stating that there was no evidence from urinalysis to suggest this. Unfortunately, they did not specify whether there was myoglobin in the urine or not. Creatine kinase activities up to 40 000 U/l have been noted during baclofen withdrawal (24c ), compared with which creatine kinase activity in this case was much lower, suggesting only moderate muscle damage. One might assume that muscle damage after baclofen withdrawal correlates with the duration and intensity of muscular hyperactivity. In addition, prolonged muscular hyperactivity may be expected to be followed by an increase in both body temperature and heart rate, owing to hypermetabolism and sympathetic activation. Sweating will result from sympathetic activation and a thermoregulatory response to hyperthermia and is not necessarily an autonomic disturbance. Disorientation is also an expected symptom of baclofen withdrawal. In conclusion, this patient’s combination of symptoms could have been explained by baclofen withdrawal alone. Assuming that disturbances in central dopaminergic systems could have been involved, as in neuroleptic malignant syndrome, is speculative. This is not the first report of similarities between the neuroleptic malignant syndrome and baclofen withdrawal (24c , 25cr , 26c ). In addition, hyperthermia seems to be common in baclofen withdrawal (25cr ).

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If a patient stops taking baclofen, a blood sample for baclofen serum concentration measurement should be taken if possible, to confirm the diagnosis post hoc if hyperthermia occurs. If a patient taking long-term baclofen presents with similar symptoms, baclofen withdrawal should be considered and baclofen should be given. If this is not effective and the patient deteriorates, with hyperthermia, increasing creatine kinase activity, and metabolic sequelae, dantrolene can be given. Dantrolene is lifesaving in malignant hyperthermia associated with volatile anesthetics and succinylcholine and is also the drug of choice for the treatment of neuroleptic malignant syndrome. In one case of baclofen withdrawal, dantrolene was given with success (24c ). It should be stressed that baclofen withdrawal is a potentially fatal emergency requiring intensive care. The effects of renal impairment Baclofen is cleared predominantly by renal excretion. Thus, if a patient taking baclofen has deteriorating renal function one would expect relative baclofen overdose and would reduce the dosage. • An 82-year-old man with left ventricular dysfunction and gout had worsening renal function (27A ). He was taking lisinopril, furosemide, naproxen, allopurinol, and baclofen 20 mg tds. As no reason could be found for the use of baclofen the dose was halved and then stopped 10 days later. The next day he had visual hallucinations, confusion, and agitation, and required sedation with diazepam. He was afebrile, with normal inflammatory markers, and a CT scan of the brain showed only cerebral atrophy. Baclofen was reintroduced, with complete resolution of neuropsychiatric symptoms within 48 hours.

A reduced dosage of baclofen may be necessary in patients with renal insufficiency. On the other hand underdosing can result in withdrawal symptoms and an inadequate therapeutic effect. Both overdosing and underdosing will cause significant morbidity and a prolonged hospital stay. Measuring baclofen serum concentrations in problem patients could be helpful for dosage adjustments and might be cost effective. Withdrawal from baclofen should be performed with extreme caution. In selected patients, hospital admission for this purpose may be justified, for example in elderly patients who live on their own without someone looking after them.

154 Fetotoxicity Convulsions have been attributed to baclofen withdrawal after in utero exposure (28A ). • A 7-day-old baby was admitted to hospital with generalized convulsions, which did not respond to phenobarbital, phenytoin, clonazepam, lidocaine, or pyridoxine. A variety of investigations all gave negative results. Electroencephalography 4 days later showed prolonged episodes of epileptic activity. At that time baclofen withdrawal was suspected, as the paraplegic mother had been taking baclofen 20 mg tds throughout pregnancy. The baby was given baclofen 0.25 mg/kg qds and 30 minutes after the first dose the convulsions stopped. The baclofen was then slowly withdrawn over 2 weeks. An MRI scan of the brain on day 17 suggested a hypoxic ischemic insult in the perinatal period, which was considered to have been secondary to convulsions.

This is the first published case of baclofen withdrawal after intrauterine exposure. As convincingly presented by the authors, baclofen withdrawal was the most likely explanation for the convulsions. In discussing the possible mechanisms of the delayed onset of convulsions

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the authors assumed that a secondary increase in baclofen serum concentration due to redistribution might have prevented earlier onset of the withdrawal symptoms. This is of course speculative; nothing is known about baclofen pharmacokinetics in neonates. On the other hand, the authors stated that the mother had noted some abnormal movements starting on the second day post-partum, which might have represented the first signs of withdrawal. The half-life of baclofen in adults is 3–6 hours, and adults usually become symptomatic 24–72 hours after baclofen is reduced or withdrawn (25cr ). In conclusion, baclofen withdrawal should be suspected if postnatal convulsions occur after intrauterine exposure. The first priority in such a case is to rule out other causes, such as infections, electrolyte disturbances, and intracranial pathology, and to prevent secondary brain damage due to prolonged convulsions. Baclofen should probably be considered at an early stage, as it might be the most effective anticonvulsant in such cases.

REFERENCES 1. Tobias JD, Johnson JO, Sprague K, Johnson G. Effects of rapacuronium on respiratory function during general anesthesia: a comparison with cisatracurium. Anesthesiology 2001; 95: 908–12. 2. Levy JH, Pitts M, Thanopoulos A, Szlam F, Bastian R, Kim J. The effects of rapacuronium on histamine release and hemodynamics in adult patients undergoing general anesthesia. Anesth Analg 1999; 89: 290–5. 3. Zappi L, Song P, Nicosia S, Nicosia F, Rehder K. Do pipecuronium and rocuronium affect human bronchial smooth muscle? Anesthesiology 1999; 91: 1616–21. 4. Rose M, Fisher M. Rocuronium: high risk of anaphylaxis? Br J Anaesth 2001; 86: 678–82. 5. Watkins J. Incidence of UK reactions involving rocuronium may simply reflect market use. Br J Anaesth 2001; 87: 522. 6. Laxenaire MC. Epidémiologie des réactions anaphylactoïdes peranesthésiques. Quatrième enquête multicentrique (Juillet 1994–Décembre 1996). Ann Fr Anesth Reanim 1999; 18: 796–809. 7. Booij LHDJ, Houweling PJ. Rocuronium: high risk for anaphylaxis? Br J Anaesth 2001; 87: 805–6. 8. Laxenaire MC, Mertes PM. Anaphylaxis during anaesthesia. Results of a two-year survey in France. Br J Anaesth 2001; 87: 549–58.

9. Laake J, Rottingen J. Rocuronium and anaphylaxis—a statistical challenge. Acta Anaesthesiol Scand 2001; 45: 1196–203. 10. Fisher M, Baldo BA. Anaphylaxis during anaesthesia: current aspects of diagnosis and prevention. Eur J Anaesthesiol 1994; 11: 263–84. 11. Krombach J, Hunzelmann N, Koster F, Bischoff A, Hoffmann-Menzel H, Buzello W. Anaphylactoid reactions after cisatracurium administration in six patients. Anesth Analg 2001; 93: 1257–9. 12. Legros CB, Orliaguet GA, Mayer MN, Labbez F, Carli PA. Severe anaphylactic reaction to cisatracurium in a child. Anesth Analg 2001; 92: 648–9. 13. Briassoulis G, Hatzis T, Mammi P, Alikatora A. Persistent anaphylactic reaction after induction with thiopentone and cisatracurium. Paediatr Anaesth 2000; 10: 429–34. 14. Clancy M, Halford S, Walls R, Murphy M. In patients with head injuries who undergo rapid sequence intubation using succinylcholine, does pretreatment with a competitive neuromuscular blocking agent improve outcome? A literature review. Emerg Med J 2001; 18: 373–5. 15. Kovarik WD, Mayberg TS, Lam AM, Mathisen TL, Winn HR. Succinylcholine does not change intracranial pressure, cerebral blood flow velocity, or the electroencephalogram in patients with neurologic injury. Anesth Analg 1994; 78: 469–73.

Neuromuscular blocking agents and skeletal muscle relaxants 16. Brown MM, Parr MJ, Manara AR. The effect of suxamethonium on intracranial pressure and cerebral perfusion pressure in patients with severe head injuries following blunt trauma. Eur J Anaesthesiol 1996; 13: 474–7. 17. Minton MD, Grosslight K, Stirt JA, Bedford RF. Increases in intracranial pressure from succinylcholine: prevention by prior nondepolarizing blockade. Anesthesiology 1986; 65: 165–9. 18. Stirt JA, Grosslight KR, Bedford RF, Vollmer D. “Defasciculation” with metocurine prevents succinylcholine induced increases in intracranial pressure. Anesthesiology 1987; 67: 50–3. 19. Gronert GA. Cardiac arrest after succinylcholine: mortality greater with rhabdomyolysis than receptor upregulation. Anesthesiology 2001; 94: 523–9. 20. Booij LHDJ. Is succinylcholine appropriate or obsolete in the intensive care unit? Crit Care 2001; 5: 245–6. 21. Al-Khafaji AH, Dewhirst WE, Cornell CJ Jr, Quill TJ. Succinylcholine-induced hyperkalemia in a patient with mucositis secondary to chemotherapy. Crit Care Med 2001; 29: 1274–6. 22. Martyn J, White D, Gronert G, Jaffe R, Ward J. Up-and-down regulation of skeletal muscle

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acetylcholine receptors. Anesthesiology 1992; 76: 822–43. 23. Turner MR, Gainsborough N. Neuroleptic malignant-like syndrome after abrupt withdrawal of baclofen. J Psychopharmacol 2001; 15: 61–3. 24. Khorasani A, Peruzzi WT. Dantrolene treatment for abrupt intrathecal baclofen withdrawal. Anesth Analg 1995; 80: 1054–6. 25. Green LB, Nelson VS. Death after acute withdrawal of intrathecal baclofen: case report and literature review. Arch Phys Med Rehabil 1999; 80: 1600–4. 26. Reeves RK, Stolp-Smith KA, Christopherson MW. Hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation associated with baclofen pump catheter failure. Arch Phys Med Rehabil 1998; 79: 353–6. 27. O’Rourke F, Steinberg R, Ghosh P, Khan S. Withdrawal of baclofen may cause acute confusion in elderly patients. Br Med J 2001; 323: 870. 28. Ratnayaka BD, Dhaliwal H, Watkin S. Drug points. Neonatal convulsions after withdrawal of baclofen. Br Med J 2001; 323: 85.

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Drugs that affect autonomic functions or the extrapyramidal system

It is not by choice that this chapter gets longer every year—the number of references has increased steadily since SEDA-20. Anyone who reads the lay press will see that the adverse effects of drugs are increasingly the subject of news reports. Indeed, at the time of writing the possible toxic effects of Ephedra may be the subject of criminal investigations in the USA, although this does not fall within the scope of this edition. Once again the many problems associated with the treatment of Parkinson’s disease form the most prominent feature of this chapter, while the widespread use of anticholinergic drugs to mitigate bladder dysfunction has also drawn considerable attention. This year the chapter includes, in addition to the usual survey of the past year, a review of the safety and tolerability of midodrine, an alpha1 -adrenoceptor agonist used in some countries in the management of postural hypotension.

10 mg have been compared with oral doses of (−)ephedrine 50 mg in 16 healthy Caucasian men with no drug/alcohol/nicotine abuse or dependence (1c ). Intranasal ephedrine caused an increase in blood pressure but associated orthostatic hypotension. The growing controversy about the toxic effects of Ephedra can be seen in the correspondence section of the New England Journal of Medicine. With reference to an earlier paper a pathologist, who is also consultant to the Ephedra Education Council, has questioned the involvement of Ephedra in the deaths of eight patients, pointing out that several had preexisting conditions such as chest pain and hypertension (2r ). The authors responded, surely justifiably, that these were contraindications to the use of Ephedra in the first place, and they cast doubt on the adequacy of the warnings provided (3r ). In the same issue of the Journal a group from the New York City Poison Control Center have reported a case of myocardial infarction attributed to Ephedra (4A ).

DRUGS THAT STIMULATE BOTH ALPHA- AND BETA-ADRENOCEPTORS

• A previously healthy 19-year-old man took tablets containing a total of 24 mg of Ephedra alkaloids and 100 mg of caffeine, and 15 minutes later developed severe chest pain radiating down the left arm. An electrocardiogram showed an inferolateral myocardial infarct, confirmed by creatine kinase and troponin I measurements. He made a full recovery, and coronary angiography showed only minimal atherosclerotic disease of the left anterior descending artery.

(SED-14, 414; SEDA-23, 155; SEDA-24, 163; SEDA-25, 166)

Ephedra, ephedrine, and pseudoephedrine Cardiovascular The cardiovascular effects, subjective effects, and abuse potential of single intranasal doses of ephedrine 5 mg and © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

156

The authors emphasized the dangers of Ephedracontaining over-the-counter formulations, even in fit young people. Severe hypertension has been attributed to pseudoephedrine abuse (5A ). • A 36-year-old man with hypertension taking no less than seven antihypertensive drugs had outpatient systolic pressures of over 190 mmHg.

Drugs that affect autonomic functions or the extrapyramidal system Investigations for primary causes of hypertension were negative and there was increasing suspicion of treatment non-compliance or factitious hypertension. Urine screening showed the presence of pseudoephedrine, which the patient could not explain. When he was given his normal antihypertensive drugs under close supervision his systolic blood pressure fell to 70 mmHg and his serum creatinine doubled. His blood pressure became normal when his medication was briefly suspended but he continued to deny any deliberate attempt to alter his blood pressure and discharged himself soon afterwards.

The authors concluded that this represented factitious hypertension due to pseudoephedrine, the first such case reported and a very unusual example of Munchausen’s syndrome. Psychiatric Pseudoephedrine is often used by scuba divers to avoid ear barotrauma. The psychometric and cardiac effects of pseudoephedrine have been evaluated at one atmosphere (100 kPa, sea level) and three atmospheres (30 kPa, 20 m) in a double-blind, placebo-controlled, crossover study in 30 active divers in a hyperbaric chamber (6C ). Pseudoephedrine did not cause significant alterations in psychometric performance at 3 atmospheres. Gastrointestinal Ischemic colitis has been attributed to pseudoephedrine abuse (7A ).

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• A 21-year-old man developed acute myocardial ischemia. Smoking was the only risk factor for coronary artery disease and he denied using cocaine. Angiography showed normal coronary arteries. He had recently started to take amfebutamone for smoking cessation and pseudoephedrine as a non-prescription influenza remedy.

The authors postulated that the combination of two sympathomimetics had caused acute coronary artery vasospasm. This is the first report linking amfebutamone to acute coronary syndrome, and one of a few cases associated with pseudoephedrine. It is also possible that erythromycin, which this patient was also taking, could have impaired the hepatic metabolism of amfebutamone.

DRUGS THAT PREDOMINANTLY STIMULATE ALPHA-ADRENOCEPTORS (SED-14, 417; SEDA-23, 155; SEDA-24, 164; SEDA-25, 167)

Methoxamine

• A 51-year-old woman presented for the second time in 4 months with abdominal pain. On this as on the previous occasion, emergency laparotomy was needed and she was found to have patchy infarction of the terminal ileum and the ascending colon. It emerged that she had been taking pseudoephedrine for 2 years, because she found that it relieved her headaches. In fact she had often noticed abdominal pain and distention, with occasional bloody diarrhea, after taking pseudoephedrine. Before each of her two admissions she had been taking the remarkably high dose of 900 mg/day, and on many other occasions had taken as much as 600 mg/day. She made a good recovery and was said to have stopped taking pseudoephedrine.

Methoxamine, a relatively selective alpha1 adrenoceptor agonist, has been used to a limited extent in the management of urinary stress incontinence. Its effects have been examined in a double-blind placebo-controlled trial in only six women (9c ). There was little effect on maximum urethral pressure, the surrogate end-point used in the trial. The drug was given by intravenous infusion at a maximum dose of 1.0 mg/70 kg/min. There was a significant rise in systolic blood pressure of about 13 mmHg and a fall in pulse rate of some 18 beats/minute. All subjects taking methoxamine had headache, cold extremities, and piloerection. The authors understandably concluded that this is not a very promising treatment for stress incontinence.

The authors quoted seven other published cases of pseudoephedrine-related ischemic colitis, all occurring at much lower dosages, at most 240 mg/day.

Midodrine

Drug interactions Acute coronary syndrome has been attributed to a combination of pseudoephedrine with amfebutamone (bupropion) (8A ).

Orthostatic hypotension forms a potentially very disabling component of several types of autonomic disturbance. It is relatively common in all age groups, but the cause varies. It

158 is commonly due to drugs (such as diuretics, antihypertensive drugs, and neuroleptic drugs) and to neurocardiogenic or vasovagal syncope, which occurs at all ages, usually without any obvious triggers. Hypotension can also form part of autonomic neuropathies, such as those associated with diabetes and less commonly with amyloid. It is also associated with neurodegenerative diseases such as multiple system atrophy and can occur after spinal cord injury, during hemodialysis, and in astronauts. It has also been suggested that orthostatic hypotension is an essential element of the chronic fatigue syndrome in most or all affected individuals, but this is controversial. One relatively common cause of orthostatic hypotension is iatrogenic, in which case withdrawal of the causative drugs solves the problem. In other cases, or when hypotensive drugs cannot be withdrawn, a very wide range of therapies have been tried, reflecting their relative lack of efficacy. Extracellular fluid expansion, with salt and mineralocorticoids, such as fludrocortisone, is of low efficacy and considerable risk, and can lead to cardiac failure or supine hypertension. An alternative approach involves increasing peripheral resistance pharmacologically: ergot alkaloids are among the agents used for this, but their toxicity needs no elaboration. Midodrine is a potential alternative that has now been extensively tested in several of the orthostatic hypotension syndromes, including: neurogenic hypertension due to autonomic neuropathies (10c , 11c ); neurocardiogenic syncope (12c , 13C , 14c , 15M , 16C ); the controversial syndrome of orthostatic hypotension and tachycardia that may be associated with chronic fatigue (17M , 18c ); the hypotension seen during hemodialysis (19M ); and hypotension due to neuroleptic drugs (20c ). Midodrine is a prodrug, whose active metabolite is relatively selective for vascular post-junctional alpha1 -adrenoceptors and therefore increases peripheral resistance by arteriolar constriction, with some venoconstriction in capacitance vessels (21M ). It has minimal activity in the central nervous system, since it does not cross the blood–brain barrier. It can be given orally and has a systemic availability of over 90% by this route. The half-life of the active deglycinated metabolite is relatively short (2–3 hours). The dosage range is 2.5–10 mg tds, and is usually towards the upper end of this range.

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Few of the above-mentioned studies have systematically addressed problems of safety and adverse effects, but on the whole the effects described are predictable from the adrenergic properties of the drug and are dose-related. The most common adverse effect, in up to 15% of patients, is piloerection, with or without paresthesia especially of the scalp and face, most commonly in the form of pruritus. Urinary urgency, increased frequency, and even retention have also been recorded; when they occur they constitute the single most common reason for withdrawal. Less common but more serious is the problem of supine hypertension in up to 3% of subjects, although it is not clear how the underlying pathology of the hypotension influences the likelihood of this reaction. An unexpected reaction has been described in a 33year-old schizophrenic woman who took midodrine 4 mg/day because of postural hypotension due to risperidone 6 mg/day (22A ). She developed an acute dystonic reaction, which recurred several times on rechallenge, and the dose of risperidone had to be halved to minimize the hypotension. Overall, midodrine is a relatively efficacious drug with good tolerability, but with some adverse effects that can usually be anticipated. Monitoring of supine blood pressure is essential.

Phenylpropanolamine Nervous system Cerebral hemorrhage has been attributed to phenylpropanolamine (23A ). • A 37-year-old woman took an over-the-counter formulation containing phenylpropanolamine 100 mg. About 90 minutes later she developed very severe bilateral headache resistant to analgesics. Her blood pressure was 180/100 mmHg but fell rapidly to 110/70 mmHg. A CT scan showed multiple small frontal and parietal hemorrhages, and angiography showed extensive segmental vasospasm. She was treated with nimodipine and prednisolone, followed by verapamil. She made an uneventful recovery and there was angiographic resolution of the vascular lesions.

The authors reviewed a number of other case reports of phenylpropanolamine-induced cerebral vasospasm associated with hemorrhages

Drugs that affect autonomic functions or the extrapyramidal system

and drew a parallel with similar effects of amphetamines.

DRUGS THAT STIMULATE PREDOMINANTLY BETA1 -ADRENOCEPTORS (SED-14, 420; SEDA-23, 156; SEDA-24, 165; SEDA-25, 167) There are still some concerns about the safety of dobutamine stress testing, especially if an accelerated protocol is used. In 47 consecutive patients (mean age 64 years, 46 men) with three or more cardiovascular risk factors, intravenous dobutamine was given at a rate of 40 micrograms/kg/min until the target heart rate was achieved, which took a mean of 11.6 minutes (24c ). Subjective sensations occurred in 49% of the patients (palpitation 21%, chest pain 6%, nausea 6%, headache 6%, dizziness 13%), while half the patients had abnormal cardiac rhythms (ventricular extra beats 38%, supraventricular tachycardia 10%, nonsustained ventricular tachycardia 2%). The authors concluded that the safety and tolerability of this procedure is comparable to that of standard dobutamine stress testing, although its specificity and selectivity are still uncertain. Cardiovascular Even in the absence of overt clinical effects there might be concern that dobutamine may damage the myocardium. In 47 patients in Mannheim (mean age 61 years, 34 men) dobutamine echocardiography was carried out, with blood sampling immediately before and after the procedure and then at 1, 2, 4, 6, and 12 hours (25c ). Assays were carried out for creatine kinase-MB, troponins I and T, myoglobin, and fibrin monomer antigen. There were no significant increases in these markers of myocardial damage and coagulation, regardless of the outcome of the stress test. These findings have confirmed those of an earlier study, although the data do not absolutely exclude abnormal findings in a minority of individuals (26c ). Dobutamine does of course have therapeutic as well as diagnostic uses. Cardiac dysrhythmias have been reported.

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• A 74-year-old man with idiopathic dilated cardiomyopathy was given dobutamine (5 mg/kg/min) to determine whether it would produce a positive inotropic effect (27A ). After 14 minutes he developed asymptomatic pulsus alternans, which resolved with 20 minutes of withdrawal.

A much more serious complication of dobutamine therapy is ventricular dysrhythmias. Of 305 patients with acutely decompensated congestive heart failure, 58 were given dobutamine (although it is difficult to ascertain the dose), 44 were given other standard inotropic drugs such as milrinone, and 203 were treated with brain natriuretic peptide (nesiritide, 0.015 or 0.03 µg/kg/min) (28C ). Of those given dobutamine 7% had sustained ventricular tachycardia, 17% had non-sustained ventricular tachycardia, and 5% had a cardiac arrest. In contrast, the figures for nesiritide were 1, 11, and 0% respectively. There was no analysis of other outcomes but these results certainly do not encourage the use of dobutamine in these very vulnerable patients.

DRUGS THAT ACT ON DOPAMINE RECEPTORS

(SED-14, 421; SEDA-23, 156; SEDA-24, 165; SEDA-25, 168)

Levodopa and dopamine receptor agonists Cardiovascular Dopamine receptor agonists can cause postural hypotension. The efficacy of domperidone in preventing this has been reported in patients taking a dopamine receptor agonist, CQA 206-291, that was never marketed but is said to be as effective as currently used agents (29c ). Apomorphine, one of the oldest and most potent of dopamine receptor agonists, is being increasingly used in patients with severe motor fluctuations in Parkinson’s disease. It is usually given by subcutaneous infusion, but this is associated with the development of persistent nodules, causing major problems in about 10% of patients after 3 or more years. One solution is to give the drug intravenously using an indwelling cannula. Six patients, who

160 had responded well to subcutaneous apomorphine before nodules developed, had such cannulae inserted (30c ). The apomorphine was given at a mean rate of 9.0 mg/hour to a total mean dose of 257 mg/day, very similar to the subcutaneous dosage. The intravenous therapy virtually abolished “off” periods, reduced oral antiparkinsonian drug dosages by 59%, and produced a marked (but unquantified) reduction in dyskinesias and an improved quality of life. However, there were major problems. Two patients receiving high doses of apomorphine (450 and 290 mg/day, in the latter case a deliberate overdose) developed thromboembolic complications, following crystal formation, in one case to the right lung and in the other with obstruction to the superior vena cava. Both required surgical intervention. Both recovered fully, but the authors understandably commented that this therapeutic approach still needs further development. Respiratory Pleuropulmonary disease, especially with a fibrotic component, has been reported with all the ergot alkaloids after longterm use. • A 65-year-old man, who had been taking pergolide 3.5 mg/day for 3 years to treat restless legs syndrome, presented with progressive weight loss, fatigue, and dyspnea (31A ). The history was of at least 2 years duration. A chest X-ray showed a loculated right hydropneumothorax, and a bloody pleural exudate was aspirated with no cytological evidence of malignancy. An open biopsy showed inflammatory changes and fibrosis. After withdrawal of pergolide and a short course of corticosteroids he made a full clinical and radiological recovery.

Nervous system In the USA bromocriptine has not been licensed for the suppression of lactation since 1994. Up to that time there had been no reports of intracranial hemorrhage associated with bromocriptine, but since the withdrawal of the license for this indication there have been 15 case reports of this disastrous adverse effect. • Three women aged 22, 24, and 40 years took bromocriptine 2.5 mg bd for 2–5 days post-partum and complained of headache; two lost consciousness (32A ). One subsequently died and another had a residual neurological deficit. In all three cases intracerebral hemorrhage, confirmed by CT or MRI scans, occurred on the sixth day of administration. Maximal recorded blood pressures were 200/100, 173/120, and 180/118 mmHg.

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It hardly needs emphasis that the use of bromocriptine to suppress lactation is difficult to justify, given these potentially catastrophic, if rare, consequences. The successful use of ergot derivatives to shrink macroprolactinomas can have unwanted neurological consequences, and this has been described in two case reports. • Three Italian men aged 39, 42, and 53 years with invasive prolactinomas took cabergoline 1.0–3.0 mg/week and all developed CSF rhinorrhea after 2–7 months (33A ). This was clearly a consequence of loss of the “stopper” effect of the tumor, owing to shrinkage, and in each case was successfully treated by endoscopic trans-sphenoidal surgery. • A 42-year-old Spanish man took cabergoline (up to 3 mg/day) for a large prolactinoma causing hypopituitarism and symptomatic chiasmal compression (34A ). After 18 months there was only a minimal tumor remnant on the floor of the sella turcica, but there was chiasmal herniation. However, there were no clinical effects of this, and in particular the visual fields were normal.

A much less well-known adverse effect of levodopa and dopamine receptor agonists is impairment of proprioception (35c ). In 17 Parkinsonian patients three tests of proprioception were carried out 1 hour after the administration of levodopa or a dopamine receptor agonist. Although data were not provided for individual patients, there was an overall 11–31% deterioration in the mean scores in all three of the tests. There was no difference between patients with and without dyskinesias, but the authors suggested that abnormal proprioception may be a factor in drug-induced dyskinesia.

Sleep disorders with dopamine receptor agonists The apparent association of some newer dopamine agonists with “sleep attacks” continues to attract a great deal of interest. Some remarkable case reports have previously been published (SEDA-25, 169) and reports continue to appear, supplemented by prospective studies and other analyses. For instance, 11 studies involving ropinirole or pramipexole in a total of 2066 patients have been reviewed (36M ). Four of these (two each with ropinirole and pramipexole) were placebo-controlled.

Drugs that affect autonomic functions or the extrapyramidal system

The pooled relative risk of somnolence was 4.98 compared with placebo: there was a nonsignificant trend for greater somnolence with ropinirole, but the confidence intervals were much wider than with pramipexole. In the other studies levodopa alone was compared with levodopa plus the newer drugs; the relative risk was 2.06 compared with levodopa alone. It must be borne in mind that somnolence and sleep attacks may be separate phenomena, although this is controversial. The whole field of sleep disorders in Parkinson’s disease has been reviewed in a consecutive series of 320 patients from Houston, with analysable data from 303 (sex distribution unknown) (37C ). The mean age was 67 years and the mean duration of the disease was 9.1 years. All the patients completed the Epworth Sleepiness Scale and answered specific questions about falling asleep while driving and about the restless legs syndrome. The mean sleepiness score was 11.1, values greater than 10 being regarded as abnormal. As one would expect, just over half the patients had scores at that level. Higher scores correlated with longer duration and greater severity of the disease, with male sex, and with the use of dopamine receptor agonists. There was no apparent difference in this regard between the three most commonly prescribed drugs in these patients (pergolide, ropinirole, and pramipexole, the last being the most frequent). Among those currently driving, 23% reported falling asleep in the car and nearly 20% had features of the restless legs syndrome. This study has therefore reinforced the view that sleep disorders are common in Parkinson’s disease, especially in its advanced stages, and are exacerbated by dopamine agonists as a class. However, one can draw no conclusions about individual drugs from this review. The effects of pramipexole, cabergoline, and levodopa on daytime sleepiness have been assessed in three groups of patients with Parkinson’s disease (38c ). The first group was 19 patients taking pramipexole (mean age 60 years, mean dosage 4.5 mg/day, eight as monotherapy, the remainder with levodopa); the second group was 22 patients taking cabergoline (mean age 63 years, mean dosage 4.1 mg/day, 10 as monotherapy); the third group was 14 patients taking levodopa (mean age 69 years, mean dosage 789 mg/day) as monotherapy.

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The scores on the Epworth Sleepiness Scale were virtually identical (8.0, 8.1, 8.1). Scores of greater than 16, indicating excessive daytime sleepiness, were also evenly distributed across the three groups, and were attributed to only four individuals; there were no reports of sleep attacks. These results have been supported by a study in 160 patients with Parkinson’s disease (mean age 66 years) divided into four equal groups and taking levodopa alone, levodopa with bromocriptine, levodopa with ropinirole, or levodopa with pramipexole (39C ). They were compared with 40 healthy younger controls (mean age 58 years). All the subjects were evaluated using the Epworth sleepiness scales. All the drug regimens were associated with increased sleepiness compared with the controls but there were no distinct sleep attacks. The authors noted that all the drug regimens produced similar levels of sedation, although the data appeared to show a trend towards greater somnolence with ropinirole and more particularly pramipexole. However, these are not uncontested findings. In a study that was described as prospective, but was strictly speaking not, 236 patients (106 men, 130 women, mean age 67 years) were questioned (40C ). All but one was in Hoehn– Yahr stages II–IV. Sleep attacks were reported by 72 patients, of whom 70% were considered to have autonomic dysfunction. The authors concluded that the highest risk was attributable to ropinirole (OR = 7.35), followed by bromocriptine (5.78) and lisuride (5.68); for comparison, the figure for levodopa was 0.61. No patients took pramipexole. Again, it is uncertain whether sleep attacks can truly be distinguished from “ordinary” sleepiness, but the results emphasize the sedative potential of dopamine receptor agonists. On the other hand, these results have been disputed in another report, with authors in common with the previous report. They presented four case studies, three men and one woman, aged 49–87 years, who had had Parkinson’s disease for 8–17 years; the longest duration was in the youngest patient (41A ). All four were taking levodopa (300–1500 mg/day) plus a decarboxylase inhibitor. All four reported sudden irresistible sleep episodes, even during conversations: two also complained of sleepiness distinct from these attacks. Two of the patients

162 also had definite autonomic disturbances. The authors concluded that sleep attacks do occur and may be associated with levodopa as well as with dopamine receptor agonists. The sedative potential of levodopa has been examined in 16 healthy volunteers (mean age 25 years, eight men), although of course this represents a very different neuropsychological context from Parkinson’s disease (42c ). They were given levodopa 200 mg or a placebo as a single dose, with domperidone to minimize peripheral adverse effects, followed by the active drug or control in a cross-over design. Sedation was assessed using a visual analogue scale and reaction time by the response to a light stimulus. There was no overall change in reaction time, but this concealed considerable interindividual variation. Four subjects complained of nausea and one of excitation after levodopa and all had slower reaction times without complaining of sedation. However, seven subjects reported a greater level of sedation with levodopa than placebo, and this correlated (r = 0.7) with their reaction times. In other words, levodopa can cause sedation in normal young people but does not necessarily do so, at least after a single dose. The extent to which these results can be extrapolated to elderly Parkinsonian patients is debatable. Overall, therefore, the current evidence suggests that sedation is a class effect of all dopaminergic drugs, including levodopa. It may be more severe with the newer synthetic agents pramipexole and ropinirole, but this cannot yet be stated with certainty. The existence of discrete sleep attacks also remains controversial, although on balance one would conclude that they can occur. Psychiatric In a prospective study of 89 patients with Parkinson’s disease, of whom 60 were free of hallucinations at entry, though most of these had disturbed sleep patterns, after 4 years 50% of the original non-hallucinators were experiencing hallucinations, while only 14% of those with hallucinations at entry were no longer affected by them (43C ). Those classified as having severe hallucinations increased from 10% at entry to 35% after 4 years. The development or worsening of hallucinations was not associated with levodopa dosage but was strongly correlated with the use of dopamine receptor agonists in combination

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with levodopa: some 59% of patients with hallucinations were taking agonists as against 33% of non-hallucinators. Drug interactions Ropinirole has been reported to enhance the effects of warfarin (44A ). • A 63-year-old man taking co-careldopa and warfarin 4 mg/day (it is not entirely clear why) was also given ropinirole 0.75 mg/day to allow levodopa sparing. After 9 days of ropinirole his INR had increased to 4.6 from a previously stable value of 1.8–2.1, little changed in 2 years. There was no clinical evidence of bleeding. Warfarin was withheld for 4 days and then restarted at 25% of its previous dose. The ropinirole was then withdrawn because of gastrointestinal adverse effects and the warfarin dosage was restored to its previous level.

The mechanism of this interaction has not been elucidated. Ropinirole is metabolized by CYP1A2, but that is not the major isoform involved in warfarin metabolism.

OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY (SED-14, 424; SEDA-24, 167; SEDA-25, 171)

Amantadine Nervous system The popularity of amantadine has waned in recent years, but it is still used in many Parkinsonian patients, especially the more elderly. A new adverse effect has been described in three Japanese women aged 78–87 years (45A ). They had taken amantadine 100–200 mg/day for 1 month to 5 years, in two cases together with co-careldopa. All three developed multifocal myoclonus and two were confused. Amantadine concentrations were high in the two patients in whom they were measured, at over 3000 ng/ml; a concentration over 1000 ng/ml is regarded as toxic. Amantadine was withdrawn and the myoclonus disappeared within 1–2 weeks and did not recur. Cortical myoclonus has also been described with levodopa and bromocriptine, but the mechanism is not known.

Drugs that affect autonomic functions or the extrapyramidal system

Catechol-O-methyl transferase inhibitors Tolcapone was very effective but was withdrawn in 1998 because of liver toxicity. It has been replaced by entacapone, which appears to lack this serious adverse effect, although some neurologists also consider it to be less effective. In 40 patients (mean age 64 years, 22 men) who took tolcapone for 3–7 months and were given entacapone in dosages titrated to 800–2000 mg/day after a transition period of 3–6 months with co-beneldopa, the improvements in “on” and “off” times were less impressive than they had been with tolcapone and there were more adverse effects (46c ). One patient had diarrhea and orthostatic hypertension with both drugs, but another six patients had increased dyskinesias and hallucinations and one developed myoclonus. There was no evidence of liver toxicity with either drug. The authors pointed out that entacapone, unlike tolcapone, not only increases the half-life of levodopa but also its peak concentration, causing significantly enhanced levodopa-related adverse effects. There is therefore a paradox: entacapone appears to be safer but overall causes more adverse effects. The safety issue has been specifically addressed in a Finnish study in 326 patients (mean age 62 years, 217 men) taking levodopa plus a decarboxylase inhibitor (47C ). Two-thirds were randomized to take entacapone 200 mg/day and the remainder to placebo. The withdrawal rate due to adverse events was 14% with entacapone compared to 11% with placebo. Dyskinesias were greatly increased in the former (29% vs 11%) and entacapone was also associated with increased incidences of diarrhea (9.2% vs 1.9%), dry mouth (6.0% vs 0), and discolored urine (6.9% vs 0). However, there was no evidence of liver toxicity with entacapone.

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Cardiovascular Vasospasm is a well-known adverse effect of ergot alkaloids. • A 48-year-old woman developed a cold pulseless right leg and no measurable blood pressure at the right ankle (48Ar ). She was a migraine sufferer and had been taking over-the-counter medications, some of which contained ergot derivatives, although the nature and quantity were not specified. Arteriography showed severe stenosis of the superficial femoral artery, with no identifiable tibial vessels. There was an initial improvement with intra-arterial glyceryl trinitrate infusion, and sustained normalization of the circulation in the leg after administration of sodium nitroprusside, nifedipine, prazosin, and heparin. She made a full recovery.

The authors reviewed the pharmacology of the ergot alkaloids and the acute and subclinical ischemic syndromes that they can produce. They pointed out that in some countries, notably in Latin America, ergot-containing formulations are freely available without a prescription. • A 34-year-old woman has a myocardial infarction after being given ergonovine for an atonic uterus after cesarean section (49A ). Within minutes she became unresponsive, with bradycardia and then asystole followed by ventricular fibrillation during cardiopulmonary resuscitation. An electrocardiogram showed an acute anterior infarct and coronary angiography showed diffuse spasm of the circumflex and left anterior descending arteries, with subtotal occlusion of the latter. The spasm was reversed with intracoronary glyceryl trinitrate but she required ventilation for another 2 days and was eventually discharged 11 days after the infarct, with a borderline left ventricular ejection fraction of 45%.

The authors commented that the patient was of Asian origin and that such individuals are thought to have increased susceptibility to the vasoconstrictor effects of ergot derivatives. Any vascular bed is susceptible to the vasospastic effects of ergot alkaloids.

SEDA-23, 157; SEDA-24, 168; SEDA-25, 171)

• A 50-year-old woman developed ischemic necrosis of the stomach wall after taking up to 5 mg/day of ergotamine tablets for 10 years because of daily headaches (50A ). The necrosis was on the greater curvature and was about 10 cm in diameter. She required laparotomy because of peritonitis and there was a 4 cm area of full-thickness necrosis within the ischemic area. She made a full recovery.

Ergot-related adverse effects are still remarkably frequent and severe.

The authors noted that this is an extremely rare manifestation of ergot-induced ischemia.

THE ERGOT ALKALOIDS AND RELATED AGENTS (SED-14, 431;

164 Drug interactions It is important to remember that ergot derivatives are subject to metabolism by cytochrome P450 and hence to drug interactions. This has been highlighted by two cases of interactions, one with clarithromycin the other with ritonavir. • A 41-year-old woman presented with pain and pallor in the leg and a sensation of coolness exacerbated by exercise (51A ). For many years she had been taking a formulation containing ergotamine 1 mg plus caffeine 100 mg, at a dose of one or two tablets daily, for both prophylaxis and treatment of migraine. For 7 days she had also taken clarithromycin (dose is not stated) for a chest infection. Her legs were cool and cyanosed, with no palpable popliteal or foot pulses and an ankle–brachial index of only 0.6 (normal > 0.8). The authors concluded that her symptoms had been precipitated by the introduction of clarithromycin, a cytochrome P450 inhibitor like the other macrolide antibiotics. However, she was also taking omeprazole, another inhibitor, which may have contributed to the problem. All drugs were withdrawn and nifedipine was given, with full recovery within a couple of days. • A 37-year-old woman with AIDS who had been taking ritonavir developed acute dysphasia and right-sided weakness having taken a total of 10 mg of ergotamine in suppository form for severe headaches that were presumed to be migraine (52A ). Transcranial Doppler and angiography showed multiple stenoses in vessels in the circle of Willis, and an MRI scan showed watershed infarcts in the right and left hemispheres. It was presumed that she had had ergotamine-induced vasospasm due to inhibition of ergotamine metabolism by ritonavir. She was treated with “hemodilution, hypertension and hypervolemia”, and her cerebral flow velocities normalized over the next 18 days and the angiographic appearances by day 90. She was left with a slight right expressive dysphasia and weakness in the right leg.

DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM (SED-14, 436; SEDA-23, 158; SEDA-24, 168; SEDA-25, 172)

Acetycholinesterase inhibitors Cardiovascular The cholinesterase inhibitors are potentially very dangerous drugs, as two American case reports of asystole have testified.

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Michael Schachter

• A 67-year-old man underwent left upper lobectomy for a presumed malignancy 11 years after cardiac transplantation (53A ). He had had no cardiac symptoms since his transplant. Succinylcholine was used as a muscle relaxant and was reversed with glycopyrrolate 0.8 mg and neostigmine 4 mg. Within a few minutes he developed asystole, which lasted for about 45 seconds. He subsequently made a full recovery.

The authors speculated that some degree of cardiac re-innervation may have occurred; they recommended that this type of response should be anticipated in future anesthesia in such patients and that therapeutic measures, such as a beta-adrenoceptor agonist, should be available. Another case of asystole has been reported with the very short-acting cholinesterase inhibitor edrophonium (54A ). • A 49-year-old woman was given intravenous edrophonium chloride 2 mg as part of the investigation of an acute myopathy following gastrointestinal surgery. She had also received a total of 60 mg of intravenous labetalol in the 14 hours before the edrophonium was given: presumably this was for a raised blood pressure, but that was not specified. Labetalol caused transient but severe bradycardia (heart rate about 20 beats/min). Immediately after the injection of edrophonium she developed asystole, which was treated immediately with atropine and recovered in 10 seconds.

Such reactions are extremely rare, but in this case the risk was undoubtedly enhanced by previous beta-blockade.

Anticholinergic drugs The adverse effects of the antimuscarinic anticholinergic drugs in patients with incontinence and bladder overactivity has been emphasized in several recent reviews (55M , 56C , 57M , 58C ). The findings are not unexpected: dry mouth is by far the most commonly reported adverse effect, with a frequency of about 40% in patients taking 2 mg of the immediate-release formulation bd. The next most common effects are consistently headache, constipation, and abdominal discomfort. Hallucinations and tachycardia have also been reported. It is agreed that higher doses should not be used because of the risk of urinary retention. About 5% of patients stopped taking tolterodine because of adverse effects and in about 10% the dosage

Drugs that affect autonomic functions or the extrapyramidal system

was reduced. In one comparison of tolterodine 2 mg bd with 4 mg od in an modified-release formulation the latter produced about a 23% lower incidence of dry mouth, with increased efficacy (59C ). Cardiovascular Non-sustained ventricular tachycardia has been attributed to orphenadrine (60A ). • A 57-year-old woman had been taking a formulation containing orphenadrine 15 mg and paracetamol 450 mg bd for musculoskeletal pain. She was also taking propafenone 600 mg/day for paroxysmal atrial fibrillation. After 5 days she developed severe palpitation. Holter monitoring showed frequent brief episodes not only of atrial fibrillation but also of non-sustained ventricular tachycardia. After the orphenadrine was withdrawn the palpitation ceased.

The authors pointed out the potential problems of anticholinergic drugs like orphenadrine in patients taking antidysrhythmic drugs. Possible precipitation of acute myocardial infarction has been discussed by two American emergency medicine specialists (61A ). • A 62-year-old woman developed chest pain and sinus bradycardia (41 beats/min). She had thirddegree heart block and was given atropine 1 mg intravenously. Three minutes later her chest pain increased and the electrocardiogram now showed

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an acute inferior myocardial infarction, confirmed by serum markers. Angioplasty recanalized the right coronary artery.

The authors discuss the possibility, suggested by others, that atropine can precipitate acute myocardial infarction in an ischemic setting. They concluded that while this may be true, on the whole the advantages of successfully correcting bradycardia outweigh the risks of this rare complication. Salivary glands The reference drug for tolterodine is oxybutynin, and there have been several comparisons of the two. All agree that the older drug, in its standard formulation at a dose of 5 mg bd, while of similar efficacy, produces significantly more adverse effects (62C ). The incidence of dry mouth reached 60%, and over 75% in patients taking the highest dose of 5 mg tds. Direct measurements of saliva production confirmed that oxybutynin 5 mg/day reduces saliva output significantly more than tolterodine 2 mg or a modified-release formulation of oxybutynin 10 mg, all given as single doses (63c ). In over 300 patients modifiedrelease oxybutynin once daily produced less dry mouth (28% vs 33%) than immediate-release tolterodine 2 mg bd (64C ).

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baric environment. S Pac Underw Med Soc J 2001; 31: 50–7. 7. Klestov A, Kubler P, Meulet J. Recurrent ischaemic colitis associated with pseudoephedrine use. Intern Med J 2001; 31: 195–6. 8. Pederson KJ, Kuntz DH, Garbe GJ. Acute myocardial ischaemia associated with ingestion of bupropion and pseudoephedrine in a 21-year-old man. Can J Cardiol 2001; 17: 599–601. 9. Radley SC, Chapple CR, Bryan NP, Clarke DE, Craig DA. Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, doubleblind crossover study. Neurourol Urodyn 2001; 20: 43–52. 10. Low PA, Gilden JL, Freeman R, Sheng K-N, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. J Am Med Assoc 1997; 277: 1046–51.

166 11. Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med 1995; 99: 604–10. 12. Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the management of neurocardiogenic syncope. Heart 1998; 79: 45–9. 13. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M, Fouad-Tarazi FM. Neurogenic orthostatic hypotension: a doubleblind, placebo-controlled study with midodrine. Am J Med 1993; 95: 38–48. 14. Sra J, Maglio C, Biehl M, Dhala A, Blanck Z, Deshpande S, Jazayeri MR, Akhtar M. Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol 1997; 8: 42–6. 15. Calkins H. Pharmacologic approaches to therapy for vasovagal syncope. Am J Cardiol 1999; 84: 20Q–25Q. 16. Perez-Lugones A, Schweikert R, Pavia S, Sra J, Akhtar M, Jaeger F, Tomassoni GF, Saliba W, Leonelli FM, Bash D, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol 2001; 12: 935–8. 17. Rowe PC, Calkins H. Neurally mediated hypotension and chronic fatigue syndrome. Am J Med 1998; 105: 14S–21S. 18. Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance and cognitive impairment in adolescents. PACE 2000; 23: 344–51. 19. Perazella MA. Pharmacologic options available to treat symptomatic intradialytic hypotension. Am J Kidney Dis 2001; 38 Suppl 4: S26–S36. 20. Gairard A-C, Cordonnier A-L, Charles A, Viala A, Patri E, Germain C, Lafay N, Gury C. Recherche de la dose efficace de la midodrine dans l’hypertension orthostatique iatrogène à partir d’une étude pilote. J Pharm Clin 2000; 19: 256–9. 21. Mauro VF. Focus on midodrine: an oral peripheral-acting alpha-agonist for the treatment of orthostatic hypotension. Formulary 1997; 32: 225–31. 22. Takahashi H. Acute dystonia induced by adding midodrine, a selective alpha 1 agonist, to risperidone in a patient with catatonic schizophrenia. J Neuropsychiatry Clin Neurosci 2000; 12: 285–6. 23. Yeyrac G, Huguenin H, Guillon B, Chiffoleau A, Thajte N, Bourin M, Jolliet P. Hémorragie cérébroméningée et angiopathie cérébrale aiguë associées à la prise de phénylopropanolamine: un noveau cas. Thérapie 2001; 56: 321–7. 24. Lu D, Greenberg MD, Little R, Malik Q, Fernicola DJ. Accelerated dobutamine stress testing: safety and feasibility in patients with known or suspected coronary artery disease. Clin Cardiol 2001; 24: 141–5. 25. Pfleger S, Scherhag A, Latsch A, Dempfle CE, Simonis B, Haux P, Voelker W, Gaudron P. Safety of dobutamine echocardiography: no signs of myocardial cell damage or activation of the coag-

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ulation system. Dis Manage Clin Outcomes 2001; 3: 15–19. 26. Beckmann S, Bocksch W, Muller C, Schartl M. Does dobutamine stress echocardiography induce damage during viability diagnosis of patients with chronic regional dysfunction after myocardial infarction? J Am Soc Echocardiogr 1998; 11: 181–7. 27. Kahn JHL, Starling MR, Supiano MA. Transient dobutamine-mediated pulsus alternans. Can J Cardiol 2001; 17: 203–5. 28. Burger AJ, Elkayam U, Neibaur MT, Haught H, Ghali J, Horton DP, Aronson D. Comparison of the occurrence of ventricular arrhythmias in patients with acutely decompensated congestive heart failure receiving dobutamine versus nesiritide therapy. Am J Cardiol 2001; 88: 35–9. 29. Lang AE. Acute orthostatic hypotension when starting dopamine agonist therapy in Parkinson disease: the role of domperidone therapy. Arch Neurol 2001; 58: 835. 30. Manson AJ, Hanagasi H, Turner K, Patsalos PN, Carey P, Ratnaraj N, Lees AJ. Intravenous diamorphine therapy in Parkinson’s disease. Clinical and pharmacokinetic observations. Brain 2001; 124: 331–40. 31. Danoff SK, Grasso ME, Terry PB, Flynn JA. Pleuropulmonary disease due to pergolide use for restless legs syndrome. Chest 2001; 120: 313–16. 32. Kirsch C, Iffy L, Zito GE, McArdle JJ. The role of hypertension in bromocriptine-related puerperal intracranial hemorrhage. Neuroradiology 2001; 43: 302–4. 33. Cappabianca P, Lodrini S, Felisati G, Peca C, Cozzi R, Di Sarno A, Cavallo LM, Giombini S, Colao A. Cabergoline-induced CSF rhinorrhea in patients with macroprolactinoma. J Endocrinol Invest 2001; 24: 183–7. 34. Marcos L, De Luis DA, Botella I, Hurtado A. Tumour shrinkage and chiasmal herniation after successful cabergoline treatment for a macroprolactinoma. Clin Endocrinol 2001; 54: 126–7. 35. O’Suilleabhain P, Bullard J, Dewey RB. Proprioception in Parkinson’s disease is acutely depressed by dopaminergic medications. J Neurol Neurosurg Psychiatry 2001; 71: 607–10. 36. Etminan M, Samii A, Takkouche B, Rochon PA. Increased risk of somnolence with the new dopamine agonists in patients with Parkinson’s disease. A meta-analysis of randomised controlled trials. Drug Saf 2001; 24: 863–8. 37. Ondo WG, Vuong KD, Khan H, Atassi F, Kwak C, Jankovic J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology 2001; 57: 1392–6. 38. Pal S, Bhattacharya KF, Agapito C, Chaudhuri KR. A study of excessive daytime sleepiness and its clinical significance in three groups of Parkinson’s disease patients taking pramipexole, cabergoline and levodopa mono and combination therapy. J Neural Transm 2001; 108: 71–7. 39. Sanjiv CC, Schulzer M, Mak E, Fleming J, Martin WRW, Brown T, Calne SM, Tsui J, Stoessl AJ, Lee CS, Calne DB. Daytime somnolence in patients with Parkinson’s disease. Parkinsonism Relat Disord 2001; 7: 283–6.

Drugs that affect autonomic functions or the extrapyramidal system 40. Montastruc J-L, Brefel-Courbon C, Senard J-M, Bagheri H, Ferreira J, Rascol O, Lapeyre-Mestre M. Sleep attacks and antiparkinsonian drugs: a pilot prospective pharmacoepidemiologic study. Clin Neuropharmacol 2001; 24: 181–3. 41. Ferreira JJ, Thalamas C, Monastruc JL, CastroCaldas A, Rascol O. Levodopa monotherapy can induce “sleep attacks” in Parkinson’s disease patients. J Neurol 2001; 248: 426–7. 42. Micallef-Roll J, Rihet P, Hasbroucq T, Possamaï C, Blin O. Levodopa-induced drowsiness in healthy volunteers: results of a choice reaction time test combined with a subjective evaluation of sedation. Clin Neuropharmacol 2001; 24: 91–4. 43. Goetz CG, Leurgans S, Pappert EJ, Raman R, Stemer AB. Prospective longitudinal assessment of hallucinations in Parkinson’s disease. Neurology 2001; 57: 2078–82. 44. Bair JD, Oppelt TF. Warfarin and ropinirole interaction. Ann Pharmacother 2001; 35: 1202–4. 45. Matunaga K, Uozomi T, Qingrui L, Hashimoto T, Tsuji S. Amantadine-induced cortical myoclonus. Neurology 2001; 56: 279–80. 46. Onofrj M, Thomas A, Iacono D, Di Iorio A, Bonanni L. Switch-over from tolcapone to entacapone in severe Parkinson’s disease patients. Eur Neurol 2001; 46: 11–16. 47. Myllylä VV, Kultalahti E-R, Haapaniemi H, Leinonen M. Twelve-month safety of entacapone in patients with Parkinson’s disease. Eur J Neurol 2001; 8: 53–60. 48. Zavaleta EG, Fernandez BB, Grove MK, Kaye MD. St Anthony’s fire (ergotamine induced leg ischemia). A case report and review of the literature. Angiology 2001; 52: 349–56. 49. Tsui BCH, Stewart B, Fitzmaurice A, Williams R. Cardiac arrest and myocardial infarction induced by postpartum intravenous ergonovine administration. Anesthesiology 2001; 94: 363–4. 50. Papalampros EL, Salakou SG, Felekouras ES, Scopa C, Tsamandas AC, Bastounis E. Ischemic necrosis of gastric wall after long-term ergotamine pill abuse. Case report and review of the literature. Dig Dis Sci 2001; 46: 981–4. 51. Ausband SC, Goodman PE. An unusual case of clarithromycin associated ergotism. J Emerg Med 2001; 21: 411–13. 52. Spiegel M, Schmidauer C, Kampfl A, Sarcletti M, Poewe W. Cerebral ergotism under treatment

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with ergotamine and ritonavir. Neurology 2001; 57: 743–4. 53. Bjerke RJ, Mangione MP. Asystole after intravenous neostigmine in a heart transplant recipient. Can J Anesth 2001; 48: 305-7. 54. Okun MS, Charriez CM, Bhatti MT, Watson RT, Swift TR. Asystole induced by edrophonium following beta blockade. Neurology 2001; 57: 739. 55. Clemett D, Jarvis B. Tolterodine. A review of its use in the treatment of the overactive bladder. Drugs Aging 2001; 18: 277–304. 56. Abrams P, Malone-Lee J, Jacquetin B, Wyndaele J-J, Tammela T, Jonas U, Wein A. Twelvemonth treatment of overactive bladder. Efficacy and tolerability of tolterodine. Drugs Aging 2001; 18: 551–60. 57. Crandall C. Tolterodine: a clinical review. J Women’s Health Gender Med 2001; 10: 735–43. 58. Layton D, Pearce GL, Shakir SAW. Safety profile of tolterodine as used in general practice in England. Drug Saf 2001; 24: 703–13. 59. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 2001; 57: 414–21. 60. Dilaversi P, Pantazis A, Vlasseros J, Gialafos J. Non-sustained ventricular tachycardia due to lowdose orphenadrine. Am J Med 2001; 111: 418–19. 61. Brady WJ, Perron AD. Administration of atropine in the setting of acute myocardial infarction: potentiation of the ischaemic process? Am J Emerg Med 2001; 19: 81–3. 62. Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol 2001; 165: 1452–6. 63. Chancellor MB, Appell RA, Sathyan G, Gupta SK. A comparison of the effects on saliva output of oxybutynin chloride and tolterodine tartrate. Clin Ther 2001; 23: 753–60. 64. Appell RA, Sand P, Dmochowski R, Anderson R, Zinner N, Lama D, Roach M, Miklos J, Saltzstein D, Boone T, Staskin DR, Albrecht D. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT study. Mayo Clin Proc 2001; 76: 358–63.

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14

Dermatological drugs and topical agents

CONTACT ALLERGY Miscellaneous reports of contact allergy to ingredients of topical drugs and cosmetics are listed in Table 1.

Antiviral drugs Topical antiviral drugs rarely cause contact dermatitis. Skin reactions are mostly mild and transitory, including pruritus, pain, rashes, contact dermatitis, and photoallergic contact dermatitis. However, serious reactions occasionally occur (31R ). Antiviral drugs that have been implicated include topical aciclovir, cidofovir, idoxuridine, imiquimod, lamivudine, penciclovir, podophyllin, podophyllotoxin, trifluridine, tromantadine, vidarabine, intralesional and ophthalmic solutions of interferon, intravitreal injections of fomivirsen and foscarnet, and intraocular implants of ganciclovir. Patch testing in these cases only rarely caused positive reactions to the antiviral drug. • In a 44-year-old woman who used topical aciclovir for genital herpes, aciclovir contact allergy was associated with a systemic contact allergic reaction with an erythematous vesiculobullous eruption in the labial and perioral skin and a rash on the upper trunk and extremities (32A ). Patch tests were positive to aciclovir, valaciclovir, and ganciclovir, but not to famciclovir.

have replaced castor oil and lanolin as major components of lipsticks. These fatty acid esters have low allergenic potential. Recently, another case of contact allergy to di-isostearyl malate (patch tested in 7.7% in petrolatum) has been reported (33A ). In another case, a 23-year-old woman, who had cheilitis from her lipstick, showed contact allergy to glyceryl monoisostearate monomyristate; according to the authors, contact allergy to this compound has not previously been reported (34A ).

Cocamidopropyl betaine Cocamidopropyl betaine is the most commonly used amphoteric surfactant in shampoos, bath products, and other cosmetic products. It is popular because of its relatively low irritation potential. Contact allergic reactions are infrequent and have been attributed to sensitizing intermediates rather than cocamidopropyl betaine itself. Of 30 patients who were allergic to cocamidopropyl betaine, all reacted to 3-dimethylaminopropylamine (35c ). More recently, two studies have shown that cocamidopropylamine is the more relevant impurity (36c , 37c ).

Colophonium and gum resins Branched-chain fatty acid esters Branched-chain fatty acid esters, such as glyceryl di-isostearate and di-isostearyl malate, © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

168

Colophonium, a natural unmodified gum resin used in cosmetics such as mascara, lipsticks, creams, and hair removal products, is a known contact allergen. Modifications have been made to colophonium, resulting in a variety of ester gums. In a retrospective study, 1270 patients with leg ulcers were tested for contact allergy with colophonium and the modified ester gum:

Dermatological drugs and topical agents

169

Chapter 14

Table 1. Contact allergy to ingredients of topical drugs and cosmetics Ingredient

Use

Test conc. & vehicle

Number studied

Comments

Reference

Alkylammonium amidobenzoate (Osmaron B)

Biocide in milking cream

Not stated

3135

63 positive of 3135 patients tested; alkylammonium amidobenzoate allergy may increase, owing to the use of milking cream as “natural” skin remedy

(1c )

Aminoethanolamine

Surfactant, mild foaming and cleansing agent in cosmetics

0.005, 0.1, and 0.5% in aqua

4

Rare synthesizer

(2A )

Basic Red 22

Synthetic dye used in cosmetics and textiles

1% aqua

1

Contact allergy in a patient who had used a paraphenylenediaminefree hair-colouring mousse

(3A )

Black iron oxide

Mascara

5% petrolatum

1

Eyelid dermatitis; rare

(4A )

Butylhydroxyanisole

Antioxidant in pharmaceutical products, cosmetics, and food

2% petrolatum

2

Positive reaction to pharmaceutical grade but not to analytical grade

(5A )

Chlorhexidine digluconate

Widely used topical disinfectant and preservative in topical skin products

1% alcohol

1

Both type I and type IV positive reactions on skin testing

(6A )

Chlorhexidine digluconate

Widely used topical disinfectant and preservative in topical skin products

0.5% alcohol

1

Acute pruritic balanitis 24 hours after sexual contact with his wife, who used a lubricant gel containing chlorhexidine digluconate

(7A )

Chlorquinaldol

Colposeptina vaginal ovule

5% petrolatum

1

Cross-reactivity to clioquinol

(8A )

2-Chloro-paraphenylenediamine

Hair-coloring

1% petrolatum

2

Both patients were also positive with paraphenylenediamine

(9A )

Chloroxylenol

Antiseptic

1% petrolatum

1

Contact hypersensitivity followed by leukoderma

(10A )

Cicloproxolamine

Topical antimycotic

1% petrolatum

1

Imidazoles may be a safe alternative because of the lack of cross-reactivity between the two classes of drugs

(11A )

170

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W.M.C. Mulder and M.M.H.M. Meinardi

Table 1. (Continued) Ingredient

Use

Test conc. & vehicle

Number studied

Comments

Reference

Doxepin

Tricyclic antidepressant, used topically as an antipruritic agent

0.5 and 1% petrolatum

1

(12A )

Enoxolone (18-glycyrrhetinic acid)

Topical anti-inflammatory agent

10% petrolatum

1

(13A )

Hydroquinone

Topical bleaching cream

3-Iodo-2-propynylbutylcarbamate

Preservative in wood, cutting oils, and cosmetics

Lanoconazole

1

Weak sensitizer, in contrast to the monobenzyl ester of hydroquinone

(14A )

0.1% petrolatum

3168

7 positive of 3168 patients tested; contact allergy from use in cosmetics is rare

(15c )

Topical antifungal

0.1, 1, and 10% petrolatum

1

This patient was also positive to neticonazole 0.1, 0.3, and 1% in petrolatum, and to diethyl sebacate 1.7 and 5% in petrolatum

(16A )

Methoxy polyethylene glycol/17-dodecyl glycol copolymer (Elfacos OW100)

Emulsion stabilizer, skin-conditioning and viscosity-increasing agent in cosmetics

10% petrolatum

1

Methyldibromoglutaronitrile

Ultrasonic gel; frequently used preservative in cosmetics, coating systems, cutting fluids, adhesives, wood preservatives, color photographic processing solutions, seed disinfectants

0.3% petrolatum

1

Methyl glucose dioleate

Emollient, emulsifier

5% petrolatum

1

Metronidazole

Oral antibiotic

50% petrolatum

1

Noxurol (Clostridiopeptidase A)

Enzymatic wound debridement

As is

1

Spearmint (Mentha spicata)

Compress

2%

1

(17A )

Dermatitis 24 hours after contact with ultrasonic gel; negative reaction to phenoxyethanol; sensitization to methyldibromoglutaronitrile is slowly increasing in frequency

(18A )

(19A ) Fixed-drug eruption; positive patch on residual skin lesion

(20A )

(21A ) Essential oil extracted from the leaves is used widely in food, pharmaceutical, and cosmetics industries

(22A )

Dermatological drugs and topical agents

171

Chapter 14 Table 1. (Continued)

Ingredient

Use

Test conc. & vehicle

Number studied

Comments

Reference

Sodium dihydroxycetyl phosphate

Surfactant, wetting agent and emulsifier in cosmetics

5% petrolatum

1

Another report showed contact allergy to related chemicals

(23A )

Soybean extract

Cosmetics

1, 10, and 20% petrolatum

1

First report of delayed type allergy; did not have type I allergy to soybean extract and had not had symptoms of food allergy

(24A )

Stearyl alcohol in Efudix cream

Excipient in topical medication and cosmetics

Tea tree oil

Natural remedies and cosmetics

As is

1

Further case of erythema multiforme (SEDA-18, 170; SEDA-23, 165; SEDA-24, 177)

(26A )

Triclosan

Antiseptic in detergents, soaps, and cosmetics

2% petrolatum

1

(27A )

Triethanolamine

Emulsifier in cosmetics and topical medicaments

1 and 5% petrolatum

1

To date, the frequency of triclosan hypersensitivity is low Contact allergy from emusifiers is rare, triethanolamine being the more frequent cause

Trimebutine

Antispasmodic, oral or topical use

0.15 to 4.8 mg/ml aqua

1

Zinc ricinoleate

Cosmetics, adhesives, corrosion inhibitors, greases, varnishes, print pigments, deodorizer

(25A )

3

31 patients were positive to colophonium alone, 41 to the ester gum alone, and 33 to both colophonium and the ester gum (38c ). The authors recommended that the patch test tray for patients with leg ulcers should include both colophonium and the ester gum resin. Two other patients with cheilitis due to contact allergy to a lipstick reacted positively to glyceryl hydrogenated rosinate, an ester gum,

1

First report of contact dermatitis following 5 days of use of Proctolog, a cream for hemorrhoids and anal fissures Contact dermatitis in both axillae due to deodorant; also allergic to glyceryl ricinoleate in lipstick

(28A )

(29A )

(30A )

and the main component of the rosinate, glyceryl abietate (both patch-tested at 20% in petrolatum) (39A ).

Compositae There are over 20 000 species in the family of Compositae, including arnica, chamomile,

172 chrysanthemum, dandelion, gerbera, and marigold. Arnica, chamomile, and marigold are used in cosmetics and topical therapeutics. Delayed hypersensitivity reactions to the Compositae can arise from sesquiterpene lactones. To detect contact allergy to sesquiterpene lactones, a mixture of lactones (alantolactone, costunolide, and dehydrocostus lactone) is used. However, Compositae contain other sensitizers, such as polyacetylenes and thiophenes. In a prospective study, the lactone mixture was complemented with a mixture of Compositae (containing ether extracts of arnica, German chamomile, yarrow, tansy, and feverfew) to detect contact allergy to Compositae (40c ). Of 346 patients tested, 15 (4.3%) reacted to the mixture of Compositae, compared with eight of 1076 patients (0.7%) who gave positive results with the lactone mixture, indicating the importance of the addition of Compositae allergens to the lactone mixture. However, the authors warned that patch testing with these mixtures can cause active sensitization. An Austrian study has re-confirmed the importance of testing with not only a mixture of Compositae and a mixture of sesquiterpene lactones, but also with additional plant extracts when there is continuing clinical suspicion of allergy to one of the Compositae (41c ). By using additional short ether extracts, the authors found two of five patients who had otherwise been overlooked.

Immunomodulators Pimecrolimus is a non-steroidal ascomycin derivative with topical anti-inflammatory activity. In a 1% cream it is effective and safe in atopic dermatitis in infants, children, and adults (42C ). Tacrolimus ointment, another calcineurin inhibitor, has similar efficacy in atopic dermatitis. The main adverse effect of both drugs is local skin irritation with a stinging or burning sensation, which occurs in 30% of patients who use pimecrolimus and 50% of patients who use tacrolimus. Typically, children have less skin irritation than adults. Adverse effects such as local immunosuppression and an increased risk of local bacterial and viral infections (notably eczema herpeticum) are less common than with topical corticosteroids

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W.M.C. Mulder and M.M.H.M. Meinardi

(43C ). In addition, there is a lack of skin atrophy (44R , 45C ). However, topical corticosteroids have the advantage of better skin penetration than both pimecrolimus and tacrolimus and will therefore continue to be used for more heavily keratinized skin such as in psoriasis (46r ).

Ketoprofen Topical NSAIDs can cause allergic contact dermatitis (including erythema multiforme-like reactions), as well as phototoxicity, photoallergic contact dermatitis, immediate contact reactions (contact urticaria), and contact vasculitis (SEDA-18, 163; SEDA-22, 170). A case of contact pemphigus has now been reported. • A 65-year-old Caucasian woman developed a localized skin eruption within hours of using ketoprofen gel on her knees to relieve arthralgia (47A ). The lesions were pruritic, well-demarcated, and erythematous, and later became studded with vesicles and small bullae. Histology and immunopathology suggested autoimmune pemphigus.

Local anesthetics When injected into the skin, local anesthetics often cause pseudo-allergic reactions, with similar symptoms to immediate type allergy (48c ). However, true immediate hypersensitivity to local anesthetics is extremely rare. More frequently, local anesthetics cause delayed hypersensitivity reactions, mainly after topical application. • A 50-year-old man had local infiltrations a few days after an injection of lidocaine and dexamethasone (49A ). Prick and intradermal tests were negative after 20 minutes. However, lidocaine produced a positive patch test after 2 days, with erythema and papules. • A 58-year-old man with a urological stoma used a catheter lubricated with Braum Monodose ointment (50A ). After almost 2 years he developed severe pruritus and squamous erythematous plaques in the peristomal skin. Patch tests were positive with the lubricant ointment and one of its constituents, tetracaine. • A 79-year-old man developed a weeping dermatitis of the perianal skin, buttocks, and proximal thighs (51A ). In the previous 3 weeks he had

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Table 2. Contact urticaria to relatively rare antigens in cosmetic products and drugs Allergen

Allergen containing product

Patch tests

Skin prick tests

Remarks

Reference

Phenoxyethanol

Body lotion

Not done

Body lotion + + + Euxyl K 400 ++ Phenoxyethanol 1% + 5% + 10% ++

First report of immediate hypersensitvity

(55A )

Benzyl alcohol

Bacteriostatic saline

10 cm wheal after 24 hours

Not done

Immediate hypersensitivity rare

(56A )

Potassium persulfate

Hair dye

Nickel sulfate

Potassium persulfate (dilution not stated) 5 mm wheal

used Proctosedyl cream, which contains dibucaine (cinchocaine). Patch tests were positive with Proctosedyl cream and 5% dibucaine in petrolatum, while benzocaine, lidocaine, and clioquinol were negative. • A 62-year-old woman had a systemic contact dermatitis several days after topical administration of DoloPosterine ointment for hemorrhoids (52A ). She had erythematous vesicular lesions on her perianal area and an edematous erythematous rash on her upper thighs, elbow flexures, axillae, and face. Patch tests with the ointment and its constituents were positive with DoloPosterine and dibucaine 5% in petrolatum; patch tests with benzocaine and other local anesthetics were negative. • A 71-year-old Japanese man developed an itchy erythematous papular eruption after using an over-the-counter medicament for skin wounds (Makiron) for 1 month (53A ). Patch tests with the constituents showed positive reactions to dl-chlorpheniramine maleate and dibucaine hydrochloride (both 1% in petrolatum). Patch tests with lidocaine hydrochloride and mepivacaine hydrochloride showed no cross-sensitization.

Para-phenylenediamine

(SEDA-25,

177) Para-phenylenediamine, which is added to temporary henna tattoos to enhance their color, can cause contact allergic reactions as well as persistent contact leukoderma, as illustrated in five patients with paint-on henna tattoos (54A ). All were positive on patch testing with paraphenylenediamine. One developed erythema multiforme 4 weeks after the last application. The authors found no other causes of erythema multiforme.

(57A )

CONTACT URTICARIA AND IMMEDIATE REACTIONS Reports of contact urticaria to relatively rare antigens in both cosmetic products and drugs are shown in Table 2.

Methoxypsoralens The methoxypsoralens (5-methoxypsoralen and 8-methoxypsoralen) are furocoumarins used in oral photochemotherapy in the treatment of psoriasis. The first case of anaphylaxis to 5-methoxypsoralen has recently been reported (58A ). • A 36-year-old woman had been treated for a polymorphic light eruption with two annual courses of PUVA, three times weekly for 6 weeks, plus oral 5-methoxypsoralen 60 mg, without any adverse effects. However during the fourth course, 30 minutes after taking 5-methoxypsoralen 60 mg, she developed intense pruritus of the palms, spreading to the body. This was followed by erythema of the palms and symmetrical erythematous patches and urticarial lesions on the trunk. She had dizziness and slight difficulty in breathing. Her symptoms cleared within an hour after intravenous administration of an antihistamine and cortisone. Two months later skin prick tests with 5-methoxypsoralen were negative, but placebo-controlled oral provocation with 5-methoxypsoralen 20 mg resulted in symptoms similar to those she had experienced during PUVA.

174

Oxybenzone Oxybenzone is the most frequently used benzophenone in sunscreens, estimated to be present in 20–30% of commercial products. Phototoxicity and allergic contact dermatitis have been described, but reports of immediate type hypersensitivity are scarce. • A 22-year-old woman with a history of atopy had anaphylaxis 10 minutes after widespread application of a oxybenzone-containing sunscreen (59A ). Blinded patch tests with the sunscreen and its ingredients yielded wheal and flare reactions after 15 minutes to the sunscreen and to oxybenzone. Some days before skin testing the woman had had contact urticaria on the face after kissing a friend who had applied the same sunscreen.

PHOTOSENSITIVITY Felodipine

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5%, diclofenac 1, 5, and 10%, fepradinol 1%, ibuprofen 5%, indomethacin 1, 5, and 10%, ketoprofen 1%, naproxen 5%, paracetamol 1, 5, and 10%, phenylbutazone 1%, piroxicam 1%, salicylic acid 1 and 5%, and thiosalicylic acid 0.1%, all in petrolatum).

Oral contraceptives Diffuse prickly erythema has been attributed to ethinylestradiol in oral contraceptives (62A ). • A woman taking an oral contraceptive (Marvelon® , ethinylestradiol 30 micrograms plus desogestrel 150 micrograms) developed diffuse prickly erythema in an exposed site less than 20 minutes after sun exposure. Phototesting showed photosensitivity in the UVB and UVA ranges, but routine patch and photopatch tests with Marvelon were negative. All abnormal findings were reversed 4 months after withdrawal of the oral contraceptive, but reappeared when she started using another oral contraceptive (Microgynon 30® , ethinylestradiol 30 micrograms plus levonorgestrel 150 micrograms). Repeat phototesting was again abnormal. Her symptoms disappeared after withdrawal of the oral contraceptive. Porphyrin production was normal.

Telangiectases have been described as an adverse effect of calcium channel blockers and are sometimes photodistributed. Photodistributed telangiectases, made worse by solar radiation have been reported in a 67-year-old man taking felodipine 5 mg/day (68A ). Rosacea was also present. Felodipine was withdrawn and the telangiectases improved. Rechallenge was not performed.

Although the estrogen and progestagen were not tested separately in this patient, the photosensitivity was most probably due to the estrogen, because the oral contraceptives that she used contained ethinylestradiol 30 micrograms with different progestogens, and photosensitivity has been described with estrogens (63A ).

NSAIDs

Sunscreens

The arylpropionic acid derivatives often cause allergic and photoallergic contact dermatitis, and photoallergic dermatitis to ketoprofen, with cross-photosensitivity to benzophenone and tiaprofenic acid, has been reported (60A ). Photopatch tests to these substances were positive but patch tests were negative. A case of photoallergic contact dermatitis from aceclofenac has recently been reported (61A ). Photopatch tests were positive with aceclofenac 10% in petrolatum, but not with either aceclofenac 1% or 5% in petrolatum or with a series of NSAIDs and other analgesics (benzydamine hydrochloride 3 and 5%, bufexamac

In 19 patients with positive photopatch tests to sunscreens among all the patients that were photopatch tested between 1992 and 1999 (total not stated) there were 21 positive photopatch tests to sunscreen agents (64c ). Nine patients reacted to oxybenzone, eight to butylmethoxydibenzoylmethane, three to methoxycinnamate, and one to benzophenone. There were no reactions to para-aminobenzoic acid (PABA), reflecting the increased use of PABA-free sunscreens. Six patients also had a positive patch tests to components of the sunscreen base, such as fragrances, which can complicate the diagnosis.

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PHOTOTHERAPY Carcinogenicity The PUVA Follow up Study has prospectively evaluated 1380 patients who started using PUVA for psoriasis in 1975 and 1976. They recently reported an increased risk of melanoma in PUVA-treated patients (n = 822), beginning 15 years after first exposure (65C ). Incidence rates during 1996–9 were 10-fold higher than those expected from incidence data in the general population (data available only for 1992–6). There was an nonsignificant trend towards a higher incidence of melanoma in patients who had received more courses of PUVA (over 200). This risk should be weighed against the substantial efficacy of PUVA therapy in severe psoriasis.

PSEUDOPORPHYRIA Pseudoporphyria is a photodistributed bullous disorder with clinical and histological features similar to those of porphyria cutanea tarda, but without accompanying abnormalities of porphyrin metabolism. Drugs, in particular NSAIDs and sulfur-containing diuretics, often cause pseudoporphyria and have recently been reviewed (66R ). Another case of pseudoporphyria associated with naproxen (15 mg/kg/day) has been reported in a child (67A ).

RETINOIDS

(SED-14, 449; SEDA-25, 179; see also Chapter 38)

Acitretin Nervous system The possible negative effects of short-term oral acitretin 1 mg/kg/day on peripheral nerve function have been assessed in a small prospective study in 13 patients (69c ). Patients with conditions related to peripheral neuropathy were excluded. There was a fall in the mean amplitude of the sensory action potential of the superficial peroneal nerve after 1 and 3 months of therapy. There was a significant change in one or more neurophysiological parameters in three of 13 patients after 1 month

175

and in nine of 13 patients after 3 months. None of the patients had detectable neurological abnormalities at any time during therapy. Acitretin was withdrawn, and after 6 months three patients gradually improved. Further studies are needed to determine whether neurophysiological evaluation should be routine during treatment with oral retinoids.

Isotretinoin Respiratory Immunomodulatory effects of isotretinoin in the treatment of facial acne (40 mg/day for 4 weeks) were held responsible for the recurrence of pulmonary alveolar proteinosis in a 16-year-old girl, in whom it had been in spontaneous remission for 2 years (70A ). Although the time course of this effect was suggestive, it should be born in mind that about 25% of patients with this disease have exacerbations without a clear cause. Psychiatric In 1998 depression, psychosis, and suicidal ideation, suicide attempts, and suicide were added to the product label of isotretinoin. Since then the FDA has received increasing number of reports of these problems (71c ). From the time that isotretinoin was marketed in 1982 up to May 2000 the FDA received 37 reports of patients taking isotretinoin who committed suicide, 110 reports of patients who were hospitalized for depression, suicidal ideation, or suicide attempts, and 284 reports of patients with depression who did not need hospitalization (72r ). In 62% of the suicide cases a psychiatric history or possible contributing factors were identified, and 69% of patients hospitalized for depression had either a previous psychiatric history or possible contributing factors. Drug withdrawal led to improvement in about one-third of the patients, while in 29% depression persisted after withdrawal. In 24 cases dechallenge and rechallenge were positive. However, since this was a series of spontaneous reports, and since there are no good data on the incidence of depression and suicide among adolescents with acne, a causal relation cannot be concluded. A change in dreaming pattern has been reported in two patients, occurring within 2–3 weeks after the start of treatment with

176 isotretinoin 40 mg/day for cystic acne (73A ). One patient also reported increased irritability and bouts of depression. In both patients all the symptoms abated after 4–5 weeks without a change in isotretinoin dosage. Metabolism The incidence of raised serum lipids during therapy with oral isotretinoin 1 mg/kg/day for acne has been reviewed retrospectively in 876 patients, of whom 54 had raised serum cholesterol concentrations (over 5.2 mmol/l) and 45 had triglyceride concentrations above 2.26 mmol/l (74c ). Hematologic Transient polycythemia has been reported during treatment with isotretinoin for severe nodular acne (75A ). • A 53-year-old man’s hematocrit increased from 46% to 51% after he had taken isotretinoin for 11 months (180 mg/day for 3 months, 80 mg/day for 6 months, then 20 mg/day). No secondary causes of polycythemia were found and the hematocrit fell to 48% 3 months after withdrawal of isotretinoin.

The reference range for hematocrit in men is 41–49%, and so the clinical relevance of this observation is unclear. Gastrointestinal Another case of ulcerative colitis has been reported in a 17-year-old boy shortly after he had completed a 5-month course of isotretinoin (dose not stated) for acne (76A ). There was no family history of inflammatory bowel disease. Although three other cases of inflammatory bowel disease during isotretinoin therapy have been reported (77A – 79A ), there have also been reports of the safe use isotretinoin in patents with a history of

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inflammatory bowel disease (i.e. without exacerbation of the inflammatory bowel disease) (77A , 80A , 81A ). Since retinoids are being increasingly used to treat moderately severe acne, larger studies are needed to elucidate the relation between retinoid use and inflammatory bowel disease. Liver The incidence of raised liver enzymes during therapy with oral isotretinoin 1 mg/kg/day for acne has been retrospectively reviewed in 876 patients (74c ). Liver enzymes (AsT, AlT, γ GT) were transiently raised in a minority of patients (number not stated).

MISCELLANEOUS DRUGS Griseofulvin A 40-year-old woman had a burning sensation and erythema of the lips, buccal mucosa, palate, and vulva, which recurred within 4 hours of oral rechallenge with griseofulvin 125 mg (82A ).

Thalidomide

(SEDA-24, 171)

Three new cases of thrombosis in patient taking thalidomide (25–100 mg/day) have been reported after 2 months and 2 years therapy (83A ). However, all three patients had other risk factors (heterozygous protein C resistance in one and surgical intervention or trauma in the others), so a causal role of thalidomide was debatable.

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7. Barraza V. Connubial allergic contact balanitis due to chlorhexidine digluconate. Contact Dermatitis 2001; 45: 42. 8. Rodríguez A, Cabrerizo S, Barranco R, De Frutos C, De Barrio M. Contact cross-sensitization among quinolines. Allergy Eur J Allergy Clin Immunol 2001; 56: 795. 9. Hansson C, Thornbey-Andersson K. Allergic contact dermatitis from 2-chloro-p-phenylenediamine in a cream dye for eyelashes and eyebrows. Contact Dermatitis 2001; 45: 235–6. 10. Malakar S, Panda S. Post-inflammatory depigmentation following allergic contact dermatitis to chloroxylenol. Br J Dermatol 2001; 144: 1262–3. 11. Foti C, Diaferio A, Bonamonte D. Allergic contact dermatitis from ciclopirox olamine. Australas J Dermatol 2001; 42: 145. 12. Horn, HM, Tidman MJ, Aldridge RD. Allergic contact dermatitis due to doxepin cream in a patient with dystrophic epidermolysis bullosa. Contact Dermatitis 2001; 45: 115. 13. Tanaka S, Otsuki T, Matsumoto Y, Hayakawa R, Sugiura M. Allergic contact dermatitis from enoxolone. Contact Dermatitis 2001; 44: 192. 14. Barrientos N, Ortiz-Frutos J, Gómez E, Iglesias L. Allergic contact dermatitis from bleaching cream. Am J Contact Dermatitis 2001; 12: 33–4. 15. Bryld LE, Agner T, Menné T. Allergic contact dermatitis from 2-iodo-propynyl-butylcarbamate (IBBC)—an update. Contact Dermatitis 2001; 44: 226–8. 16. Le Coz C-J, Heid E. Allergic contact dermatitis from methoxy PEG-17/dodecyl glycol copolymer (Elfacos OW100). Contact Dermatitis 2001; 44: 308–9. 17. Umebayashi Y, Ito S. Allergic contact dermatitis due to both lanoconazole and neticonazole ointments. Contact Dermatitis 2001; 44: 48–9. 18. Erdmann SM, Merk HF. Allergic contact dermatitis due to methyldibromoglutaronitrile in Euxyl K400 in an ultrasonic gel. Contact Dermatitis 2001; 44: 39–40. 19. Corazza M, Levratti A, Virgili A. Allergic contact dermatitis due to methyl glucose dioleate. Contact Dermatitis 2001; 45: 308. 20. Gastaminza G, Anda M, Audicana T, Fernandez E, Muñoz D. Fixed-drug eruption due to metronidazole with positive topical provocation. Contact Dermatitis 2001; 44: 36. 21. Bonamonte D, Mundo L, Daddabbo M, Foti C. Allergic contact dermatitis from Mentha spicata (spearmint). Contact Dermatitis 2001; 45: 298. 22. Lisi P, Brunelli L. Extensive allergic contact dermatitis from a topical enzymatic preparation (Noruxol). Contact Dermatitis 2001; 45: 186–7. 23. Lomholt H, Rastogi SC, Andersen KE. Allergic contact dermatitis from sodium dihydroxyacetyl phosphate, a new cosmetic allergen? Contact Dermatitis 2001; 45: 143–5. 24. Shaffrali FCG, Gawkrodger DJ. Contact Dermatitis from soybean extract in a cosmetic cream. Contact Dermatitis 2001; 44: 51–2. 25. Yesudian PD, King CM. Allergic contact dermatitis from stearyl alcohol in Efudix cream. Contact Dermatitis 2001; 45: 313–14.

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178 ical treatment of atopic dermatitis. Arch Dermatol 1998; 134: 805–9. 43. Lübbe J, Pournaras CC, Saurat J-H. Eczema herpeticum during treatment of atopic dermatitis with 0.1% tacrolimus ointment. Dermatology 2000; 201: 249–51. 44. Soter NA, Fleischer AB, Webster GF. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients. Part II, Safety. J Am Acad Dermatol 2002; 44: S39–46. 45. Reitamo S, Wollenberg A, Schopf E. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol 2000; 136: 999–1006. 46. Nghiem P. “Topical immunomodulators?”: introducing old friends and a new ally, tacrolimus. J Am Acad Dermatol 2001; 44: 111–13. 47. Kanitakis J, Souillet A-L, Faure M, Claudy A. Ketoprofen-induced pemphigus-like dermatosis: localized contact pemphigus? Acta Dermatol Venereol 2001; 81: 304–5. 48. Gall H. Kaufmann R, Kalveram CM. Adverse reactions to local anaesthetics: analysis of 197 cases. J Allergy Clin Immunol 1996; 97: 933–7. 49. Breit S, Ruëff F, Przybilla B. “Deep impact” contact allergy after subcutaneous injection of local anesthetics. Contact Dermatitis 2001; 45: 296–7. 50. Fernández-Redondo V, León A, Santiago T, Toribio J. Allergic contact dermatitis from local anaesthetic on peristomal skin. Contact Dermatitis 2001; 45: 358. 51. Kearney CR, Fewings J. Allergic contact dermatitis to cinchocaine. Australas J Dermatol 2001; 42: 118–19. 52. Erdmann SM, Sachs B, Merk HF. Systemic contact dermatitis from cinchocaine. Contact Dermatitis 2001; 44: 260–1. 53. Hayashi K, Kawachi S, Saida T. Allergic contact dermatitis due to both chlorpheniramine maleate and dibucaine hydrochloride in an overthe-counter medicament. Contact Dermatitis 2001; 44: 38–9. 54. Jappe U, Hausen BM, Petzoldt D. Erythemamultiforme-like eruption and depigmentation following allergic contact dermatitis from a paint-on henna tattoo, due to para-phenylenediamine contact hypersensitivity. Contact Dermatitis 2001; 45: 249– 50. 55. Bohn S, Bircher AJ. Phenoxyethanol-induced urticaria. Allergy 2001; 56: 922–3. 56. Guin JD, Goodman J. Contact urticaria from benzyl alcohol presenting as intolerance to saline soaks. Contact Dermatitis 2001; 45: 182–3. 57. Estrada Rodríguez JL, Gozalo Reques F, Cechini Fernandez C, Rodríguez Prieto MA. Contact urticaria due to potassium persulfate. Contact Dermatitis 2001; 45: 177. 58. Legat FJ, Wolf P, Kränke B. Anaphylaxis to 5-methoxypsoralen during photochemotherapy. Br J Dermatol 2001; 145: 821–2. 59. Emonet S, Pasche-Koo F, Perin-Minisini M-J, Hauser C. Anaphylaxis to oxybenzone, a frequent constituent of sunscreens. J Allergy Clin Immunol 2001; 107: 556–7.

