Side Effects of Drugs Annual 28, Volume 28: A worldwide yearly survey of new data and trends in adverse drug reactions (Side Effects of Drugs Annual)

SIDE EFFECTS OF DRUGS ANNUAL 28

Side Effects of Drugs Annual 28 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 28 A worldwide yearly survey of new data and trends in adverse drug reactions and interactions EDITOR

J. K. ARONSON MA, DPhil, MBChB, FRCP, FBPharmacolS Reader in Clinical Pharmacology University Department of Clinical Pharmacology Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom

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First edition 2005

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Contributors M.C. ALLWOOD, P HARM , P H D University of Derby, School of Health and Community Studies, Pharmacy Academic Practice Unit, Kingsway House, Derby, DE22 3HL, UK. E-mail: [email protected] J.K. ARONSON, MA, MBC H B, D PHIL , FRCP, FBP HARMACOL S University Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, UK. E-mail: [email protected] I. AURSNES, MD University of Oslo, Department of Pharmacotherapeutics, P.O. Box 1065 Blindern, N-0316 Oslo, Norway. E-mail: [email protected] A.M. BALDACCHINO, MD, MRCP SYCH , M PHIL , D IP A DD B EH Centre for Addiction Research and Education Scotland (CARES), Medical Offices, Stratheden Hospital, Cupar, Fife, Scotland KY15 5RR. M. BEHREND, MD, P H D Klinik fur Viszeral-, Gefäß-, Thorax- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Strasse 41, D-94469 Deggendorf, Germany. E-mail: [email protected] F. BRAUN, MD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail: [email protected] J. BUSER, MD Division of Clinical Pharmacology, Department of Medicine, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected] A. CARVAJAL, MD, P H D Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected] N.H. CHOULIS, M D , P H D LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania (Attika), Greece. E-mail: [email protected] J. COSTA, MD Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra de Canyet, 08916 Badalona, Spain. E-mail: [email protected] P.J. COWEN, MD University Department of Psychiatry, Warenford Hospital, Oxford, OX3 7JX, UK. E-mail: [email protected] S. CURRAN, BS C , MBC H B, M MED S C , MRCP SYCH , P H D South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, and School of Human and Health Sciences, University of Huddersfield, Queensgate, UK. E-mail: [email protected]

v

vi

Contributors

F.A. de WOLFF, MA, P H D, E UR C LIN C HEM , ERT, FATS Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Chemistry, Pharmacy and Toxicology, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] A. DEL FAVERO, MD Istituto di Medicina Interna e Science Oncologiche, Policlinico Monteluce, 06122 Perugia, Italy. E-mail: [email protected] H.R. DALTON, BS C DP HIL FRCP D IP M ED E D Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. S. DAR, MBBS BS C MRCP Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. J. DESCOTES, MD, P H D, P HARM D Centre Antipoison – Centre de Pharmacovigilance, 162 avenue Lacassagne, 69424 Lyon cedex 03, France. E-mail: [email protected] S. DITTMANN, MD, DS C M ED 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] D.L. DUNNER, MD Department of Psychiatry & Behavioral Sciences, Center for Anxiety and Depression, University of Washington Medical School, 4225 Roosevelt Way, NE, Ste 306C, Seattle, Washington 98105, USA. E-mail: [email protected] E. ERNST, MD, P H D, FRCP, FRCP (E D ) Department of Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, 25 Victoria Park Road, Exeter, EX2 4NT, UK. E-mail: [email protected] M. FARRÉ, MD Unitat de Farmacologia, Institut Municipal d’Investigació Mèdica (IMIM-IMAS), Universitat Autònoma de Barcelona, Doctor Aiguader 80, 08003 Barcelona, Spain. E-mail: [email protected] K. FATTINGER, MD Division of Clinical Pharmacology, Department of Medicine, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected] P. FLISBERG, MD, P H D Department of Pharmacology, University of Western Australia and Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. J.A. FRANKLYN, MD, P H D, FRCP, FM ED S CI University of Birmingham, Queen Elizabeth Hospital, Department of Medicine, Edgbaston, Birmingham, B15 2TH, UK. E-mail: [email protected] M.G. FRANZOSI, P H D Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected]