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60. Kawada A, Aragane Y, Asai M, Tezuka T. Simultaneous photocontact sensitivity to ketoprofen and oxybenzone. Contact Dermatitis 2001; 44: 370. 61. Goday Buján JJ, García Alvarez-Eire GM, Martinez W, Del Pozo J, Fonseca E. Photoallergic contact dermatitis from aceclofenac. Contact Dermatitis 2001; 45: 170. 62. Cooper SM, George S. Photosensitivity reaction associated with use of the combined oral contraceptive. Br J Dermatol 2001; 144: 641–2. 63. Horkay I, Tamasi P, Prekopa A, Dalmy L. Photodermatoses induced by oral contraceptives. Arch Dermatol Res 197; 253: 53–61. 64. Cook N, Freeman S. Report of 19 cases of photoallergic contact dermatitis to sunscreens seen at the Skin and Cancer Foundation. Australas J Dermatol 2001; 42: 257–9. 65. Stern RS, for the PUVA Follow up Study. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001; 44: 755–61. 66. Green JJ, Manders SM. Pseudoporphyria. J Am Acad Dermatol 2001; 44: 100–8. 67. Maerker JM, Harm A, Foeldvari I, Höger PH. Naproxeninduzierte pseudoporphyrie. Hautarzt 2001; 52: 1026–9. 68. Silvestre JF, Albares MP, Carnero L, Botella R. Photodistributed felodipine-induced facial telangiectasia. J Am Acad Dermatol 2001; 45: 323–4. 69. Chroni E, Georgiou S, Monastirly A, Paschalis C, Tsambas D. Effects of short-term oral actretin therapy on peripheral nerve function: a prospective neurological and neurophysiological study. Acta Dermatol Venereol 2001; 81: 423–5. 70. Khurshid I, Seymour JF, Nakata K, Downie GH. Recurrent manifestations of idiopathic pulmonary alveolar proteinosis after isotretinoin (Accutane® ) treatment. Chest 2001; 120 Suppl: 335. 71. Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001; 45: 515–19. 72. Wysowski DK, Pitts M, Beitz J. Depression and suicide in patients treated with isotretinoin. New Engl J Med 2001; 344: 460. 73. Gupta MA, Gupta AK. Isotretinoin use and reports of sustained dreaming. Br J Dermatol 2001; 144: 919–20. 74. Alcalay J, Landau M, Zucker A. Analysis of laboratory data in acne patients treated with isotretinoin: is there really a need to perform routine laboratory tests? J Dermatol Treat 2001; 12: 9–12. 75. Çakmakci A, Yilmaz AS, Akbulut S, Güll Ü, Özyilkan E. Polycythemia in a patient treated with isotretinoin. Ann Pharmacother 2001; 35: 964–5. 76. Reniers DE, Howard JM. Isotretinoin-induced inflammatory bowel disease in an adolescent. Ann Pharmacother 2001; 35: 1214–16. 77. Godfrey KM, James MP. Treatment of severe acne with isotretinoin in patients with inflammatory bowel disease. Br J Dermatol 1990; 123: 653–5. 78. Martin P, Manley PN, Depew WT, Blakeman JM. Isotretinoin-associated proctosigmoiditis. Gastroenterology 1987; 93: 606–9.

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79. Brodin MD. Inflammatory bowel disease and isotretinoin. J Am Acad Dermatol 1986; 14: 843. 80. Schleicher SM. Oral isotretinoin and inflammatory bowel disease. J Am Acad Dermatol 1985; 13: 834–5. 81. Rosen T, Unkefer RP. Treatment of pyoderma faciale with isotretinoin in a patient with ulcerative colitis. Cutis 1999; 64: 107–9.

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82. Thami GP, Kaur S, Kanwar AJ. Erythema multiforme due to griseofulvin with positive reexposure test. Dermatology 2001; 203: 84–5. 83. Pouaha J, Martin S, Trechot P, Truchetet F, Barbaud A, Schmutz J-L. Thalidomide et thromboses: trois observations. Presse Med 2001; 30: 1008–9.

Garry M. Walsh

15

Antihistamines (H1 receptor antagonists)

Histamine release from mast cells and basophils makes a major contribution to the allergic response, and antihistamines are widely used in the treatment of certain symptoms of allergic disease. However, histamine also functions as a neurotransmitter in the central nervous system, being particularly important in maintaining a state of arousal or awareness (1R ). First-generation H1 receptor antagonists easily cross the blood–brain barrier, and their consequent well-documented sedative and anticholinergic effects, together with short halflives, greatly limit their use in the treatment of allergic symptoms. However, despite these deficiencies it must be remembered that firstgeneration drugs are still widely used, mainly as over-the-counter products, often in combination with other drugs. Second-generation H1 receptor antagonists have major advantages over the earlier drugs; most notably they lack significant CNS and anticholinergic adverse effects. They have proved to be important therapeutic tools in the treatment of atopic disease, including both seasonal and perennial allergic rhinitis, urticaria, and atopic dermatitis (2R ). More recently, several studies have shown that the use of second-generation antihistamines as adjunctive therapy can benefit patients whose allergic asthma co-exists with allergic rhinitis (3R ). Recently, several novel antihistamines have been developed, which are either metabolites of existing drugs or enantiomers. The aim was to develop antihistamines with improved potency, duration and onset of action, and greater predictability and safety. Drugs that to date have received regulatory approval and are effective in several allergic conditions include desloratadine, fexofenadine, and levocetirizine. These have been developed in response to widespread © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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concerns about the potential for cardiotoxicity and the impact of drug–drug interactions associated with some second-generation H1 receptor antagonists. Furthermore, the potential for sedation by some of the newer antihistamines still remains an issue for many. This is important, as many patients using antihistamines want to remain alert and active and may also use other medications. Consequently, progress with this class of drugs should involve not only increased efficacy but also improved safety and specificity.

The cardiotoxic effects of antihistamines Several antihistamines can cause ventricular dysrhythmias of the torsade de pointes type (4R ), first reported with astemizole (5r ) and later with terfenadine (6r ). With a few exceptions, antihistamines are rapidly and completely absorbed after oral administration; peak plasma concentrations are reached after 1–4 hours and are highly variable, owing to differences in metabolism and tissue distribution (2R ). Many of the second-generation antihistamines (e.g. astemizole, ebastine, loratadine, and terfenadine) undergo extensive firstpass metabolism to pharmacologically active metabolites; as a common feature, the reaction is primarily supported by CYP3A4. Under normal circumstances this extensive metabolism leads to low or undetectable plasma concentrations of the parent drug. However, sometimes metabolism of the parent compound can be compromised. Accumulation of unmetabolized astemizole or terfenadine can result in blockade of cardiac potassium channels in the ventricular myocytes that regulate the duration of the action potential; consequent prolongation

Antihistamines (H1 receptor antagonists)

Chapter 15

of the QT interval can result in potentially life-threatening ventricular tachycardia (7R ). Predisposing factors to the induction of cardiac dysrhythmias by antihistamines include: liver disease; concomitant prescribing of drugs such as macrolide antibiotics; overdose; congenital QT prolongation; ischemic heart disease; congestive cardiac failure; and electrolyte imbalance. Studies in which the cardiac safety of the newer antihistamines has been assessed are therefore of great importance. Desloratadine Desloratadine is the primary metabolite of loratadine, with proven efficacy in allergic diseases; it binds to H1 receptors with higher affinity than loratadine and is a more potent antihistamine (8R ). In a large multicenter, double-blind, placebocontrolled, parallel-group study of the efficacy and tolerability of desloratadine in 346 patients with seasonal allergic rhinitis, the symptoms improved significantly and there was no significant effect on the QTc interval (9C ). In another study in 190 patients desloratadine improved the symptoms of chronic urticaria with no adverse electrocardiographic effects (10C ). The effect of co-administration of azithromycin on plasma concentrations of desloratadine has been examined in a randomized third-partyblind, placebo-controlled, parallel-group study in 90 healthy volunteers (11C ). An initial loading dose of azithromycin (500 mg) was given on day 3, followed by 250 mg od for 4 days. Concomitant azithromycin had little effect ( 6 years. Clin Exp Allergy 2001; 31: 77–87. 56. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, Michele TM, Reiss TF, Nguyen HH, Bratton DL. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001; 108: E48. 57. Takahashi N, Iwanaga T, Aizawa H, Koto H, Watanabe K, Kishikawa R, Ikeda T, Shoji S, Nishima S, Hara N. Acute interstitial pneumonia induced by ONO-1078 (pranlukast), a leukotriene receptor antagonist. Intern Med 2001; 40: 791–4. 58. Weller PF, Plaut M, Taggart V, Trontell A. The relationship of asthma therapy and Churg–Strauss syndrome: NIH workshop summary report. Allergy Clin Immunol 2001; 108: 175–83.

59. Hayashi S, Furuya S, Imamura H. Fulminant eosinophilic endomyocarditis in an asthmatic patient treated with pranlukast after corticosteroid withdrawal. Heart 2001; 86: E7. 60. Hashimoto M, Fujishima T, Tanaka H, Kon H, Saikai T, Suzuki A, Nakatsugawa M, Abe S. Churg–Strauss syndrome after reduction of inhaled corticosteroid in a patient treated with pranlukast for asthma. Int Med 2001; 40: 432–4. 61. Katz RS, Papernik M. Zafirlukast and Churg– Strauss syndrome. J Am Med Assoc 1998; 279: 1949. 62. Green RL, Vayonis AG. Churg–Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment. Lancet 1999; 353: 725–6. 63. Tuggey JM, Hosker HS. Churg–Strauss syndrome associated with montelukast therapy. Thorax 2000; 55: 805–6. 64. Reinus JF, Persky S, Burkiewicz JS, Quan D, Bass NM, Davern TJ. Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast. Ann Intern Med 2000; 133: 964–8. 65. Actis GC, Morgando A, Lagget M, David E, Rizzetto M. Zafirlukast-related hepatitis: report of a further case. J Hepatol 2001; 35: 539–45. 66. Danese S, DeVitis I, Gasbarrini A. Severe liver injury associated with zafirlukast. Ann Intern Med 2001; 135: 930. 67. Torres M, Reddy KR. Severe liver injury. Ann Intern Med 2001; 135: 550. 68. Physician’s Desk Reference. Montvale, NJ: Medical Economics; 2001: 611–13. 69. Bostanci I, Sarioglu A, Ergin H, Aksit A, Cinbis M, Akalin N. Neonatal goiter caused by expectorant usage. J Pediatr Endocrinol Metab 2001; 14: 1161–2. 70. Taylor J, Kotch A, Rice K, Ghafouri M, Kurland CL, Fagan NM, Witek TJ. Ipratropium bromide hydrofluoroalkane inhalation aerosol is safe and effective in patients with COPD. Chest 2001; 120: 1253–61. 71. Goldberg A, Confino-Cohen R. Maintenance venom immunotherapy administered at 3-month intervals is both safe and efficacious. J Allergy Clin Immunol 2001; 107: 902–6. 72. Poli F, Longo G, Parmiani S. The safety and efficacy of immunotherapy with aluminum hydroxide-adsorbed venom extract of Vespula spp. An open, retrospective study. Allergol Immunopathol 2001; 29: 191–6.

Drugs acting on the respiratory tract

J.K. Aronson

17

Positive inotropic drugs and drugs used in dysrhythmias

CARDIAC GLYCOSIDES

(SED-14, 523; SEDA-23, 193; SEDA-24, 197; SEDA-25, 205) Cardiovascular Digoxin has previously been reported to cause ventricular fibrillation in children with Wolff–Parkinson–White syndrome (1A , 2A ). There has now been another report (3A ). • A male infant, whose narrow-complex tachycardia at birth had responded to adenosine, was treated with digoxin and 1 week later, during transesophageal electrophysiology, developed coarse ventricular fibrillation after the induction of a supraventricular tachycardia. The serum digoxin concentration was not measured. Isoprenaline was withdrawn and the dysrhythmia resolved spontaneously at 160 seconds.

The effects of digoxin, isoprenaline, and transesophageal stimulation may have combined in this case to cause ventricular fibrillation. Paroxysmal atrial tachycardia with Wenckebach (Mobitz type I) atrioventricular block has been reported in a patient with a serum digoxin concentration of 3.2 ng/ml (4A ). The electrocardiographic effects of cardiac glycoside toxicity in 688 patients have been reviewed in the context of three cases of digoxin toxicity (5Ar ). The three cases featured bidirectional tachycardia in a 50-year-old man with a plasma digoxin concentration of 3.7 ng/ml, junctional tachycardia in a 59-year-old man with a plasma digoxin concentration of 4.3 ng/ml, and complete heart block in a 90-yearold woman whose post-mortem digoxin concentration was 5.0 ng/ml. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

198

Psychiatric Acute delirium is a well-known effect of digitalis intoxication, and another case has been described in a 61-year-old man whose serum digitoxin concentration was 44 ng/ml (6A ). Digitalis toxicity can occasionally cause depression (7A ), and another case has been reported (8A ). • A 77-year-old woman developed extreme fatigue, anorexia, psychomotor retardation, and social withdrawal 1 month after starting to take digoxin 0.5 mg/day for congestive heart failure. She did not respond to intravenous clomipramine 25 mg/day for 7 months. Her serum digoxin concentration was 3.2 ng/ml. Digoxin was discontinued, and 12 days later, when her serum digoxin concentration was 0.5 ng/ml, she had improved, but was left with a memory disturbance, which was attributed to background dementia.

Endocrine Early studies suggested that when breast tumors occurred in women with congestive heart failure taking cardiac glycosides, tumor size was significantly smaller and the tumor cells more homogeneous (SEDA-7, 194). It was originally thought that this action was due to an estrogen-like effect of cardiac glycosides, but more recent evidence suggests that it occurs because inhibition of the Na/K pump is involved in inhibiting proliferation and inducing apoptosis in various cell lines (9E –12E ). In a recent study it was shown that different cardiac glycosides have different potencies in their effects on cell lines such as those of ovarian carcinoma and breast carcinoma (13E ). The order of potency was proscillaridin A > digitoxin > digoxin > ouabain > lanatoside C. Metabolism It has previously been reported that withdrawal of digoxin in three patients with diabetes mellitus led to improved glucose control, implying that digoxin had caused impaired glucose tolerance (SEDA-24, 200). This possibility has again been raised in the context of 14

Positive inotropic drugs and drugs used in dysrhythmias

patients with morbid obesity, who were being given digoxin in the hope that reduced production of cerebrospinal fluid, with the consequent reduction in pressure, might be associated with weight reduction (14c ). The dosage of digoxin (Lanacrist 0.13 mg, equivalent to 0.065 mg of digoxin) was titrated to produce a minimum serum digoxin concentration of 1.0 nmol/l. One patient was already diabetic, and five developed fasting blood glucose concentrations greater than 5.0 mmol/l on three consecutive occasions, with accompanying glycosuria. Another had fasting blood glucose concentrations of 6.0– 8.5 mmol/l. There was a significant relation between the dose of digoxin and the risk of impaired glucose tolerance. However, the diabetes mellitus did not abate after digoxin withdrawal, and since all these patients were obese, the occurrence of diabetes was probably coincidental. Reproductive system Digoxin has been used to cause fetal death before termination of pregnancy (15C ). However, in a double-blind study in 126 women who had terminations by dilatation and evacuation at 20–23 weeks gestation intra-amniotic injection of digoxin 1 mg did not alter blood loss or pain; nor did it reduce difficulties with or the complications of the procedure (16C ). Significantly more women vomited after intra-amniotic digoxin. Digoxin given by this route is slowly absorbed into the systemic circulation, with a peak plasma concentration of 0.8 ng/ml at 11 hours (17c ). Risk factors A retrospective Bayesian analysis in 60 patients has confirmed that age and renal impairment are major factors in digoxin toxicity (18c ). However, an analysis of the data from the Digitalis Investigation Group (DIG) study (SEDA-20, 173) has shown that while mortality in heart failure increases with age, the actions of digoxin are independent of age (19C ). A population pharmacokinetic study in 172 neonates and infants has shown that the clearance of digoxin is affected significantly by total body weight, age, renal function, and congestive heart failure (20C ). Drug contamination Contamination with digitalis-like substances has been suspected in a herbal dietary supplement (21A ).

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• A 26-year-old woman developed chest pain lasting 7 hours after taking a herbal supplement that contained Scutellaria lateriflora, Pedicularis canadensis, Cimifuga racemosa, Humulus lupulus, Valeriana officinalis, and Capsicum annuum. Her medical history was otherwise unremarkable. Examination of her heart showed no abnormality, but during monitoring her heart rate fell to 39 beats/min and her blood pressure to 59/36 mmHg. Her serum digoxin concentration was 0.9 ng/ml.

The authors concluded that the herbal remedy contained digoxin-like factors that had caused digitalis toxicity. Drug interactions Drug interactions with digitoxin have been briefly reviewed in the context of its use in the treatment of congestive heart failure (22r ). In three large studies using either population pharmacokinetic analysis or Bayesian techniques, drugs that inhibit the transport of digoxin by inhibiting P glycoprotein significantly increased the serum digoxin concentration (20C , 23C , 24C ). These drugs included quinidine, spironolactone, and the calcium channel blockers diltiazem, nicardipine, nifedipine, and verapamil. The effects varied from about 22% to about 36%. There have been contradictory results in studies of the effects of captopril on digoxin pharmacokinetics. In some cases, captopril increased steady-state plasma digoxin concentrations (25C ), while in others there was no evidence of an interaction (26C –29C ). In a recent study of eight patients with NHYA Class IV congestive heart failure, captopril 12.5 mg tds for 1 week increased the peak digoxin concentration, reduced the time to peak, and increased the AUC during a single dosage interval at steady state; trough digoxin concentrations did not change (30C ). There are two possible explanations for these findings: that captopril reduced the clearance of digoxin or that it increased both the rate and extent of absorption of digoxin; unfortunately, the authors did not measure either the mean steady-state concentration or the half-life, which would have clarified this. On the whole, however, it is unlikely that this interaction is of any clinical significance, since in no study has there been evidence of digoxin toxicity during concomitant captopril therapy, and in one formal study (29C ) there was evidence of no pharmacodynamic interaction.

200 In 12 healthy young adults the phosphodiesterase inhibitor cilomilast 15 mg bd for 5 days had no effect on the steady-state pharmacokinetics of digoxin, apart from a small reduction in the maximal concentration and a small increase in the time to peak (31C ). This was consistent with a small effect on the rate of digoxin absorption, which is unlikely to be of clinical significance. Digoxin had no effect on the disposition of cilomilast. In a 90-year-old woman the addition of cisapride 5 mg bd reduced the mean steady-state digoxin concentration from 0.9 ng/ml to 0.6 ng/ml and 5 mg tds reduced it to 0.4 ng/ml, with recurrence of her severe biventricular failure (32A ). When the doses of digoxin and cisapride were separated, the serum digoxin concentration rose again. The mechanism of this effect is thought to be increased gastrointestinal motility, although in this case the effect of separating the doses suggests that there might be a direct chemical interaction between the two drugs. In 11 healthy adults citalopram 40 mg/day had no effect on the pharmacokinetics of a single oral dose of digoxin 1 mg (33C ). Digoxin did not affect citalopram pharmacokinetics. In 14 healthy men dofetilide 250 micrograms bd for 5 days had no effect on the pharmacokinetics of digoxin at a steady-state trough concentration of 1.0 ng/ml (34C ). However, in a placebo-controlled study in patients with atrial fibrillation or atrial flutter, conversion to sinus rhythm in patients given dofetilide was more likely if they were also given digoxin (35C ), so there may be a pharmacodynamic interaction. Macrolide antibiotics increase the systemic availability of digoxin by at least two mechanisms: by reducing its metabolism in the gut before absorption (by inhibiting the growth of the bacterium Eubacterium glenum) and by inhibiting P glycoprotein (SEDA-25, 173). Another case of digoxin toxicity has now been reported in a neonate who was also given erythromycin (36A ). She had bradycardia and coupled extra beats. Digoxin and erythromycin were withdrawn and she was given antidigoxin antibodies. Her plasma digoxin concentration, which had previously been 1.8 ng/ml, had risen to 8.0 ng/ml. The potential of itraconazole to increase digoxin concentrations has been well documented (SEDA-25, 206). The importance of this interaction has been emphasized by a report

Chapter 17

J.K. Aronson

of two renal transplant patients who developed digoxin toxicity when they also took itraconazole (37A ). In 11 healthy adults in a double-blind, placebo-controlled study levetiracetam had no effect on the steady-state pharmacokinetics of digoxin or the actions of digoxin on the electrocardiogram (38C ). Sevelamer, a non-absorbed phosphatebinding polymer, in a dose of 2.4 g, had no effect on the pharmacokinetics of single doses of digoxin in 19 healthy volunteers (39C ). In 12 healthy subjects the 5HT4 receptor partial agonist tegaserod 6 mg bd for 3 days had a small effect on the pharmacokinetics of a single oral dose of digoxin 1 mg, reducing the mean AUC by 12% and the Cmax by 15% (40C ). There was a small delay in the time to peak, which was not significant. These results suggest that tegaserod slightly reduces the systemic availability of digoxin, perhaps because it increases gastrointestinal motility, but that the effect is of no clinical significance. It has been claimed that digoxin potentiated the effects of warfarin in a 66-year-old man (41A ). However, the discussion of the possible mechanisms of this observation was flawed, and there is no reason to expect such an interaction, which probably does not occur (42r ). Management of toxicity There has been another report of overdose of digoxin in a neonate (43A ). Complete atrioventricular block and cardiogenic shock were completely reversed within 4 hours after administration of the first dose of antidigoxin antibody; a second dose was given 48 hours later, when first-degree atrioventricular block occurred. A new formulation of antidigoxin antibody has recently been marketed. The traditional formulation (Digibind) is an ovine antibody to digoxin, whose production is stimulated by the administration of digoxin conjugated to human albumin. In contrast, the new formulation (DigiFab), also ovine, is stimulated by injected a conjugate of digoxin to keyhole-limpet hemocyanin (44r ). In 15 adults with digoxin toxicity who were given DigiFab, electrocardiographic abnormalities resolved within 4 hours in 10 patients and the signs of toxicity completely resolved within 4 hours in seven patients and within 20 hours in 14 patients. In one patient loss of the effect of digoxin resulted in

Positive inotropic drugs and drugs used in dysrhythmias

pulmonary edema, pleural effusions, and renal insufficiency. The half-life of DigiFab is slightly shorter than that of Digibind (15 versus 23 hours), but their pharmacodynamic properties are similar. It is said that DigiFab may be preferred in patients who are allergic to sheep proteins, papain, chymopapain, or bromelains. Despite the fact that hemoperfusion techniques, for example with charcoal, remove very little digoxin from the body (SEDA-12, 148), hemoperfusion continues to be reported as an effective method for treating digoxin toxicity. • In an 88-year-old woman whose serum digoxin concentration was 6.4 ng/ml, hemoperfusion with an adsorption column containing beta2 microglobulin caused a fall in serum concentration from 6 ng/ml to 2.3 ng/ml, with improvement in gastrointestinal symptoms (45A ). The serum digoxin concentration then rose again to 3.5 ng/ml over the next 3 days, and a further hemoperfusion treatment reduced it to 1.7 ng/ml, after which the serum concentration gradually fell and the patient improved. Because of chronic renal insufficiency, she also had repeated hemodialyses on alternate days, which also contributed to the reduction in serum digoxin concentrations.

In another study, the clearance of digoxin was measured in eight patients receiving hemodialysis during the use of a beta2 -microglobulin column (46C ). After 240 minutes of hemoperfusion the serum digoxin concentration fell from 1.11 to 0. 57 ng/ml and digoxin clearance was about 145 ml/min. However, this clearance rate cannot have been the true total body clearance, since it merely reflected the change in plasma concentration during hemoperfusion, which would have been almost entirely due to removal of digoxin from the plasma only and not from the tissues. This method cannot be recommended as a substitute for the use of antidigoxin antibodies in the treatment of digitalis toxicity.

OTHER POSITIVE INOTROPIC DRUGS (SED-14, 532; SEDA-23, 195; SEDA-24, 204; SEDA-25, 208) The under-reporting of the results of clinical trials in patients with heart failure has been reviewed (47R ). Some trials that have been unpublished or published only in abstract or

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preliminary form have involved drugs with positive inotropic effects, such as flosequinan, ibopamine, vesnarinone (SEDA-23, 195), and xamoterol.

Enoximone Musculoskeletal Enoximone has previously been reported to cause increased contraction in skeletal muscle in vitro in patients with a predisposition to malignant hyperthermia (48E , 49E ). Vastus lateralis muscle from a 48-year-old man with rhabdomyolysis had an increased in vitro response to increasing concentrations of enoximone above 0.6 mmol/l (50AE ). He also had a heterozygous mutation in his ryanodine receptor gene, with substitution of arginine for glycine in position 2433, a mutation that is associated with malignant hyperthermia. Phosphodiesterase inhibitors, such as enoximone, increase the release of calcium from the sarcoplasmic reticulum by activating ryanodine receptors, and the authors suggested that this may have been the mechanism whereby enoximone precipitated rhabdomyolysis in this case.

Milrinone In a randomized, open-label, parallel-group study of the hemodynamic effects of milrinone and glyceryl trinitrate in 119 patients with advanced decompensated heart failure, milrinone was significantly more effective than glyceryl trinitrate (51C ). Adverse effects caused the withdrawal of milrinone in three of the 58 patients who took it; one had ventricular extra beats, one had renal insufficiency, and one had hypokalemia. Headache was the most common adverse effect in both groups, but was less common in those who took milrinone (12% versus 29%). In a randomized, open study of milrinone and dobutamine in 120 patients with low cardiac output after cardiac surgery, the two drugs were roughly comparable in efficacy (52C ). Adverse events were more frequent with dobutamine (77%) than with milrinone (58%). With milrinone cardiovascular adverse events were the most common, including hypertension

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(13%), hypotension (20%), bradycardia (13%), new atrial fibrillation (5%), and tachycardia (8%). Other adverse events included hemorrhage and oliguria. Adverse events required withdrawal from the study in 20 patients who took milrinone. Inhaled milrinone has been used to treat patients with pulmonary hypertension after cardiac surgery (53C ). Milrinone produced a significant dose-related reduction in pulmonary vascular resistance in nine patients. There were no systemic adverse effects.

DRUGS USED IN DYSRHYTHMIAS The efficacy of a large range of antidysrhythmic drugs in converting atrial fibrillation to sinus rhythm acutely and in maintaining it during long-term treatment has been the subject of a systematic review (54M ). Adverse effects were too sporadically reported to be suitable for proper review. The results are summarized in Table 1. Cardiovascular The prodysrhythmic risks of using antidysrhythmic drugs have been mentioned in the context of a set of guidelines on the management of patients with atrial fibrillation (55Sr , 56Sr ). The recommended drugs for maintaining sinus rhythm after cardioversion vary

J.K. Aronson

depending on the presence of different risk factors for dysrhythmias: • heart failure: amiodarone and dofetilide; • coronary artery disease: sotalol and amiodarone; • hypertensive heart disease: propafenone and flecainide. The prodysrhythmic effects of antidysrhythmic drugs have also been reviewed in discussions of the pharmacological conversion of atrial fibrillation (57r ) and the relative benefits of rate control in atrial fibrillation or maintaining sinus rhythm after cardioversion (58r ). Factors that predict atrial flutter with 1 : 1 conduction as a prodysrhythmic effect of Class I antidysrhythmic drugs (cibenzoline, disopyramide, flecainide, propafenone, and quinidine) have been studied in 24 patients (aged 46–78 years) with 1 : 1 atrial flutter and in 100 controls (59C ). Underlying heart disease was present in nine patients. There was a short PR interval (PR < 0.13 msec) with normal P wave duration in leads V5 and V6 in nine of the 26 patients and only seven of the 100 controls. Signal-averaged electrocardiography showed pseudofusion between the P wave and QRS complex in 19 of the 26 patients and only 11 of the 100 controls. There was rapid atrioventricular nodal conduction (a short AH interval or second-degree atrioventricular block at atrial pacing over 200 beats/mm) in 19 of

Table 1. The results of a systematic review of the efficacy of antidysrhythmic drugs in converting atrial fibrillation to sinus rhythm and maintaining it (54M ) Drug

Amiodarone Disopyramide Dofetilide/ Ibutilide Flecainide Propafenone Quinidine Sotalol

Number of subjects

Efficacy in converting AF (OR compared with control1 )

Efficacy in maintaining sinus rhythm (OR versus control1 )

Ventricular dysrhythmias2 (%)

Other dysrhythmias3 (%)

Drug withdrawal or dosage reduction (%)

108 30 530

5.7 7.0 29

3.4

0–15 0 3–9

0–9 0

0–55

169 1168 200 34

25 4.6 2.9 0.4

3.1 3.7 4.1 7.1

0–2 0–3 0–12 0–1

0–12 0–17 0–28 2–44

0–20 0–55 0–58 4–44

1 Digoxin, diltiazem, or verapamil. 2 Ventricular fibrillation, polymorphic ventricular tachycardia, torsade de pointes. 3 Symptomatic bradycardia, junctional rhythm, non-sustained and/or monomorphic ventricular tachycardia.

Positive inotropic drugs and drugs used in dysrhythmias

the 23 patients. Pseudofusion of the P wave and QRS complex had a sensitivity of 100% and a specificity of 89% for the prediction of an atrial prodysrhythmic effect of Class I antidysrhythmic drugs. Drug overdose The use of techniques of circulatory support (extracorporeal oxygenation and intra-aortic balloon pump) in seven cases of overdose with antidysrhythmic drugs (disopyramide, flecainide, prajmaline, and quinidine) has been reviewed (60R ).

Adenosine

(SED-14, 536; SEDA-23, 197; SEDA-24, 205; SEDA-25, 210) The standard regimen for stress testing with intravenous adenosine is 140 micrograms/kg/min for 6 minutes. However, in 599 patients a 3minute infusion was associated with a lower frequency of some adverse effects (specifically flushing, headache, neck pain, and atrioventricular block) and had similar sensitivity in the diagnosis of coronary artery disease (61C ). Cardiovascular Adenosine can occasionally cause serious cardiac dysrhythmias (SEDA-20, 175), and more cases have been reported. • In a 60-year-old woman with atrial flutter with 2 : 1 block and a ventricular rate of 130/minute, the ventricular rate increased paradoxically to 260/minute with 1 : 1 conduction after intravenous administration of adenosine 6 mg; it responded to intravenous amiodarone 300 mg (62A ). • A 52-year-old woman with a wide-complex tachycardia was given adenosine 6, 12, and another 12 mg as intravenous bolus doses; immediately after the third dose she developed ventricular fibrillation (63A ). She recovered with cardioversion.

In the second case the authors did not discuss the possibility that the presence of digoxin (serum concentration 1.8 ng/ml) may have contributed; the risk of cardiac dysrhythmias after electrical cardioversion is increased in the presence of digoxin (SEDA-8, 174), and the same might be true of chemical cardioversion. In a prospective study of 187 episodes of tachycardia in 127 unselected patients adenosine was given in an average dose of 9.7 mg (64C ). In 108 cases, adenosine induced transient

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ventricular extra beats or non-sustained ventricular tachycardia after successful termination of supraventricular tachycardia; more than half had a right bundle branch block morphology that suggested that the dysrhythmias had originated from the inferior left ventricular septum. The frequency of atrioventricular block has been studied in 600 patients who underwent stress testing with intravenous adenosine 140 micrograms/kg/min for 6 minutes (65C ). The patients were young (under 49 years old; n = 75), middle-aged (50–65 years; n = 214), old (66–75 years; n = 195), or very old (over 75 years; n = 116). The respective frequencies of first-degree atrioventricular block were 15%, 9.3%, 14%, and 17% (overall average 13%), of second-degree block 15%, 7.0%, 8.7%, and 16% (overall average 10%), and of third-degree block 2.7%, 2.3%, 1.0%, and 2.6% (overall average 2.0%). The differences with age were not statistically significant. All types of atrioventricular block were of short duration, were well tolerated, and did not require withdrawal of adenosine or specific treatment. Respiratory A previous study in a few patients with chronic obstructive airways disease showed a dissociation between adenosineinduced breathlessness and bronchospasm (SEDA-24, 205). In another study, 63 of 122 patients had breathlessness during cardiac stress testing with adenosine but none had associated bronchospasm (66C ). Pre-test lung function did not predict the risk of breathlessness and neither chronic obstructive airways disease nor smoking increased the risk. The authors concluded that breathlessness during adenosine stress testing is not due to bronchospasm. Death Two cases of sudden death have been reported soon after the administration of adenosine for presumed supraventricular tachycardia, which turned out to be atrial fibrillation (67A ). The authors thought that both patients may have been unable to cope with the sudden momentary loss of cardiac function that would have occurred immediately after the administration of adenosine; in one case, a patient with chronic lung disease, bronchospasm may have contributed. Management of adverse drug reactions In 34 patients given midazolam or placebo in a

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double-blind study, midazolam significantly reduced patients’ experiences of palpitation and chest pain but had no effects on other adverse events (68C ). These effects were probably due to amnesia rather than a true reduction in the incidence of adverse events, and it is uncertain that the benefit to harm ratio is worth while. However, the authors suggested that midazolam might be useful in patients who have previously had unpleasant adverse reactions to adenosine.

Ajmaline and derivatives

(SED-14,

537; SEDA-24, 206; SEDA-25, 211) Cardiovascular Ajmaline occasionally causes cardiac dysrhythmias (SEDA-25, 211), and two cases of torsade de pointes have been reported in association with prolongation of the QT interval (69A ). Polymorphous ventricular tachycardia has been reported in three previous cases (70A –72A ).

Amiodarone

(SED-14, 537; SEDA-23, 198; SEDA-24, 206; SEDA-25, 211) The efficacy, adverse effects, and drug interactions of amiodarone have again been reviewed (73R , 74R ).

Cardiovascular Torsade de pointes occurs less commonly with amiodarone than with Class I drugs, but cases continue to be reported sporadically, as illustrated by another recent report in a 79-year-old woman who had taken 4800 mg over 6 days; the associated precipitating factors were a prolonged QT interval and hypokalemia (75A ). In another case, a 71-year-old Japanese man with bouts of sustained monomorphic ventricular tachycardia in whom non-sustained polymorphic ventricular tachycardia was induced by rapid pacing during electrophysiological studies, amiodarone therapy resulted in the appearance of three different types of sustained monomorphic ventricular tachycardia, with slightly different cycle lengths, induced and terminated by rapid pacing (76A ). The authors proposed that amiodarone had modulated

J.K. Aronson

the threshold of induction and/or termination of ventricular tachycardia. Prolongation of the QT interval and hypokalemia are well-known risk factors for torsade de pointes. In a recent study in 189 patients, five had torsade de pointes and all five had prolonged QT intervals (77C ). Two of the five, all women, also had raised blood glucose concentrations, and the authors suggested that hyperglycemia is a risk factor for torsade de pointes. However, the number of cases reported in this series was too small to justify such a conclusion. It has previously been suggested that women are more likely to develop torsade de pointes than men in response to antidysrhythmic drugs (78C ), and this has been confirmed in the case of amiodarone in a study of 189 patients given intravenous amiodarone (77C ). This is also reminiscent of the finding that prolongation of the QT interval due to quinidine is greater in women than in men at equivalent serum concentrations (79c ). In a 62-year-old man with dilated cardiomyopathy and an implantable cardioverter defibrillator for ventricular tachycardia, microvolt T wave alternans differed when amiodarone was added (80A ). The onset heart rate with T wave alternans was lower and the alternans voltage higher with amiodarone than without it. The effects of amiodarone appeared to be related to exacerbations of ventricular tachycardia and an increased defibrillation threshold. Respiratory Lung damage due to amiodarone usually presents slowly, but it can occasionally have a rapid onset, particularly in patients who are given high concentrations of inspired oxygen, and there is experimental evidence that amiodarone enhances the toxic effects of oxygen on the lungs (81E ). However, in a recent case adult respiratory distress syndrome occurred very rapidly in a 66-yearold man who took amiodarone 200 mg/day for a few weeks only (82A ). In another case pulmonary infiltrates occurred in a 72-year-old man after treatment with amiodarone (total dose 6800 mg) for only 7 days (83A ). The sialylated carbohydrate antigen KL-6 has been reported to be a serum marker of the activity of interstitial pneumonitis, and in differentiating patients with amiodarone-induced

Positive inotropic drugs and drugs used in dysrhythmias

pneumonitis from patients with similar features not associated with amiodarone (SEDA25, 181). This has been confirmed in a study of 25 patients, three of whom had proven interstitial pneumonitis and KL-6 serum concentrations of 414, 848, and 1217 U/ml; in contrast, all of the other 22 patients had normal CT scans and normal KL-6 concentrations (under 500 U/ml) (84c ). In the same study the limitations of carbon monoxide diffusing capacity in the diagnosis of amiodarone-induced lung disease (SEDA-15, 168) were again demonstrated. CT scanning can detect damage due to amiodarone, but it has also been suggested that high-resolution CT scanning may be able to detect iodine deposition from the drug (85c ). Of 16 patients taking long-term amiodarone, eight had severe respiratory and other symptoms and eight either had no symptoms or had only mild or chronic respiratory symptoms. All eight controls had negative high-resolution CT scans with no areas of high attenuation, while all eight cases had a least one high-attenuation lesion. Amiodarone can occasionally cause isolated lung masses (SEDA-15, 168) and two more cases have been reported. The first was associated with a vasculitis; the lesions resolved completely 4 months after amiodarone withdrawal (86A ). In the second an isolated mass was associated with multiple small nodules in both lungs; the lesions resolved completely 6 months after amiodarone withdrawal (87A ). Special senses Verticillate epithelial keratopathy due to amiodarone, in which there is whorl-shaped pigmentation of the cornea, has previously been proposed to be worsened by soft contact lenses (SEDA-15, 171). Two patients with hard contact lenses and amiodarone-associated keratopathy both complained of increased sensitivity to sunlight and were fitted with ultraviolet light-blocking lenses instead, as a precaution against further corneal damage; however, the authors did not think that the contact lenses had contributed to the damage (88A ). The eyes of 11 patients (eight men and three women) taking amiodarone have been compared with those of 10 healthy sex- and age-matched controls by confocal microscopy (89c ). All those taking amiodarone had bright, highly reflective intracellular inclusions in the

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epithelial layers, particularly in the basal cell layers. In eyes with advanced keratopathy there were bright microdots in the anterior and posterior stroma and on the endothelial cell layer. Keratocyte density in the anterior stroma was lower in the treated subjects than in the controls, and there was marked irregularity of the stromal nerve fibers. The authors concluded that in some patients taking long-term amiodarone corneal damage may penetrate deeper than has previously been suspected. Endocrine Amiodarone-induced thyroid disease has been reviewed in the light of a case in a 71-year-old man who was treated for hyperthyroidism with total thyroidectomy (90AR ), a 69-year-old man whose hyperthyroidism responded to carbimazole and prednisolone (91AR ), and a 74-year-old woman with hypothyroidism (91AR ). The frequency of thyroid disease in patients taking amiodarone has been retrospectively studied in 90 patients taking amiodarone 200 mg/day for a mean duration of 33 months (92c ). Hypothyroidism occurred in five patients and hyperthyroidism in 11. Hyperthyroidism became more frequent with time and was associated with recurrent supraventricular dysrhythmias in four of the 11 patients. The type of amiodarone-induced thyroid disease that occurs is said to depend on dietary iodine intake; in 229 patients taking long-term amiodarone hyperthyroidism was more common (9.6% vs. 2%) in West Tuscany, where dietary iodine intake is low, and hypothyroidism more common (22% vs. 5%) in Massachusetts, where iodine intake is adequate (SEDA-10, 148). However, other factors may play a part. In a retrospective inter-regional study in France there was a greater incidence of amiodaroneinduced hyperthyroidism in the maritime areas Aquitaine and Languedoc-Roussillon, and a greater incidence of amiodarone-induced hypothyroidism in Midi-Pyrenees, a non-maritime area, in which iodine intake is lower than in Languedoc-Roussillon (93c ). The treatment of amiodarone-induced hyperthyroidism can be problematic (SEDA-23, 199). It may not respond to thionamides (carbimazole, methimazole, or propylthiouracil); in that case corticosteroids can be added or alternatively potassium perchlorate can be used. It has been suggested that potassium perchlorate should be used in the treatment of type 1

206 hyperthyroidism (due to excess iodine and associated with normal or increased iodine uptake by the gland) and corticosteroids in the treatment of type 2 hyperthyroidism (due to a direct effect of the drug and associated with reduced iodine uptake by the gland). When five patients with type 2 amiodarone-induced hyperthyroidism were treated with a combination of an oral cholecystographic agent (sodium ipodate or sodium iopanoate) plus a thionamide (propylthiouracil or methimazole) after amiodarone withdrawal, all improved substantially within a few days and became euthyroid or hypothyroid in 15–31 weeks (94c ). Four of the five became hypothyroid and required longterm treatment with levothyroxine. In another patient taking amiodarone, with repeated episodes of ventricular fibrillation associated with hyperthyroidism, propylthiouracil plus prednisone was ineffective and subtotal thyroidectomy had to be performed (95A ). Thyroidectomy has been previously reported to be successful in some drug-resistant cases (SEDA115, 170; SEDA-17, 220). Skin Grey-blue discoloration of the skin during amiodarone therapy has been presumed to be due to lipofucsin deposition. However, it has also been suggested that amiodarone may block the maturation of melanosomes, in view of a case of discoloration associated with a reduced number of mature melanosomes and an increased number of premelanosomes in sunexposed areas of the skin, but normal numbers in non-exposed areas (96A ). Both amiodarone and minocycline can cause skin pigmentation, and this has been reported in a 70-year-old man who developed greyblue pigmentation on sun-exposed areas of his skin after taking amiodarone for 10 years and minocycline for 4 years (97A ). It has been suggested that the skin and mucosal toxicity of amiodarone may be enhanced by radiotherapy (SEDA-16, 178; SEDA-17, 221). However, in a retrospective review of 10 patients who took amiodarone when having external beam radiation therapy there were no unexpected acute sequelae (98c ). Fetotoxicity Fetal hypothyroidism can occur when a mother is given amiodarone during pregnancy (SEDA-17, 221). There has now been a report of two cases of hypothyroidism in

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neonates who had been given intravenous amiodarone as fetuses at 26 and 29 weeks and whose mothers had also taken it orally (99A ). The authors suggested that low dietary iodine intake by the mothers may have contributed, by enhancing the Wolff–Chaikoff effect. Risk factors Infancy The safety and efficacy of amiodarone for supraventricular tachycardia have been studied in 50 infants (mean age 1.0 month, 35 boys) (100C ). They had congenital heart disease (24%), congestive heart failure (36%), or ventricular dysfunction (44%). Six, who were critically ill, received a loading dose of intravenous amiodarone 5 mg/kg over 1 hour, and all took 20 mg/kg/day orally for 7–10 days, followed by 100 mg/day; if this failed to control the dysrhythmia, oral propranolol (2 mg/kg/day) was added. Follow-up was for an average of 16 months. Rhythm control was achieved in all patients. Growth and development were normal. The higher dose of amiodarone was associated with an increase in the QTc interval to over 0.44 seconds, but there were no dysrhythmias. Two infants had hypotension during intravenous loading, as has previously been reported in infants (SEDA-19, 194). AsT and AlT activities and TSH concentrations all increased, but remained within their reference ranges. There were no adverse effects that necessitated drug withdrawal. Anesthesia It has been reported that there is an increased risk of adverse reactions to amiodarone in patients undergoing anesthesia (SEDA-15, 171). However, in a retrospective survey of 12 patients who underwent anesthesia for urgent thyroidectomy due to amiodarone there were no anesthetic complications or deaths (101c ). Drug administration route The therapeutic effect of amiodarone occurs more quickly after intravenous than after oral administration, perhaps because of an effect of the diluent, polysorbate 80, that is used in the intravenous formulation (SED-14, 540). Amiodarone certainly has different electrophysiological effects when it is given intravenously. For example, intravenous amiodarone prolongs the AH interval, while oral amiodarone prolongs atrial and ventricular refractory periods and the HV interval (102C ). Furthermore, the blocking effects

Positive inotropic drugs and drugs used in dysrhythmias

of amiodarone on sodium and calcium channels and its beta-adrenoceptor blocking action occur earlier than its Class III action (103R ). Now an anecdotal report of torsade de pointes after both intravenous and oral administration of amiodarone on different occasions has underlined this difference (104A ). • A 70-year-old woman with dilated cardiomyopathy, ventricular tachydysrhythmia, and a QTc interval of 0.49 seconds was given intravenous amiodarone 240 mg over 15 minutes and 30 minutes later developed a junctional escape rhythm (48 beats/min) with QTc prolongation to 0.68 seconds; 8 hours later she developed torsade de pointes. A few years later she was given oral amiodarone 100 mg/day and 7 weeks later presented with congestive heart failure. Her QTc interval was prolonged (0.50 seconds) and increased further to 0.64 seconds after the addition of dopamine 3 micrograms/kg/min; torsade de pointes again developed. Amiodarone was withdrawn and the QTc interval shortened, but she continued to have recurrent episodes of sustained ventricular tachycardia.

The authors suggested that torsade de pointes induced by intravenous amiodarone depended on heart rate during a bout of bradycardia, while that after oral amiodarone depended on increased sympathetic nervous system activity, and that therefore different electrophysiological mechanisms had been at play. However, it is by no means clear from their description of this case that that was so. They did not report plasma concentrations of amiodarone or desethylamiodarone, its active metabolite. Drug overdose The features of amiodarone overdose and its management have been reviewed (105R ). Drug interactions Both amiodarone and cyclophosphamide can cause lung damage. Interstitial pneumonitis has been reported in a 59-year-old man, who had taken amiodarone for 18 months, 18 days after a single dose of cyclophosphamide; 1 year before he had also received six cycles of chemotherapy containing cyclophosphamide, vincristine, and prednisone, followed by four cycles of cisplatin, cytarabine, and dexamethasone (106A ). The authors suggested that the lung damage had been due to the cyclophosphamide, enhanced by the presence of amiodarone, but in view of the fact that previous similar exposure on six occasions had not resulted in the same effect, it is perhaps more

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likely that this was a long-term adverse effect of amiodarone alone. The presence of foamy histiocytes in the lung biopsy was consistent with this interpretation (SEDA-15, 168). It is true, however, that lung damage due to amiodarone is usually of a more insidious onset than was reported in this case, although a more rapid onset can occur in patients who are given high concentrations of inspired oxygen. On the other hand, lung damage has occasionally been reported to occur rapidly (82A ).

Aprindine

(SED-14, 541; SEDA-24, 210)

In a comparison of oral aprindine and propafenone in 32 patients (25 men and 7 women, aged 43–82) with paroxysmal or persistent atrial fibrillation, aprindine was effective in five of 29 and propafenone in six of 28; adverse effects were not reported (107c ).

Cibenzoline

(SED-14, 541; SEDA-23, 200; SEDA-24, 210; SEDA-25, 217)

Cardiovascular Cibenzoline is an antidysrhythmic drug of Class Ia, with some additional properties of drugs of Class III and Class IV. It can therefore cause cardiac dysrhythmias, as has been reported in a 60-year-old man with hypertrophic cardiomyopathy (108A ). In a 72-year-old woman cibenzoline was associated with left bundle branch block and heart failure (109A ). Excess cibenzoline accumulation was suspected, because of reduced renal function, but plasma cibenzoline concentrations were not reported. Metabolism Cibenzoline can cause hypoglycemia (SEDA-18, 204) and this has again been reported (110A ). The patient, a 65-yearold woman, was also taking alacepril, and the authors suggested that the hypoglycemia was associated with combined use of cibenzoline with an ACE inhibitor, since ACE inhibitors may increase insulin sensitivity (SED-14, 640). Drug overdose Fatal intoxication with cibenzoline has been reported in an 83-year-old man (111A ).

208

Disopyramide

(SED-14, 543; SEDA-23, 200; SEDA-24, 211; SEDA-25, 217)

Respiratory Pneumonitis has been attributed to disopyramide in a 72-year-old man; the symptoms began soon after the first dose (112A ). Bronchoalveolar lavage fluid contained a high percentage of lymphocytes (65%) and a high CD4 : CD8 ratio (69 : 1). The results of a lymphocyte stimulation test suggested that disopyramide had been responsible. Metabolism Hypoglycemia has again been reported in a patient taking disopyramide (113A ). Unusually, the patient, a 70-year-old woman, had type 2 diabetes mellitus, although this has been reported before (SEDA-6, 180).

Dofetilide Dofetilide is a pure Class III antidysrhythmic drug, without actions of any other class. It was developed following the observation that bis(arylalkyl)amines with methanesulfonamido moieties on both aryl groups prolong the cardiac action potential without significantly altering the maximum rate of depolarization (114ER ). The pharmacology, clinical pharmacology, uses, adverse effects, and interactions of dofetilide have been reviewed (115R –121R ). Pharmacology Dofetilide is a highly selective blocker of the rapidly activating component of the inward rectifier potassium channel, IKr (122E –128E ). It therefore delays ventricular repolarization, which becomes less heterogeneous (129E ), and prolongs the action potential duration and effective refractory period (126C , 130C , 131c ); it has the same effects in ventricular muscle in dilated cardiomyopathy and chronic ischemic cardiomyopathy (122E ). It has greater affinity for atrial than ventricular tissues in animals (132E ), but probably not in man (126C , 130C ). It preferentially blocks open channels and has Group 3 actions (SEDA-25, 209), with slow-onset kinetics (133E ) and an increased likelihood of being prodysrhythmic at slower heart rates (134E ). Dofetilide causes a dose-related and plasma concentration-related prolongation of the QTc

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interval (126C , 130C , 131C , 135C –138C , 139c ), and either reduces QTc dispersion (138C ) or has no effect on it (140C , 141C ). The effects on the QTc interval are rate-dependent, being greater at slower heart rates (142C ). Dofetilide does not usually broaden the QRS complex, but this was reported (and published twice) in a single patient with atrial fibrillation, in whom it was attributed to aberrant conduction (143A , 144A ). During repeated oral administration of dofetilide 1.0–2.5 mg/day for 5 days the effect on the QT interval was slightly greater on day 1 than on day 5 at a range of plasma concentrations of about 1–4 ng/ml; this observation suggests the occurrence of tolerance, but in that case one would have expected a clockwise hysteresis loop in the effect concentration curve, and no hysteresis was seen either after a single dose or at steady state (137C ). Dofetilide has a small positive inotropic effect in animal hearts (145E , 146E ). In a doubleblind placebo-controlled study of oral dofetilide 125, 250, or 500 mg bd for the maintenance of sinus rhythm after cardioversion of sustained atrial fibrillation or flutter in 201 patients there were small changes in echocardiographic measures of atrial contractility, but no changes in stroke volume or cardiac output (147C ). Clinical pharmacology The pharmacokinetics of dofetilide are linear after single oral doses of 2–10 micrograms/kg (148C , 149C ) and repeated doses of 1.0–2.5 mg/day (137C ). Dofetilide is well absorbed (about 90%) after oral administration (136C , 148C –150C ). Its absorption is relatively slow and peak concentrations are not reached for 1–2.5 hours; absorption is slower after food. It is a low clearance drug, with a clearance rate of about 6 ml/min/kg, and has a volume of distribution of about 3 l/kg (135C , 150C ). It is mostly excreted unchanged by the kidneys, with a half-life of about 8 hours. Its clearance is therefore roughly proportional to creatinine clearance, particularly at high rates of clearance. A small proportion is metabolized in the liver by CYP3A4 to inactive metabolites (151C ). In a pharmacokinetic–pharmacodynamic study in 10 healthy volunteers intravenous dofetilide 0.5 mg caused a mean maximum prolongation of the QTc interval of 121 msec and the mean plasma concentration associated with half-maximal effect was 2.2 ng/ml (150C ).

Positive inotropic drugs and drugs used in dysrhythmias

Uses Dofetilide has been used to convert atrial fibrillation and atrial flutter to sinus rhythm, in maintaining sinus rhythm thereafter, in suppressing paroxysmal supraventricular tachycardia, inducible atrioventricular nodal re-entry tachycardia, and inducible sustained ventricular tachycardia, in suppressing the dysrhythmias of the Wolff–Parkinson–White syndrome, and in facilitating conversion of ventricular fibrillation. Open clinical studies In 19 patients with atrial fibrillation and five with atrial flutter, dofetilide 2.5–8.0 micrograms/kg caused conversion to sinus rhythm in 14 (10 with atrial fibrillation and four with atrial flutter) (152c ). In patients with sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation, who had previously been unsuccessfully treated with 0–7 other drugs, intravenous dofetilide 3–15 micrograms/kg suppressed or slowed inducible ventricular tachycardia in 17 of 41 patients, compared with none of nine patients who received only 1.5 micrograms/kg (131c ). Intravenous dofetilide 2.5–5.0 micrograms/kg produced sinus rhythm in seven patients with paroxysmal atrial fibrillation of recent onset (under 7 days) and terminated paroxysmal supraventricular tachycardia in four of six patients (153c ). In patients with electrically inducible atrioventricular re-entrant tachycardia intravenous dofetilide 1.5–15 micrograms/kg had no effect on tachycardia inducibility at the two lower doses but prevented the reinduction of tachycardia at the three higher doses in 11 of 31 patients (154c ). Placebo-controlled studies Conversion of atrial fibrillation and flutter In a crossover placebo-controlled study in 16 patients with recent onset atrial fibrillation, cardioversion was achieved in two of six patients who received dofetilide 8 micrograms/kg and in two of nine who received 12 micrograms/kg (155C ). None cardioverted with placebo. However, the average duration of atrial fibrillation was 35 days in those who cardioverted with dofetilide and 83 days in those who did not. The authors concluded that dofetilide had only limited effect in cardioverting atrial fibrillation of moderate duration.

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In a double-blind, placebo-controlled study 98 patients, who developed atrial fibrillation/flutter within 1–6 days after coronary artery bypass graft surgery, were given dofetilide 4 or 8 micrograms/kg intravenously over 15 min (156C ). Eight of 33 patients converted to sinus rhythm after placebo, 12 of 33 after dofetilide 4 micrograms/kg, and 14 of 32 after dofetilide 8 micrograms/kg. In a double-blind, placebo-controlled study in patients with sustained atrial fibrillation (n = 75) or atrial flutter (n = 16), dofetilide 8 micrograms/kg terminated the dysrhythmia in nine of 29 patients, compared with only four of 32 who received 4 micrograms/kg and none of 30 who received placebo (157C ). Patients with atrial flutter had a greater response to dofetilide (six of 11) than those with atrial fibrillation (five of 49). In a placebo-controlled study in patients with atrial fibrillation or atrial flutter with a median dysrhythmia duration of 62 (range 1– 180) days, there was conversion to sinus rhythm in 20 of 66 patients given dofetilide, compared with one of 30 patients given placebo (36C ). The conversion rate was higher in atrial flutter (7 of 11 patients) than in atrial fibrillation (13 of 55). In a double-blind placebo-controlled study in 325 patients with atrial fibrillation or flutter cardioversion rates for dofetilide 125, 250, and 500 micrograms bd were 6.1%, 9.8%, and 30% respectively, compared with 1.2% with placebo (158C ). The probabilities of remaining in sinus rhythm at 1 year with dofetilide 125, 250, and 500 micrograms bd were 0.40, 0.37, and 0.58 respectively, and 0.25 for placebo. In a double-blind, placebo-controlled study in 69 patients with atrial fibrillation or flutter, intravenous dofetilide 2–8 micrograms/kg caused conversion to sinus rhythm in 16 of 51 patients, compared with one of 18 who were given placebo; conversion of atrial flutter occurred in five of seven who were given dofetilide compared with none of three who were given placebo (159CA ). In a randomized, placebo-controlled, crossover study in 15 men, mean age 34 (range 18–63) years, with Wolff–Parkinson–White syndrome and atrial fibrillation or atrioventricular re-entrant tachycardia induced electrophysiologically, six of ten patients who were given dofetilide converted to sinus rhythm, compared with one of five who were given placebo (160C ). There were no dysrhythmias.

210 Ventricular tachydysrhythmias In a placebo-controlled study, sustained ventricular tachycardia or fibrillation, reproducibly inducible electrophysiologically, was no longer inducible in eight of 18 patients who were given intravenous dofetilide 0.1–8.0 ng/ml, compared with one of six patients who received placebo (161C ). In a randomized, double-blind, placebocontrolled study in 32 patients with ventricular extra beats (more than 30/hour on two consecutive 24-hour Holter recordings while drug free and more than 50/hour during 2-hour telemetric electrocardiography), dofetilide 7.5 micrograms/kg produced an 83% and placebo a 2.9% median reduction in ventricular extra beats (162C ). Sudden death The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) study comprised two studies in patients at high risk of sudden death: one in patients with congestive heart failure and one in patients with acute myocardial infarction within the previous 7 days (163S ). In the congestive heart failure study, 1518 patients with symptomatic congestive heart failure and severe left ventricular dysfunction were recruited at 34 Danish hospitals; 762 were randomized double-blind to dofetilide and 756 to placebo (164C ). After 1 month, 22 of 190 patients with atrial fibrillation at baseline had sinus rhythm restored by dofetilide, compared with only three of 201 who took placebo. Dofetilide was also significantly more effective than placebo in maintaining sinus rhythm (hazard ratio for the recurrence of atrial fibrillation = 0.35; CI = 0.22, 0.57). Dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio = 0.75; CI = 0.63, 0.89). During a median follow-up of 18 months, 311 patients taking dofetilide and 317 patients taking placebo died (hazard ratio = 0.95; CI = 0.81, 1.11). In the myocardial infarction study, 1510 patients with severe left ventricular dysfunction after myocardial infarction were recruited in 37 Danish coronary-care units; 749 were randomized double-blind to dofetilide and 761 to placebo (165C ). There were no significant differences between dofetilide and placebo in allcause mortality or total dysrhythmic deaths. Dofetilide was significantly better than placebo at restoring sinus rhythm in patients with atrial fibrillation or flutter.

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Comparison studies with other antidysrhythmic drugs Amiodarone In a comparison of intravenous dofetilide (8 micrograms/kg; n = 48), amiodarone (5 mg/kg; n = 50), or placebo (n = 52) in converting atrial fibrillation or flutter to sinus rhythm in 150 patients, sinus rhythm was restored in 35%, 4%, and 4% respectively (166C ). Flecainide In a non-randomized comparison of flecainide (2 mg/kg; n = 11) and dofetilide (8 micrograms/kg; n = 10) in patients with atrial flutter, only one patient given flecainide converted to sinus rhythm compared with seven of the 10 patients given dofetilide (167c ). Propafenone In a randomized, placebocontrolled, parallel-group comparison of oral dofetilide 500 micrograms bd, propafenone 150 mg tds, or placebo in preventing the recurrence of paroxysmal supraventricular tachycardia in 122 symptomatic patients, the respective probabilities of remaining free of episodes of paroxysmal supraventricular tachycardia were 50%, 54%, and 6%; both dofetilide and propafenone also reduced the frequency of episodes (median numbers 1, 0.5, and 5 respectively) (168C ). Sotalol In a double-blind, randomized, crossover comparison of oral dofetilide 500 micrograms bd with sotalol 160 mg bd in 128 patients with ischemic heart disease and inducible sustained ventricular tachycardia, 46 patients responded to dofetilide and 43 to sotalol; however, only 23 patients responded to both dofetilide and sotalol (169C ). Adverse effects Cardiovascular adverse effects of dofetilide are the most troublesome. Other common effects have included mild headache, dizziness, dyspepsia, nausea, and vomiting (169C ). Cardiovascular Because dofetilide prolongs the QTc interval, there is a risk of ventricular tachydysrhythmias, which have often been reported, after both intravenous and oral administration. In 154 patients with implantable cardioverter–defibrillators randomly assigned to dofetilide or placebo, there were pause-dependent runs of polymorphic ventricular tachycardia in 15 of the 87 patients who received dofetilide and in only five of the 87 who received placebo (170C ). There were five early events (at less than 3 days of therapy), all torsade de pointes

Positive inotropic drugs and drugs used in dysrhythmias

in patients taking dofetilide. There were 15 late events, 10 with dofetilide and five with placebo. The median time to a late event was 22 (range 6–107) days for dofetilide and 99 (34–207) days for placebo. In the DIAMOND study in congestive heart failure there were 25 cases of torsade de pointes in the dofetilide group (3.3%) compared with none in the placebo group (164C ). In the DIAMOND myocardial infarction study there were seven cases of torsade de pointes (0.93%), all in those who were given dofetilide (165C ). In a double-blind, placebo-controlled study in 325 patients with atrial fibrillation or atrial flutter randomized to dofetilide 125, 250, or 500 micrograms bd or placebo there were two cases of torsade de pointes, 1 on day 2 and the other on day 3 (0.8% of all patients given the active drug); there was one sudden cardiac death, classified as prodysrhythmic, on day 8 (0.4% of all patients given the active drug). The authors recommended that dosage adjustment based on QTc interval and renal function would minimize the small but not negligible prodysrhythmic risk of dofetilide. In 128 patients who received dofetilide and sotalol in a crossover study, there were treatment-related adverse events in 2.3% of the patients who received dofetilide and 8.6% of those who received sotalol (169C ). Three patients who took dofetilide had torsade de pointes. In a comparison of intravenous dofetilide (8 micrograms/kg; n = 48), amiodarone (5 mg/kg; n = 50), or placebo (n = 52) in converting atrial fibrillation or flutter to sinus rhythm in 150 patients, two patients given dofetilide had non-sustained ventricular tachycardias; four had torsade de pointes, in one case requiring electrical cardioversion (166C ). • In one of 10 healthy men given intravenous dofetilide 0.5 micrograms/kg there was prolongation of the QTc interval from 451 to 808 msec 5 minutes after the end of the infusion; this was associated with five beats of polymorphic ventricular tachycardia, several multifocal ventricular extra beats, and ventricular couplets and triplets, all within 10 minutes after the end of the infusion (149cA ). • In a 37-year-old woman with atrial flutter with 1 : 1 conduction and partial right bundle branch block, intravenous dofetilide 5 micrograms/kg given over 5 minutes suppressed the atrioventricular nodal block to 2 : 1 or 3 : 1 but also caused complete right bundle branch block and QT interval prolongation (171A ).

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• Self-limiting torsade de pointes developed in a 67year-old man who was given 12.8 micrograms/kg (plasma concentration 7.1 ng/ml) in an open study; the QTc interval was prolonged to over 600 msec (131cA ). This patient had stopped taking amiodarone 1 month before the administration of dofetilide, and that may have contributed to the prolongation of the QTc interval. • A woman with atrial fibrillation developed torsade de pointes after receiving intravenous dofetilide 6 micrograms/kg (plasma concentration 26 ng/ml) (155C ). • A patient with atrial fibrillation received intravenous dofetilide 8 micrograms/kg and developed torsade de pointes before reverting to sinus rhythm (155C ). • One of 18 patients with sustained ventricular tachycardia or fibrillation, reproducibly inducible electrophysiologically, developed torsade de pointes after receiving intravenous dofetilide 8 micrograms/kg (plasma concentration 5.3 ng/ml) (161C ). • Short episodes of aberrant ventricular conduction and ventricular tachycardia occurred in three of 32 patients with atrial fibrillation who were given dofetilide 8 micrograms/kg (156C ). • Torsade de pointes occurred in two of 62 patients with atrial tachydysrhythmias who received dofetilide 4 or 8 micrograms/kg; two other patients had ventricular extra beats associated with prolongation of the QTc interval (157C ). • In a placebo-controlled study of the effect of dofetilide 8 micrograms/kg in converting atrial fibrillation or flutter, transient torsade de pointes occurred in two men, aged 57 and 67, with prolongation of the QTc interval from 370 and 420 msec to 450 and 510 msec respectively (36CA ). • A 58-year-old woman developed torsade de pointes with prolongation of the QTc interval to 490 msec after receiving intravenous dofetilide 4.3 micrograms/kg; she responded to intravenous magnesium sulfate plus isoprenaline (159CA ).

Other cardiac dysrhythmias that have been reported have included episodes of junctional rhythm with bundle branch block, spontaneous atrioventricular re-entrant tachycardia, and sustained supraventricular tachycardia (154c ). The risk of death in patients with supraventricular dysrhythmias taking dofetilide has been studied in a systematic review of randomized controlled trials (172M ). After adjusting for the effects of dysrhythmia diagnosis, age, sex, and structural heart disease, the hazard ratio was 1.1 (CI = 0.3, 4.3). Hypotension occasionally occurs after intravenous dofetilide (154c ). Drug interactions Digoxin In 14 healthy men dofetilide 250 micrograms bd for 5 days had no effect on the pharmacokinetics of digoxin

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at a steady-state trough concentration of 1.0 ng/ml (35C ). However, in a placebo-controlled study in patients with atrial fibrillation or atrial flutter, conversion to sinus rhythm in patients given dofetilide was more likely if they were also given digoxin (36C ), suggesting that there may be a pharmacodynamic interaction. Histamine (H2 ) receptor antagonists In a randomized, placebo-controlled study of the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide 500 micrograms in 20 healthy men, ranitidine 150 mg bd did not affect the pharmacokinetics or pharmacodynamics of dofetilide, but there was a dose-dependent increase in exposure to dofetilide with cimetidine (173C ). With cimetidine 100 and 400 mg bd the AUC of dofetilide increased by 11% and 48%, the maximum plasma dofetilide concentration increased by 11% and 29%, renal clearance fell by 13% and 33%, and non-renal clearance by 5% and 21%; dofetilide-induced prolongation of the QTc interval was increased by 22% and 33%. The authors suggested that cimetidine inhibited renal tubular dofetilide secretion, an effect that is specific to cimetidine in its class. Cimetidine should be avoided in patients taking dofetilide. Verapamil Pharmacokinetic and pharmacodynamic interactions between dofetilide 0.5 mg bd and verapamil 80 mg tds have been studied in 12 healthy men (174C ). At steady state verapamil increased the peak plasma concentration of dofetilide from 2.40 to 3.43 ng/ml, without other pharmacokinetic effects. This was accompanied by a small increase in the prolongation of the QTc interval produced by dofetilide alone, from 20 to 26 msec. Although this small effect is unlikely to be of clinical significance, it would be wise to avoid verapamil in patients taking dofetilide.

Flecainide

(SED-14, 545; SEDA-24, 211;

SEDA-25, 217) Cardiovascular Cardiac dysrhythmias are less common with flecainide (Class Ic) than with other antidysrhythmic drugs of Class I. When dysrhythmias occur, prolongation of the QT interval is an important mechanism, and in a recent report syncope occurred in a

J.K. Aronson

patient whose QRS complex duration was prolonged (175A ). In another patient, a 67-year-old woman taking flecainide 150 mg bd, widening of the QRS complex occurred during exercise; the effect did not occur at rest or with a dose of 50 mg bd (176A ). Hypokalemia can increase the risk of torsade de pointes with flecainide, as with other antidysrhythmic drugs. Torsade de pointes has been attributed to mosapride (which is related to cisapride) and flecainide in a 68-year-old man with a plasma potassium concentration of 3.2 mmol/l and prolongation of the QTc interval from 0.48 to 0.56 seconds (177A ). His plasma flecainide concentration was just above the target range at 1013 ng/ml, but the mosapride concentration was not reported. The authors speculated that mosapride may have inhibited the metabolism of flecainide by CYP2D6. In a retrospective analysis of 24 patients who developed atrial flutter while taking flecainide (n = 12) or propafenone (n = 12), the electrocardiogram was classified as typical atrial flutter in 13 cases, atypical atrial flutter in eight, or coarse atrial fibrillation in three (178c ). Counterclockwise atrial flutter was the predominant dysrhythmia. The acute results of ablation suggested that the flutter circuit was located in the right atrium and that the isthmus was involved in the re-entry mechanism. There was better long-term control of recurrent atrial fibrillation in patients with typical atrial flutter (85%) compared with atypical atrial flutter (50%). The authors suggested that patients who develop coarse drug-induced atrial fibrillation may not be candidates for ablation. Antidysrhythmic drugs increase the pacing threshold, but failure to capture is a rare consequence. It has, however, been reported twice with flecainide (179A , 180A ). The Brugada syndrome is partial right bundle branch block with ST segment elevation in the right precordial leads of the electrocardiogram; it is due to an abnormality of sodium channels and occurs in 0.05–0.1% of the population; some cases are inherited (181R ). Flecainide can bring out Brugada-type changes on the electrocardiogram (182c , 183C , 184C ). Sensory systems Ocular adverse effects of flecainide have included corneal deposits in two patients, due to deposition of flecainide (185A ). In 38 patients taking flecainide 100– 300 mg/day there were brown corneal epithelial

Positive inotropic drugs and drugs used in dysrhythmias

deposits in 11 eyes, dryness in eight eyes, and slight blurring of vision on lateral gaze in four patients (186c ). Four patients had local symptoms, including tearing, itching, and burning. Color vision, contrast sensitivity, and visual fields were all unaffected. Drug overdose Death has been reported in a two patients who took flecainide (187A ). The post-mortem femoral blood flecainide concentrations were 5.4 and 1.2 mg/l (target range 0.2–1.0).

Mexiletine

(SED-14, 547; SEDA-23, 200; SEDA-24, 212; SEDA-25, 219) Sensory systems In addition to its use as an antidysrhythmic drug, mexiletine has also been used in the treatment of various types of neuropathic pain and dystonias. In two patients with neuropathic pain and pre-existing ocular disease, mexiletine caused persistent ophthalmic changes (188A ). • A 39-year-old woman took mexiletine 300 mg tds for 3 days and developed transient blindness with residual reduced visual acuity due to an acute pigmentary retinopathy. Her vision improved markedly after withdrawal of mexiletine, but when she restarted it she developed clouding of the vision, which resolved again on withdrawal. The pigmentary changes persisted. • A man with a history of glaucoma took mexiletine 300 mg tds and developed worsening visual acuity. Mexiletine was withdrawn and he took carbamazepine 200 mg/day instead. However, he started to see red and green spots. The serum carbamazepine concentration was below that usually associated with visual disturbances. No structural abnormalities were detected.

Skin Mexiletine rarely causes skin reactions, but another case of acute exanthematous pustular eruption has recently been reported in a 56-year-old man who had taken mexiletine 300 mg/day for 1 month (189A ). There was mild liver dysfunction. Patch tests with mexiletine 10 and 20% were subsequently positive, but a lymphocyte stimulation test was negative. Drug interactions Mexiletine is metabolized by CYP2D6, CYP1A2, and CYP3A4; fluvoxamine inhibits CYP1A2. It is not surprising therefore that fluvoxamine 50 mg bd for 7

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days increased the Cmax and AUC of a single oral dose of mexiletine 200 mg in six healthy Japanese men (190C ).

Moricizine (moracizine, ethmozine) (SED-14, 548; SEDA-21, 202) In a retrospective study of 85 patients with recurrent atrial fibrillation (mean left atrial size 46 mm, mean left ventricular ejection fraction 0.51), 69 of whom had structural heart disease, moricizine (mean dose 609 mg/day) was withdrawn because of unacceptable adverse effects in 6 patients: frequent ventricular extra beats and short runs of non-sustained ventricular tachycardia (n = 2); significant widening of the QRS complex (n = 1); first-degree heart block (n = 1); a significant rise in liver enzymes (n = 1); and a severe rash (n = 1) (191c ). Six patients developed transient adverse effects that resolved spontaneously without withdrawal: brief self-limiting episodes of atrial flutter (n = 2); a small increase in blood pressure (n = 1); generalized weakness and tremor (n = 2); and reduced appetite (n = 1).

Procainamide

(SED-14, 548; SEDA-23,

201; SEDA-24, 213) Immunologic Thymus function in 10 patients with symptomatic procainamide-induced lupus has been compared with that in 13 asymptomatic patients who only developed druginduced autoantibodies (192c ). Newly generated T cells were detected in all the subjects. Although there was no overall quantitative difference between the symptomatic and asymptomatic patients, there was a correlation between the level of T cell receptor rearrangement excision circles in peripheral lymphocytes and serum IgG antichromatin antibody activity in patients with drug-induced lupus. These results support the hypothesis that the thymus is important in the genesis of drug-induced lupus-like syndrome and that the production of autoreactive T cells starts in the thymus when procainamide hydroxylamine alters T cell tolerance.

214

Propafenone

(SED-14, 551; SEDA-23, 202; SEDA-24, 214; SEDA-25, 220) In a randomized double-blind, placebo-controlled comparison of propafenone (mean dose 13 mg/kg/day; n = 102) and sotalol (mean dose 3 mg/kg/day; n = 106) in maintaining sinus rhythm after conversion of recurrent symptomatic atrial fibrillation in 300 patients, efficacy was comparable (193C ). Tolerable adverse effects in those who took propafenone were gastrointestinal discomfort (n = 15), neurological disturbances (n = 9), a metallic taste (n = 4), and generalized weakness (n = 1); nine patients withdrew owing to adverse effects, four with gastrointestinal disorders, three with dizziness, and two with headache; there were no prodysrhythmias. Cardiovascular The adverse effects of a single oral dose of propafenone for cardioversion of recent-onset atrial fibrillation have been evaluated in a systematic review (194M ). The adverse effects were transient dysrhythmias (atrial flutter, bradycardia, pauses, and junctional rhythm), reversible widening of the QRS complex, transient hypotension, and mild non-cardiac effects (nausea, headache, gastrointestinal disturbances, dizziness, and paresthesia). Risk factors Poor and extensive oxidation phenotypes for CYP2D6, which metabolizes propafenone, have been studied in 42 patients, aged 36–75 years, with paroxysmal atrial fibrillation (195C ). Efficacy was 100% in poor metabolizers, 61% in extensive metabolizers, and 0% in very extensive metabolizers. There was a significant correlation between oxidation phenotype and the ability to maintain sinus rhythm. Drug overdose The mortality from propafenone overdose is 23%, according to a retrospective series of 120 patients in Germany over 14 years (196R ). Severity was related to cardiac conduction disorders and cardiac hyperexcitability. Seizures have been reported in a case of overdose (197A ). • A 22-year-old woman took an overdose of propafenone (amount unknown) and developed tetany and then generalized convulsions requiring intra-

Chapter 17

J.K. Aronson

venous clonazepam. She had a low blood pressure and first-degree atrioventricular block associated with prolonged intraventricular conduction. She was intubated and given intravenous fluids, equimolar sodium lactate, dopamine, and adrenaline. Her cardiac conduction returned to normal.

About 60 cases of propafenone poisoning have been reported. Even low doses can lead to serious poisoning. Some symptoms, such as gastrointestinal or neurological symptoms, are misleading. Cardiovascular abnormalities include bradycardia, atrioventricular block, abnormal intraventricular conduction, shock, and electromechanical dissociation. The simultaneous presence of neurological symptoms (especially seizures) and abnormal cardiac conduction suggests serious poisoning. Treatment is symptomatic. Lactate may be required for abnormal intraventricular conduction. Plasma exchange has been successfully used to treat propafenone overdose (198A ). • An 18-year-old woman took 35 tablets of propafenone, 300 mg each. She had dilated, non-reactive pupils and greatly increased activity of neuronspecific enolase. She had atrioventricular and intraventricular conduction disorders, and repeated resuscitation was necessary. Propafenone was eliminated by plasma exchange, and the conduction disturbances disappeared rapidly during treatment.

Quinidine

(SED-14, 552; SEDA-23, 202; SEDA-24, 214; SEDA-25, 221) Skin In a review of drug-induced skin disorders, from a list of 26 drugs or groups of drugs, only quinidine was mentioned of all antidysrhythmic drugs (199R ). The reaction rate was quoted as 12 per 1000 recipients. Drug interactions Stimulation of CYP3A4 by quinidine increased the 4′ -hydroxylation of S-warfarin and the 10-hydroxylation of Rwarfarin in human liver microsomes and intact hepatocytes (200E ). The increases were concentration-dependent and respectively maximized at about three and five times control values. In contrast, warfarin did not affect the 3-hydroxylation of quinidine. These results are consistent with previous findings suggesting that there is more than one binding site on CYP3A4 through which interactions can occur.

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A.P. Maggioni, M.G. Franzosi, and R. Latini

18

Beta-adrenoceptor antagonists and antianginal drugs

BETA-ADRENOCEPTOR ANTAGONISTS (SED-13, 488; SEDA-23, 206; SEDA-24, 220; SEDA-25, 227)

INDIVIDUAL BETA-ADRENOCEPTOR ANTAGONISTS Carvedilol

ORGANS AND SYSTEMS Metabolism That beta-blockers have unfavorable effects on lipids or insulin sensitivity is the main argument against their primary use in patients with hypertension. Another potential drawback is their propensity to cause weight gain in some patients. A systematic analysis of eight prospective randomized trials in 7048 patients with hypertension (3205 of whom were taking beta-blockers) confirmed that body weight was higher in those taking beta-blockers than in controls at the end of the studies (1M ). The median difference in body weight was 1.2 kg (range −0.4 to 3.5 kg). There was no relation between demographic characteristics and changes in body weight. The weight gain was observed in the first few months of treatment and thereafter there was no further weight gain compared with controls. The possible mechanisms of this weight gain include reduction in resting energy expenditure, reduction in exercise tolerance, inhibition of lipolysis, and exacerbation of insulin resistance. This observation suggests that first-line use of beta-blockers in obese patients with hypertension should be considered with caution.

© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Sexual function In a comparison of carvedilol with valsartan in 160 patients with hypertension (mean age 46 years) each treatment was continued for 16 weeks, with crossover after 4 weeks of placebo (2C ). Blood pressure was significantly lowered by both drugs (48% normalization with valsartan and 45% with carvedilol). In the first month of treatment, sexual activity (assessed as the number of episodes of sexual intercourse per month) fell with both treatments compared with baseline, although the change was statistically significant only with carvedilol. After the first month of treatment, sexual activity further worsened with carvedilol, but it improved or recovered fully with valsartan. The results were confirmed by the crossover. This confirms that beta-blockers can cause chronic worsening of sexual function.

Labetalol Life-threatening hyperkalemia has been reported after intravenous labetalol (3A ). • A 28-year-old man with severe hypertension and end-stage renal disease was given two intravenous doses of labetalol 20 mg 1 hour apart for malignant hypertension. The serum potassium concentration before treatment was 6.2 mmol/l but 8 hours after labetalol it rose to 9.9 mmol/l and the patient developed left bundle branch block, ventricular tachycardia, and hypotension. He was given intravenous calcium gluconate, sodium bicarbonate, and lidocaine and reverted to sinus rhythm. The potassium concentration after 2 hours was 8.0 mmol/l. After hemodialysis the potassium concentration fell to 6.1 mmol/l.

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Patients with end-stage renal disease on dialysis can have an enhanced hyperkalemic response to labetalol, which can be partly attributed to electrochemical disturbances in the cells, characterized by an increase in intracellular sodium and chloride and a decrease in intracellular potassium.

Sotalol Cardiovascular Several publications involving 962 patients treated with an intravenous infusion of racemic sotalol have been reviewed, with the aim of describing the risk of torsade de pointes (4M ). Torsade de pointes occurred in only one case (0.1%; 95% CI = 0.003, 0.6), which is less often than with oral sotalol (2– 4%). This difference can be explained by the shorter duration of treatment. The other reported complications were hypotension (0.3%), severe bradycardia (0.2%), and atrioventricular block necessitating drug withdrawal (0.03%). Risk factors Some patients with thyrotoxicosis have occult cardiac dysfunction. However, the use of beta-blockers in the treatment of thyrotoxicosis can have severe consequences in terms of severe cardiac dysfunction (5A ). • A 52-year-old woman developed atrial fibrillation with a ventricular rate of 220/minute. She had had thyrotoxicosis 20 years before, but was taking no medications. She had an 8-month history of weight loss with a normal appetite. During the previous month she had had excessive sweating, palpitation, and exercise intolerance. The diagnosis was thyroid storm. She was given intravenous sotalol 1 mg/kg over 15 minutes and within 5 minutes sinus rhythm was restored, with improvement of symptoms. However, immediately after the infusion she had an episode of ventricular tachycardia followed by sinus bradycardia, with a resultant fall in blood pressure, followed by an asystolic cardiac arrest. She underwent endotracheal intubation and was treated with inotropes. Right heart catheterization showed severe cardiac dysfunction (cardiac index 1.2 l/min). She made an uneventful recovery.

Patients with severe hyperthyroidism can have an occult cardiomyopathy that makes them extremely sensitive to beta-blockers. The long duration of action of sotalol in this case necessitated prolonged inotropic and vasopressor support. A shorter acting beta-blocker, such as esmolol, could theoretically be safer in such cases.

A.P. Maggioni, M.G. Franzosi, and R. Latini

NITRATE DERIVATIVES

(SED-14, 594; 218; SEDA-23, 207; SEDA-24, 222; SEDA-25, 228)

Glyceryl trinitrate (nitroglycerin) Drug withdrawal Adverse reactions to industrial exposure to glyceryl trinitrate were first reported in 1914 (6r ), and subsequently there have been several reports of symptoms during the weekend resulting from withdrawal of the sustained vasodilator response of nitrates. Vasoconstriction ensues and can cause Raynaud’s phenomenon, angina pectoris, or myocardial infarction, as has recently been reported again (7A ). • A 41-year-old man employed in a munitions factory was admitted with crushing chest pain on a Sunday morning. There was evidence of an acute inferior myocardial infarction, and cardiac catheterization showed 80% narrowing of the proximal right coronary artery, which was reduced to 10% by intracoronary administration of glyceryl trinitrate. The electrocardiogram became normal.

Despite continuing reports of adverse reactions to withdrawal from chronic occupational exposure to nitrates, there is no clear evidence of similar events in patients taking chronic nitrate therapy. However, since this risk cannot be excluded, patients taking chronic nitrates should be carefully advised and monitored. Gene toxicity In view of the hypothesis that nitric oxide can have mutagenic or carcinogenic effects, chromosomal alterations have been sought in blood lymphocytes from patients taking chronic nitrates and after in vitro exposure to a nitric oxide donor (8E ). No structural alterations were found in vivo or in vitro, only an increased frequency of micronucleus formation, a nuclear morphological change that has been suggested to be associated with a risk of cancer. However, this first report of a genotoxic effect of nitrates probably has no clinical relevance. Pregnancy An authoritative overview of the published evidence on the use of glyceryl trinitrate to induce uterine relaxation in obstetric emergencies has shown that it is safe for fetus and mother (9R ). However, the evidence of benefit is still to be proven by larger well-designed controlled trials.

Beta-adrenoceptor antagonists and antianginal drugs

Chapter 18

Drug interactions An elderly patient with anginal pain died after treatment with glyceryl trinitrate (10A ). The family physician discovered that the patient had also taken sildenafil, and he suggested suicidal intent, since he claimed that the patient was aware of the adverse cardiac events of the association of these two drugs.

Diltiazem

CALCIUM CHANNEL BLOCKERS (SED-14, 578; SEDA-23, 208; SEDA-24, 222; SEDA-25, 229)

Amlodipine Skin Calcium antagonists can cause lichen planus, as has again been described (11A ). • A 56-year-old Nigerian woman, with a previous history of sickle cell trait, osteoarthritis, and noninsulin-dependent diabetes mellitus, took amlodipine 5 mg/day for hypertension for 2 weeks and developed a lichenoid eruption. Histological examination confirmed the diagnosis of lichen planus. Amlodipine was withdrawn and there was rapid symptomatic and clinical improvement after treatment with corticosteroids and antihistamines.

Drug overdose A case of amlodipine overdose has been reported (12A ). • A 23-year-old woman took 60 tablets of amlodipine intentionally and developed tachycardia and severe hypotension. She did not improve with intensive therapy and developed left ventricular failure and oliguria and underwent hemodiafiltration. Her condition slowly improved over 4 days.

Barnidipine Barnidipine is a new dihydropyridine with antihypertensive activity and tolerability similar to that of other calcium antagonists of the same class. The most frequent adverse events are edema, headache, and flushing, but it does not cause reflex tachycardia (13R ).

225

Nervous system Parkinsonism associated with diltiazem has been reported (14A ). • A 53-year-old man with hypertension took diltiazem 60–120 mg/day for 5 years and then developed Parkinsonism. His neurological symptoms were treated without success and only after the substitution of diltiazem with an ACE inhibitor did his Parkinsonian symptoms began to regress, with eventual complete recovery.

Skin Four cases of photodistributed hyperpigmentation associated with long-term administration of a modified-release formulation of diltiazem hydrochloride have been reported (15A ). All the patients were African– American women, mean age 62 (range 49–72) years. The duration of diltiazem administration before the development of hyperpigmentation was 6–11 months. The hyperpigmentation was slate-gray and reticulated. Phototesting during diltiazem therapy showed a reduced minimal erythema dose to UV-A in one patient. Histological examination showed lichenoid dermatitis with prominent pigmentary incontinence. Electron microscopy showed multiple melanosome complexes. Withdrawal of diltiazem resulted in gradual resolution of the hyperpigmentation. Lichenoid purpura of 6 months’ duration occurred in a 65-year-old man with hypertension who had taken diltiazem for 1 month; topical therapy with a very potent glucocorticoid was not effective and the eruption began to regress only after diltiazem withdrawal and disappeared 3 weeks later (16A ). Drug overdose The optimum treatment of overdose with calcium antagonists has yet to be defined and has included several approaches, including gastric lavage, repeated oral doses of activated charcoal, intravenous calcium, atropine, sympathomimetic amines, digoxin, glucagon, glucose combined with insulin, ventricular pacing, charcoal hemoperfusion, and plasma exchange. Three more cases of diltiazem overdose have been reported, each treated differently (see also amlodipine above). • A 15-year-old woman intentionally took 10 modified-release tablets of diltiazem 200 mg. She developed hypertension, oliguria, pulmonary edema, and respiratory distress syndrome, and required

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mechanical ventilation for 3 days, besides intravenous calcium, dopamine, and noradrenaline. After 5 days in an intensive care unit, she was transferred to a psychiatric hospital in good physical condition (17A ). • A 50-year-old man who had taken 28 modifiedrelease tablets of diltiazem 240 mg and 28 tablets of hydrochlorothiazide presented 12–14 hours later lethargic but oriented and complaining of nausea and dizziness; he had bradypnea, hypotension, and second-degree heart block with bradycardia (18A ). He was given activated charcoal, oxygen, atropine, glucagon, and calcium gluconate by prolonged infusion. His heart rate, blood pressure, and electrocardiogram recovered to baseline over the next 24 hours, with no further episodes of dysrhythmias or hypotension. • A 38-year-old white man with a history of coronary artery disease, myocardial infarction, coronary artery by-pass, alcoholism, and depression took a combined massive overdose of diltiazem and atenolol (19A ). He underwent cardiopulmonary resuscitation because of cardiac arrest; bradycardia, hypotension, and oliguria followed and were resistant to intravenous pacing and multiple pharmacological interventions, including intravenous fluids, calcium, dopamine, dobutamine, adrenaline, prenalterol, and glucagon. Adequate mean arterial pressure and urine output were restored only after the addition of phenylephrine and transvenous pacing. He survived despite myocardial infarction and pneumonia.

Drug interactions Simvastatin is metabolized by CYP3A4, which is inhibited by diltiazem. A case of rhabdomyolysis due to an interaction of simvastatin with diltiazem has been reported (20A ). • A 75-year-old-man taking simvastatin 80 mg/day and diltiazem 240 mg/day developed extreme weakness and diffuse muscle pain. All drugs were withdrawn and he underwent hemodialysis. Within 3 weeks his muscle pain disappeared and he regained function in his legs. The activities of creatine kinase and transaminases gradually returned to normal, but he continued to need hemodialysis.

Preliminary results from two clinical studies of the interaction of diltiazem with simvastatin have shown that diltiazem increased the Cmax of simvastatin (21c ) and enhanced its cholesterolreducing effect (22c ). In 10 healthy volunteers taking oral simvastatin 20 mg/day diltiazem 120 mg bd for 2 weeks significantly increased the simvastatin Cmax 3.6-fold, the AUC 5-fold, and the half-life 2.3-fold (21c ). There were no changes in the tmax of simvastatin or simvastatin acid. Of 135 patients attending a hypertension clinic who were taking simvastatin for primary

A.P. Maggioni, M.G. Franzosi, and R. Latini

or secondary prevention of coronary heart disease, 19 were also taking diltiazem (22c ). The cholesterol reduction in the 19 patients taking diltiazem was significantly higher than in the other 116 (33% vs 25%), with less interindividual variability. Concurrent diltiazem therapy, age, and the starting dose of simvastatin were significant independent predictors of the percentage cholesterol response. The pharmacokinetic interaction of a single oral dose of diltiazem 120 mg with a single oral dose of sirolimus 10 mg has been studied in 18 healthy subjects, 12 men and 6 women, 20–43 years old, in an open, three-period, randomized, crossover study (23C ). The wholeblood sirolimus AUC increased by 60% and the Cmax by 43% with diltiazem co-administration; the apparent oral clearance and volume of distribution of sirolimus fell by 38% and 45% respectively, consistent with the change in halflife from 79 to 67 hours. Sirolimus had no effect on the pharmacokinetics of diltiazem or on the effects of diltiazem on either diastolic or systolic blood pressures or the electrocardiogram. Single-dose diltiazem co-administration leads to higher sirolimus exposure, presumably by inhibition of first-pass metabolism. Because of pronounced intersubject variability in this interaction, whole-blood sirolimus concentrations should be monitored closely in patients taking the two drugs.

Felodipine Facial telangiectasia, already attributed to other calcium channel blockers, has been attributed to felodipine (24A ). • A 67-year-old man who had taken felodipine 5 mg/day for 4 years developed facial telangiectatic lesions that worsened with solar exposure for 9 months before felodipine was withdrawn; 2 months later the lesions had markedly diminished.

Manidipine Manidipine is a new dihydropyridine calcium channel blocker that can be given once a day for hypertension. In a comparison of manidipine 10 mg/day and amlodipine 5 mg/day in a multicenter, randomized, double-blind study

Beta-adrenoceptor antagonists and antianginal drugs

in 530 patients with mild-to-moderate hypertension the two drugs had comparable antihypertensive effects, but manidipine was associated with a significantly lower incidence of ankle edema (25C ). Nevertheless, adverse events caused withdrawal from treatment in a similar number of patients, 23 with manidipine and 26 with amlodipine.

Nicardipine Hypertensive emergencies in children require intravenous infusion of antihypertensive drugs. Intravenous nicardipine reduced systolic (16%) and diastolic (23%) blood pressures in a retrospective uncontrolled series of 29 children aged 2 days to 18 years (26c ). Tachycardia was recorded in four patients, palpitation in one, and flushing in one.

Nifedipine Mouth and teeth Nifedipine and ciclosporin can cause gingival hyperplasia, which is associated with gingival inflammation and can be mitigated by careful oral hygiene, although this has not been clearly shown. In gingival biopsies from nine nifedipine-treated cardiac out-patients, 13 immunosuppressant-treated renal transplant recipients, nine of whom were also taking nifedipine, and 30 healthy individuals there were significant differences in macrophage and lymphocyte subpopulations in gingival connective tissue from patients with nifedipine-associated gingival lesions compared with healthy individuals (27c ). For example, the proportion of CD8-labelled cells was significantly higher and the CD4/CD8 ratio significantly lower in connective tissue beneath the sulcular epithelium in those taking nifedipine. The authors suggested that the immune response may be altered in drug-induced gingival overgrowth. In another study gingival samples were collected from 19 healthy individuals, 12 nifedipine-treated cardiac patients, and 22 immunosuppressant-treated organ transplant recipients, 11 of whom were also taking nifedipine (28c ). Mitotic activity was measured in the basal cell layer, and the results suggested that the increased epithelial thickness observed

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in nifedipine- and ciclosporin-induced gingival overgrowth is associated with increased mitotic activity. The true prevalence of gingival overgrowth induced by chronic treatment with calcium channel blockers is still uncertain, since most studies have been small. In a cross-sectional study in 65 patients taking nifedipine and 147 controls in a primary-care center in Barcelona there was a higher prevalence of gingival overgrowth in patients taking nifedipine (34% vs 4.1%) (29c ). Pregnancy Beta-adrenoceptor agonists reduce the incidence of preterm birth, but this has not led to a lower incidence of neonatal morbidity and mortality. The calcium channel blocker nifedipine has been used for the same indication. In a review of almost 800 patients randomized to beta-adrenoceptor agonists or nifedipine the latter was associated with more frequent prolongation of pregnancy, a lower incidence of respiratory distress syndrome, and lower incidences of maternal and fetal adverse effects (30R ).

Nimodipine In the absence of effective neuroprotective treatment for ischemic stroke, a double-blind, randomized, placebo-controlled trial has been performed in 454 patients in primary care (31c ). Nimodipine 30 mg/day or placebo was started within 6 hours after the onset of the stroke and continued for 10 days. Nimodipine had no effect on all-cause mortality or dependency in daily life. In patients with ischemic stroke documented by CT scan nimodipine had a borderline significant adverse effect on outcome. Nimodipine was tolerated as well as placebo (7 vs 8 treatment withdrawals respectively), but the lack of benefit does not support the use of any voltage-sensitive calcium antagonist in ischemic stroke.

Verapamil Cardiovascular Another case of cardiogenic shock after the ingestion of verapamil has been reported, but on this occasion with a small dose (32A ).

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• A 78-year-old woman with a history of biventricular heart failure had cardiogenic shock after she took a single tablet of verapamil 80 mg. She was resuscitated with artificial ventilation, dobutamine, noradrenaline, and calcium gluconate. Toxicological analysis showed an unexpectedly high plasma verapamil concentration, which was attributed to liver failure.

In patients with advanced heart failure a single oral therapeutic dose of verapamil may have a severe toxic effect. Nervous system Myoclonic seizures have been attributed to verapamil (33A ). • An 18-month-old girl with supraventricular tachycardia was given intravenous verapamil 0.2 mg/kg, which was discontinued after half the dose had been given, because she developed irregular, repetitive, jerky movements in both upper and lower limbs which lasted for 2 minutes. As the supraventricular tachycardia had not responded, second and third doses of 0.2 mg/kg were given intravenously under diazepam cover, but similar myoclonic seizures occurred again. There were no predisposing factors.

Musculoskeletal Arthralgia has been associated with verapamil (34A ). • A 28-year-old man with migraine and vascular pain of the face was given verapamil 480 mg/day when sumatriptan did not control the pain. Verapamil was withdrawn after 1 month and reintroduced in a dosage of 960 mg/day after a new episode of pain. He then developed arthralgia in the right hand and arm, which disappeared after withdrawal and recurred after rechallenge.

A.P. Maggioni, M.G. Franzosi, and R. Latini

Drug interactions By increasing its rate of absorption, verapamil produced transient rises in peak plasma concentrations of dofetilide in 12 young healthy male volunteers (35c ). During combination treatment at steady state there was a significant, albeit modest, increase in the mean Cmax and AUC of dofetilide. These changes were associated with corresponding short-lived increases in its pharmacodynamic effect, as measured by changes in the QTc interval. These two drugs should not be administered concurrently. An interaction of high-dose verapamil with erythromycin reportedly resulted in a lifethreatening dysrhythmia (36A ). • A 79-year-old white woman developed extreme fatigue and dizziness. Her heart rate was 40/minute and her blood pressure 80/40 mmHg. An electrocardiogram showed complete atrioventricular block, an escape rhythm at 50/minute, and QTc interval prolongation to 583 msec. This event was attributed to concomitant treatment with verapamil 480 mg/day and erythromycin 2000 mg/day, which had been prescribed 1 week before admission.

This is the first report of complete AV block and prolongation of the QTc interval after coadministration of erythromycin and verapamil, both of which are principally metabolized by CYP3A4. Both drugs are potent inhibitors of CYP3A4 and P glycoprotein, which may be the basis of this interaction.

REFERENCES 1. Sharma AM, Pischon T, Hardt S, Kunz I, Luft FC. Hypothesis. Beta-adrenergic receptor blockers and weight gain: a systematic analysis. Hypertension 2001; 37: 250–4. 2. Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L. Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study. Am J Hypertens 2001; 14: 27–31. 3. Hamad A, Salameh M, Zihlif M, Feinfeld DA, Carvounis CP. Life-threatening hyperkalemia after intravenous labetolol injection for hypertensive emergency in a hemodialysis patient. Am J Nephrol 2001; 21: 241–4. 4. Marill KA, Runge T. Meta-analysis of the risk of torsades de pointes in patients treated with intra-

venous racemic sotalol. Acad Emerg Med 2001; 8: 117–24. 5. Fraser T, Green D. Weathering the storm: betablockade and the potential for disaster in severe hyperthyroidism. Emerg Med 2001; 13: 376–80. 6. Ebright GE. The effects of nitroglycerin on those engaged in its manufacture. J Am Med Assoc 1914; 62: 201. 7. RuDusky BM. Acute myocardial infarction secondary to coronary vasospasm during withdrawal from industrial nitroglycerin exposure. A case report. Angiology 2001; 52: 143–4. 8. Andreassi MG, Picano E, Del Ry S, Botto N, Colombo MG, Giannessi D, Lubrano V, Vassalle C, Biagini A. Chronic long-term nitrate therapy:

Beta-adrenoceptor antagonists and antianginal drugs possible cytogenetic effect in humans? Mutagenesis 2001; 16: 517–21. 9. Caponas G. Glyceryl trinitrate and acute uterine relaxation: a literature review. Anaesth Intensive Care 2001: 29: 163–77. 10. Bhalerao S. A new suicide. J Fam Pract 2001; 50: 551. 11. Swale VJ, McGregor JM. Amlodipine-associated lichen planus. Br J Dermatol 2001; 144: 920–1. 12. Feldman R, Glinska-Serwin M. Deep hypotension with transient oliguria and severe heart failure in of acute intentional poisoning with amlodipine. Pol Arch Med Wewn 2001; 105: 495–9. 13. Malhotra HS, Plosker GL. Barnidipine. Drugs 2001; 61: 989–96. 14. Remblier C, Kassir A, Richard D, Pérault MC, Guibert S. Syndrome parkinsonien sous diltiazem. Thérapie 2001; 56: 57–9. 15. Scherschun L, Lee MW, Lim HW. Diltiazemassociated photodistributed hyperpigmentation. A review of 4 cases. Arch Dermatol 2001; 137: 179– 82. 16. Inui S, Itami S, Yoshikawa K. A case of lichenoid purpura possibly caused by diltiazem hydrochloride. J Dermatol 2001; 28: 100–2. 17. Quispel R, Baur HJCM. Tentamen suicidii door diltiazem met gereguleerde afgifte. Ned Tijdschr Geneeskd 2001; 145: 918–22. 18. Shah SJ, Quartin AA, Schein RMH. Diltiazem overdose—a case report. JK Pract 2001; 8: 40–2. 19. Snook CP, Sigvaldason K, Kristinsson J. Severe atenolol and diltiazem overdose. J Toxicol Clin Toxicol 2000; 38: 661–5. 20. Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem. Nephron 2001; 89: 117–18. 21. Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67: 267–74. 22. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients. Br J Clin Pharmacol 1999; 48: 610–15. 23. Bottiger Y, Sawe J, Brattstrom C, Tollemar J, Burke JT, Zimmerman JJ. Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers. Clin Pharmacol Ther 2001; 69: 32–40. 24. Silvestre JF, Albares MP, Carnero L, Botella R. Photodistributed felodipine-induced facial telangiectasia. J Am Acad Dermatol 2001; 45: 323–4.

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25. Zanchetti A, Omboni S, La Commare P, De Cesaris R, Palatini P. Efficacy, tolerability, and impact on quality of life of long-term treatment with manidipine or amlodipine in patients with essential hypertension. J Cardiovasc Pharmacol 2001; 38: 642– 50. 26. Flynn JT, Mottes TA, Brophy PD, Kershaw DB, Smoyer WE, Bunchman T. Intravenous nicardipine for treatment of severe hypertension in children. J Pediatr 2001; 139: 38–43. 27. Pernu HE, Knuuttila MLE. Macrophages and lymphocyte subpopulations in nifedipine- and cyclosporin A-associated human gingival overgrowth. J Periodontol 2001; 72: 160–6. 28. Nurmenniemi PK, Pernu HE, Knuuttila MLE. Mitotic activity of keratinocytes in nifedipineand immunosuppressive medication-induced gingival overgrowth. J Periodontol 2001; 72: 167–73. 29. Miranda J, Brunet L, Roset P, Berini L, Farré M, Mendieta C. Prevalence and risk of gingival enlargement in patients treated with nifedipine. J Periodontol 2001; 72: 605–11. 30. Papatsonis DNM, Lok CAR, Bos JM, Geijn HP, Dekker GA. Calcium channel blockers in the management of preterm labor and hypertension in pregnancy. Eur J Obstet Gynecol Reprod Biol 2001; 97: 122–40. 31. Horn J, de Haan RJ, Vermeulen M, Limburg M. Very early nimodipine use in stroke (VENUS). A randomized, double-blind, placebo-controlled trial. Stroke 2001; 32: 461–5. 32. Stajer D, Bervar M, Horvat M. Cardiogenic shock following a single therapeutic oral dose of verapamil. Int J Clin Pract 2001; 55: 69–70. 33. Maiteh M, Daoud AS. Myoclonic seizure following intravenous verapamil injection: case report and review of the literature. Ann Trop Paediatr 2001; 21: 271–3. 34. Nicolas X, Bellard S, Zagnoli F. Arthralgies induites par de fortes doses de vérapamil. Presse Med 2001; 30: 1256–7. 35. Johnson BF, Cheng S-L, Venitz J. Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic. J Clin Pharmacol 2001; 41: 1248–56. 36. Goldschmidt N, Azaz-Livshits T, Gotsman I, Nir-Paz R, Ben-Yehuda A, Muszkat M. Compound cardiac toxicity of oral erythromycin and verapamil. Ann Pharmacother 2001; 35: 1396–9.

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19

Drugs acting on the cerebral and peripheral circulations

DRUGS USED IN THE TREATMENT OF ARTERIAL DISORDERS OF THE BRAIN AND LIMBS Cilostazol

developed sudden chest pain, with inferior ST segment elevation. Emergency coronary angiography showed an occlusion of the circumflex coronary artery, for which a stent was inserted. At angiography 3 years earlier his coronary arteries had been normal. He died 5 months later from cardiogenic pulmonary edema.

(SED-14, 630; SEDA-24, 229;

SEDA-25, 236) Safety data relating to the use of cilostazol in 2702 patients who participated in eight USA– UK placebo-controlled trials have been reanalysed (1R ). The most frequently recorded adverse events were headache (32%), diarrhea (17%), and abnormal stools (14%). Palpitation, tachycardia, and dizziness were additional events that occurred more often in cilostazoltreated patients and were considered to be probably related to treatment. Headache led to withdrawal of cilostazol in 3.5% of patients and palpitation and diarrhea led to withdrawal in another 1%. All adverse events quickly resolved after withdrawal. Cardiovascular and allcause mortality were similar with cilostazol and placebo. Cardiovascular Myocardial ischemia is unusual during infusion of iloprost. It mainly occurs in patients with pre-existing coronary disease, when it is ascribed to a steal phenomenon detrimental to the subendocardial tissue. As a rule it is transient and exceptionally proceeds to infarction. However, such an event has now been reported in a patient with systemic sclerosis (2A ). • A 57-year-old man with a 1-year history of systemic sclerosis and ischemia of several digits received a first infusion of iloprost using the recommended stepwise increasing dosage scheme and © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

230

DRUGS USED IN THE TREATMENT OF MIGRAINE Triptans

(SED-14, 635; SEDA-23, 215; SEDA-24, 229; SEDA-25, 237) Seven triptans have been compared and rated as generally very well-tolerated (3R ). Naratriptan, almotriptan, and frovatriptan were considered to have the best safety profiles, although the differences are minor. Coronary vasoconstriction is a potential risk of the entire class, but the risk is minimal in the absence of coronary artery disease or uncontrolled hypertension; significant vascular disease is therefore a hazard of using any of the triptans. Patient preference, however, appears to be more closely related to efficacy than to tolerance. Teratogenicity The safety of drugs for migraine during pregnancy is not well established. There are now data from the Swedish Medical Birth Registry relating to 912 infants, whose mothers, at their first antenatal visit, had reported using migraine therapies, in most cases (658) sumatriptan (4R ). There was no increase in the rate of congenital malformations; slightly more infants than expected were preterm and had a birth weight lower than 2500 g, but none of the differences was statistically significant. These data suggest that sumatriptan is not teratogenic.

Drugs acting on the cerebral and peripheral circulations

OTHER PERIPHERAL VASODILATORS Sildenafil (SED-14, 636; SEDA-23, 215; SEDA-24, 231; SEDA-25, 238) The adverse effects of a single dose of sildenafil 50 mg have been evaluated in a placebocontrolled study in 40 young healthy volunteers (5c ). The most commonly reported adverse effects with sildenafil and placebo respectively were flushing (75 and 0%), headache (50 and 5%), and dyspepsia (15 and 5%). This adverse effects profile was similar to that observed in clinical trials. Heart rate changed significantly, but blood pressure did not. Nervous system Clinical trials of sildenafil have not shown increased risks of stroke or myocardial infarction. However, postmarketing drug surveillance programs have mentioned strokes associated with sildenafil, and the first case reports have now been published. • A 50-year-old man took sildenafil 50 mg, and 2 hours later developed a right-sided hemiparesis and altered hemibody sensation, a right facial paresis, and slurred speech (6A ). The symptoms gradually disappeared 4 hours later, but recurred the next week when he took sildenafil 100 mg. On the second occasion the symptoms did not resolve, and an MRI scan showed a recent infarct in the left internal capsule and lateral thalamus. No other cause of the stroke was found by evaluation of the heart and extracranial vessels. The symptoms gradually improved over 6 months. • A 44-year-old man developed a severe headache and vomiting after taking four tablets of sildenafil (of unknown strength) followed by sexual intercourse (7A ). A CT scan showed a left-sided temporal intracranial hemorrhage. He died of cerebral edema and pneumonia a few days later. Autopsy showed no vascular abnormality. • A 67-year-old man took two 25 mg tablets of sildenafil 1 hour apart (8A ). He complained of headache, confusion, and nervousness after the

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first tablet, and his symptoms increased and he developed language difficulty after the second tablet. He did not have sexual intercourse. A few days later an MRI scan showed a large left temporal subcortical hemorrhage. The symptoms resolved partially over a few days.

Whereas the suspected mechanism for ischemic stroke is analogous to that leading to myocardial infarction (hypoperfusion distal to a critical lesion), intracerebral bleeding (7A , 8A ) may be more difficult to explain. The authors considered the likelihood of sildenafilinduced spontaneous intracerebral hemorrhage due to the vasodilatory effects of the drug on the cerebral vasculature (as evidenced by headache, flushing, and nasal congestion). Sensory systems Anterior ischemic optic neuropathy is a disorder whose pathophysiology is poorly understood. The difference between the intraocular pressure and the perfusion pressure in the posterior ciliary arteries determines the circulation in the optic disc, and a reduction in this difference may contribute to ischemia. • A 42-year-old man presented with anterior ischemic optic neuropathy, leading to a visual field defect in that eye (9A ). Because the symptoms occurred within 24 hours of sildenafil, an association with the drug was suspected.

Drug interactions The effects of sildenafil can be potentiated by drugs that are metabolized by CYP3A4. Tacrolimus is an example. When sildenafil was given to patients with kidney transplants taking regular tacrolimus, peak concentrations were much higher and the halflife much longer than expected from data in healthy volunteers (10c ). However, an effect of the underlying disease and other concomitant drugs obviously could not be excluded.

REFERENCES 1. Cariski AT. Cilostazol: a novel treatment option in intermittent claudication. Int J Clin Pract 2001; Suppl 119: 11–18. 2. Marroun I, Fialip J, Deleveaux I, André M, Lamaison D, Cabane J, Piette JC, Eschalier A, Aumaitre O. Infarctus du myocarde sous iloprost chez

un patient atteint de sclérodermie. Thérapie 2001; 56: 627–33. 3. Rapoport AM, Tepper SJ. All triptans are not the same. J Headache Pain 2001; 2: S87–92. 4. Källén B, Lygner PE. Delivery outcome in women who used drugs for migraine during

232 pregnancy with special reference to sumatriptan. Headache 2001; 41: 351–6. 5. Dundar M, Kocak I, Dundar SO, Erol H. Evaluation of side effects of sildenafil in group of young healthy volunteers. Int Urol Nephrol 2001; 32: 705– 8. 6. Morgan JC, Alhatou M, Oberlies J, Johnston KC. Transient ischemic attack and stroke associated with sildenafil (Viagra) use. Neurology 2001; 57: 1730–1. 7. Buxton N, Flannery T, Wild D, Bassi S. Sildenafil (Viagra)-induced spontaneous intracerebral haemorrhage. Br J Neurosurg 2001, 15: 347–9.

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R. Verhaeghe

8. Monastero R, Pipia C, Camarda LKC, Camarda R. Intracerebral haemorrhage associated with sildenafil citrate. J Neurol 2001; 248: 141–2. 9. Cunningham AV, Smith KH. Anterior ischemic optic neuropathy associated with Viagra. J NeuroOphthalmol 2001; 21: 22–5. 10. Christ B, Brockmeier D, Hauck EW, Friemann S. Interactions of sildenafil and tacrolimus in men with erectile dysfunction after kidney transplantation. Urology 2001; 58: 589–93.

Pieter Joubert

20

Antihypertensive drugs

The role of endothelin receptor antagonists in hypertension It is disappointing that mechanistically novel antihypertensive drugs have not emerged during the last decade or two. The only real novelty of the last decade was the addition of angiotensin II receptor antagonists as a refinement of the approach introduced with ACE inhibitors. The expectations for direct renin antagonists have not been realized. Some of the cornerstone classes of antihypertensive drugs, such as the diuretics, beta-adrenoceptor antagonists, calcium channel blockers, and direct vasodilators, have been around for several decades. Advances have predominantly been made in the pharmacokinetic properties and pharmacodynamic specificities of compounds in existing antihypertensive drug classes. With the emergence of knowledge about endothelial factors such as nitric oxide and endothelin, there was much expectation that endothelin antagonists would become useful in the management of hypertension. Endothelin was discovered in 1988 (1R ) and is the most potent vasoconstrictor known. In terms of pathophysiology, endothelin receptor antagonists could play a role in a variety of diseases associated with vasoconstriction, such as hypertension, renal disease, occlusive vascular disease, pulmonary hypertension, and congestive heart failure (2R ). Apart from vasoconstriction, endothelin is also involved in the structural changes associated with these diseases, and it is now recognized that there is a wider target in hypertension treatment than lowering blood pressure. Vascular and myocardial remodeling may be key issues in determining long-term outcome (3R ) and effects on myocardial fibrosis and vascular compliance may be as important as lowering blood pressure. ACE inhibitor © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

treatment can produce regression of hypertensive myocardial fibrosis in animal models (4E ) and in hypertensive patients (5C ). Bosentan, an endothelinA and endothelinB receptor antagonist, is effective in pulmonary arterial hypertension (6C , 7C ) and is being marketed for this indication. The studies showed an improvement in exercise capacity and dyspnea and an increased time to clinical worsening. Efficacy in pulmonary hypertension has also been reported in an open study with a selective endothelinA receptor antagonist (8C ). As far as hypertension is concerned, there is a substantial body of preclinical evidence of the potential efficacy of endothelin antagonists in hypertension, and this has been extensively reviewed (9R ). Circulating endothelin concentrations are not increased in hypertension, but it is postulated that there is an imbalance between the vasodilatory effects of nitric oxide and the vasoconstrictor effects of endothelin at a local vascular level, resulting in increased endothelin vasoconstrictor tone and endothelinmediated end-organ damage (10R , 11R ). In a dose-finding study with bosentan (100, 500, 1000, and 2000 mg/day) in 293 hypertensive patients (12C ) there were statistically significant falls in diastolic blood pressure with the 500 and 2000 mg/day doses. The effects were similar to that of enalapril 20 mg/day. The lowering of blood pressure was not associated with any changes in heart rate, plasma noradrenaline concentrations, plasma renin activity, or angiotensin II concentrations. If endothelin antagonists do become one of the therapeutic options in hypertension, they may also bring a new adverse effects profile. The major safety issue that has emerged with bosentan, the endothelin receptor antagonist that has been most extensively studied in man, has been dose-dependent reversible impairment of hepatic function (3% with 125 mg, 7% with 250 mg), manifesting as raised transaminases (7C ). The effect of bosentan on hepatocanalicular bile salt transport has been studied in rats in

233

234 conjunction with a re-examination of the safety database from two clinical trials (in hypertension and congestive cardiac failure) and measurement of bile salt concentrations in stored blood samples from these trials (13E ). Hepatic injury was defined as a three-fold increase in ALT activity. In the hypertension trial there were no cases of hepatic injury with placebo or enalapril. With bosentan, the frequencies were 2%, 4%, 11%, and 8% at dosages of 100, 500, 1000, and 2000 mg/day respectively. There was a dose-dependent increase in bile salt concentrations. In the study in patients with heart failure (New York Heart Association classes III/IV), liver injury occurred in 4% of 126 patients taking placebo and 18% of 244 patients taking bosentan 500 mg bd. A subgroup analysis showed a higher incidence of hepatic injury in patients taking concomitant bosentan and glibenclamide. Patients with hepatic injury had raised bile salt concentrations. In rats, intravenous bosentan produced a dose-dependent increase in plasma bile salts. The effect was potentiated when glibenclamide was co-administered. In vitro studies in rat canalicular liver plasma membranes confirmed inhibition of bile-salt transport. Three bosentan metabolites were also investigated. The M2 metabolite was more potent than bosentan, whereas the M1 and M3 metabolites produced less inhibition of bile acid transport than bosentan. These data suggest that bosentan causes cholestatic liver injury due to inhibition of bile salt efflux and damage due to intracellular accumulation of bile salts.

ANGIOTENSIN CONVERTING ENZYME INHIBITORS (SED-14, 638; SEDA-23, 217; SEDA-24, 233; SEDA-25, 240) Respiratory The genetic basis of ACE inhibitor-induced cough and its relation to bradykinin have been further explored in a study of the effect of cilazapril in two groups of healthy volunteers genotyped for ACE insertion/deletion (I/D) polymorphism (14C ). The cough threshold to inhaled capsaicin was significantly lower in the genotype II group than in the DD group.

Chapter 20

Pieter Joubert

Skin responses to intradermal bradykinin were significantly enhanced in the II group. There was no difference in responsiveness to intradermal substance P. The authors suggested that these findings provide further evidence of the link between ACE inhibitor-induced cough and I/D polymorphism of the ACE gene, and that this supports the hypothesis that ACE inhibitors cause cough by modulating tissue concentrations of bradykinin. Hematologic ACE inhibitors are used to treat erythrocytosis, for example after transplantation (15C ). Efficacy in treating erythrocytosis in chronic obstructive pulmonary disease has also been described with the angiotensin II receptor antagonist losartan (16C ). ACE inhibitors can also lower normal erythrocyte counts and cause anemia (17C ). This effect has been assessed in a retrospective study of 92 patients after transplantation with and without erythrocytosis, comparing patients taking the same anti-rejection therapy (steroids and ciclosporin or steroids, ciclosporin, and azathioprine) taking ACE inhibitors with those not taking ACE inhibitors (18c ). There were significantly lower hemoglobin and erythropoietin concentrations in patients taking ACE inhibitors. When enalapril was given to those who had not previously taken an ACE inhibitor, the hemoglobin concentration fell by around 10% and erythropoietin by around 40%. These effects were not affected by the presence or absence of azathioprine. Although the hemoglobin-lowering effect of ACE inhibition is not a new finding, the lack of an influence of azathioprine adds some further understanding to the effect.

Captopril

(SED-14, 642; SEDA-24, 237;

SEDA-25, 242) Pancreas Two new cases of pancreatitis with captopril have been reported (19A , 20A ). It has been suggested that early detection of raised serum amylase and lipase activities can prevent the development of full-blown pancreatitis (20A ).

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Enalapril

(SED-14, 643; SEDA-23, 219; SEDA-24, 237; SEDA-25, 242) Neuromuscular function Muscular weakness, believed to be the first case, has been reported in a patient with mild renal impairment taking enalapril (21A ).

• A 78-year-old man, taking enalapril (10 mg/day), furosemide, and digoxin for cardiac failure due to ischemic heart disease, suddenly developed generalized muscle weakness. He had grade 3/5 weakness of all four limbs, his cranial nerves were intact, and there was no sensory impairment. His tendon reflexes were reduced and he had flexor plantar reflexes. The initial diagnosis was Guillain–Barré syndrome. Further investigation showed peaked T waves on his electrocardiogram, with a serum potassium of 9.4 mmol/l and a creatinine of 266 µmol/l. He was treated with glucose plus insulin, calcium gluconate, and sodium bicarbonate. Enalapril was withdrawn. His potassium concentration normalized.

Hyperkalemic muscle paralysis has been reported in renal insufficiency and trauma and in patients taking spironolactone and amiloride plus hydrochlorothiazide (co-amilozide). ACE inhibitors inhibit the release of aldosterone, reducing renal potassium loss, which can be enhanced by potassium-sparing diuretics or preexisting renal insufficiency. Hematologic An equivocal case of neutropenia has been ascribed to enalapril (22A ). • A 52-year-old male renal transplant recipient on stable therapy (4.5 months) with ciclosporin, mycophenolate mofetil, and co-trimoxazole developed erythrocytosis and hypertension. His leukocyte count fell 19 days after he started to take enalapril. Enalapril was withdrawn, the dose of co-trimoxazole was halved, and the dose of mycophenolate was first reduced and then withdrawn on day 25. On day 28 the leukocyte and neutrophil counts were so low that granulocyte-stimulating factor had to be used. The leukocyte count normalized during continued treatment with ciclosporin and co-trimoxazole. CMV tests were negative.

The authors suggested a synergistic effect between enalapril and mycophenolate. As leukopenia is the commonest clinically significant adverse effect of mycophenolate, the evidence in this case is inadequate to support this hypothesis, particularly in the absence of information on mycophenolate blood concentrations.

Skin As pemphigus vulgaris has been attributed to ACE inhibitors, it is not surprising that giving an ACE inhibitor to a patient with pemphigus could worsen the disease. Recently aggravation of pre-existing childhood pemphigus by enalapril has been reported (23A ). • A 12-year-old boy with pemphigus vulgaris was treated with intravenous dexamethasone and prednisolone. He developed severe hypertension, which was unresponsive to atenolol, and he was given enalapril 2.5 mg bd. Although the blood pressure responded, the pemphigus deteriorated markedly over the next 2 weeks. Additional dexamethasone did not produce improvement. Enalapril was replaced by amlodipine, and the disease resolved over 3 weeks.

The evidence to date suggests that ACE inhibitors should be avoided in patients with preexisting pemphigus. Immunologic A case of eosinophilic gastroenteritis after enalapril has been described (24Ar ). The authors briefly reviewed this rare condition, which is diagnosed on the basis of the presence of gastrointestinal symptoms, eosinophilic infiltration of the gastrointestinal tract, and the absence of parasitic or extraintestinal disease. It has also been reported after clofazimine and naproxen. • A 63-year-old hypertensive woman, who had a carcinoma of the distal esophagus resected 19 months earlier, developed chronic diarrhea. Clostridium difficile toxin was identified in her stools and the diarrhea resolved after treatment with metronidazole. Enalapril was added to her antihypertensive treatment, and 3 months later the diarrhea recurred. Stool examination was negative and there was no Clostridium difficile toxin. Her condition worsened and she lost 5 kg. She had marked eosinophilia (2.4 × 109 /l), and a small bowel biopsy showed mild chronic inflammation and edema, partial villous atrophy, and large clusters of eosinophils in the lamina propria with some focal infiltration of the epithelium. She stopped taking enalapril and her diarrhea promptly abated and the eosinophil count fell to 0.5 × 109 /l at 3 weeks and 0.1 × 109 /l at 2 months.

Fosinopril Liver Hepatic injury has been described from time to time with ACE inhibitors. The first case of severe, prolonged cholestatic jaundice has

236

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been reported with fosinopril, a phosphoruscontaining ester prodrug of the ACE inhibitor fosinoprilat (25A ). The evidence of a link to fosinopril was convincing.

Urinary tract A further convincing case of ACE inhibitor-related renal insufficiency has been described with irbesartan and losartan (27A ).

• A 61-year-old man developed weakness, severe jaundice and pruritus, and weight loss over 2 weeks. He had started to take metoprolol, fosinopril and diazepam for hypertension 5 weeks before. He had raised hepatic transaminases and bilirubin. A liver biopsy showed cholestasis in a normal cellular architecture. A lymphocyte transformation assay showed reactivity to fosinopril but not diazepam or metoprolol. Bilirubin concentrations took 4 months to normalize and pruritus persisted for 6 months.

• A 67-year-old woman with congestive heart failure developed oliguric renal insufficiency 2 days after the introduction of irbesartan. She rapidly recovered after withdrawal, and was then given losartan. The condition recurred shortly afterwards and subsided when losartan was stopped.

Lisinopril

Urinary tract A further case of convincing anuric renal insufficiency (see also the case above under irbesartan) after losartan has been described in a 70-year-old man with a solitary kidney (28A ). An interesting feature was that the patient’s blood pressure could be controlled with captopril without the development of anuria. This is in line with a study in dogs, in which there was a greater deterioration in glomerular filtration with angiotensin II receptor inhibition than with ACE inhibition, for the same effect on blood pressure (29E ).

(SEDA-23, 220; SEDA-24, 238; SEDA-25, 242) Drug interactions Raised clozapine blood concentrations have been reported after the introduction of lisinopril (26A ). • A 39-year-old man with schizophrenia and diabetes, who had taken clozapine 300 mg/day and glipizide 10 mg/day for a year, took lisinopril 5 mg/day for newly diagnosed hypertension. On several occasions afterwards he had roughly a doubling of his blood concentrations of clozapine and norclozapine. He had typical effects of clozapine toxicity. After replacement of lisinopril by diltiazem, the blood concentrations of clozapine and norclozapine returned to the values that were present before lisinopril was introduced.

The information given here was sketchy and there was no information on the timing of blood samples relative to the dose of clozapine. Clozapine is metabolized by CYP1A2 and CYP3A4, but there is no evidence that lisinopril affects these pathways.

ANGIOTENSIN II RECEPTOR ANTAGONISTS (SED-14, 644; SEDA-23, 220; SEDA-24, 23; SEDA-25, 243)

Irbesartan

(SEDA-24, 240, SEDA-25,

Losartan

(SED-14, 645; SEDA-23, 221; SEDA-24, 240; SEDA-25, 245)

Drug interactions Administration of grapefruit juice (which inhibits both cytochrome P450 and P glycoprotein) to healthy volunteers resulted in an increased serum concentration ratio of losartan to its active metabolite E3174 (30c ). As both losartan and its metabolite contribute to the therapeutic effects, the absence of pharmacodynamic measurements in this study obviated conclusions about the clinical implications of this interaction. Teratogenicity A woman who took losartan from 17 to 31 weeks of gestation developed oligohydramnios and delivered a stillborn fetus with deformities of the extremities and face (31A ).

244) REFERENCES 1. Yanagisawa M, Kurihara H, Kimura S. A novel potent vasoconstrictor peptide produced by vascu-

lar endothelial cells. Nature 1988; 332: 411–15. 2. Lüscher TF, Barton M. Endothelins and endothe-

Antihypertensive drugs

Chapter 20

lin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 2000; 102: 2434–40. 3. Weber KT. Cardioreparation in hypertensive heart disease. Hypertension 2001; 38: 588–91. 4. Brilla CG, Matsubara L, Weber KT. Advanced hypertensive disease in spontaneously hypertensive rats: lisinopril-mediated regression of myocardial fibrosis. Hypertension 1996; 28: 269–75. 5. Brilla CG, Funk RC, Rupp H. Lisinoprilmediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 2000; 102: 1388–93. 6. Channick RN, Simmoneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch BD, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358; 1119– 23. 7. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simmoneau G. Bosentan therapy for pulmonary arterial hypertension. New Engl J Med 2002; 346: 896–903. 8. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension. Chest 2002; 121: 1860–8. 9. Moreau P. Endothelin in hypertension: a role for receptor antagonists? Cardiovasc Res 1998; 39: 534–42. 10. Taddei S, Virdis A, Ghiadoni L, Sudano I, Magagna A, Salvetti A. Role of endothelin in the control of peripheral vascular tone in human hypertension. Heart Failure Rev 2001; 6: 277–85. 11. Donckier JE. Therapeutic role for bosentan in hypertension: lessons from the model of perinephric hypertension. Heart Failure Rev 2001; 6: 253–64. 12. Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V. The effect of an endothelin antagonist, bosentan, on blood pressure in patients with essential hypertension. New Engl J Med 1998; 338: 784–90. 13. Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier P. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001; 69: 223–31. 14. Takahashi T, Yamaguchi K, Furuya K, Kawakami Y. The ACE gene polymorphism and cough threshold for capsaicin after cilazapril usage. Respir Med 2001; 95: 130–5. 15. Mazalli M, Filho GA. Use of aminophylline and enalapril in posttransplant polycythemia. Transplantation 1998; 65 1461–3. 16. Ölger AF, Özlem ÖK, Özgur K, Peri A, Doganay A. Effects of losartan on the renin– angiotensin–aldosterone system and erythrocytosis in patients with chronic obstructive pulmonary dis-

237 eases and systemic hypertension. Clin Drug Invest 2001; 21: 337–43. 17. Gossmann J, Kachel HG, Schoepe W. Enalapril associated anemia in renal transplant recipients treated for hypertension. Transplantation 1993; 56: 585–9. 18. Montanaro D, Gropuzzo P, Tulissi G, Boscutti A, Risaliti U, Baccarani U, Mioni G. Angiotensinconverting enzyme inhibitors reduce hemoglobin concentrations, hematocrit and serum erythropoietin levels in renal transplant recipients without posttransplantation erythrocytosis. Transpl Proc 2001; 33: 2038–40. 19. Iliopoulo A, Giannakopoulos G, Pagoy H, Toubanakis C, Spiropoulos T. Acute pancreatitis due to captopril treatment. Dig Dis Sci 2001; 46: 1882–3. 20. Borgia MC, Celestini A, Caravella P, Catalano C. Angiotensin-converting-enzyme inhibitor administration must be monitored for serum amylases and lipase in order to prevent an acute pancreatitis. Angiology 2001; 52: 645–7. 21. Dutta D, Fischer M, McClung A. Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis. Postgrad Med J 2001; 77: 114–15. 22. Donadio C, Lucchesi A. Neutropenia after treatment of posttransplantation erythrocytosis with enalapril. Transplantation 2001; 15: 553–4. 23. Thami GP. Severe childhood pemphigus vulgaris aggravated by enalapril. Dermatology 2001; 202: 341. 24. Barak N, Hart J, Sitrin MD. Enalapril-induced eosinophilic gastroenteritis. J Clin Gastroenterol 2001; 33: 157–8. 25. Nunes ACR, Amaro P, Maç_as F, Cipriano A, Martins I, Rosa A, Pimenta I, Donato A, Freitas D. Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report. Eur J Gastroenterol Hepatol 2001;13: 279–82. 26. Abraham G, Grunberg B, Gratz S. Possible interaction of clozapine and lisinopril. Am J Psychiatry 2001; 15: 969. 27. Lee H, Kim C, Acute oliguric renal failure associated with angiotensin II receptor antagonists. Am J Med 2001; 111: 162–3. 28. Maillard J, Descombes E, Fellay G, Regamey C. Repeated transient anuria following losartan administration in a patient with a solitary kidney. Renal Fail 2001; 23: 143–7. 29. Brooks DP, De Palma PD, Ruffolo RR. Effect of captopril and the nonpeptide angiotensin II antagonists, SKF 108566 and EXP3174, on renal function in dogs with a renal artery stenosis. J Pharmacol Exp Ther 1992; 263: 422–7. 30. Zaidenstein R, Soback S, Gips M, Avni B, Dishi V, Weissgarten Y, Golik A, Scapa E. Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. Ther Drug Monit 2001; 23: 369–73. 31. Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects. Lancet 2001; 357: 363.

Domenic A. Sica

21 GENERAL Sexual function Diuretics remain important in the pharmacotherapy of hypertension. Highdose diuretic therapy was the therapeutic norm in the 1980s, but in the 1990s a low-dose stratagem was instituted. With this change the incidence of diuretic-related electrolyte and metabolic adverse effects has fallen. Now the adverse effect of diuretics that is a major obstacle to their use is sexual dysfunction. The exact incidence is poorly documented, perhaps because of the personal nature of the problem and the reluctance of patients and/or physicians to discuss it. The adverse effects of thiazide and thiazide-like diuretics on male sexual function include reduced libido, erectile dysfunction, and difficulty in ejaculating. These abnormalities have been reported with incidence rates of 3–32%. The true incidence of sexual dysfunction probably lies closer to the lower end of this range (1R ). In a meta-analysis of 13 randomized placebo-controlled trials conducted over a mean of 4 years the NNH (number needed to harm) for erectile impotence with thiazide diuretics in hypertension was 20 and the relative risk was 5.0 (2M ). The mechanisms by which thiazides affect erectile dysfunction or libido are unclear, but it has been suggested that they have a direct effect on vascular smooth muscle cells or reduce the response to catecholamines. Sexual dysfunction does not appear to be mediated by either a low serum potassium concentration or a low blood pressure. The incidence of diuretic-related impotence is much lower when weight loss occurs. Since sexual dysfunction can adversely affect the quality of life of hypertensive patients, physicians or health-care providers should take an accurate baseline sexual history and monitor sexual status for changes during therapy. If © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

238

Diuretics there are significant changes in sexual function diuretic therapy can be withdrawn and an alternative drug class substituted. However, not uncommonly sexual dysfunction will persist despite withdrawal of the diuretic, suggesting that elements of the hypertensive state itself contribute to the process.

CARBONIC ANHYDRASE INHIBITORS (SED-14, 669; SEDA-23, 229; SEDA-24, 249; SEDA-25, 249)

Acetazolamide Electrolyte balance Acetazolamide, a noncompetitive carbonic anhydrase inhibitor, can produce severe lactic acidosis, with an increased lactate:pyruvate ratio, ketosis with a low beta-hydroxybutyrate:acetoacetate ratio, and a urinary organic acid profile consistent with pyruvate carboxylase deficiency. The acquired enzymatic injury that results from inhibition of mitochondrial carbonic anhydrase V, which provides bicarbonate to pyruvate carboxylase, can damage the tricarboxylic acid cycle. Four preterm neonates with posthemorrhagic ventricular dilatation developed severe metabolic acidosis after being given acetazolamide (3c ). The acidosis suddenly disappeared after a transfusion of packed erythrocytes, which was attributed to the citrate contained in the blood. Urinary tract Renal tubular acidosis occurred in a preterm boy shortly after birth (4A ). His mother had taken oral acetazolamide during pregnancy for glaucoma. When renal tubular acidosis developed, acetazolamide was detected in his serum, demonstrating transplacental passage of acetazolamide. Acetazolamide therapy is ill-advised in pregnancy.

Diuretics

Chapter 21

239

Immunologic A case of non-fatal anaphylactic shock with acute pulmonary edema has been reported in a 79-year-old woman after a first dose of acetazolamide (5A ). There was no history of sulfonamide allergy and she had been taking hydrochlorothiazide for some time. Anaphylactic shock with acetazolamide should be recognized to occur as a first-dose phenomenon with no prior demonstrable sulfonamide allergy.

Electrolyte balance In a hospital-based survey of hypertensive patients with hyponatremia (serum sodium concentration below 135 mmol/l) the odds ratio for hyponatremia was three times higher in women. In those over 65 years there was a ten-fold higher risk. In many instances hyponatremia was insidious in its presentation and did not occur until several months after therapy had begun (10c ). However, hyponatremia can develop rapidly.

Drug overdose Acetazolamide overdose and its sequelae have not been previously reported in children.

• A 69-year-old woman with uncontrolled hypertension took two doses of hydrochlorothiazide 25 mg and her serum sodium fell to 115 mmol/l within 24 hours, with accompanying neurological symptoms (11A ). She recovered fully with the administration of 3% saline.

• A 12-month-old girl, weighing 10 kg, developed metabolic acidosis after taking 500–1250 mg of acetazolamide (6A ). The maximum base deficit recorded was 11.6. She was treated with sodium bicarbonate and recovered completely.

Accidental poisoning with acetazolamide should be included in the differential diagnosis of metabolic acidosis.

Dorzolamide Skin Topical dorzolamide caused severe periorbital dermatitis after an average exposure time of 20 weeks in 14 patients (7c ). Although the dermatitis may resolve when dorzolamide is withdrawn, this does not always occur, and in some patients all topical medications containing benzalkonium chloride must be withdrawn. Allergic contact blepharoconjunctivitis has also been reported with dorzolamide in a 72year-old man (8A ).

THIAZIDE AND LOOP DIURETICS (SED-14, 656; SEDA-23, 228; SEDA-24, 250; SEDA-25, 252) Cardiovascular A 72-year-old woman had repeated episodes of sudden-onset pulmonary edema, each occurring immediately after the ingestion of hydrochlorothiazide 12.5 mg (9A ). The close temporal relation between the ingestion of hydrochlorothiazide and the onset of symptoms, together with rapid and full clinical recovery after withdrawal of therapy, suggested drug-induced pulmonary edema and possible anaphylactoid hypotension.

Urinary tract Although it is often described in children, medullary nephrocalcinosis with furosemide has been rarely described in adults, but has now been reported in a 40-year-old woman who had taken furosemide (40–160 mg/day) for 15 years (12A ). Urinary tract A 25-year-old woman developed biopsy-proven chronic tubulointerstitial nephritis with accompanying distal renal tubular acidosis in association with furosemide abuse (up to 1.2 g/day for several months) (13A ). Chronic tubulointerstitial nephritis has not previously been reported with furosemide. Skin The first case of pemphigus foliaceus in relation to indapamide has been described (14A ). Carcinogenicity Recent studies have suggested that long-term diuretic therapy may be associated with an increased risk of renal cell carcinoma. Other cancer types have now been evaluated for their association with diuretic therapy. The development of colon cancer has been studied in 14 166 patients aged 45–74 years with a previous myocardial infarction and/or stable anginal, screened for participation in the Bezafibrate Infarction Prevention Study (15C ). Of these, 2153 used diuretics and 12 013 did not. Multivariate analysis identified diuretics as an independent predictor of an increased incidence of colon cancer (hazard ratio 2.0) and colon cancer mortality (hazard ratio 3.7). However, the association between diuretic therapy and a higher incidence of colon cancer was observed only among non-users of aspirin. There

240 was a relatively lower incidence of colon cancer in furosemide users and a higher incidence in the small combined subgroup of those who took amiloride and or hydrochlorothiazide. Further studies to test the association between diuretics and colon cancer, as well as the potential protective effects of aspirin, are needed. Until these data become available, physicians should be aware of the potential effects of diuretics, especially when choosing long-term treatment for young patients with mild hypertension. Drug interactions Intravenous furosemide is commonly given to patients with acute heart failure to relieve pulmonary congestion. Symptomatic relief occurs before the onset of diuresis, and the beneficial effect is believed to result from a venodilator action of furosemide, which precedes its diuretic effect. This venodilator response is inhibited by the cyclo-oxygenase inhibitor indomethacin, suggesting that it occurs through local prostaglandin release. Aspirin 75 mg/day and 300 mg/day has now also been shown to inhibit the venodilator effect of furosemide (16C ). These data raise the issue of whether aspirin should be routinely used in patients with congestive heart failure using furosemide.

ALDOSTERONE RECEPTOR ANTAGONISTS (SED-14, 674; SEDA-23, 239; SEDA-24, 251; SEDA-25, 254)

Spironolactone Liver A 50-year-old woman taking spironolactone for androgenic alopecia developed hepatitis with minimal cholestasis 6 weeks after starting therapy (17A ). After withdrawal of spironolactone, her symptoms resolved and liver function tests improved. She was not rechallenged. Skin A 76-year-old patient developed eczemalike lesions and severe pruritus; histological and immunological investigations showed pemphigoid (18A ). The skin lesions regressed spontaneously within 15 days of spironolactone withdrawal and no relapse was noted over the next 30 months.

Chapter 21

Domenic A. Sica

POTASSIUM-SPARING DIURETICS (SED-14, 674; SEDA-23, 239; SEDA-24, 251)

Amiloride Electrolyte balance Amiloride is a therapeutic option in reducing potassium losses in patients receiving amphotericin. When it was given to 19 oncology patients with marked amphotericin-induced potassium depletion mean serum potassium concentrations increased in the 5 days before and after administration (from 3.4 to 3.9 mmol/l) (19c ). There was also a trend towards reduced potassium supplementation (48 versus 29 mmol/day). Adverse reactions were limited to hyperkalemia in two patients who took amiloride 20 mg/day and a high potassium intake.

Triamterene Urinary tract Triamterene can cause nephrolithiasis. The frequency with which this occurs is unknown, but a recent survey from France has shed some light (20E ). In an analysis of 22 510 urinary calculi performed by infrared spectroscopy, drug-induced urolithiasis was divided into two categories: first, stones with drugs physically embedded (n = 238; 1.0%), notably indinavir monohydrate (n = 126; 53%), followed by triamterene (n = 43; 18%), sulfonamides (n = 29; 12%), and amorphous silica (n = 24; 10%); secondly, metabolic nephrolithiasis induced by drugs (n = 140; 0.6%), involving mainly calcium/vitamin D supplementation (n = 56; 40%) and carbonic anhydrase inhibitors (n = 33; 24%). Druginduced stones are responsible for about 1.6% of all calculi in France. Physical analysis and a thorough drug history are important elements in the diagnosis. The frequency with which triamterene stones occur will relate to the regional patterns of its use. Teratogenicity Neural tube defects, characterized by a failure of the neural tube to close properly after conception, affect about one in 1000 live births in the USA. Periconceptional folic acid supplementation reduces the

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risk. To determine whether periconceptional exposure to folic acid antagonists might therefore increase the risk of neural tube defects, data from a case-control study of birth defects (1979–1998) in the USA and Canada have been examined (21C ). Data on 1242 infants with neural tube defects (spina bifida, anencephaly, and encephalocele) were compared with data from a control group of 6660 infants with malformations not related to vitamin supplementation. Triamterene is a folic acid antagonist and in this series was associated with the development of neural tube defects, but there were too few cases to estimate an odds ratio. Triamterene should be avoided in pregnancy. Risk factors Age Diuretics often cause adverse effects in elderly people, often as a consequence of drug–drug interactions. In addition, multiple chronic diseases, age-dependent pharmacokinetic and pharmacodynamic changes, and impaired homeostasis complicate diuretic therapy in the elderly. Triamterene is often

241 given in combination with the thiazide diuretic bemetizide. The pharmacokinetics and the pharmacodynamics of a fixed combination of bemetizide 25 mg and triamterene 50 mg have been evaluated in 15 elderly patients (aged 70–84 years) and 10 young volunteers (aged 18–30 years) after single doses (on day 1) and multiple doses (at steady state on day 8) (22C ). Mean plasma concentrations of bemetizide, triamterene, and the active metabolite of triamterene, hydroxytriamterene, were significantly higher in the elderly subjects after single and multiple doses and urine flow and sodium excretion rates fell in tandem with the accumulation of these drugs. The glomerular filtration rate, known to be reduced in elderly people, was further reduced at higher concentrations of bemetizide and triamterene, which may explain why there were limited diuretic and saluretic effects after multiple doses. This study clearly points to a modulating effect of the degree of renal function on the diuretic actions of these compounds in the elderly.

REFERENCES 1. Fogari R, Zoppi A. Effects of antihypertensive therapy on sexual activity in hypertensive men. Curr Hypertens Rep 2002; 4: 202–10. 2. Loke Y. Hypertension 1999; 34: 710. 3. Filippi L, Bagnoli F, Margollicci M, Zammarchi E, Tronchin M, Rubaltelli FF. Pathogenic mechanism, prophylaxis, and therapy of symptomatic acidosis induced by acetazolamide. J Invest Med 2002; 50: 125–32. 4. Ozawa H, Azuma E, Shindo K, Higashigawa M, Mukouhara R, Komada Y. Transient renal tubular acidosis in a neonate following transplacental acetazolamide. Eur J Pediatr 2001; 160: 321–2. 5. Gallerani M, Manzoli N, Fellin R, Simonato M, Orzincolo C. Anaphylactic shock and acute pulmonary edema after a single oral dose of acetazolamide. Am J Emerg Med 2002; 20: 371–2. 6. Baer E, Reith DM. Acetazolamide poisoning in a toddler. J Paediatr Child Health 2001; 37: 411–12. 7. Delaney YM, Salmon JF, Mossa F, Gee B, Beehne K, Powell S. Periorbital dermatitis as a side effect of topical dorzolamide. Br J Ophthalmol 2002; 86: 378–80. 8. Mancuso G, Berdondini RM. Allergic contact blepharoconjunctivitis from dorzolamide. Contact Dermatitis 2001; 45: 243. 9. D’Aloia A, Fiorina C, Vizzardi E, Faggiano P, Cas LD. Episodi ricorrenti di edema polmonare acuto non cardiogeno indotti dall’assunzione di idroclorotiazide. Ital Heart J Suppl 2001; 2: 904–7.

10. Sharabi Y, Illan R, Kamari Y, Cohen H, Nadler M, Messerli FH, Grossman E. Diuretic induced hyponatremia in elderly hypertensive women. J Hum Hypertens 2002; 16: 631–5. 11. Al-Salman J, Pursell R. Hyponatremic encephalopathy induced by thiazides. West J Med 2001; 175: 87. 12. Simoes A, Domingos F, Prata MM. Nephrocalcinosis induced by furosemide in an adult patient with incomplete renal tubular acidosis. Nephrol Dial Transplant 2001; 16: 1073–4. 13. Park CW, You HY, Kim YK, Chang YS, Shin YS, Hong CK, Kim YC, Bang BK. Chronic tubulointerstitial nephritis and distal renal tubular acidosis in a patient with frusemide abuse. Nephrol Dial Transplant 2001; 16: 867–9. 14. Bayramgurler D, Ercin C, Apaydin R, Unal G. Indapamide-induced pemphigus foliaceus. J Dermatol Treat 2001; 12: 175–7. 15. Tenenbaum A, Grossman E, Fisman EZ, Adler Y, Boyko V, Jonas M, Behar S, Motro M, ReicherReiss H. Long-term diuretic therapy in patients with coronary disease: increased colon cancer-related mortality over a 5-year follow-up. J Hum Hypertens 2001; 15: 373–9. 16. Jhund PS, Davie AP, McMurray JJ. Aspirin inhibits the acute venodilator response to furosemide in patients with chronic heart failure. J Am Coll Cardiol 2001; 37: 1234–8.

242 17. Thai KE, Sinclair RD. Spironolactone-induced hepatitis. Australas J Dermatol 2001; 42: 180–2. 18. Modeste A-B, Cordel N, Courville Ph, Gilbert D, Lauret Ph, Jolly P. Pemphigoide regressive apres arret d’un diuretique contenant de l’aldactone. Ann Dermatol Venereol 2002; 129: 56–8. 19. Bearden DT, Muncey LA. The effect of amiloride on amphotericin B-induced hypokalaemia. J Antimicrob Chemother 2001; 48: 109–11. 20. Cohen-Solal F, Abdelmoula J, Hoarau MP, Jungers P, Lacour B, Daudon M. Les lithiases uri-

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naires d’origine medicamenteuse. Thérapie 2001; 56: 743–50. 21. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol 2001; 153: 961–8. 22. Muhlberg W, Mutschler E, Hofner A, SpahnLanguth H, Arnold O. The influence of age on the pharmacokinetics and pharmacodynamics of bemetizide and triamterene: a single and multiple dose study. Arch Gerontol Geriatr 2001; 32: 265–73.

Gijsbert B. van der Voet and Frederik A. de Wolff

22 Aluminium

(SED-14, 683; SEDA-23, 231; SEDA-24, 253; SEDA-25, 257) Aluminium is toxic in patients on chronic hemodialysis and peritoneal dialysis and in those taking oral aluminium-containing medications. Aspects of aluminium safety (1R ) and metabolism (2R ) have been reviewed. The association between aluminium in drinking water and Alzheimer’s disease continues to be discussed and remains controversial (3R ). Nervous system Recently, acute neurotoxic adverse effects of aluminium have been reported, caused by the use of aluminiumcontaining surgical cement. • A 52-year-old woman had a resection of an acoustic neuroma (4A ). Bone reconstruction was performed with an aluminium-containing cement and 6 weeks later she had loss of consciousness, myoclonic jerks, and persistent tonic–clonic seizures, effects resembling those of dialysis encephalopathy. She died 6 months later with septic complications. Light microscopy and electron microscopy of the brain showed pathognomonic aluminium-containing intracytoplasmic argyrophylic inclusions in the choroid plexus epithelia, neurons, and cortical glia. These changes are characteristic of dialysis-associated encephalopathy. Atomic absorption spectrometry showed an increase in the mean aluminium concentration in the cortex and subcortex, up to 9.3 µg/g (reference range under 2 µg/g); a laser microprobe showed increased aluminium in subcellular structures.

This case shows again the extraordinary neurotoxic potency of aluminium, which was initiated by about 30 mg and apparently caused by direct access of aluminium to the brain parenchyma via cerebrospinal fluid leakage. Skin Persistent skin lesions occurred in three patients after the administration of aluminium hydroxide-containing vaccines. The mechanism of these persistent lesions is controversial. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Metals • A 19-year-old woman presented with multiple itchy nodules on the outer aspects of the upper arms at the sites of previous vaccine injections (5A ). There were several nodules, ranging from a few millimeters to 1 cm in diameter, some with overlying hyperpigmented skin. She had been receiving hyposensitization vaccines to treat recurrent extrinsic asthma and rhinitis for the previous 4 years. A skin biopsy showed a normal epidermis and upper dermis. There were multifocal unencapsulated granulomatous infiltrates in the deep dermis and subcutaneous tissues, disrupting the normal architecture of the latter. The infiltrate was predominantly composed of histiocytes with foreign body giant cells. There were also fibroblasts, fibrosis, and perivascular lymphocytes and plasma cells, with a few eosinophils. There was a granular basophilic material within the cytoplasm of some histiocytes. However, patch tests with aluminium chloride, nickel sulfate, and potassium dichromate were all negative. She was treated with potent topical corticosteroids and oral antihistamines, with some relief, but the nodules persisted 2 years later. • A 37-year-old woman with a 5-year history of multiple itchy nodules on the outer aspects of the upper parts of the arms at sites of previous vaccine injections had been receiving hyposensitization vaccines to treat recurrent extrinsic asthma and rhinitis for 10 years (5A ). Physical examination and a biopsy of one of the nodules were identical to those of the previous case. Patch tests with aluminium chloride were negative. Symptomatic relief was obtained with topical corticosteroids and oral antihistamines. The nodules persisted for at least 3 years. • A 52-year-old woman, allergic to wasp venom, was hyposensitized with a vaccine containing wasp venom precipitated on aluminium hydroxide (6A ). Each subcutaneous injection of the extract was followed by cooling of the acute local reaction at the injection site for about 1 hour. As soon as 24 hours after the second maintenance dose, she developed tender, erythematous, ill-demarcated, indurated plaques at the injection sites on both lateral thighs. The lesions resolved spontaneously after several weeks, leaving residual hyperpigmentation and subcutaneous atrophy. They reappeared with each treatment, even after the vaccine was changed to a lyophilized, aluminium-free extract. No further lesions occurred when the injection sites were not cooled, even though the aluminium hydroxide vaccine was continued. Patch tests with the vaccine, aluminium hydroxide, human albumin, phenol, and aluminium chloride hexahydrate were all negative. A biopsy of the skin lesions

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showed lobular panniculitis, with lipocyte necrosis and a mixed cellular infiltrate of neutrophils, lymphocytes, and histiocytes. Ultrasound examination of the atrophic areas showed significantly thinner subcutaneous tissue than in the normal contralateral skin. Rechallenge with an ice pack alone on the upper arm caused a similar skin lesion to appear within 24 hours.

Various mechanisms were postulated to explain these persistent lesions, such as a non-allergic direct toxic effect of aluminium and a delayed hypersensitivity reaction to aluminium.

Antimony

(SED-14, 683; SEDA-24, 254;

SEDA-25, 258) Pancreas Acute pancreatitis, rarely reported, developed during treatment with meglumine antimoniate for visceral leishmaniasis in a young boy (7A ). • A 2-year-old boy with a history of intermittent high-grade fever, sweating, and abdominal distension, developed visceral leishmaniasis. He was given meglumine antimoniate (Glucantime® , Rhone Poulenc, France) 5 mg/kg/day, and the dosage was doubled every other day to reach 20 mg/kg/day. Two days after he had reached the full dose, his temperature returned to normal, his general condition improved, and his liver and spleen began to shrink. However, the serum amylase increased to 254 units/l. Because he was asymptomatic, treatment with meglumine antimoniate was continued. However, on day 10 he complained of vomiting and abdominal pain with rebound tenderness. Acute pancreatitis was confirmed by serum amylase and lipase values up to 1557 and 320 units/l respectively and by ultrasound findings of dilatation and edema of the pancreatic ducts. Meglumine antimoniate was withdrawn and the pancreatitis was managed conservatively. Two days later his fever increased and the spleen and liver began to enlarge. He was given allopurinol (20 mg/kg/day) and ketoconazole (5 mg/kg/day) and became afebrile; the spleen and liver began to shrink, his pancytopenia improved, and the albumin : globulin ratio and serum amylase and lipase activities returned to normal. The acute pancreatitis recovered uneventfully.

Arsenic

(SED-14, 686; SEDA-23, 232; SEDA-24, 254; SEDA-25, 258) Arsenic trioxide is used to treat acute promyelocytic leukemia (8R ) and is emerging as a

Gijsbert B. van der Voet and Frederik A. de Wolff

therapy for multiple myeloma (9R ). It is also found in ethnic medicines. Cardiovascular In 19 patients with hematological malignancies given arsenic trioxide 10–20 mg in 500 ml of 5% dextrose/isotonic saline over 3 hours daily for up to 60 days, there were three cases of torsade de pointes (10AC ). Nervous system Arsenic-induced neurotoxicity in a child was caused by the use of an Indian ethnic remedy. • A 5-year-old child who had been taking Indian ethnic remedies for congenital bilateral retinoblastoma became anorexic and restless, with nausea, fatigue, paresthesia, and progressive weakness of the legs (11A ). A year later he developed vomiting, cough, hoarseness, and a recurrent fever. Blood tests showed a severe normochromic anemia and a leukopenia with relative and absolute neutropenia. Electromyography showed a moderate distal chronic axonal polyneuropathy. The urinary arsenic concentration was not high (15 µg/g creatinine; reference range below 40), but the hair arsenic concentration was 6.6 mg/kg (reference range below 1 mg/kg). Chronic arsenic poisoning was diagnosed. Arsenic (184 mg/g) was found in one of the ethnic remedies.

Bismuth

(SED-14, 686; SEDA-23, 232; SEDA-24, 255; SEDA-25, 259) Bismuth compounds are traditionally used in gastrointestinal disorders, including the eradication of Helicobacter pylori (12R ). Bismuth is also used topically as a bacteriostatic. Adverse effects that were reported decades ago and almost forgotten are being observed again. Skin A black tongue was reportedly caused by exogenous pigment in chewable bismuth subsalicylate tablets. • A 51-year-old white woman developed a black discoloration of her tongue (13A ). The black substance was easily removed by scraping the surface of the tongue. She denied using tobacco products or alcohol. Her medications included alprazolam, montelukast, amitriptyline, hydroxychloroquine, triamcinolone acetonide, omeprazole, cisapride, and calcium carbonate. She had recently started to chew three to six bismuth subsalicylate tablets daily. She was advised to stop using bismuth subsalicylate and to brush her tongue with

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a soft bristled toothbrush. The discoloration improved within a couple of hours and eventually disappeared completely. She continued to take hydroxychloroquine, a known cause of oral mucosal pigmentation.

Immunologic Sensitization to bismuth derivatives has been reported but is rare. • A 33-year-old woman with atopic hand eczema and allergic rhinitis was given Noviform® , an eye ointment containing bibrocathol (bismuth oxide and tetrabromocathechol), for periorbital dermatitis and noticed an exacerbation of her dermatitis (14A ). A patch-tested was positive for bismuth oxide.

Chromium

(SED-14, 683; SEDA-23, 231; SEDA-24, 255; SEDA-25, 259) Chromium compounds continue to be used in oral and parenteral nutrition, as radiopharmaceuticals, and in artificial hip and knee joints. No new adverse effects have been reported, but the mechanisms of chromium toxicity, carcinogenicity, and allergenicity have been reviewed (15R ).

significant pathology of the mesenchymal tissues, including skeletal abnormalities, vascular degeneration, and bladder diverticula. The central nervous system, in contrast, showed minimal pathology of copper metabolism compared with classical Menkes’ disease. The differential sensitivity of central nervous system and mesenchymal tissues to copper histidine may be due to heterogeneity in the responses of different copper-dependent enzymes.

Urinary tract Abuse of copper sulfate can cause nephrotoxicity. • A 21-year-old pharmacist developed acute renal insufficiency (20A ). Three days before he had dissolved a small quantity of copper sulfate in 5 ml of tap water and injected it intravenously in a suicide attempt. The serum copper concentration was 1950 µg/l (31 µmol/l). He was dialysed and gradually improved over 6 weeks. His serum copper concentration a month after the incident was 500 µg/l (8 µmol/l). At 8 weeks a renal biopsy showed marked patchy tubular atrophy with interstitial fibrosis and mild focal chronic interstitial inflammation. Some tubules showed regenerating epithelial cells with multilayering and mitosis, with a predominant loss of proximal tubules. The findings were suggestive of chronic tubulointerstitial nephritis.

Gallium Copper

(SED-14, 688; SEDA-23, 233; SEDA-24, 256; SEDA-25, 259)

Copper chloride and copper sulfate are used in parenteral nutrition solutions. However, the bulk of publications deal with the metabolism of copper as an essential trace element and the role of copper in Menkes’ disease, Wilson’s disease, and Alzheimer’s disease (16R ) and recently also in prion disease (17R ). A new compound, copper histidine, is increasingly being used in Menkes’ disease and is effective. Copper-containing intrauterine devices are still in use (18R ), without new information about adverse effects. Copper histidine modifies the severity of Menkes’ disease and allows survival into adolescence (19A ). The neurological abnormalities respond better than the connective tissue abnormalities. • A male with Menkes’ disease and low plasma concentrations of copper (3.6 µmol/l) and ceruloplasmin (50 mg/l) received copper histidine and died aged 10. Post-mortem examination showed

(SED-14, 690; SEDA-23, 234; SEDA-24, 256; SEDA-25, 260) Gallium alloys are used in dental restoration materials. Gallium compounds containing 67 Ga are also used in diagnostic imaging of cancers, inflammation, and infection (21R ). Abnormal uptake of 67 Ga is reported as an adverse effect in diagnostic procedures, as in three cases: • a 72-year-old man with acute lymphocytic leukemia who had normal 67 Ga uptake in all tissues except the liver (22A ); • a 26-year-old pregnant woman with a mediastinal lymphoma that did not accumulate 67 Ga (23A ); • a 49-year-old man with fever and increased 67 Ga uptake in the lungs but no other evidence of infection or cancer (24A ).

Gold

(SED-14, 690; SEDA-23, 234; SEDA-24, 257; SEDA-25, 260) Gold compounds still form an integral part of the armamentarium of antirheumatic drug ther-

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apy (25R ). The molecular mechanisms of action of gold have recently been reviewed (26R ). Nervous system Intrathecal colloidal gold has been used as an adjunct in the treatment of childhood neoplasms, including medulloblastoma and leukemia. Long-term follow-up of patients treated with intrathecal colloidal gold has been described and the high incidence of delayed cerebrovascular complications and their management has been emphasized (27C ). Between 1967 and 1970, 14 children with a posterior fossa medulloblastoma underwent treatment consisting of surgical resection, external beam radiotherapy, and intrathecal colloidal gold. All had persistent or recurrent disease and six died within 2 years of treatment. The eight surviving patients developed significant neurovascular complications 5–20 years after treatment. Three patients died as a result of aneurysmal subarachnoid hemorrhage, and five developed cerebral ischemic symptoms from a severe vasculopathy that resembled moyamoya disease. Although therapy with colloidal gold results in long-term survival in a number of cases of childhood medulloblastoma, this study suggests that its severe cerebrovascular adverse effects fail to justify its use. The authors recommended routine screening of any long-term survivors after colloidal gold therapy to exclude the presence of an intracranial aneurysm and to document the possibility of moyamoya disease. Respiratory Pneumonitis associated with gold has been reported in a woman with rheumatoid arthritis. • A 77-year-old woman with rheumatoid arthritis was given sodium aurothiomalate 50 mg intramuscularly weekly, following a test dose of 10 mg (28A ). Her rheumatoid arthritis responded well, but after a cumulative dose of 560 mg of gold she became progressively short of breath on exertion and generally felt unwell. She had bilateral basal inspiratory crackles and widespread ill-defined shadowing on the chest X-ray, predominantly in the middle and lower zones of both lungs. A highresolution CT scan showed ground glass opacities, particularly in the upper zones, and thickening of the peribronchovascular interstitium and interlobular septa in the middle and lower zones. Pulmonary function tests showed a restrictive lung defect.The gold injections were discontinued and she responded well to methylprednisolone. A CT scan 10 months later showed almost complete resolution, with some heterogeneity of lung density posteriorly in the lower lobes.

Gijsbert B. van der Voet and Frederik A. de Wolff

Sensory systems Gold keratopathy has been reported in a woman with rheumatoid arthritis (29A ). • A-60-year-old woman with rheumatoid arthritis who was taking prednisone, azathioprine, sulindac, plaquenil, and intramuscular injections of gold sodium thiomalate (50 mg once weekly) developed intense, bilateral ocular irritation and photophobia. She had received a total of 7.4 g of gold over the past 3 years. Her conjunctivae were mildly injected, with bilateral perilimbal chemosis. The peripheral corneae showed 360◦ stromal edema. Mid-stromal vessels were seen entering the edematous stroma from the limbus. She was given topical prednisolone acetate hourly for rheumatoid marginal keratitis. Over the next 2 months her symptoms gradually resolved, but granular, golden-brown, pigmented deposits appeared in the corneal stroma in the same peripheral ring-like distribution as the resolved stromal keratitis. Gold was discontinued. Over the next 6 months, the stromal deposits partially cleared. She then had a milder episode of photophobia and irritation, with stromal edema in the same distribution. This was controlled by topical prednisolone. One year later, she continued to use topical prednisolone once a day and was asymptomatic, with no stromal inflammation, but persistent fine golden granules.

Hematologic Lymphadenopathy is a rare complication of gold injections. • A 34-year-old woman was given intramuscular sodium aurothiomalate for rheumatoid arthritis after little response to anti-inflammatory drugs (30A ). After the sixth injection she developed enlarged neck and axillary lymph nodes. Biopsy showed subtotal infarction of a reactive node, confirmed by histochemical, immunohistochemical, and molecular techniques. Gold was discontinued and the lymphadenopathy gradually resolved over the next 2 months. She continued to suffer from rheumatoid arthritis with no evidence of malignant lymphoma after 3 years.

This case provides strong evidence that gold salts can cause malignant lymphoma. Nails Gold has been reported to cause yellow thickening of the nails and onycholysis (31A ). • A 34-year-old woman with severe rheumatoid arthritis developed yellow thickening of all 20 nails 2 years after starting gold therapy. She had received 50 mg of gold salts intramuscularly at intervals of 2–4 weeks after an initial course of weekly injections (total cumulative dose 90 mg/kg) over 4 years. There was associated thickening of the nail plate, increased transverse curvature, and mild subungual hyperkeratosis. There was onycholysis of both thumbnails and the right little fingernail. There was no associated chrysiasis. Gold

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was withdrawn. The yellow discoloration began to grow out and fingernail growth increased in the next 3 months. Six months later there was further improvement, although light yellow discoloration of all nails persisted and there was markedly increased longitudinal growth. Both thumbnails showed transverse depressions of the nail plate (Beau’s lines) where the change in growth rate had presumably occurred.

Iron

(SED-14, 697; SEDA-23, 235; SEDA-24, 257; SEDA-25, 260) A flow of articles continues to be published regarding the efficacy of iron compounds (such as iron dextran, iron sucrose, iron gluconate) in the parenteral treatment of anemia in conditions such as pregnancy and renal insufficiency. The adverse effects of the available formulations have resulted in trials to optimize dose regimens. New oral formulations with improved intestinal iron absorption are being marketed and their efficacy and toxicity are being studied (32R ). Despite the use of recombinant erythropoietin, anemia remains a significant problem for patients with end-stage renal disease (33C ). Because oral iron formulations are relatively ineffective and poorly tolerated, intravenous iron dextran has been widely used, despite the risk of adverse effects. A large database of clinical variance reports from Fresenius Medical Care North America (FMCNA) has been analysed to determine the incidence of suspected adverse drug reactions of iron dextran and the associated patient characteristics, dialysis practice patterns, and outcomes (33C ). A case–cohort design was used, comparing individuals who had suspected adverse drug reactions with the overall population. Out of 841 252 intravenous iron dextran administrations over 6 months, there were 165 reported suspected adverse drug reactions, corresponding to an overall rate of 0.000196%, or about 20 per 100 000 doses. Hospital evaluation was required in 43 patients (26%), 18 (11%) required hospitalization, and one (0.6%) died. Dyspnea (43%), nausea (34%), vomiting (23%), flushing (27%), pruritus (25%), hypotension (23%), and neurological symptoms (23%) were the most common adverse reactions. Serious adverse reactions to intravenous

247 iron dextran are rare and difficult to predict; the risk appears to depend on the specific formulation of intravenous iron dextran. Large doses of intravenous iron dextran and iron saccharate have been compared in a retrospective study of 379 patients who had attended peritoneal dialysis clinics in the past 5 years (34C ). Of these, 62 were selected to receive intravenous iron based on ferrokinetic markers of iron deficiency, non-compliance with or ineffectiveness of oral iron, or increased erythropoietin requirements. Intravenous iron was given as two injections of 500 mg each 1 week apart in 61 patients, 33 of whom received iron dextran, 23 iron saccharate, and five both iron dextran and iron saccharate. One patient developed anaphylaxis to a test dose of iron dextran and was excluded from further therapy. Blood samples were collected before and 3 and 6 months after iron infusions. Five of the 34 patients who received iron dextran developed minor adverse effects and one had anaphylaxis to the test dose. Of the 23 patients who received iron saccharate, one had an anaphylactic reaction and two had transient chest pain, which subsided without therapy. There were more adverse effects with iron dextran (7.4% of injections) compared with iron saccharate (4.3% of injections), but this difference was not statistically significant. The number of episodes of peritonitis also increased during the 6 months after intravenous iron infusion, especially with iron dextran, compared with the number of episodes during the 6 months before iron infusions, although the difference was not statistically significant. Cardiovascular Non-transferrin-bound iron, which increases after intravenous ferric saccharate, has been suggested to act as a catalytic agent in oxygen radical formation in vitro, and may therefore contribute to endothelial impairment in vivo (35C ). The effect of 10 mg ferric saccharate infusion has been investigated in 20 healthy volunteers. Ferric saccharate caused a greater than four-fold increase in non-transferrin-bound iron and transient significant reduction in flow-mediated dilatation 10 minutes after infusion of ferric saccharate. The generation of superoxide in whole blood increased significantly 10 and 240 minutes after infusion of ferric saccharate by 70% and 53% respectively. Thus, infusion of iron leads to increased oxygen radical stress and acute endothelial dysfunction.

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Lead

(SED-14, 701; SEDA-24, 258; SEDA-25, 261) Lead poisoning from occupational and environmental sources continues to be reported. The biological chemistry of lead has recently been reviewed (36R ). Lead compounds have no medical uses, but they are found in some Asian herbal medicines and can cause lead poisoning. • A 23-year-old Asian butcher developed diffuse abdominal pain, vomiting, and diarrhea, followed by constipation (37A ). He had a sinus tachycardia and generalized abdominal tenderness without peritonism. His serum bilirubin concentration and alanine transaminase activity were raised, but alkaline phosphatase activity, albumin concentration, and prothrombin time were normal. He had a blood lead concentration of 3.7 µmol/l and a raised zinc protoporphyrin concentration, diagnostic of lead poisoning. He had taken a herbal medicine, purchased in India, for vague ailments. He stopped taking it, and was asymptomatic 3 months later, with normal liver function tests and marked falls in blood lead (1.9 µmol/l) and zinc protoporphyrin.

Manganese

(SED-14, 702; SEDA-23, 235; SEDA-24, 259; SEDA-25, 261) Trace elements are required in patients receiving long-term parenteral nutrition (38A ) and the use of manganese has recently been reviewed (39R ). Adverse effects continue to be reported. Two cases of manganese intoxication during intermittent parenteral nutrition have been reported. In one case manganese had been given once or twice a week for 4 years and in the other case twice a month for 5 years. Both patients had mild headache and dizziness. One had mild hepatic dysfunction. After withdrawal of manganese the symptoms all disappeared. Patients should be carefully monitored when receiving long-term parenteral nutrition including manganese, even when the manganese dose is small and administration infrequent.

Mercury

(SED-14, 702; SEDA-23, 235; SEDA-24, 260; SEDA-25, 262) Controversy about mercury toxicity from dental amalgam continues. A recent meta-analysis

Gijsbert B. van der Voet and Frederik A. de Wolff

has shown numerous logical and methodological errors in the anti-amalgam literature (40M ). The author concluded that the evidence supporting the safety of amalgam is compelling. Mercury compounds, including thiomersal, are used as preservatives in eye drops and injection solutions. Ethylmercury toxicity and sensitization from thiomersal-containing vaccines have been indecisively discussed (41R , 42R ). The toxicity of ethylmercury has also been discussed (43R ). The use of homeopathic medicines can cause mercury allergy (baboon syndrome). • A 5-year-old girl developed an itchy erythematous macular rash, symmetrically distributed in the anogenital area and thighs (44A ). The lesions developed into a widespread maculopapular vesicular rash in 48 hours, sparing the face, palms, and soles. The eruption cleared after systemic corticosteroids and antihistamines, with scaling and post-inflammatory hypopigmentation. She had developed neonatal periumbilical dermatitis associated with the application of merbromin to the cord, and 24 hours before the onset of the rash had taken a single homeopathic tablet (Mercurius Heel® ), which contained soluble mercury. Allergy tests to a standard series of foods and respiratory allergens were negative and total IgE was normal. Patch testing to allergens showed positive reactions to thiomersal and metallic mercury.

Nickel (SED-14, 704; SEDA-23, 235; SEDA-24, 260; SEDA-25, 262) Nickel allergy is not new and continues to be an adverse effect of the use of nickel-containing medical appliances, such as orthopedic metal alloys, dental materials, and implants (45R ). Immunologic No new adverse effects have been reported, but cases of nickel allergy continue to appear in relation to medical appliances. • A 35-year-old non-atopic diver with no previous history of metal allergy slipped on a wet pier and sustained a multiple compound trimalleolar fracture of the right ankle (46A ). The tibia and fibula were immediately surgically realigned and retained by metal plates and screws, and the ankle was immobilized in plaster for 5 weeks. One month later he developed itching, scaling, vesiculopapular dermatitis on several fingers of both

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hands, which worsened over the next few months. Patch testing was positive to nickel sulfate, chromate, and cobalt.

The author concluded that the patient had become sensitized to nickel and chromate in the orthopedic metals. It was also apparent that sensitization to cobalt had occurred, even though no cobalt could be shown on analysis. The hand dermatitis improved after removal of the metal from the ankle, but nevertheless continued to relapse.

Selenium

(SED-14, 704; SEDA-23, 236; SEDA-24, 260; SEDA-25, 263) Selenium sulfide continues to be used as an antimycotic in shampoos, and selenite in mineral supplements and parenteral nutrition. The protective effects of selenium against cancer have recently been reviewed (47R ).

fective in boosting immunity. The serum silver concentration was 3.4 µmol/l (reference range under 0.02 µmol/l). Silver was withdrawn and her serum silver concentrations normalized some months later.

Reproductive system Vaginal argyrosis has been attributed to a combination of silver sulfadiazine and Aci-Jel (a buffered acid jelly containing acetic acid) (50A ). • A 67-year-old woman with a sore vulva applied flamazine cream (containing 1% silver sulfadiazine) topically for nearly 10 years and then AciJel. She developed widespread black deposits in the vagina consistent with argyrosis. There were dark pigmented areas around the urethral meatus, Skene’s ducts, and hymeneal remnants, and a circumferential deposit around the upper third of the vagina. Biopsies showed mild acanthosis and a mild chronic inflammatory infiltrate in the upper dermis, with black pigment granules 0.5–2 µm in size in the superficial dermis. Electron probe analysis confirmed the presence of silver. The creams were withdrawn and 6 months later the vagina showed no signs of argyrosis.

(SED-14, 705; SEDA-23, 236; SEDA-24, 261; SEDA-25, 263)

It is likely that reducing agents in the gel base of Aci-Jel interacted with the silver sulfadiazine, causing deposition of silver and discoloration of the vagina.

Cardiovascular A chronic inflammatory reaction in a prosthetic valve has been attributed to silver (48A ).

Titanium

Silver

• A prosthetic mitral valve (St Jude Medical Silzone) was implanted in a 72-year-old woman, and 4 months later she had acute cardiac failure due to partial detachment of the prosthetic valve. The mitral annulus was ulcerated and there were multiple erosions in the tissues in contact with the valve. Histology showed chronic inflammation with hemosiderin deposits and giant cells. She was not allergic to silver.

The silver-coated sewing cuff had caused a chronic inflammatory reaction due to a toxic reaction to silver. The Silzone valve was withdrawn from the market in January 2000. Nutrition Failure to thrive in a child has been attributed to silver toxicity (49A ). • A 12-month-old girl with failure to thrive had been treated with various supplements and alternative therapies (including a blend of kelp, Lactobacillus acidophilus, wheat, rye, and barley) or with colloidal silver. The silver was given in the form of a suspension and was thought to be ef-

(SED-14, 706; SEDA-23, 237; SEDA-24, 261; SEDA-25, 263) Titanium is used in a large number of medical devices, including dental material (51R ) and prostheses. A cohort of 120 consecutive patients (66 women, 54 men; mean age 66 years) with 126 prostheses inserted between March and December 1989 were followed prospectively both clinically and radiologically for a mean of 9.1 years (52C ). Forty patients (41 hips) died, 9 patients (9 hips) were interviewed by telephone, and 71 (76 hips) were available for follow up. Four hips had been revised: two of them because of aseptic loosening of the femoral component, one because of a late infection—all after 9 years— and one because of a periprosthetic fracture after 6 years. The 9-year survival was 97% and for aseptic loosening of the stem 98%. None of the cups had to be revised for aseptic loosening. The result was excellent or good in 88%,

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Chapter 22

moderate in 8%, and poor in 4%. Radiological analysis showed no osteolysis or radiolucent lines in 59 prostheses (78%). Nine stems (12%) showed a radiolucent line. Focal osteolysis was detected in eight cases (10%) in one or more Gruen zones. The distribution of the osteolytic areas showed that zones VII, VI, V, and II were predominantly affected in decreasing frequency. There was no osteolysis on the acetabular side. These results do not confirm the high rate of osteolysis and revisions with the Muller titanium alloy Straight Stem used in some other institutions. Skin Exacerbation of atopic dermatitis has been attributed to titanium clips (53A ). • A 28-year-old woman with breast cancer underwent breast conservation, and three titanium clips were placed at the margin of the excision cavity, followed 2 months later by rapid exacerbation of her atopic dermatitis. The skin lesions developed progressively and involved the whole body. Patch tests and lymphocyte stimulation tests could not be performed, owing to the severity of the skin lesions. Various drugs were suspected, but the results of a bidigital O-ring test suggested an allergic reaction to titanium clips. She underwent a second operation to remove the titanium clips under local anesthesia. By 12 months after surgery, the atopic dermatitis had not completely resolved.

Zinc

(SED-14, 706; SEDA-23, 237; SEDA-24, 261; SEDA-25, 264) Zinc compounds are used as minerals, adjuvants, and adstringents. They are usually very

Gijsbert B. van der Voet and Frederik A. de Wolff

safe. The use of zinc acetate in Wilson’s disease has recently been reviewed and recommended rather than copper chelation, because of limited adverse effects. Zinc acetate (Galzin® , Gate Pharmaceutical Co), developed for the treatment of Wilson’s disease (54R ), has been approved (by the US FDA) for maintenance therapy of adult and pediatric disease, but it also has efficacy in the treatment of pregnant women and presymptomatic patients from the start. It also has value as adjunctive therapy for the initial treatment of symptomatic patients. Its mechanism of action involves induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract. Negative copper balance is caused by blockade not only of absorption of food copper but by blockade of reabsorption of the considerable amount of endogenously secreted copper in saliva, gastric juice, and intestinal secretions. It is therefore effective in controlling copper concentrations and toxicity in Wilson’s disease. Zinc’s main advantage over other anticopper agents is its extremely low toxicity. The only adverse effect is some degree of initial gastric irritation in about 10% of patients, which usually abates and becomes insignificant over time. As with all long-term therapies, compliance is a problem in some patients and dictates regular monitoring by measurement of 24-hour urine copper and zinc. As with all anticopper therapies, overtreatment can cause copper deficiency over a long period of time. This is to be avoided, particularly in children, because copper is required for growth.

REFERENCES 1. Hemstreet BA. Use of sucralfate in renal failure. Ann Pharmacother 2001; 35: 360–4. 2. Yokel RA, McNamara PJ. Aluminium toxicokinetics: an updated minireview. Pharmacol Toxicol 2001; 88: 159–67. 3. Flaten TP. Aluminium as a risk factor in Alzheimer’s disease, with emphasis on drinking water. Brain Res Bull 2001; 55: 187–96. 4. Reusche E, Pilz P, Oberascher G, Lindner B, Egensperger R, Gloeckner K, Trinka E, Iglseder B. Subacute fatal aluminum encephalopathy after reconstructive otoneurosurgery: a case report. Hum Pathol 2001; 32: 1136–40.

5. Nagore E, Martinez-Escribano JA, Tato A, Sabater V, Vilata JJ. Subcutaneous nodules following treatment with aluminium-containing allergen extracts. Eur J Dermatol 2001; 11: 138–40. 6. Mooser G, Gall H, Weber L, Peter RU. Cold panniculitis—an unusual differential diagnosis from aluminium allergy in a patient hyposensitized with aluminium-precipitated antigen extract. Contact Dermatitis 2001; 44: 368. 7. Kuyucu N, Kara C, Bakirtaç A, Teziç T. Successful treatment of visceral leishmaniasis with allopurinol plus ketoconazole in an infant who developed pancreatitis caused by meglumine antimoniate. Pediatr Infect Dis J 2001; 20: 455–7.

Metals

Chapter 22

8. Zhang T-D, Chen G-Q, Wang Z-G, Wang Z-Y, Chen S-J, Chen Z. Arsenic trioxide, a therapeutic agent for APL. Oncogene 2001; 20: 7146–53. 9. Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma. Oncologist 2001; 6: 17–21. 10. Unnikrishnan D, Dutcher JP, Varhneya N, Lucariello R, Api M, Garl S, Wiernik PH, Chiaramida S. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001; 97: 1514–16. 11. Muzi G, Dell’Omo, M, Madeo G, Abbritti G, Caroli S. Arsenic poisoning caused by Indian ethnic remedies. J Pediatr 2001; 139: 169. 12. Trust TJ, Alm RA, Pappo J. Helicobacter pylori: today’s treatment and possible future treatment. Eur J Surg Suppl 2001; 586: 82–8. 13. Ioffreda MD, Gordon CA, Adams DR, Naides SJ, Miller JJ. Black tongue. Arch Dermatol 2001; 137: 968–9. 14. Wictorin Å, Hansson C. Allergic contact dermatitis from a bismuth compound in an eye ointment. Contact Dermatitis 2001; 45: 318. 15. Dayan AD, Paine AJ. Mechanisms of chromium toxicity, carcinogenicity and allergenicity: review of the literature from 1985 to 2000. Hum Exp Toxicol 2001; 20: 439–51. 16. Strausak D, Mercer JF, Dieter HH, Stremmel W, Multhaup G. Copper in disorders with neurological symptoms: Alzheimer’s, Menkes and Wilson diseases. Brain Res Bull 2001; 55: 175–85. 17. Brown DR. Copper and prion disease. Brain Res Bull 2001; 55: 165–73. 18. Thonneau P, Goulard H, Goyaux N. Risk factors for intrauterine device failure: a review. Contraception 2001; 64: 33–7. 19. George DH, Casey RE. Menkes disease after copper histidine replacement therapy: case report. Pediatr Dev Pathol 2001; 4: 281–8. 20. Bhowmik D, Mathur R, Bhargava Y, Dinda AK, Agarwal SK, Tiwari SC, Dash SC. Chronic interstitial nephritis following parenteral copper sulfate poisoning. Renal Fail 2001; 23: 731–5. 21. Boerman OC, Rennen H, Oyen WJ, Corstens FH. Radiopharmaceuticals to image infection and inflammation. Semin Nucl Med 2001; 31: 286–95. 22. Nakahara T, Fujii H, Nakamura K, Hashimoto J, Kubo A. Inexplicable suppression of hepatic uptake of gallium-67, a case report. Ann Nucl Med 2001; 15: 377–9. 23. Kurosaki H, Saito Y, Kawashima M, Ebara T, Yamakawa M, Mitsuhashi N. Accumulation of 67 Ga citrate in early pregnancy. Ann Nucl Med 2001; 15: 289–91. 24. Bernstine H, Bar-Sever Z, Cohen M, Hardoff R. Misleading thoracic Ga-67 uptake caused by splenic displacement. Clin Nucl Med 2001; 26: 147–8. 25. Gabriel SE, Coyle D, Moreland LW. A clinical and economic review of disease-modifying antirheumatic drugs. Pharmacoeconomics 2001; 19: 715–28. 26. Burmester GR. Molekulare wirkungsmechanismen von gold bei der behandlung der rheuma-

251 toiden arthritis–ein update. Z Rheumatol 2001; 60: 167–73. 27. Nussbaum ES, Sebring LA, Neglia JP, Chu R, Mattsen ND, Erickson DL. Delayed cerebrovascular complications of intrathecal colloidal gold. Neurosurgery 2001; 49: 1308–12. 28. Sinha A, Silverstone EJ, O’Sullivan MM. Goldinduced pneumonitis: computed tomography findings in a patient with rheumatoid arthritis. Rheumatology 2001; 40: 712–14. 29. Zamir E, Read RW, Affeldt JC, Ramaswamy D, Rao NA. Gold induced interstitial keratitis. Br J Ophthalmol 2001; 85: 1386–7. 30. Roberts C, Batstone PJ, Goodlad JR. Lymphadenopathy and lymph node infarction as a result of gold injections. J Clin Pathol 2001; 54: 562–4. 31. Roest MAB, Ratnavel R. Yellow nails associated with gold therapy for rheumatoid arthritis. Br J Dermatol 2001; 145: 855–6. 32. Jeppsen RB. Toxicology and safety of Ferrochel and other iron amino acid chelates. Arch Latinoam Nutr 2001; 51: 26–34. 33. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis 2001; 37: 743–9. 34. Prakash S, Walele A, Dimkovic N, Bargmans J, Vas S, Oreopoulos D. Experience with a large dose (500 mg) of intravenous iron dextran and iron saccharate in peritoneal dialysis patients. Peritoneal Dial Int 2001; 21: 290–5. 35. Rooyakkers TM, Stroes ES, Kooistra MP, Van Faassen EE, Hider R, Rabelink TJ, Marx JJ. Ferric saccharate induces radical stress and endothelial dysfunction in vivo. Eur J Clin Invest 2002; 32: 9–16. 36. Godwin HA. The biological chemistry of lead. Curr Opin Chem Biol 2001; 5: 223–7. 37. Anderson NR, Gama R, Kapadia S. Herbal remedy poisoning presenting with acute abdomen and raised urine porphyrins. Ann Clin Biochem 2001; 38: 408–10. 38. Masumoto K, Suita S, Taguchi T, Yamanouchi T, Nagano M, Ogita K, Nakamura M, Mihara F. Manganese intoxication during intermittent parenteral nutrition: report of two cases. J Parenter Enter Nutr 2001; 25: 95–9. 39. Dickerson RN. Manganese intoxication and parenteral nutrition. Nutrition 2001; 17: 689–93. 40. Dodes JE. The amalgam controversy. An evidence-based analysis. J Am Dent Assoc 2001; 132: 348–56. 41. Clements CJ, Ball LK, Ball R, Pratt RD. Thiomersal in vaccines: is removal warranted? Drug Saf 2001; 24: 567–74. 42. Van‘t Veen AJ. Vaccines without thiomersal: why so necessary, why so long coming? Drugs 2001; 61: 565–72. 43. Magos L. Review on the toxicity of ethylmercury, including its presence as a preservative in biological and pharmaceutical products. J Appl Toxicol 2001; 21: 1–5. 44. Audicana M, Bernedo N, Gonzalez I, Munoz D, Fernandez E, Gastaminza G. An unusual case

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of baboon syndrome due to mercury present in a homeopathic medicine. Contact Dermatitis 2001; 45: 185. 45. Grimaudo NJ. Biocompatibility of nickel and cobalt dental alloys. Gen Dent 2001; 49: 498–503. 46. Kanerva L, Förström L. Allergic nickel and chromate hand dermatitis induced by orthopaedic metal implant. Contact Dermatitis 2001; 44: 103–4. 47. Combs GF Jr, Clark LC, Turnbull BW. An analysis of cancer prevention by selenium. BioFactors 2001; 14: 153–9. 48. Tozzi P, Al-Darweesh A, Vogt P, Stumpe F. Silver-coated prosthetic heart valve: a doublebladed weapon. Eur J Cardio-Thorac Surg 2001; 19: 729–31. 49. McIntyre E, Wilcox J, McGill J, Lewindon PJ. Silver toxicity in an infant of strict vegan parents. J Pediatr Gastroenterol Nutr 2001; 33: 501–2.

Gijsbert B. van der Voet and Frederik A. de Wolff 50. Thomas K, Sproston ARM, Kingsland CR. A case of vaginal argyrosis: all that glistens isn’t gold. Br J Obstet Gynaecol 2001; 108: 890–1. 51. Kononen M, Kivilahti J. Fusing of dental ceramics to titanium. J Dent Res 2001; 80: 848–54. 52. Acklin YP, Berli BJ, Frick W, Elke R, Morscher EW. Nine-year results of Muller cemented titanium straight stems in total hip replacement. Arch Orthop Trauma Surg 2001; 121: 391–8. 53. Tamai K, Mitsumori M, Fujishiro S, Kokubo M, Ooya N, Nagata Y, Sasai K, Hiraoka M, Inamoto T. A case of allergic reaction to surgical metal clips inserted for postoperative boost irradiation in a patient undergoing breast conserving therapy. Breast Cancer 2001; 8: 90–2. 54. Brewer GJ. Zinc acetate for the treatment of Wilson’s disease. Expert Opin Pharmacother 2001; 2: 1473–7.

R.H.B. Meyboom

23 Calcitetracemate The use of calcitetracemate in the treatment of lead poisoning has been described (1cr ). A total of 58 courses were given to 16 patients, as calcitetracemate infusions 500 mg bd for 5 days. No adverse events were observed in any of these patients.

Metal antagonists tions, improve compliance, and facilitate individualization of therapy. Increasing understanding of the kinetics of iron metabolism, iron overload, and the complexity of chelation should further improve therapeutic strategies.

Deferiprone

(SED-14, 719; SEDA-23, 240; SEDA-24, 265; SEDA-25, 268)

IRON CHELATORS Iron chelation treatment has dramatically improved the prognosis of patients with betathalassemia (2R ). Parenteral deferoxamine reduces tissue iron stores, prevents iron-induced organ damage, and reduces morbidity and mortality. However, the burden of prolonged subcutaneous portable pump infusions, adverse reactions, patient non-compliance, and high cost are limiting factors, which have stimulated the development of orally active compounds. Combinations of chemically different types of chelators, which have different iron-carrying capacities and access different iron compartments, may work synergistically and result in increased efficacy, whereas lower doses of individual drugs may be less toxic (3R ). Examples are parenteral deferoxamine, oral deferiprone or 2,3-dihydroxybenzoic acid (2,3DHB), or oral deferiprone with oral N,N′ -bis(2hydroxybenzyl)ethylenediamine-N,N′ -diacetic acid (HDEB). Iron bound to a “shuttle”, an oral agent that mobilizes tissue iron, is exchanged in the blood stream with a “sink”, such as parenteral deferoxamine, and excreted via the kidneys, while the shuttle is reused. Combinations of different iron chelators can enhance iron excretion, target specific iron compartments, minimize adverse effects, increase treatment op© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Deferiprone and deferoxamine have been compared in Lebanese patients, mainly with thalassemia major, of whom 17 used oral deferiprone, 75 mg/kg/day, and 40 received subcutaneous deferoxamine, 20–50 mg/kg/day on 5 days a week; the patients were followed for 2 years (4cr ). All those who took deferiprone did so because deferoxamine had not been suitable, because of either non-compliance or adverse reactions. One of those taking deferiprone withdrew for unknown reasons (and was excluded from the study). Deferiprone was commonly associated with orange discoloration of the urine. Six patients complained of joint pains, mainly in large joints (moderate to severe in two and mild in four), not requiring drug withdrawal. Seven patients reported nausea, four had headaches, two rashes, and two fatigue. Abdominal discomfort, mouth ulcers, and sore throat each occurred in one patient. Although two patients had transient falls in neutrophil count (to 1.3 and 1.44 × 109 /l), presumably secondary to a viral infection, there were no cases of agranulocytosis.

Deferoxamine (SED-14, 714; SEDA-23, 240; SEDA-24, 265; SEDA-25, 267) Deferiprone and deferoxamine have been compared in Lebanese patients, mainly with thalassemia major, of whom 17 used oral deferiprone, 75 mg/kg/day for 2 years, and 40

253

254 received subcutaneous deferoxamine, 20–50 mg/kg/day on 5 days a week (4cr ). Those who received deferoxamine had done so for 4–24 years and were followed for 2 years. Infusion site reactions occurred in 34 patients, including pain, tenderness, itching, burning, erythema, swelling, induration, and lipodystrophy. Five patients had disturbances of vision and hearing, three had growth retardation. Six patients had increased heart rates, four had dizziness, and one had leg cramps. The use of sonography as a cheap and easy tool in the assessment of deferoxamineinduced bone dysplasia of the knee has been studied in 32 patients with thalassemia major (5CR ). Characteristic lesions were notching at the metaphyseal corner, a blurred or irregular peripheral juxtaphyseal metaphyseal contour, and widening of the peripheral juxtaphyseal metaphyseal echogenic interface. There were 14 true-positive results, 10 true-negative, 7 false-negative, and 1 false-positive. Thus, sonography is specific but not sensitive in the diagnosis of deferoxamine-induced dysplasia. Because of its high specificity, low cost, and non-invasiveness sonography may have a role in the longitudinal monitoring of deferoxamineinduced bone dysplasia. Nervous system Optic neuropathy and sensorineural hearing loss have been attributed to deferoxamine (6CR ). • A 25-year-old woman with beta-thalassemia, who had received subcutaneous deferoxamine 2 g/day (50 mg/kg) for 7 days a week for 3 years, developed visual loss. Her best-corrected visual acuity was 20/60 bilaterally. Automated perimetry showed bilateral central scotomata, and a Farnsworth Panel D-15 test showed an irregular pattern of errors. There were no lens opacities, and fundoscopy and fluorescein angiography were normal. Audiometry showed a bilateral high-frequency sensorineural deficit. Two days after withdrawal of deferoxamine and oral administration of zinc sulfate 20 mg/day the central scotomata disappeared and her color vision and audiographic abnormalities reversed completely. The serum ferritin concentration was 656 ng/l.

Since the serum ferritin concentration was relatively low, the original dose of deferoxamine may have been too high. Although zinc concentrations were not measured before treatment, the rapid and complete improvement in 48 hours after starting zinc sulfate suggested that deferoxamine-induced zinc deficiency may also have played a role.

Chapter 23

R.H.B. Meyboom

Edetate

(SED-14, 721; SEDA-23, 242; SEDA-25, 268) Despite controversy for more than a quarter of a century, chelation therapy for atherosclerotic cardiovascular disease is still widely used and accounts for about 800 000 patient visits in the USA each year. However, there is still no proof of efficacy, while the dangers are obvious (SED-14, 722; 7R ).

PENICILLAMINE AND RELATED DRUGS Bucillamine

(SED-14, 736)

Skin Bucillamine is a DMARD, particularly used in Japan, with similar autoimmunogenic properties to penicillamine. A patient taking bucillamine developed a skin eruption that simultaneously had features of pemphigus foliaceus and pemphigus vulgaris and was associated with glomerulonephritis (8CR ). • A 62-year-old man with rheumatoid arthritis developed a rash on the neck, chest, and legs after taking oral bucillamine (dose not specified) for 6 months. The lesions were of two different types: small pigmented, vesicular, erythematous macules, similar to pemphigus foliaceus, and skin erosions as seen in pemphigus vulgaris. There was no mucosal involvement. Serology was positive for antinuclear antibodies (1 : 320, nucleolar type). A biopsy showed acantholysis in the granular, spinous, and suprabasal layers. Direct immunofluorescence showed intercellular deposits of IgG and C3 throughout the epidermis, but not in the basement membrane. Indirect immunofluorescence of donor skin showed IgG reactivity in the nuclei of keratinocytes. An enzyme-linked immunoadsorbent assay (ELISA), using baculovirus-expressed recombinant desmogleins as antigen, was positive and indifferent to circulating anti-Dsg1 and antiDsg3 antibodies.

This patient also had the nephrotic syndrome (proteinuria 8.7 g/day, total serum protein 59 g/l, serum total cholesterol 10.2 mmol/l), probably also due to bucillamine. A renal biopsy was consistent with membranous glomerulonephritis. The skin lesions improved within 1 month of bucillamine withdrawal, but full recovery of both cutaneous and renal injury was achieved only after the use of prednisone, 40 mg/day for 2 weeks.

Metal antagonists

Chapter 23

Penicillamine

(SED-14, 723; SEDA-23, 242; SEDA-24, 266; SEDA-25, 269)

Although penicillamine and gold compounds were both originally used on the basis of erroneous pharmacological hypotheses, they have been strongholds in the treatment of debilitating rheumatoid arthritis for more than a quarter of a century (9R ). Whereas they do not have much effect on the progression of joint damage, they have unexpectedly been found to be associated with a remarkable diversity of serious adverse reactions. In hindsight, they have played central roles in improvements in the understanding of the pathology of rheumatoid arthritis and of the methods of studying the benefits and harms of therapeutic strategies in rheumatoid arthritis and other chronic progressive diseases. The recent advent of novel drugs with different mechanisms of action, such as cytokine antagonists, has empowered rheumatologists with effective new instruments (10R –12R ). The effect of a patient education program, taught by rheumatology nurse practitioners, on adherence of patients to treatment with penicillamine has been studied (13CR ). The program significantly and persistently increased adherence over a period of 6 months in 51 patients compared with 49 controls (who used penicillamine without the educational program). Most of the patients (in both groups) had adverse effects, including thrombocytopenia in two and myasthenia gravis in one. The number of patients who asked to have penicillamine withdrawn was far higher in the control group (n = 12) compared with the patient education group (n = 2). Taste disturbances, for example, led to self-withdrawal in four patients, all in the control group. On the other hand, the patients in the patient education group were much more reluctant to withdraw, even in the event of serious adverse effects. A diagnostic and monitoring database program called DIAMOND runs across a network of personal computers throughout the Staffordshire Rheumatology Centre (14CR ). For about 10 years drug histories, blood test results, and clinical correspondence files for about 2000 patients have been accessible, and the system is linked to the main hospital pathology database. The DIAMOND system has been used to study adverse reactions and durations of treatment for commonly prescribed DMARDs, including penicillamine (combination treatments

255 excluded). With a median survival time of 34 months, penicillamine held an intermediate position, between methotrexate (>96) and azathioprine (13) at the extremes; 38% of the patients continued to take penicillamine after 5 years. There were strong associations between penicillamine and both proteinuria and thrombocytopenia (both well established adverse effects of penicillamine; SED-14, 727-8). Myasthenia gravis occurred in eight of 582 penicillamine users (1.4%) and not in patients using other DMARDs. Endocrine Excessive enlargement of the breasts has again been attributed to penicillamine (SED-14, 733). There has now been a report of a case in which breast enlargement was accompanied by systemic lupus erythematosus (15CR ). • A 37-year-old woman had a 7-year history of rheumatoid arthritis for which she had taken penicillamine for about 1–2 years (dose not specified). When she presented at the Cambridge Breast Unit she had had rapidly increasing painful enlargement of the breasts for 7 months. The breasts were symmetrically enlarged (from an A cup to DD) and had thickened and erythematous skin. There were several palpable masses; mammography showed no evidence of malignancy and an ultrasound scan showed large hypo-echoic nodules with engorged vessels. Histology of a large lump in the left breast showed a fibroadenoma. Immunohistochemistry for estrogen receptors showed 50% nuclear staining. She had stopped taking penicillamine 2 months before because of a lupus-like syndrome with thrombocytopenia, lymphopenia, and positive ANA and DNA antibodies (whether single-stranded or double-stranded was not stated).

Although breast gigantism is a rare manifestation of idiopathic SLE, autoimmune substances could have stimulated mammary duct proliferation or mimicked estrogen or other growth factors in the breast. Liver Copper and iron are both capable of electron exchange and play a complex role in oxygen utilization. Copper proteins are critical in the transfer and transport of iron (16R ). In four patients with Wilson’s disease the fall in serum ceruloplasmin concentrations after treatment with penicillamine was associated with increased hepatic iron content; in two of these patients serum ferritin was increased (17CR ). In another patient a liver biopsy taken after 15 years of treatment

256 with penicillamine (600 mg/day) and zinc sulfate (400 mg/day) showed iron-laden hepatocytes, whereas histochemically detectable iron had been absent from an initial biopsy (18C ). The copper-containing proteins ceruloplasmin and its membrane-bound homologue hephaestin are pivotal in iron metabolism. In addition there are intracellular transfer proteins (“chaperone”) that deliver copper to ferroxidase proteins. Intracellular ferroxidase proteins accelerate the efflux of iron through stimulating the conversion of Fe2+ to Fe3+ and subsequent binding to transferrin. Presumably excess loss of copper due to penicillamine or penicillamine plus zinc, can reduce ferroxidase activity and cause intracellular iron deposition and paradoxical deterioration in liver function. Therefore, during treatment of Wilson’s disease when the non-ceruloplasmin-bound copper falls to within the reference range ( 3000 mg/m2 ) with no signs of dysesthesia or paresthesia causing functional impairment, indicating high interindividual variability with respect to sensitivity to oxaliplatin-induced cumulative neuropathy (58r , 59r ). Whether cumulative sensory neuropathy can occur as a result of accumulation of dichloro-DACH-platinum, a biotransformation product of DACH-platinum, in the axonal and dorsal root ganglia neurons, needs further investigation (43E ). The risk of oxaliplatin-induced neurosensory toxicity may be increased after surgery. Of 12 patients with metastatic colorectal cancer, seven reported immediate postoperative aggravation of pre-existing neurotoxicity. Before surgery they had only acral paresthesia without any functional impairment, whereas after surgery they complained of major worsening of symptoms, including loss of hand grip strength, leading to dependence in dressing, eating, and use of the toilet, or loss of sensitivity, interfering with walking, which could persist for several months (66c ). The authors speculated that perioperative hemolysis had caused an increase in unconjugated bilirubin and the release of ultrafilterable oxaliplatin, which had previously been confined to the intraerythrocytic compartment. In addition, diffusion of ultrafilterable oxaliplatin out of erythrocytes into the plasma during hemodilution can contribute to the undesirable perioperative increase in unbound oxaliplatin in the plasma. In 15 patients with metastatic colorectal cancer who were given gabapentin (100 mg bd or tds) if neuropathic symptoms developed with oxaliplatin, the symptoms disappeared in all patients, even in those who received up to 14 courses of oxaliplatin. Withdrawal of gabapentin resulted in recurrence. However, a controlled trial is required to verify these encouraging preliminary results. It has been suggested that chronomodulated delivery of oxaliplatin might reduce the incidence of platinum-induced neurotoxicity (67c , 68R ). In a randomized multicenter trial in patients with previously untreated metastases from colorectal cancer, 93 patients were assigned chronotherapy and 93 were assigned constantrate infusion (69C ). Chronotherapy reduced the

Chapter 45

Hans-Peter Lipp et al.

rate of severe mucositis five-fold and halved the rate of functional impairment from peripheral sensitive neuropathy. Median and 3-year survival times were similar in the two groups. Preliminary results have suggested that glutathione may be neuroprotective in patients receiving oxaliplatin (70C ). In a pilot study in 15 patients, subcutaneous amifostine was given 20 minutes before oxaliplatin, in order to counteract oxaliplatininduced peripheral neurosensory toxicity. In 10 patients, this regimen reduced the severity of cumulative neuropathy without compromising antitumor efficacy; the amifostine was well tolerated (71c ). Conventional dosages of carboplatin have been associated with the lowest risk of peripheral neuropathy (e.g. mild paresthesia) among the approved platinum compounds. It has been estimated that about 4–6% of patients who receive carboplatin develop a peripheral neuropathy. Patients over 65 years of age or patients pretreated with other neurotoxic agents may be at a slightly higher risk (72A ). CNS effects are uncommon after treatment with cisplatin. However, there have been case reports of cerebral herniation and coma, severe encephalopathy, tonic–clonic seizures with concomitant visual disturbances and changed mental state, insomnia, anxiety, and Parkinsonian symptoms. The symptoms generally resolved within several weeks (47R –49R , 50A , 73A ). In some studies the CNS effects were the consequence of cisplatin-induced electrolyte disturbances (e.g. hyponatremia, hypocalcemia, or hypomagnesemia) rather than a direct action of the platinum derivative in the CNS (74A – 76A ). For example, mental status improved in one patient who was given 3% sodium chloride in order to increase the serum sodium from 118 to 128 mmol/l, whereas diazepam, phenytoin, phenobarbital, and dexamethasone were ineffective (77A ). Sensory systems Ototoxicity Cisplatin is ototoxic. Tinnitus and bilateral high-frequency hearing loss (threshold 3000 Hz) have been observed in up to 31% of patients treated with initial intravenous doses of cisplatin of 50 mg/m2 . Single doses exceeding 150 mg given over a short period of time and higher cumulative doses have been reported to be associated with bilateral, symmetrical, progressive, and

Cytostatic drugs

Chapter 45

irreversible hearing disorders, which suggests that peak plasma concentrations as well cumulative effects contribute to this adverse effect. Other risk factors include young age, previous cranial irradiation, pre-existing renal dysfunction or inner ear damage, and the concomitant use of other potentially ototoxic agents, such as aminoglycosides, loop diuretics, or tirapazamine (78C –82C , 83R , 84r , 85r ). The mechanisms of cisplatin-induced damage to the outer hairy cells of the cochlea may include the formation of highly reactive oxygen radicals and depletion of glutathione (86E ). The role of amifostine and glutathione in preventing cisplatin-induced ototoxicity has therefore been studied (87R , 88c ). The data are not sufficient to support the use of glutathione in this indication. In contrast, there is some evidence that amifostine may provide protection (89R ). No ototoxicity developed in 18 patients who received amifostine over 15 minutes, 15–20 minutes before the intravenous administration of cisplatin 50–120 mg/m2 over 20 minutes. There was transient hearing loss and mild persistent audiometric abnormalities in only 30% of the patients who received cisplatin 150 mg/m2 . Ototoxicity after carboplatin therapy is thought to be rare (90A ). Only 1.1% of evaluable patients had symptoms, such as tinnitus, or subclinical audiographic changes. Routine audiometric monitoring is therefore not recommended during carboplatin therapy. However, after otoacoustic emission testing in 19 children who received cisplatin the authors suggested that this is better at detecting the early cochlear damage associated with cisplatin ototoxicity than traditional pure-tone audiometry, particularly in children, in whom early detection is of the utmost importance (91C ). Previous use of aminoglycosides increases the risk of ototoxicity. In patients who receive high-dose carboplatin, preliminary results suggest that there may be a correlation between the risk of ototoxicity and carboplatin serum concentrations (AUC) during the first course. Patients with high-grade ototoxicity had higher median carboplatin AUCs than patients without any symptoms (92R , 93R ). There is as yet no evidence that oxaliplatin causes ototoxicity (94E ). Visual disturbances Ocular effects, including optic neuritis, papilledema, and retrobulbular neuritis, are uncommon adverse effects

497 of cisplatin-containing cancer chemotherapy. The risk of retinal toxicity is restricted to highdose cisplatin therapy (e.g. 200 mg/m2 over 5 days) and can result in blurred vision and altered color perception, which can persist for several months. In contrast to cisplatin, carboplatin is seldom involved in drug-induced visual disturbances. In two cases there was a relation between the administration of carboplatin (800–1200 mg/m2 ) and the occurrence of clinical cortical blindness (92R ). However, both patients had impaired renal function before the start of therapy with carboplatin. Endocrine The long-term effects of chemotherapy in 244 patients with germ cell tumors on Leydig cell function have been studied by measuring concentrations of sex hormonebinding globulin, luteinizing hormone, and follicle-stimulating hormone at least 74 months after chemotherapy (95C ). The population was divided into groups by cumulative cisplatin exposure (above and below 400 mg/m2 ). Lowdose cisplatin exposure had no effect on Leydig cell function, but cumulative high-dose chemotherapy caused persistent impairment. Electrolyte balance About 75% of patients treated with cisplatin develop hypomagnesemia (serum concentrations below 1.5 mmol/l), which appears to be associated with druginduced renal tubular damage (96A , 97A , 98c ). The symptoms include tetany, muscular weakness, tremulousness, dizziness, personality changes, and perioral and peripheral paresthesia (99R ). Magnesium supplementation is generally recommended during treatment courses with cisplatin (97A , 100R ). Sometimes hypomagnesemia resolves rather slowly and can last several weeks. A significant reduction in serum magnesium and other effects associated with progressive renal dysfunction appear to correlate with high cumulative doses of carboplatin (e.g. a median cumulative dose of 2590 mg/m2 in children or in adults undergoing high-dose chemotherapy with peripheral blood stem cell support). Other electrolyte disturbances induced by cisplatin include hypocalcemia, hypophosphatemia, hyponatremia, and hypokalemia (101R , 102R ). However, these changes are rarely associated with symptoms (103C , 104A ).

498 Hematologic Compared with cisplatin and oxaliplatin, carboplatin has the highest myelotoxic potential. Carboplatin-induced myelosuppression is dose-related and results in thrombocytopenia and neutropenia. At conventional doses (AUC 4–7 min.mg.ml−1 ) about 20–40% of patients develop thrombocytopenia (platelet counts below 50 × 1012 /l). In contrast, severe neutropenia is less pronounced with conventional doses; about 16–21% of patients develop neutrophil counts less than 1 × 109 /l. The lowest leukocyte and platelet counts usually occur at 14–28 days after drug administration. The hemoglobin concentration was below 11 g/dl in 71–91% of patients and below 8 g/dl in 8–21% (93R ). The severity of drug-induced thrombocytopenia is inversely correlated with the endogenous formation and release of thrombopoietin, which is an important cytokine for de novo platelet formation in the bone-marrow. In contrast to conventional dosages, high-dose chemotherapy containing carboplatin is generally associated with severe and life-threatening forms of hematological toxicity, requiring the prophylactic use of recombinant hemopoietic growth factors, such as G-CSF, and peripheral blood stem cell support (105r ). Underlying risk factors, which predispose patients to more severe forms of myelosuppression, include lower initial blood cell counts, renal impairment, poor performance status, extensive prior chemotherapy, and advanced age. There is a strong correlation between carboplatin pharmacokinetics and the severity of myelosuppressive adverse effects; an AUC-adapted dosage of carboplatin is therefore highly recommended during conventional dose chemotherapy (22r , 23r , 93R ). Cisplatin belongs to the most important causative agents for the induction of treatmentrelated anemia requiring the prophylactic use of erythropoietin or intermittent transfusion of erythrocytes, whereas drug-induced leukopenia and thrombocytopenia are generally mild and transient (105r , 106C ). In a pharmacokinetic study non-protein-bound platinum concentrations in patients with significant falls in hemoglobin (3 g/dl or more) were significantly higher (mean 53 ng/ml) than in patients who did not have significant falls in hemoglobin. The authors suggested that early and simple platinum pharmacokinetic control on the day after first drug administration might be useful

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in targeting patients who are likely to develop more severe forms of cisplatin-related anemia (107R ). Myelosuppression caused by oxaliplatin is generally mild. Grade III/IV anemia, neutropenia, and thrombocytopenia are observed in only 2–3% of patients. In combination with fluorouracil/folinic acid the frequency is slightly higher, depending on the dose of fluorouracil (8R , 9R ). Gastrointestinal Of the approved platinum compounds, cisplatin has the greatest emetogenic potential (108R ). Whereas about 65–94% of patients who receive conventional dosages of carboplatin complain of mild to moderate nausea or vomiting, more than 90% of those who receive cisplatin have more than 10 vomiting episodes within the first day of administration in the absence of effective antiemetic therapy. An emetogenic episode occurring within 24 hours after drug administration is usually classified as acute emesis; nausea and vomiting that occur thereafter are classified as delayed emesis and may persist over several days. There appears to be a correlation between the time of cisplatin administration and the severity of drug-induced vomiting (109C ). When cisplatin was given in the morning (0500 h) vomiting was greater than when it was given in the evening (1700 h). However, the prophylactic use of a 5-HT3 receptor antagonist reduced the time-ofday dependency. 5-HT3 receptor antagonists, such as dolasetron, granisetron, ondansetron, or tropisetron, particularly in combination with dexamethasone, reduce the severity of acute emesis occurring within the first 24 hours after cisplatin. In contrast, the satisfactory prevention of delayed emesis remains a challenge. There is increasing evidence that the introduction of a novel class of antiemetic agents, the neurokinin-1-receptor antagonists, such as MK869 (aprepitant), may be associated with additional benefit in combination with a 5-HT3 receptor antagonist in reducing cisplatin-induced nausea and vomiting, both acute and delayed (110C ). Nausea, vomiting, and diarrhea are common adverse effects of oxaliplatin and carboplatin, but they are generally mild to moderate, and both are less emetogenic than cisplatin. However, patients who have previously received cisplatin may be at greater risk of vomiting with carboplatin or oxaliplatin (1R , 8R , 9R ).

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Liver Mild reversible increases in liver function tests can occur in patients who have received platinum compounds (111A ). However, the platinum compounds are generally not classified as hepatotoxic drugs. Urinary tract Of the approved platinum compounds cisplatin has the greatest nephrotoxic potential. If dosages exceed 100 mg/m2 per course or per day, nephrotoxicity is the most severe drug-related adverse effect. Irreversible renal insufficiency has been described after accidental overdosage with cisplatin. Cisplatininduced degenerative renal lesions are primarily observed in the proximal tubules, and are characterized by hydropic degeneration, necrosis, and occasional tubular atrophy. Sensitive indicators of cisplatin-related renal tubular toxicity include changes in creatinine clearance or in urinary alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase activities. Blood urea nitrogen and serum creatinine are poor indicators of early renal damage. The exact mechanisms of cisplatin-induced nephrotoxicity have not been fully elucidated. Like several nephrotoxic heavy metals (e.g. mercury), cisplatin may accumulate in the kidney, where it can interact with sulfhydryl compounds, resulting in increased membrane fragility and depletion of intracellular glutathione. There is some evidence that cisplatin can induce apoptosis and necrosis of kidney cells dose-dependently. In vitro studies have suggested that the constitutive expression of antiapoptotic proteins (e.g. bcl-X) might be inversely correlated with the sensitivity of renal tubular cells (87R , 112R , 113E , 114E ). Several supportive measures have been proposed in order to circumvent cisplatin-induced nephrotoxicity. These include: • adequate hydration before and during cisplatin administration and afterwards, in combination with an osmotic diuretic such as mannitol (the current standard method); • prolongation of the infusion time (e.g. 6 hours instead of 2 hours); • fractionation over several days; • the use of a chronomodulated schedule; • the use of nephroprotective agents, such as organic thiosulfate compounds. Experimental study drugs that may be useful in renal protection include BNP7787

499 (dimesna), selenium, and silibinin (87R , 115R , 116R , 117c –121c , 122E , 123E ). Regarding prolongation of infusion, it has been suggested that there is a correlation between higher plasma platinum concentrations and the risk of cisplatin-induced nephrotoxicity. If platinum concentrations exceed 6 μg/ml more patients develop nephrotoxicity. These drug concentrations were measured shortly after the end of infusion (e.g. 5 minutes after intravenous infusions of 100–120 mg/m2 ), suggesting that high blood concentrations rather than trough concentrations may be predictively important. As a result, prolongation of cisplatin infusion (e.g. 6 hours) has been proposed to reduce the risk of cisplatin-induced renal insufficiency (88c , 124C ). However, in practice a 1-hour infusion remains the common standard. Dose fractionation over several days has been associated with less kidney damage. The glomerular filtration rate was maintained in patients who received cisplatin 20 mg/m2 /day over 5 consecutive days (125c , 126C ). However, patients still had a significant increase in sensitive urinary markers, such as low molecular weight proteins, N-acetyl-beta-Dglucosaminidase (NAG), and alpha-1-microglobulin, showing that conventional approaches can reduce but not completely prevent nephrotoxicity (87R , 112R ). Chronomodulated administration of cisplatin can also reduce drug-induced organ toxicity, e.g. nephrotoxicity (127R , 128E ). Administration of cisplatin in the evening caused markedly less nephrotoxicity and neurotoxicity than morning administration. There is also increasing evidence that all platinum-based anticancer drugs are better tolerated if they are given in the late afternoon or early evening, with less frequent and severe nephrotoxicity, thrombocytopenia, and cumulative peripheral neuropathy after cisplatin, carboplatin, and oxaliplatin. As chronomodulated scheduling appears to affect the adverse effects of all platinum compounds, the mechanism may be based on circadian variation in renal tubular excretion and plasma filtration of platinum compounds, increased plasma protein binding, and reduced tissue susceptibility at about 1600 h (127R , 128E , 129C ). Intensified carboplatin-containing regimens can predispose patients to drug-induced renal dysfunction when cisplatin has previously been

500 used or when renal function is already impaired (104A , 130r ). Amifostine (WR-2721, ethyofos, 2-[3-aminopropyl)amino]ethylphosphorothioic acid) is an organic thiophosphate. It is a prodrug, because dephosphorylation by tissue-bound alkaline phosphatase is necessary to form its active metabolite, WR-1065. Its cytoprotective role in the alleviation of drug-induced or radiationinduced toxicity in normal cells appears to be based on free radical scavenging, hydrogen ion donation, and the prevention or removal of DNA platinum adducts (131R ). In a randomized study, 242 patients with advanced ovarian cancer received intravenous cisplatin 100 mg/m2 and cyclophosphamide 1000 mg/m2 once every 3 weeks with or without amifostine 910 mg/m2 . Besides a significant reduction in chemotherapy-induced neutropenia and thrombocytopenia, amifostine produced significant protection against cisplatin-induced nephrotoxicity. Creatinine clearance fell by more than 40% in 60% of the control group compared with 12% of those in the treated group. In addition, the incidence of cisplatinrelated hypomagnesemia was less pronounced in the patients who received amifostine. In several studies intravenous amifostine (910 mg/m2 ) preserved glomerular filtration rate when it was co-administered with cisplatincontaining regimens (131R ). Even after two cycles containing intravenous cisplatin 50 mg/m2 plus intravenous ifosfamide and etoposide or paclitaxel, GFR can fall by more than 30%, but concomitant use of amifostine prevented this. Even lower dosages of intravenous amifostine (e.g. 740 mg/m2 ) may be effective (132C , 133C ). Because preclinical results suggested that intracellular glutathione may be involved in the modulation of cisplatin-induced toxicity, several trials (two uncontrolled and two randomized) have been conducted to evaluate the efficacy and tolerability of standard doses of cisplatin with concomitant glutathione. In some studies glutathione reduced cisplatinrelated toxicity without impairing its antineoplastic activity (56R ). However, a cisplatin dose-escalation study with concomitant administration of glutathione had to be terminated prematurely because of unacceptable ototoxicity. Glutathione has not yet received FDA approval for chemoprotection. In contrast to cisplatin, severe nephrotoxicity is less common or absent in patients who

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receive carboplatin. In addition, carboplatininduced alterations in creatinine clearance or electrolytes are usually mild and transient. Concomitant intravenous hydration and monitoring is not needed when carboplatin is given in conventional dosages. However, during doseintensified treatment with carboplatin the risk of impaired renal function increases. In addition, other nephrotoxic drugs, such as ifosfamide, are often part of those high-dose combination regimens. During a study of the use of highdose carboplatin (1500 mg/m2 /day or more) on 3 consecutive days the nephrotoxic profile was comparable to a standard single dose of cisplatin (126C ). In a randomized study of the prophylactic use of amifostine during dose-intensified chemotherapy including carboplatin and ifosfamide, patients in the control arm had a median loss of GFR of 37% compared with baseline after one cycle, and 35% of these patients had GFRs below 60 ml/min on day 10 after treatment. In patients who received amifostine during dose-intensified chemotherapy the GFR fell only by a median of 10% and no patient developed a GFR below 60 ml/min by day 10 (134C ). Oxaliplatin, when given alone or in combination with fluorouracil, is considered not to be nephrotoxic (103C , 104A , 130r ). There has been a single case of acute tubular necrosis probably caused by oxaliplatin and not related to dehydration or pre-renal failure (135c ). Skin Even in cases of accidental extravasation the risk of skin ulceration is low. Severe cisplatin-related extravasation injury appears to be primarily restricted to the use of high concentrations (e.g. 0.75 mg/ml) and infusion over a short time. In such circumstances it is advisable to give a local injection of isotonic thiosulfate solution (0.16 mol/l). Since carboplatin is more slowly activated than cisplatin to active DNA binding moieties and is more water soluble, there have been no reports of severe carboplatin extravasation and no antidote is necessary (136A , 137A ). Accidental subcutaneous administration of oxaliplatin resulted in a red-brown painful swelling and sclerosis of the skin within 8 days (138A ). The symptoms were worst 1 week after extravasation and lasted for about 5 weeks, but the patient, a 52-year-old woman, recovered

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fully. Acute intervention included local fluid instillation to dilute the extravasation, removal of the cannula, cold packs, and a gel containing aescin and diethylamine salicylate. Recently two other cases of oxaliplatin extravasation have been reported (139A ). Both occurred when the intraport needle disconnected. The initial symptoms were swelling and tenderness at the port site. The patients developed severe inflammation after 3 days. Treatment included local cool packs, diclofenac ointment, and oral indomethacin, morphine, or dexamethasone. The authors avoided saline instillation because sodium chloride and oxaliplatin may be incompatible in combination (68R ). Both patients recovered without any sign of local necrosis and long-term sequelae (139A ). Immunologic Cisplatin can cause anaphylactic shock, asthma, or urticaria (140A ). Hypersensitivity reactions, probably of type I, have also been reported after the administration of cisplatin, carboplatin, and oxaliplatin (141A –144A , 145c , 146c ). These allergic reactions can include respiratory dysfunction (e.g. wheezing, dyspnea), gastrointestinal discomfort (e.g. abdominal cramps, diarrhea), and rashes (e.g. pruritus, urticaria, facial erythema, and swelling). The risk of exfoliative dermatitis is very low. In most patients the first signs of hypersensitivity reactions usually occurred after the administration of multiple intravenous courses containing platinum compounds. Whether patients who are hypersensitive to one platinum compound also react to another cannot be excluded, since some case reports have suggested possible cross-reactions among platinum compounds (147c ). Sometimes, successful retreatment may be feasible through premedication with steroids and antihistamines (142A ). The risk of carboplatin-induced hypersensitivity reactions is 2–9%. According to one retrospective analysis mild carboplatin-related hypersensitivity reactions, with itching and mild erythema, occurred in 20 of 194 patients, whereas 12 patients developed severe forms of reactions, including diffuse erythroderma, rigor, facial swelling, throat and chest tightness, tachycardia, bronchospasm, and hypertension or hypotension (146c ). The most important interventive measures in patients with severe

501 forms of hypersensitivity reactions include intravenous adrenaline, corticosteroids, and antihistamines. Severe anaphylaxis has been reported in five patients who had already received several cycles (5–12) containing oxaliplatin 100 mg/m2 every 2 weeks (144A ). The predominant symptoms included reduced systolic blood pressure, flushing, sweating, headache, tachycardia, and respiratory distress. If retreatment with the causative platinum compound is required in such cases, premedication with a glucocorticoid and antihistamine may prevent recurrence. However, symptoms can occur despite premedication, making drug withdrawal necessary. The term “oxaliplatin-induced hypersensitivity reaction” can refer to (a) acute neurosensory symptoms, (b) a cytokine release syndrome related to increased plasma concentrations of interleukin-6 and TNF-alpha, and (c) an immunological reaction involving antibody formation and histamine release (141A ). In order to prove an underlying allergic disorder an intradermal skin test with commercial formulations of the platinum compound in different concentrations (e.g. 0.003 mg/ml to 1 mg/ml) can be done (148A ). An effective carboplatin desensitization protocol has been reported in a child with hypersensitivity, allowing additional months of carboplatin treatment (149A ). After premedication with diphenhydramine, ranitidine, and methylprednisolone, eight dilutions of carboplatin (0.01–50.0 mg) were given intravenously at 15-minute intervals at a rate of 1 mg/min. Subsequently, carboplatin 600 mg was given as a continuous infusion over 3 hours without adverse effects. Whether desensitization is generally suitable for overcoming allergic adverse events should be tested prospectively (150A ). Body temperature Oxaliplatin is generally well tolerated. Some patients develop fever, which appears to be related to a transient increase in cytokines, particularly interleukin6 (IL-6) and TNF-alpha. In one study the oxaliplatin-induced increase in body temperature correlated with a marked increase in IL-6 serum concentrations (peak 133 pg/ml) (151c ). IL-6 is a proinflammatory cytokine, which stimulates acute phase proteins and B lymphocytes. Premedication with metamizol, dexamethasone, and clarithromycin, which interferes with IL-6,

502 did not prevent the fever. The roles of IL-6 and TNF-alpha in the development of fever is strengthened by the observation that their serum concentrations fell during resolution of the fever (152E ). Mutagenicity and carcinogenicity There is some evidence that platinum compounds are mutagenic in bacteria and can cause chromosomal aberrations in animal cells in tissue culture (153E ). The risk of secondary leukemia in 28 971 patients with ovarian cancers receiving platinum-based chemotherapy has been evaluated; 96 developed a secondary leukemia (154C ). The authors concluded that the risk of developing a secondary leukemia while receiving a platinum-based protocol may be increased four-fold. The relative risks for carboplatin and cisplatin were estimated at 6.5 and 3.3 respectively. The relative risks of leukemia after cumulative doses of platinum of less than 500 mg, 500–749 mg, 750–999 mg and 1000 mg were 1.9, 2.1, 4.1, and 7.6 respectively. The delay between the start of platinum-containing chemotherapy and the occurrence of secondary malignancies was 2.8–7.7 years. In children who received an average cumulative dose of cisplatin of 600 mg/m2 , the estimated incidence of chemotherapy-induced leukemia was 1.5% (155C ). Concomitant radiation therapy or administration of other carcinogenic agents increases the risk. Fertility There is experimental evidence that several anticancer drugs can cause abnormalities of sperm chromosomes. Preliminary data have suggested that after platinum-containing chemotherapy for testicular cancer, penetration of eggs can be severely impaired. Cytogenetic study of the spermatozoa has shown that many of the abnormalities correspond to structural aberrations that may not have a pathogenic effect in the production of abortions or children with chromosome abnormalities (156R ). Teratogenicity Cisplatin and related compounds cross the placenta and can therefore cause fetal damage. Cisplatin is teratogenic in mice and embryotoxic in mice and rats. The platins should only be used during pregnancy in life-threatening situations. The patient should be informed of the potential hazard to the fetus (157R ).

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Drug overdose In a 68-year-old woman who received an accidental overdose of cisplatin 480 mg there was severe vomiting and myelosuppression, irreversible renal failure, and deafness; other effects included seizures, hallucinations, loss of vision, and hepatotoxicity (158A ). Drug interactions Antiepileptic drugs Cisplatin caused subtherapeutic carbamazepine and valproic acid concentrations in a 38-yearold woman with epilepsy undergoing cytotoxic cancer chemotherapy with doxorubicin and cisplatin, resulting in tonic–clonic seizures (159R ). The mechanism was not clear. Plasma concentrations of antiepileptic drugs (e.g. carbamazepine, valproic acid, phenytoin) should be measured more frequently during cisplatincontaining cancer chemotherapy (159R , 160A ). Irinotecan The concomitant use of irinotecan as a 1-hour infusion immediately following a 2-hour infusion of oxaliplatin resulted in more severe hypersalivation and abdominal pain than irinotecan monotherapy (161A ). Acute intervention with atropine alleviated these adverse effects. When the drugs were separated by 1 day, the cholinergic symptoms were not exacerbated. The authors postulated that oxaliplatin might have some acetylcholinesterase inhibitory activity. Lithium Some data have suggested that cisplatin-containing chemotherapy can alter lithium clearance through impaired renal function, and lithium therapy should be closely monitored during treatment with cisplatincontaining regimens (162A ). Nephrotoxic drugs Based on its considerable nephrotoxic potential, cisplatin should be given after, rather than before, other anticancer drugs and other drugs with a low therapeutic index (e.g. aminoglycoside antibiotics) that are primarily excreted in the urine in unchanged form. Concomitant use of potentially nephrotoxic agents (e.g. conventional amphotericin, tacrolimus) with cisplatin should be avoided (163A , 164A ). Neurotoxic drugs The concomitant or previous use of potentially neurotoxic drugs (e.g. paclitaxel, vinca alkaloids, or hexamethylmelamine) may increase the risk of peripheral neuropathy due to platinum compounds (48R , 49R ).

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Paclitaxel There is some evidence that there is a clinically significant pharmacokinetic interaction of paclitaxel with cisplatin. When cisplatin was given before paclitaxel, the clearance rate of paclitaxel was 25% less than when the two drugs were given in the opposite sequence. In addition, neutropenia was more profound with the former schedule (165C ). In addition, in experimental studies cytotoxicity increased when human ovarian carcinoma cells were exposed to paclitaxel before cisplatin, whereas the interaction was antagonistic when a 1-hour exposure to cisplatin was followed by a 20-hour exposure to taxol, or when the cells were exposed to cisplatin and taxol for 1 hour concurrently (166E ). The biochemical basis of this interaction has not been elucidated. The pharmacodynamic interaction may be related to cisplatin-induced alterations in cell-specific and non-specific binding sites for paclitaxel (167E ). In view of these results, paclitaxel should be given before cisplatin (168R ). There is no similar interaction of paclitaxel with carboplatin (169R ).

GENERAL Recent reviews have increased our understanding not only of the adverse effects profiles of individual drugs (170R ) but also of the factors that contribute to the adverse effects of chemotherapy, which are not purely related to the pharmacology of the cytostatic drugs themselves. For example, there are some dramatic scheduling effects, particularly in hematological toxicity, depending on whether the patient receives doxorubicin followed by docetaxel or the same doses but in reverse order (171c ). Sex also has an effect: women suffer more frequent and more severe toxicity with fluorouracil than men (172M ). Finally, there has long been debate in oncology circles about whether toxicity is a surrogate for efficacy, based on the premise that the greater the toxicity and the effect on the organ or hematological cell line, the greater the effect on the cancer cells. Two recent papers have supported this premise (173c , 174R ). Cardiovascular The cardiotoxicity of anthracyclines still continues to be teased apart. The authors of a recent study used MRI scans

503 to assess the subclinical effects of the anthracyclines. They concluded that increased MRI enhancement equal to or greater than 5 on day 3 compared with the baseline predicted significant reduction in ejection fraction at day 28 (175c ). In 1000 patients given doxorubicin chemotherapy and irradiation there were six cases of congestive heart failure and three cases of myocardial infarction; there was a cumulative cardiac mortality of 0.4% in all anthracycline-exposed patients (176C ). Respiratory Various authors have discussed the differences in busulfan-induced idiopathic pneumonia syndrome, as a result of either chronic low-dose or short-course high-dose therapy. One group found that chronic low-dose therapy (even at cumulative doses of busulfan of up to 3 g) caused different lung damage from the clinical characteristics, radiological, and pathological features of the idiopathic pneumonia syndrome (177c ). Nervous system The sensory neuropathy caused by paclitaxel is well documented. A high-dose study has shown dose-related toxicity, with a dose-limiting ceiling at 775 mg/m2 , when paresthesia occurs (178c ). The late effect of chemotherapy and radiotherapy for CNS lymphoma has been studied in 15 patients, of whom 10 had severe symptomatic diffuse changes in the white matter within 8 months of completing treatment (179c ). Metabolism Hyperglycemia was reported in 21 of 56 patients who received weekly paclitaxel with oral estramustine and carboplatin (four-weekly); less than 10% required pharmacological intervention (180c ). There was mild hyperphosphatemia in 24. Fasting hypoglycemia was noted in 19 of 35 children with acute lymphoblastic leukemia receiving maintenance therapy of daily oral 6-mercaptopurine and weekly oral methotrexate; the authors noted that all the children improved on withdrawal of chemotherapy and 10 of 15 normalized (181c ). Liver Of 54 patients with non-small-cell lung cancers treated with a combination of gemcitabine 1000 mg/m2 on days 1 and 8 and paclitaxel 200 mg/m2 on day 1, six had abnormal but significantly raised liver enzymes (AsT

504 or AlT) (182C ). The authors believed that this was drug induced, but could not rule out underlying liver disease. Skin and nails Of 99 patients who received low-dose docetaxel (60 mg/m2 every 3 or 4 weeks), 25 had skin toxicity, mainly erythema and nail changes (183C ). Of a subset of 25 patients who received irradiation before docetaxel, four had recall dermatitis during their first infusion of docetaxel. All had previously received doxorubicin, which may in part have explained some of the toxicity. Hydroxyurea has featured prominently in recent reports of skin toxicity, including reports of Behçet’s disease, hyperpigmentation of the nails and palmar creases, and leg ulcers (184A , 185A , 186c ). Acral erythema, dermatomyositislike changes on the backs of the hands, squamous cell neoplasms on sun-exposed sites, and ulcers on the legs, genitalia, and oral mucosae have also been reported (187M ). Musculoskeletal In 26 men who took androgen deprivation therapy for prostate cancer for 10 years there was reduced bone mineral density with increasing duration of androgen deprivation therapy across the whole 10-year period (188c ). The authors also noted that patients taking intermittent therapy had similar loss of bone mineral density at years 2 and 4, but less bone loss from year 6 onwards. Reproductive system The gynecological consequences of antiestrogens (tamoxifen and toremifene) have been evaluated in 167 postmenopausal breast cancer patients in a 3-year prospective study (189C ). There was a proliferative endometrium more often in the tamoxifen group than in the toremifene group, but this did not translate into an increase in the rate of endometrial cancer. The authors did not recommend routine surveillance of the endometrium. Immunologic Asparaginase is well known to cause allergic reactions, which increase with the number of doses within a cycle and the number of exposures, irrespective of drug-free intervals. There is now a pegylated formulation (PEG-ASNase; Oncaspar™) with supposedly improved pharmacokinetics and lower allergenic properties. These claims have been investigated, and the authors concluded that although

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the hypersensitivity rate was lower it was still significant; furthermore, there was no crosssensitivity in previously treated patients (190C ). Carcinogenicity Among 679 patients receiving chemotherapy for advanced Hodgkin’s disease there were four deaths due to secondary malignancies (191C ). There were 75 deaths in all during 3 years, of which the vast majority were related to disseminated Hodgkin’s disease. Exposure to diethylstilbestrol during pregnancy in 4836 women has been reported to carry a relative risk of 1.27 of breast cancer later in life (192c ). However, the authors found no evidence to support the link between diethylstilbestrol exposure and ovarian, endometrial, or other cancers. Fertility Of 17 adult men who had been treated before puberty for sarcoma with highdose pulse cyclophosphamide (median dose 20.5 m/m2 ) as part of regimens containing vincristine, actinomycin, and cyclophosphamide, with or without doxorubicin, 10 had azoospermia, five had oligospermia, and only two had normal sperm counts (193c ). The authors concluded that the previous suggestion that puberty acts as a protection to infertility was not borne out and that the risk of infertility was proportional to the cumulative dose of cyclophosphamide. Drug administration route In the UK guidance on the safe administration of intrathecal chemotherapy has been issued (194S ), following a case in which vincristine was fatally injected into the cerebrospinal fluid (195S ). Two reports have reported the safe administration of etoposide intraventricularly (196c ) and a new long-acting formulation of cytarabine intrathecally (197c ). Of course, neither of these interventions is completely free from adverse effects, and mild reversible CNS effects are predictable. Drug interactions Diarrhea ameliorated in six of seven patients treated with irinotecan in combination with oral neomycin at 1000 mg tds (198C ). Neomycin had no effect on the pharmacokinetics of irinotecan and its major metabolites.

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509 domized trial of amifostine in patients with highdose VIC chemotherapy plus autologous blood stem cell transplantation. Br J Cancer 2001; 84: 313–20. 135. Pinotti G, Martinelli B. A case of acute tubular necrosis due to oxaliplatin. Ann Oncol 2002; 13: 1951. 136. Marnocha Mutch R, Hutson PR. Intradermal carboplatin and ifosfamide extravasation in the mouse. Cancer 1992; 70: 850–3. 137. Al Lamki Z, Pearson P, Jaffe N. Localized cisplatin hyperpigmentation induced by pressure. Cancer 1996; 77: 1578–81. 138. Baur M, Kienzer H-R, Rath T. Extravasation of oxaliplatin—clinical course. Onkologie 2000; 23; 468–71. 139. Kretzschmar A, Thuss-Patience PC, Pink D, Benter T, Jost D, Scholz C, Reichardt P. Extravasations of oxaliplatin. Proc Am Soc Clin Oncol 2002; 21: A2900. 140. Khan A, Hill JM, Grater W, Loeb E, MacLellan A, Hill N. Atopic hypersensitivity to cisdichlorodiammineplatinum (II) and other platinum complexes. Cancer Res 1975; 35: 2766. 141. Goldberg A, Altaras MM, Mekori YA, Beyth Y, Confino-Cohen R. Anaphylaxis to cisplatin: diagnosis and the value of pretreatment in prevention of recurrent allergic reactions. Ann Allergy 1994; 73: 271–2. 142. Rose PG, Fusco N, Fluellen L, Rodriguez M. Carboplatin hypersensitivity reactions in patients with ovarian and peritoneal carcinoma. Int J Gynecol Obstet 1998; 8: 365–8. 143. Schiavetti A, Varrasso G, Maurizi P, Castello MA. Hypersensitivity to carboplatin in children. Med Pediatr Oncol 1999; 32: 183–5. 144. Tournigaud C, Maindrault-Goebel F, Louvet C, De Gramont A, Krulik M. Severe anaphylactic reactions to oxaliplatin. Cancer 1998; 34: 1297–8. 145. Weidmann B, Mülleneisen N, Bojko P, Niederle N. Hypersensitivity reactions to carboplatin. Cancer 1994; 73: 2218–22. 146. Polyzos A, Tsavaris N, Kosmas C, Arnaouti T, Kalahanis N, Tsigris C, Giannopoulos A, Karatzas G, Giannikos L, Sfikakis PP. Hypersensitivity reactions to carboplatin administration are common but not always severe: a 10-year experience. Oncology 2001; 61: 129–33. 147. Dold F, Hoey D, Carberry M, Musket A, Friedberg V, Mitchell E. Hypersensitivity in patients with metastatic colorectal carcinoma undergoing chemotherapy with oxaliplatin. Proc Am Soc Clin Oncol 2002; 21: A1478. 148. Meyer L, Zuberbier T, Worm M, Oettle H, Riess H. Hypersensitivity reactions to oxaliplatin: cross-reactivity to carboplatin and the introduction of a desensitization schedule. J Clin Oncol 2002; 20: 1146–7. 149. Sims-McCallum RP. Outpatient carboplatin desensitization in a pediatric patient with bilateral optic glioma. Ann Pharmacother 2000; 34: 477–8. 150. Goldberg A, Confino-Cohen R, Fishman A, Beyth Y, Altaras M. A modified prolonged desensitization protocol in carboplatin allergy. J Allergy Clin Immunol 1996; 98: 841–3.

510 151. Ulrich-Pur H, Fiebiger WCC, Schüll B, Kornek GV, Scheithauer W, Raderer M. Oxaliplatininduced fever and release of IL-6. Oncology 2000; 59: 187–9. 152. Chiche D, Pico JL, Bernaudin JF, Chouaib S, Wollman E, Arnoux A, Denizot Y, Nitenberg G. Pulmonary edema and shock after high-dose aracytidine for lymphoma: possible role of TNF-alfa and PAF. Eur Cytokine Netw 1993; 4: 147–51. 153. Beck DJ, Brubaker RR. Mutagenic properties of cis-platinum (II)diamminedichloride in Escherichia coli. Mutat Res 1975; 27: 181. 154. Travis LB, Holowaty EJ, Bergfeldt K, Lynch CF, Kohler BA, Wiklund T, Curtis RE, Hall P, Andersson M, Pukkala E, Sturgeon J, Stovall M. Risk of leukemia after platinum-based chemotherapy for ovarian cancer. New Engl J Med 1999; 340: 351–7. 155. Duffner PK, Krischer JP, Horowitz ME, Cohen ME, Burger PC, Friedman HS, Kun LE. Second malignancies in young children with primary brain tumors following treatment with prolonged postoperative chemotherapy and delayed irradiation: a Pediatric Oncology Group study. Ann Neurol 1998; 44: 313–16. 156. Pont J, Albrecht W. Fertility after chemotherapy for testicular germ cell cancer. Fertil Steril 1997; 68: 1–5. 157. Lamont EB, Schilsky RL. Gonadal toxicity and teratogenicity after cytotoxic chemotherapy. In: Lipp H-P, editor. Anticancer Drug Toxicity; Prevention, Management and Clinical Pharmacokinetics. New York–Basel: Marcel Dekker Inc, 1999: 491– 523. 158. Chu G, Mantin R, Shen Y-M, Baskett G, Sussman H. Massive cisplatin overdose by accidental substitution for carboplatin. Cancer 1993; 72: 3707–14. 159. Neef C, De Voogd-Van der Straaten I. An interaction between cytostatics and anticonvulsant drugs. Clin Pharmacol Ther 1988; 43; 372–5. 160. Dofferhoff ASM, Berendson HH. Decreased phenytoin level after carboplatin treatment. Am J Med 1990; 89: 247–8. 161. Dodds HM, Bishop JF, Rivory LP. More about: irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin. J Natl Cancer Inst 1999; 91: 91–2. 162. Beijnen JH, Vlasveld LT, Wanders J, Ten Bokkel Huinink WW, Rodenhuis S. Effect of cisplatin containing chemotherapy on lithium serum concentrations. Ann Pharmacother 1992; 26: 488–90. 163. Haas A, Anderson L, Lad T. The influence of aminoglycosides on the nephrotoxicity of cisdiamminedichloroplatinum in cancer patients. J Infect Dis 1983; 147: 363. 164. Sleijfer S, Van der Mark TW, SchraffordtKoops H, Mulder NH. Enhanced effects of bleomycin on pulmonary function disturbances in patients with decreased renal function due to cisplatin. Eur J Cancer 1996; 32A: 550–2. 165. Rowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow LB, Forastiere AA, Ettinger DS, Lubejko BG, Clark B, Sartorius SE, Cornblath DR,

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Hendricks CB, Donehower RC. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 1991; 9; 1692–703. 166. Jekunen AP, Christen RD, Shalinsky DR, Howell SB. Synergistic interaction between cisplatin and taxol in human ovarian carcinoma cells in vitro. Br J Cancer 1994; 69; 299–306. 167. Vanhoefer U, Harstrick A, Wilke H, Schleucher N, Walles H, Schröder J, Seeber S. Schedule-dependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro. Eur J Cancer 1995; 31A; 92–7. 168. Sonnichsen DS, Relling MV. Clinical pharmacokinetics of paclitaxel. Clin Pharmacokinet 1994; 27; 256–69. 169. Baker AF, Dorr RT. Drug interactions with the taxanes: clinical implications. Cancer Treatment Rev 2001; 27; 221–33. 170. Safra T, Groshen S, Jeffers S, Tsao-Wel D, Zhou L, Muderspach L, Roman, L, Morrow C, Burnett A, Muggia FM. Treatment of patients with ovarian carcinoma with pegylated liposomal doxorubicin. Cancer 2001; 91: 90–100. 171. Cardoso F, Ferreira Filho A, Crown J, Dolci S, Paesmans M, Riva A, Di Leo A, Piccart MJ. Doxorubicin followed by docetaxel versus docetaxel followed by doxorubicin in the adjuvant treatment of node positive breast cancer: results of a feasibility study. Anticancer Res 2001; 21: 789–95. 172. Sloan JA, Goldberg RM, Sargent DJ, VargasChanes D, Nair S, Cha SS, Novotny PJ, Poon MA, O’Connell MJ, Loprinzi CL. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 2002; 20; 1491–8. 173. Jodrell DI, Stewart M, Aird R, Knowles G, Bowman A, Wall L, Cummings J, McLean C. 5-Fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer. Br J Cancer 2001; 84: 600–3. 174. Mayers C, Panzarella T, Tannock IF. Analysis of the prognostic effects of inclusion in a clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma. Cancer 2001; 91: 2246–57. 175. Wassmuth R, Lentzsch S, Erdbruegger U, Schulz-Menger J, Doerken B, Dietz R, Friedrich MG. Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging—a pilot study. Am Heart J 2001; 141: 1007–13. 176. Zambetti M, Moliterni A, Materazzo C, Sefanelli M, Cipriani S, Valagussa P, Bonadonna G, Gianni L. Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol 2001; 19: 37–43. 177. Bilgrami SFA, Metersky ML, McNally D, Naqvi BH, Kapur D, Raible D, Bona RD, Edwards RL, Feingold JM, Clive JM, Tutschka PJ. Idiopathic pneumonia syndrome following myeloablative chemotherapy and autologous transplantation Ann Pharmacother 2001; 35: 196–201.

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178. Somlo G, Doroshow JH, Synold T, Longmate J, Reardon D, Chow W, Forman SJ, Leong LA, Margolin KA, Morgan RJ Jr, Raschko JW, Shibata SI, Tetef ML, Yen Y, Kogut N, Schriber J, Alvarnas J. High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome. Br J Cancer 2001; 84: 1591–8. 179. Herrlinger U, Schabet M, Brugger W, Kortman R-D, Kanz L, Bamberg M, Dichgans J, Weller M. Primary central nervous system lymphoma 1991– 1997. Outcome and late adverse effects after combined modality treatment. Cancer 2001; 91: 130–5. 180. Kelly WK, Curley T, Slovin S, Heller G, McCaffrey J, Bajorin D, Ciolino A, Regan K, Schwartz M, Kantoff P, George D, Oh W, Smith M, Kaufman D, Small EJ, Schwartz L, Larson S, Tong W, Scher H. Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer. J Clin Oncol 2001; 19: 44–53. 181. Halonen P, Salo MK, Makipernaa A. Fasting hypoglycemia is common during maintenance therapy for childhood acute lymphoblastic leukemia. J Pediatr 2001; 138: 428–31. 182. Douillard JY, Lerouge D, Monnier A, Bennouna J, Haller AM, Sun XS, Assouline D, Grau B, Rivière A. Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: a multicentre phase II study. Br J Cancer 2001; 87: 1179–84. 183. Ando M, Watanabe T, Nagata K, Narabayashi M, Adachi I, Katsumata N. Efficacy of docetaxel 60 mg/m2 in patients with metastatic breast cancer according to the status of anthracycline resistance. J Clin Oncol 2001; 19: 336–42. 184. Vaiopoulos G, Terpos E, Viniou N, Nodaros K, Rombos J, Loukopoula D. Behçet’s disease in a patient with chronic myelogenous leukemia under hydroxyurea treatment: a case report and review of the literature. Am J Hematol 2001; 66: 57–8. 185. O’Branski EE, Ware RE, Prose NS, Kinney TR. Skin and nail changes in children with sickle cell anemia receiving hydroxyurea therapy. J Am Acad Dermatol 2001; 44: 859–61. 186. Chaine B, Neonato M-G, Girot R, Aractingi S. Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease. Arch Dermatol 2001; 137: 467–70. 187. Vassallo C, Passamonti F, Merante S, Ardigo M, Nolli G, Mangiacavalli S, Borroni G. Mucocutaneous changes during long-term therapy with hydroxyurea in chronic myeloid leukaemia. Clin Exp Dermatol 2001; 26: 141–8. 188. Kiratli BJ, Srinivas S, Perkash I, Terris MK. Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer. Urology 2001; 57: 127–32. 189. Marttuene MB, Cacciatore B, Hietanen P, Pyrhonen S, Tiitinen A, Wahistrom T, Ylikorkala

511 O. Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women. Br J Cancer 2001; 84: 897–902. 190. Vieira Pinheiro JP, Muller HJ, Schwabe D, Gunkel M, Casimiro da Palma J, Henze G, Von Schutz V, Winkelhorst M, Wurthwein G, Boos J. Drug monitoring of low-dose PEG-asparaginase (Oncaspar™) in children with relapsed acute lymphoblastic leukaemia. Br J Haematol 2001; 113: 115–19. 191. Hancock BW, Gregory WM, Cullen MH, Vaughan-Hudson G, Burton A, Selby P, Maclennan KA, Jack A, Bessell EM, Smith P, Linch DC, on behalf of the British National Lymphoma Investigation and Central Lymphoma Group. ChiVPP alternating with PABIOE is superior to PABIOE alone in the initial treatment of advanced Hodgkin’s disease: results of a British National Lymphoma Investigation/Central Lymphoma Group randomized controlled trial. Br J Cancer 2001; 84: 1293–300. 192. Titus-Ernstoff L, Hatch EE, Hoover RN, Palmer J, Greenberg ER, Ricker W, Kaufman R, Noller K, Herbst AL, Colton T, Hartge P. Longterm cancer risk in women given diethylstilbestrol (DES) during pregnancy. Br J Cancer 2001; 84: 126–33. 193. Kenny LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 2001; 91: 613–21. 194. Toft B. Toft Report. External enquiry into the adverse incident that occurred at Queen’s Medical Centre, Nottingham, 4 March, 2001. London: Department of Health, 2001. 195. NHS Executive. National guidance on the safe administration of intrathecal chemotherapy. HSC 2001: 022. 196. Fleischhack G, Reif S, Hasan C, Jaehde U, Hettmer S, Bode U. Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours. Br J Cancer 2001; 84: 1453–9. 197. Jaeckle KA, Phuphanich S, Van den Bent MJ, Aiken R, Batchelor T, Campbell T, Fulton D, Gilbert M, Heros D, Rogers L, O’Day SJ, Akerley W, Allen J, Baisdas S, Gertler SZ, Greenberg HS, LaFollette S, Lesser G, Mason W, Recht L, Wong E, Chamberlain MC, Cohn A, Glantz MJ, Gutheil JC, Maria B, Moots P, New P, Russell C, Shapiro W, Swinnen L, Howell SB. Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 2001; 84: 157–63. 198. Kehrer DFS, Sparreboom A, Verweij J, De Bruijn P, Nierop CA, Van de Schraaf J, Ruijgrok EJ, De Jonge MJA. Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 2001; 7: 1136–41.

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46

Radiological contrast agents

TYPES OF CONTRAST AGENTS Iodinated water soluble contrast agents are of four types: • High-osmolar ionic monomer (e.g. diatrizoate, iothalamate, metrizoate). • Low-osmolar ionic dimers (e.g. ioxaglate). • Low-osmolar non-ionic monomers (e.g. iopitridole, iohexol, iomeprole, iopamidole, iopromide, ioversol). • Iso-osmolar non-ionic dimer (e.g. iodixonal, iotrolan). They are mainly used intravascularly, but can also be injected into body cavities, particularly the low-osmolar contrast agents. The high-osmolar water-soluble contrast agent diatrizoate (Gastrografin) is suitable only for oral or rectal administration. Oil-based iodinated contrast agents, such as Lipiodol, are also available and can be used to outline the ducts of the salivary glands and the lacrimal ducts. Currently the low-osmolar contrast agents are routinely used for these applications. There are also contrast agents that enhance the diagnostic information provided by ultrasound scanning and magnetic resonance imaging. The latter are mainly based on gadolinium, but new non-gadolinium paramagnetic contrast agents have recently become available. Ultrasound contrast agents are microbubbles that provide acoustic enhancement. Liposomal contrast agents have recently been developed, mainly for hepatic CT imaging. They are not yet available for routine clinical use and their safety is currently being evaluated. Adverse reactions to contrast agents are generally few, and serious reactions are uncommon. Ultrasound contrast agents are particularly safe.

© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

512

INTRAVASCULAR IODINATED CONTRAST AGENTS Water-soluble iodinated contrast agents for intravascular use (SEDA-23, 494; SEDA-24, 519; SEDA-25, 557) Adverse reactions to intravascular iodinated contrast agents can be minor, intermediate, or severe and life-threatening. All types of reactions to low-osmolar contrast agents are five times less common than reactions to highosmolar contrast agents. There are no important differences in the safety profiles of low-osmolar non-ionic monomers (SEDA-25, 557). In a study from Taiwan the incidence of adverse reactions has been investigated in 28 364 patients after intravenous injection of contrast agents during intravenous urography and CT scanning (1CR ). There were adverse reactions in 495 patients (1.75%), including 467 patients of 20 260 (2.03%) examined with ionic contrast agents and 28 of 8076 patients (0.34%) examined with non-ionic contrast agents. The authors concluded that the risk of adverse reactions to non-ionic contrast agents is significantly lower than with ionic agents. Skin rashes, such as urticaria, were the most common adverse effects, followed by nausea and vomiting. Shock requiring cardiopulmonary resuscitation was rare and occurred in only six patients (0.02%); there were no deaths in this series. The safety of the non-ionic contrast agents has also been emphasized in a review from Germany, in which the authors documented a reduced risk of adverse drug reactions with nonionic contrast agents during interventional cardiology (2CR ). According to reports to the FDA, the incidence of lethal complications was 3.9% with ionic monomers, 6.39% with the ionic dimer ioxaglate, and 2.07% with non-ionic monomers. The authors also stated that nonionic contrast agents do not have thrombogenic

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potential, a previous concern; currently most authors would support this view (SEDA-22, 501; SEDA-23, 497). Adverse reactions to contrast agents have been linked to an in vivo interaction with enzymes involved in cholinergic activity. However, experimental results on this topic are conflicting. A study of the in vivo effects of the non-ionic monomer iohexol and the high-osmolar ionic monomer diatrizoate on human plasma acetylcholinesterase and butyrylcholinesterase has shown that both contrast agents significantly reduce the activities of these enzymes (3C ). The effect was more pronounced with iohexol, which has a lower incidence of adverse effects than diatrizoate. The significance of this observation is not certain, but activation of these enzymes is not likely to be important in mediating the adverse effects of contrast agents.

Delayed reactions to iodinated water-soluble contrast agents (SEDA-23, 495; SEDA-25, 558) Delayed contrast reactions usually occur after 1 hour but within 7 days of contrast injection. Several of the reported delayed adverse effects, such as headache, musculoskeletal pain, and flu-like symptoms, may not be caused by the contrast agents, but delayed allergic-like skin reactions are most likely to be. Delayed skin reactions tend to be commoner with non-ionic dimers than with other types of contrast agents (SEDA-22, 499). Delayed reactions are generally benign, but not always. The incidence of delayed adverse reactions has been investigated in 2001 patients who underwent cardiac angiography with either iopamidole 340 (a non-ionic monomer; n = 738, ages 22–88 years, mean dose 1.79 ml/kg), ioxaglate 320 (an ionic dimer; n = 644, ages 28–86 years, mean dose 1.8 ml/kg) or iodixanol 320 (a non-ionic dimer; n = 619, ages 26–85 years, mean dose 1.74 ml/kg) (4CR ). The authors considered reactions that occurred within 24 hours as early reactions and those that occurred after 24 h but within 1 week of the cardiac catheterization as late reactions. The incidences of early reactions

513 were 22% with ioxaglate, 8.8% with iopamidol, and 7.6% with iodixanol. The commonest early reactions were urticaria and nausea and vomiting, the respective incidences being 6.8% and 4.0% with ioxaglate, 0.8% and 1.0% with iopamidole, and 0.5% and 1.1% with iodixanol. A few patients developed sudden hypotension, 0.5% with iopamidole, 1.4% with ioxaglate, and 0.3% with iodixanol. Cardiac arrest occurred in two patients with iopamidole, three with ioxaglate, and one with iodixanol. The frequencies of delayed skin reactions, which were generally benign, were 12% with iodixanol, 4.3% with ioxaglate, and 4.2% with iopamidol. The authors concluded that selection of a contrast agent for diagnostic cardiac catheterization should take account of adverse effects. Iodixanol was the best tolerated agent in the early phase of the study, but it was associated with a higher incidence of delayed skin reactions. The authors did not consider that the skin reactions represented a contraindication to iodixanol, although patients should be advised of this particular adverse effect. Furthermore, no contrast agent was free from these effects. Ioxaglate was the least well tolerated agent in the early phase, with a much greater chance of causing nausea/vomiting and allergic reactions. Delayed adverse reactions to ioxaglate have been documented after coronary angiography with ioxaglate (5A ). • A 63-year-old housewife had an acute myocardial infarction. Diagnostic coronary angiography was performed with ioxaglate and repeated 1 week later. On the morning after she had intense shivering and generalized malaise, a temperature of 39.2◦ C, and hypotension. Several hours later she developed a non-pruritic maculopapular rash, starting on the face and extending within the next 48 hours to cover the entire body but sparing the mucous membranes. She had a mild eosinophilia (600 × 106 /l) with a raised erythrocyte sedimentation rate (52 mm at 1 hour). Her IgE concentration was raised at 1593 kU/l. Blood cultures were negative. The initial clinical impression was that she had sepsis and she was therefore given vancomycin, netilmicin, and cefotaxime (dosages not stated). She improved rapidly and the fever and the rash resolved completely. She was discharged taking atenolol 100 mg/day and lysine acetylsalicylate 250 mg/day, but 3 days later she returned with a temperature of 39.8◦ C and recurrence of the skin rash. She had a marked eosinophilia (1.4 × 109 /l) and raised liver enzymes (AsT 125 IU/l, AlT 116 IU/l, alkaline phosphatase 374 mIU/l). Lactate dehydrogenase

514 (116 mU/ml) and aldolase (125 mU/ml) were raised, but creatine kinase was in the reference range. She had a significantly raised concentration of circulating immune complexes (107 mg/l; reference range below 25 mg/l). Her IgE was 1479 kU/l. Atenolol and lysine acetylsalicylate were withdrawn and she was given acenocoumarol 2 mg/day and amlodipine 5 mg/day. The inflammatory syndrome rapidly disappeared and the enzymes and eosinophil count returned to normal. She had immunological investigations 2 months later. The total IgE was still raised at 1649 kU/l. The leukocyte count and C reactive protein concentration were within the reference ranges. The serum antinuclear antibody titer was 1/256 and the antimitochondrial antibody titer was 1/128. Tests for anti-native DNA, antihistone, and antismooth muscle antibodies were negative. Skin prick tests, intradermal tests, and patch tests with lysine acetylsalicylate, atenolol, heparins, vancomycin, netilmicin, cefotaxime, and the contrast agents ioxaglate, sodium ioxathalamate, iopamidol, and iohexol were negative at 15 minutes, but at 48 hours indurated erythematous papules were observed with ioxaglate, ioxothalamate, and iopamidol. Histological examination of a biopsy from the ioxaglate skin reaction showed discrete spongiosis of the epidermis associated with slight lymphocytic exocytosis. The basal layer contained numerous apoptotic keratinocytes. The superficial dermis was edematous and there was a perivascular inflammatory infiltrate composed mainly of T lymphocytes. There were no mast cells or eosinophils. Immunohistological examination showed no staining with anti IgE, IgG, IgM, C1q, C3, or C4. During follow-up she was completely normal at up to 1 year, with a normal eosinophil count and an IgE concentration of 440 kU/l.

This report documents a rare clinical reaction to ioxaglate, with a combination of a maculopapular rash, fever, hepatic and muscle involvement, eosinophilia, and a very high serum IgE concentration. The intradermal tests confirmed a delayed hypersensitivity reaction to ioxaglate. Histological examination of a skin biopsy identified the predominantly T lymphocyte nature of the infiltrate. A contributing role of the beta-blocker atenolol to the seriousness of the clinical syndrome must also be considered. Delayed skin reactions after intravascular iodinated contrast agents have previously been documented and showed the features of true delayed hypersensitivity reactions with positive skin tests (SEDA-24, 523; SEDA-25, 561). Cardiovascular It is well established that low-osmolar contrast agents are in general bet-

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ter tolerated than high-osmolar ionic agents in cardiac and coronary angiography, and it has recently been suggested that the non-ionic iso-osmolar dimer iodixanol has minimal cardiotoxic effects (SEDA-25, 558). The safety of iodixanol 320 and iohexol 350 has been investigated in Swedish patients undergoing cardiac angiography for suspected coronary artery disease (6C ). Of 1020 patients, 502 aged 25–83 years received iohexol (median dose 105 ml, range 20–440) and 518 aged 18–85 years received iodixanol (median dose 115 ml, range 30–400). There were 134 patients with unstable angina in the iohexol group and 167 in the iodixanol group. Cardiac adverse events (angina pectoris, dysrhythmias, and dyspnea) within 24 hours of the examination were reported by 9% of the patients who received iohexol and 7% of patients who received iodixanol. There were two cases of ventricular fibrillation, both after iohexol. Cardiac adverse events in patients aged 65 years or more occurred in 11% with iohexol and 7% with iodixanol. The proportions of patients with unstable angina and cardiac adverse events were 18% with iohexol and 12% with iodixanol. The authors concluded that iodixanol could be advantageous in old patients and in those with unstable angina. Nervous system Transient cortical blindness is a well recognized complication of vertebral angiography (SEDA-23, 497; SEDA-24, 521; SEDA-25, 559). Now transient contrast encephalopathy has been reported after carotid artery stenting (7A ). • An 82-year-old right-handed man was given 50 ml of the ionic low-osmolar contrast agent ioxaglate 320 for carotid angiography. The next day his right internal carotid artery was stented and a total of 180 ml of ioxaglate was used. Aspirin, ticlopidine, and heparin 5000 units were given during the procedure. While he was still on the table he developed rapidly worsening confusion and a left hemiparesis. A CT scan without contrast 4 h later showed marked cortical enhancement and cerebral edema in the distribution of the right anterior and middle cerebral arteries. He rapidly improved and had complete neurological recovery after 48 hours; 1 month later he was asymptomatic.

The cerebral contrast enhancement on the CT scan suggested disruption of the blood– brain barrier. This could have been due to the large volume of contrast medium used during

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the stenting procedure. This complication must be differentiated from massive cerebral infarction and hyperperfusion syndrome: the rapid radiological resolution and clinical recovery excluded cerebral infarction; hyperperfusion syndrome would have involved the carotid distribution exclusively, rather than both the ipsilateral carotid and posterior circulations. The authors recommended close follow-up of patients after such procedures. The safety of subsequent cerebral angiography in a patient with a history of such a reaction has not been studied extensively, and extreme caution must be exercised should the need for repeat angiography arise later. Sensory systems A few cases of hearing impairment attributed to contrast agents have previously been reported. A case of severe sensorineural hearing loss after drip intravenous pyelography with iohexol has now been reported (8A ). • A 37-year-old man with recurrent attacks of low back pain underwent drip intravenous pyelography to exclude the possibility of stones of the urinary tract. Iohexol 300 was used, but the total volume was not documented. He had had drip intravenous pyelography for suspected urinary calculi 5 years before. A few hours after the procedure he suddenly had bilateral hearing loss and tinnitus in the right ear. He complained of dizziness and nausea but had no rotatory vertigo or skin rash. A puretone audiogram 2 days later showed complete right-sided and partial left-sided deafness. CT and MRI scans showed no abnormalities in the inner ear, internal auditory canal, or posterior fossa. He was given intravenous high-dose hydrocortisone sodium succinate, 10% dextran, and batroxobin, but there was no improvement in hearing. The dizziness and tinnitus in the right ear persisted, as did the deafness, for a further 2 months.

Hearing disturbances attributable to contrast agents are extremely rare. The hearing loss in this patient developed more than 1 hour after the injection of iohexol, without any evidence of other causes. The authors suggested that the hearing disturbance might have been attributable to cochlear impairment caused by a delayed allergic reaction or chemical toxicity of the contrast medium. Endocrine Hyperthyroidism and hypothyroidism have both reportedly been precipitated by iodinated contrast agents (SEDA-21, 478; SEDA-23, 497; SEDA-25, 559). Thyroid

515 metabolism has been prospectively investigated in 102 patients undergoing diagnostic coronary angiography (9C ). Thyroid function tests (T3 , rT3, T4 , free T4 , and TSH) and urinary iodine excretion were measured before and 3 weeks after diagnostic intra-arterial administration of iodinated contrast agents. Only euthyroid patients were included, in order to determine whether the administration of non-ionic iodinecontaining contrast agents causes significant thyroid function changes in euthyroid patients and whether thyroid morphology is a prognostic factor for the risk of hyperthyroidism. Serum concentrations of thyroid autoantibodies (TPO-Ab, Tg-Ab, TSH-receptor-Ab) were measured. Thyroid ultrasound showed that 37 patients had normal thyroid glands. The gland was of normal size but nodular in 16 patients, there was a diffuse goiter in 15 patients, and a nodular goitre in 34 patients. In 25 patients Tg-Ab was positive and in 13 patients TPO-Ab was positive; TSH-receptor-Ab was not detected in any patient. T3 concentrations did not change significantly after the administration of iodine. T4 and free T4 concentrations underwent significantly different changes in the four groups. The amount of iodine given did not affect the changes in the serum concentrations of TSH, T3 , T4 , free T4 , or rT3. Raised concentrations of urinary iodine correlated with the amount of contrast medium given. There were no cases of hyperthyroidism. The study showed that thyroid function was significantly altered after coronary angiography, independent of antibody status and the amount of contrast agent given, but dependent on thyroid morphology. Hematologic Iodinated water-soluble contrast agents have traditionally been contraindicated in patients with sickle cell disease, because of possible shrinkage of erythrocytes secondary to the high osmolality of these agents, which can lead to impaired blood flow through the microcirculation and can precipitate or exacerbate a sickle cell crisis. The hematological and rheological effects in vitro of four contrast agents of different osmolalities (iodixanol 290 mmol/kg, ioxaglate 600 mmol/kg, iohexol 844 mmol/kg, and diatrizoate 1940 mmol/kg) have been compared (10E ). Blood was tested from 10 healthy and 10 sickle cell donors at drug concentrations of

516 0, 1, 10, and 30% w/v in an attempt to approximate the circulating concentrations of contrast medium that might occur during bolus injection. There were significant hematological effects in the blood of both the healthy and sickle cell donors: there was a concentration-related reduction in hematocrit and MCV and an increase in MCHC, all of which varied directly with the osmolality of the contrast medium (diatrizoate > iohexol > ioxaglate > iodixanol). Only with diatrizoate at concentration of 10–30% was there marked echinocytosis. There was no significant increase in the number of irreversibly sickled cells in donors with hemoglobin S. The filterability of erythrocyte suspensions through capillary sized pores was impaired in both healthy and sickle cell samples in direct proportion to the osmolality of the contrast medium. Filterability effects were greater with sickle cells than healthy erythrocytes. Iodixanol, which is iso-osmolar with blood, had little effect on erythrocyte volume and had no significant effect on the filterability of healthy or sickle cells. These results suggest that microcirculatory impairment after infusion of contrast agents can occur in sickle cell disease because of the unusual rheological sensitivity of HbSS erythrocytes and may be avoided by using low-osmolar or iso-osmolar contrast agents. In another study the effects of contrast agents on leukocytes, platelets, and endothelium have been investigated in 19 subjects (mean age 63 years) undergoing angiography with the non-ionic contrast medium iohexol 350 (median volume 40–160 ml) for leg ischemia (11c ). Blood was obtained from the external iliac vein before and at several intervals after the injection of the contrast agent into the ipsilateral femoral artery. Markers of endothelial cell injury (von Willebrand factor), platelet activation (soluble P-selectin), and leukocyte activation (neutrophil elastase and soluble L-selectin) were measured in citrated plasma. Soluble intracellular adhesion molecule-1 and thromboxane B2, which are non-specific markers of inflammation, were also measured. Compared with the sample before angiography, concentrations of soluble L-selectin and soluble intracellular adhesion molecule-1 were reduced immediately after passage of the last bolus of contrast medium; 15 min later the concentrations returned to normal, but the concentration

Chapter 46

Sameh K. Morcos

of von Willebrand factor had increased. After 30 minutes only thromboxane B2 concentrations were increased. On the next day both von Willebrand factor and soluble P-selectin were increased. These data point to both early and late effects of contrast agents on markers of endothelial, platelet, and leukocyte function. The authors suggested that these adverse changes may increase the risk of coagulopathy and thrombosis after contrast examination and increase the risk of re-stenosis after angioplasty. Gastrointestinal Iodinated water-soluble contrast agents can be used for imaging the gastrointestinal tract, particularly when leakage from the bowel lumen is suspected. The use of the high-osmolar sodium diatrizoate (Gastrografin) as an agent for pre-operative mechanical bowel preparation has been investigated in 58 patients (aged 45–80 years) listed for elective colorectal operations (12C ). One group (30 patients, mean age 67 years) was given oral Gastrografin 200 ml and 3 liters of water for 2 days before the operation. The rest (28 patients, mean age 65 years) were given Ringer’s solution 5–20 l, warmed to body temperature, through a nasogastric tube; preparation was considered complete when the patient excreted clear fluid. All were given metronidazole and cefuroxime as antibiotic prophylaxis during the perioperative period. There were no significant adverse effects in the Gastrografin group, apart from nausea in six patients. In the Ringer’s solution group there was nausea in 15 patients and vomiting in eight. A clean colon was found at operation in 93% of patients in both groups. The authors concluded that Gastrografin is well tolerated and can be used successfully for mechanical bowel preparation before elective colorectal surgery. The rectal administration of Gastrografin 400–1000 ml in patients with suspected diverticulitis before CT examination of the abdomen has been investigated in 308 patients (aged 19–97 years) (13C ). None of the CT scans showed extravasated contrast material in the peritoneal cavity as a sign of bowel perforation. No patient had sudden clinical deterioration after the examination. All tolerated the contrast medium well and there were no allergic reactions. High-quality diagnostic examinations were obtained in all patients.

Radiological contrast agents

Chapter 46

Urinary tract Renal insufficiency induced by contrast agents remains a source of concern. The renal effects of low-osmolar contrast agents (iopromide, ioversole, and ioxaglate) have been evaluated in 45 patients who underwent cardiac angiography (14C ). Iopromide (370 mg I/ml, mean dose 1.9 g/kg) was used in 15 patients (mean age 62 years, mean serum creatinine 107 µmol/l, mean creatinine clearance 67 ml/min), ioversole (320 mg I/ml, mean dose 1.8 g/kg) in 15 patients (mean age 62 years, mean serum creatinine 103 µmol/l, mean creatinine clearance 71 ml/min), and ioxaglate (320 mg I/ml, mean dose 1.8 g/kg) in 15 patients (mean age 63 years, mean serum creatinine 100 µmol/l, mean creatinine clearance 71 ml/min). All were normally hydrated and none had been examined with contrast agents in the months before the study or had been treated with nephrotoxic drugs. There were minor increases in serum creatinine 24 h after ioversole (from 103 to 107 µmol/l) and ioxaglate (from 100 to 106 µmol/l) and at 48 hours after iopromide (from 107 to 115 µmol/l). Plasma concentrations of beta2 microglobulin increased only with ioxaglate (from 1.9 to 2.0 mg/l at 24 hours). There was a reduction in creatinine clearance from 71 to 55 ml/min only with ioxaglate 6 h after the administration, but it returned to baseline 24 hours later. There were no significant variations in creatinine clearance at 48 hours after angiography. There were increases in the activities of different tubular enzymes in the urine after angiography with all the contrast agents, but the changes were larger after ioxaglate. The tubular effects were maximum at 6–24 hours and returned to baseline within 72 hours after angiography. In summary all three low-osmolar contrast agents caused reversible tubular damage, indicated by increased enzymuria, which was higher after ioxaglate. In addition, ioxaglate slightly impaired glomerular function. None of the observed changes in renal function were clinically relevant and they were not statistically significant. In summary, none of the three low-osmolar contrast agents caused significant changes in renal function. However, the authors suggested that ioxaglate is probably more nephrotoxic than non-ionic monomeric agents, and that other physicochemical properties beside osmolality play a role in nephrotoxicity due to contrast agents.

517 Acute reduction in renal perfusion is considered important in the pathophysiology of contrast agent-induced nephrotoxicity. Colorcoded duplex sonography has been used in assessing intrarenal vascular resistance in 10 patients (mean age 51 years) after intravenous injection of 100 ml of the low-osmolar contrast medium iopamidole (300 mg I/ml) (15C ). The resistive index was measured at 1 minute intervals over 10 minutes after injection in each patient. There was a statistically significant rise in resistive index at 2, 3, 4, and 5 minutes after injection, mean values 0.74, 0.75, 0.72, and 0.75 respectively. The resistive index then fell progressively to baseline values (mean 0.70) within 10 minutes. The authors concluded that colorcoded duplex sonography is a simple method for checking changes in renal flow resistance after intravascular contrast agents. They suggested that arterial Doppler flow measurement is ideal for investigating the pathophysiological mechanism of contrast agent-induced nephrotoxicity. The pharmacokinetics and safety of the lowosmolar non-ionic contrast agent iomeprole have been investigated in healthy volunteers and patients with various degrees of renal impairment (16C ). Six patients had normal renal function (glomerular filtration rate over 100 ml/min, aged 22–58 years), six had mild renal impairment (glomerular filtration rate 51–75 ml/min, aged 36–74 years), six had moderate renal insufficiency (glomerular filtration rate 26–50 ml/min, aged 58–79 years), and four had severe renal impairment (glomerular filtration rate below 25 ml/min; aged 34–73 years). Eight patients (aged 24–62 years) with end-stage renal disease who were receiving chronic hemodialysis were also studied. All received a single intravenous 50-ml bolus injection of iomeprole 400 mg I/ml and dialysis was performed about 2 hours later. The halflife of iomeprol increased progressively with increasing renal impairment. The half-life was 2 hours in patients with normal renal function, 4–6 hours in those with mild renal impairment, and 16–48 hours in those with severe renal impairment. Fecal excretion over 120 h ranged from 1.6% of the total dose in healthy subjects to 7.2% in those with severe renal impairment. Thus, the pharmacokinetics of iomeprole are similar to those of other water-soluble contrast agents.

518 In patients receiving hemodialysis the mean plasma iomeprole concentration fell by 36% at 2 hours after administration when hemodialysis was started. The mean half-life on dialysis was 4.4 hours. The effective fall in plasma iomeprole concentration after a single dialysis was about 70%. The mean fraction of the dose recovered in the dialysate was 58%. The mean dialysis clearance was 81 ml/min. The extraction efficiency of the dialyser was about 40%. The only adverse effect was infection of an arteriovenous fistula in a patient with end-stage renal disease, which was unrelated to the contrast agent. There were also mild to moderate adverse effects, but all resolved without sequelae. The most common adverse effects were headaches and sensations of warmth. Others were paresthesia, abdominal pain, taste disturbance, and nausea. None of the events was considered to be clinically important. There were no clinically important changes in vital signs, physical examination, electrocardiography, or clinical laboratory evaluations. The authors concluded that iomeprole is safe and well tolerated and can be almost completely eliminated both in patients with renal impairment and in patients receiving dialysis. The use of hemodialysis immediately after intravascular administration of contrast agents to prevent the development of nephrotoxicity in patients with renal impairment has been investigated in 15 patients with a mean serum creatinine of 234 µmol/l before contrast injection (17c ). The patients were randomized to receive either conservative treatment or hemodialysis for 2–3 hours, starting as early as possible (mean 106 minutes) after administration of the contrast agent. The increase in serum creatinine on days 2 and 3 after contrast injection was higher in the dialysed group. The incidence of nephrotoxicity, defined as an increase in serum creatinine by more than 44 µmol/l within 48 hours after administration of the contrast agent, was significantly higher in the dialysed group (43% versus 13%). The authors concluded that hemodialysis performed within 2 hours after contrast injection did not prevent the development of nephrotoxicity in patients with reduced renal function; indeed, it seems to have made things worse.

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Sameh K. Morcos

The use of prophylactic hemodialysis, in most cases starting more than 20 minutes after injection of a contrast agent, has been investigated in 113 patients with renal insufficiency (serum creatinine concentration over 200 µmol/l) (18C ). Hemodialysis did not reduce the incidence of contrast nephrotoxicity. This failure could have been related to the rapid onset of renal injury after the administration of the contrast agent. Skin Delayed skin reactions after intravascular administration of contrast agents have previously been reported (SEDA-24, 523; SEDA-25, 561). There has now been a report of toxic epidermal necrolysis after intravenous injection of the non-ionic monomer iohexol (19A ). • A 33-year-old man had three contrast-enhanced CT scans with iohexol over about 2 weeks, and developed a disseminated erythematous skin rash. Because drug allergy was suspected, all drugs were withdrawn. Because of a persistent fever a fourth CT scan was performed with iohexol, and 2 hours later he developed malaise, pruritic erythema, hypotension, and cutaneous bullae affecting 50% of his body surface and his oral mucosa. He was treated for toxic epidermal necrolysis and his skin healed without scarring or altered pigmentation. Skin patch tests, prick tests, intradermal tests, and intravenous and oral single-blind challenges with the antibiotics he had received were negative. However, a patch test with iohexol 300 mg I/ml was positive at 48 hours: erythema and multiple small flaking blisters appeared in the patch area. Identical patch tests in healthy controls were negative.

The authors concluded that the patient had had a delayed hypersensitivity reaction to iohexol, causing toxic epidermal necrolysis. Oil-based contrast agents have been used regularly in the past for sialography and dacrocystography. Extravasation of these contrast agents can cause lipogranuloma formation (20A ). • A four-year-old boy with epiphora had a left dacrocystogram with the iodinized oil-based contrast agent Lipiodol under general anesthesia. During injection a false passage was inadvertently formed, with extravasation of the contrast agent from the lacrimal duct into the surrounding tissues. This was confirmed radiographically. He developed swelling and erythema, which gradually resolved over 6 months.

Currently, iso-osmolar non-ionic dimers, such as iotrolan or iodixanol, are the safest contrast

Radiological contrast agents

Chapter 46

agents for such a procedure. Extravasation of these agents causes minimal tissue reaction. Immunologic French workers investigating the causes of severe reactions to iodinated contrast agents suggested that any patient who has had a severe anaphylactoid or anaphylactic reaction after the injection of a contrast agent should undergo immunological assessment (21CR ). The diagnosis of drug anaphylaxis is usually based on the history, proof of mediator release, and the presence of drug-specific IgE antibodies or positive skin tests. In five patients with severe anaphylactoid reactions after the intravascular injection of an iodinated contrast agent, the clinical symptoms, biology, and skin tests were consistent with anaphylaxis. The authors also reported that no premedication has proved effective in preventing subsequent allergic reactions to contrast agents. Drug formulations There are several new formulations of liposome-encapsulated iodinated contrast agents under evaluation, particularly for liver imaging by CT (SEDA-25, 561). A new formulation of liposome-encapsulated iodixanol has been evaluated as part of a phase 1 assessment of diagnostic efficacy and safety (22C ). The formulation is a ready-to-use suspension of multilamellar liposomes with a mean size of 340 nm. The main constituents of the liposome wall are phosphatidylcholine and phosphatidylserine. The concentration of iodixanol in the formulation is 200 mg I/ml (80 mg encapsulated I/ml). The encapsulated iodine to lipid ratio is 1 : 5. This new formulation was injected in doses of 10, 30, 70, and 100 mg of encapsulated I/kg in 5, 8, 8, and 8 healthy volunteers (mean age 30 years). Saline was given to two volunteers in each dose group, in a volume matching that of iodixanol at the 70 mg dose. The intravenous injection was carried out using a power injector at a rate of 2 ml/s. There were dose-dependent changes in leukocyte counts. During the first 2 hours the leukocyte count fell and then rose. At 10 and 30 mg doses the changes were small and in most of the volunteers did not exceed the reference range. At higher doses there was a prominent increase in neutrophils with rod-shaped nuclei, suggesting increased release from the bone-marrow. C-reactive protein also rose dosedependently, suggesting a cytokine-mediated

519 reaction. Leukocyte count and C-reactive protein normalized spontaneously after 24 hours. The volunteers had subjective adverse events at doses of 70 and 100 mg; these included chills (88%), back pain (25%), flu-like symptoms (13%), and nausea and vomiting (38%); they started within 1 hour and recovered spontaneously within 3 hours. No adverse events were interpreted as severe, but they were judged to be too pronounced to be clinically acceptable. Research is needed to find a formulation that causes fewer adverse events without compromising diagnostic quality. Another new hepatocyte-specific contrast formulation, dysprosium-ethoxybenzyltris(carboxylatomethyl)triazaundecanedioic acid-diethylenetriaminepenta-acetic acid (Dy-EOBDTPA), has been used for liver CT imaging (23C ). It contains calcium-EOB-DTPA (0.5 mg/ml), trometamol (1.2 mg/ml), and hydrochloric acid (final pH 7.4). It has been described as a stable metal chelate with high tolerability in vitro and in animal studies, in which a long-lasting increase in CT density of about 30 Hounsfield units has been reported. A total of 40 healthy male volunteers (mean age 33 years) received intravenous infusions of Dy-EOB-DTPA, 0.05, 0.1, 0.25, 0.375, or 0.5 mmol/kg over 10 minutes (n = 6 in each group), or placebo (n = 2 in each group). There were adverse effects in four of the 10 patients who were given placebo and 22 of the 30 who were given Dy-EOB-DTPA. The most common adverse events were nausea (25%), headache (18%), paresthesia (15%), loss of appetite, allergic reactions, back pain, and injection site hemorrhage (7.5%). The adverse effects were generally mild or moderate, but there was a slight increase in intensity at the higher doses. There were gastrointestinal adverse events in all six of the volunteers who received 0.5 mmol/kg. Nausea was the longest lasting and in one case it was severe. The results of laboratory tests did not exceed the reference ranges. Vital signs, hemodynamic parameters, and electrocardiography were not affected by the contrast agent. Over 50% of the adverse events were considered to be unrelated to the drug. The authors concluded that this liverspecific contrast formulation has a good safety profile.

520

Chapter 46

MRI CONTRAST AGENTS Gadolinium

(SEDA-24, 256; SEDA-25,

562) Adverse events associated with the non-ionic gadolinium-based contrast agent gadodiamide have been reported in 1–2% of patients. Most of the commonly reported adverse events have been headache, dizziness, or nausea and vomiting. The safety and effectiveness of gadodiamideenhanced magnetic resonance angiography (MRA) with single and triple doses in the assessment of abdominal arterial stenosis has been investigated in 105 patients, of whom 53 (aged 45–83 years) received 0.1 mmol/kg and 52 (aged 38–85 years) received 0.3 mmol/kg (24C ). There were no serious adverse events. Six patients in the single-dose group felt a sensation of heat or warmth in the abdomen, lumbar spine, upper legs, hips, or groin; five of these events were mild and one was moderate; one patient felt a mild cold sensation at the injection site. Six patients in the triple-dose group felt a warm discomfort in the abdomen, pelvis, or buttocks (two mild and four moderate); four other patients felt a cold sensation at the injection site or in the arm (three mild and one moderate). The authors concluded that gadodiamide-enhanced MRA performed with single and triple doses is safe and effective in assessing major abdominal arterial stenosis. Triple-dose MRA was better at evaluating image quality and the degree of arterial stenosis. The safety of gadodiamide-enhanced MRI in staging suspected or recurrent soft tissue tumors of the head and neck has been investigated in 48 patients (aged 37–86) (25C ). There was only one adverse event, moderate thirst. The authors concluded that the use of gadodiamide for MRI contrast-enhanced examination of the head and neck is safe and provides more diagnostic information than unenhanced images. Gadobenate dimeglumine (Multihance, Gd-BOPTA) is a new gadolinium-based contrast agent that has been approved for MRI contrast enhancement of the central nervous system and liver. It is eliminated from the body by renal and hepatobiliary excretion. It binds weakly to serum albumin, and has an in vivo T1 relaxivity that approaches twice that of the conventional extracellular gadolinium chelates

Sameh K. Morcos

used as MRI contrast agents. The safety of gadobenate dimeglumine has been evaluated in 2367 adults aged 18–88 years and 173 children. The overall incidence of adverse events was 20%. Events related to the contrast agent were reported in 15% of the adults. Most of the adverse events were mild and transient and resolved spontaneously. Headache, injection site reactions, nausea, taste disturbance, and vasodilatation were the most common, with frequencies of 1–2.6%. Serious adverse events potentially related to the contrast agent were reported in 0.2%. These events included laryngospasm, which developed 10 minutes after the contrast injection in a 51-year-old woman, severe vomiting in a 5-year-old child, and pulmonary edema in a 65-year-old patient. In controlled studies gadobenate dimeglumine has been compared with gadolinium chelates in 222 patients and with placebo in 189 patients (26C ). There were no serious events and no differences in the incidence of adverse effects between the groups. Adverse effects included vomiting, dizziness, and rashes. Similarly, there were no differences between children and adults or between subjects with renal or liver insufficiency. The authors concluded that gadobenate dimeglumine is safe, with a very low incidence of serious events, and that it compares favorably with other MR contrast agents, such as gadolinium DTPA. Gadobenate dimeglumine, in cumulative doses of 0.15 and 0.2 mmol/kg, has been compared with gadodiamide (Omniscan) 0.3 mmol/kg in 205 patients (aged 20–88 years) with suspected central nervous system lesions (27C ). Gadobenate dimeglumine was well tolerated and the safety profile was similar to that observed with gadodiamide. In the three groups adverse effects occurred in 28%, 23%, and 32% respectively. The most common adverse events of gadobenate dimeglumine were headache (16%), dizziness (4.6%), and taste disturbances (4.6%); the most common adverse events of gadodiamide were headache (7.2%), nausea (5.8%), and taste disturbances (5.8%). All adverse events were classified as mild to moderate. There were no significant changes in vital signs, hematology, or serum chemistry in any group. There were no significant differences in the diagnostic quality of the examination.

Radiological contrast agents

Chapter 46

MS-325 is an intravascular MRI contrast agent that binds strongly but reversibly to human serum albumin in plasma (28C ). Because of albumin binding it has a long half-life and increased relaxivity. These properties are particularly useful for contrast-enhanced threedimensional MRA. The safety and diagnostic efficacy of MS-325 in MRA of the carotid arteries has been investigated in 26 patients aged 42–81 years with suspected carotid artery stenosis. It was given intravenously to 4, 9, and 13 patients in single doses of 0.01, 0.03, or 0.05 mmol/kg respectively. There were no serious or severe adverse events. Two patients who received 0.05 mmol/kg had five adverse events within 3 h after the injection (nausea, cramps, metallic taste, and pruritus), which were rated as mild. There were no significant changes in serum chemistry. High-quality MRA scans were obtained in all the patients. Pancreas Although several studies have shown that intravascular gadolinium-based contrast agents have favorable safety profiles in patients with renal insufficiency, severe adverse reactions can still occur, even with standard doses (maximum 0.3 mmol/kg). Acute pancreatitis with acute renal insufficiency complicating angiography with a gadolinium-based contrast agent has been reported (29A ). • A 68-year-old woman with long-standing peripheral vascular disease and chronic renal insufficiency (serum creatinine 334 µmol/l) had peripheral angiography with gadodiamide (dose not stated) and 6 hours later developed nausea, epigastric pain, and two episodes of vomiting, with further epigastric pain 5 hours later. Her serum amylase and lipase activities were 246 U/l and 1314 U/l respectively (reference ranges 0–140 and 0–200 U/l). The next morning they were 684 U/l and 1646 U/l respectively. Ultrasound scan of the liver and gallbladder was normal. She subsequently developed acute renal insufficiency, electrolyte imbalance, and pulmonary edema. Urine microscopy showed muddy brown casts consistent with acute tubular necrosis. Her pancreatitis resolved without any further complications.

The authors highlighted the fact that there is no recommended maximum safe dose of gadolinium, nor a minimum creatinine clearance below which gadolinium should not be used. Urinary tract Although the use of gadolinium-based contrast agents in patients with a

521 history of serious adverse reactions to iodinated contrast agents seems to be reasonable, these agents can be nephrotoxic in doses over 0.3 mmol/kg. Several reports have unwisely recommended them as alternatives to iodinated contrast agents in patients with renal impairment (SEDA-25, 563). Intravenous gadoterate meglumine 35 ml has been used as a contrast agent for arm venography using digital fluorography in 45 patients with end-stage renal insufficiency (age 26–88 years, serum creatinine 262–1360 µmol/l) before the creation of an arteriovenous fistula (30C ). The mean serum creatinine did not change significantly. There were no significant adverse effects. Only one patient developed vomiting. A good diagnostic examination was obtained in all cases. The use of gadolinium as a contrast agent has been described in a patient with chronic renal insufficiency who required a stent for an infrarenal aortic aneurysm (31A ). • A 64-year-old obese man with a history of radiocontrast-induced nephropathy had an MRI scan, which confirmed the presence of an aortic aneurysm from just below the renal arteries to the aortic bifurcation. Percutaneous stenting of the aortic aneurysm was carried out with 0.5 mol/l gadoteridol solution 90 ml (0.375 mmol/kg) instead of an iodinated contrast agent. There was no further deterioration in renal function.

The authors erroneously concluded that gadolinium-containing contrast agents are not nephrotoxic, and they recommended their use in patients in whom conventional iodinated contrast agents are contraindicated. However, gadolinium-based contrast agents have more nephrotoxic potential than iodinated contrast agents in equimolar concentrations. Their use in patients with renal impairment should be carried out with care and the dosage should not exceed 0.3 mmol/kg. The use of a gadolinium-based contrast agent for renal angiography has been described in France (32A ). • A 67-year-old woman with chronic renal insufficiency secondary to interstitial nephritis had rapid deterioration over several months, with a rise in serum creatinine from 150 to 290 µmol/l. Renal artery stenosis was suspected. She had anaphylaxis during spiral CT angiography with an iodinated contrast medium (details not given), which showed right renal artery stenosis. After further

522 deterioration in renal function (serum creatinine 480 µmol/l) she underwent renal arteriography with 30 ml of a gadolinium-based contrast agent (0.3 mmol/kg) injected into the abdominal aorta just above the renal arteries. Her renal function was monitored for 15 days after the procedure, and there was no further rise in serum creatinine.

There is still misunderstanding about the nephrotoxic potential of gadolinium-based contrast agents. They should not replace iodinated contrast agents in patients with renal insufficiency. The recommended doses of up to 0.3 mmol/kg will not give satisfactory radiographic diagnostic information in most cases. In addition, gadolinium-based contrast agents are not licensed for radiography. Immunologic The use of gadolinium-based contrast agents as an alternative to iodinated contrast agents has been reported in a patient with a history of allergy to the latter (33A ). • A 77-year-old woman had a gadolinium-enhanced MRI scan followed by gadolinium-enhanced spiral CT pulmonary angiography for suspected pulmonary embolism. Gadodiamide 0.4 mmol/kg (60 ml) was injected intravenously at a rate of 2 ml/s. There were no adverse reactions.

Chapter 46

Sameh K. Morcos

hyperplasia (one patient) (34C ). The dose of iron was 6–11.7 µmol/kg. Patients under 60 kg received 0.9 ml as a bolus intravenous injection and patients over 60 kg received 1.4 ml. None of the 19 patients reported any pain or discomfort at the injection site. One had a diffuse erythematous rash associated with a feeling of pressure in the thorax, which lasted for 30 minutes. There was a significant increase in systolic blood pressure (from 137 to 141 mmHg) 5 minutes after injection; it returned to normal within 4 hours. There was a statistically significant fall in diastolic blood pressure from 75 to 70 mmHg at 4 hours after the injection. These changes were not considered to be of clinical importance. There were also minimal changes in the results of blood tests, which were not of clinical importance. High-quality diagnostic information was provided by the MRI examination.

ULTRASOUND CONTRAST AGENTS (SEDA-23, 501; SEDA-24, 529; SEDA-25, 564)

Optison SUPERPARAMAGNETIC IRON OXIDE PARTICLES (SPIO) MRI CONTRAST AGENTS (SEDA-25, 564) SH U 555 A (Resovist) is a new contrast agent that consists of iron oxide microparticles coated with carboxydextran. After intravenous injection it is sequestered by the reticuloendothelial system, mostly in the liver and spleen. MRI iron oxide causes loss of signal intensity, especially on T1 and T2 weighted images and the contrast between the lesions and the surrounding tissues is increased owing to loss of signal in the healthy tissues. The diagnostic efficacy and safety of SH U 555 A has been investigated in 19 patients aged 43–89 years who had been referred for investigation of hepatocellular carcinoma (eight patients), liver metastases (four patients), liver hemangioma (four patients), cholangiocarcinoma (two patients), and focal nodular

Optison is a second-generation ultrasound contrast agent based on sonicated human albumin. Its safety has been demonstrated in previous studies (SEDA-25, 565). In 50 patients (mean age 59 years) in an intensive care unit who underwent echocardiography examination with intravenous Optison (dose 0.5–1.5 ml), there were no contrastrelated adverse effects (35C ). Good quality echocardiography was obtained in all cases.

Sono Vue

(SEDA-25, 565)

Sono Vue is an ultrasound contrast agent that consists of microbubbles containing sulfur hexafluoride gas stabilized by phospholipids. Its safety has been demonstrated in previous studies (SEDA-25, 565). The safety of Sono Vue as an intravenous bolus injection of 0.3, 0.6, 1.2, or 2.4 ml in

Radiological contrast agents

Chapter 46

transcranial Doppler examination of the cerebral arteries has been investigated in 40 patients (mean age 64 years) (36C ). The interval between each dose was at least 10 minutes or until total disappearance of the contrast effect from the previous dose. Eight patients reported 12 adverse events. There were no serious adverse events and no patient withdrew because of an adverse event. The most common adverse events were pain at the injection site, headache, and a feeling of warmth; all were mild. The safety of Sono Vue has been evaluated in 36 healthy volunteers who were given a single dose of isotonic saline or Sono Vue, 0.003, 0.01, 0.03, 0.06, 0.09, or 0.12 ml/kg and in 30 volunteers who were given cumulative doses of 0.15–0.6 ml/kg (37C ). The volunteers were

523 aged 20–35 years. Another 12 subjects, patients with chronic obstructive airways disease, were given a single dose of Sono Vue 4 ml and placebo (isotonic saline 4 ml) in two sessions separated by 48–72 h. All adverse events were minor or mild and rapidly resolved. The adverse effects in the healthy volunteers were heat at the injection site, facial flushing, headache, and a tingling sensation in the hand (one patient each). There were no differences in the frequencies of adverse events in the different dosages groups or between Sono Vue and placebo. In the patients with chronic obstructive airways disease, vomiting and lethargy occurred in one patient each. There were no significant changes in respiratory function tests (FEV1 , FVC, forced mid-expiratory flow, and oxygen saturation).

REFERENCES 1. Yang HC, Lee RC, Teng MMH, Chang CY. Adverse reactions to intravenous administration iodinated contrast media. Experience in a medical center. Chin J Radiol 2001; 26: 17–21. 2. Schraeder R. Contrast media selection in interventional cardiology. J Clin Basic Cardiol 2001; 4: 245–8. 3. Mironidou M, Katsimba D, Kokkas B, Kaitartzis C, Karamanos G. Effetti in vivo dello iohexolo e del diatrizoato sull’attivita plasmatica umana dell’acetil- e della butiril-colinesterasi. Radiol Med 2001; 101: 183–6. 4. Sutton AGC, Finn P, Grech ED, Hall JA, Stewart MJ, Davies A. Early and late reactions after the use of iopamidol 340, ioxaglate 320 and iodixanol 320 in cardiac catheterisation. Am Heart J 2001; 141: 677–83. 5. Kanny G, Marie B, Hoen B, Trechot P, MoneretVautrin DA. Delayed adverse reaction to sodium ioxaglic acid-meglumine. Eur J Dermatol 2001; 11: 134–7. 6. Flinck A, Gottfridsson B. Experiences with iohexol and iodixanol during cardioangiography in an unselected patient population. Int J Cardiol 2001; 80: 143–51. 7. Dangas G, Monsein LH, Laureno R, Peterson MA, Laird JR Jr. Transient contrast encephalopathy after carotid artery stenting. J Endovasc Ther 2001; 8: 111–13. 8. Karino S, Fukaya T. Sudden hearing loss following drip intravenous pyelography with iohexol: a case report. Auris Nasus Larynx 2001; 28: 95–7. 9. Fassbender WJ, Schluter S, Stracke H, Bretzel G. Wass W, Tillmanns H. Schilddrusenfunktion nach gabe jodhaltigen Röntgenkontrastmittels bei Koronarangiographie–eine prospektive Unter-

suchung euthyreoten Patienten. Z Kardiol 2001; 90: 751–9. 10. Losco P, Nash G, Stone P, Ventre J. Comparison of the effects of radiographic contrast media on dehydration and filterability of red blood cells from donors homozygous for haemoglobin A or haemoglobin S. Am J Hematol 2001; 68: 149–58. 11. Blann AD, Adams R, Ashleigh R, Naser S, Kirkpatrick U, McCollum CN. Changes in endothelial, leucocyte and platelet markers following contrast medium injection during angiography in patients with peripheral artery disease. Br J Radiol 2001; 74: 811–17. 12. Koussidis GA, Koussidis A. Preoperative bowel preparation with meglumine and sodium diatrizoate (Gastrografin): a prospective randomised comparison. Eur J Surg 2001; 167: 899–902. 13. Kircher MF, Kihiczak D, Rhea JT, Novelline RA, Maglinte DDT. Safety of colon contrast material in (helical) CT examination of patients with suspected diverticulitis. Emerg Radiol 2001; 8: 94–8. 14. Donadio C, Lucchesi A, Ardini M, Tramonti G, Chella P, Magagnini E, Bianchi C. Renal effects of cardiac angiography with different low-osmolar contrast media. Renal Fail 2001; 23: 385–96. 15. Hetze GR, May P, Hollenbeck M, Voiculescu A, Modder U, Grabensee B. Assessment of radiocontrast media induced renal vasoconstriction by color coded duplexsonography. Renal Fail 2001; 23: 77–83. 16. Lorusso V, Taroni P, Alvino S, Spinazzi A. Pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with renal impairment or end-stage renal disease requiring hemodialysis. Invest Radiol 2001; 36: 309–16. 17. Berger ED, Bader BD, Bosker J, Risler T, Erley CM. Kontrastmittelinduziertes Nierenversagen

524 lasst sich durch Hämodialyse nicht verhindern. Dtsch Med Wochenschr 2001; 126: 162–6. 18. Vogt B, Ferrari P, Schonholzer C, Marti H-P, Mohaupt M, Wiederkehr M, Cereghetti C, Serra A, Huynh-Do U, Uehlinger D, Frey FJ. Prophylactic hemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful. Am J Med 2001; 111: 692–8. 19. Rosado A, Canto G, Veleiro B, Rodriguez J. Toxic epidermal necrolysis after repeated injections of iohexol. Am J Roentgenol 2001; 176: 262–3. 20. Delaney Y, Khooshabeh R. Lipogranuloma following traumatic dacryocystography in a 4-year-old boy. Eye 2001; 15: 683–4. 21. Dewachter P, Moulton-Faivre C. Reactions sévères avec les produits de contraste iodes: l’anaphylaxie est-elle responsable? J Radiol 2001; 82: 973–7. 22. Leander P, Hoglund P, Borseth A, Kloster Y, Berg A. A new liposomal liver-specific contrast agent for CT: first human phase-I clinical trial assessing efficacy and safety. Eur Radiol 2001; 11: 698–704. 23. Krause W, Mahler M, Hanke B, Milius W, Kaufmann J, Rogalla P, Hamm B. Dy-EOB-DTPA: tolerance and pharmacokinetics in healthy volunteers and preliminary liver imaging in patients. Invest Radiol 2001; 36: 431–44. 24. Thurnher SA, Capelastegui A, Herraiz del Olmo F, Dondelinger RF, Gervas C, Jassoy AG, Keto P, Loewe C, Ludman CN, Marti-Bonmati L, Meusel M, Palmero da Cruz J, Pruvo JP, Sanjuan VM, Vogl T. Safety and effectiveness of singleversus triple-dose gadodiamide injection-enhanced MR angiography of the abdomen: a phase III double-blind multicenter study. Radiology 2001; 219: 137–46. 25. Ekholm SE, Bjork-Eriksson T, Western A, Nellstrom H, Jonsson E, Johansson A, Lonn L, Mercke C, Tollesson PO. MRI staging using gadodiamide for soft-tissue tumors of the head and neck region. Results from a phase II trial and a 5-year clinical follow-up. Eur J Radiol 2001; 39: 168–75. 26. Kirchin MA, Pirovano G, Venetianer C, Spinazzi A. Safety assessment of gadobenate dimeglumine (MultiHance® ): extended clinical experience from phase I studies to post-marketing surveillance. J Magn Reson Imaging 2001; 14: 281–94. 27. Runge VM, Armstrong MR, Barr RG, Berger BL, Czervionke LF, Gonzalez CF, Halford HH, Kanal E, Kuhn MJ, Levin JM, Low RN, Tanenbaum LN, Wang A-M, Wong W, Yuh WTC, Zoarski GH. A clinical comparison of the safety and efficacy of

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MultiHance (gadobenate dimeglumine) and Omniscan (gadodiamide) in magnetic resonance imaging in patients with central nervous system pathology. Invest Radiol 2001; 36: 65–71. 28. Bluemke DA, Stillman AE, Bis KG, Grist TM, Baum RA, D’Agostino R, Malden ES, Pierro JA, Yucel EK. Carotid MR angiography: Phase II study of safety and efficacy for MS-3251. Radiology 2001; 219: 114–22. 29. Schenker MP, Solomon JA, Roberts DA. Gadolinium arteriography complicated by acute pancreatitis and acute renal failure. J Vasc Intervent Radiol 2001; 12: 393. 30. Geoffroy O, Tassart M, Le Blanche A-F, Khalil A, Duedal V, Rossert J, Bigot J-M, Boudghene FP. Upper extremity digital subtraction venography with gadoterate meglumine before fistula creation for hemodialysis. Kidney Int 2001; 59: 1491–7. 31. Wagner H-J, Storck M. Endovaskulare stentgraftgestutzte Exklusion eines infrarenalen Aortenaneurysmas mit Gadolinium als Kontrastmittel bei Niereninsuffizienz. Dtsch Med Wochenschr 2001; 126: 616–20. 32. Bassilios N, Vantelon C, Cluzel P, Baumelou A, Deray G. Use of gadolinium-based contrast agent for renal angiography: case report and review of the literature. Renal Fail 2001; 23: 857–61. 33. Coche EE, Hammer FD, Goffette PP. Demonstration of pulmonary embolism with dynamic gadolinium-enhanced spiral CT. Eur Radiol 2001; 11: 2306–9. 34. Kehagias DT, Gouliamos AD, Smyrniotis V, Vlahos LJ. Diagnostic efficacy and safety of MRI of the liver with superparamagnetic iron oxide particles (SH U 555 A). J Magn Reson Imaging 2001; 14: 595–601. 35. Daniel GK, Chawla MK, Sawada SG, GradusPizlo I, Feigenbaum H, Segar DS. Echocardiographic imaging of technically difficult patients in the intensive care unit: Use of optison in combination with fundamental and harmonic imaging. J Am Soc Echocardiogr 2001; 14: 917–20. 36. Kaps M, Legemate DA, Ries F, Ackerstaff RGA, Markus H, Pezzoli C, Llull J-B, Spinazzi A. SonoVue™ in transcranial Doppler investigations of the cerebral arteries. J Neuroimaging 2001; 11: 261–7. 37. Bokor D, Chambers JB, Rees PJ, Mant TGK, Luzzani F, Spinazzi A. Clinical safety of SonoVue™, a new contrast agent for ultrasound imaging, in healthy volunteers and in patients with chronic obstructive pulmonary disease. Invest Radiol 2001; 36: 104–9.

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47

Drugs used in ocular treatment

ANTIGLAUCOMATOUS DRUGS Adrenoceptor agonists Brimonidine is a third-generation alpha2 selective adrenoceptor agonist. It is distinguished from clonidine by a chemical modification that reduces its ability to cross the blood–brain barrier. Its adverse effects include allergic conjunctivitis and ocular pruritus (1r ). There is a potential for serious toxic effects, especially in children. • An one-month-old infant with Peters anomaly had recurrent episodes of unresponsiveness, hypotension, hypotonia, and bradycardia (2r ). Extensive medical evaluation showed that these episodes were caused by the ophthalmic use of brimonidine.

Beta-adrenoceptor antagonists (SED 14, 1639) It has been more than a quarter of a century since the discovery that oral propranolol reduces intraocular pressure in patients with glaucoma. However, the use of propranolol for glaucoma was limited by its local anesthetic action (membrane-stabilizing activity). Topical timolol was released for general use in 1978. That timolol is systemically absorbed was suggested by early reports of reduced intraocular pressure in the untreated eyes of patients using monocular treatment. About 80–90% of a topically administered drop drains through the nasolacrimal duct and enters the systemic circulation through the highly vascular nasal mucosa, without the benefit of first-pass © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

metabolism in the liver; only a small fraction is swallowed. Thus, topical ophthalmic dosing is probably more akin to intravenous delivery than to oral dosing, and systemic adverse reactions are potentially serious. However, although patients may give their physicians a detailed list of current medications, they often fail to mention the use of eye drops, about which physicians are often either unaware or do not have time to ask specific questions. Betaxolol is a beta1 -selective adrenoceptor antagonist without significant membranestabilizing activity or intrinsic sympathomimetic activity. It may be no more effective than other drugs in reducing intraocular pressure, but it may be safer for some patients, particularly those with bronchospastic disease (but see Respiratory below) (3R ). Partial agonist activity (intrinsic sympathomimetic activity) of beta-blockers may help to prevent ocular nerve damage and subsequent visual field loss associated with glaucoma. Such damage may be related to a reduction in ocular perfusion, as might occur if an ocular betablocker caused local vasoconstriction. An agent with intrinsic sympathomimetic activity might preserve ocular perfusion through local vasodilatation or by minimizing local vasoconstriction. The data are sparse and inconclusive, but carteolol appears to have no effect on retinal blood flow or may even increase it, making it suitable as a neuroprotective drug (3R , 4R ). Cardiovascular Significant cardiovascular adverse effects have been reported after topical administration of timolol maleate. Bradycardia with frank syncope can occur, especially in elderly patients (3R ). After topical administration its action begins in 20 minutes, peaks in 4 hours, and lasts 24 hours. Episodes of dizziness and occasional falls can occur 1–2 hours after instillation of timolol, as has been described in an otherwise healthy elderly patient (5A ).

525

526 • An 80-year-old woman with gastrointestinal bleeding had a sinus bradycardia (52 beats/minute) despite acute blood loss. The only drug she had used that was an AV nodal depressant was timolol maleate 0.5%, one drop to both eyes every day. Continuous electrocardiography showed transient complete AV block without ventricular escape for nearly 6 seconds about 1 hour after instillation of timolol eye drops. She also reported having previously had episodes of dizziness and occasional falls 1–2 hours after instillation of her eye drops. Timolol was withheld and a temporary pacemaker was inserted. Rechallenge with timolol was associated with recurrence of third-degree AV block. She subsequently had a permanent dual chamber pacemaker implanted.

Respiratory Bronchospasm, which can be life-threatening, can be precipitated by betablocker eye drops. Even beta1 -selective antagonists, such as betaxolol, can cause a substantial reduction in forced expiratory volume. Wheezing and dyspnea have been reported among patients using betaxolol: the symptoms resolved after withdrawal. A cross-sectional study has shown that ophthalmologists were more aware than chest physicians about the use of betablocker eye drops by patients with obstructive airways disease; patient awareness was also poor (3R , 6c ). Psychiatric Depressive symptoms were reported in 17 of 165 patients after the administration of timolol over two decades (7A ). Depression accounted for 17% of 369 central nervous system reactions to timolol reported to a National Registry of Drug-induced Ocular Side Effects during 7 years: of these, 20 cases were of acute suicidal depression. Metabolism Topical beta-blockers can cause rises in serum triglyceride concentrations and falls in serum high-density lipoprotein concentrations; this makes them less suitable in patients with coronary heart disease (3R , 8c ). Inhibition of glycogenolysis and glucose mobilization can occur (3R ). This makes topical beta-blockers less suitable for patients with insulin-dependent diabetes mellitus prone to hypoglycemia. Immunologic Contact allergy to topical betablockers can occur. A 68-year-old woman developed contact allergy after many year of using befunolol (9A ). Patch-testing showed cross-

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B.C.P. Polak

sensitivity to carteolol. Evidence of such crosssensitivity has not previously been reported.

Prostaglandin analogues Travoprost is a synthetic prostaglandin analog, believed to reduce intraocular pressure by increasing uveoscleral outflow. Its adverse effects include gradual darkening of the color of the iris and the eyelid skin, increased thickness, number, and darkness of the eyelashes, conjunctival hyperemia, and ocular pruritus (1r ). Latanoprost is a prostaglandin F analogue used to treat open-angle glaucoma, targeting the uveoscleral outflow of ocular aqueous humor. Ocular adverse effects include conjunctival hyperemia, iris pigmentation, periocular skin color changes, anterior uveitis, and cystoid macular edema in pseudophakic patients (10R , 11A ). Herpes simplex dendritic keratitis has been reported after treatment with latanoprost (12r ). In patients with uveitic glaucoma latanoprost can cause increased intraocular pressure and recurrence of inflammation (13c ). Cardiovascular Recently exacerbation of angina pectoris has been described in association with latanoprost (14r ). Prostaglandin F is a vasoconstrictor, and systemic absorption of topically applied latanoprost can cause vasoconstriction in coronary arteries. Nervous system Three patients had new onset of migraine after using latanoprost, perhaps through activation of the trigeminal vascular system (15A ).

Prostamides Bimatoprost is the first synthetic prostamide analog. It is believed to lower intraocular pressure by increasing the outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Its adverse effects include gradual darkening of the color of the eyes and the eyelid skin, increased thickness, numbers and darkness of eyelashes, conjunctival hyperemia, and ocular pruritus (16R ).

Drugs used in ocular treatment

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REFERENCES 1. Chernin T. The eyes have it. FDA clears several ophthalmic drops for glaucoma in a row. Drug Topics 2001; 145: 20. 2. Berlin RJ, Lee UT, Samples JR, Rich LF, TangLiu DDS, Sing KA, Steiner RD. Ophthalmic drops causing coma in an infant. J Pediatr 2001; 138: 441–3. 3. Frishman WH, Kowalski M, Nagnur S, Warshafsky S, Sica D. Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension. Focus on beta-adrenergic blockade. Heart Dis 2001; 3: 386–97. 4. Girkin CA. Neuroprotection: does it work for any neurological diseases? Ophthalmic Pract 2001; 19: 298–302. 5. Sharifi M, Koch JM, Steele RJ, Adler D, Pompili VJ, Sopko J. Third degree AV block due to ophthalmic timolol solution. Int J Cardiol 2001; 80: 257–9. 6. Malik A, Memon AM. Beta-blocker eye drops related airway obstruction. J Pak Med Assoc 2001; 51: 202–4. 7. Schweitzer I, Maguire K, Tuckwell V. Antiglaucoma medication and clinical depression. Aust NZ J Psychiatry 2001; 35: 569–71. 8. Gavalas C, Costantino O, Zuppardi E, Scaramucci S, Doronzo E, Aharrh-Gnama A, Nubile M, Di Nuzzo S, De Nicola GC. Variazioni della colesterolemia in pazienti sottoposti a terapia topica con

il timololo. Ann Ottalmol Clin Ocul 2001; 127: 9–14. 9. Nini M, Suppa F, Ayala F, Balato N. Allergic contact dermatitis due to the beta-blocker befunolol in eyedrops, with cross-sensitivity to carteolol. Contact Dermatitis 2001; 44: 369. 10. Linden C. Therapeutic potential of prostaglandin analogues in glaucoma. Expert Opin Invest Drugs 2001; 10: 679–94. 11. Wand M, Ritch R, Isbey EK, Zimmerman TJ. Latanoprost and periocular skin color changes. Arch Ophthalmol 2001; 119: 614–15. 12. Ekatomatis P. Herpes simplex dendritic keratitis after treatment with latanoprost for primary open angle glaucoma. Br J Ophthalmol 2001; 85: 1008–9. 13. Sacca S, Pascotto A, Siniscalchi C, Rolando M. Ocular complications of latanoprost in uveitic glaucoma: three case reports. J Ocul Pharmacol Ther 2001; 17: 107–13. 14. Mitra M, Chang B, James T. Exacerbation of angina associated with latanoprost. Br Med J 2001; 323: 783. 15. Weston BC. Migraine headache associated with latanoprost. Arch Ophthalmol 2001; 119: 300–1. 16. Cantor LB. Bimatoprost: a member of a new class of agents, the prostamides, for glaucoma management. Expert Opin Invest Drugs 2001; 10: 721–31.

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Treatments used in complementary and alternative medicine

Complementary and alternative forms of medicine remain popular. Numerous surveys are being published, showing that the prevalence of use is high and increasing. For instance, 43% of all patients attending an emergency department in the USA had used at least one such therapy at some time and 24% were current users (1R ). All complementary treatments were considered to be safe by 16% of the patients and 33% of all users failed to tell their physicians. Furthermore, 15% of the women and 7% of the men believed that complementary therapies do not interact with other medications. As the popularity of complementary medicine rises, so does the research interest in this subject (2R ), including research into direct and indirect risks (3R –5R ).

almost six-fold (7R ). And survey data from the USA have suggested that herb–drug interactions may be a significant problem in a sizeable proportion of patients (8R ). Several herbal medicines pose serious problems for surgical patients, for example through an increased bleeding tendency (9R , 10R ). Vulnerable populations also include children (11R ), and too few safety data are available to recommend herbal medicines during pregnancy or lactation (2R ). Several investigators have pointed out the potential of herbal medicines to harm certain organs, e.g. the liver (12R ) or the skin (13R ). Laxatives are often based on herbal extracts, and the risks of herbal laxatives have been emphasized (14R ). Many authors have reviewed the risks of herbal medicines in general terms (15R , 16R ).

HERBAL MEDICAMENTS (SED-14, 1651; SEDA-23, 506; SEDA-24, 537; SEDA-25, 567) Herbal medicines, often self-prescribed by patients, are particularly popular. The myth that they are devoid of risk continues to be promoted, not least by the popular press. However, a hospital-based study from Oman has suggested that 15% of all cases of self-poisoning seen in this setting are with traditional medicines (6R ). A case series from Thailand has suggested that in patients with oral squamous cell carcinoma the use of herbal medicines before the first consultation with a healthcare professional increases the risk of an advanced stage © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

528

ASIAN HERBAL MIXTURES Nervous system An 8-year-old boy became agitated, vomited repeatedly, and became unrousable (17A ). His mother had applied a homemade paste topically for his eczema, according to a recipe in a Bangladeshi book. The paste was made from a mixture of ground tobacco leaves, lime, and lyophilized coffee. Acute nicotine poisoning was confirmed through blood and urine analyses. The boy recovered fully within 2 days. Drug contamination A total of 54 samples of Asian remedies, purchased in Vietnam, Hong Kong, Florida, New York, and New Jersey, were analysed for heavy metal contamination (18A ). They contained concentrations of arsenic, lead, and mercury that ranged from merely exceeding

Treatments used in complementary and alternative medicine

published guidelines (74%) to toxic (49%). The authors concluded that “the public health hazards of traditional herbal Asian remedies should be identified and disclosed”.

Allium sativum (garlic)

(SED-14,

1652) Skin A 50-year-old Romanian man was advised by his herbalist to treat his asthma with a compress of freshly crushed garlic (19A ). He wore the compress on his forehead overnight and subsequently developed second-degree burns in this area. Specific Jg E RAST tests for garlic were negative. He was treated conservatively and made an uneventful recovery. Two Korean patients used topical garlic for the treatment of pruritus and subsequently developed irritant contact dermatitis of the treated skin areas (20A ). Withdrawal of this folk remedy resulted in full recovery.

Anso Comfort The California State Health Director has warned consumers to stop using the herbal product Anso Comfort capsules immediately, because the product contains the undeclared prescription drug chlordiazepoxide. Chlordiazepoxide, available by prescription either by its generic name or under the brand name of Librium, is used for anxiety and as a sedative and can be dangerous if not taken under medical supervision (21Ar ). Anso Comfort capsules, available by mail or telephone order from the distributor in 60-capsule bottles, are clear with dark green powder inside. The label is yellow with green English printing and a picture of a plant. An investigation by the California Department of Health Services Food and Drug Branch and Food and Drug Laboratory showed that the product contains chlordiazepoxide. The ingredients for the product were imported from China and the capsules were manufactured in California. Advertising for the product claims that the capsules are useful for the treatment of a wide variety of illnesses, including high blood pressure and high cholesterol, in addition to claims

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that it is a natural herbal dietary supplement. The advertising also claims that the product contains only Chinese herbal ingredients and that consumers may reduce or stop their need for prescribed medicines. No clear medical evidence supports any of these claims. The distributor, NuMeridian (formerly known as Top Line Project), is voluntarily recalling the product nationwide. Metabolic A San Francisco woman with a history of diabetes and high blood pressure was hospitalized in January 2001 with lifethreatening hypoglycemia after she consumed Anso Comfort capsules. This may have been due to an interaction of chlordiazepoxide with other unspecified medications that she was taking.

Aristolochia

(SED-14, 1654; SEDA-25,

568) Urinary tract In June 2001, the FDA issued a nationwide alert, recalling 13 “Treasure of the East” herbal products containing aristolochic acid. Aristolochic acid, found in certain plants and botanicals is a potent carcinogen and can cause serious kidney damage (22R ). Before this alert, the FDA had issued several warnings: 1. On 4 April 2001 a “Dear Health Professional” letter was sent, drawing attention to serious renal disease associated with the use of aristolochic acid-containing dietary supplements or “traditional medicines”. Health professionals were urged to review patients who had had unexplained renal disease, especially those with urothelial tract tumors and interstitial nephritis with end-stage renal insufficiency, to determine if such products had been used. 2. On 9 April 2001 a letter was sent to industry associations, detailing the reported cases of renal disease associated with aristolochic acid. 3. On 11 April 2001 the FDA cautioned consumers to immediately discontinue any dietary supplements or “traditional medicines” that contain aristolochic acid, including products with “Aristolochia”, “Bragantia”, or “Asarum” listed as their ingredients.

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Chapter 48

In a related action, Health Canada has warned consumers not to use the pediatric product Tao Chih Pien. This Chinese product, which is sold in the form of tablets, is said to be a diuretic and a laxative. It is not labelled to contain aristolochic acid. However the Chinese labelling says that it contains Mu Tong, a traditional term used to describe numerous herbs, including aristolochia; subsequent product analysis has shown that Tao Chih Pien does indeed contain aristolochic acid. Health Canada has now advised individuals in possession of this product not to consume it and to return it to the place of purchase. It has also issued a Customs Alert for the product to prevent the importation and sale of Tao Chih Pien. Chinese herb nephropathy, a rapidly progressive fibrosing interstitial nephritis, was first reported in 1993 after Belgian patients took Chinese herbal mixtures containing aristolochic acid. Numerous reports from many countries have confirmed that plants from the Aristolochia species are the cause (23A , 24A ), and the toxic agent has been confirmed to be aristolochic acid (25A ). • A 46-year-old Chinese woman, living in Belgium and China, developed subacute renal insufficiency (26A ). Her creatine concentrations had increased from 80 µmol/l (November 1998) to 327 µmol/l (January 2000). During the preceding 6 months she had taken a patent medicine bought in China “for waste discharging and youth keeping”. The package insert did not list any herbs of the Aristolochia species. Kidney biopsy showed extensive hypocellular interstitial fibrosis, tubular atrophy, and glomerulosclerosis. Analysis of the Chinese medicine demonstrated the presence of aristolochic acid. She required hemodialysis in June 2000 and received a renal transplant 4 months later. • A 58-year-old Japanese woman with CREST syndrome (calcinosis, Raynaud’s syndrome, esophageal sclerosis, sclerodactyly, and telangiectasia) developed progressive renal dysfunction (27A ). Renal biopsy showed changes typical of Chinese herb nephropathy. Analyses of Chinese herbs she had taken for several years demonstrated the presence of aristolochic acid. Oral prednisolone improved her renal function and anemia.

Arnica montana (arnica)

(SED-14,

1654) Skin Of 443 individuals who were tested for contact sensitization, five had a positive reac-

E. Ernst

tion to arnica and nine to marigold (28C ). Both plants are compositae, and a mixture of the two was positive in 18 cases. Sensitization was often accompanied by reactions to nickel, Myroxylon pereirae resin, fragrance mix, propolis, and colophon.

Calendula officinalis (marigold) Skin Of 443 individuals who were tested for contact sensitization, nine had a positive reaction to marigold and five to arnica (28C ). Both plants are compositae, and a mixture of the two was positive in 18 cases. Sensitization was often accompanied by reactions to nickel, Myroxylon pereirae resin, fragrance mix, propolis, and colophon.

Cardiac glycosides Cardiovascular A 26-year-old woman had taken a herbal supplement for stress-relief which contained Scutellaria lateriflora, Pedicularis canadensis, Cimicifuga racemosa, Humulus lupulus, Valeriana officinalis, and Capsicum annuum (29A ). She was admitted with chest pain of 7 hours duration. Her medical history was otherwise unremarkable. Examination of her heart showed no abnormality, but during monitoring her heart rate fell to 39 beats/min and her blood pressure to 59/36 mmHg. Her serum digoxin concentration was 0.9 ng/ml. The authors therefore concluded that the herbal remedy contained digoxin-like factors that had caused digitalis toxicity.

Citrus auranticum (bergamot) Skin In aromatherapy volatile plant oils (often incorrectly termed “essential oils”) are used and are usually applied by gentle massage. Bergamot oil (Citrus auranticum spp. bergamia) is often used in this way. It has photosensitive and melanogenic properties and is potentially phototoxic and photomutagenic. Two patients had localized and disseminated bullous phototoxic skin reactions 48–72 hours

Treatments used in complementary and alternative medicine

after exposure to bergamot aromatherapy and ultraviolet light (30A ). One developed bullous skin lesions after exposure to aerosolized aromatherapy oil in a sauna.

Ecballium elaterium (squirting cucumber) (SED-14, 1658) Ecballium elaterium is used in the Mediterranean as a purgative and in treating sinusitis. In a retrospective chart analysis in a Greek ENT department 42 patients with allergic reactions to this remedy, including upper airway edema, were identified (31c ). Treatment with corticosteroids and antihistamines resulted in full recovery in all cases.

Echinacea

(SED-14, 1658; SEDA-25,

569) A 41-year-old man, who had taken Echinacea intermittently for the previous 18 months, had four episodes of erythema nodosum, preceded by myalgia and arthralgia, fever, headache, and malaise (32A ). The skin lesions resolved within 2–5 weeks and responded to oral prednisolone. He was advised to discontinue Echinacea and 1 year later remained free from further recurrence.

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531

A 56-year-old man had a stroke without apparent risk factors (34A ). A CT scan confirmed a right parietal hematoma. He had not taken any medications, except for a Ginkgo extract (3×40 mg/day) which he had started 18 months before. The authors argued that the antiplatelet effects of Ginkgo might have contributed to this case of intracerebral bleeding. Hematologic A 34-year-old woman had a laparoscopic cholecystectomy and started bleeding into the surgical wound postoperatively (35A ). This led to a fall in hemoglobin from 16.5 to 12.4 g/dl. She was given blood transfusions and recovered uneventfully. The surgeons believed that self-medication with Ginkgo had caused the postoperative bleeding. Skin A 40-year-old Afro-American woman developed an exfoliative rash and blistering and swelling of the tongue (36A ). A diagnosis of Stevens–Johnson syndrome was made. She had not taken any medications other than two doses of a Ginkgo-containing formulation. Her condition responded to treatment with prednisolone, clotrimazole, and famotidine. Ginkgo was withdrawn and no further events occurred. However, 5 months later she still had tenderness in the soles of the feet, peeling of the nails, and discoloration of the skin.

Glycyrrhiza radix (licorice) (SED-14, 1659; SEDA-25, 569)

Ginkgo biloba (maidenhair tree) (SED-14, 1658) Nervous system A 78-year-old man and an 84-year-old woman with previously well controlled epilepsy presented with recurrent seizures (33A ). There were no obvious reasons for these events, and the investigator suspected self-medication with Ginkgo biloba extracts. Both patients had started taking Ginkgo within 2 weeks of the start of the seizures. The herbal remedy was withdrawn and both patients remained seizure-free several months later. No other change of medication was made. The author postulated that 4-0-methylpyridoxine, a constituent of Ginkgo and a known neurotoxin, had caused the seizures.

In healthy volunteers who took licorice corresponding to glycyrrhetinic acid 75–540 mg/day for periods of 2–4 weeks, there was an average increase in systolic blood pressure of 3.1–14.4 mmHg (37c ). The increase in blood pressure was dose related and the authors concluded that as little as 50 g/day of licorice for 2 weeks would have caused a significant rise in blood pressure.

Hydroxycut Hydroxycut is a US dietary supplement that contains ephedra and guarana extract; both have sympathomimetic properties, which may be problematic.

532 • A 22-year-old man had taken hydroxycut for muscle-enhancing purposes for 2 weeks when he developed a seizure-like episode without tonic– clonic movements, followed by coma (38A ). He required mechanical ventilation and was treated with intravenous methylprednisolone. He became arousable only 2 days later, after which he made a full recovery within 3 days but had no memory of the event. After 2 years he was free of adverse sequelae.

Hypericum perforatum (St John’s wort) (SED-14, 1660; SEDA-25, 570) Nervous system Delirium and serotonin syndrome have been attributed to St John’s wort. • A 76-year-old woman began taking an extract of St John’s wort (75 mg/day) and developed delirium and psychosis 3 weeks later (39A ). She had no relevant medical history and did not take any other medications. She was given risperidone and donepezil hydrochloride, and her paranoid delusions and visual hallucinations improved. The final diagnosis was acute psychotic delirium associated with St John’s wort in a woman with underlying Alzheimer’s dementia. • A 40-year-old man with a history of anxiety disorder and depression presented with flushing, sweating, agitation, weakness of the legs, dry mouth, tightness in the chest, and inability to focus (40A ). He was taking clonazepam (0.5 mg bd) and had started to take St John’s wort 10 days before. He had previously had two similar episodes after having taken sertraline. The authors concluded that self-medication with St John’s wort, which has SSRI activity, had caused the serotonin syndrome.

Endocrine In a retrospective case–control study, 37 patients with raised TSH concentrations were compared with 37 individuals with normal TSH concentrations (41c ). Exposure to St John’s wort during the previous 3–6 months increased the odds of a raised TSH concentration by a factor of 2.12 (95% CI = 0.36, 12). The authors concluded that an association between St John’s wort and raised TSH concentrations is probable. Hair A 24-year-old schizophrenic patient who self-medicated with St John’s wort while also taking olanzapine (5–10 mg/day) developed hair loss on her scalp and eyebrows 5 months later; it persisted for 12 months (40A ). Her medical history was otherwise unremarkable and the authors speculated that, like SSRIs, St John’s wort can cause hair loss.

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Drug interactions Oral contraceptives A 36-year-old woman became pregnant whilst taking an oral contraceptive, ethinylestradol/ dienogest (doses not stated) (42A ). She had also taken St John’s wort extract, which is a hepatic enzyme inducer. As no other cause for contraceptive failure could be identified, the authors concluded that the St John’s wort had been responsible. Ciclosporin Two patients who took ciclosporin after kidney transplantation self-medicated with St John’s wort, and their ciclosporin concentrations became subtherapeutic (43A ). One subsequently had an acute transplant rejection. Withdrawal of St John’s wort resulted in normalization of ciclosporin concentrations. This effect of St John’s wort was probably due to enzyme induction. After a kidney transplant for end-stage renal insufficiency a 58-year-old man was given ciclosporin, azathioprine, and prednisolone (44A ). Four years later he started to take St John’s wort (300 mg bd) for depression, and 2 weeks later his previously stable ciclosporin concentrations had halved. Withdrawal of the St John’s wort resulted in normalization of his ciclosporin concentrations.

Larrea tridentata (chaparral) (SED-14, 1660) Liver In four patients who were given topical chaparral tincture there was no evidence of liver damage (45A ).

Laurus nobilis (laurel oil) Laurel (Laurus nobilis) has well-known analgesic, diaphoretic, antipyretic, and diuretic effects (46R ), and is widely used in rheumatic, pyrexial, and infective disorders (47R ), as well as in the perfume and soap industries (46R ). Skin Laurel contact allergy is usually seen in aromatherapists or their clients (48A , 49C , 50A ).

Treatments used in complementary and alternative medicine • A 55-year-old woman developed erythema and edema over her knees (48A ). She had applied laurel oil, obtained from a herbalist, to her knees to relieve joint pain 15 days earlier. After 3 days, the erythema and edema had begun to appear. She had erythema, edema, and papules over her patellae, and eczema around the eye. She was treated with an oral antihistamine and a topical corticosteroid. Two days later, the lesions worsened and systemic corticosteroid therapy was needed. The lesions started to heal, leaving slight post-inflammatory hyperpigmentation. Patch testing was performed with a European standard series and commercial laurel oil 1 month later. There was a reaction to the oil only, and no reaction to either fragrance mix or Myroxylon Pereirae Resin in the standard series. The same preparation of laurel oil was negative on patch testing in 15 control subjects.

Lycium barbarum (Chinese wolfberry) Drug interactions A 61-year-old woman, who had taken warfarin for atrial fibrillation in weekly doses of 18–19 mg for years and had been completely stable, developed a raised INR after she consumed a tea made from Chinese wolfberry (51A ). Four days after drinking the tea (180 ml/day), she had an INR of 4.1. After discontinuation of the herbal tea her INR returned to within the target range and remained stable. No mechanism was suggested.

Piper methysticum (kava)

(SED-14,

1663; SEDA-25, 571) Nervous system Kava and valerian are herbal remedies, claimed to have anxiolytic and sedative properties respectively, without dependence potential or any appreciable adverse effects. Kava is an extract of the roots of the Polynesian plant Piper methysticum. Valerian is derived from Valeriana officinalis. In a pilot study, 24 patients with stress-induced insomnia were treated for 6 weeks with kava 120 mg/day, followed by a 2-week washout period and then treatment with valerian 600 mg/day for another 6 weeks (52c ). Stress was measured in three areas, including social, personal, and life events, and insomnia was assessed by evaluating the time taken to fall asleep, the number of hours

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slept, and waking mood. Total stress severity and insomnia were significantly improved by both compounds, with no significant differences. The most commonly reported adverse events were vivid dreams with valerian (16%) and dizziness with kava (12%). In 24 patients treated with kava for generalized anxiety disorder for 4 weeks in an open, crossover, randomized trial, two dosage schedules were compared: 120 mg od and 45 mg tds (53c ). There were significant reductions in mean Hamilton Anxiety Rating Scale scores, irrespective of dose schedule, treatment order, or sex. The impact of adverse effects was relatively low, and only one patient had to withdraw from the study (tds schedule) because of nausea. There was daytime drowsiness in 33% of patients taking the thrice-daily regimen compared with 9% in those taking a once-daily dose. A 45-year-old woman with a family history of essential tremor developed severe and persistent Parkinsonism after taking kava extract (65 mg/day) for 10 days (54A ). Her symptoms responded to anticholinergic drugs, but slowness and tremor at rest persisted. The authors concluded that kava might cause Parkinsonism in individuals with a genetic susceptibility. Liver Three cases of liver damage have been attributed to kava. • A 33-year-old woman took a kava extract equivalent to 210 mg of kavalactones daily for 3 weeks (55A ). She developed malaise, loss of appetite, and jaundice. Her liver enzymes were raised 3to 60-fold. Viral hepatitis was excluded and liver biopsy confirmed toxic hepatitis. Kava was withdrawn, and within 8 weeks the liver enzymes returned to normal. A lymphocyte transformation test showed strong concentration-dependent T-cell reactivity to kava. Phenotyping of CYP2D6 activity showed that she was a poor metabolizer.

The authors concluded that the liver damage in this case was due to an immune-mediated reaction, possibly mediated by a reactive metabolite of kava, although she was a poor metabolizer. • A 60-year-old patient, who had taken no medications other than kava extract, developed liver and kidney failure and progressive encephalopathy (56A ). Viral, metabolic, and autoimmune causes were excluded. Liver biopsy was consistent with toxic liver damage. The patient eventually received an orthotopic liver transplant and made a good recovery.

534 • A 50-year-old man developed jaundice. He had noticed fatigue for a month, a “tanned” skin, and dark urine (57A ). The medical history was unremarkable, apart from slight anxiety, for which he had been taking three or four capsules of kava extract daily for 2 months. He took no other drugs and did not consume alcohol. Liver function tests showed 60-fold and 70-fold increases in AsT and alanine AlT respectively. He subsequently developed stage IV encephalopathy but made a good recovery after a liver transplant operation.

Polygonum multiflorum (Shou wu Pian) Liver Polygonum multiflorum was prescribed by a Chinese herbalist for a 46-year-old woman with graying hair (58A ). After taking it for 2 weeks she developed signs and symptoms of hepatitis. The history revealed no plausible cause for hepatitis and viral infection was ruled out. After withdrawal of the Polygonum multiflorum her liver enzymes normalized and she recovered fully.

Scutellaria lateriflora (skullcap) (SED-14, 1665) Respiratory A 53-year-old Japanese man, who had taken skullcap intermittently for hemorrhoids, developed recurrent interstitial pneumonitis (59A ). Re-challenge, after he had discontinued the herbal remedy and had become symptom free, resulted in a high fever and signs and symptoms of interstitial pneumonitis. Transbronchial lung biopsy showed lymphocytic alveolitis with eosinophilic infiltration. The symptoms subsided again after withdrawal.

Selaginella doederleinii Hematologic A 52-year-old woman with cholangiocarcinoma developed severe bonemarrow suppression after taking Selaginella doederleinii daily for 2 weeks (60A ). She developed severe pancytopenia with skin ecchymoses and gum bleeding. A bone-marrow smear and biopsy showed severe hypocellularity without malignant cell infiltration. One week

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after withdrawal her blood count became normal.

Serenoa repens (saw palmetto) Hematologic A 53-year-old man, who had self-medicated with a saw palmetto supplement for benign prostatic hyperplasia, had profuse bleeding (estimated blood loss 2 liters) after resection of a meningioma and required 4 units of packed red cells, 3 units of platelets, and 3 units of fresh frozen plasma (61A ). Postoperatively his bleeding time was 21 min (reference range 2–10 min) but all other coagulation tests were normal. He made an uneventful recovery. The authors concluded that the cyclo-oxygenase inhibitory activity of saw palmetto had caused platelet dysfunction, which had resulted in abnormal bleeding.

Uncaria tomentosa (cat’s claw) Liver A 59-year-old woman with mantle-cell lymphoma and no hepatic involvement took a range of unconventional medicines (62A ). During a routine check-up she had raised liver enzymes, and self-medication with cat’s claw was deemed the most likely cause. Cat’s claw was withdrawn and her liver tests normalized within 60 days.

Vaccinium macrocarpon (cranberry) Hematologic After transurethral resection of his prostate, a 68-year-old man developed immune thrombocytopenic purpura (platelet count 1 × 109 /l). He had self-medicated with cranberry juice for 10 days before the operation and had also taken amlodipine and aspirin (63A ). He had oral petechiae, bleeding gums, hematuria, and bruises. He recovered within 3 days of being given human immunoglobulin and oral prednisolone, and 18 months later his platelet count was still normal. Cranberry juice may contain small amounts of quinine, which can cause immune thrombocytopenia.

Treatments used in complementary and alternative medicine

ACUPUNCTURE (SED-14, 1673; SEDA-23, 511; SEDA-24, 540; SEDA-25, 573) A systematic review of all prospective studies of adverse effects associated with acupuncture included nine primary investigations (64M ). The most commonly reported adverse events were needle pain (1–45%), tiredness (2–41%), and bleeding (0.03–38%). Pneumothorax was the only serious complication in these studies; it was reported twice in about 250 000 patients. Two prospective UK studies with a total of about 70 000 consultations have confirmed that serious adverse events of acupuncture are true rarities in Britain (65C , 66C ). Bleeding and needle pain were the most frequent adverse events, with a prevalence of about 1 : 1000. A systematic review of all adverse events associated with acupuncture in the Japanese medical literature located 124 cases (67M ). These included 25 cases of pneumothorax, 18 cases of spinal cord injury, 11 cases of hepatitis B, and 10 cases of localized argyria. An 82-year-old woman was scheduled for gastrectomy with an epidural anesthetic (68A ). She had previously had many acupuncture treatments with a Japanese technique (okibari), in which small needles are left in situ. Her preoperative chest and abdominal X-rays showed hundreds of needles around the vertebrae. The anesthesiologists feared that an epidural anesthetic might lead to spinal cord injury or pneumothorax, and general anesthesia was chosen instead. Respiratory Two further cases of pneumothorax have been reported in association with acupuncture (69A , 70A ). • A 28-year-old Chinese woman developed bilateral pneumothoraces after receiving acupuncture in the upper thoracic and paraspinal regions (70A ). She was treated conservatively and was discharged after 2 days.

Skin A 59-year-old woman presented with a 1-month history of non-pruritic papules on the dorsa of both feet (71A ). During the previous year she had repeatedly received acupuncture in this area. A biopsy showed mixed lichenoid, spongiotic, and granulomatous dermatitis. Ultrastructural examination showed macrophages containing silicone. At follow-up new lesions on her mid calves were noted, and again she

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explained she had recently received acupuncture at these sites. It was discovered that the acupuncturist used silicone-coated needles and silicone deposition was thus caused by acupuncture. Infection risk Infection is a well-known risk of acupuncture and cases continue to be reported. • A 79-year-old woman presented with induration of the right leg three months after receiving acupuncture in this area (72A ). Radiography showed a focal dystrophic calcification at this point and histological studies showed suppurative granulomatous inflammation with microabscesses and caseous necrosis due to infection with Mycobacterium chelonae. She made a full recovery after antibiotic treatment. • A 42-year-old woman with Marfan’s syndrome, who had previously had an aortic root and valve replacement, presented with fever and polyarthralgia 6 days after receiving acupuncture for back pain (73A ). Examination of the valve showed no abnormalities, but Staphylococcus aureus was grown from blood cultures. Extensive investigations did not identify a cause for the infection. Her condition deteriorated despite antibiotic therapy, and emergency aortic root and valve replacement became necessary. She eventually made a full recovery. The authors concluded that the acupuncture had been the most likely cause of the infection.

LEECH THERAPY Skin Leeches are still used in complementary medicine to treat a large variety of conditions. A 69-year-old patient with polyarthralgia was treated with leeches in the lumbar region (74A ). She developed pruritus in that area and treatment was discontinued. One year later she returned with keloid-like skin lesions at the sites of the leech bites. Biopsy showed pseudolymphomatous inflammatory infiltrates with follicular hyperplasia and eosinophilic infiltration. The authors concluded that the lesions were a reaction to arthropods.

MASSAGE THERAPY An 80-year-old Japanese man with a recent history of cerebral infarction received a shiatsu

536 massage in the neck area to relieve a headache (75A ). Immediately after he had right visual field impairment. Thorough ophthalmological and neurological tests show multiple branch occlusions of the central retinal artery and multiple small infarctions in the right frontoparietal lobe. He was given urokinase for 7 days, and made an almost complete recovery. The authors concluded that the forceful neck massage had caused his problem.

SPINAL MANIPULATION (SED-14, 1674; SEDA-23, 512; SEDA-24, 540; SEDA-25, 575) A systematic review of all prospective studies of the risks associated with spinal manipulation included five primary investigations (76M ). The most valid studies suggested that about half of all patients who see a chiropractor will have adverse effects, which are usually mild and transient. No reliable data about serious adverse events were uncovered. However, a review of recent case reports has shown that spinal manipulation was associated with several serious adverse effects, including dissection of the vertebral and internal carotid arteries, resulting in strokes and at least one death (77M ). Other recent instances relate to epidural hematoma, intracranial aneurysm, cauda equina syndrome, contusion of the spinal cord, myelopathy, radiculopathy, and palsy of the long thoracic nerve. Nervous system A survey of 323 UK neurologists disclosed 35 previously unreported cases of serious neurological complications of spinal manipulation (78c ). This means that in this particular series, under-reporting of adverse events had been 100%.

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• A 34-year-old man with a whiplash injury consulted a chiropractor for his neck pain, and 36 hours after one particularly painful treatment he experienced throbbing, positional headache, dizziness, diplopia, otorrhea, and rhinorrhea (79A ). After thorough neurological examination the author concluded that the patient had suffered a dural tear due to cervical manipulation. • A 34-year-old woman had memory loss, ataxia, and poor co-ordination of the right arm associated with right neck pain after consulting a chiropractor (80A ). An MRI scan confirmed a right cerebellar infarct, most probably caused by upper spinal manipulation. She made a full recovery within 1 month. • A 41-year-old man with neck pain sought chiropractic care and the evening after felt unable to breathe in the recumbent position (81A ). Diaphragmatic paralysis was attributed to phrenic nerve injury during cervical manipulation. He remained short of breath and had persistent difficulties breathing in the supine position.

UNCONVENTIONAL DIETS Kwashiorkor unrelated to chronic illness has been reported in 12 cases over 9 years by US pediatric dermatologists (82c ). The children had the characteristic rash and the overall clinical presentation typical of kwashiorkor. Most of the cases were due to nutritional ignorance, perceived milk intolerance, and food faddism. • A 10-year-old boy developed a cognitive disorder, pyramidal symptoms in his legs, involvement of the posterior spinal cord, and peripheral motor and sensory degeneration (83A ). He was a member of a religious community adhering to a strict vegan diet. The cause of the problems was identified as vitamin B12 hypovitaminosis.

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Yamaguchi K. Pneumonitis induced by Ou–gon (skullcap). Intern Med 2001; 40: 764–8. 60. Pan KY, Lin JL, Chen JS. Severe reversible bone marrow suppression induced by Selaginella doederleinii. Clin Toxicol 2001; 39: 637–9. 61. Cheema P, El-Mefty O, Jazieh AR. Intraoperative haemorrhage associated with the use of extract of saw palmetto herb: a case report and review of literature. J Intern Med 2001; 250: 167–9. 62. Gertz MA, Bauer BA. Caring (really) for patients who use alternative therapies for cancer. J Clin Oncol 2001; 19: 4346–9. 63. Davies JK, Ahktar N, Ranasinge E. A juicy problem. Lancet 2001; 358: 2126. 64. Ernst E, White AR. Prospective studies of the safety of acupuncture: a systematic review. Am J Med 2001; 110: 481–5. 65. White A, Hayhoe S, Hart A, Ernst E. Adverse events following acupuncture: prospective survey of 32 000 consultations with doctors and physiotherapists. Br Med J 2001; 323: 485–6. 66. MacPherson H, Thomas K, Walters S, Fitter M. The York acupuncture safety study: prospective survey of 34 000 treatments by traditional acupuncturists. Br Med J 2001; 323: 486–7. 67. Yamashita H, Tsukayama H, White AR, Tanno Y, Sugishita C, Ernst E. Systematic review of adverse events following acupuncture: the Japanese literature. Complement Ther Med 2001; 9: 98–104. 68. Koga K, Noguchi T. Should epidurals be avoided in acupunctured patients? Anaesthesia 2001; 56: 291–2. 69. Shen D, Zhang M. A case of pneumothorax caused by acupuncture. Int J Clin Acupunct 2001; 12: 79. 70. Kao CL, Chang JP. Bilateral pneumothorax after acupuncture. J Emerg Med 2002; 22: 101–2. 71. Alani RM, Busam K. Acupuncture granulomas. J Am Acad Dermatol 2001; 45: 225–6. 72. Woo PCY, Li JHC, Tang WM, Yuen KY. Acupuncture mycobacteriosis. New Engl J Med 2001; 345: 842–3. 73. Nambiar P, Ratnatunga C. Prosthetic valve endocarditis in a patient with Marfan’s syndrome following acupuncture. J Heart Valve Dis 2001; 10: 689–90. 74. Beer A-M, Fey S, Kuhnen C, Mentzel T. Kutane Arthropodenreaktion nach Blutegeltherapie. Aktuel Dermatol 2001; 27: 42–6. 75. Ernst E. Prospective investigations into the safety of spinal manipulation. J Pain Symptom Manage 2001; 21: 238–42. 76. Ernst E. Life-threatening complications of spinal manipulation. Stroke 2001; 32: 809–10. 77. Stevinson C, Honan W, Cooke B, Ernst E. Neurological complications of cervical spine manipulation. J R Soc Med 2001; 94: 107–10. 78. Jeret JS. More complications of spinal manipulation. Stroke 2001; 32: 1936–7. 79. Ng KPL, Doube A. Stroke after neck manipulation in the post partum period. NZ Med J 2001; 114: 498. 80. Schram DJ, Vosik W. Diaphragmatic paralysis following cervical chiropractic manipulation: case report and review. Chest 2001; 119: 638–40.

Treatments used in complementary and alternative medicine 81. Tsuboi K. Retinal and cerebral artery embolism after “Shiatsu” on the neck. Stroke 2001; 32: 2441. 82. Liu T, Howard RM, Mancini AJ, Weston WL, Paller AS, Drolet BA, Esterly NB, Levy ML, Schachner L, Frieden IJ. Kwashiorkor in the United

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States. Arch Dermatol 2001; 137: 630–6. 83. Cornejo W, Gonzalez F, Toro ME, Cabrera D. Degeneración combinada subaguda. Descriptión de un caso en un nino vegetariano estricto. Rev Neurol 2001; 33: 1154–7.

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Miscellaneous drugs, materials, and medical devices

Acamprosate Acamprosate (calcium acetylhomotaurinate) has been postulated to act by restoring the alcohol-induced neurotransmission imbalance of inhibition–excitation inputs believed to underlie alcohol dependence (1R , 2r ). The molecular structure of acamprosate explains its specificity towards the basic molecular mechanisms involved in the pathophysiology of alcohol dependence. A competitive interaction has been described between spermidine and acamprosate, suggesting a specific binding site for acamprosate on N -methyl-D-aspartate receptors (3r ). To test the role of acamprosate as an aid in preventing relapse after detoxification, 296 alcohol-dependent patients entered a prospective, multicenter, randomized, doubleblind, placebo-controlled study of acamprosate 666 mg tablets tds for 180 days (4C ). Unlike previous studies, acamprosate was prescribed from the start of alcohol withdrawal, rather than after the detoxification process. During the treatment period, 110 patients dropped out. The two treatment groups were balanced with regard to baseline values and reasons for discontinuation. There was no difference between the groups in the severity of withdrawal symptoms, as measured by the CIWA–Ar (Clinical Institute Withdrawal Assessment for Alcohol scale). Acamprosate given during withdrawal did not cause unwanted effects. The overall incidence of adverse events was similar in the two groups. The number of patients who presented at least one new adverse event (not present at baseline) during the course of the study was 99 with acamprosate and 94 with placebo. Nevertheless, there was a trend for gastrointestinal © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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adverse events to be reported more often in the acamprosate-treated patients (n = 61) compared with placebo (n = 46). The individual adverse events that were reported more often with acamprosate were diarrhea, dyspepsia, constipation, and flatulence. Pruritus was reported by seven of those who took acamprosate and five of those who took placebo.

Buffergel Since there is an urgent need for topical microbicides that women can administer vaginally to protect themselves from HIV infection and possibly other sexually transmitted diseases and pregnancy, BufferGel (ReProtect LLC, Baltimore, MD), an aqueous gel of a spermicidal microbicide, formulated at pH 3.9, which acidifies twice its volume of semen to a pH of 5 and maintains the protective acidity of the vagina, should be ideal. The safety of BufferGel has been evaluated in a high-dose tolerance trial in 98 women, of whom 91 (26 sexually abstinent and 65 sexually active) completed the study (5c ). Reasons for withdrawal included: an inability to adhere to the protocol (one woman); breakthrough menstrual bleeding (two women); the presence of yeast on day 7 (two asymptomatic cases and one symptomatic case); and refusal to continue (one woman). The percentage of women with at least one sign or symptom judged by a clinician as potentially related to the product was 29% in India, 33% in Thailand, 35% in Malawi, and 33% in Zimbabwe. There were no differences in the proportions of sexually abstinent and sexually active women with at least one potentially product-related sign or symptom at each study site. In all, there were 45 potentially product-related signs and symptoms. Two were judged to be definitely related

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541

to the product (vaginal itching after product insertion) and 43 as possibly or probably related. All were categorized as mild (84%) or moderate (16%). Excluding participants who withdrew by day 7, 71% of the signs and symptoms resolved during the trial and 24% within 3 days of product withdrawal at the end of the trial; 5% persisted at the end of the trial (one woman was given treatment for a yeast infection and one was not re-evaluated for itching). Minor self-reported symptoms of irritation of limited duration accounted for 64% of reported signs and symptoms and were approximately equally distributed across study sites. They included vulvar and vaginal itching or burning, burning when urinating, and genital rash. The overall rate of symptoms of irritation for all sites combined was 0.58 events per woman-week of observation (95% CI = 0.3, 0.88). Other signs and symptoms included lower abdominal pain or backache, symptomatic yeast infection, and vaginal discharge.

Because of the short duration and severity of the metabolic acidosis, together with a near-normal lactate concentration, acid ingestion was the most likely cause for his acid-base disorder. This diagnosis was confirmed once the composition of the ingested fluid was known.

Citric acid

Cyanamide

Cardiovascular Citric acid toxicity has been reported previously, but only after intravenous administration. It was originally seen with massive transfusion of blood products with citrate as the anticoagulant. Two case reports have described accidental intravenous administration of citrate or citric acid, and at a maximum serum concentration of citrate (4.1 mmol/l) there were profound alterations in blood pressure and QT interval; these were reversed by calcium infusion (6Ac ). Metabolism Although there is a long list of causes of metabolic acidosis with an increased anion gap (7A , 8c ), clinical clues may help diagnosis. A case report has illustrated the acute metabolic and hemodynamic effects of ingestion of a massive load of oral citric acid. The principal findings included a metabolic acidosis accompanied by an increase in the plasma anion gap, not due to lactic acidosis, hyperkalemia, and the abrupt onset of hypotension (9C ). • A 42-year-old previously healthy male prisoner drank a large volume of a commercial solution of unknown composition. His medical history was non-contributory, except for severe epigastric pain.

Within an hour, his condition deteriorated; he was ashen, his blood pressure was 80/40 mmHg, and his pulse rate was 102 beats/min. His neck vessels were flat and his breath sounds were equal bilaterally, with occasional expiratory wheezes at both bases. There were no cardiac murmurs. The abdomen was soft and the bowel sounds were active. His extremities were warm with no cyanosis or edema. There were no neurological abnormalities. Fortuitously, because of therapy to avoid cardiac complications of hyperkalemia, he was given 1 g of calcium chloride, 50 mmol of sodium bicarbonate, 25 g of glucose, and 10 units of regular insulin intravenously. His blood pressure immediately increased to 116/76 mmHg and his pulse rate fell to 90 beats/min. By the next morning his plasma acid-base balance was normal, as was his ionized calcium concentration (1.1 mmol/l).

Skin Rashes due to cyanamide have been reported in two cases (10c ). • A 37-year-old man developed itchy erythema on his trunk and legs after taking cyanamide (dose not specified) for 3 days. He had an eosinophilia of 22%. Patch testing with cyanamide was positive. The eruption subsided after withdrawal of cyanamide. • A 60-year-old man developed keratotic erythema on his trunk and extremities after taking cyanamide (dose not specified) for 1 month. Patch testing with cyanamide was positive. The eruption subsided after withdrawal of cyanamide, but itch and redness persisted for 9 months.

Disulfiram

(SED-14, 1697; SEDA-23, 516; SEDA-25, 580) Disulfiram (tetraethylthiuram) has been widely used since the late 1940s to facilitate abstinence from alcohol. Concomitant use of alcohol during disulfiram therapy results in an autonomic symptom complex that can involve headache, flushing, nausea and vomiting,

542 sweating, tachycardia, hypotension, and confusion. The mechanism of action of disulfiram is inhibition of aldehyde dehydrogenase; alcohol is metabolized to acetaldehyde, which accumulates (11A ). Nervous system A 20-year-old woman was referred for implantation of an intrathecal baclofen pump (12c ). She had had severe dystonia and spasticity following a suicide attempt with disulfiram at age 14 years. T1-weighted MRI scanning of her brain showed bilateral globus pallidus infarction. She had profound relief of spasticity after intrathecal test injections of baclofen and underwent implantation of an intrathecal baclofen pump. Her spasticity subsequently improved. Disulfiram-induced neurotoxicity caused Parkinsonism in a man who had been an alcoholic for 10 years (13c ). • A 52-year-old alcoholic stopped drinking in August 1996 and started to take disulfiram 500 mg/day. His usual medications had been aspirin 300 mg/day and levothyroxine 100 microgram/day. He had had severe loss of visual acuity (2/10) in the left eye 3 months before admission. He was admitted to hospital because of drowsiness. Neurological examination showed severe hypophonia, difficulty in swallowing, and mild rigidity of the limbs. Disulfiram was withdrawn but the other medications were maintained. His drowsiness improved over 5 days, but he remained bradykinetic, with extrapyramidal hypertonia, facial hypomobility, and abnormal posture. His gait was slow and shuffling.

Psychiatric Neuropsychiatric effects of disulfiram have been reported, and have been characterized by symptoms such as paranoia, impaired memory and concentration, ataxia, dysarthria, and frontal release signs (signs that can be indicative of permanent structural damage or temporary metabolic or infectious changes to the brain’s frontal lobes), such as snout and grasp reflexes (11A , 14R ). Prolonged toxic delirium related to disulfiram and alcohol intake has been reported (15c ). The predominant presenting feature was neuropsychiatric rather than autonomic symptoms. • A 50-year-old woman with a history of bipolar disorder type I and alcohol dependence taking disulfiram had a 4-day history of a change in mental status, including visual hallucinations and deficits in orientation and concentration. Other features included a tachycardia and non-focal neurological

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signs. Extensive metabolic, infectious, and neurological investigations revealed no abnormalities that alone could explain her acute confusional state. It was subsequently discovered that she had drunk alcohol on at least two separate occasions while taking disulfiram before her change in mental status, and that a similar, although shorter, episode had occurred previously.

Fluorescein Fluorescein retinal angiography was first described in 1961 (16A ) and has since proved to be a valuable clinical investigation. Rapid intravenous injection has become the standard method of administering the dye. This technique displays retinal circulation velocity and the fine architecture and integrity of the blood retinal barrier. This is associated with minor adverse events in 21% of cases and potential life-threatening adverse events in 0.5% (17c ). The fluorescein is always diluted in cerebrospinal fluid, resulting in a hyperdense solution. For this reason it is necessary to put the patient in the Trendelenburg position for 30–40 minutes so that the fluorescein reaches the cerebral cisterns and is visualized at the level of the fistulae. Complications of the use of fluorescein, all of which were reversible in a few hours or days, have been reported (18c , 19c ). Most of the complications were associated with the use of a larger quantity of fluorescein than recommended. Three patients out of 84 in another study had urticaria, which settled within half an hour of administration of an oral antihistamine, and one had nausea, which subsided without treatment (20c ).

Gammahydroxybutyrate The Expert Advisory Committee on Drugs (EACD) in New Zealand has advised the New Zealand Medicines and Medical Devices Safety Authority to schedule gammahydroxybutyrate, 1,4 butanediol, and other “party drugs” under the Misuse of Drugs Act 1975 (21A ).

Miscellaneous drugs, materials, and medical devices

Isosulfan blue Isosulfan blue 1% aqueous solution (Lymphazurin 1%), a triphenylmethane-based dye, is the dye most commonly used for injection when sentinel node mapping is used to detect the lymphatic drainage basin of a primary malignancy. Isosulfan blue, one of the rosaniline dyes, has other names, including 129-17-9, patent blue, patent blue violet, alphazurine 26, alphazurine 2G, and Lymphazurin 1%. This dye was popular for lymphography in the 1960s and 1970s, but it has largely been replaced by newer techniques. During that period there were a few reports of severe allergic reactions (22r , 23r ). Currently, the reported incidence of allergic reactions is as high as 2.5% (24c ). Two cases of anaphylaxis and three cases of “blue hives” occurred after injection with isosulfan blue in 267 patients who had intraoperative lymphatic mapping (25c ). The two patients with anaphylaxis had cardiovascular collapse, erythema, perioral edema, urticaria, and uvular edema. The blue hives in three patients resolved and transformed to blue patches during the course of the procedures. Urticaria has also been described in three other patients. • A 52-year-old woman with history of ulcerative colitis, hypertension, and asthma underwent preoperative lymphoscintigraphy and 45 min after intraparenchymal peritumoral injections of 2 ml of 1% isosulfan blue dye her right arm and right chest became covered with blue hives (25c ). • A 57-year-old woman with a history of gastroesophageal reflux underwent preoperative lymphoscintigraphy and 25 min after intraparechymal peritumoral injections of 2 ml of 1% isosulfan blue dye she developed widespread blue urticaria involving both breasts and the entire interior abdominal wall, extending to her groin (26c ). • A 52-year-old woman with a previously removed invasive breast carcinoma had 5 ml of 1% isosulfan blue injected and the breast gently massaged, for lymphatic mapping prior to further breast surgery (27c ). She developed diffuse urticaria and was given diphenhydramine hydrochloride; hypotension responded to ephedrine. A blue-stained histologically positive lymph node was identified within a small axillary incision. Because of the hypotension, mammoplasty was abandoned, but segmental mastectomy was performed. Postoperatively, she had severe edema. She was monitored in the intensive care unit, extubated, and discharged the next

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day. Axillary node dissection and bilateral reduction mammoplasty were performed 2 weeks later with no reaction to the antibiotic and anesthetic agents.

Menthol Menthol is a cyclic alcohol, obtained from the volatile oils of various species of Mentha. It is largely used as a flavoring or olfactory agent in a variety of products, including cigarettes, liqueurs, cough drops, mouthwashes, toothpastes, and shampoos. Menthol has been used in different medications to relieve symptoms of asthma and rhinitis. It can cause perioral dermatitis, urticaria, and stomatitis (28A ). Respiratory Some reports have pointed out a relation between menthol present in toothpaste and worsening of asthma in some patients, most of them sensitive to aspirin (29R , 30R ). Cases of menthol-induced asthma are almost always associated with sensitivity to aspirin (31C ), but an exception has been reported (32c ). • A 40-year-old woman with no personal or family history of asthma had dyspnea, wheezing, and nasal symptoms for 2 years whenever she used toothpaste and/or ingested mint confections. She had no history of aspirin sensitivity, and a challenge test with a menthol solution diluted in alcohol ruled out any possibility that the asthma had been caused by preservatives, dyes, or other additives.

Skin There have been reports of urticaria and contact reactions due to menthol (28A , 29R ).

Para-phenylenediamine (Mehindi tattooing) Mehindi is an ancient art of painting the skin using a paste made from the leaves of Lawsonia inermis. This is the botanical denomination of a small shrub that grows in Egypt, Tunisia, Iran, India, Arabia, and tropical Africa, also known as henne, al-Khanna, and alhenna. The leaves of the plant are dried and then powdered, in order to obtain a yellow-green powder, which is dissolved in hot water at the time of use. Application of this paste to the skin

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for 30–40 minutes leaves a temporary tattoo. The most probable cause of contact dermatitis due to mehindi is the presence of paraphenylenediamine, which is added to the paste to strengthen its color. Among numerous mixtures that contain henna and chemical coloring agents, there is the so-called “black henna” used to perform skin drawings; it may contain natural henna, a rare and weak sensitizer, which probably contains para-phenylenediamine. • A 39-year-old housewife developed acute blistering eruptions on her upper back and left arm, the shape of which corresponded exactly to temporary tattoos made with “black henna” during a holiday in Egypt (33c ). She complained of intense itching and burning localized at the side of the dermatitis.

Silicone

(SEDA-25, 583)

Silicone has been used for more than 30 years in various medical applications, including the construction of joint prostheses and breast implants, and in tissue augmentation procedures. Foreign body giant cell granulomas were first reported after liquid silicone injection in 1965 (34A ). Since then, numerous reports have been published demonstrating granulomatous reactions to silicone at application sites and distal sites after hematogenous or lymphatic migration (35R ). • An otherwise healthy 59-year-old woman had received acupuncture for a sprained ankle several times over the previous year (36c ). She had numerous 2–5 mm waxy orange-brown papules on the dorsal aspects of both feet and ankles. A punch biopsy of one of these showed a mixed lichenoid, spongiotic, and granulomatous dermatitis. Macrophages, including many foreign body-type giant cells, were arranged in a granuloma annulare-like pattern around dermal collagen with focal mucinous alteration. Ultrastructural examination showed macrophages containing amorphous foreign material consistent with silicone. The acupuncturist had switched to silicone-plated acupuncture needles over the recent months, and she was believed to have cutaneous granulomas secondary to silicone deposition. She was treated with potent topical steroids and continued acupuncture with non-coated needles. The lesions slowly resolved over the ensuing months.

This case raises the possibility of silicone deposition from cutaneous manipulation with silicone-coated instruments over a relatively

N.H. Choulis

short duration of time. In addition, the case is remarkable in that the latency from exposure to the foreign material to the onset of lesions was relatively short (6–12 months).

Talc Pleurodesis with talc has been used for more than 50 years in the USA and Europe, and has proven to be a secure and effective method in patients with malignant pleural effusions. Malignant pleural effusions represent 25–50% of all pleural effusions seen in a general hospital (37A ). Lung, breast, ovarian, genitourinary, and gastrointestinal tract malignancies are often associated with pleural effusions, and malignant effusion is often the first manifestation of malignancy (38R , 39R ). Of 51 patients with malignant pleural effusions 14 underwent slurry talc pleurodesis via a chest tube, 14 had talc poudrage during Video-Assisted Thoracoscopic exploration of the pleural cavity for suspected malignant effusion, and 24 underwent chemical pleurodesis with bleomycin via a chest tube (40c ). The most common adverse effects were chest pain and fever. The duration of adverse effects after talc pleurodesis was longer (2–3 days) than after bleomycin. There was chest pain in 15 of the 28 patients who received talc, with a duration of 18–52 (median 31) hours. There was fever in 22 of those who received talc, with a duration of 5–34 (median 12.5) hours. Complications were more common in those who received talc, such as thoracic empyema (n = 1), wound infection (n = 2) and respiratory distress (n = 5).

Thiuram Thiurams are a group of chemicals that have been in commercial use since the 1920s. Their main uses are as accelerators and vulcanizing agents during rubber processing and as fungicides on seeds and plants. Skin Allergic contact dermatitis following exposure to thiuram compounds in rubber products, such as disposable rubber gloves, is well recognized (41R ).

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Table 1. Miscellaneous reports Drug

Adverse effect(s)

Blue dye Butyl hydroxyanisole Cinnamic aldehyde Enoxolone Fluoride Indigo carmine Indocyanine green Laureth-A (polidocanol) Methyl glucose dialate Polyoxyethylene lauryl ether Rasburicase

Contact dermatitis Allergic contact dermatitis Cutaneous vasodilatation Allergic contact dermatitis Hyperparathyroidism Allergic alveolitis Burning sensation Allergic contact dermatitis Erythematous dermatitis Contact dermatitis Skin rash, respiratory reaction, hemolysis Contact dermatitis Anaphylactic reactions Contact dermatitis Foreign body reactions, tumors, pulmonary complications Contact dermatitis

Stearyl alcohol Sulfan blue Tetraethylthiuramdisulfide Walnut oil White flower

• A 49-year-old man developed acute pruritic dermatitis of the hand, which settled quickly with oral corticosteroids and antibiotics (42c ). Six months later he developed a similar eruption, which became more widespread, involving the trunk and limbs. He had no personal or family history of atopy, and had no known allergies or previous history of skin disease. He had a widespread dry eczematous eruption, most marked in exposed areas. The rash had developed soon after he had handled plants that had been sprayed with a fungicide. The safety data sheet for this product indicated that it contained 80% thiuram. Full blood count and serum electrolytes were normal, and autoantibodies and a porphyrin screen were negative. Biopsy of the lesion showed significantly sun-damaged skin with a superficial perivascular chronic inflammatory infiltrate, confluent surface parakeratosis, and epidermal acanthosis with moderate spongiosis, consistent with a spongiotic dermatitis. He denied any previous contact with rubber gloves in both occupational and social settings and had not had dermatitis before. He was treated with sun protection, topical and oral corticosteroids, and a moisturizer. He had no further contact with the fungicide and the eruption resolved completely. He was advised to avoid all thiuram products, including rubber products and fungicides, in the future. Despite this, he subsequently developed one recurrence of hand dermatitis when he again used rubber gloves for protection at work.

MISCELLANEOUS SUBSTANCES Reports on adverse effects of other miscellaneous substances are listed in Table 1.

Reference (43c ) (44c ) (45c ) (46c ) (47R ) (48R ) (49c ) (50c ) (51c ) (52c ) (53A ) (54c ) (55c ) (56c ) (57c ) (58c )

MEDICAL DEVICES Central venous catheters

(SEDA-25,

583) Central venous catheters are reluctantly used as blood access for hemodialysis because of safety concerns and frequent complications, e.g. sepsis, thrombosis, and vessel stenosis. Nevertheless, 20% or more of all patients rely on atrial catheters for chronic dialysis because of lack of other access. Potentially fatal risks related to central venous catheters include air embolism (59c ), severe blood loss (60c ), and electric shock (61c ). These specific risks have been substantially eliminated by the inherent design and implantation of Dialock (Biolink Corporation, USA). Dialock is a subcutaneous device consisting of a titanium housing with two passages with integrated valves connected to two silicone catheters. The system is implanted subcutaneously below the clavicle. The tips of the catheters are placed in the right atrium. The port is accessed percutaneously with needle cannulas. The results of a study of Dialock® /CLS, the first study using an antimicrobial catheter locking solution in a large number of patients, have been reported in 70 patients (29 men, 41 women; mean age at implantation 63 (range 30–88) years), of whom 42 had no infection (45 when infections occurring within 30 days after implantation were omitted) (62R ). Excluding these early events, 25 patients had a total of

546 30 infections. The majority (22 events in 20 patients) were pocket infections. The first seven of these pocket infections caused loss of the Dialock. After local treatment with gentamicin no further devices were lost through pocket infection. No infections were recorded during the last 3 months, although the expected rate calculated on the basis of previous occurrences

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would have been about four. This may have been related to increased nursing care. Immunologic Anaphylaxis to a central venous catheter (ARROWg+ ard Blue® Catheter) coated with chlorhexidine and sulfadiazine has been reported in a 50-year-old man (63A ).

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28. Morton CA, Garioch J, Todd P, Lamey PJ, Forsyth A. Contact sensitivity to menthol and peppermint in patients with intra-oral symptoms. Contact Dermatitis 1995; 32: 281–4. 29. McGowan EM. Menthol urticaria. Arch Dermatol 1966; 94: 62–3. 30. Kwane H. Aspirin-induced asthma and artificial flavors. Chest 1994; 106: 654–5. 31. Kwane H. Menthol and aspirin-induced asthma. Respir Med 1996; 90: 247–9. 32. Dos Santos MA, Galrao CES, Castro FM. Menthol-induced asthma: a case report. J Invest Allergol Clin Immunol 2001; 11: 56–8. 33. Schiera A, Battifoglio ML, Rossi L, Nicoletti A, Galbiati G. Contact dermatitis caused by mehindi. Acta Dermatovenereol Alp Panonica Adriat 2001; 10: 57–61. 34. Ballantyne DL Jr, Rees TD, Seldman I. Silicone fluid: response to massive subcutaneous injections of dimethylpolysiloxane fluid in animals. Plast Reconstr Surg 1965; 6: 330–8. 35. Travis WD, Balogh K, Abraham JL. Silicone granulomas: report of three cases and review of the literature. Hum Pathol 1985; 16: 19–27. 36. Alani RM, Busam K. Acupuncture granulomas J Am Acad Dermatol 2001; 45: S225–6. 37. Deslauriers J, Beauchamp J, Desmeules M. Pleural neoplasms and malignant pleural effusion. In: Baue AE, Geha AS, Hammond GL, Laks H, Naunheim KS, editors. Glenn’s Thoracic and Cardiovascular Surgery, 5th edition, volume 1. Prentice-Hall International Inc, 1991; 473–8. 38. Sahn SA. Malignant pleural effusions. In: Shields TW, LoCicero J, Ponn RB, editors. General Thoracic Surgery, 5th edition, volume 1. Philadelphia: Lippincott Williams and Wilkins, 2000: 795–803. 39. Rodrigeuz-Panadero F, Borderas Naranjo F, Lopez Mejias J. Pleural metastatic tumors and effusions. Frequency and pathogenic mechanisms in a post-mortem series. Eur Resp J 1989; 2: 366–9. 40. Foroulis CN, Kotoulas C, Konstantinou M, Lioulias A. The management of malignant pleural effusions: talc pleurodesis versus bleomycin pleurodesis. J BUON 2001; 6: 397–400. 41. Von Hinzenstern J, Heese A, Koch HU, Peters KP, Hornstein OP. Frequency, spectrum and occupational relevance of type IV allergies to rubber chemicals. Contact Dermatitis 1991; 24: 244– 52. 42. Saunders H, Watkins F. Allergic contact dermatitis due to thiuram exposure from a fungicide. Aust J Dermatol 2001; 42: 217–18. 43. Guin JD. Seat-belt dermatitis from disperse blue dyes. Contact Dermatitis, 2001; 44: 263. 44. Orton DI, Shaw S. Allergic contact dermatitis from pharmaceutical grade BHA in Timodine® , with no patch test reaction to analytical grade BHA. Contact Dermatitis 2001; 44: 191–2. 45. VemderEude DS, Morrow JD. Release of markedly increased quantities of prostaglandin D2 from the skin in vivo in humans after the application of cinnamic aldehyde. J Am Acad Dermatol 2001; 45: 62–7.

46. Tanaka S, Oksuki T, Matsumoto Y, Hayakawa R, Sugiura M. Allergic contact dermatitis from enoxolone. Contact Dermatitis 2001; 44: 192. 47. Gupta SK, Khan TI, Gupta RC, Gupta AB, Gupta KC, Jain P, Gupta A. Compensatory hyperparathyroidism following high fluoride ingestion. A clinico-biochemical correction. Indian Pediatr 2001; 38: 139–46. 48. Steurich F, Feyerabend R. Campari-/Karmin/Cochenille-Allergie. Farbstoffe in Lebensuitteln, Medikamenten und Kosmetika. Allergologie 2001; 24: 66–72. 49. Szeimies RM, Lorenzen T, Karrer S, Abels C, Plettenberg A. Photochemotherapy of cutaneous AIDS-related Kaposi sarcoma with indocyanine green and laser light. Hautarzt 2001; 54: 322–6. 50. Gallo R, Basso M, Voltolini S, Guarrera M. Allergic contact dermatitis from laureth-9 and polyquaternium-7 in a skin-care product. Contact Dermatitis 2001; 45: 356–7. 51. Corazza M, Levratti A, Virgili A. Allergic contact dermatitis due to methyl glucose dioleate. Contact Dermatitis 2001; 45: 308. 52. Kimura M, Kawada A. Follicular contact dermatitis due to polyoxyethylene laurylether. J Am Acad Dermatol 2001; 42: 879–80. 53. Easton J, Noble S, Jarvis B. Rasburicase. Paediatr Drugs 2001; 3: 433–7. 54. Yesudian PD, King CM. Allergic contact dermatitis from stearyl alcohol in Efudix cream. Contact Dermatitis 2001; 45: 313–14. 55. Gimenez J, Botella-Estrada R, Hernandez D, Carbenell M, Martinez MA, Guillen C, Vazquez C. Anaphylaxis after peritumoral injection of sulpham blue 1% for identification of the sentinel node in lymphatic mapping of the breast: case report. Eur J Surg 2001; 167: 921–3. 56. Gutgesell C, Fuchs T. Orally elicited allergic contact dermatitis to tetraethylthiuramdisulfide. Am J Contact Dermatitis 2001; 12: 235–6. 57. Munch IC, Hvolris JJ. Intramuscular injection of walnut oil as an aid to body-building. Ugeskr Laeg 2001; 163: 6758. 58. Saary MJ, Holness DL. Contact dermatitis from white flower embrocation. Contact Dermatitis 2001; 44: 100. 59. Orebaugh SL. Venous air embolism: clinical and experimental considerations. Crit Care Med 1992; 20: 1169–77. 60. Lau G. Iatrogenically-related, fatal haemorrhage occurring in end-stage renal failure: a series of three cases. Forens Sci Int 1995; 73: 117–24. 61. Jonsson P, Stegmayr BG. Current leakage in haemodialysis machines varies. Int J Artif Organs 1999; 22: 425. 62. Sodemann K, Polaschegg HD, Feldmer B. Two years experience with Dialock® and CLS™ (a new antimicrobial lock solution). Blood Purif 2001; 19: 251–4. 63. Stephens R, Mythen M, Kallis P, Davies DW, Egner W, Rickards A. Two episodes of life-threatening anaphylaxis in the same patient to a chlorhexidine–sulphadiazine-coated central venous catheter. Br J Anaesth 2001; 87: 306–8.

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The WHO International Drug Monitoring Programme

History The WHO International Drug Monitoring Programme was established in 1968 as a pilot project, with the participation of ten countries that had organized national pharmacovigilance systems at that time. The intention was to develop international collaboration to make it easier to detect rare adverse drug reactions not revealed during clinical trials. The International Drug Monitoring Centre was moved from WHO headquarters in Geneva, Switzerland, to a WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, in 1978. This was the result of an agreement between the WHO and the Swedish Government, by which Sweden assumed the operational responsibility for the Programme. WHO headquarters in Geneva retained the responsibility for policy matters. The Collaborating Centre is often referred to as the Uppsala Monitoring Centre (UMC). Information about the WHO and the UMC can be obtained from their websites: www.who.int/medicines and www.whoumc.org. A new negotiation between the WHO and the Swedish Government was completed in 2001, and the Uppsala Monitoring Centre is now a non-profit-making foundation, with a Board appointed partly by the WHO and partly by the Swedish Government, as well as having a jointly agreed Director.

Vision and goals of the Uppsala Monitoring Centre It is the aim of the Uppsala Monitoring Centre to support WHO’s leadership in the field of world health by providing excellence: • in the science and concepts of all aspects of pharmacovigilance; • to prevent harm to humans from the effects of medicines; • to gather and share objective intelligence and opinion in the field of drug safety through open and transparent means of communication; • to support the promotion of the rational use of drugs, and the achievement of improved patient therapy and public health; • in global education and communications in benefit, harm, effectiveness, and risk in medical therapy. This will be achieved by the following activities: • developing leading-edge systems and science for the identification and communication of safety hazards from drugs and other substances used in medicine; • carrying out research that pushes forward the ethical, intellectual, and scientific boundaries of theory and practice in pharmacovigilance; • pursuing active collaboration and communication with all stakeholders; • pursuing the goal of a single global database for drug safety data. The Uppsala Monitoring Centre will particularly:

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• ensure that effective, timely, international collective effort will never miss a signal of a potential hazard;

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Table 1. Members of the WHO International Drug Monitoring Programme and their year of entry Country

Year of entry

Country

Year of entry

Country

Year of entry

Argentina Armenia Australia Austria Belgium Brazil Bulgaria Canada Chile China, PR Costa Rica Croatia Cuba Cyprus Czech Republic Denmark Egypt Estonia Fiji Islands Finland France Germany Ghana Greece

1994 2001 1968 1991 1977 2001 1975 1968 1996 1998 1991 1992 1994 2000 1992 1968 2001 1998 1999 1974 1986 1968 2001 1990

Guatemala Hungary Iceland India Indonesia Iran Ireland Israel Italy Japan Jordan Korea, Republic of Latvia Macedonia Malaysia Mexico Moldova Morocco Netherlands New Zealand Norway Oman Peru Philippines

2002 1990 1990 1998 1990 1998 1968 1973 1975 1972 2002 1992 2002 2000 1990 1998 2003 1992 1968 1968 1971 1995 2002 1995

Poland Portugal Romania Russia Singapore Slovak Republic South Africa Spain Sri Lanka Sweden Switzerland Tanzania Thailand Tunisia Turkey Ukraine United Kingdom Uruguay USA Venezuela Vietnam Yugoslavia FR Zimbabwe

1972 1993 1976 1998 1993 1993 1992 1984 2000 1968 1991 1993 1984 1993 1987 2002 1968 2001 1968 1995 1999 2000 1998

Associated member countries: Netherlands Antilles Bahrain

Belarus Kyrgyztan

• ensure that all stakeholders evaluate and learn from decisions and actions through positive impact assessment, follow-up, and debate; • encourage the growth of pharmacovigilance activities around the world, in particular the establishment of new National Centres; • promote existing National Centres and other stakeholders in the field; • contribute actively to the global vision of the WHO Programme; • use and share available information openly and transparently; • sponsor and support others in their pharmacovigilance activities; • exploit fully the resources of the Uppsala Monitoring Centre; • stimulate the development of coherent, harmonized systems worldwide for pharmacovigilance, through education, training, promoting and participating in international forums, promoting best practice, and the publication of guidelines; • maintain and develop useful products, services, and tools in pursuit of the vision and

Pakistan Zambia

goals of the WHO Programme and the Uppsala Monitoring Centre.

Current programme structure At present 71 countries are active members of the WHO Programme. Six countries have formally applied for membership, and they are considered as associated members while the issue of the technical compatibility of their reports with the WHO requirements is established. Member countries and associated member countries are listed in Table 1. In each country a national centre or system, designated by the competent health authority, is responsible for collecting, processing, and evaluating adverse reaction case reports submitted by health professionals. Information obtained from these reports is passed back to the professionals on a national basis, but is also submitted to the WHO Centre for inclusion in the international database. Collectively the centres

550 annually provide over 200 000 individual reports to the WHO of reactions suspected of being drug-induced. The cumulative database of the WHO Programme now comprises nearly 3 million case reports. Case reports submitted to the WHO are checked for technical correctness and are then incorporated into the international database in a daily routine. Reports may be submitted either in the format recommended by the E2b working party of ICH (International Conference on Harmonization) or in the format previously agreed within the WHO Drug Monitoring Programme. In 2002 a new database that allows the storage of much more information, as proposed by the Council of Organizations of Medical Sciences (CIOMS) monograph 1(a) (1S ) and adapted by the ICH project E2b, was introduced.

Signal finding Each national centre reasonably focuses on its own country’s issues and data, turning to international information for secondary support. The WHO Programme has the only international repository of adverse drug reaction reports, in which one can look at the pooled information for signals on all reported medicinal products from around the world. The need for automated tools to help deal with all this information is great, but the tools must be such that they do not obscure the tentative nature of the information and conclusions. The tools must aid human review and not replace it. It is a truism that people do not cope with large amounts of information, let alone multiple variables, missing data, and data of variable quality. A combination of automatic signalling devices and scanning by experienced medical personnel is now considered by the Uppsala Monitoring Centre most advantageous in successfully fulfilling the original aim of the programme, i.e. the early identification of new adverse drug reactions. In 1998 a new method developed at the Uppsala Monitoring Centre, using a Bayesian Confidence Propagation Neural Network (BCPNN) (2, 3) in analysing the database, was put into routine use. This method provides a quantitative measure of the strength of association of a drug/reaction combination in the database (4).

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The BCPNN method has been tested as a routine tool for finding new adverse drug reactions in the WHO database; its positive predictive value is a little less than 50%, but its negative predictive value is about 85% (5). When the new data have been processed and entered into the database, a BCPNN scan is run to generate statistical measurements for each combination of drug and adverse reaction. The resulting combinations database is made available to national centres and pharmaceutical companies, in the latter case as a subscription service on selected drugs. The database is presented in a computerized form, with software that facilitates searching and sorting of the information. Associations are selected from the combinations database based on a preset threshold. Based on the results of the test runs of the BCPNN, the threshold for associations is set to the lower 95% confidence limit of the Information Component (IC) crossing zero when a new batch of reports is added. The Information Component in information theory is a measure of disproportionality, indicating how strongly a data field or complex of data fields stands out from the background of information value. The UMC puts greatest emphasis on identifying early signals concerning serious, potentially fatal reactions reported with new medicines. A series of criteria are used for focusing on the prioritized areas: • drugs first entered into the WHO database in the last 1–2 years; • serious reactions included in the WHO List of Critical Terms; • at least one report having a fatal outcome; • the drug–ADR combination exceeds the statistical threshold of having a lower 95% confidence limit of the IC above zero; • few reports about the combination. In addition, attention is given to drug–reaction combinations that fulfil the statistical threshold mentioned above, when the IC has increased at least two-fold since the last quarterly analysis. Special consideration is also given to certain reactions that are often drug induced e.g. Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, and rhabdomyolysis. The combinations selected by any of the above criteria are checked by the UMC staff for

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occurrence in the available product information literature, e.g. the Physician’s Desk Reference or Martindale’s Extra Pharmacopoeia or using Medline and Reactions Weekly. If the reaction is not found or not sufficiently well described, case reports are retrieved from the WHO database. The collected documentation is submitted to the most appropriate expert in the UMC panel of signal reviewers, who is asked to assess the evidence that the reaction was caused by the suspected drug. Short summaries of reviewers’ findings are circulated to participating national centres in a memorandum called “Signal”. Selected associations are followed for 2 years, the data being checked at 6-monthly intervals. After the final listing, an association may be reintroduced for another 2-year follow-up. Investigations have shown that the WHO Programme is successful in finding new drug– reaction associations at an early stage and in providing useful information about them to national centres. Individualized sections of the “Signal” document are provided to companies (only on their patented products). Companies are invited to provide an analysis of the suspected drug problem for inclusion in the “Signal” document. A larger number of variables than the routine drug–reaction combinations can also be considered using the Bayesian approach described above. Searching and sorting of the associations data can be done, not only on drug, adverse reaction, and the various statistical measurements, but also on System Organ Class and on therapeutic drug groups using the Anatomical– Therapeutic–Chemical (ATC) classification (6). The system can be used in other ways. For example, the effects of including drugs reported as “concomitant medications” can be studied using the BCPNN. One of the outcomes of these analyses might be to identify patient subgroups at particularly high risk of a specific adverse reaction to a specific drug. Another possibility is to establish that a drug safety problem is related to a particular country, region, or time period. However, it should be pointed out that, in order for these data to be useful, a substantial number of case reports is required. The BCPNN has also been used for the first time for “unsupervised pattern recognition” of multiple variables in the database. This is being developed into a routine tool.

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Reference source and database The database of the WHO Programme is a unique reference source that is used in many different circumstances. When a national centre receives the first report of an unfamiliar drug– reaction association, the WHO database is often consulted to find out whether a similar observation has been made elsewhere in the world. If so, the initial signal may be strengthened. National centres are provided with an annual reference document on CD-ROM that provides summary figures of suspected drug–reaction associations reported to the WHO. On-line search facilities, accessible over the Internet, are also at the disposal of national centres for up-to-date checking of what has been reported. In order to speed up the accrual of useful case data, a primary consideration is the structure of databases. In the past, database structure has been limited in the number of fields provided, partly because of limited computer storage capacity, but also because single-sheet reporting forms have been thought to be user friendly and that reporters would be put off reporting by what appeared to be a lengthy questionnaire. This has meant that the information sent to national centres has been limited by the design of the forms used, and that sent to the WHO database has been further limited because of storage capacity. In the modern world all that has changed. It is possible to capture information for reporting from the doctor’s notes and prescribing information in an automated way, thus making the reporting of more data much easier. We have collaborated with ICH on international agreement on information technology standards for the transmission of data in a secure way. With first CIOMS (1) and then ICH we have developed a comprehensive set of data fields; these have been included in our new database, Vigibase (7, 8). The new database has great complexity, and it seems unlikely that many of the available fields will be completed until a “paperless” system comes into operation in several countries. The new database is fully compatible with the old one. To provide flexibility for users with varying requirements and sophistication is a great challenge, but we are hopeful that Vigibase will pave the way for the international availability of much more useful case data, without recourse to the original provider for more details.

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Quantification There is a general need to quantify adverse drug reactions information. Under-reporting of adverse reactions in routine monitoring is the norm. However, the degree of under-reporting differs from time to time, from place to place, and from drug to drug. The WHO centre is working jointly with IMS International, to analyse adverse reaction reports together with drug use data from different countries. This allows national differences in reporting rates to be further analysed for reasons that may be due to differences in indications for use, medical practice, demographics, etc. Several new signals have been evaluated in this way, often making it clearer what biases might be present both geographically and over time. Bearing such problems in mind, cautious comparisons of reporting rates between medicinal products are often revealing (9–12). This type of analysis of international data serves as a guide to the need for more precise pharmacoepidemiological investigations.

A clearing house for information The Uppsala Monitoring Centre has an important role to play as a communication centre—a clearing house for information on drug safety at the service of drug regulatory agencies, the pharmaceutical industry, researchers, and other groups in need of drug safety information (13). Requests for special database searches and investigations are received from these parties at a rate of around 300 per year. In addition, flexible on-line retrieval programmes are made available through Internet, by which database users can perform a variety of standardized searches by themselves. Access for non-member parties is subjected to confidentiality restrictions agreed by Programme members. Countries have the right to refuse the release of their own information if they so wish, and some do. Use of the information released is subject to a caveat document as to its proper use. Detailed manuals for the on-line service and the customized retrievals on request are available from the Uppsala centre.

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WHO member countries are provided with the WHO Pharmaceuticals Newsletter, distributed by the Health Technology & Pharmaceuticals department of WHO headquarters. The Uppsala Monitoring Centre is responsible for the information that is included in the drug safety section of this newsletter, which is also available from the WHO web site. An agreement with Adis International has allowed information from newsletters produced by members of the WHO Programme to be printed in “Reactions Weekly”. The agreement includes making this journal available to national centres at heavily discounted subscription rates, greatly enhancing their access to up-to-the-minute information on adverse drug reactions. “Uppsala Reports” is the name of a bulletin that is made freely available to all interested parties by the Uppsala Monitoring Centre. It provides an easy-to-read account of news about pharmacovigilance in general, the WHO Programme, and its members and services. Communications within the WHO Programme have improved with the increasing use of electronic communications media. The Uppsala Monitoring Centre maintains an e-mail discussion group called “Vigimed”, which allows rapid exchange of information around the world on drug safety matters. Membership is restricted to persons connected with national pharmacovigilance centres. The Internet home page of the WHO Programme (http://www.who-umc.org) was introduced in 1996. It is intended to be developed into a dynamic tool for communications with all clients of the Uppsala Monitoring Centre. Recently, internet-based seminars and training courses were introduced on the Uppsala Monitoring Centre web site. The Uppsala Monitoring Centre publishes a book, “National Pharmacovigilance Systems— Country Profiles and Overview” (14), in which the operating procedures of the national centres that participate in the WHO Programme are described.

Terminology and standards The WHO Programme has assumed responsibility for developing a standardized adverse

The WHO International Drug Monitoring Programme

reactions terminology (WHO–ART) and a comprehensive index of reported drugs (WHO– DD), both of which have a utility beyond their importance to the monitoring system. These tools are used in the premarketing safety area, as well as for postmarketing studies by many pharmaceutical companies. WHO–ART has also been adopted by the International Programme on Chemical Safety as the medical terminology to describe poisoning incidents. The WHO Drug Dictionary (WHO–DD) is unique in its coverage of drugs marketed throughout the world. It is available in hard copy or as computer files. The Uppsala Centre is developing it further, to incorporate more detailed information and to make it compatible with the prestandard proposed by the European Committee for Standardization (CEN). In response to the challenge to safety monitoring offered by traditional herbal remedies, the WHO centre has taken initiatives to improve the classification systems for such medicines. In a joint project (15–18) with institutions such as the Royal Botanical Gardens, Kew, in the UK, others in South Africa and the Netherlands, and including the phytotherapy industry, a system compatible with the ATC system used for modern synthetic medicines has been developed. This is now being implemented in the WHO–DD. Input from experts from all parts of the world, representing different therapeutic traditions, will be indispensable for the further development of this project. The way in which adverse drug reactions terminology is used is an important factor in data mining. The development of definitions and guidelines for the use of terms is paramount. We have worked with CIOMS in this area, resulting in the publication of definitions that are useful in pharmacovigilance (19). It is hoped that this work can be extended. In data mining, the hierarchical linkage between terms is less important. On the other hand we are aware of the need by many people for some harmony in this area. The advent of MedDRA as a commercial terminology has caused some difficulties, since it is not yet clear that it represents a clear overall improvement. The WHO and Uppsala Monitoring Centre are actively looking at ways in which the different types of terminology can be used in a parallel fashion, while we find a way forward that will offer clear benefits. One obvious proposal is to link WHO–ART

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with the world standard, the International Classification of Disease (ICD 9 and 10). We are pursuing this, since ICD has the advantage of having a core structure on to which variants can be grafted in a transparent way. There are already domain versions of ICD, for example in neurology and psychiatry, which follow the common ICD logic. Definitions for terms are already available in ICD. The advantage to WHO in maintaining such a unbiased normative terminology, which can be used for any aspect of public health epidemiology in any country in the world, and at minimal cost, must be clear. Within the WHO Programme a number of definitions of commonly used terms (such as adverse reaction, side effect, adverse event, signal) have been worked out. These definitions contribute to a harmonized way of communicating both inside and outside the Programme (20). However, approaches to, and the extent of, pharmacovigilance are being considered all the time. New definitions therefore need to be considered (21R ).

Education In order to foster education and communication in pharmacovigilance, every second year the WHO Centre offers a 2-week training course in “Pharmacovigilance—the Study of Adverse Drug Reactions” in Uppsala, to which 25 health-care professionals are accepted. The course is divided into two modules. The first is about spontaneous monitoring and the practicalities of managing a drug monitoring centre. This section also offers hands-on experience in using the database of the WHO Programme. The second module is an introduction to wider issues in pharmacoepidemiology. There is an increasing trend towards local and regional meetings and courses in pharmacovigilance. The WHO Programme often takes part in such meetings, particularly those organized in developing countries, to provide support and technical advice.

Support to national centres Along with the provision of the new database, Vigibase (which is also offered as a singlestop repository for industry reports, rather than

554 their sending them to each national centre), we have developed a computer software suitable for processing and managing adverse reaction reports at a National Centre. The UMC has been collaborating with the Swiss medicines agency, Swissmedic, on the challenge of improving ADR reporting and feedback in the age of the Internet. The web has made possible the creation of a channel for improved communication between reporting physicians and a pharmacovigilance centre. The system accesses Vigibase over the Internet; thus, no local installations are required, and therefore no licenses of database systems and servers. Reports can be entered and assessed via a secure Internet connection by the individual who reports an ADR. Assessors from a regional centre and the national centre then access the report. The collaboration with the Swiss agency has guaranteed a solution that solves the basic needs of a National Centre, and it can be developed to add new useful functionality. When the report is completed it is downloaded to the Vigibase database, where it will be available for searching by the reporting centre and all other National Centres. It will also be available for statistical analysis by the UMC.

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Communication Through its consultants, the Uppsala Monitoring Centre continues to offer advice and training on all aspects of the communication of the complex messages of benefit and harm, effectiveness and risk to all stakeholders in drug safety (25). The WHO and the Uppsala Monitoring Centre have recently developed and published several guidelines and position documents, with the aims of improving general knowledge of basic concepts in benefit/harm assessment and pharmacovigilance, and of expanding the horizons beyond searching for new signals to new medicinal products (26, 27). This includes issues that vary from new professional concerns (such as poisoning by drugs, fraudulent drugs, and adverse reactions to herbal remedies) to promoting the view that consumer reports have unique importance in telling us what patients feel about the adverse events they experience. They may not be telling us about new adverse reactions, but they are giving us their concerns, which must be considered and acted upon (28, 29). A new UMC monograph on key issues of communication in the medicines safety area was published in 2002 (30).

Annual meetings Harm and risk The consideration of benefit/effectiveness versus harm/risk has so far been almost entirely at a descriptive level. Most of the work so far in this area is confined to describing the benefits and the risks separately for each medicinal product. The more difficult task of deriving a useful analysis and then a synthesis of the information is accorded much less attention. The situation is changing and there is an increasing effort to give semi-quantitative tabular summaries of information for all medicines that might be used for a specific indication. On the other hand, there is a need for an improved conceptual approach to what is benefit and harm, effectiveness and risk, as well as more technical thinking over how to improve comparisons between medicinal products (22–24).

Every year representatives of national centres are invited to a meeting arranged jointly by the WHO and one of the participating countries. At these meetings technical issues are discussed, in relation to how to improve global drug monitoring in general and concerning individual drug safety problems. Since the meetings have very high attendance rates, they are important for establishment and maintenance of personal relationships and subsequently contribute to good communications.

Collaboration with other organizations Co-operation with organizations that are interested in developing early signals of significance is of importance in achieving safer drug

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therapy. The International Society for Pharmacoepidemiology (ISPE) is specifically interested in the science of pharmacovigilance, and the Council for International Organizations of Medical Sciences (CIOMS) is pivotal in bringing interested parties together to mount various collaborative projects. Much support has been given to the International Society of Pharmacovigilance (ISoP). The WHO is also involved in the ICH processes, as observers at all meetings, and the Uppsala Monitoring Centre provides additional technical advice to WHO when required.

Developments needed in the immediate future Given the considerations discussed above, the biggest challenge we face is how to manage efficiently the large amount of risk information that accumulates while a medicinal product is being aggressively marketed (31). Our failure to cope with this challenge can have two opposite consequences: failure to recognize a signal early, causing unnecessary exposure of patients to harm, and deletion of a medicinal product due to hasty action on poorly considered information. Many will argue that pharmacoepidemiology and the use of, mainly, case-control studies will provide a surer answer to safety questions. The extent to which this is true is very limited, for the following reasons. Most medicines safety signals, including those that arise from how the particular product was used, come from experience contained in accumulated single case reports. It is not possible to perform an epidemiological analysis of each signal: the cost is prohibitive. Case–control studies suffer from biases, just as case reports do. Case– control studies, while very suitable for rare events, often have problems of power from a practical standpoint. Rare but clinically serious events are not easily investigated without long multicentre studies, and sometimes cannot be reasonably investigated at all by this method. The use of continuous, comprehensive, and rigorously collected data on medicinal products, and their use to provide information on benefit and harm, has long been seen as attractive. Postmarketing surveillance of a restricted

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number of medicines (used as a continuous method in New Zealand and the UK) has provided useful new information on a limited range of medical products, with limited comparative opportunities. Health-care databases mainly in the USA and UK have also been useful. Their limitations are size and their structure, which does not necessarily allow all the relevant information to be collected, nor for the finding of new signals relating to properties of medicines or their use: their role has been restricted to hypothesis testing using nested studies. Almost the whole effort of this vast collection machinery for clinical case report information is directed towards finding new adverse reactions signals. Little use is made of the data for other signal work, such as finding atrisk groups (do some adverse reactions occur disproportionately with age?), interactions (do known reactions occur more frequently with certain drug combinations?), or use-related adverse reactions (do certain reactions occur more often in certain countries? at higher doses?). This is not surprising, since the quantity of data is so great and most national centres have few resources. Several needs are apparent if we are to meet the challenges of the future. Amongst the most important are: I. To encourage clinicians to report their clinical experience. The concentration only on new and rare adverse reactions to new drugs is not going to help us get information that will allow us to tackle avoidable reactions adequately (32). II. To give advice about the diagnosis and management of adverse reactions. III. To improve the rapid transmission of quality information to national centres and industry, and thence to the WHO database. IV. To bridge the gap between a tentative signal from raw adverse reactions data to observational studies that use specific protocols and to clinical outcomes (33). V. To link genetic information with adverse reactions. In 2002 the World Health Assembly passed a resolution on Quality of Care–Patient Safety emphasizing the need to establish and strengthen science-based systems for improving patient safety and monitoring of adverse events.

556 Whether or not this kind of work should be linked to the current work of national regulatory agencies and the WHO Programme for International Drug Monitoring is a consideration. Perhaps the overlap in the work will be regarded as large enough to warrant using the existing adverse reactions monitoring machinery, but much depends on how far there will be monitoring of other medical misadventures and the attitude of national monitoring agencies. It is clear to any clinical pharmacologist that causation of disease by medicines is often missed in the differential diagnosis. Failure to take an adequate medication history is one reason, but the complexities of polypharmacy in elderly patients with multiple diseases make diagnosis difficult. Education of undergraduates and postgraduates in the logical approach to a diagnosis of medicine-related injury has been neglected. The reason for failure to report adverse drug reactions is an old topic. Redoubled efforts with new initiatives are required. Modern communications theory throws some light on reasons for under-reporting. Failure to understand the motivation of doctors and the need for health professionals to understand the adverse drug reactions reporting schemes and to see why they

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are important to them in their clinical practice are critical issues. It is likely that modern information technology can contribute to better reporting in some countries. This need not be only in the most developed countries. Argentina had one of the first e-mail adverse drug reactions reporting systems to function on a routine basis, linking regional centres, based in hospitals, to the national regulatory authority. The gap between the analysis of raw data to find a signal and the need to perform more formal studies is of great importance. The decision to perform the latter must be based on the seriousness of the event, the strength of the causal relation, and an idea of the medicine-related fraction of that event. The latter piece of information is much helped by having information on where, how, and how widely a medicine is used. Unfortunately, there still seem to be problems in obtaining full information on the use of medicines. The advent of genotyping technology throws open the possibility of not only genotyping for pharmacokinetic phenotypic variation, but also of examining pharmacodynamic phenotypes. This should allow the identification of people at risk and the possibility of preventing some adverse reactions.

REFERENCES 1. CIOMS. Harmonization of data fields for electronic transmission of case-report information internationally. Public report. Geneva: CIOMS, 1995. 2. Orre R, Lansner A, Bate A, Lindquist M. Bayesian neural networks with confidence estimations applied to data mining. Comput Stat Data Analysis 2000; 34: 473–93. 3. Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 1998; 54: 315–21. 4. Lindquist M, Edwards IR, Bate A, Fucik H, Nunes AM, Ståhl M. From Association to Alert— a revised approach to International Signal Analysis. Pharmacoepidemiol Drug Saf 1999; 8: S15–25. 5. Lindquist M, Ståhl M, Bate A, Edwards IR, Meyboom RHB. A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database. Drug Saf 2000; 23: 533–42. 6. Bate A, Lindquist M, Orre R, Edwards IR, Meyboom RHB Data mining analyses of pharmacovig-

ilance signals in relation to relevant comparison drugs. Eur J Clin Pharmacol 2002; 58: 483–490. 7. Lindquist M, Edwards IR. The WHO Programme for International Drug Monitoring, its database, and the technical support of the Uppsala Monitoring Center. J Rheumatol 2001; 28: 1180–7. 8. Lindquist M. The WHO Programme for International Drug Monitoring: the Present and Future. In: Mitchard M (editor). Electronic Communication Technologies. Buffalo Grove: Interpharm Press Inc, 1998; 527–49. 9. Lindquist M, Edwards IR. Risks of non-sedating antihistamines. Lancet 1997; 349: 1322. 10. Lindquist M, Pettersson M, Edwards IR, Sanderson J, Taylor N, Fletcher P, Schou J, Fraunfelder FT. Omeprazole and visual disorders: seeing alternatives. Pharmacoepidemiol Drug Saf 1996; 5: 27–32. 11. Lindquist M, Pettersson M, Edwards IR, Sanderson J, Taylor N, Fletcher P, Schou JS, Savage R. How does cystitis affect a comparative risk profile of tiaprofenic acid with other non-steroidal antiinflammatory drugs? An international study based

The WHO International Drug Monitoring Programme on spontaneous reports and drug usage data. Pharmacol Toxicol 1997; 80: 211–17. 12. Lindquist M, Sanderson J, Claesson C, Imbs JL, Rohan A, Edwards IR. New pharmacovigilance information on an old drug—an international study of spontaneous reports on digoxin. Drug Invest 1994; 8: 73–80. 13. Olsson, S. The role of the WHO Programme on International Drug Monitoring in coordinating worldwide drug safety efforts. Drug Saf 1998; 19: 1–10. 14. Olsson S (editor). National Pharmacovigilance Systems: Uppsala Monitoring Centre. 2nd edition. Uppsala: The Uppsala Monitoring Centre, 1999. 15. Edwards IR. Monitoring the safety of herbal remedies: WHO project is under way. Br Med J 1995; 311: 1569–70. 16. Farah MH. Consumer protection and herbal remedies. WHO Drug Inf 1998; 12: 141. 17. Farah MH, Edwards IR, Lindquist M, Leon C, Shaw D. International monitoring of adverse health effects associated with herbal medicines. Pharmacoepidemiol Drug Saf 2000; 9: 105–12. 18. Fucik H, Farah MH, Meyboom RHB, Lindquist M, Edwards IR, Olsson S. Vigilance of herbal medicines at the Uppsala Monitoring Centre. Minerva Med 2001; 92: 24–6. 19. CIOMS. Reporting of adverse drug reactions: definitions of terms and criteria for their use. Report No. 9290360712. Geneva: CIOMS, 1999. 20. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994; 10: 93–102. 21. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255–9. 22. Edwards IR, Lindquist, M. Understanding and communication of key concepts in therapeu-

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tics. In: Velo G (editor). Moments of truth— communicating drug safety. Verona: Elsevier Science, 2000: 9–14. 23. Edwards IR, Wiholm B-E, Martinez C. Concepts in risk–benefit assessment. Drug Saf 1996; 15: 1–7. 24. CIOMS, editor. Benefit-risk balance for marketed drugs: evaluating safety signals, 1st edition. Geneva: World Health Organization, 1998. 25. Edwards IR, Hugman B. The challenge of effectively communicating risk–benefit information. Drug Saf 1997; 17: 216–27. 26. WHO Collaborating Centre for International Drug Monitoring, Viewpoint—Watching for safer medicines. Part 1. Uppsala, Sweden: Uppsala Monitoring Centre, 2002. 27. World Health Organization. The Importance of Pharmacovigilance. Geneva: World Health Organization, 2002. 28. Edwards IR. Who cares about pharmacovigilance? Eur J Clin Pharmacol 1997; 53: 83–8. 29. Edwards IR. Spontaneous reporting—of what? Clinical concerns about drugs. Br J Clin Pharmacol 1999; 48: 138–41. 30. WHO Collaborating Centre for International Drug Monitoring. Dialogue in Pharmacovigilance—More Effective Communication. Uppsala, Sweden: Uppsala Monitoring Centre, 2002. 31. Edwards IR. The accelerating need for pharmacovigilance. J R Coll Phys Lond 2000; 34: 48–51. 32. Biriell C, Edwards IR. Reasons for reporting adverse drug reactions—some thoughts based on an international review. Pharmacoepidemiol Drug Saf 1997; 6: 21–6. 33. Edwards IR, Fucik H. Impact and credibility of the WHO adverse reaction signals. Drug Inf J 1996; 30: 461–4.

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Address list of national centres that participate in the WHO Drug Monitoring Programme Editor’s note: The details given here were correct at the time of going to press in January 2003. However, details of this sort often change, and readers should contact the WHO Monitoring Programme at Uppsala if they are unable to reach any of the agencies listed using the information given. Argentina (ARG) Dra Mabel Teresa Foppiano Head Tel: +54-1-340 0866 Fax: +54-1-340 0866 E-mail: [email protected] Website: anmat.gov.ar Armenia (ARM) Dr Samvel Azatyan Deputy director Tel: +374-1-584 020, 584 120 Fax: +374-1-542 406 E-mail: [email protected] Website: pharm.am Australia (AUS) Dr John McEwen Director Tel: +61-2-6232 8113 Fax: +61-2-6232 8392 E-mail: [email protected] Website: www.health.gov.au

Administración Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT) Sistema Nacional de Farmacovigilancia Avenida de Mayo 869, piso 11o (1084) Buenos Aires, Argentina

Department of Pharmacovigilance and Rational Use of Drugs Armenian Drug and Medical Technology Agency 15, Moskowian Street Yerevan 375001, Armenia Adverse Drug Reactions Unit Therapeutic Goods Administration PO Box 100 Woden, ACT 2606, Australia

Austria (AUT) Eugen Obermayr Head Tel: +43-1-711 00, ext 4638 Fax: +43-1-712 0823 E-mail: [email protected] Website: bmsg.gv.at

Federal Ministry for Social Security and Generations Pharmacovigilance Unit VIII/A/3 Radetzkystrase 2 A-1031 Vienna, Austria

Bahrain (BHR) Ms Layla Abdur-Rahman Director Tel: +973-25 86 68 Fax: +973-27 93 57 E-mail: [email protected]

Ministry of Health Pharmacy and Drug Control PO Box 12 Manama, Bahrain

559

560 Belarus, Republic of (BLR) Mr Godovalnikov Tel: +7-017-289 55 14 Fax: +7-017-289 53 48

Address list of national centres

Ministry of Health Center for Examinations and Test Health Service Republican Unitary Enterprise 22 0037 Minsk, 2-a Tovarishcheskij Per Republic of Belarus

Belgium (BEL) Mr André Pauwels Head Tel: +32-2-227 5567 Fax: +32-2-227 5528 E-mail: [email protected]

Federal Ministry Social Affairs, Public Health and Environment, Pharmaceutical Inspectorate National Centre for Pharmacovigilance Boulevard Bischoffsheim 33, 1st floor B-1000 Brussels, Belgium

Brazil (BRA) Mr Murilo Freitas Dias Pharmacovigilance Manager Tel: +55-61-448 1219 Fax: +55-61-448 1275 E-mail: [email protected]

Brazilian Pharmacovigilance Center Unidade de Farmacovigilancia (UFARM) Agência Nacional de Vigilância Sanitárita SEPN 515 Bl.B Ed. Omega 2 Andar, Sala 2 CEP 70770-502 Brasilia DF, Brazil

Brazil (BRA) Dr Anthony Wong Tel: +55-11-3088 9431 Fax: +55-11-3088 9431 E-mail: [email protected]

Bulgaria (BUL) Ms Daniela Encheva Head Tel: +359-2-4347 356 Fax: +359-2-9434 487 E-mail: [email protected] Website: bda.bg Canada (VAR) Dr Wikke Walop Head, Vaccine Safety Epidemiologist Tel: +1-613-954 5590 Fax: +1-613-957 1340 or 998 6413 E-mail: [email protected] Website: hc-sc.gc.ca

Canada (CAN) Ms Heather Sutcliffe Head Tel: +1-613-946 1138 or 957 0337 Fax: +1-613-957 0335 E-mail: [email protected] Website: hc-sc.gc.ca

CEATOX, Sao Paulo Regional Poison and Pharmacovigilance Centre Inst. Crianca Reference Centre Avenida Dr Enéas de Carvalho Aguiar, 647 05403-903 Sao Paulo SP, Brazil

Bulgarian Drug Agency Department of Pharmacovigilance Eurointegration and Pharmacopoeia 26 Yanko Sakazov Boulevard BG-1504 Sofia, Bulgaria

VAAE Surveillance Section Division of Immunization Centre for Infectious Diseases, Prevention & Control Population and Public Health Branch Tunney’s Pasture 0603EI Ottawa Ontario K1A OL2, Canada

Marketed Health Products Directorate Health Canada Finance Bldg, 1st Floor, Tunney’s Pasture A/L 0201 C2 Ottawa Ontario K1A 1B9, Canada

561

Address list of national centres

Chile (CHL) Dr Q F Cecilia Morgado-Cadiz Head Tel: +56-2-239 8769 Fax: +56-2-239 8760 E-mail: [email protected] China, People’s Republic of (CHN) Prof Li Shaoli Director-General Tel: +86-10-6716 4982 Fax: +86-10-6716 4984 E-mail: [email protected] Website: cdr.gov.cn Costa Rica (COR) Dra Jetty Murillo Ocampo Farmacéutica responsable Tel: +506-222 1878 Fax: +506-257 7004 E-mail: [email protected] Croatia (CRO) Dr Igor Francetic Head Tel: +385-1-2421 875 Fax: +385-1-2388 279 E-mail: [email protected]

Cuba (CUB) Lic Francisco Debesa García Head Tel: +53-7-24 09 24 Fax: +53-7-24 72 27 E-mail: [email protected]

Cyprus (CYP) Dr Athos Tsinontides Clinical Pharmacist Tel: +357-240 7101 Fax: +357-233 9623 E-mail: [email protected] Czech Republic (CZE) Dr Ivana Koblikova Head Tel: +42-2-7218 5848, 7218 5111 Fax: +42-2-7143 2377, 7218 5816 E-mail: [email protected]

Instituto de Salud Publica de Chile CENIMEF Avenida Marathon 1000 3 piso, Nuñoa-Casilla 48 Santiago, Chile

Center for Drug Re-evaluation (CDR) National Center for ADR Monitoring Building 11, Fa-Hua-Nan-Li Chongwen District Beijing 100061, People’s Republic of China

Caja Costarricense de Seguro Social Centro Nacional de Farmacovigilancia Avenida Segunda San José 1000, Costa Rica

Croatian Adverse Reaction Monitoring Centre of Drugs and Medical Devices Division of Clinical Pharmacology Department of Medicine University Hospital Centre 12 Kispaticeva 10000 Zagreb, Croatia

National Coordinating Unit of Pharmacovigilance Pharmacoepidemiology Development Center 44 No 502 esq 5a Ave Miramar, Playa Havana CP 11300, Cuba

Pharmaceutical Services Ministry of Health 1475 Lefkosia, Cyprus

Branch of Clinical Trials and Pharmacovigilance State Institute for Drug Control Srobarova 48 10041 Prague 10, Czech Republic

562 Denmark (DEN) Ms Margit Handlos Head of Pharmacovigilance Tel: +45-44-88 91 11 Fax: +45-44-91 73 73 E-mail: [email protected] Website: dkma.dk Egypt (EGY) Prof Abdulla Molokhia Chairman, NODCAR Tel: +20-2-7484 989 Fax: +20-2-3379 445 E-mail: [email protected] Estonia (EST) Dr Maia Uusküla Head Tel: +372-7-374 140 Fax: +372-7-374 142 E-mail: [email protected] Website: sam.ee

Address list of national centres

Danish Medicines Agency Department of Medicines Evaluation 378, Frederikssundsvej DK-2700 Bronshoj, Denmark

Ministry of Health National Organization for Drug Control and Research PO Box 29 51 Wezaret Al-Ziraa, Agouza Cairo, Egypt Ravimiamet State Agency of Medicines 19 Ravila Street 50411 Tartu, Estonia

Fiji (FJI) Mr Peter Zinck Chief Pharmacist Tel: +679-315 022 Fax: +679-304 199 E-mail: [email protected]

Business and Essential Drugs (BED) Fiji Pharmaceutical Services Box 106 Suva, Fiji

Finland (FIN) Prof Erkki Palva Research Director Tel: +358-9-4733 4288 Fax: +358-9-4733 4297 E-mail: [email protected] Website: nam.fi

National Agency for Medicines—Lääkelaitos Drug Information Centre PO Box 55 Mannerheimintie 166 SF-00301 Helsinki, Finland

France (FRA) Dr Carmen Kreft Jaïs Head Tel: +33-1-5587 3533 Fax: +33-1-5587 3532 E-mail: [email protected] Website: agmed.sante.gouv.fr/fr/htm/2/2000.htm

Agence Francaise de Securité Sanitaire des Produits de Sonti (AFSSAPS) 143-147, Boulevard Anatole France Unité de Pharmacovigilance F-93285 Saint-Denis, Cedex, France

Germany (GFR) Dr Jürgen Beckmann Head Tel: +49-30-4548 3311 Fax: +49-30-4548 3515 E-mail: [email protected] Website: bfarm.de

Pharmacovigilance Department Federal Institute for Drugs and Medical Devices Kurt-Georg-Kiesinger-Allee 3 53113 Bonn, Germany

563

Address list of national centres

Ghana (GHA) Dr Alex Dodoo Tel: +233-21-675 885 Fax: +233-21-666 8219 E-mail: [email protected]

Greece (GRC) Dr Georgia Athanassiou Head of Pharmacovigilance Unit Tel: +30-1-06507 337 Fax: +30-1-0654 9585 E-mail: [email protected] Website: eof.gr Guatemala (GTM) Licda Yanira Gicela Ruano Muños Tel: +502-471 9842 Fax: +502-440 8267 E-mail: [email protected]

Hungary (HUN) Dr Sándor Elek Head Tel: +36-1-266 2874 Fax: +36-1-266 6073 E-mail: [email protected] Iceland (ICE) Prof. Magnús Jóhannsson Tel: +354-5-20 2114 Fax: +354-5-61 2170 E-mail: [email protected] Website: lyfjastofnun.is India (IND) Prof Suresh K Gupta Chief Tel: +91-11-659 3633 Fax: +91-11-686 2663 or 652 10 41 E-mail: [email protected]; [email protected] Indonesia (INO) Dra Engko Sosialine M Head Tel: +62-21-4245 459 Fax: +62-21-4243 605 E-mail: [email protected]

Centre for Tropical Clinical Pharmacology & Therapeutics University of Ghana Medical School Korle-Bu Teaching Hospital Accra, Ghana

National Organization for Medicines Adverse Drug Reactions Section 284 Messogion Avenue GR-155 62 Athens-Holargos, Greece

Coordinadora del Programa Nacional de Farmacovigilancia Ministerio de Salud y Asistencia Social 11 Ave. “A” 11-57 zona 7 Finca La Verbena Guatemala, Guatemala

National Institute of PharmacyAdverse Drug Reactions Monitoring Centre Zrínyi u. 3-1051 PO Box 450 H-1372 Budapest, Hungary

The Icelandic Medicines Control Agency Eidistorg 13-15 172 Seltjarnarnes, Iceland

National Pharmacovigilance Centre Department of Pharmacology All India Institute of Medical Sciences Ansari Nagar New Delhi 110029, India

Section of Adverse Drug Reaction Surveillance Directorate of Drug and Biological Product Evaluation National Agency for Drug and Food Control Jalan Percetakan Negara 23 Jakarta 10560, Indonesia

564 Iran, Islamic Republic of (IRN) Dr Gloria Shalviri Director Tel: +98-21-640 5569 Fax: +98-21-641 7252 E-mail: [email protected]

Ireland (IRE) Ms Niamh Arthur Pharmacovigilance Co-ordinator Tel: +353-1-676 4971 Fax: +353-1-676 7836 E-mail: [email protected] Website: imb.ie Israel (ISR) Dr Dina Hemo Head Tel: +972-2-568 1219 Fax: +972-2-672 5820 E-mail: [email protected] Italy (ITA) Dr Roberto Raschetti Tel: +39-06-599 41 Fax: +39-6-5994 3554 E-mail: [email protected]

Japan (JPN) Dr Tatsuo Kurokawa Director, Safety Division Tel: +81-3-3595 2435 Fax: +81-3-3508 4364 E-mail: [email protected] Jordan (JOR) Ms Nancy Ghabboun Tel: +962-6 5660 028 Fax: +962-6 5660 028 E-mail: [email protected] Korea, Republic of (KOR) Dr Joon-Shik Chang Head Tel: +82-2-382 0185 Fax: +82-2-386 0843 E-mail: [email protected] Website: kfda.go.kr

Address list of national centres

Ministry of Health and Medical Education Iranian ADR Centre Under-Secretary for Food and Drug Affairs Building no. 3 Fakhr-e-Razi Street, Enghlab Avenue Teheran 13145, Islamic Republic of Iran

Pharmacovigilance Unit Irish Medicines Board Earlsfort Terrace Earlsfort Centre Dublin 2, Ireland

Ministry of Health Department of Clinical Pharmacology Drug Monitoring Center 29 Rivka Street, PO Box 1176 Jerusalem 91010, Israel

Ministry of Health Medicines Evaluation and Pharmacovigilance General Direction Pharmacovigilance Centre Viale della Civilta Romana 7 I-00144 Rome, Italy

Pharmaceutical and Medical Safety Bureau Ministry of Health, Labor and Welfare 1-2-2, Kasumigaseki, Chiyoda-Ku Tokyo 100-8916, Japan

Drug Directorate Ministry of Health PO Box 86 Amman, Jordan

Korea Food and Drug Administration Pharmaceutical Safety Bureau 5 Nokbun-dong Eunpyong-ku Seoul 122-704, Republic of Korea

565

Address list of national centres

Kyrgyzstan (KGZ) Saliya Karimbaeva Tel: +996-312-54 29 40 Fax: +996-312-54 29 10 E-mail: [email protected]

Drug Information Centre Ministry of Health 3rd Liniya Street 720044 Bishkek, Kyrgyzstan

Latvia (LVA) Dr Inese Studere Tel: +371-2-707 8442 Fax: +371-2-707 8442 E-mail: [email protected]

State Agency of Medicine of Latvia (SAM) ADR Monitoring Department Jersikas St. 15 LV-1003 Riga, Latvia

Macedonia, Republic of (MKD) Ms Biljana Celevska Tel: +389-2-11 93 75, 23 76 69 Fax: +389-2-23 08 57, 11 30 14 E-mail: [email protected] Malaysia (MAL) Mr Mohd Zin Che Awang Director of Pharmaceutical Services Tel: +60-3-4045 7389 Fax: +60-3-7968 2222 E-mail: [email protected] Website: madrac.gov.my/madrac Mexico (MEX) Dr Carmen Becerril Martinez Head Tel: +52-5-203 4378 Fax: +52-5-203 4378 E-mail: [email protected]

Ministry of Health ul. 50 Divizija bb 1000 Skopje, Republic of Macedonia

Pharmaceutical Services Division Ministry of Health 11th floor Bangunan Perkim Jalan IPOM 51200 Kuala Lumpur, Malaysia

Ministry of Health Gauss No 4, 7 piso Col. Casa Blanca Mexico City, DF CP 11590, Mexico

Moldova (MDA) Dr Lucia Tsurcan Head Tel: +373-2-73 70 02, 73 87 86 Fax: +373-2-73 70 45 E-mail: [email protected]

National Centre for Adverse Reaction Monitoring of the Republic of Moldova National Institute of Pharmacy Str. Korolenko 2/1 Chisinau 2028, Moldova

Morocco (MOR) Dr Rachida Soulaymani-Bencheikh Head Tel: +212-37-68 64 64 or 6110 47 45 (gsm) Fax: +212-37-77 60 87 or 77 20 67 E-mail: [email protected]

Centre Anti Poisons et de Pharmacovigilance Rue Lamfedel Cherkaoui Rabat Institute Medinate AP Irfane BP 769 Rabat, Morocco

Netherlands Antilles (ANT) Dr Peter H. M. Fontilus Director Tel: +599-9-737 4877 Fax: +599-9-737 4844 E-mail: [email protected]

Bureau of Pharmaceutical Affairs Groot Davelaar K-139-140 PO Box 3824 Curacao, Netherlands Antilles

566

Address list of national centres

Netherlands (NET) Dr A. C. van Grootheest Director Tel: +31-73-646 9700 Fax: +31-73-642 6136 E-mail: [email protected] Website: lareb.nl

Netherlands Pharmacovigilance Foundation LAREB Goudsbloemvallei 7 NL-5237 MH S-Hertogenbosch The Netherlands

New Zealand (NEZ) Dr Michael Tatley Head Tel: +64-3-479 7247 Fax: +64-3-479 0509 E-mail: [email protected]

Centre for Adverse Reactions Monitoring Dunedin School of Medicine PO Box 913 Dunedin 9000, New Zealand

Norway (NOR) Ms Ingebjorg Buajordet Head Tel: +47-22-89 77 00 Fax: +47-22-89 77 99 E-mail: [email protected] Website: slk.no Oman (OMN) Dr Sawsan Ahmad Jaffar Head Tel: +968-600 016 Fax: +968-602 287 E-mail: [email protected] Pakistan (PAK) Prof Akhlaque Un-Nabi Khan Tel: +92-21-588 2997, 589 2801 Fax: +92-21-588 1444, 589 3062 E-mail: [email protected]

Norwegian Medicines Agency Statens Legemiddelverk Adverse Drug Reaction Section Sven Oftedals vei 6 N-0950 Oslo, Norway

Ministry of Health Directorate General of Pharmaceutical Affairs and Drug Control PO Box 393 Muscat, Sultanate of Oman 113

College of Physicians & Surgeons Pakistan (CPSP) Department of Clinical Pharmacology 7th Central Street Phase II Phase II, Defence Housing Authority Karachi 75500, Pakistan

Peru (PER) Dra Susana Vasquez Lezcano Jefe de CENAFIM Tel: +51-14-71 62 46 Fax: +51-14-71 63 53 E-mail: [email protected] Website: minsa.gob.pe

Presidenta del Comite Tecnico Nacional de Farmacovigilancia CENAFIM, DIGEMID Ministerio de Salud 11 Avenue Arenales # 1302 - Of. 318-319 Lima 11, Peru

Philippines (PHL) Ms Marissa Macaraeg Information Officer Tel: +63-2-807 8517 Fax: +63-2-807 8285 E-mail: [email protected]

Adverse Drug Reaction Monitoring Bureau of Food and Drugs Department of Health Filinvest Corporate City, Alabang Muntinlipa City 1770, Philippines

567

Address list of national centres

Poland (POL) Dr Agata Maciejczyk Head Tel: +48-22-841 6742 Fax: +48-22-851 4366 E-mail: [email protected] Website: il.waw.pl

Drug Institute Pharmacoepidemiology Centre Centre for Adverse Drug Reactions Monitoring 30/34 Chelmska Street PL-00725 Warsaw, Poland

Portugal (POR) Dr Regina Carmona Head Tel: +351-21-798 7153 Fax: +351-21-798 7155 E-mail: [email protected] Website: infarmed.pt

National Pharmacovigilance Centre INFARMED Parque de Saúde de Lisboa Avenida do Brasil, no. 53 1749-004 Lisboa, Portugal

Romania (ROM) Dr Juliana Daniela Stanciu Head Tel: +40-1-224 1102, 224 1710 Fax: +40-1-224 3497 E-mail: [email protected] Russia (RUS) Prof Victor Cheltsov Head Tel: +7-95-434 52 44 Fax: +7-95-434 02 92 E-mail: [email protected] Singapore (SIN) Ms Chan Cheng Leng Head of Pharmacovigilance Tel: +65-325 5604, 325 5610 Fax: +65-325 5448 E-mail: [email protected] Slovakia (SVK) Dr Pavol Gibala Head Tel: +421-2-5293 1735, 5293 1732 Fax: +421-2-5293 1734 E-mail: [email protected] Website: sukl.sk South Africa (SOA) Ms Ushma Mehta Head Tel: +27-21-447 1618 Fax: +27-21-448 6181 E-mail: [email protected]

National Medicines Agency Str Aviator Sanatescu no 48 Sector 1 R-71 324 Bucuresti, Romania

Department of Clinical Pharmacology Miklukho-Maklay Street, 8 117198 Moscow, Russia

Centre for Pharmaceutical Administration Health Sciences Authority No. 2 Jalan Bukit Merah, Singapore 169547

National Centre for Monitoring Adverse Reactions to Drugs State Institute for Drug Control Kvetná 11 825 08 Bratislava 26, Slovakia

National Adverse Drug Event Monitoring Centre Division of Pharmacology, Medical School Faculty of Medicine University of Cape Town, K45 Old Main Building Observatory 7925, South Africa

568 Spain (SPA) Dr Francisco José de Abajo Head Tel: +34-91-596 7711 Fax: +34-91-596 7891 E-mail: [email protected] Website: msc.es/agemed Sri Lanka (LKA) Dr Bernadette Mignonne Rohini Fernandopulle Senior lecturer Tel: +94-1-695 300 ext. 41 03 17 Fax: +94-1-695 300 E-mail: [email protected] Sweden (SWE) Prof Ingemar Persson Head Tel: +46-18-17 46 44 Fax: +46-18-54 85 66 E-mail: [email protected] Website: mpa.se Switzerland (SCH) Dr Ruedi Stoller Head Tel: +41-31-322 0348 Fax: +41-31-322 0418 E-mail: [email protected] Website: iks.ch

Address list of national centres

Agencia Española del Medicamento División de Farmacoepidemiología y Farmacovigilancia Carretera a Pozuelo, Km 2 E-28220 Majadahonda (Madrid), Spain

Faculty of Medicine University of Colombo Kynsey Road PO Box 271 Colombo 8, Sri Lanka

Adverse Drug Reaction Unit Pharmacovigilance Unit Medical Product Agency PO Box 26 S-751 03 Uppsala, Sweden

Swissmedic, Schweizerisches Heilmittelinstitut Pharmacovigilance Zentrum Erlachstrasse 8 CH-3000 Bern 9, Switzerland

Tanzania (TAN) Mr Henry Irunde Tel: +255-22-2450 512, 245 07 51 Fax: +255-22-2450 793 E-mail: [email protected]

Tanzania Drug and Toxicology Information Service (TADATIS) PO Box 77150 Dar Es Salaam, Tanzania

Thailand (THA) Ms Pornpit Silkavute Director Tel: +66-2-590 72 81 Fax: +66-2-591 84 57 E-mail: [email protected] Website: fda.moph.go.th/APR

Thai National ADRM Centre Technical Division Food and Drug Administration Ministry of Public Health Ti-wa-nondh Road Nonthaburi 1100, Thailand

Tunisia (TUN) Prof Chalbi Belkahia Head Tel: +216-1-562 098 Fax: +216-1-571 390 or 57 81 96 E-mail: [email protected]

Centre National de Pharmacovigilance Sis Hôpital Ch Nicolle Bd du 9 Avril Tunis 1006, Tunisia

569

Address list of national centres

Turkey (TUR) Prof Dr Orban Canbolat Head Tel: +90-312-230 1674, 230 2769 Fax: +90-312-230 1610 E-mail: [email protected]

General Directorate of Drugs and Pharmacy Ministry of Health Ilkiz Sokak No 4 Sihhiye Ankara 06430, Turkey

Ukraine (UKR) Dr Marina Sharayeva Head Tel: +7-358 4468 2500 Fax: +7-358 4468 2500 E-mail: [email protected]

Pharmacovigilance Department State Pharmacological Center Ministry of Health of Ukraine 18 Chygorina Str. 01042 Kiev, Ukraine

United Kingdom (UNK) Dr June Raine Head Tel: +44-207-273 0400 Fax: +44-207-273 0282, 273 0675 E-mail: [email protected] Website: open.gov.uk/mca/ United States of America (USA) Dr M Miles Braun Director Tel: +1-301-827 3974 Fax: +1-301-827 3529 E-mail: [email protected] United States of America (USA) Dr Paul Seligman Director Tel: +1-301-827 6276 Fax: +1-301-827 6276 E-mail: [email protected]

Uruguay (URY) Dr Carolina Seade Fournie Tel: +598-2 487 27 02 Fax: +598-2 6226 969 E-mail: [email protected] Uruguay (URY) Dra Mabel Burger Tel: +598-2-480 4000 Fax: +598-2-487 0300 E-mail: [email protected] Website: ciat.hc.edu.uy

Post-licensing Division Medicines Control Agency Market Towers 1 Nine Elms Lane London SW8 5NQ, United Kingdom

Food and Drug Administration Center for Biologics Evaluation and Research Division of Epidemiology 1401 Rockville Pike, HFM-220 Rockville, MD 20852-1448, USA

Office of Pharmacoepidemiology and Statistical Science Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane, Room 15 B33 Rockville, MD 20857, USA

Departamento de Farmacologia Hospital de Clinicas Avda Italia s/n piso 1, 11600 Montevideo, Uruguay

Deptartamento de Toxicologia Hospital de Clínicas Avda Italia s/n, piso 7 11600 Montevideo, Uruguay

570 Venezuela (VEN) Dr Jesús Querales Castillo Head Tel: +58-2-6624 797 Fax: +58-2-6624 797, 693 1455

Vietnam (VNM) Prof Hoang Tich Huyên Head Tel: +84-4-245 292 Fax: +84-4-823 1253 E-mail: [email protected] Yugoslavia, Federal Republic of (YUG) Prof Vaso Antunovic Head Tel: +381-11-361 5531 Fax: +381-11-361 56 30

Zimbabwe (ZWE) Mrs Sakhile Dube-Mwedzi Regulatory Officer Tel: +263-4-736981-5 Fax: +263-4-736980 E-mail: [email protected]

Address list of national centres

Presidente, Instituto Nac. de Higiene “Rafael Rangel” Apartado Postal 60.412-Ofic. del Este Ciudad Universitaria Caracas, Venezuela

Adverse Drug Reaction Centre Institute for Drug Quality Control Ministry of Health 48 Hai Ba Trung Street Hanoi, Vietnam

Clinical Centre of Serbia National Centre for Adverse Drug Reactions Visegradska 26 YU-11000 Belgrade Federal Republic of Yugoslavia

Medicines Control Authority of Zimbabwe 106 Baines Ave Harare, Zimbabwe

Institutions EMEA Ms Priya Bahri Tel: +44-207-418 8454 Fax: +44-207-418 8668 E-mail: [email protected]

EC Emer Cooke Tel: +32-2-296 7072 Fax: +32-2-296 1520 E-mail: [email protected] WHO Dr Mary Couper Tel: +41-22-791 3643 Fax: +41-22-791 4730 E-mail: [email protected]

EMEA—The European Agency for the Evaluation of Medicinal Products Pharmacovigilance Section 7 Westferry Circus, Canary Wharf London E14 4HB, UK

European Commission Directorate General III—Industry Rue de la Loi 200 B-1049 Brussels, Belgium

World Health Organization Department of Essential Drugs & Medicines Policy Quality Assurance & Safety Medicines CH-1211 Geneva 27, Switzerland

Index of drugs Notes: For any therapy, see under the specific item and the class; for example lisinopril and angiotensin-converting enzyme inhibitors. Boldface page numbers refer to main discussions. abacavir, 330 acamprosate, 540 acarbose gastrointestinal system, 467 liver, 467 metabolic effects, 467 metformin concentration, 468 ACE inhibitors. see angiotensin converting enzyme inhibitors aceclofenac, 115 acetaminophen. see paracetamol acetazolamide electrolyte balance, 238 immunologic system, 239 overdose, 239 urinary tract, 238 acetylcholinesterase inhibitors, 164 acetylsalicylic acid (aspirin) antiplatelet activity, +ibuprofen, 115 asthma, 118 furosemide inhibition, 240 gastrointestinal system, 113 liver, 113 renal insufficiency, 112 vitamin E, concomitant use, 423 aciclovir, 329 acitretin, 175 activated charcoal, 387 acupuncture, 535 adefovir, 335 adenosine adverse drug reactions, management, 203–204 cardiovascular system, 203 death, 203 respiratory system, 203 adrenaline, 143 alfa- and beta-adrenoceptor agonists cardiovascular system, 156 gastrointestinal system, 157 interactions, 157 psychiatric effects, 157 alfa2 -adrenoceptor agonists, 525 beta-adrenoceptor agonists cardiovascular system, 159, 190–191, 525–526 immunologic system, 526 metabolic effects, 223, 526 psychiatric effects, 526

respiratory system, 526 beta-adrenoceptor antagonists amphetamine interaction, 30 ajmaline, 204 alatrofloxacin, 276 albendazole, 344–345 albumin, 363 alcohol hepatotoxicity, +paracetamol, 114–115 performance impairment, +zaleplon, 49 aldose reductase inhibitors, 472 alfentanil, 89 alkylammonium amidobenzoate, 169 all-trans retinoic acid cardiovascular system, 417 mineral balance, 417–418 pancreas, 418 retinoic acid syndrome, 417 toxicity, 418 urinary tract, 418–419 Allium sativum (garlic), 529 allopurinol, 125–126 alosetron concomitant alprazolam, 46 concomitant fluoxetine, 383 gastrointestinal system, 383 alpha-glucosidase inhibitors gastrointestinal system, 467 interactions, 467 liver, 467 metabolic effects, 466–467 alprazolam, 46 alprostadil (prostaglandin E1 ), 430 alteplase, 49 aluminium, 243–244 aluminium hydroxide, 457 amantadine nervous system, 162 psychiatric effects, 334 AMD473. see ZD0473 amfebutamone death, 15 myocardial ischemia, +pseudoephedrine, 157 overdose, 15–16 seizures, +lithium, 25–26 amikacin nephrotoxicity, +amphotericin B deoxycholate (DAMB), 302

sensory systems, 271 urinary tract, 271 amiloride electrolyte balance, 240 lithium toxicity, 291 aminoethanolamine, 169 aminoglycosides, 271 aminosalicylates, 387 amiodarone administration route, 206–207 cardiovascular system, 204 vs. dofetilide, 210 efficacy, 202 endocrine systems, 205–206 fetotoxicity, 206 overdose, 207 respiratory system, 204–205, 207 risk factors, 206 skin, 206 special senses, 205 amisulpride, 58–59 amlodipine, 225 amodiaquine, 315 amoxicillin, 263. see also co-amoxiclav amphetamine cardiovascular system, 30 ecstasy interaction, 32 nervous system, 30 amphetamines cardiovascular system, 3 nervous system, 3–4 overdose, 4 risk factors, 4 teratogenicity, 4 amphotericin B colloidal dispersion (ABCD), 302 amphotericin B deoxycholate (DAMB), 302 amphotericin B lipid complex (ABLC), 302–303 amphotericin B liposomal, 303 amprenavir, 332 anabolic steroids, 450 anakinra, 397–398 androgenic anabolic steroids, 450 androgens, 437 anesthesia. see specific agents, such as benzocaine; ropivacaine anesthetic vapors. see specific gases, such as halothane; nitrous oxide

571

572 angiotensin converting enzyme inhibitors, 234. see also specific drugs, such as captopril; lisinopril angiotensin II receptor antagonists. see irbesartan Anso Comfort general effects, 529 recall, 47 antacids, 279 anthracyclines cardiovascular system, 503 liver, 503–504 metabolic effects, 503 nervous system, 503 respiratory system, 503 anthrax vaccine, 354 anti-inflammatory drugs, 280 antiandrogens, 451 antibiotics. see also specific drugs and classes, such as cephalosporins; minocycline anticholinergic drugs, 165 antidysrhythmic drugs, 202–203 antiepileptics. see also specific drugs and classes, such as benzodiazepines; gabapentin death, 71 endocrine system, 70 metabolic effects, 71 musculoskeletal, 71 psychiatric effects, 70 reproductive, 70–71 teratogenicity, 71 antihistamines (H1 ). see also specific drugs such as fexofenadine; loratadine cardiotoxicity, 180–182 central nervous system, 182–183 antimony, 244 antipsychotic drugs body temperature, 58 cardiovascular system, 54 vs. clozapine, 53 endocrine system, 56 gastrointestinal system, 58 metabolic effects, 56 nervous system, 54 overdose, 58 sensory systems, 55 skin, 58 weight gain, 56–58 antispasmodic agents (gastrointestinal), 389 antithrombin III, 363 antituberculous agents, 339–340 antiviral drugs methadone concentration, 96 skin, 168 aprindine, 207 aristolochic acid, 529–530 Arnica montana skin, 530

Index of drugs arsenic, 244 Artemisia derivatives, 319–320 articaine, 144 ASA. see acetylsalicylic acid ascorbic acid. see vitamin C Asian herbal mixtures, 528 aspart insulin, 463 aspirin. see acetylsalicylic acid atorvastatin clearance, nelfinavir, 333 erythromycin interaction, 287 hematologic system, 487 musculoskeletal system, 487 skin, 487 atovaquone general effects, 320 +proguanil, adherence, 317 +proguanil, neuropsychiatric effects, 319 azathioprine +aminosalicylate, leukopenia, 388 gastrointestinal system, 404 hematologic system, 404 azithromycin cardiovascular system, 285 clearance, fexofenadine, 181 concomitant desloratadine, 181 hematologic system, 285 immunologic system, 285 interactions, 286 pregnancy, 285 +pyrimethamine, general effects, 322–323 risk factors, 286 sensory systems, 285 tolerability, 284–285 Bacille Calmette-Guérin vaccine administration route, 355 skin, 354 bacitracin, 292 baclofen clinical presentation, 153 effects of renal impairment, 153 fetotoxicity, 154 withdrawal syndrome, 152–154 barnidipine, 225 Basic Red 22, 169 BBR3464, 492 BCG. see Bacille Calmette-Guérin vaccine befunolol, 526 benzimidazoles, 344–345 benzocaine, 144–145 benzodiazepines effects, 72 overdose, 72 sedation, +macrolides, 284 sedation, +miocamycin, 288 trauma, 46 benzyl alcohol, 173 bergamot, 530–531

betaxolol, 525, 526 bile acids, 389 bimatoprost, 430, 526 biotin. see vitamin H bismuth, 244–245 black iron oxide, 169 beta-blockers. see beta-adrenoceptor antagonists blood substitutes, 363 blue dye, 545 brachial plexus anesthesia, 140–141 branched-chain fatty acid esters, 168 Brighton Collaboration, 354 bromazepam, 46 Bryostatin I, 409 bucillamine, 254 BufferGel, 540–541 buprenorphine, 104 bupropion. see amfebutamone buserelin, 478 buspirone, 49 busulfan, 503 butylhydroxyanisole, 169, 545 cabergoline, 160 caffeine cardiovascular system effects, 1 lithium interaction, 26 musculoskeletal system, 1–2 nervous system, 1 calciferol. see vitamin D calcineurin inhibitors, 306 calcitetracemate, 253 calcitonin, 477 calcitriol, 422 calcium carbonate, 457–458 calcium channel blockers. see specific drugs, such as felodipine; verapamil Calendula officinalis (marigold), 530 cannabinoids cardiovascular system, 36–37 nervous system, 37 cannabis animal toxicology, xxxiii–xxxiv cardiovascular system, xxxvi cognitive function, xxxv–xxxvi, xxxviii–xxxix dependence, xxxix–xli MDMA interaction, 33–34 memory, xxxv neurotoxicity claims, xxxvi–xxxvii in pregnancy, xli psychiatric illness, xxxvii–xxxviii psychoactive effects, xxxiv psychomotor impairment, xxxiv–xxxv smoke and cancer, xlii–xliv smoke and lung effects, xlii

573

Index of drugs smoke and smoking behavior, xli–xlii tolerance, xxxix–xli captopril digoxin interaction, 199 pancreas, 234 carbamazepine cardiovascular system, 72 clonazepam interaction, 47 concentration, cisplatin + doxorubicin, 502 concomitant lamotrigine, 73 electrolyte balance, 72–73 hyponatremia, desmopressin, 482–483 vs. lamotrigine, 74 lincomycin interaction, 284 lithium interaction, 25, 26 metabolic effects, 72 miocamycin interaction, 288 psychiatric effects, 72 risperidone concentration, 65 skin, 73 teratogenesis, 73 carbimazole, 459 carbohydrate-rich diet, 349 carboplatin adverse effects, 491–492 hematologic system, 498 immunologic system, 501 mechanism of action, 490 pharmacokinetics, 490–491 urinary tract, 499–500 cardiac glycosides cardiovascular system, 198, 530 contamination of herbal products, 199 endocrine system, 198 interactions, 199 metabolic effects, 198–199 psychiatric effects, 198 reproductive system, 199 risk factors, 199 carvedilol, 223 caspofungin, 311 catechol-O-methyl transferase inhibitors, 163 cat’s claw, 534 caudal anesthesia, 141 cefaclor, 264 cefazolin, 264 cefdinir, 264 cefepime, 264–265 celecoxib gastrointestinal system, 123–124 hemorrhage, +clopidogrel, 124 liver, 124 psychiatric effects, 123 skin, 124 urinary tract, 124 central venous catheters, 545–546 cerivastatin, 487

cetrorelix, 479 chaparral, 532 Chinese wolfberry, 533 chiropractic, 536 chitosan, 280 chloramphenicol gastrointestinal system, 274 general effects, 273–274 hematologic system, 273 chlordiazepoxide in Anso Comfort, 47, 529 formulations, 47 hematologic system, 46–47 chlorhexidine, 256 chlorhexidine digluconate, 169 2-chloro-paraphenylenediamine, 169 chloroquine cardiovascular system, 315 formulations, 317 nervous system, 315–316 overdose, 316–317 pregnancy, 316 +proguanil, adherence, 317 sensory systems, 316 skin, 316 chloroxylenol, 169 chlorprocaine, 145 chlorquinaldol, 169 cholestyramine, 457 chromium, 245 cibenzoline, 207 cicloproxolamine, 169 ciclosporin carcinogenicity, 406 concentration, fluconazole, 306 concentration, methylphenidate, 5 concentration, oxcarbazepine, 76 concentration, St. John’s wort, 532 concomitant ketoconazole, 304 hematologic system, 405 interactions, 405 metabolic effects, 404 musculoskeletal system, 405 nervous system, 404 pregnancy, 406 rhabdomyolysis, +lovastatin, 487 rhabdomyolysis, +simvastatin, 487 urinary tract, 405 cidofovir, 328 cilomilast, 200 cilostazol, 230 cimetidine clarithromycin absorption, 286 dofetilide concentration, 212 dystonic reaction, 384 praziquantel concentration, 349 cinchocaine, 145–146 cinnamic aldehyde, 545

ciprofloxacin gastrointestinal system, 276 interactions, 277 lithium interaction, 26 liver, 276 musculoskeletal system, 276–277 nervous system, 276 psychiatric effects, 276 risk factors, 277 sensory systems, 276 skin, 276 urinary tract, 276 cisapride cardiovascular system, 382 digoxin concentration, 200 interactions, 382 cisplatin adverse effects, 491–492 electrolyte balance, 497–498 endocrine system, 497 gastrointestinal system, 498 hematologic system, 498 immunologic system, 501 lithium clearance, 502 mechanism of action, 490 nephrotoxicity, 502 nervous system, 494–496 neurotoxicity, 502 ototoxicity, 496 overdose, 502 paclitaxel clearance, 503 pharmacokinetics, 490–491 skin, 500 teratogenicity, 502 urinary tract, 499–500 visual disturbances, 497 citalopram cardiovascular system, 12 concomitant digoxin, 200 concomitant ketoconazole, 304 concomitant methylphenidate, 5 ejaculation, 14 sexual function, 13 citric acid, 541 Citrus auranticum (bergamot), 530–531 clarithromycin cardiovascular system, 286 circulation, +ergotamine, 164 immunologic system, 286 interactions, 286–287 psychiatric effects, 286 repaglinide concentration, 469 rifabutin concentration, 341 skin, 286 clenbuterol, 191 clindamycin gastrointestinal system, 284 pregnancy, 284 sensory systems, 283–284 skin, 284 clomethiazole, 49

574 clomiphene citrate, 434 clomipramine, 11 clonazepam, 47 clopidogrel hematologic system, 380 hemorrhage, +celecoxib, 124 immunologic system, 380 clotting factors. see also factors; porcine factors; recombinant factor VIII:C body temperature, 368 cardiovascular system, 366 hematologic system, 366–367 immunologic system, 367 infection risk, 367–368 respiratory system, 366 skin, 367 clozapine vs. antipsychotic drugs, 53 cardiovascular system, 59 concentration, nefazodone, 16 concentration, risperidone, 60, 65–66 concomitant ketoconazole, 304 hematologic, 59–60 interactions, 60–61 lisinopril interaction, 236 liver, 60 metabolic effects, 59 vs. olanzapine, 61 salivary glands, 60 co-amoxiclav, 379 co-trimoxazole anticoagulation, 379 concentration, rifampicin, 342 dosage regimen, 322 drug tolerance, 292 effectiveness, 320–321 electrolyte balance, 291–292, 321 hematologic system, 292 immunologic system, 292 interactions, 292, 322 metabolic effects, 321 nervous system, 291, 321 reproductive system, 321–322 respiratory system, 291 skin, 292, 321 coagulation factor gene therapy, 368 cocaine cardiovascular system, 37–38 drug abuse, 40 ear, nose, throat, 38 fetotoxicity, 40–41 nervous system, 38–39 pregnancy, 41–42 psychological effects, 39 respiratory system, 38 sexual function, 40 urinary tract, 39 cocamidopropyl betaine, 168 codeine drug abuse, 90

Index of drugs nervous system, 89 skin, 90 colchicine, 286 colestipol, 488 colistin, 289 colophonium, 168 Compositae species, 171–172 contrast agents, iodinated renal insufficiency, + IV immunoglobulin, 366 contrast agents, oil-based iodinated erythema, 518 swelling, 518 contrast agents, water-soluble iodinated cardiovascular system, 514 delayed reactions, 513–514 endocrine system, 515 formulations, 519 gastrointestinal system, 516 hematologic system, 515–516 immunologic system, 519 nervous system, 514–515 sensory systems, 515 skin, 518–519 urinary tract, 517–518 contrast agents, water-soluble iodinated, intravascular cholinesterase activity, 513 general effects, 512–513 copper, 245 corticosteroids concomitant, praziquantel, 349 hiccups, 450 corticosteroids, inhaled endocrine system, 188 growth in children, 186–187 immunologic system, 190 infection risk, 190 musculoskeletal system, 188–190 sensory systems, 188 skin, 188 systemic availability, 187 cough syrup. see codeine coumarin interactions, 379 potentiation, co-trimoxazole, 292 COX-2 inhibitors. see also celecoxib; rofecoxib angio-edema, 122–123 cardiovascular system, 117–118 gastrointestinal system, 119–121 lithium interaction, 26 reproductive system, 123 respiratory system, 118–119 safe prescribing, comparison with non-selective NSAIDs, 116 sulfonamide-like allergic adverse reactions, 122

urticaria, 122–123 “crack.” see cocaine cranberry, 534 cryotherapy, 345 Cucurbicin, 422 cyanamide, 541 cyclophosphamide amiodarone interaction, 207 carcinogenicity, 406 reproductive system, 406 cytotoxic drugs. see anthracyclines dacluzumab, 402 dairy products, 280 dapsone, 340 daptomycin, 292 darbepoetin, 368 daunorubicin. see anthracyclines DDAVP. see desmopressin deferiprone, 253 deferoxamine general effects, 253–254 nervous system, 254 delta-9-tetrahydrocannabinol, 37 denileukin diftitox, 398 depolarizing neuromuscular blocking agents electrolyte balance, 151–152 nervous system, 151 desensitization therapy, 195 desloratadine cardiotoxic effects, 181 CNS effects, 182 desmopressin cardiovascular system, 482 electrolyte balance, 482 interactions, 482–483 dexamethasone, 429–430 dextrans, 374 dextromethorphan general effects, 90–91 neuromuscular, 91 pregnancy, 91 diamorphine drug use, 42 vs. morphine, 91–92 nervous system, 42, 92 sensory systems, 42, 92 diatrizoate cholinesterase activity, 513 described, 512 safety, 516 diazepam nervous system, 47, 137 overdose, 47 diclofenac, 115 didanosine, 329 diethylcarbamazine, 345–346 diethylstilbestrol, 436 diets, unconventional, 536 digoxin absorption, alpha-glucosidase inhibitors, 467 concentration, fluoxetine, 14

575

Index of drugs concentration, cisapride, 382 concomitant itraconazole, 308 concomitant moxifloxacin, 279 dofetilide interaction, 211–212 interactions, 199 management of toxicity, 200–201 reproductive system, 199 toxicity, clarithromycin, 286–287 dihydrocodeine, 92 dihydroergotamine, 288 diltiazem concentration, sirolimus (rapamycin), 408 digoxin concentration, 199 impaired renal function, simvastatin, 488 interactions, 226 nervous system, 225 overdose, 225–226 skin, 225 diphtheria-tetanus vaccine (DT, Td), 356 dipyridamole, 380 disopyramide efficacy, 202 macrolide interaction, 287 disulfiram, 542 ditrizoate, 516 diuretics, 238. see also specific drugs and classes, such as furosemide; loop diuretics dobutamine, 159 dofetilide adverse effects, 210 vs. amiodarone, 210 cardiovascular system, 210–211 clinical pharmacology, 208–209 concentration, +verapamil, 228 effectiveness, +digoxin, 200 efficacy, 202 vs. flecainide, 210 interactions, 211–212 open clinical studies, 209 pharmacology, 208 vs. propafenone, 210 vs. sotalol, 210 ventricular tachydysrhythmias, 210 donepezil, 7 dopamine receptor agonists cardiovascular system, 159–160 nervous system, 160 psychiatric, 162 respiratory system, 160 sleep disorders, 160–162 dorzolamide, 239 doxepin, 170 doxorubicin. see anthracyclines doxycycline, 265

droperidol, 383 DTP-Hib vaccine cardiovascular system, 357 pre-term infants, 356 sensory systems, 357 skin, 357 dysprosium-ethoxybenzyltris (carboxylatomethyl) triazaundecanedioic aciddiethylenetriaminepenta-acetic acid (Dy-EOB-DTPA), 519 ebastine, 181 Ecballium elaterium (squirting cucumber), 531 Echinacea (coneflower), 531 echinocandins, 311 ecstasy. see methylenedioxymethamphetamine (MDMA, ecstasy) edetate, 254 efavirenz immunologic system, 331 interactions, 331 methadone concentration, 96 psychiatric effects, 331 reproductive system, 331 skin, 331 Elohes® , 374–375 emedastine cardiotoxicity, 181 concomitant ketoconazole, 304 EMLA cream, 144 enalapril, 235 endothelin receptor antagonists, 233–234 enoximone, 201 enoxolone, 170, 545 Ephedra, 531–532 ephedrine cardiovascular system, 156 gastrointestinal system, 157 interactions, 157 psychiatric effects, 157 epidural anesthesia, 141–142 epirubicin. see anthracyclines epoetin. see also erythropoietin in children, 370 effectiveness, 368 ergot alkaloids cardiovascular system, 163 interactions, 164 ritonavir interactions, 333 ergotamine ergotism, +miocamycin, 288 ergotism, +troleandomycin, 288 erythromycin interaction, 287 lincomycin interaction, 284 metabolism, clarithromycin, 287 erythromycin cardiovascular system, 287 digoxin availability, 200

dysrhythmia, +verapamil, 228 interactions, 287 ritonavir/saquinavir concentration, 334 erythropoietin body temperature, 370 cardiovascular system, 369 gastrointestinal system, 369 general effects, 368–369 hair, 369 hematologic system, 369 immunologic system, 370 nervous system, 369 risk factors, 370 skin, 369 esomeprazole, 385 estradiol, 480 etanercept endocrine system, 399 hematologic system, 399–400 immunologic system, 400 infection risk, 400 nervous system, 399 risk factors, 400 skin, 400 ethmozine. see moricizine ethyl alcohol. see alcohol ethylene oxide, 256 ethylmercury, 248 etomidate, 135 everolimus, 406 factor VIIa (recombinant) myocardial infarction, 366 thrombophlebitis, 366 factor VIII:C, 367 factor VIII:C (porcine), 367 factor IX:C shortness of breath, 366 urticarial rash, 367 factor IX (recombinant), 366 famciclovir, 329–330 felbamate, 73 felodipine skin, 226 telangiectases, 174 fenfluramine cardiovascular system, 6 hematologic, 6–7 fenofibrate, 486 fentanyl effectiveness, 92–94 formulations, 94 lithium interaction, 25 respiratory system, 94 skin, 94 urinary tract, 94 ferrous sulfate, 457 fexofenadine cardiotoxic effects, 181–182 concentration, azithromycin, 286 fibrates, 486 filgrastim, 399 finasteride, 451

576 flecainide cardiovascular system, 212 vs. dofetilide, 210 efficacy, 202 overdose, 213 sensory systems, 212–213 Fleet enema, 387 fleroxacin, 277 fluconazole cardiovascular system, 305 concomitant oral contraceptives, 445 concomitant ritonavir, 333 interactions, 306 metabolic effects, 305 teratogenicity, 305 fluorescein, 542 fluoride, 545 fluoroquinolones cardiovascular system effects, 274 diagnostic tests, interference, 275 dosage regimens, 275 infection risk, 275 interactions, 275 musculoskeletal system, 275 nervous system, 274–275 skin, 275, 340–341 5-fluorouracil, 347–348 fluoxetine cardiovascular system, 12 endocrine, 13 mania, +tramadol, 103 QT interval prolongation, 11–12 skin, 13 flutamide gastrointestinal system, 452 hematologic system, 451 fluvastatin formulations, 488 liver, 487–488 fluvoxamine in breast milk, 14 ejaculation, 14 mexiletine clearance, 213 nervous system, 12–13 olanzapine interaction, 63 sex drive, 13 fomivirsen, 328 formoterol, 191 foscarnet, 328 fosfomycin effectiveness, 292 hematologic system, 292 kidney protection, +glycopeptides, 281–282 liver, 292 fosinopril, 235–236 fosphenytoin drug administration route, 77 immunology, 76 skin, 77

Index of drugs furazolidone, 386 furosemide, 363 fusidic acid, 281 gabapentin drug administration, 74 drug withdrawal, 74 immunologic system, 74 nervous system, 73–74 psychiatric effects, 74 urinary tract, 74 gadobenate dimeglumine, 520 gadodiamide, 520 gadolinium general effects, 520–521 immunologic system, 522 pancreas, 521 urinary tract, 521 gadoterate meglumine, 521 gallium, 245 gammahydroxybutyrate, 542 ganciclovir, 329 ganirelix, 479 garlic, 529 gatifloxacin, 277 gelatin, 24 gemeprost, +mifepristone, 430 gemfibrozil, 486 gemifloxacin intestinal flora, 278 liver, 277–278 gemtuzumab ozogamicin, 402 gene therapy, 368 general anesthetics effectiveness trials, 131 gastrointestinal system, 131–132 nervous system, 131 gentamicin dosage regimens, 272 immunologic system, 272 interactions, 272 nervous system, 271 sensory systems, 271 urinary tract, 272 Ginkgo biloba (maidenhair tree), 531 glargine insulin, 463–464 glibenclamide alpha-glucosidase inhibitors interaction, 467 death, 470 interactions, 470 introduction, 469–470 metabolic effects, 467 pancreas, 470 gliclazide metabolic effects, 467, 470 nervous system, 470 overdose, 470 potentiation, fluconazole, 306 glimepiride potentiation, fluconazole, 306 studies, 470

glipizide, 471 glucagon, 466 glucocorticoids, 482 glucocorticosteroids, systemic death, 429 fetotoxicity, 429–430 immunologic system, 429 infection risk, 429 metabolic effects, 427 musculoskeletal system, 428–429 psychiatric effects, 427 respiratory system, 427 risk factors, 429 skin, 427 glutathione, 500 glyburide. see glibenclamide glyceryl trinitrate (nitroglycerin), 224 glycopeptides drug tolerance (antibacterial resistance), 282 urinary tract, 281–282 Glycyrrhiza (licorice), 531 GnRH. see gonadrotrophin-releasing hormone gold hematologic system, 246 nails, 246–247 nervous system, 246 respiratory system, 246 sensory systems, 246 gonadorelin. see gonadrotrophin-releasing hormone gonadotrophin-releasing hormone antagonists, 479 gonadotrophin-releasing hormone (GnRH, gonadorelin) ear, nose and throat, 477 metabolic effects, 478 musculoskeletal system, 478 nervous system, 477 ovarian hyperstimulation syndrome, 477–478 skin, 478 gonadotrophins, 434 granisetron, 383–384 granulocyte colony-stimulating factor (G-CSF) gastrointestinal system effects, 398 musculoskeletal system, 399 skin, 399 urinary tract, 399 granulocyte-macrophage colony-stimulating factor (GM-CSF), 398 grapefruit juice fexofenadine availability, 181 irbesartan concentration, 236 grepafloxacin, 278 griseofulvin, 176

577

Index of drugs growth hormone (human growth hormone, hGH, somatotropin) cardiovascular system, 479 endocrine system, 479–480 immunologic system, 480 interactions, 480 nervous system, 479 skin, 480 growth hormone release-inhibiting hormone (somatostatin) biliary, 480 endocrine system, 480 gastrointestinal system, 480 immunologic system, 480–481 pregnancy, 481 guarana general effects, 531–532 ventricular fibrillation, 1 gum resins, 168, 171 halofantrine, 317 haloperidol psychoactive effects, +lithium, 26 vs. risperidone, 64 halothane, 132 Helicobacter pylori eradication therapies, 386–387 hemodialyis, 73 hemoglobin-based oxygen carriers, 363–364 henna tattoos, 543–544 heparins, 379 hepatitis A and B vaccines, 358 hepatitis A vaccine, 358 hepatitis B vaccine hematologic system, 358 immunologic system, 358 mouth, 358 nervous system, 357–358 optic neuritis, +hepatitis A vaccine, 358 sensory systems, 358 hepatitis E vaccine, 358 heptaplatin, 492 herbal diuretics, 26 herbal medications, 528 heroin. see diamorphine hetastarch. see hydroxyethyl starch hirudin, 379 histamine H2 receptor agonists comparison, 384 dofetilide interaction, 212 HMG coenzyme-A reductase inhibitors, 487 metabolism, clarithromycin, 287 rhabdomyolysis, +macrolides, 284 rhabdomyolysis, +miocamycin, 287–288 hormone replacement therapy

cardiovascular system, 437–438, 441 general effects, 436–437 hematologic system, 439–440 metabolic effects, 438–439 musculoskeletal system, 440 nervous system, 438 prolactin release, 13 reproductive system, 440–441 skin, 440 urinary tract, 440 5-HT3 receptor antagonists, 382–383 human growth hormone. see growth hormone human papilloma virus vaccine, 358 hydrocortisone aceponate cream, 427 hydromorphone, 94 hydroquinone, 170 hydroxychloroquine, 469 Hydroxycut, 531–532 hydroxyethyl starch hematologic system, 374–375 reproductive system, 375–376 skin, 374 urinary tract, 375 Hypericum perforatum. see St. John’s wort hypochlorite, 259 hypoglycemic drugs, oral, 466 ibuprofen gentamicin interaction, 272 interactions, 115 lithium interaction, 26 ibutilide, 202 idarubicin. see anthracyclines ifosfamide, 304–305 iloprost, 430 immunizations. see vaccines immunomodulators, 172 indigo carmine, 545 indinavir amprenavir concentration, 332 cardiovascular system, 332 interactions, 333 liver, 333 metabolic effects, 333 skin, 333 urinary tract, 333 indocyanine green, 545 indomethacin, 240 infiltration anesthesia, 143 infliximab cardiovascular system, 400–401 immunologic system, 401–402 infection risk, 402 nervous system, 401 respiratory system, 401 skin, 401 influenza vaccine

general effects, 358–359 skin, 359 insulin. see also aspart insulin; glargine insulin; lispro insulin fluid balance, 462 immunologic system, 462 liver, 462 metabolic effects, 461–462 modes of administration, 464–466 pregnancy, 463, 466 risk factors, 463 skin, 462 insulin-like growth factor-I, 466 interferon, 23 interferon alfa endocrine system, 394–395 hematologic system, 395 immunologic system, 396 interactions, 396–397 musculoskeletal system, 396 nervous system, 393–394 neuromuscular function, 394 pregnancy, 396 psychiatric effects, 394 respiratory system, 393 sensory systems, 394 skin, 395–396 interferon beta, 397 interleukin-1 receptor antagonist, 397–398 interleukin-2 (IL-2) concentration, lithium, 23 general effects, 397–398 interleukin-4 (IL-4), 23 interleukin-10 (IL-10), 23 interleukin-11 (IL-11), oprelvekin, 398 interscalene catheterization, 140 intrathecal (spinal) anesthesia, 142–143 intravenous immunoglobulin cardiovascular system, 365 general effects, 364–365 hematologic system, 365 immunologic system, 366 infection risk, 366 interactions, 366 nervous system, 365 respiratory system, 365 skin, 366 urinary tract, 365 intravenous regional anesthesia, 144 iodine. see also contrast agents, water-soluble iodinated fetotoxicity, 194 overdose, 459 iodixanol cardiac arrest, 513 cardiovascular system, 514 iodixanol, liposome-encapsulated, 519

578 3-iodo-2propynylbutylcarbamate, 170 iohexol cardiovascular system, 514 cholinesterase activity, 513 hearing impairment, 515 toxic epidermal necrolysis, 518 iopamidole, 513 ioxaglate general effects, 513–514 urinary tract, 517 irbesartan, 236 irinotecan, 502 iron, 247 isepamicin, 272 isoniazid hepatotoxicity, 340 musculoskeletal system, 341 pancreas, 341 isosulfan blue, 543 isotretinoin gastrointestinal system, 176 hematologic, 176 liver, 176 metabolic effects, 176 psychiatric effects, 175–176 respiratory system, 175 itraconazole cardiovascular system, 307 digoxin concentration, 200 dosage regimen, 307 general effects, 306–307 interactions, 308 liver, 307 skin, 308 ivermectin, 346–347 Japanese encephalitis vaccine, 359 JM473. see ZD0473 josamycin, 287 kava (Piper methysticum), 533–534 ketamine, 135 ketoconazole effectiveness, 304 hematologic system, 304 interactions, 304 liver, 304 ritonavir/saquinavir concentration, 334 ketolides, 283 ketoprofen respiratory system, 116 skin, 172 ketorolac, 134 LAAM. see levomethadyl acetate HCl labetalol, 223–224 Lactobacillus GG, 387

Index of drugs lactulose, 387 lamotrigine bone metabolism, +valproate, 71 vs. carbamazepine, 74 clearance, desmopressin, 483 concentration, oral contraceptives, 75 concomitant carbamazepine, 73 interactions, 75 metabolic effects, 75 overdose, 75 psychiatric effects, 74–75 lanoconazole, 170 Larrea tridentata (chaparral), 532 latanoprost cardiovascular system, 526 hair, 431 infection risk, 431 nervous system, 430–431, 526 ocular effects, 526 sensory systems, 431 skin, 431 laureth-A (polidocanol), 545 Laurus nobilis (laurel), 532–533 laxatives, 387 lead, 248 leech therapy, 535 lenograstim, 399 lepirudin, 379–380 letrozole, 445 leucovorin, 347 leuprorelin, 478 levalbuterol. see levosalbutamol levamisole aphthous ulcers treatment, 348 colorectal cancer treatment, 347–348 head and neck carcinoma treatment, 348 nephrotic syndrome treatment, 348 nervous system, 347 pediculosis capitis treatment, 347 warts treatment, 347 levetiracetam concomitant warfarin, 76 interactions, 76 psychiatric effects, 75–76 levobupivacaine, 146 levocetirizine, 182 levodopa cardiovascular system, 159–160 methylphenidate interaction, 5 nervous system, 160 respiratory system, 160 levofloxacin cardiovascular system, 278 interactions, 279 liver, 278 musculoskeletal system, 279 nervous system, 278

pancreas, 279 risk factors, 279 seizures, 274 sensory systems, 278 skin, 279 theophylline interaction, 2 levomethadyl acetate HCl (LAAM), 95 levonorgestrel, 447–448 levosalbutamol (levalbuterol), 191–192 licorice, 531 lidocaine cardiovascular system, 146 comparison trials, 142 hematologic, 146 interactions, 147 skin, 146–147 lignocaine. see lidocaine lincomycin, 284 linezolid, 288–289 liposome-encapsulated iodixanol, 519 lisinopril, 236 lispro insulin, 464 lithium additives, 24 administration route, 24 cardiovascular system, 19–20 cisplatin clearance, 502 death, 23 diabetes mellitus, 21 dosage regimens, 24 electrolyte balance, 21 endocrine system, 20–21 formulations, 24 hair, 22–23 hematologic system, 21–22 immunologic system, 23 interactions, 25–26 intoxication, 25 lactation, 23 mouth and teeth, 22 nervous system, 20 neuromuscular system, 20 overdose, 24–25 pancreas, 22 parathyroid gland, 21 pregnancy, 23 reproductive system, 23 respiratory system, 20 risk factors, 23–24 sexual function, 23 skin, 22–23 toxicity, 25 toxicity, trimethoprim, 291 urinary tract, 22 withdrawal, 23 LJP 394, 409 local anesthetics, 172–173 lopinavir/ritonavir fluid balance, 333 gastrointestinal system, 333 sensory systems, 333

579

Index of drugs loratadine cardiotoxic effects, 182 nefazodone interaction, 16 lorazepam administration route, 48 hip fractures, 46 metabolic effects, 48 nervous system, 47–48, 48 neuroleptic malignant syndrome, 55 lovastatin concentration, gemfibrozil, 486 pain and weakness, +clarithromycin, 488 rhabdomyolysis, +ciclosporin, 487 rhabdomyolysis, +miocamycin, 288 skin, 487 loxapine, 61 loxoprofen, 116 Lycium barbarum (Chinese wolfberry), 533 Lyme disease vaccine, 357 Ma-huang. see ephedrine macrolides. see specific drugs such as clindamycin; josamycin maidenhair tree, 531 manganese, 248 manidipine, 226–227 mannitol psychiatric effects, 376 skin, 376–377 marigold, 530 marijuana. see cannabinoids; cannabis massage therapy, 535–536 MDMA. see methylenedioxymethamphetamine (MDMA) measles-mumps-rubella (MMR) vaccine hematologic system, 359–360 nervous system, 359 psychiatric effects, 359 measles vaccine, 359 mebendazole, 324 medroxyprogesterone described, 448 general effects, 444 mefloquine concomitant ritonavir, 333 neuropsychiatric, 317–318 vs. pyrimethamine + sulfadoxine, 318 risk factors, 318 mehindi tattooing, 543–544 melarsoprol, 323 meloxicam, 116 Mentha spicata, 170 menthol respiratory system, 543

skin, 543 meperidine. see pethidine mercaptopurine, 388 mercury, 248 meropenem, 265 mesalazine, 388 metalloproteinases, 266–267 metformin alpha-glucosidase inhibitors interaction, 467 concomitant miglitol, 468 contraindications, 467 death, 468 gastrointestinal system, 468 interactions, 468 liver, 468 metabolic effects, 468 methadone cardiovascular system, 95 concentration, amprenavir, 332 concentration, efavirenz, 331 concentration, nevirapine, 332 interactions, 96 neuromuscular, 96 psychological, 96 respiratory system, 95 risk factors, 96 methamphetamine amphetamine interaction, 30 drug dependence, 31 psychiatric effects, 30–31 methandrostenolone, 450 methimazole hematologic system, 458 teratogenicity, 459 methotrexate carcinogenicity, 407 ciprofloxacin clearance, 277 clearance, rofecoxib, 125 hematologic system, 406–407 methoxamine, 157 methoxy polyethylene glycol, 170 methoxypsoralens, 173 methyl glucose dialate, 170, 545 methyldibromoglutamate, 170 methylenedioxymethamphetamine (MDMA, ecstasy) cardiovascular system, 32 drug contamination, 36 liver, 35 pregnancy, 35–36 psychiatric effects, 34 respiratory system, 32 reversal with diamorphine, 42 risk factors, 34 methylphenidate, 5 methylprednisolone, 308 metoclopramide, 383 metoprolol, 487 metronidazole in children, vs. mebendazole, 324 contact allergy, 170 general effects, 323–324

nervous system, 324 pregnancy, 324 mexazolam, 48 mexiletine, 213 midazolam cardiovascular system, 137 nervous system, 131, 137 vs. propofol, 131 temperature regulation, 137 midodrine, 157–158 mifepristone plus gemeprost, 430 mifepristone (RU 486) introduction, 448–449 mineral balance, 449 reproductive system, 449 miglitol alpha-glucosidase inhibitors interaction, 467 concomitant metformin, 468 glibenclamide clearance, 470 metabolic effects, 467 milrinone, 201 minocycline, 265–266 miocamycin, 287–288 Mirena, 447, 448 misoprostol general effects, 431–432 reproductive system, 432 uterine rupture, +oxytocin, 481 mizolastine, 182 modafinil, 5–6 moricizine, 213 morphine adverse effects management, 98–99 vs. diamorphine, 91–92 effectiveness, 97 pregnancy, 97 moxifloxacin cardiovascular system, 279 concomitant theophylline, 3 interactions, 279–280 skin, 279 MS-325, 521 mumps vaccine. see measles-mumps-rubella (MMR) vaccine mycophenolate mofetil immunologic system, 407 infection risk, 407 pregnancy, 407–408 myrrh, 348–349 N-deamino-8-d-argenine vasopressin. see desmopressin nadroparin, 379 nafarelin, 477 nalbuphine, 104–105 nalidixic acid, 280 nalmefene effects, 21 safety, 105 naloxone, 105 naltrexone, 105–106 naproxen

580 vs. COX-2 inhibitors, 117–118 hematologic system, 116 nateglinide, 468 nedaplatin, 492 nefazodone concentration, zopiclone, 51 liver, 16 loratadine concentration, 182 nefopam, 106 nelfinavir, 333 neomycin, 273 netilmicin, 273 neuromuscular blocking agents electrolyte balance, 151–152 irreversibility, +polymyxins, 289 nervous system, 151 nevirapine, 332 niacin. see nicotinic acid nicardipine children, 227 digoxin concentration, 199 nickel, 248–249 nicotine, 528 nicotinic acid (niacin) and nicotinamide, 419–420 nifedipine digoxin concentration, 199 mouth and teeth, 227 pregnancy, 227 nilutamide, 452 nimesulide lithium interaction, 26 liver, 125 nimodipine, 227 nitrofurantoin, 288 nitroglycerin. see glyceryl trinitrate nitrous oxide, 134 nizatidine, 384 non-steroidal anti-inflammatory drugs (NSAIDs). see also specific drugs such as ketoprofen anaphylaxis, 121–122 angio-edema, 122–123 cardiovascular system, 117–118 chronic renal disease, 111–112 gastrointestinal system, 119–121 immunologic system, 121 pregnancy and teratogenicity, 112–113 pseudoporphyria, 175 renal insufficiency, 111–112 reproductive system, 123 skin, 174 urticaria, 122–123 19-nor-1α, 25-dihydroxycholecalciferol. see paricalcitol norfloxacin, 280 Norplant, 444

Index of drugs noxurol, 170 NSAIDs. see non-steroidal anti-inflammatory drugs (NSAIDs) nucleoside analogue reverse transcriptase inhibitors (NRTI), 330 octreotide, 480 ofloxacin endocrine system, 280 formulations, 280 interactions, 280 salivary glands, 280 skin, 280 for tuberculosis, safety, 339 olanzapine cardiovascular system, 61–62 vs. clozapine, 61 concentration, fluvoxamine, 14 hair loss, St. John’s wort, 532 hematologic, 62–63 immunologic system, 63 interactions, 63 lithium interaction, 26 metabolic effects, 62 nervous system, 62 pancreas, 63 psychiatric effects, 62 sexual function, 63 olsalazine, 389 omalizumab, 402–403 omeprazole in children, 385–386 clarithromycin metabolism, 286 interactions, 386 skin, 386 urinary tract, 386 ondansetron, 103 oprelvekin, 398 Optison, 522 oral contraceptives concentration, +fluconazole, 306 failure, +St. John’s wort, 532 formulations, 444–445 interactions, 445 lamotrigine concentration, 75 liver, 443–444 skin, 174 third-generation assessment, 442–443 oral hypoglycemic drugs, 466 oseltamivir, 334 ovulation induction, 478 oxaliplatin acetylcholinesterase activity, 502 body temperature, 501–502 hematologic system, 498 immunologic system, 501 interleukin-6 concentration, 501

mechanism of action, 490 nervous system, 494–496 pharmacokinetics, 490–491 skin, 500–501 TNF-alpha concentration, 501 oxazepam, 48 oxazolidinones effectiveness, 288–289 hematologic system, 289 interactions, 289 oxcarbazepine, 76 oxybenzone, 174 oxybuprocaine, 147 oxycodone, 99 oxygen carriers, 363–364 oxymetholone, 450 oxytocic drugs, 431–432 oxytocin, 481 paclitaxel clearance, cisplatin, 503 concentration, ciclosporin, 406 palivizumab, 403 pancreatic enzyme supplements, 389 pantoprazole, 386 para-phenylenediamine general effects, 543–544 skin, 173 paracetamol hematological system, 113 interactions, 114–115 overdose, 114 renal insufficiency, 112 paramethoxyamphetamine (PMA), 36 parathyroid hormone (PTH), 481 parecoxib, 124 parenteral nutrition, 377 paricalcitol, 422 paromomycin, 273 paroxetine endocrine, 13 and interferon alfa, 394 lithium interaction, 25 risperidone concentration, 65 sexual function, 13 skin, 13 Passiflora incarnata (passion flower), 48 pefloxacin arthropathy, 275 immunologic system, 281 risk factors, 281 pemoline, 7 penicillamine endocrine system, 255 liver, 255 pregnancy, 256 skin, 256 urinary tract, 256 penicillins immunologic reaction, 262–263 liver, 262

581

Index of drugs pentamidine, 323 perfluorocarbons, 364 pethidine, 99 phenolic compounds, 260 phenoxyethanol, 173 phenylpropanolamine, 158–159 phenytoin concentration, fluvoxamine, 14 drug administration route, 77 immunology, 76 skin, 77 phototherapy, 175 phytomenadione. see vitamin K pimozide potentiation, clarithromycin, 286 vs. risperidone, 63 pioglitazone, 471 Piper methysticum (kava), 533–534 piperacillin, 263–264 piracetam, 7–8 piroxicam, 286 platinum compounds body temperature, 501–502 effectiveness, 490 electrolyte balance, 497–498 endocrine system, 497 fertility, 502 gastrointestinal system, 498 general effects, 491–492 hematologic system, 498 immunologic system, 501 interactions, 502–503 liver, 499 mutagenicity and carcinogenicity, 502 nervous system, 494–496 overdose, 502 sensory systems, 496–497 skin, 500–501 teratogenicity, 502 urinary tract, 499–500 visual disturbances, 497 PMA. see paramethoxyamphetamine polidocanol, 545 poliomyelitis vaccine. see DTP-HiB vaccine polyestradiol phosphate, 451 polygeline, 376 Polygonum multiflorum (Shou wu Pian), 534 polymyxins, 289 polyoxyethylene lauryl ether, 545 polyvalent cations, 279 porcine factor VIII:C bronchospasm, 366 periorbital edema, 367 safety, 367 urticaria, 367 potassium iodide, 459 potassium persulfate, 173 pramipexole, 160

pravastatin, 488 praziquantel cysticercosis treatment, 344 interactions, 349 neurocysticercosis treatment, 349–350 paragonimiasis treatment, 350 prednisolone, 427 prednisone, 427 primaquine, 318–319 pristinamycin, 289–290 probenecid, 134 procainamide, 213 procaine, 147 progesterone, 450 progestogens, 447–448 proguanil adherence, +atovaquone, 317 adherence, +chloroquine, 317 neuropsychiatric effects, +atovaquone, 319 promethazine, 55 propafenone cardiovascular system, 214 vs. dofetilide, 210 efficacy, 202 overdose, 214 risk factors, 214 proparacaine, 147 propofol anti-nausea effectiveness, 131 bradycardia, +lithium, 25 cardiovascular system, 135 -infusion syndrome, 135–136 liver, 136 vs. midazolam, 131 nervous system, 135 pancreas, 136 respiratory system, 135 propylthiouracil immunologic system, 459 liver, 458 prostaglandin analogues, 526 prostamides, 526 protease inhibitors concentration, fluconazole, 306 metabolic effects, 332 protirelin. see thyrotropin-releasing hormone (TRH) proton pump inhibitors, 384–385 pseudoephedrine. see ephedrine psyllium, 387 PTH. see parathyroid hormone PUVA, 175 pyrazinamide, 339–340 pyridoxine. see vitamin B6 pyrimethamine, 320, 322 quetiapine, 63 quinidine digoxin concentration, 199 efficacy, 202 interactions, 214

skin, 214 quinine, 318 quinupristin/dalfopristin, 290 rabeprazole, 386 raloxifene, 445–446 ranitidine concomitant moxifloxacin, 280 skin, 384 urinary tract, 384 rapacuronium, 150 rapamycin. see sirolimus rasburicase, 545 recombinant factor IX, 366 recombinant factor VIIa, 366–367 recombinant human activated protein C, 363 recombinant human chorionic gonadotrophin (RhCG), 435–436 Red Bull, 1 remacemide, 77 remifentanil cardiovascular system, 101 general effects, 99–101 nervous system, 101 pregnancy, 101 repaglinide vs. glipizide, 471 interactions, 469 metabolic effects, 469 risk factors, 469 retinol. see vitamin A ribavirin clotting disorders, +interferon alfa, 395 didanosine concentration, 329 hematologic system, 329 metabolic effects, 329 rifabutin interactions, 341 metabolism, clarithromycin, 286 musculoskeletal system, 341 rifampicin co-trimoxazole concentration, 292, 322 concomitant ritonavir, 334 interactions, 342 liver function, +paracetamol, 115 ritonavir/saquinavir concentration, 334 urinary tract, 341–342 rimonabant, xxxiv risperidone clozapine clearance, +nefazodone, 16 clozapine concentration, 60–61 concentration, paroxetine, 15 effectiveness, 63–64 endocrine system, 65 interactions, 65 liver, 65 nervous system, 64

582 overdose, 65 vs. pimozide, 63 salivary glands, 65 sexual function, 65 ritodrine, 192 ritonavir. see also lopinavir/ritonavir amprenavir concentration, 332 clarithromycin metabolism, 286 concentration, fluconazole, 306 ergotamine metabolism, 164 indinavir concentration, 333 interactions, 333–334 rituximab, 403 rivastigmine, 8 rocuronium, 150–151 rofecoxib interactions, 125 nervous system, 124–125 urinary tract, 125 urticaria/angio-edema safety, 122 ropinirole interactions, 162 sleep disorders, 160 ropivacaine concomitant itraconazole, 308 nervous system, 147–148 rosiglitazone, 472 rotavirus vaccine, 360 roxithromycin, 288 RU 486. see mifepristone rubella vaccine, 360. see also measles-mumps-rubella (MMR) vaccine salmeterol, 192–193 saquinavir amprenavir concentration, 332 concentration, fluconazole, 306 concentration, ritonavir, 334 sartraplatin, 492–493 saw palmetto, 534. see also Cucurbicin Scutellaria lateriflora (skullcap), 534 Selaginella doederleinii, 534 selective serotonin re-uptake inhibitors (SSRIs) cardiovascular system, 12 death risks, 11–12 electrolyte balance, 13 endrocrine, 13 interactions, 14 lactation, 14 nervous system, 12–13 sexual function, 13–14 skin, 13 selegiline, 308 selenium, 249 Serenoa repens (saw palmetto), 534. see also Cucurbicin sertindole, 66

Index of drugs sertraline oxazolidinones interaction, 289 Parkinsonism, 12 sevelamer concomitant digoxin, 200 concomitant warfarin, 379 sevoflurane cardiovascular system, 132 interactions, 134 liver, 133 musculoskeletal system, 134 nervous system, 132–133 psychiatric effects, 133 respiratory system, 132 urinary tract, 133–134 SH U 555 A, 522 Shou wu pian, 534 sibutramine, 7 sildenafil death, +glyceryl nitrate, 225 interactions, 231 nervous system, 231 sensory systems, 231 silicone, 544 silver, 249 simvastatin concentration, ciclosporin, 405 concentration, diltiazem, 226 concentration, nelfinavir, 333 hematologic system, 487 interactions, 488 musculoskeletal system, 487 rhabdomyolysis, +ciclosporin, 487 rhabdomyolysis, +miocamycin, 288 sleep disturbance, +metoprolol, 487 sirolimus (rapamycin), 226, 408 sitafloxacin, 281 skullcap, 534 sodium diatrizoate, 516 sodium dihydroxyacetyl phosphate, 171 sodium fusidate. see fusidic acid sodium polystyrene sulfonate, 256 somatostatin endocrine system, 480 immunologic system, 480 pregnancy, 481 somatotropin. see growth hormone Sono Vue (sulfur hexafluoride), 522–523 sotalol cardiovascular system, 224 comparison with dofetilide, 210 efficacy, 202 risk factors, 224 soybean extract, 171 sparfloxacin cardiovascular system, 281

phototoxicity, 341 risk factors, 281 skin, 281 spearmint, 170 SPI-77, 493 spinal manipulation, 536 spironolactone digoxin concentration, 199 liver, 240 skin, 240 squirting cucumber, 531 SSRIs. see selective serotonin re-uptake inhibitors (SSRIs) St. John’s wort concentration, ciclosporin, 405–406 endocrine system, 532 hair, 532 interactions, 532 nervous system, 532 nevirapine concentration, 332 statin concentration, 487 tricyclic antidepressant concentration, 11 statins. see HMG coenzyme-A reductase inhibitors stavudine, 331 stearyl alcohol, 171, 545 streptomycin, 273 strychnine, 6 succinylcholine, 151–152 sucralfate, 279 sufentanil, 101–102 sulfadiazine, 323 sulfadoxine, 320, 322 sulfamethoxazole. see co-trimoxazole sulfan blue, 545 sulfasalazine, 389 sulfonamides immunologic system, 290 interactions, 290–291 skin, 290 teratogenicity, 290 sulfonylureas, 115 sumatriptan, 15 sunscreen, 174 suramin glioma, recurrent high-grade, 350–351 prostate cancer, hormone-refractory, metastatic, 350 renal cell carcinoma treatment, 351 tacrine, 8 tacrolimus concentration, fluconazole, 306 concentration, itraconazole, 308 infection risk, 409 liver, 408 metabolic effects, 408 nervous system, 408

583

Index of drugs sildenafil concentration, 231 skin, 408 talc, 544 tamoxifen carcinogenicity, 447 cardiovascular system, 446 hair, 446 metabolic effects, 446 reproductive system, 446–447 tea tree oil, 171 tegaserod concomitant theophylline, 3 digoxin availability, 200 teicoplanin adverse reactions, management, 283 administration route, 283 drug tolerance (antibacterial resistance), 283 formulations, 283 hematologic system, 282 immunologic system, 282–283 skin, 282 telithromycin, 283 temazepam nervous system, 48 vs. zolpidem, 50 tenofovir, 331 terbinafine dosage regimen, in children, 310–311 hair, 310 hematologic system, 309 immunologic system, 310 interactions, 311 liver, 309–310 musculoskeletal system, 310 skin, 310 terfenadine, 16 terlipressin (triglycyl-lysine vasopressin), 483 testosterone, 449–450 tetanus/pertussis vaccine, 356 tetracyclines, chemically modified, 268 tetraethylthiuramdisulfide, 545 tetraplatin, 493 thalidomide neurotoxicity, +interferon alfa, 397 thrombosis, 176 theophylline clearance, +fluoroquinolones, 275 clearance, levofloxacin, 279 concomitant moxifloxacin, 280 diagnostic test interference, 2 interactions, 2–3 in neonates, 2 overdose, 2 risk factors, 2 thiazide diuretics carcinogenicity, 239–240 cardiovascular system, 239

electrolyte balance, 239 interactions, 240 skin, 239 urinary tract, 239 thimerosal bacitracin allergy, 292 vaccines, 259–260 thionamides hematologic system, 458 immunologic system, 458–459 teratogenicity, 459 thiuram, 544–545 thyroid stimulating hormone (TSH, thyrotropin), 481–482 thyrotropin-releasing hormone (TRH, protirelin), 482 thyroxine cardiovascular system, 457 drug abuse, 457 interactions, 457–458 tiagabine, 77–78 tibolone, 452 ticlopidine, 381 timolol, 525–526 titanium, 249–250 tobramycin, 273 tocopherols. see vitamin E tolbutamide fluvoxamine interaction, 14 inhibition, sulfonamides, 290 tonic water, 318 topical anesthesia, 144 topiramate acid-base balance, 80 body temperature, 80 cognitive effects, 78–79 administration, 80 effects, 78 lithium interaction, 25 psychiatric effects, 79 sensory systems, 79 toremifene, 447 tosufloxacin, 281 tramadol dependence, 103 efficacy, 102–103 interactions, 103–104 overdose, 103 tranexamic acid, 381 trastuzumab, 403 travoprost general effects, 432 ocular effects, 526 tretinoin, 419 triamterene risk factors, 241 teratogenicity, 240–241 urinary tract, 240 triazolam zaleplon interaction, 49 vs. zopiclone + zolpidem, 51 tribavirin. see ribavirin trichloroethylene, 134 triclosan, 171

tricyclic antidepressants, 11 triethanolamine, 171 trimebutine, 171 trimethoprim. see also co-trimoxazole concomitant theophylline, 3 electrolyte balance, 291 interactions, 291 lithium concentration, 25 triphenylmethane dyes, 259 triptans SSRI interaction, 15 teratogenicity, 230 triptorelin, 478 troglitazone, 472 troleandomycin, 288 tropicamide, 147 tropisetron, 384 trovafloxacin, 276 TSH. see thyroid stimulating hormone (TSH, thyrotropin) tylosin, 288 Uncaria tomentosa (cat’s claw), 534 ursodeoxycholic acid, 389 vaccines monitoring needs, 353–354 trial size, 353 Vaccinium macrocarpon (cranberry) hematologic system, 534 valaciclovir, 330 valerian, 533 valproate bone metabolism, +lamotrigine, 71 polycystic ovary syndrome, 81 valproate sodium body temperature, 81–82 fetotoxicity, 82 infection risk, 81 liver, 80–81 metabolic effects, 80 nervous system, 80 skin, 81 valproic acid, 502 Varicella vaccine, 360 venlafaxine drug withdrawal, 17 hair, 16–17 indinavir concentration, 333 lithium interaction, 25–26 overdose, 17 verapamil cardiovascular system, 227–228 digoxin concentration, 199 dofetilide concentration, 212 interactions, 228 musculoskeletal system, 228 nervous system, 228 vertebral angiography, 514–515

584 vigabatrin general effects, 82 long term safety, 83 visual field defects, 82–84 vinca alkaloids, 308 virginiamycin drug tolerance (antibacterial resistance), 293 resistance to quinupristin/dalfopristin, 290 vitamin A, 416 vitamin B2 (riboflavin), 420 vitamin B5 , 424 vitamin B6 (pyridoxine), 420–421 vitamin C (ascorbic acid), 421 vitamin D (calciferol), 421 vitamin E acetylsalicylic acid, concomitant use, 423 hematologic system, 422 vitamin H (biotin), 424 vitamin K, 424 voglibose, 466–467 voriconazole, 309

Index of drugs walnut oil, 545 warfarin absorption, alpha-glucosidase inhibitors, 467 clearance, +raloxifene, 445–446 clearance, +rifampicin, 342 concentration, fluvoxamine, 14 concomitant digoxin, 200 concomitant levetiracetam, 76 concomitant suramin, 350 dosage, nevirapine, 332 efficacy, rofecoxib, 125 hypoprothrombinemia, +macrolides, 284 hypoprothrombinemia, +miocamycin, 288 INR, Chinese wolfberry, 533 INR, +clarithromycin, 287 INR, +Cucurbicin, 422 INR, +doxycycline, 265 INR, +ropinirole, 162 metabolism, quinidine, 214 white flower, 545

withdrawal levofloxacin interaction, 279 xenon, 134–135 zafirlukast, 194 zaleplon, 49 zanamivir, 334–335 ZD0473, 493 zinc, 250 zinc ricinoleate, 171 zolpidem drug abuse, 50–51 nervous system, 50 overdose, 51 psychiatric effects, 50 vs. zopiclone + triazolam, 51 zonisamide, 84 zopiclone bitter taste, 50 interactions, 51 nervous system, 51 overdose, 51 vs. zolpidem, 50

Index of adverse effects ABCR gene chloroquine, 316 abdominal discomfort anticholinergic drugs, 164 deferiprone, 253 famciclovir, 329–330 hemoglobin-based oxygen carriers, 363 abdominal distension antipsychotic drugs, 58 leuprorelin acetate, 478 octreotide, 480 voglibose, 466 abdominal fat glibenclamide, 466, 469 voglibose, 466 abdominal pain amphotericin B liposomal, 303 antipsychotic drugs, 58 Artemisia derivatives, 320 atovaquone, 320 azathioprine, 404 BufferGel, 541 celecoxib, 123 erythromycin, 284 irinotecan + oxaliplatin, 502 itraconazole, 307 leuprorelin acetate, 478 levofloxacin, 278 mesalazine, 387 metformin, 468 methotrexate, 407 methylphenidate, 5 moxifloxacin, 279 naltrexone, 105 NRTIs, 330 oral contraceptives, 444 primaquine, 319 progestogens, 448 proton pump inhibitors, 385 pseudoephedrine, 157 quinine, 318 rabeprazole, 386 suramin, 351 abdominal tenderness antipsychotic drugs, 58 lead, 248 propofol, 136 abnormal posture disulfiram, 542 abnormal stools cilostazol, 230 lopinavir/ritonavir, 333 abscesses leuprorelin acetate, 478 absence seizures

valproate sodium, 80 acanthosis silver, 249 acanthosis nigricans fusidic acid, 281 acetylcholinesterase activity contrast agents, 513 aches interleukin-11 (oprelvekin), 398 acidosis cocaine, 39 diclofenac, 115 propofol, 135–136 topiramate, 80 acne lithium, 22 Mirena, 447 acral erythema docetaxel, 504 acute respiratory distress syndrome (ARDS) all-trans retinoic acid, 417, 418 amiodarone, 204 infliximab, 401 tetracycline therapy, 268 addiction methamphetamine, 30 adenocarcinoma hormone replacement therapy, 441 adrenal insufficiency fluconazole, 305 inhaled corticosteroids, 188 aggression amfebutamone, 16 androgenic anabolic steroids, 450 cannabis in animals, xxxiii gabapentin, 74 gliclazide, 470 midazolam, 136 piracetam, 8 vigabatrin, 82 agitation amfebutamone, 16 baclofen, 153 cefepime, 265 haloperidol, 53 infiltration anesthesia, 143 levetiracetam, 76 midazolam, 136 nicotine poisoning, 528 paracetamol + rifampicin, 115 piracetam, 8 risperidone, 53

rofecoxib, 123 sevoflurane, 133 St. John’s wort, 532 theophylline, 2 zolpidem, 50, 51 agranulocytosis clozapine, 59–60 dapsone, 340 olanzapine, 62, 63 terbinafine, 309 thionamide drugs, 458 air embolism central venous catheters, 545 airway obstruction triphenylmethane dyes, 259 akathisia antipsychotic drugs, 54 cocaine, 38 diphenhydramine, 54 haloperidol, 64 prochlorperazine, 54, 55 risperidone, 64 alkaline phosphatase blood activity quinupristin/dalfopristin, 290 allergic conjunctivitis adrenoceptor agonists, 525 allergic reaction albumin, 363 asparaginase, 504 calcitonin, 472 Dy-EOB-DTPA, 519 epoetin, 370 fibrates, 486 inhaled corticosteroids, 190 iodinated water-soluble contrast agents, 513 isosulfan blue, 543 Japanese encephalitis vaccine, 359 mercury, 248 nickel, 248 para-phenylenediamine, 173 penicillin, 262–263 rocuronium, 150–151 squirting cucumber, 531 steroids, 450 vitamin B6 , 420 alopecia epoetin, 369 lithium, 23 Mirena, 447 Norplant, 444 St. John’s wort + olanzapine, 532 tamoxifen, 446

585

586 terbinafine, 310 venlafaxine, 16–17 alveolitis indigo carmine, 545 amenorrhea Mirena, 447 risperidone, 65 aminotransferase activity HMG-CoA reductase inhibitors, 487 linezolid, 289 MDMA, 35 amnesia efavirenz, 331 lorazepam, 48 anaphylaxis/anapylactoid reactions acetazolamide, 239 albumin, 363 anthrax vaccine, 355 cefazolin, 264 chlorhexidine, 258 chlorhexidine + sulfadiazine, 290 cisplatin, 501 diphtheria vaccine, 356 etomidate, 135 intravenous immunoglobulin, 366 iodinated contrast agents, 519 iron dextran, 247 isosulfan blue, 543 5-methoxypsoralen, 173 NSAIDs, 121–122 oxaliplatin, 501 polygeline, 376 rocuronium, 150–151 sulfan blue, 545 thiazide + loop diuretics, 239 vancomycin, 282–283 vitamin B2 , 420 anemia ACE inhibitors, 234 arsenic, 244 cisplatin, 498 interleukin-11, oprelvekin, 398 methotrexate, 407 ribavirin, 329 suramin, 351 vitamin D, 421 anemia, aplastic anthrax vaccine, 355 chloramphenicol, 273 clopidogrel, 380 ketoconazole, 303 anemia, hemolytic intravenous immunoglobulin, 365 anemia, sideroblastic chemically modified tetracyclines, 268 linezolid, 289 anencephaly triamterene, 241

Index of adverse effects aneurysmal subarachnoid hemorrhage cocaine, 39 gold, 246 anger prednisone, 427 angina see also cardiac ischemia dipyridamole, 380 hormone replacement therapy, 438 iodixanol, 514 iohexol, 514 latanoprost, 526 nitroglycerin, 224 thyroxine, 457 angio-edema meloxicam, 116 NSAIDs, 121–122, 122–123 pioglitazone, 471 vitamin B2 , 420 anhidrosis brachial plexus anesthesia, 140 anorexia Artemisia derivatives, 320 clozapine, 60 digoxin, 198 ecstasy, 35 phenytoin + fosphenytoin, 76 vitamin A, 416 zonisamide, 84 anorgasmia SSRIs, 13–14 anovulatory cycles valproate sodium, 81 anteroseptal defects dipyridamole, 380 antibacterial resistance chemically modified tetracyclines, 269 fusidic acid, 281 glycopeptides, 282 quinupristin/dalfopristin, 290 virginiamycin, 293 antibody formation epoetin, 370 human growth hormone, 480 interferon alfa, 394 lepirudin, 379–380 parathyroid hormone, 481 antibody function factor VIII:C, 367 anxiety antituberculous agents, 339 cannabis, xxxiv, xxxviii cefepime, 265 cisplatin, 496 efavirenz, 331 gabapentin, 74 levofloxacin, 278 lithium, 20 MDMA, 34 mefloquine, 318 methamphetamine, 30

nefazodone, 16 remifentanil, 100 zolpidem, 51 aortic dissection cocaine, 37 aortic regurgitation fenfluramine, 6 aphasia gonadorelin receptor antagonists, 478 leuprorelin, 478 aplasia cutis congenita carbimazole, 459 apnea alprostadil, 430 DTP-Hib vaccines, 356 methadone, 95 apoptosis cisplatin, 499 appetite, change in cannabis in animals, xxxiii Dy-EOB-DTPA, 519 fentanyl, 94 kava, 533 methylphenidate, 4, 5 moricizine, 213 piracetam, 8 risperidone, 64 ARDS see acute respiratory distress syndrome (ARDS) argyria acupuncture, 535 argyrosis, vaginal silver, 249 artery vasculitis hepatitis B vaccine, 358 arthralgia all-trans retinoic acid, 417 anthrax vaccine, 355 Echinacea, 531 intravenous immunoglobulin, 365 nicardipine, 228 propylthiouracil, 458 quinupristin/dalfopristin, 290 rubella vaccine, 360 terbinafine, 310 arthritis Lyme vaccine, 358 rubella vaccine, 360 arthropathy ciprofloxacin, 277 fluoroquinolones, 275 arthrosis rubella vaccine, 360 ascites albumin, 363 leuprorelin acetate, 478 aseptic meningitis allopurinol, 125 co-trimoxazole, 291, 321 gentamicin, 271 infliximab, 401

587

Index of adverse effects intravenous immunoglobulin, 365 rofecoxib, 124–125 valaciclovir, 330 aseptic necrosis systemic glucocorticosteroids, 429 asthma aspirin-induced, 117–118 cisplatin, 501 cocaine, 38 ketoprofen, 116 menthol, 543 NSAIDs, 121–122 asymmetrical head shape ganirelix + follicle stimulating hormone, 479 asystole acetylcholinesterase inhibitors, 164 ergot alkaloids, 163 remifentanil, 101 ataxia disulfiram, 542 gabapentin, 74 heroin, 92 lamotrigine, 74 macrolides, 284 miocamycin, 288 oxcarbazepine, 76 remacemide, 77 spinal manipulation, 536 zonisamide, 84 atherogenesis triptorelin, 478 atherosclerotic plaque rupture cannibinoids, 36 atopic dermatitis titanium, 250 atopy and immunizations, 355 atrial fibrillation dofetilide, 209 fluoroquinolones, 274 milrinone, 202 venlafaxine, 17 atrial flutter dofetilide, 209 moricizine, 213 atrioventricular block adenosine, 203 propafenone, 214 sotalol, 224 atrium, heart see entries at heart– auditory disturbance see entries at hearing– autism measles-mumps-rubella vaccine, 359 valproate sodium, 82 autonomic symptoms insulin, 461, 462 avascular necrosis

systemic glucocorticosteroids, 429 azoospermia cyclophosphamide, 406, 504 azotemia lithium, 21, 22 baboon syndrome nickel, 248 terbinafine, 310 back pain denileukin diftitox, 398 Dy-EOB-DTPA, 519 hormone replacement therapy, 440 liposome-encapsulated iodixanol, 519 backache BufferGel, 541 intravenous immunoglobulin, 364 balance amphetamine, 30 cannabis, xxxv streptomycin, prenatal, 273 zolpidem, 50 balanitis co-trimoxazole, 321–322 Beckwith-Weidemann syndrome ganirelix + follicle stimulating hormone, 479 behavioral changes topiramate, 79 behavioral control vigabatrin, 82 Behçet’s disease docetaxel, 504 bilirubin concentration all-trans retinoic acid, 418 celecoxib, 124 bioterrorism anthrax vaccine, 354–355 birth defects antiepileptic drugs, 71, 73 cetrorelix, 479 fluconazole, 305–306 losartan, 236 nalidixic acid, 280 birth weight antiepileptic drugs, 73 cocaine, 40 dexamethasone, 429 somatostatin, 481 bitter taste azelastine, 183 zolpidem, 50 black tongue arsenic, 244 bladder diverticula copper, 245 bladder stones felbamate, 73 bleeding

acupuncture, 535 recombinant human activated protein C, 363 saw palmetto, 534 bleeding tendency, increased herbal medicines, 528 blepharoconjunctivitis dorzolamide, 239 blindness gonadorelin, 477 mexiletine, 213 blistering Ginkgo biloba, 531 henna tattooing, 544 blood, dark-colored benzocaine, 145 blood clots MDMA, 35 blood dyscrasias dapsone, 340 terbinafine, 309 blood glucose control pancreatic enzyme supplements, 389 blood loss central venous catheters, 545 blood pressure changes citric acid, 541 intravenous immunoglobulin, 364 “blue hives” isosulfan blue, 543 blurred vision brachial plexus anesthesia, 140, 141 cisplatin, 497 flecainide, 213 human growth hormone, 479 latanoprost, 431 mexazolam, 48 bone dysplasia deferiprone, 254 bone loss G-CSF, 399 systemic glucocorticosteroids, 428 bone marrow suppression pyrimethamine + azithromycin, 322 Selaginella doederleinii, 534 thionamide drugs, 458 bone metabolism ciclosporin, 405 valproate + lamotrigine, 71 bone mineral density androgen deprivation therapy, 504 antiandrogens, 450 inhaled corticosteroids, 186, 188–190 bone pain all-trans retinoic acid, 417, 418 bowel sounds dextromethorphan, 91

588 bradycardia adrenoceptor agonists, 525 alprostadil, 430 cisplatin, 494 desmopressin, 482 diltiazem, 226 DTP-Hib vaccines, 356 ergot alkaloids, 163 labetalol, 164 lithium, 24, 25 milrinone, 202 propafenone, 214 propofol, 136 remifentanil, 100 sotalol, 224 terlipressin, 483 timolol, 525 bradypnea diltiazem, 226 breakthrough bleeding, menstrual BufferGel, 540 breakthrough infections voriconazole, 309 breakthrough pain fentanyl, 92 breast enlargement finasteride, 450 penicillamine, 255 breast pain antiandrogens, 450 breast swelling gonadotrophin-releasing hormone, 477 breast tenderness finasteride, 450 hormone replacement therapy, 436 progestogens, 448 risperidone, 65 breathing, difficulty in adenosine, 203 leuprorelin acetate, 478 spinal manipulation, 536 vitamin B6 , 424 vitamin H, 424 bronchiolitis obliterans mesalazine, 388 bronchoconstriction propofol, 135 bronchopneumonia gliclazide, 470 bronchopulmonary dysplasia cocaine, 41 bronchospasm adenosine, 203 beta-adrenoceptor agonists, 526 carboplatin, 501 clarithromycin, 286 hypochlorite, 259 intravenous immunoglobulin, 365 rapacuronium, 150 zanamivir, 334–335

Index of adverse effects bronzing of the skin antituberculous agents, 339 Brugada syndrome flecainide, 212 bruising cranberry, 534 ganirelix, 479 bruxism paramethoxyamphetamine (PMA), 36 buccal movement methylphenidate, 4 bullous emphysema cocaine, 38 bullous erruptions melarsoprol, 323 bullous pemphigoid influenza vaccine, 359 Td-IPV vaccine, 358 bullous phototoxic skin reactions bergamot, 530 burning, skin henna tattooing, 544 tacrolimus, 408 burning eyes aminoglycosides, 273 bimatoprost, 430 flecainide, 213 burning mouth clonazepam, 47 inhaled corticosteroids, 188 burning sensation calcineurin inhibitors, 172 griseofulvin, 176 indocyanine green, 545 burns, second degree garlic, 529 butyrylcholinesterase activity contrast agents, 513 calcinosis aristolochic acid, 530 heparins, 377 calcium blood concentration vitamin A, 416 cancer ethylene oxide, 258 cancer, breast diethylstilbestrol (stilbestrol), 436 hormone replacement therapy, 441 cancer, colon thiazide + loop diuretics, 239 cancer, endometrial hormone replacement therapy, 441 tamoxifen, 447 cancer, esophageal trichloroethylene, 134 cancer, skin cyclophosphamide, 406 cancer, vaginal

diethylstilbestrol (stilbestrol), 436 Candida infection fluoroquinolones, 275 inhaled corticosteroids, 187, 190 carcinogenic effects nitroglycerin, 224 carcinoma, renal cell thiazide + loop diuretics, 239 cardiac see also entries at coronary–; heart– cardiac arrest see also myocardial infarction depolarizing neuromuscular blocking agents, 151, 152 diltiazem, 226 iodixanol, 513 iopamidol, 513 ioxaglate, 513 pethidine, 99 propofol, 136 cardiac collapse polygeline, 376 cardiac dysfunction ecstasy, 32 cardiac dysrhythmia adenosine, 203 ajmaline and derivatives, 204 antihistamines, 181 beta-adrenoceptor agonists, 190 carbamazepine, 72 dobutamine, 159 flecainide, 212 ritodrine, 192 sertindole, 65 cardiac ischemia nitrous oxide, 134 pseudoephedrine + amfebutamone, 157 terlipressin, 483 thyroxine, 457 cardiogenic shock nicardipine, 228 pranlukast, 193 cardiomegaly human growth hormone, 479 infiltration anesthesia, 143 cardiomyopathy antipsychotic drugs, 54 chloroquine, 315 clozapine, 59 lithium, 19 olanzapine, 63 cardiotoxicity antihistamines, 180–181 loratadine + nefazodone, 16 trastuzumab, 403 cardiovascular collapse isosulfan blue, 543 propofol, 135–136 cardiovascular events darbepoetin, 368

589

Index of adverse effects epoetin, 368 erythropoietin, 368, 369 cardiovascular teratogenesis lithium, 19 carotid artery dissection spinal manipulation, 536 caseous necrosis acupuncture, 535 cataracts erythromycin + statins, 287 inhaled corticosteroids, 188 catatonia alprazolam, 46 bromazepam, 46 catecholaminergic neurotransmission cocaine, 39 cauda equina syndrome lidocaine, 143 spinal manipulation, 536 central retinal artery, branch occlusions massage therapy, 536 cerebellar infarct spinal manipulation, 536 cerebellar sequelae lithium, 20 cerebral damage gliclazide, 470 cerebral edema desmopressin, 482 sildenafil, 231 cerebral hemorrhage phenylpropanolamine, 158–159 cerebral herniation cisplatin, 496 cerebral infarction tamoxifen, 446 cerebral ischemic symptom gold, 246 cerebral sinus thrombosis tamoxifen, 446 cerebral venous thrombosis oxymetholone, 450 cerebrospinal fluid pressure all-trans retinoic acid, 417 cervical cancer trichloroethylene, 134 cervical lacerations misoprostol, 432 cheilitis glyceryl hydrogenated rosinate, 171 chest discomfort intravenous immunoglobulin, 365 chest pain cardiac glycosides, 530 cocaine, 37 desmopressin, 482 dipyridamole, 380 dobutamine, 159 Ephedra, 156 iloprost, 230

MDMA, 32 talc, 544 vitamin B6 , 424 vitamin H, 424 chest tightness amphotericin B liposomal, 303 carboplatin, 501 fibrates, 486 intravenous immunoglobulin, 364 chewing methylphenidate, 4 Cheyne-Stokes respiration lithium, 25 chiasmal herniation cabergoline, 160 chills all-trans retinoic acid, 417 interferon alfa, 397 intravenous immunoglobulin, 364 liposome-encapsulated iodixanol, 519 misoprostol, 431 quinine, 318 Chinese herb nephropathy aristolochic acid, 530 choanal atresia methimazole, 459 cholangitis MDMA, 35 cholestasic jaundice, 377 cholestasis ecstasy, 35 cholestatic hepatitis celecoxib, 124 cholestatic jaundice metformin, 468 cholesterol blood concentration testosterone, 449–450 cholesterol ratio acarbose, 466–467 antipsychotic drugs, 56 gliclazide, 466–467 gonadorelin receptor antagonists, 478 triptorelin, 478 choluria celecoxib, 124 chorea interferon alfa, 393–394 choreiform movements methadone, 96 choreoathetosis cocaine, 38 Churg-Strauss syndrome pranlukast, 193 clotting disorders fenfluramine, 6–7 interferon alfa + ribavirin, 395 coagulation, intravascular piperacillin, 263–264 coagulopathy contrast agents, 516

ecstasy, 32 cognitive deficits carbamazepine, 72 gabapentin, 72 cognitive function cannabis, xxxv ecstasy, 33 lithium, 25 topiramate, 78–79 unconventional diets, 536 cold, sensation of gadolinium, 520 cold extremities methoxamine, 157 colds levetiracetam, 75 colitis isotretinoin, 176 meloxicam, 116 collapse benzocaine, 145 colonic necrosis sodium polystyrene sulfonate, 256 colonic ulceration loxoprofen, 116 color vision cisplatin, 497 coma benzocaine, 145 cefepime, 265 cisplatin, 496 Hydroxycut, 531 insulin, 463 lithium, 25 melarsoprol, 323 zolpidem, 51 concentration, difficulty chlorpromazine, 53 clozapine, 53 disulfiram, 542 lithium, 25 morphine, 97 salmeterol, 192 conduction disturbances chloroquine, 315, 316–317 confusion amantadine, 162 amfebutamone, 16 efavirenz, 331 etanercept, 399 mefloquine, 318 paracetamol + rifampicin, 115 rofecoxib, 123 sildenafil, 231 topiramate, 79 conjunctival hyperemia bimatoprost, 430, 526 brachial plexus anesthesia, 140 latanoprost, 526 conjunctival inflammation clindamycin, 284 conjunctival injection co-trimoxazole, 321

590 interleukin-11 (oprelvekin), 398 conscious recollection diazepam, 47–48 lorazepam, 47–48 consciousness alteration baclofen, 153 constipation acamprosate, 540 alosetron, 383 anticholinergic drugs, 164 antipsychotic drugs, 58 codeine, 90 ecstasy, 35 fentanyl, 92 granisetron, 384 linezolid, 289 morphine, 97 olanzapine, 61 contact allergies antiviral drugs, 168 befunolol, 526 branched-chain fatty acid esters, 168 cocamidopropyl betaine, 168 colophonium, 168 Compositae species, 172 gum resins, 168, 171 laurel oil, 532 para-phenylenediamine, 173 sesquiterpene lactones, 172 topical drugs and cosmetics, 169–171 contact blepharoconjunctivitis dorzolamide, 239 contact dermatitis azithromycin, 285 benzocaine, 145 blue dye, 545 butyl hydroxyanisole, 545 cefepime, 265 cinchocaine, 145–146 DoloPosterine, 173 enoxolone, 545 gentamicin, 272 henna tattooing, 544 hormone replacement therapy, 440 hydrocortisone aceponate cream, 427 inhaled corticosteroids, 188 ketoprofen, 172 laureth-A (polidocanol), 545 NSAIDs, 174 oxybenzone, 174 polidocanol, 545 polyoxyethylene lauryl ether, 545 proparacaine, 147 stearyl alcohol, 545 talc, 544–545 tetraethylthiuramdisulfide, 545 vitamin B6 , 420 vitamin C, 421

Index of adverse effects white flower, 545 contact hypersensitivity vitamin B6 , 420 contact leukoderma para-phenylenediamine, 173 contact pemphigus ketoprofen, 172 contact reactions menthol, 543 contact sensitization arnica, 530 marigold, 530 contact vasculitis ketoprofen, 172 contusion of the spinal cord spinal manipulation, 536 convulsions baclofen, 153 cannabis, animals, xxxiv ecstasy, 32 fentanyl, 93 fluoroquinolones, 274 gliclazide, 470 glucagon, 466 levetiracetam, 75 levofloxacin, 278 melarsoprol, 323 paramethoxyamphetamine (PMA), 36 sevoflurane, 132 cooperation midazolam, 137 coordination codeine, 90 spinal manipulation, 536 zolpidem, 50 copper deficiency zinc, 250 corneal deposits flecainide, 212–213 corneal microprecipitates ciprofloxacin, 276 coronary see also entries at cardi–; heart– coronary arteritis anthrax vaccine, 355 coronary artery dissection cocaine, 37 coronary thrombosis all-trans retinoic acid, 417 coronary vasoconstriction triptans, 230 cough ACE inhibitors, 234 arsenic, 244 fentanyl, 94 inhaled corticosteroids, 187, 188 nasal insulin, 465 primaquine, 319 crabbiness methylphenidate, 4 cramps

MS-325, 521 cramps (abdominal) BBR3464, 492 cisplatin, 501 cramps (muscle) oxaliplatin, 495 cranial nerve palsy measles-mumps-rubella vaccine, 359 craniosynostosis valproate sodium, 82 creatine kinase activity baclofen, 153 isoniazid, 341 tenofovir, 331 creatine phosphokinase concentration pioglitazone, 471 creatinine concentration amphotericin B liposomal, 303 carboplatin, 500 ciclosporin, 404 cidofovir, 328 cisplatin, 500 lithium, 22 penicillamine, 256 propofol, 136 suramin, 351 tenofovir, 331 CREST syndrome aristolochic acid, 530 Creutzfeldt-Jakob disease human growth hormone, 479 crystal accumulation sodium polystyrene sulfonate, 256–257 cutaneous bullae iohexol, 518 cutaneous granulomas silicone, 544 cutaneous lupus erythematosus etanercept, 400 cutaneous necrosis interferon alfa, 395 cutaneous polyarteritis minocycline, 266 cutaneous pseudolymphoma valproate sodium, 81 cutaneous vasculitis infliximab, 401 cutaneous vasodilatation cinnamic aldehyde, 545 cutis laxa penicillamine, 256 cyanosis benzocaine, 145 cocaine, 37 EMLA cream, 144 lidocaine, 146 CYP1A2 fluvoxamine, 12 inhibition, fluvoxamine, 63 inhibition, olanzapine, 14 inhibition, risperidone, 60–61

591

Index of adverse effects mexiletine, 213 norfloxacin, 280 risperidone, 65 CYP2C9 co-trimoxazole, 321 fluconazole, 306 inhibition, fluvoxamine, 14 sulfonamides, 290 voriconazole, 309 CYP2C19 inhibition, fluvoxamine, 14 inhibition, risperidone, 60–61 risperidone, 66 voriconazole, 309 CYP2D6 almotriptan, 15 inhibition, risperidone, 60–61 mexiletine, 213 risperidone, 15, 65 terbinafine, 311 CYP2E1 alcohol + paracetamol, 114 CYP3A4 clarithromycin, 286, 287 efavirenz, 331 erythromycin, 228 inhibition, nefazodone, 16 macrolides, 284 mexiletine, 213 miocamycin, 287–288 nevirapine, 332 quinupristin/dalfopristin, 290 sildenafil, 231 St. John’s wort, 487 substrate, benzodiazepines, 16 substrate, carbamazepine, 16 substrate, ciclosporin, 16 verapamil, 228 voriconazole, 309 CYP3A (unspecified) everolimus, 406 cystoid macular edema latanoprost, 526 cytochrome C oxidase activity propofol, 136 cytokine release syndrome oxaliplatin, 501 cytomegalovirus reaction dacluzumab, 402 rituximab, 403 cytotoxicity paclitaxel + cisplatin, 502 dapsone syndrome dapsone, 340 dark urine celecoxib, 124 entacapone, 163 darkening of the iris bimatoprost, 430 latanoprost, 431 deafness cisplatin, 502 heroin, 41, 92

death adenosine, 203 antiepileptic drugs, 71 benzocaine, 145 beta-adrenoceptor agonists, 190 bromocriptine, 160 chemotherapy, 504 dacluzumab, 402 dofetilide, 210 gold, 246 hormone replacement therapy, 438 insulin, 462 itraconazole, 307 lithium, 24 methadone, 96 nitrogen + sildenafil, 225 paramethoxyamphetamine (PMA), 36 propylthiouracil, 458, 459 thyroxine, 457 vincristine, 504 deep vein thrombosis cocaine, 37 erythropoietin, 369 tamoxifen, 446 defiance vigabatrin, 82 deformities losartan, 236 dehydration lithium, 21 déjà vu amantadine + phenylpropanolamine, 334 delayed follicular rupture COX-2 inhibitors, 123 delirium ciprofloxacin, 276 cocaine, 39 digitalis, 198 disulfiram, 542 lithium, 20, 22 sevoflurane, 132, 133 St. John’s wort, 532 demyelination etanercept, 399 heroin, 92 dependence zolpidem, 50–51 depersonalization zaleplon, 49 depression androgenic anabolic steroids, 450 antituberculous agents, 339 buspirone, 49 cannabis, xxxviii digitalis, 198 ecstasy, 34 isotretinoin, 175 levetiracetam, 75 mefloquine, 318 pimozide, 64

risperidone, 64 timolol, 526 topiramate, 79 dermatitis see also contact dermatitis; eczematous dermatitis; exfoliative dermatitis antiviral drugs, 168 azithromycin, 285 benzocaine, 145 cinchocaine, 145–146 diltiazem, 225 DoloPosterine, 173 dorzolamide, 239 gentamicin, 272 henna tattooing, 544 inhaled corticosteroids, 187, 188 ketoprofen, 172 lidocaine, 146–147 nickel, 248–249 NSAIDs, 174 oxybenzone, 174 oxybuprocaine, 147 proparacaine, 147 titanium, 250 dermatomyositis docetaxel, 504 dermographism atorvastatin, 487 dermopathy penicillamine, 256 desaturation DTP-Hib vaccines, 356 deterioration vigabatrin, 82 diabetes insipidus lithium, 21, 22 ofloxacin, 280 diabetes mellitus interferon alfa, 394 medroxyprogesterone, 444 olanzapine, 62 tacrolimus, 408 diabetes (unspecified) tamoxifen, 446 dialysis azithromycin, 286 dialysis-associated encephalopathy aluminium, 243 diaphragmatic paralysis spinal manipulation, 536 diarrhea acamprosate, 540 acarbose, 467 all-trans retinoic acid, 417 amprenavir, 332 anorexia, 493 Artemisia derivatives, 319, 320 atovaquone, 320 azathioprine, 404 azithromycin + rifabutin, 285 BBR3464, 492

592 buspirone, 49 carboplatin, 498 celecoxib, 123 cilostazol, 230 ciprofloxacin, 276 cisplatin, 501 clarithromycin, 286 clindamycin, 284 dipyridamole, 380 enalapril, 235 entacapone, 163 erythromycin, 284 famciclovir, 329–330 fentanyl, 92 fluvastatin, 488 granisetron, 384 iloprost, 430 irinotecan + neomycin, 504 itraconazole, 306, 307 lactulose, 387 levamisole, 348 levofloxacin, 278 linezolid, 289 lithium, 20, 24, 25 lopinavir/ritonavir, 333 mesalazine, 387 metformin, 468 mifepristone, 448 miglitol, 467 misoprostol, 431 moxifloxacin, 279 nicotinic acid, 420 norfloxacin, 280 octreotide, 480 olsalazine, 389 oxaliplatin, 498 phenytoin + fosphenytoin, 76 proton pump inhibitors, 384, 385 pseudoephedrine, 157 quinine, 318 quinupristin/dalfopristin, 290 rabeprazole, 386 roxithromycin, 288 salmeterol, 192 suramin, 351 telithromycin, 283 thiabendazole, 345 diarrhea, bloody phenytoin + fosphenytoin, 76 digitalis toxicity cardiac glycosides, 530 digoxin concentration cardiac glycosides, 530 fluoxetine, 15 diplopia diazepam, 47 lamotrigine, 74 spinal manipulation, 536 discoid lupus etanercept, 400 disorientation amfebutamone, 16 baclofen, 153

Index of adverse effects ecstasy, 35 lithium, 25 zolpidem, 50 disseminated intravascular coagulation lamotrigine, 74 disulfiram-like reaction with alcohol metronidazole, 323 divergent gaze amphetamine, 30 diverticula, bladder copper, 245 dizziness benzocaine, 145 buspirone, 49 cilostazol, 230 cisplatin, 497 desmopressin, 482 dextromethorphan, 91 diazepam, 47 diltiazem, 226 dobutamine, 159 epoetin, 369 famciclovir, 329–330 fluoroquinolones, 274 gabapentin, 74 gadobenate dimeglumine, 520 gadolinium, 520 kava, 533 lamotrigine, 74 levetiracetam, 75 levofloxacin, 278 linezolid, 289 manganese, 248 5-methoxypsoralen, 173 mexazolam, 48 misoprostol, 431 nasal insulin, 465 nefazodone, 16 nicardipine + erythromycin, 228 olanzapine, 61 oxcarbazepine, 76 parathyroid hormone, 481 praziquantel, 350 propafenone, 214 quinine, 318 remacemide, 77 spinal manipulation, 536 strychnine, 6 telithromycin, 283 thiabendazole, 344, 345 tiagabine, 77 timolol, 525, 526 topiramate, 78 tramadol, 103 vitamin B2 , 420 zonisamide, 84 dream disturbance isotretinoin, 175 valerian, 533 drowsiness cannabis, xxxv

clozapine, 61 diazepam, 47 disulfiram, 542 intravenous immunoglobulin, 365 mexazolam, 48 naltrexone, 105 vitamin B2 , 420 zopiclone, 51 dry eyes bimatoprost, 430 flecainide, 213 dry mouth anticholinergic drugs, 164, 165 clarithromycin, 286 dihydrocodeine, 92 entacapone, 163 inhaled corticosteroids, 188 olanzapine, 61 risperidone, 64 dry skin all-trans retinoic acid, 417, 418 Duchenne’s muscular dystrophy androgenic anabolic steroids, 450 dull/listless appearance methylphenidate, 4 dural tear spinal manipulation, 536 dynamic compliance rapacuronium, 150 dysarthria amphetamine, 30 cocaine, 38 diazepam, 47 disulfiram, 542 heroin, 92 human growth hormone, 479 infiltration anesthesia, 143 metronidazole, 324 dysdiadochokinesis metronidazole, 324 dysesthesia oxaliplatin, 495 phenolic compounds, 260 dysgeusia levamisole, 348 dyskinesia ciprofloxacin, 276 dextromethorphan, 91 entacapone, 163 gabapentin, 73 dyslexia hepatitis B vaccine, 358 dysmetria amphetamine, 30 cocaine, 38 heroin, 92 metronidazole, 324 dysosmia levamisole, 348 dyspepsia acamprosate, 540

593

Index of adverse effects buspirone, 49 mesalazine, 387 sildenafil, 231 sulfasalazine, 387 dysphagia methimazole, 458 dysphasia gliclazide, 470 dysphonia inhaled corticosteroids, 187 dyspnea all-trans retinoic acid, 417 amphotericin B liposomal, 303 benzocaine, 145 betaxolol, 526 carboplatin, 501 cisplatin, 501 denileukin diftitox, 398 iodixanol, 514 iohexol, 514 iron dextran, 247 lidocaine, 146 menthol, 543 oxaliplatin, 501 pergolide, 160 pioglitazone, 471 suramin, 351 tobramycin, 273 vitamin B2 , 420 dysrhythmia adenosine, 203 benzocaine, 145 cisapride, 382 COX-2 inhibitors, 117 dobutamine, 159 flecainide, 212 iodixanol, 514 iohexol, 514 nicardipine + erythromycin, 228 propafenone, 214 dystonia cimetidine, 384 cocaine, 38 disulfiram, 542 tiagabine, 77 dystrophic calcification acupuncture, 535 echinocytosis sodium diatrizoate, 516 eczema aceclofenac, 115 inhaled corticosteroids, 188 intravenous immunoglobulin, 366 vitamin B6 , 420 vitamin C, 421 edema barnidipine, 225 denileukin diftitox, 398 desmopressin, 482 EMLA cream, 144

hormone replacement therapy, 436 human growth hormone, 479 inhaled corticosteroids, 188 isosulfan blue, 543 laurel oil, 533 lopinavir/ritonavir, 333 manidipine, 227 mesalazine, 387 morphine, 97 olanzapine, 63 pioglitazone, 471 rosiglitazone, 471, 472 edema, ankle manidipine, 227 ejaculatory dysfunction diuretics, 238 finasteride, 450 risperidone, 65 SSRIs, 13–14 electric shock central venous catheters, 545 electrocardiographic changes see also QT interval prolongation clozapine, 59 salmeterol, 192 electrolyte disturbances pentamidine, 323 embryopathy antiepileptic drugs, 71 methimazole, 459 emesis see vomiting emotional lability gabapentin, 73 emphysema MDMA, 32 empty sella syndrome androgenic anabolic steroids, 450 thyroid hormones, 457 encephalitis systemic glucocorticosteroids, 429 encephalocele triamterene, 241 encephalopathy albendazole, 344 aluminium, 243 cisplatin, 496 erythropoietin, 369 kava, 534 lamotrigine, 75 melarsoprol, 323 paracetamol + rifampicin, 115 tacrolimus, 408 endometrial disorders hormone replacement therapy, 440 mifepristone, 449 tamoxifen, 447 tamoxifen + toremifene, 504 toremifene, 447

endomyocarditis pranlukast, 193 endothelial impairment iron dextran, 247 enlarged spleen gabapentin, 74 enophthalmos brachial plexus anesthesia, 140 enuresis chlorpromazine, 53 dibucaine, 143 enzymuria ioxaglate, 517 eosinophilia clozapine, 60 cyanamide, 541 ioxaglate, 513, 514 MDMA, 35 olanzapine, 63 pranlukast, 193 trovafloxacin, 276 eosinophilic endomyocarditis pranlukast, 193 eosinophilic folliculitis foscarnet, 328 eosinophilic gastroenteritis clofazimine, 235 enalapril, 235 naproxen, 235 eosinophilic infiltration leech therapy, 535 eosinophilic pleural effusion with eosinophilic pericardial tamponade vitamin B6 , 424 vitamin H, 424 eosinophilic pneumonia levofloxacin epidural hematoma spinal manipulation, 536 epigastric pain oral contraceptives, 444 epileptiform activity alfentanil, 89 baclofen, 153 sevoflurane, 132–133 erectile dysfunction diuretics, 238 risperidone, 65 ergotism erythromycin + ergotamine, 287 macrolides, 284 miocamycin, 288 ritonavir + ergotamine, 333 troleandomycin + ergotamine, 288 erythema cisplatin, 501 cyanamide, 541 docetaxel, 504 etanercept, 400 griseofulvin, 176 human growth hormone, 480

594 inhaled corticosteroids, 188 intravenous immunoglobulin, 366 iodinized oil-based contrast agent, 518 iohexol, 518 isosulfan blue, 543 laurel oil, 533 leuprorelin acetate, 478 lidocaine, 147 oral contraceptives, 174 suramin, 351 tacrolimus, 408 erythema, facial carboplatin, 501 cisplatin, 501 oxaliplatin, 501 erythema exsudativum multiforme lenograstim, 399 erythema multiforme para-phenylenediamine, 173 erythema nodosum Echinacea, 531 erythematous dermatitis methyl glucose dialate, 545 erythematous lesions fentanyl, 94 erythematous rash interferon beta, 397 SH U 555 A, 522 erythrocyte folate concentrations antiepileptic drugs, 72 erythroderma carboplatin, 501 olanzapine, 63 omeprazole, 386 esophageal atresia methimazole, 459 esophageal dysfunction hemoglobin-based oxygen carriers, 363 esophageal laceration activated charcoal, 387 esophageal sclerosis aristolochic acid, 530 exanthematous pustulosis mexiletine, 213 teicoplanin, 282 terbinafine, 310 excitability efavirenz, 331 excitation dopamine receptor agonists, 162 exercise intolerance topiramate, 80 exfoliative dermatitis all-trans retinoic acid, 417 carboplatin, 501 denileukin diftitox, 398 oxaliplatin, 501 explicit memory

Index of adverse effects temazepam, 48 explosive behavior methylphenidate, 4, 5 external ophthalmoplegia cocaine, 40 extrapyramidal effects antipsychotic drugs, 56 disulfiram, 542 pimozide, 64 risperidone, 64 extravasation cisplatin, 500 mannitol, 376–377 eyelash changes bimatoprost, 526 latanoprost, 431 misoprostol, 432 travoprost, 526 eyelid pigmentation changes bimatoprost, 526 travopost, 526 facial hypomobility disulfiram, 542 facial paresis sildenafil, 231 factitious hypoglycemia repaglinide, 469 failure to capture flecainide, 212 failure to thrive silver, 249 falls clozapine, 61 levamisole, 347 timolol, 525, 526 fat deposits tamoxifen, 446 fatigue acarbose, 467 amprenavir, 332 anorexia, 493 azithromycin + rifabutin, 285 celecoxib, 124 deferiprone, 253 digoxin, 198 gabapentin, 74 kava, 534 lithium, 24 myrrh, 349 nicardipine + erythromycin, 228 oxcarbazepine, 76 pergolide, 160 pimozide, 64 risperidone, 64 sartraplatin, 493 suramin, 350, 351 topiramate, 79 zaleplon, 49 zonisamide, 84 fatty liver disease tamoxifen, 446 febrile reactions

albumin, 363 feeding intolerance DTP-Hib vaccines, 356 fertility (male) sulfasalazine, 387 fetal hypothroidism amiodarone, 206 fetal valproate syndrome valproate sodium, 82 FEV1 colistin, 289 fever acupuncture, 535 all-trans retinoic acid, 417, 418 alprostadil, 430 amphotericin B liposomal, 303 arsenic, 244 caspofungin, 311 clozapine, 60 co-trimoxazole, 322 diethylcarbamazine + ivermectin, 346 diethylcarbamazine, 345 Echinacea, 531 epoetin, 370 interferon alfa, 397 intravenous immunoglobulin, 364 ioxaglate, 513–514, 514 itraconazole, 307 melarsoprol, 323 mesalazine, 387 misoprostol, 431 olanzapine, 63 phenytoin + fosphenytoin, 76 pranlukast, 193 praziquantel, 349 primethamine, 290 propylthiouracil, 458 quinine, 318 suramin, 351 talc, 544 topiramate, 80 vancomycin, 283 fibroadenomata ciclosporin, 406 fibrosing colonopathy mesalazine, 388 fibrosis pergolide, 160 fidgetiness levamisole, 347 fixed drug eruption clarithromycin, 286 co-trimoxazole, 292, 321 fexofenadine, 183 terbinafine, 310 flank pain amphotericin B liposomal, 303 flatulence acamprosate, 540 acarbose, 467 lactulose, 387 miglitol, 467

595

Index of adverse effects rabeprazole, 386 tenofovir, 331 voglibose, 466 flu-like symptoms darbepoetin, 368 denileukin diftitox, 398 epoetin, 368 erythropoietin, 368 iodinated water-soluble contrast agents, 513 levamisole, 348 liposome-encapsulated iodixanol, 519 tacrolimus, 408 fluid retention rosiglitazone, 471 flushing alprostadil, 430 barnidipine, 225 desmopressin, 482 heroin, 91 intravenous immunoglobulin, 3634 iron dextran, 247 misoprostol, 431 nicardipine, 227 nicotinic acid, 419, 420 oxaliplatin, 501 sildenafil, 231 Sono Vue, 523 St. John’s wort, 532 thyrotropin-releasing hormone, 482 vitamin B2 , 420 zolpidem, 51 focal dystrophic calcification acupuncture, 535 follicular hyperplasia leech therapy, 535 follicular mycoses fungoides lithium, 22–23 follicular rupture COX-2 inhibitors, 123 foreign body reaction walnut oil, 545 fractures benzodiazepines, 46 inhaled corticosteroids, 189 systemic glucocorticosteroids, 428 frontal release signs disulfiram, 542 frontoparietal lobe infarctions massage therapy, 536 gait disturbance cannabis, xxxv heroin, 92 levamisole, 347 methadone, 96 olanzapine, 61 galactorrhea risperidone, 65 SSRIs, 13

gallbladder disease Norplant, 444 gallstones octreotide, 480 ganglion cells tobramycin, 273 gangrene ergotamine + erythromycin, 287 ergotamine + troleandomycin, 288 gastric irritation zinc, 250 gastric nodules omeprazole, 385 gastric upset levamisole, 348 salmeterol, 192 gastritis antituberculous agents, 339 gastrointestinal bleeding naproxen, 116 timolol, 526 gastrointestinal discomfort acamprosate, 540 azithromycin, 285 azithromycin + rifabutin, 341 carboplatin, 501 chloroquine, 315 cisplatin, 501 denileukin diftitox, 398 fentanyl, 92 oseltamivir, 33 oxaliplatin, 501 propafenone, 214 pyrimethamine + azithromycin, 322 remacemide, 77 tramadol, 102 gastrointestinal hemorrhage COX-2 inhibitors, 120–121 metformin, 468 gastrointestinal toxicity flutamide, 450 levamisole, 348 gastrotoxicity aspirin, 113 giddiness diethylcarbamazine + ivermectin, 346 myrrh, 349 glaucoma promethazine, 183 topiramate, 79 glomerular filtration test results theophylline, 2 glomerular function ioxaglate, 517 glomerulosclerosis aristolochic acid, 530 glucose concentration human growth hormone, 479 nicotinic acid, 420 salmeterol, 192

glucose intolerance human growth hormone, 480 tacrolimus, 408 glucose tolerance digoxin, 198 glucose transporter type I (Glut 1) deficiency syndrome caffeine, 2 glutathione-S-transferase T1 null genotype ethylene oxide, 258 glycogenolysis inhibition beta-adrenoceptor agonists, 526 goiter lithium, 20 zafirlukast, 194 graft-vs.-host disease interferon alfa, 396 granulocytopenia clozapine, 60 lithium, 21–22 olanzapine, 62 granuloma formation octreotide, 480 granulomatosis of the lung infliximab, 401 granulomatous dermatitis acupuncture, 535 silicone, 544 granulomatous reaction silicone, 544 growth retardation deferiprone, 254 gum bleeding cranberry, 534 Selaginella doederleinii, 534 gynecomastia antiandrogens, 450 risperidone, 65 hair cells tobramycin, 273 hair loss see alopecia hallucinations (auditory) cefepime, 265 valaciclovir, 330 hallucinations (unspecified) amfebutamone, 16 anticholinergic drugs, 164 baclofen, 153 cefepime, 265 celecoxib, 123 cisplatin, 502 dextromethorphan, 90, 91 disulfiram, 542 dopamine receptor agonists, 162 entacapone, 163 fentanyl, 93 levetiracetam, 76 mefloquine, 318 rofecoxib, 123 topiramate, 79 valaciclovir, 330

596 voriconazole, 309 zaleplon, 49 hallucinations (visual) cefepime, 265 disulfiram, 542 valaciclovir, 330 headache all-trans retinoic acid, 417, 418 amphetamine, 30 amprenavir, 332 anthrax vaccine, 355 anticholinergic drugs, 164 Artemisia derivatives, 320 articaine, 144 azithromycin + rifabutin, 285 barnidipine, 225 benzocaine, 145 bromocriptine, 160 buspirone, 49 caspofungin, 311 ciclosporin, 404 cilostazol, 230 codeine, 89 colistin, 289 darbepoetin, 368 deferiprone, 253 desmopressin, 482 diethylcarbamazine, 345 diethylcarbamazine + ivermectin, 346 dihydrocodeine, 92 dipyridamole, 380 dobutamine, 159 Dy-EOB-DTPA, 519 Echinacea, 531 epoetin, 368, 369 famciclovir, 329–330 fentanyl, 94 fluvastatin, 488 gadobenate dimeglumine, 520 gadodiamide, 520 gadolinium, 520 gonadorelin, 477 heroin, 91 human growth hormone, 479 iloprost, 430 interferon alfa, 397 intravenous immunoglobulin, 364, 365 iodinated water-soluble contrast agents, 513 latanoprost, 430 levamisole, 348 levetiracetam, 75 levofloxacin, 278 linezolid, 289 lithium, 25 manganese, 248 melarsoprol, 323 mesalazine, 387, 388 methoxamine, 157 methylphenidate, 5 metoclopramide, 383 milrinone, 201

Index of adverse effects misoprostol, 431 naltrexone, 105 Norplant, 444 omeprazole, 386 oxaliplatin, 501 oxcarbazepine, 76 parathyroid hormone, 481 praziquantel, 349, 350 primaquine, 319 progestogens, 448 propafenone, 214 proton pump inhibitors, 384, 385 rabeprazole, 386 repaglinide, 469 rosiglitazone, 471 sildenafil, 231 Sono Vue, 523 sulfasalazine, 387 tacrolimus, 408 thyroid stimulating hormone, 481–482 topiramate, 78 zolpidem, 50 zonisamide, 84 headache, positional spinal manipulation, 536 hearing disturbance streptomycin, prenatal, 273 hearing disturbances deferiprone, 254 iohexol, 515 hearing loss aminoglycosides, 271 azithromycin, 285 deferiprone, 254 gentamicin, 271 heroin, 41 human growth hormone, 479 streptomycin, 273 heart see also entries at cardi–; coronary– heart beat see cardiac dysrhythmias; tachycardia; specific conditions, such as sinus node dysfunction heart block cardiac glycosides, 198 moricizine, 213 heart failure all-trans retinoic acid, 417 cibenzoline, 207 doxorubicin, 503 intravenous immunoglobulin, 365 rosiglitazone, 471 trastuzumab, 403 heart failure, congestive doxorubicin, 503 infliximab, 400 itraconazole, 307 heart rate increase

cannabis, xxxvi cannibinoids, 36 deferiprone, 254 heat, sensation of gadolinium, 520 heat intolerance topiramate, 80 heat stroke zonisamide, 84 hematuria cranberry, 534 felbamate, 73 hemianopia hepatitis B vaccine, 358 hemidiaphragm paralysis brachial plexus anesthesia, 140 hemiparesis gonadorelin receptor antagonists, 478 infiltration anesthesia, 143 leuprorelin, 478 sildenafil, 231 hemodialysis vancomycin, 283 hemodilution pioglitazone, 471 rosiglitazone, 471 hemoglobin concentration pioglitazone, 471 hemolysis primaquine, 318 quinine, 318 rasburicase, 545 hemolytic uremic syndrome quinine, 318 hemopoietic suppression co-trimoxazole, 292 hemorrhage antithrombin III, 363 bromocriptine, 160 clopidogrel, 124 cocaine, 41 GM-CSF, 398 milrinone, 202 paramethoxyamphetamine (PMA), 36 sildenafil, 231 hemostasis hydroxyethyl starch, 375 hepat– see also entries at liver– hepatic insufficiency lamotrigine, 74 hepatic veno-occlusive disease, 402 gemtuzumab ozogamicin, 402 hepatitis acarbose, 467 acupuncture, 535 buprenorphine, 104 cetirizine, 183 ciprofloxacin, 276 clozapine, 60 dapsone, 340

597

Index of adverse effects ecstasy, 35 fluvastatin, 487–488 gatifloxacin, 277 gliclazide, 470 kava, 533 MDMA, 35 minocycline, 268 olanzapine, 63 propofol, 136 propylthiouracil, 458 Shou wu Pian, 534 spironolactone, 240 zafirlukast, 194 hepatitis, fulminant rabeprazole + terbinafine, 386 terbinafine, 310 hepatitis B, fulminant rituximab, 403 hepatitis C infection intravenous immunoglobulin, 366 hepatocellular injury pioglitazone, 471 propofol, 136 hepatomegaly ecstasy, 35 hepatosplenomegaly dapsone, 340 hepatotixicity dapsone, 340 insulin, 462 kava, 533 propylthiouracil, 458 hepatotoxicity alcohol + paracetamol, 114 amphotericin B liposomal, 303 antituberculous agents, 339–340 benzylpenicillin, 262 cisplatin, 502 colestipol, 488 fosfomycin, 293 imipenem/cilastatin, 262 isoniazid, 340 levofloxacin, 278 MDMA, 35 nefazodone, 16 nimesulide, 125 paracetamol + rifampicin, 115 pemoline, 7 penicillin, 262 piperacillin, 262 pyrimethamine + azithromycin, 322 risperidone, 65 sevoflurane, 133 tacrine, 8 tolcapone, 163 troglitazone, 472 trovafloxacin, 276 zafirlukast, 193 herpes simplex dendritic keratitis latanoprost, 526

herpes simplex retinitis methotrexate, 407 hiccups anabolic steroids, 450 corticosteroids, 450 progesterone, 450 hirsutism valproate sodium, 81 histiocytes MDMA, 35 histological damage lidocaine, 143 histoplasmosis infliximab, 402 hoarseness arsenic, 244 inhaled corticosteroids, 187 homicidal ideation interferon alfa, 394 homocysteine concentration antiepileptic drugs, 72 atorvastatin, 486 co-trimoxazole, 321 fenofibrate, 486 Horner’s syndrome brachial plexus anesthesia, 140 interscalene catheterization, 140 hostility gabapentin, 73 levetiracetam, 75 hot flushes gonadotrophin-releasing hormone, 477 polyestradiol phosphate, 450 hydropic degeneration cisplatin, 499 21 β-hydroxylase antibodies interferon alfa, 394 hydroxyurea docetaxel, 504 hyperandrogenism valproate sodium, 81 hyperbilirubinemia amphotericin B liposomal, 303 indinavir, 333 itraconazole, 307 quinupristin/dalfopristin, 290 hypercalolcemia all-trans retinoic acid, 417 calcitriol, 422 lithium, 19, 21 parathyroid hormone, 481 vitamin A, 416 vitamin D, 421 hypercapnia intravenous immunoglobulin, 365 zolpidem, 51 hypercholesterolemia all-trans retinoic acid, 417 hyperesthesia articaine, 144 hyperglycemia

abacavir, 330 clozapine, 59 indinavir, 333 insulin, 461 olanzapine, 62 oxcarbazepine, 76 paclitaxel + estramustine + carboplatin, 503 pentamidine, 323 somatostatin, 480 hyperinsulinemia co-trimoxazole, 321 valproate sodium, 81 hyperkalemia amiloride, 240 beta-adrenoceptor antagonists, 223–224 citric acid, 541 co-trimoxazole, 291, 321 depolarizing neuromuscular blocking agents, 151–152 diclofenac, 115 ecstasy, 32 trimethoprim, 291 hyperkalemic cardiac arrest depolarizing neuromuscular blocking agents, 151, 152 hyperkeratotic follicular papules lithium, 22–23 hyperkinesia haloperidol, 53 levamisole, 347 risperidone, 53 hyperlactatemia lorazepam, 48 hyperlipidemia ciclosporin, 404 tacrolimus, 408 vitamin D, 421 hypernatremia lithium, 21, 22 olanzapine, 62 hyperostosis alprostadil, 430 hyperparathyroidism fluoride, 545 lithium, 21 hyperphosphatemia paclitaxel + estramustine + carboplatin, 503 hyperpigmentation aluminium, 243 buserelin, 478 diltiazem, 225 docetaxel, 504 EMLA cream, 144 hyperplastic polyp omeprazole, 385 hyperprolactinemia antipsychotic drugs, 56 risperidone, 65 hyperpyrexia ecstasy, 32

598 hypersalivation clozapine, 60 irinotecan + oxaliplatin, 502 olanzapine, 61 risperidone, 65 hypersensitivity lung disease co-trimoxazole, 291 hypersensitivity pneumonitis with eosinophilia pravastatin, 488 hypersensitivity reaction abacavir, 330 allopurinol, 125–126 azithromycin, 285 cisplatin, 501 clopidogrel, 380 co-trimoxazole, 292 denileukin diftitox, 398 gabapentin, 74 infliximab, 401 insulin, 462–463 interferon alfa, 396 iohexol, 518 ioxaglate, 514 lidocaine, 147 local anesthetics, 172 olanzapine, 63 oxybenzone, 174 suramin, 351 thimerosal, 259 vitamin B6 , 420 hypersplenism G-CSF, 398 hypertension amphetamine, 30 amphetamines, 3 buspirone, 49 cannibinoids, 36 carboplatin, 501 ciclosporin, 404 clozapine, 59 cocaine, 39 diltiazem, 225 entacapone, 163 epoetin, 368 erythropoietin, 368, 369 hemoglobin-based oxygen carriers, 363 indinavir, 332 intravenous immunoglobulin, 365 MDMA, 34 midodrine, 158 milrinone, 201 moricizine, 213 Norplant, 444 olanzapine, 62 pseudoephedrine, 156–157 remifentanil, 100 tacrolimus, 408 terlipressin, 483 testosterone, 449 thyrotropin-releasing hormone, 482

Index of adverse effects hypertension, intracranial mesalazine, 388 hypertension, pulmonary artery interferon alfa, 393 hypertensive crisis moxifloxacin, 279 hypertensive encephalopathy erythropoietin, 369 hyperthermia baclofen, 153 cocaine, 39 fenofibrate, 486 olanzapine, 62 paramethoxyamphetamine (PMA), 36 sevoflurane, 134 topiramate, 80 zonisamide, 84 hyperthyroidism amiodarone, 205–206 etanercept, 399 human growth hormone, 480 iodinated contrast agents, 515 lithium, 20 hypertrichosis measles vaccine, 359 hypertriglyceridemia all-trans retinoic acid, 417 tamoxifen, 446 hypertrophy of subcutaneous tissues insulin, 462 hyperventilation topiramate, 80 hypoactivity EMLA cream, 144 hypoalbuminemia caspofungin, 311 denileukin diftitox, 398 hypocalcemia cisplatin, 497 ecstasy, 32 hypocellularity Selaginella doederleinii, 534 hypogammaglobulinemia systemic glucocorticosteroids, 429 hypoglycemia Anso Comfort, 529 chlordiazepoxide, 529 cibenzoline, 207 co-trimoxazole, 321 diagnosis, 461 disopyramide, 208 glargine insulin, 464 gliclazide, 467, 470 glimepiride, 470 insulin, 463 pentamidine, 323 pioglitazone, 471 quinine, 318 repaglinide, 469 hypokalemia amphotericin B liposomal, 303

caffeine, 1 chloroquine, 316–317 cisplatin, 497 clenbuterol, 191 mifepristone, 449 milrinone, 201 hypokalemic paralysis lithium, 21 hypokinesis cocaine, 37 hypomagnesemia clenbuterol, 191 hypomobility, facial disulfiram, 542 hyponatremia antiepileptic drugs, 72–73 cisplatin, 497 co-trimoxazole, 291–292 desmopressin, 482 glucagon, 466 leuprorelin acetate, 478 oxcarbazepine, 76 SSRIs, 13 thiazide and loop diuretics, 239 hypophonia disulfiram, 542 hypophosphatemia cisplatin, 497 clenbuterol, 191 cocaine, 38 stavudine, 331 hypopigmented retinal spots vigabatrin, 82 hypoprothrombinemia macrolides, 284 miocamycin, 288 hyporeflexia cannibinoids, 37 hypotension adrenoceptor agonists, 525 all-trans retinoic acid, 417, 418 alprostadil, 430 amfebutamone, 15 amphotericin B liposomal, 303 cannabinoids, 36 cannabis, xxxvi cannibinoids, 36 carboplatin, 501 chloroquine, 316–317 citric acid, 541 clomipramine, 11 cocaine, 37 denileukin diftitox, 398 diltiazem, 226 dopamine receptor agonists, 159–160 ephedrine, 156 epidural anesthesia, 141 fentanyl, 93 fibrates, 486 heroin, 91 iloprost, 430 intravenous immunoglobulin, 365

599

Index of adverse effects iohexol, 518 ioxaglate, 513 iron dextran, 247 ivermectin, 346 licorice, 531 lidocaine, 146 melarsoprol, 323 midazolam, 136 milrinone, 202 nefazodone, 16 NSAIDs, 121–122 oxaliplatin, 501 parathyroid hormone, 481 pentamidine, 323 propafenone, 214 remifentanil, 100 risperidone, 65 sotalol, 224 sufentanil, 101 suramin, 351 thiazide and loop diuretics, 239 tricyclic antidepressants, 11 vitamin B2 , 420 hypotension, arterial all-trans retinoic acid, 417, 418 hypothalamic-pituitary-adrenal axis function inhaled corticosteroids, 188 hypothermia antipsychotic drugs, 58 bromazepam, 46 midazolam, 136 valproate sodium, 81–82 hypothyroidism amiodarone, 205, 206 iodinated contrast agents, 515 lithium, 19, 20 hypotonia adrenoceptor agonists, 525 diazepam, 47 hypoventilation fentanyl, 92 hypoxemia all-trans retinoic acid, 417 cocaine, 37 pranlukast, 193 hypoxia all-trans retinoic acid, 417 benzocaine, 145 zolpidem, 51 ichthyosiform eruption lovastatin, 487 idiopathic pneumonia syndrome busulfan, 503 idiopathic pulmonary fibrosis lithium, 20 ileus acarbose, 467 illusions zaleplon, 49 immune thrombocytopenic purpura

cranberry, 534 impotence carbamazepine, 70 finasteride, 450 gonadotrophin-releasing hormone, 477 risperidone, 64 indurated plaques aluminium, 243 induration acupuncture, 535 insulin, 463 leuprorelin acetate, 478 infarctions see cerebral infarction; myocardial infarction infection acupuncture, 535 articaine, 144 cannabis smoking, xlii talc, 544 voriconazole, 309 inferior defects dipyridamole, 380 infertility COX-2 inhibitors, 123 thyroid hormones, 457 inflammatory bowel disease celecoxib, 123 infusion-related reactions amphotericin B deoxycholate (DAMB), 302 amphotericin B lipid complex (ABLC), 302–303 amphotericin B liposomal, 303 voriconazole, 309 infusion site reactions deferiprone, 254 inhibitor formation clotting factors, 367 injection site reactions darbepoetin, 368 Dy-EOB-DTPA, 519 epoetin, 368 erythropoietin, 368 etanercept, 400 gadobenate dimeglumine, 520 ganirelix, 479 gentamicin, 272 human growth hormone, 480 influenza vaccine, 359 interferon alfa, 395 interferon beta, 397 octreotide, 480 omalizumab, 402–403 oxaliplatin, 501 palivizumab, 403 parathyroid hormone, 481 quinine, 318 Sono Vue, 523 triptorelin, 478 injury cannabis, xxxv rosiglitazone, 471

insomnia cisplatin, 496 efavirenz, 331 felbamate, 73 fentanyl, 94 fluoroquinolones, 274 levofloxacin, 278 linezolid, 289 mexazolam, 48 prednisone, 427 theophylline, 2–3 topiramate, 78 vigabatrin, 82 insulin dependent diabetes mellitus interferon alfa, 394 insulin release tacrolimus, 408 insulin resistance human growth hormone, 479 infused insulin, 465 medroxyprogesterone, 444 intention tremor cocaine, 38 interferon concentration lithium, 23 interleukin-2 concentration lithium, 23 interleukin-4 concentration lithium, 23 interleukin-10 concentration lithium, 23 interstitial fibrosis aristolochic acid, 530 interstitial nephritis aristolochic acid, 529, 530 mesalazine, 388 omeprazole, 386 ranitidine, 384 rifampicin, 341–342 interstitial pneumonia interferon alfa, 393 interstitial pneumonitis amiodarone, 204–205 pranlukast, 193 skullcap, 534 interstitial pulmonary disease mesalazine, 388 intestinal dilatation antipsychotic drugs, 58 intestinal discomfort lactulose, 387 intestinal pseudo-obstruction antipsychotic drugs, 58 intoxication digitalis, 198 lithium, 25 manganese, 248 tramadol, 103 vitamin D, 421 intracellular inclusions amiodarone, 205 intracranial aneurysm spinal manipulation, 536

600 intracranial hemorrhage bromocriptine, 160 sildenafil, 231 intracranial hypertension human growth hormone, 479 praziquantel, 349 intracranial pressure all-trans retinoic acid, 418 androgenic anabolic steroids, 450 depolarizing neuromuscular blocking agents, 151 intramural hematoma of the ascending aorta cocaine, 37 intraocular inflammation fomivirsen, 328 intravascular papillary endothelial hyperplasia interferon beta, 397 intussusception rotavirus vaccine, 360 invasive pulmonary aspergillosis infliximab, 402 iris pigmentation changes bimatoprost, 526 latanoprost, 526 misoprostol, 432 travoprost, 526 irritability efavirenz, 331 fentanyl, 94 levetiracetam, 75 palivizumab, 403 piracetam, 8 prednisone, 427 topiramate, 79, 80 valproate sodium, 82 vigabatrin, 82 irritation BufferGel, 541 gold, 246 ischemia sildenafil, 231 ischemic colitis alosetron, 383 meloxicam, 116 pseudoephedrine, 157 ischemic necrosis cocaine, 37–38, 38 ergot alkaloids, 163 ischemic nephropathy cocaine, 39 islet cell-specific autoantibodies interferon alfa, 394 isolated lung masses amiodarone, 205 itching all-trans retinoic acid, 418 Artemisia derivatives, 319 buserelin, 478 calcitonin, 477 flecainide, 213

Index of adverse effects ganirelix, 479 henna tattooing, 544 lidocaine, 147 nickel, 248 nicotinic acid, 420 propylthiouracil, 458 quinupristin/dalfopristin, 290 somatostatin, 481 itchy eyes aminoglycosides, 273 jaundice, 377 acarbose, 467 buprenorphine, 104 celecoxib, 124 ecstasy, 32 fosinopril, 236 hemoglobin-based oxygen carriers, 363 kava, 533, 534 MDMA, 35 metformin, 468 propylthiouracil, 458 joint disease rubella vaccine, 360 joint pain all-trans retinoic acid, 418 deferiprone, 253 hormone replacement therapy, 436 interleukin-11, oprelvekin, 398 keloid-like skin lesions leech therapy, 535 keratopathy amiodarone, 205 gold, 246 keratotic erythema cyanamide, 541 ketosis acetazolamide, 238 kidney see also entries at nephro-; renalkidney stones felbamate, 73 kwashiorkor unconventional diets, 536 lactic acidemia ribavirin, 329 lactic acidosis acetazolamide, 238 NRTIs, 330 vancomycin, 282 language difficulty sildenafil, 231 laryngospasm gadobenate dimeglumine, 520 laryngotracheitis triphenylmethane dyes, 259 leaning olanzapine, 61

learning disabilities antiepileptic drugs, 71–72 prenatal cocaine exposure, 41 left bundle branch block cibenzoline, 207 moxifloxacin, 279 lesions, skin aluminium, 243 fentanyl, 94 infiltration anesthesia, 143 lethargy alprostadil, 430 benzocaine, 145 clozapine, 60 codeine, 90 diltiazem, 226 EMLA cream, 144 gliclazide, 470 infiltration anesthesia, 143 interferon alfa, 397 risperidone, 65 Sono Vue, 523 suramin, 350 valproate sodium, 82 vitamin A, 416 leukemia carboplatin, 502 cisplatin, 502 platinum compounds, 502 leukocytoclastic vasculitis insulin, 463 leukocytosis all-trans retinoic acid, 417, 418 alprostadil, 430 clozapine, 60 cocaine, 38 leukoderma para-phenylenediamine, 173 leukoencephalitis hepatitis B vaccine, 358 leukopenia alatrofloxacin, 276 arsenic, 244 intravenous immunoglobulin, 365 mesalazine, 388 methotrexate, 407 mycophenolate, 235 olanzapine, 62 oxcarbazepine, 76 suramin, 351 teicoplanin, 282 libido, reduced carbamazepine, 70 diuretics, 238 finasteride, 450 gonadotrophin-releasing hormone, 477 lichen planus amlodipine, 225 lichenoid dermatitis acupuncture, 535 diltiazem, 225 silicone, 544

601

Index of adverse effects lichenoid eruptions ursodeoxycholic acid, 389 lichenoid lesions hepatitis B vaccine, 358 lichenoid purpura diltiazem, 225 lightheadedness buspirone, 49 dextromethorphan, 90 fentanyl, 92 strychnine, 6 zaleplon, 49 limp olanzapine, 61 linear IgA bullous disease lovastatin, 487 vancomycin, 282 lipid changes hormone replacement therapy, 438 isotretinoin, 176 lipoatrophy human growth hormone, 480 lipodystrophy syndrome protease inhibitors, 332 stavudine, 331 lipogranuloma formation iohexol, 518 listeriosis infliximab, 402 liver see also entries at hepat– liver, occlusive disease GM-CSF, 398 liver adenomatosis oral contraceptives, 443 liver atrophy ecstasy, 35 liver dysfunction dapsone, 340 manganese, 248 quinine, 318 roxithromycin, 288 liver enzyme activities acarbose, 467 all-trans retinoic acid, 417 antituberculosis protocol, 340 azithromycin, 285 caspofungin, 311 cat’s claw, 534 celecoxib, 124 ciprofloxacin, 276 gemcitabine + paclitaxel, 503–504 gemifloxacin, 277–278 ioxaglate, 513 isotretinoin, 176 kava, 533 moricizine, 213 pefloxacin, 281 tacrolimus, 408 valproate sodium, 80–81 voriconazole, 309 liver failure

ecstasy, 32 kava, 533 ketoconazole, 303 paracetamol + rifampicin, 115 roxithromycin, 288 terbinafine, 309–310 liver focal nodular hyperplasia itraconazole, 307 liver function itraconazole, 307 moxifloxacin, 279 liver injury fosinopril, 235–236 liver iron content penicillamine, 255–256 liver necrosis buprenorphine, 104 nitrofurantoin, 288 propylthiouracil, 458 lower limb weakness colistin, 289 lung masses amiodarone, 205 lupus-like syndrome chemically modified tetracyclines, 268–269 etanercept, 400 minocycline, 266, 268 procainamide, 213 terbinafine, 310 ticlopidine, 380 zonisamide, 84 lupus vulgaris BCG vaccine, 355 lymphadenopathy carbamazepine, 71 lymphopenia suramin, 350 lymphoproliferative disorders antiepileptic drugs, 73 macrophage activation syndrome etanercept, 399–400 maculopapular rash codeine, 90 efavirenz, 331 ioxaglate, 513–514 phenytoin + fosphenytoin, 76 primethamine, 290 maculopathy chloroquine, 316 malaise Echinacea, 531 ecstasy, 35 heroin, 91 insulin, 461 kava, 533 lithium, 25 NRTIs, 330 suramin, 350 malignancy albendazole therapy, 345 methotrexate, 407

malignant hyperthermia sevoflurane, 134 mammary hyperplasia, benign ciclosporin, 406 mania olanzapine, 62 Red Bull, 1 risperidone, 64 tramadol + fluoxetine, 104 maxillary sinusitis nafarelin, 477 medullary injury infiltration anesthesia, 143 medullary nephrocalcinosis thiazide and loop diuretics, 239 melanoma fertility treatment, 434 phototherapy, 175 melatonin concentration nervous system, 12–13 memory impairment cannabis, xxxv disulfiram, 542 ecstasy, 32–33 human growth hormone, 479 methadone, 96 morphine, 97 spinal manipulation, 536 meningism praziquantel, 349 meningitis co-trimoxazole, 321 menopause-like problems tamoxifen, 446 menstrual disturbances levonorgestrel, 448 morphine, 97 valproate sodium, 81 mental status alteration gabapentin, 74 metabolic acidosis co-trimoxazole, 321 diclofenac, 115 lorazepam, 48 propofol, 135–136 topiramate, 80 metallic taste levamisole, 347 metronidazole, 323 MS-325, 521 propafenone, 214 methemoglobin concentration benzocaine, 144–145 dapsone, 340 EMLA cream, 144 flutamide, 450 lidocaine, 146 primaquine, 319 MI see myocardial infarction microalbuminuria hormone replacement therapy, 440 microangiopathic hemolytic anemia

602 quinine, 318 microvesicular steatosis buprenorphine, 104 migraine latanoprost, 526 miscarriage NSAIDs, 112 mitochondrial dysfunction NRTIs, 330 mitochondrial myopathy propofol, 136 mitral regurgitation fenfluramine, 6 mood changes progestogens, 448 motor degeneration unconventional diets, 536 motor peripheral neuropathy tetraplatin, 493 mouth, burning clonazepam, 47 movement disorders dextromethorphan, 91 mucosal toxicity amiodarone, 206 mucosal ulceration triphenylmethane dyes, 259 mucositis levamisole, 348 methotrexate, 407 mucous membrane irritation hypochlorite, 259 muscle pain all-trans retinoic acid, 418 muscle rigidity baclofen, 153 remifentanil, 100 muscle spasm lithium, 25 oxaliplatin, 495 muscular hypotonia diazepam, 47 musculoskeletal pain iodinated water-soluble contrast agents, 513 vitamin D, 421 mutagenicity nitroglycerin, 224 mutism alprazolam, 46 bromazepam, 46 myalgia ciclosporin, 404 diethylcarbamazine, 345 Echinacea, 531 interferon alfa, 397 intravenous immunoglobulin, 364 norfloxacin, 280 quinupristin/dalfopristin, 290 myasthenia cocaine, 40 myasthenia gravis interferon alfa, 394

Index of adverse effects penicillamine, 255 mydriasis tropicamide, 147 myelopathy nitrous oxide, 134 spinal manipulation, 536 myelosuppression anorexia, 493 azathioprine, 404 cisplatin, 502 clarithromycin + rifabutin, 341 oxaliplatin, 498 ZD0473, 493 myelotoxicity carboplatin, 491–492 myocardial damage ecstasy, 32 myocardial infarction see also cardiac arrest amphetamine, 30 atropine, 165 cannibinoids, 36 cocaine, 37 COX-2 inhibitors, 117–118 desmopressin, 482 dipyridamole, 380 doxorubicin, 503 Ephedra, 156 erythropoietin, 369 hormone replacement therapy, 438 intravenous immunoglobulin, 365 methadone, 95 nitroglycerin, 224 recombinant factor VIIa, 366 thyroxine, 457 myocarditis antipsychotic drugs, 54 clozapine, 59 myoclonic jerks aluminium, 243 myoclonic-like movements midazolam, 136 myoclonic seizures nicardipine, 228 myoclonus amantadine, 162 entacapone, 163 gatifloxacin, 277 morphine, 98 myoglobinuria ecstasy, 32 lamotrigine, 74 myopathy caffeine, 1 myopericarditis Td-IPV vaccine, 357 myopia topiramate, 79 myosis brachial plexus anesthesia, 140 myotoxicity erythromycin + statins, 287

nail changes docetaxel, 504 gold, 246 nasal congestion naltrexone, 105 sildenafil, 231 nasal symptoms desmopressin, 482 menthol, 543 nausea albumin, 363 alfentanil, 89 all-trans retinoic acid, 417 amphetamine, 30 amprenavir, 332 Artemisia derivatives, 320 atovaquone, 320 BBR3464, 492 buspirone, 49 cannibinoids, 37 carboplatin, 498 cidofovir, 328 cisplatin, 498 clarithromycin, 286 cocaine, 37 deferiprone, 253 desmopressin, 482 dextromethorphan, 90 diltiazem, 226 dobutamine, 159 dopamine receptor agonists, 162 Dy-EOB-DTPA, 519 ecstasy, 35 epoetin, 369 fentanyl, 92, 93, 94 fibrates, 486 fluorescin, 542 gadobenate dimeglumine, 520 gadodiamide, 520 gadolinium, 520 gemeprost + mifepristone, 430 gonadorelin, 477 heroin, 91 hydromorphone, 94 iloprost, 430 intravenous immunoglobulin, 364, 365 iopamidol, 513 ioxaglate, 513 iron dextran, 247 itraconazole, 306, 307 josamycin, 287 lactulose, 387 levamisole, 347, 348 levofloxacin, 278 linezolid, 289 liposome-encapsulated iodixanol, 519 lithium, 20, 25 lopinavir/ritonavir, 333 metformin, 468 metronidazole, 323 mexazolam, 48 mifepristone, 448

603

Index of adverse effects misoprostol, 431 morphine, 97 moxifloxacin, 279 MS-325, 521 naltrexone, 105 nefopam, 106 nicotinic acid, 420 NRTIs, 330 olanzapine, 61 oseltamivir, 334 oxaliplatin, 498 oxcarbazepine, 76 parathyroid hormone, 481 praziquantel, 350 primaquine, 319 propafenone, 214 propofol, 136 proton pump inhibitors, 384 quinine, 318 rabeprazole, 386 remifentanil, 100, 101 Ringer’s solution, 516 risperidone, 64 salmeterol, 192 sartraplatin, 493 sodium diatrizoate, 516 sufentanil, 101 telithromycin, 283 thiabendazole, 344, 345 thyroid stimulating hormone, 481–482 thyrotropin-releasing hormone, 482 topiramate, 78 tramadol, 103 vitamin B2 , 420 water-soluble iodinated contrast agents, 512 ZD0473, 493 zonisamide, 84 neck pain spinal manipulation, 536 necrosis cisplatin, 499 cocaine, 37, 38 ecstasy, 35 necrosis of kidney cells cisplatin, 499 needle pain acupuncture, 535 neonatal goiter zafirlukast, 194 nephr– see also entries at kidney–; renal– nephritic syndrome dapsone, 340 nephrocalcinosis gentamicin, 272 nephrolithiasis indinavir, 333 sulfadiazine, 323 triamterene, 240 nephrotic syndrome

bucillamine, 254 lithium, 22 nephrotoxicity adefovir, 335 amikacin, 271 aminoglycosides, 271 amphotericin B deoxycholate (DAMB), 302 ciclosporin, 405 cidofovir, 328 cisplatin, 499, 502 colistin, 289 contrast agent, 518 gadolinium, 521 gentamicin, 272 glycopeptides, 281–282 isepamicin, 272 itraconazole, 307 lithium, 22 nedaplatin, 492 paromomycin, 273 sevoflurane, 133 vancomycin, 283 voriconazole, 309 nervousness felbamate, 73 palivizumab, 403 sildenafil, 231 neural tube defects triamterene, 240 neuroglycopenic symptoms insulin, 461, 462 neuroleptic malignant syndrome antipsychotic drugs, 55 baclofen, 153 chlorpromazine, 53 olanzapine, 62 SSRIs, 11–12 neurological disturbances dapsone, 340 iron dextran, 247 praziquantel, 349 propafenone, 214 neuromuscular blockade chlorprocaine, 145 neuropathy interleukin-11, oprelvekin, 398 oxaliplatin, 495 neurosarcoidosis interferon beta, 397 neurosensory symptoms oxaliplatin, 495, 501 neurotoxicity aluminium, 243 amphetamines, 3–4 arsenic, 244 cisplatin, 494 lithium, 24 methamphetamines, 3–4 oxaliplatin, 495, 496 ropivacaine, 148 neutropenia albendazole, 345

arsenic, 244 azithromycin, 285 azithromycin + rifabutin, 285 BBR3464, 492 chlorpromazine, 53 cidofovir, 328 co-trimoxazole, 321 cyclophosphamide, 348 enalapril, 235 interferon alfa, 393, 395 intravenous immunoglobulin, 365 linezolid, 289 olanzapine, 62 oxaliplatin, 498 paclitaxel + cisplatin, 502 rifabutin, 341 ZD0473, 493 neutropenic sepsis suramin, 351 neutrophil count deferiprone, 253 neutrophilic dermatoses G-CSF, 399 nevus ganirelix + follicle stimulating hormone, 479 night sweats fentanyl, 94 nightmares cefepime, 265 nocturia vitamin A, 416 non-Hodgkin’s lymphoma cyclophosphamide, 406 trichloroethylene, 134 non-pruritic papules acupuncture, 535 non-sustained ventricular tachycardia moricizine, 213 numbness cocaine, 37 nystagmus cocaine, 38 obesity clozapine, 59 valproate sodium, 81 obsessive-compulsive symptoms methylphenidate, 5 obtundation amphetamine, 30 olanzapine, 62 ocular dysmetria cocaine, 38 ocular effects travoprost, 526 ocular pain topiramate, 79 ocular pigmentation antipsychotic drugs, 55 ocular pruritus adrenoceptor agonists, 525

604 bimatoprost, 430, 526 travoprost, 526 ocular syndrome topiramate, 79 odynophagia inhaled corticosteroids, 188 Ogilvie’s syndrome antipsychotic drugs, 58 OHSS see ovarian hyperstimulation syndrome oligohidrosis zonisamide, 84 oligohydramnios losartan, 236 oligospermia cyclophosphamide, 406, 504 oliguria amlodipine, 225 diltiazem, 225, 226 milrinone, 202 propofol, 136 onycholysis gold, 246 ophthalmic changes mexiletine, 213 opiate testing fluoroquinolones, 275 opisthotonos strychnine, 6 opportunistic infections ciclosporin, 404 systemic glucocorticosteroids, 429 opposition vigabatrin, 82 optic atrophy vigabatrin, 82 optic neuritis cisplatin, 497 etanercept, 399 hepatitis A and B vaccines, 358 Td-IPV vaccine, 358 optic neuropathy deferiprone, 254 sildenafil, 231 oral candidiasis inhaled corticosteroids, 190 oral pemphigus interferon alfa, 395 oral petechiae cranberry, 534 orthostatic hypertension entacapone, 163 orthostatic hypotension clozapine, 61 ephedrine, 156 osteoarticular tuberculosis etanercept, 400 osteocartilaginous erosion cocaine, 38 osteomyelitis cocaine, 38 osteonecrosis

Index of adverse effects all-trans retinoic acid, 418 systemic glucocorticosteroids, 429 osteopenia G-CSF, 399 osteoporosis gonadotropin agonist therapy, 478 systemic glucocorticosteroids, 428 otorrhea spinal manipulation, 536 ototoxicity amikacin, 271 azithromycin, 285 cisplatin, 496 isepamicin, 272 lopinavir/ritonavir, 333 nedaplatin, 492 paromomycin, 273 pyrimethamine + azithromycin, 322 tobramycin, 273 ovarian cysts tamoxifen, 446 ovarian enlargement leuprorelin acetate, 478 ovarian hyperstimulation syndrome gonadotrophins, 477–478 hydroxyethyl starch, 375–376 ovarian stimulation gonadotrophins, 434 oversleeping lithium, 20 ovulation induction thromboembolic disease, 478 oxygen requirements DTP-Hib vaccines, 356 P50 auditory evoked response cocaine, 39 pain cocaine, 37 fenofibrate, 486 ganirelix, 479 iodinated water-soluble contrast agents, 513 simvastatin + clarithromycin, 488 pain scores remifentanil, 100 pallor EMLA cream, 144 palpitation cilostazol, 230 dobutamine, 159 nicardipine, 227 salmeterol, 192 palsy of the long thoracic nerve spinal manipulation, 536 pancerebellar dysfunction cocaine, 38–39 pancreatitis

all-trans retinoic acid, 418 amphotericin B liposomal, 303 antimony, 244 captopril, 234 glibenclamide, 470 isoniazid, 341 levofloxacin, 279 olanzapine, 63 pentamidine, 323 propofol, 136 pancytopenia fenofibrate, 486 hepatitis B vaccine, 358 methotrexate, 407 olanzapine, 63 Selaginella doederleinii, 534 thionamide drugs, 458 panic cannabis, xxxiv topiramate, 79 panlobular liver necrosis buprenorphine, 104 panniculitis interferon beta, 397 papilledema all-trans retinoic acid, 417 cisplatin, 497 human growth hormone, 479 paralysis brachial plexus anesthesia, 136 lithium, 21 paralysis, diaphragmatic spinal manipulation, 536 paranoia disulfiram, 542 mefloquine, 318 parathyroid hormone concentration lithium, 21 parathyroid tumors lithium, 21 paresthesia articaine, 144 colistin, 289 Dy-EOB-DTPA, 519 etanercept, 399 levamisole, 347 oxaliplatin, 495 propafenone, 214 topiramate, 78 Parkinson’s disease risperidone, 15 Parkinsonian symptoms cisplatin, 496 diltiazem, 225 disulfiram, 542 haloperidol, 64 kava, 533 risperidone, 64 risperidone + paroxetine, 65 paronychia indinavir, 333 paroxysmal atrial fibrillation cannibinoids, 37

605

Index of adverse effects paroxysmal atrial tachycardia digoxin, 198 parvovirus-induced red cell aplasia rituximab, 403 pathogen transmission albumin, 363 peak expiratory flow rate rapacuronium, 150 peak inflating pressure rapacuronium, 150 peak inspiratory flow rate rapacuronium, 150 pedal edema interleukin-11, oprelvekin, 398 pemphigoid spironolactone, 240 pemphigus ketoprofen, 172 phenolic compounds, 260 pemphigus foliaceus thiazide and loop diuretics, 239 pemphigus vulgaris enalapril, 235 perceptual changes MDMA, 34 pericardial effusions all-trans retinoic acid, 418 pericarditis mesalazine, 388 perineal sensation dibucaine, 143 periobital dermatitis dorzolamide, 239 periocular skin color change latanoprost, 431, 526 perioral dermatitis inhaled corticosteroids, 187 menthol, 543 perioral edema isosulfan blue, 543 perioral paresthesia cisplatin, 497 peripheral edema proton pump inhibitors, 385 peripheral eosinophilia pranlukast, 193 peripheral motor and sensory degeneration unconventional diets, 536 peripheral neuropathy antituberculous agents, 339 dapsone, 340 metronidazole, 323 platinum compounds, 499, 502 peripheral paresthesia cisplatin, 497 periportal hepatic edema MDMA, 35 peritonitis iron dextran, 247 pernicious anemia interferon alfa, 395 personality changes

cisplatin, 497 petechiae interleukin-11, oprelvekin, 398 pharyngitis rabeprazole, 386 phlebitis bryostatin I, 409 caspofungin, 311 clarithromycin, 286 vancomycin, 283 photoallergic dermatitis ketoprofen, 172 NSAIDs, 174 photomutagenicity bergamot, 530 photophobia gold, 246 intravenous immunoglobulin, 365 latanoprost, 431 photosensitivity aceclofenac, 115 chloroquine, 316 dapsone, 340 efavirenz, 331 oral contraceptives, 174 tretinoin + prochlorperazine + fluorouracil, 419 vitamin B6 , 420 phototoxicity bergamot, 530 fluoroquinolones, 340–341 ketoprofen, 172 levofloxacin, 279 lincomycin, 284 oxybenzone, 174 pefloxacin, 281 phrenic nerve blockade brachial plexus anesthesia, 136 phrenic nerve injury spinal manipulation, 536 pigmentary retinopathy mexiletine, 213 piloerection methoxamine, 157 midodrine, 158 pituitary apoplexy gonadorelin, 477 placental transfer somatostatin, 481 platelet count vancomycin, 282 pleural effusion all-trans retinoic acid, 417, 418 pleuropulmonary disease pergolide, 160 pneumatosis intestinalis lactulose, 387 pneumocystosis infliximab, 402 pneumomediastinum cocaine, 38 MDMA, 32 pneumonia

ecstasy, 32 hypochlorite, 259 methyl-prednisolone sodium succinate, 427 nitrofurantoin, 288 sildenafil, 231 pneumonia, aspiration ecstasy, 32 pneumonitis disopyramide, 208 gold, 246 itraconazole, 307 pneumoperitoneum lactulose, 387 pneumothorax acupuncture, 535 cocaine, 38 pocket infections central venous catheters, 545 polyangiitis propylthiouracil, 459 polyarteritis nodosa hepatitis B vaccine, 358 polyarthralgia acupuncture, 535 rifabutin, 341 polycystic ovary syndrome valproate sodium, 81 polycythemia isotretinoin, 176 polydipsia vitamin D, 422 polymorphic ventricular tachycardia dofetilide, 210, 211 polyneuropathy, Guillain–Barré type nitrous oxide, 134 suramin, 350 polyradiculoneuropathy hepatitis B vaccine, 358 polyuria vitamin D, 422 polyuria-polydipsia syndrome lithium, 19 poor handling DTP-Hib vaccines, 356 porcine factor VIII:C safety, 367 positional headache spinal manipulation, 536 postoperative myocardial ischemia nitrous oxide, 134 postoperative vomiting general anesthetics, 131–132 postural hypotension cannabis, xxxvi dopamine receptor agonists, 159–160 potassium concentration propofol, 136 salmeterol, 192 premature birth

606 ciclosporin, 406 cocaine, 40 prerenal azotemia lithium, 22 priapism cocaine, 40 olanzapine, 63 risperidone, 65 prickly erythema, diffuse oral contraceptives, 174 prolactin concentration antipsychotic drugs, 56 SSRIs, 13 proliferative endometrium tamoxifen + toremifene, 504 prolonged QT interval see QT interval prolongation prolonged reaction times ecstasy, 33 proprioception levodopa and dopamine receptor agonists, 160 prosthetic valves, inflammatory reactions silver, 249 prostration alprazolam, 46 proteinuria cidofovir, 328 colistin, 289 penicillamine, 256 pruritic erythematous dermatitis benzocaine, 145 pruritus all-trans retinoic acid, 417 anthrax vaccine, 355 antiviral drugs, 168 carboplatin, 501 celecoxib, 124 chloroquine, 315, 316 cisplatin, 501 co-trimoxazole, 321 dapsone, 340 fentanyl, 93 fosinopril, 236 hydromorphone, 94 hydroxyethyl starch, 374 inhaled corticosteroids, 188 intravenous immunoglobulin, 366 iron dextran, 247 ivermectin, 346 ketoprofen, 172 leech therapy, 535 local anesthetics, 172 5-methoxypsoralen, 173 midodrine, 158 Mirena, 447 morphine, 97 MS-325, 521 nasal insulin, 465 nelfinavir, 333 olanzapine, 63

Index of adverse effects oxaliplatin, 501 procaine, 147 propylthiouracil, 458 remifentanil, 101 sufentanil, 101, 102 tacrolimus, 408 “pseudo-myocardial infarct pattern” lithium, 19 pseudolymphomatous inflammatory infiltrates leech therapy, 535 pseudomembranous colitis clarithromycin + metronidazole + omeprazole, 387 pristinamycin, 289–290 pseudopheochromocytoma clozapine, 59 pseudoporphyria causes, 175 pseudotumor cerebri all-trans retinoic acid, 417 psychiatric effects dapsone, 340 psychological symptoms hormone replacement therapy, 436 psychomotor effects lorazepam, 48 psychomotor retardation digoxin, 198 psychomotor skills cannabis, xxxiv–xxxv psychomotor slowing topiramate, 78–79, 79 psychomotor speed temazepam, 48 psychosis cannabis, xxxvii dapsone, 340 ecstasy, 34 fluoroquinolones, 274 isotretinoin, 175 methamphetamine, 30 St. John’s wort, 532 psychotic delirium St. John’s wort, 532 psychotic reactions melarsoprol, 323 ptosis brachial plexus anesthesia, 140 ptosis, bilateral cocaine, 40 pulmonary alveolar proteinosis isotretinoin, 175 pulmonary artery hypertension interferon alfa, 393 pulmonary complications walnut oil, 545 pulmonary edema diltiazem, 225 ecstasy, 32 gadobenate dimeglumine, 520 hypochlorite, 259

iloprost, 230 thiazide and loop diuretics, 239 pulmonary embolism tamoxifen, 446 pulmonary fibrosis nitrofurantoin, 288 pulmonary function brachial plexus anesthesia, 140 pulmonary function, reductions in brachial plexus anesthesia, 140 pulmonary infarction cocaine, 37, 38 pulmonary infiltration all-trans retinoic acid, 417, 418 amiodarone, 204 BCG vaccine, 356 pranlukast, 193 tosufloxacin, 281 pulmonary interstitial infiltrates efavirenz, 331 pulmonic regurgitation fenfluramine, 6 pupil dilatation dextromethorphan, 91 propafenone, 214 pupils, fixed lithium, 25 pupils, fluctuating diameter olanzapine, 62 purpuric hemorrhage naproxen, 116 pyloric stenosis ganirelix + follicle stimulating hormone, 479 nalidixic acid, 280 pyramidal symptoms unconventional diets, 536 pyrexia baclofen, 153 dextromethorphan, 91 infiltration anesthesia, 143 QT interval prolongation, 19 amiodarone, 206, 207 amisulpride, 58–59 amodiaquine, 315 antipsychotic drugs, 54 azithromycin, 285 cisapride, 382 citric acid, 541 clozapine, 59 dofetilide, 208, 211 flecainide, 212 fluconazole, 305 fluoroquinolones, 274 fluoxetine, 11–12 halofantrine, 317 haloperidol, 54 levofloxacin, 278 loratadine, 182 methadone, 95 moxifloxacin, 279

607

Index of adverse effects nicardipine + erythromycin, 228 olanzapine, 61–62 pefloxacin, 281 sertindole, 65 sevoflurane, 132 SSRIs, 12 terfenadine, 16 quadriparesis diclofenac, 115 radiation recall dermatitis interferon alfa, 395 radiculopathy spinal manipulation, 536 raised body temperature olanzapine, 62 raised hepatic enzymes quetiapine, 63 rash aciclovir, 329 Artemisia derivatives, 319 articaine, 144 carboplatin, 501 caspofungin, 311 celecoxib, 124 cisplatin, 501 co-trimoxazole, 321, 322 codeine, 90 cyanamide, 541 darbepoetin, 368 deferiprone, 253 epoetin, 368, 369 erythromycin, 284 erythropoietin, 368 fentanyl, 94 gadobenate dimeglumine, 520 Ginkgo biloba, 531 iohexol, 518 ioxaglate, 513–514 itraconazole, 306 ivermectin, 346 lamotrigine, 74 levamisole, 348 levofloxacin, 278 linezolid, 289 mesalazine, 387 moricizine, 213 nelfinavir, 333 nevirapine, 332 olanzapine, 63 oxilaplatin, 501 propylthiouracil, 458 pyrimethamine + sulfadoxine, 322 rasburicase, 545 SH U 555 A, 522 sulfasalazine, 387 suramin, 350 teicoplanin, 282 vitamin B2 , 420 water-soluble iodinated contrast agents, 512 Raynaud’s phenomenon

aristolochic acid, 530 nitroglycerin, 224 re-stenosis after angioplasty contrast agents, 516 rectal bleeding celecoxib, 123 red cell hypoplasia linezolid, 289 red eyes aminoglycosides, 273 red man disease vancomycin, 282 redness diphtheria, tetanus vaccines, 356 EMLA cream, 144 ganirelix, 479 reflex sympathetic dystrophy heroin, 41 rejection methotrexate, 407 rejection site reactions phenolic compounds, 260 renal see also entries at kidney –; nephr– renal cell carcinoma thiazide and loop diuretics, 239 renal cortical necrosis tranexamic acid, 380 renal disease aristolochic acid, 529–530 renal dysfunction carboplatin, 499 G-CSF, 399 quinine, 318 renal function fibrates, 486 lithium + cisplatin, 502 mesalazine, 387 renal impairment and baclofen withdrawal syndrome, 153 ecstasy, 32 pefloxacin, 281 pentamidine, 323 renal infarction cocaine, 39 renal insufficiency all-trans retinoic acid, 418 amphotericin B liposomal, 303 aristolochic acid, 529, 530 aspirin, 111–112 ciprofloxacin, 276 cisplatin, 499, 502 cocaine, 39 copper, 245 dextrans, 374 gentamicin + ibuprofen, 272 hydroxyethyl starch, 375 intravenous immunoglobulin, 365 irbesartan, 236 kava, 533

lamotrigine, 74 leuprorelin acetate, 478 lithium, 25 losartan, 236 milrinone, 201 paracetamol, 111–112 rofecoxib, 125 sevoflurane, 134 suramin, 350 renal lesions cisplatin, 499 renal papillary necrosis dapsone, 340 renal toxicity cisplatin, 497 renal tubular acidosis acetazolamide, 238 renal tubular damage cisplatin, 497 renal tubular dysfunction stavudine, 331 renal vasoconstriction cocaine, 39 respiratory burst anti-inflammatory drugs + ofloxacin, 280 respiratory depression alprostadil, 430 epidural anesthesia, 141 remifentanil, 100 sufentanil, 102 zolpidem, 51 respiratory distress infiltration anesthesia, 143 oxaliplatin, 501 talc, 544 respiratory distress syndrome diltiazem, 225 respiratory dysfunction carboplatin, 501 cisplatin, 501 Norplant, 444 oxaliplatin, 501 respiratory failure diazepam, 47 leuprorelin acetate, 478 respiratory function rapacuronium, 150 respiratory reaction rasburicase, 545 respiratory tract infection etanercept, 400 levetiracetam, 75 methotrexate, 407 rosiglitazone, 471 salmeterol, 192 respiratory tract infections repaglinide, 469 restlessness gabapentin, 74 risperidone, 64 theophylline, 2 retinal injury vigabatrin, 82–84

608 retinal pigmentation fomivirsen, 328 vigabatrin, 82 retinoic acid syndrome all-trans retinoic acid, 418 retinopathy chloroquine, 316 interferon beta, 397 retrobulbular neuritis cisplatin, 497 Reye’s syndrome aspirin, 113 rhabdomyolysis cerivastatin, 487 ciclosporin + lovastatin, 487 ciclosporin + simvastatin, 487 clarithromycin + simvastatin, 287 cocaine, 39 depolarizing neuromuscular blocking agents, 151 diltiazem + simvastatin, 226 ecstasy, 32 interferon alfa, 396 interferon beta, 397 isoniazid, 341 lamotrigine, 74 miocamycin, 287–288 propofol, 135–136 theophylline, 2 rheumatoid arthritis doxycycline trials, 267–268 rhinitis buspirone, 49 gonadotrophin-releasing hormone, 477 rabeprazole, 386 zonisamide, 84 rhinorrhea nasal insulin, 465 spinal manipulation, 536 rhinorrhea, CSF cabergoline, 160 right bundle branch block dofetilide, 211 rigidity baclofen, 153 disulfiram, 542 olanzapine, 62 remifentanil, 100 rigor carboplatin, 501 rosacea Mirena, 447 rosacea fulminans vitamin B6 , 420–421 ruptured uterus oxytocin + misoprostol, 481 saddle-nose deformities cocaine, 38 salivary gland function ofloxacin, 280 sarcoidosis

Index of adverse effects interferon alfa, 395–396 scaling nickel, 248 sclerodactyly aristolochic acid, 530 scleroderma-pulmonary-renal syndrome penicillamine, 256 sclerosis of the skin oxaliplatin, 500–501 secondary bone infection cocaine, 38 sedation codeine, 90 dextromethorphan, 90, 91 diphenhydramine, 54 dopamine receptor agonists, 162 droperidol, 383 fentanyl, 94 hydromorphone, 94 macrolides, 284 metoclopramide, 383 miocamycin, 288 nefopam, 106 risperidone, 64 topiramate, 78 tramadol, 103 vigabatrin, 82 seizures aluminium, 243 amfebutamone, 15–16 antipsychotic drugs, 54 benzocaine, 145 brachial plexus anesthesia, 140 cefepime, 265 chloroquine, 315–316 chlorpromazine, 53 ciclosporin, 404 cisplatin, 496, 502 clozapine, 54 desmopressin, 482 epoetin, 369 fluoroquinolones, 274 gatifloxacin, 277 Ginkgo biloba, 531 interferon alfa, 397 lithium, 20 nicardipine, 228 olanzapine, 54 propafenone, 214 remifentanil, 101 ropivacaine, 147–148 strychnine, 6 sulfasalazine, 389 tramadol, 103 selective auditory attention chlorpheniramine, 183 self-injurious behavior vigabatrin, 82 sensitization bismuth, 245 sensory ataxia oxaliplatin, 495

sensory degeneration unconventional diets, 536 sensory impairment lidocaine, 143 sensory loss oxaliplatin, 495 sensory neuropathy carboplatin, 494 cisplatin, 494 metronidazole, 324 oxaliplatin, 494 paclitaxel, 503 sartraplatin, 494 tetraplatin, 493 sepsis central venous catheters, 545 sepsis-like hypersensitivity reaction co-trimoxazole, 292 septal perforation cocaine, 38 serotonin neurotoxicity ecstasy, 33 serotonin syndrome ecstasy, 32 linezolid + sertraline, 289 lithium, 20, 25 St. John’s wort, 532 tramadol + fluoxetine, 104 serotonin toxicity SSRIs, 12 serum sickness amoxicillin, 263 cefaclor, 264 co-amoxiclav, 263 minocycline, 265 penicillin, 263 severe acute necrotizing eosinophilic endomyocarditis pranlukast, 193 severe gait deterioration clozapine, 61 sexual arousal piracetam, 8 sexual desire SSRIs, 13 sexual function carvedilol, 223 diuretics, 238 morphine, 97 SSRIs, 13 shivering ioxaglate, 513 remifentanil, 100 shock acetazolamide, 239 nicardipine, 228 water-soluble iodinated contrast agents, 512 shortness of breath factor IX:C, 366 sialorrhea haloperidol, 64 risperidone, 64

609

Index of adverse effects sick sinus syndrome lithium, 19 sickle cell disease iodinated water-soluble contrast agents, 515–516 silicone deposition acupuncture, 535 silicone, 544 sinonasal structural damage cocaine, 38 sinus bradycardia amisulpride, 58–59 amodiaquine, 315 cisplatin, 494 lithium, 19, 20 timolol, 526 sinus node dysfunction lithium, 19, 20 sinus rhythm cannibinoids, 37 sinus tachycardia lead, 248 moxifloxacin, 279 theophylline, 2 sinusitis cocaine, 38 skin discoloration amiodarone, 206 skin ecchymoses Selaginella doederleinii, 534 skin hypertrophy insulin, 462 skin irritation calcineurin inhibitors, 172 skin lesions dapsone, 340 skin pigmentation amiodarone, 206 skin problems lithium, 19 skin reaction dapsone, 340 fentanyl, 92 primethamine + sulfadoxine, 290 skin tags ganirelix + follicle stimulating hormone, 479 skin toxicity docetaxel, 504 sleep disorders dopamine receptor agonists, 160–162 fluvoxamine, 12 methadone, 95 modafinil, 5–6 nervous system, 12–13 pramipexole, 160 ropinirole, 160 sleep disturbance methylphenidate, 4 metoprolol + simvastatin, 487 slow reactions dopamine receptor agonists, 162

zolpidem, 50 slurred speech dextromethorphan, 90 sildenafil, 231 topiramate, 79 zolpidem, 50 sneezing calcitonin, 477 nasal insulin, 465 social withdrawal digoxin, 198 somnolence buspirone, 49 clozapine, 61 dopamine receptor agonists, 161 ecstasy, 35 felbamate, 73 gabapentin, 73, 74 haloperidol, 53 levetiracetam, 75 myrrh, 349 nervous system, 13 nicotine poisoning, 528 pimozide, 64 progesterone, 448 risperidone, 53, 64 tiagabine, 77 zonisamide, 84 sore throat deferiprone, 253 methimazole, 458 phenytoin + fosphenytoin, 76 pioglitazone, 471 salmeterol, 192 spastic paraparesis methadone, 96 spasticity disulfiram, 542 sperm motility lithium, 23 spina bifida triamterene, 241 spinal cord injury acupuncture, 535 spinal cord ischemia intravenous immunoglobulin, 365 spleen, enlarged gabapentin, 74 splenomegaly carbamazepine + phenytoin, 76 G-CSF, 398 spongiotic dermatitis acupuncture, 535 silicone, 544 squamous cell neoplasms docetaxel, 504 squamous erythematous plaques local anesthetics, 172 ST segment depression remifentanil, 100 status epilepticus

lithium, 25 tiagabine, 77 steatosis of the liver insulin, 462 stenosis cocaine, 39 ergot alkaloids, 163 stenosis, vessel central venous catheters, 545 Stevens–Johnson syndrome celecoxib, 124 Ginkgo biloba, 531 nevirapine, 332 pyrimethamine + sulfadoxine, 290, 322 ranitidine, 384 suramin, 350 stillborn fetus losartan, 236 stimulation theophylline, 2–3 stomach ache methylphenidate, 4 stomach discomfort roxithromycin, 288 stomatitis all-trans retinoic acid, 417 menthol, 543 stool, light-colored MDMA, 35 stooped posture olanzapine, 61 stroke Ginkgo biloba, 531 sildenafil, 231 stromal edema gold, 246 stuttering antipsychotic drugs, 55 lithium, 20 subacute cutaneous lupus erythematosus terbinafine, 310 subcapsular blebs quetiapine, 63 subcortical hemorrhage sildenafil, 231 subdural hematoma oxymetholone, 450 subependymal cyst formation cocaine, 41 sudden cardiac death clozapine, 59 sudden death adenosine, 203 antipsychotic drugs, 54 beta-adrenoceptor agonists, 190 dofetilide, 210 olanzapine, 61 sertindole, 65 suicidal ideation isotretinoin, 175 suicide antipsychotic drugs, 58 isotretinoin, 175

610 sulfonamide hypersensitivity COX-2 inhibitors, 122 supine hypertension midodrine, 158 suppurative granulomatous inflammation acupuncture, 535 supraventricular tachycardia digoxin, 198 swallowing difficulty disulfiram, 542 sweating baclofen, 153 clozapine, 59 cocaine, 37 gabapentin, 74 lithium, 20 morphine, 97 nefopam, 106 olanzapine, 62 oxaliplatin, 501 St. John’s wort, 532 tramadol, 102 sweating, reduced topiramate, 80 zonisamide, 84 Sweet’s syndrome celecoxib, 124 swelling carboplatin, 501 cisplatin, 501 cocaine, 37 diphtheria, tetanus vaccines, 356 ganirelix, 479 Ginkgo biloba, 5310 heroin, 91 insulin, 463 iodinized oil-based contrast agent, 518 oxaliplatin, 500–501 pioglitazone, 471 swelling (facial) co-trimoxazole, 321 swelling (neck) brachial plexus anesthesia, 140, 141 MDMA, 32 syncope lithium, 19 methadone, 95 systemic contact dermatitis cinchocaine, 146 systemic lupus erythematosus etanercept, 400 penicillamine, 255 terbinafine, 310 systolic hypotension melarsoprol, 323 T lymphocyte proliferation pefloxacin, 281 T wave changes caudal anesthesia, 141

Index of adverse effects tachycardia amfebutamone, 16 anticholinergic drugs, 164 antihistamines, 181 benzocaine, 145 cannibinoids, 37 carboplatin, 501 cardiac glycoside, 198 cilostazol, 230 clenbuterol, 191 dextromethorphan, 91 digoxin, 198 disulfiram, 542 dobutamine, 159 dofetilide, 210, 211 ecstasy, 32 gabapentin, 74 heroin, 91 intravenous immunoglobulin, 364 lithium, 19 milrinone, 202 moricizine, 213 nefopam, 106 nicardipine, 227 olanzapine, 62 orphenadrine, 165 oxaliplatin, 501 parathyroid hormone, 481 risperidone, 65 sevoflurane, 132 theophylline + levofloxacin + clarithromycin, 2 vitamin B2 , 420 tachydysrhythmia methadone, 95 theophylline, 2 tachypnea benzocaine, 145 talipes ganirelix + follicle stimulating hormone, 479 tardive dyskinesia antipsychotic drugs, 55, 56 antipsychotics, 53 clozapine, 53 haloperidol, 64 risperidone, 64 taste disturbance anorexia, 493 clarithromycin, 286 codeine, 90 gadobenate dimeglumine, 520 gadodiamide, 520 levofloxacin, 278 metronidazole, 323 penicillamine, 255 tearfulness methylphenidate, 4 tearing flecainide, 213 telangiectasia aristolochic acid, 530 felodipine, 174, 226

temperature body, increased zonisamide, 84 temperature instability DTP-Hib vaccines, 356 tenderness oxaliplatin, 501 tendinitis ciprofloxacin, 276–277 fluoroquinolones, 275 tendinopathy atorvastatin, 487 levofloxacin, 279 simvastatin, 487 tendon rupture fluoroquinolones, 275 teratogenesis THC, no effect, xxxiii tetany cisplatin, 497 strychnine, 6 thinking, difficulty in morphine, 97 thirst inhaled corticosteroids, 187 vitamin A, 416 thoracic empyema talc, 544 throat tightness carboplatin, 501 throbbing spinal manipulation, 536 thrombocytopenia aspirin, 113 carboplatin, 498 cidofovir, 328 clotting factors, 366 darbepoetin, 368 epoetin, 368 erythropoietin, 368 glucagon, 466 interferon alfa, 395 intravenous immunoglobulin, 365 linezolid, 289 naproxen, 116 neutropenia, 498 olanzapine, 62 oxaliplatin, 498 penicillamine, 255 platinum compounds, 499 quinine, 318 rituximab, 403 ZD0473, 493 thrombocytopenic purpura clordiazepoxide, 46–47 measles-mumps-rubella vaccine, 359–360 quinine, 318 thromboembolic complications apomorphine, 160 thromboembolic disease epoetin, 369 ovulation induction, 478 thromboembolism

611

Index of adverse effects gonadorelin receptor antagonists, 478 thrombophlebitis darbepoetin, 368 epoetin, 368 thrombosis central venous catheters, 545 contrast agents, 516 erythropoietin, 368 hormone replacement therapy, 438 intravenous immunoglobulin, 365 thalidomide, 176 thrombosis, arterial infliximab, 400–401 thrombotic events all-trans retinoic acid, 417 thrombotic microangiopathy ciclosporin, 405 thrombotic thrombocytopenic purpura atorvastatin, 487 simvastatin, 487 thyroid dysfunction amiodarone, 205 lithium, 20–21 thyroid immunity interferon alfa, 394–395 thyrotoxicosis lithium, 20, 21 thyrotropin concentration thyroxine, 457 tics methylphenidate, 5 tingling sensation Sono Vue, 523 tinnitus buspirone, 49 cisplatin, 496 hepatitis B vaccine, 358 heroin, 41 lidocaine, 144 quinine, 318 tiredness acupuncture, 535 dihydrocodeine, 92 ecstasy, 35 risperidone, 64 tongue, black arsenic, 244 tongue hypertrophy inhaled corticosteroids, 187 tonic-clonic seizures ciclosporin, 404 cisplatin, 496 cisplatin + doxorubicin, 502 torsade de pointes amiodarone, 204, 207 antipsychotic drugs, 54 arsenic, 244 dofetilide, 210, 211 erythromycin, 287 fluoroquinolones, 274

grepafloxacin, 278 haloperidol, 54 levomethadyl acetate HCl (LAAM), 95 methadone, 95 mosapride, 212 olanzapine, 61 sevoflurane, 132 sotalol, 224 torticollis ganirelix + follicle stimulating hormone, 479 Tourette syndrome methylphenidate, 5 toxic delirium disulfiram, 542 toxic epidermal necrolysis antipsychotic drugs, 58 chloroquine, 316 co-trimoxazole, 292, 321 iohexol, 518 ofloxacin, 280 toxicity gabapentin, 74 lithium, 25 mercury, 248 silver, 249 transaminase activity adefovir, 335 all-trans retinoic acid, 418 fluvastatin, 488 heparins, 377 interferon alfa, 395 transient cortical blindness vertebral angiography, 514–515 transient dysrhythmia propafenone, 214 transient polycythemia isotretinoin, 176 transient radicular irritation intrathecal (spinal) anesthesia, 142 trembling lithium, 25 tremor haloperidol, 64 lithium, 19, 20, 24 methadone, 96 moricizine, 213 olanzapine, 62 risperidone, 64 salmeterol, 192 zolpidem, 51 tremor, intention metronidazole, 324 tremulousness cisplatin, 497 tricuspid regurgitation fenfluramine, 6 triglyceride concentration all-trans retinoic acid, 418 antipsychotic drugs, 56 beta-adrenoceptor agonists, 526 trigonocephaly

valproate sodium, 82 truncal ataxia cocaine, 38 TSH concentration St. John’s wort, 532 TT virus infection intravenous immunoglobulin, 366 tuberculosis etanercept, 400 infliximab, 402 tubular atrophy aristolochic acid, 530 cisplatin, 499 tubular damage ioxaglate, 517 tubular necrosis cocaine, 39 oxaliplatin, 500 tubulointerstitial nephritis cefdinir, 264 copper, 245 rofecoxib, 125 thiazide and loop diuretics, 239 tumor expansion thyroid stimulating hormone, 481–482 tumor lysis syndrome rituximab, 403 tumors walnut oil, 545 tumors, parathyroid lithium, 21 ulcerative colitis isotretinoin, 176 lamotrigine, 74 ulcers (aphthous) Fleet enema, 387 ulcers (gastrointestinal) NSAIDs, 120 ulcers (genital) co-trimoxazole, 321–322 ulcers (hip) leuprorelin acetate, 478 ulcers (leg) docetaxel, 504 ulcers (oral) articaine, 144 deferiprone, 253 methotrexate, 407 ultraviolet recall tobramycin, 273 ultraviolet sensitivity fluoroquinolones, 275 unawareness insulin, 461 unconsciousness bromocriptine, 160 cannibinoids, 37 cocaine, 37 desmopressin, 482 fibrates, 486 unresponsiveness

612 adrenoceptor agonists, 525 ergot alkaloids, 163 zolpidem, 51 unsteadiness human growth hormone, 479 lithium, 25 urea concentration itraconazole, 307 propofol, 136 uremia see azotemia urethral obstruction suramin, 351 urethral stones felbamate, 73 urinary retention codeine, 90 felbamate, 73 fentanyl, 94 midodrine, 158 urinary tract infection methotrexate, 407 urinary urgency midodrine, 158 urine discoloration celecoxib, 124 deferiprone, 253 entacapone, 163 kava, 534 MDMA, 35 urothelial tract tumors aristolochic acid, 529 urticaria carboplatin, 501 cisplatin, 501 factor IX:C, 367 fibrates, 486 fluorescein, 542 heroin, 91 inhaled corticosteroids, 188 insulin, 463 intravenous immunoglobulin, 365, 366 iodixanol, 513 iopamidol, 513 ioxaglate, 513 isosulfan blue, 543 meloxicam, 116 menthol, 543 NSAIDs, 121–122, 122–123 omalizumab, 403 oxaliplatin, 501 oxybenzone, 174 praziquantel, 350 rare antigens in cosmetic products and drugs, 173 systemic glucocorticosteroids, 427 urticaria, consort amoxicillin, 263 urticarial rash factor IX:C, 367 uterine bleeding hormone replacement therapy, 440

Index of adverse effects uterine rupture misoprostol, 432 UV photosensitivity efavirenz, 331 uveitis cidofovir, 328 uveitis, anterior latanoprost, 526 uvular edema isosulfan blue, 543 vaginal argyrosis silver, 249 vaginal bleeding hormone replacement therapy, 437 vaginal discharge BufferGel, 541 vaginal discomfort BufferGel, 541 vaginal dryness toremifene, 447 valvular regurgitation fenfluramines, 6 Varicella zoster rituximab, 403 vascular degeneration copper, 245 vascular disruption cocaine, 40 vascular leak syndrome denileukin diftitox, 398 vascular sheathing vigabatrin, 82 vasculitis cocaine, 39 doxycycline, 265 ketoprofen, 172 minocycline, 266 SSRIs, 13 thionamides, 458–459 vasoconstriction nitroglycerin, 224 vasodilatation gadobenate dimeglumine, 520 vasomotor symptoms toremifene, 447 vasospasm ergot alkaloids, 163 venous thromboembolism clozapine, 59 oral contraceptives, 442–443 venous thrombosis hormone replacement therapy, 438 ventricular dysrhythmia dobutamine, 159 ventricular extra beats milrinone, 201 moricizine, 213 ventricular fibrillation digoxin, 198 ergot alkaloids, 163 iohexol, 514

ventricular tachycardia dofetilide, 210, 211 levofloxacin, 278 sevoflurane, 132 ventricular tachydysrhythmias methadone, 95 vertebral artery dissection amphetamines, 3 amphetamine, 30 verticillate epithelial keratopathy amiodarone, 205 vertigo dihydrocodeine, 92 vesiculopapular dermatitis nickel, 248–249 vessel stenosis central venous catheters, 545 vestibular dysfunction heroin, 41 vestibulopathy heroin, 41 vestibulotoxicity isepamicin, 272 violent behavior midazolam, 136 viral infection clotting factors, 367 viral pneumonia etanercept, 400 virus dermatitis latanoprost, 431 vision disturbances cisplatin, 496 deferiprone, 254 mefloquine, 317–318 voriconazole, 309 vision loss amphetamine, 30 cisplatin, 502 human growth hormone, 479 interferon alfa, 394 visual acuity disulfiram, 542 mexiletine, 213 topiramate, 79 visual field impairment massage therapy, 536 vitamin B12 hypovitaminosis unconventional diets, 536 vomiting albumin, 363 all-trans retinoic acid, 417 amphetamine, 30 antipsychotic drugs, 58 arsenic, 244 Artemisia derivatives, 320 BBR3464, 492 cannibinoids, 37 carboplatin, 498 chloramphenicol, 274 cidofovir, 328 cisplatin, 498, 502 dextromethorphan, 90 digoxin, 199

613

Index of adverse effects erythromycin, 284 famciclovir, 329–330 fentanyl, 92 fibrates, 486 gadobenate dimeglumine, 520 gadolinium, 520 gadoterate meglumine, 521 general anesthetics, 131–132 gliclazide, 470 gonadorelin, 477 human growth hormone, 479 hydromorphone, 94 iloprost, 430 infiltration anesthesia, 143 intravenous immunoglobulin, 364 iodixanol, 513 iopamidol, 513 ioxaglate, 513 iron dextran, 247 itraconazole, 306, 307 josamycin, 287 levamisole, 348 levofloxacin, 278 linezolid, 289 liposome-encapsulated iodixanol, 519 lithium, 20 MDMA, 32, 35 mefloquine, 318 metformin, 468 mifepristone, 448 misoprostol, 431 morphine, 97 nicotine poisoning, 528 NRTIs, 330 oxaliplatin, 498 oxcarbazepine, 76 praziquantel, 350 propofol, 136 quinine, 318 quinupristin/dalfopristin, 290 remifentanil, 100, 101 salmeterol, 192 sildenafil, 231 Sono Vue, 523 telithromycin, 283 theophylline, 2 thiabendazole, 344 thyrotropin-releasing hormone, 482 tramadol, 103 vitamin D, 422

water-soluble iodinated contrast agents, 512 ZD0473, 493 zonisamide, 84 von Willebrand’s disease hydroxyethyl starch, 374–375 vulvar discomfort BufferGel, 541 warmth, sensation of gadolinium, 520 Sono Vue, 523 water intoxication desmopressin, 482 weakness acarbose, 467 anthrax vaccine, 355 cisplatin, 497 colistin, 289 diethylcarbamazine + ivermectin, 346 ecstasy, 35 enalapril, 235 fenofibrate, 486 fosinopril, 236 granisetron, 384 levetiracetam, 75 propafenone, 214 simvastatin + clarithromycin, 488 St. John’s wort, 532 tiagabine, 77 weakness (facial) amphetamine, 30 weeping dermatitis cinchocaine, 146 weight changes antiepileptic drugs, 71 weight gain all-trans retinoic acid, 417, 418 antipsychotic drugs, 56–58 beta-adrenoceptor antagonists, 223 chlorpromazine, 53 clozapine, 53 haloperidol, 53 lithium, 19 medroxyprogesterone, 444 mexazolam, 48 morphine, 97 pioglitazone, 471 quetiapine, 63 risperidone, 53, 64 rosiglitazone, 471

troglitazone, 472 valproate sodium, 80 weight loss felbamate, 73 fosinopril, 236 glibenclamide, 466, 469 MDMA, 35 pergolide, 160 topiramate, 78 voglibose, 466 wheal-and-flare reactions insulin, 463 wheezing betaxolol, 526 carboplatin, 501 cisplatin, 501 fibrates, 486 intravenous immunoglobulin, 364 menthol, 543 oxaliplatin, 501 white matter changes paclitaxel, 503 WHO Uppsala Monitoring Center origins, xxvii–xxviii wind see flatulence withdrawal alprazolam, 46 androgenic anabolic steroids, 450 baclofen, 152–153 caffeine + lithium, 25 cannabis, xxxix–xl levofloxacin interaction, 279 lithium, 19 nitroglycerin, 224 olanzapine, 46 venlafaxine, 17 withdrawal bleeding hormone replacement therapy, 436 withdrawal symptoms fentanyl, 93 Wolbachia bacteria after diethylcarbamazine therapy, 345 wound infection talc, 544 yeast infection BufferGel, 540, 541