Contributors

vii

A.H. GHODSE, MD, P H D, DS C , FRCP, FRCPE, FRCP SYCH , FFPH International Centre for Drug Policy (ICDP), St. George’s University of London, 2nd Floor Hunter Wing, Cranmer Terrace, London, SW17 0RE, UK. E-mail: [email protected] A. GIL-NAGEL, MD Hospital Ruber Internacional, La Masó 38, Mirasierra, 28034 Madrid, Spain. Phone: +349138752520, Cellular phone: +34618647657, E-mail: [email protected] A.H. GROLL, MD Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, Muenster, Germany. E-mail: [email protected] J.T. HARTMANN, P H D, MD 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] K. HARTMANN, MS C P HARM Berna Biotech Ltd, Head Global Pharmacovigilance, 3000 Berne, Switzerland. E-mail: [email protected] A. IMHOF, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected] S.A. JACKSON, FRACA, DCH Department of Pharmacology, University of Western Australia and Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. N. JIMENO, MD, P H D Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. MARKUS JOERGER, MD Department of Pharmacy & Pharmacology, Slotervaart Hospital and Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, 1066 EC Amsterdam, The Netherlands. E-mail: [email protected] P. JOUBERT, BS C , MBB CH , M MED S C , FCP(SA), MD Honorary Professor of Pharmacology and Therapeutics, Medical University of Southern Africa (MEDUNSA), Pretoria, South Africa, c/o Eikerstrasse 9, 4325 Schupfard, Switzerland. E-mail: [email protected] DAVID M. KEELING, BS C MD FRCP FRCPATH Oxford Haemophilia Centre and Thrombosis Unit, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail: [email protected] SANDRA R. KNOWLES, BS C P HM Drug Safety Clinic, Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, ON M4N 3M5, Canada. E-mail: [email protected] H. KOLVE Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, Muenster, Germany.

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Contributors

H.M.J. KRANS, MD Dept. of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] MAX KUHN, MD Department of Internal Medicine, Division of Pneumology, Kantonsspital, Loestrasse 170, 7000 CHUR, Switzerland. E-mail: [email protected] R. LATINI, MD Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] M. LEUWER, MD The University of Liverpool, University Department of Anaesthesia, The Duncan Building, Daulby Street, Liverpool, L69 3GA, England. E-mail: [email protected] H.-P. LIPP, P H D Eberhard-Karls-University Tübingen, Department of Clinical Pharmacy, Röntgenweg 9, 72076 Tübingen, Germany. P. MAGEE, BS C , MS C , MRP HARM S Director of Pharmaceutical Sciences, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, UK. E-mail: [email protected] A.P. MAGGIONI, MD Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] L.H. MARTÍN ARIAS, MD, P H D Instituto de Farmacoepidemiologia, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected] R.H.B. MEYBOOM, MD, P H D Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands. T. MIDTVEDT, MD, P H D Karolinska Institutet, Laboratory of Medical Microbial Ecology, Von Eulers v. 5, Karolinska Institutet, Box 60 400, S-171 77 Stockholm, Sweden. E-mail: [email protected] S.K. MORCOS, FRCS, FFRRCSI, FRCR Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Sheffield, S5 7AU, UK. E-mail: [email protected] S. MUSA, MB C H B, MRCP SYCH Consultant Old Age Psychiatrist, South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, UK. D.J. O’CONNOR, MBC H B Department of Pharmacology, University of Western Australia and Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. R. PAGE, MD FRCP MA(E D ) Endocrine unit, Dundee House, Nottingham City Hospital, Hucknall Rd., Nottingham, NG5 1PB, UK. E-mail: [email protected]

Contributors

ix

J.K. PATEL, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail: [email protected] B.C.P. POLAK, MD VU University Medical Center, Department of Ophthalmology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: [email protected] T.E. RALSTON, MA Department of Psychiatry, University of Massachusetts Medical School, 361 Plantation Street, Worcester, Massachusetts 01605, USA. E-mail: [email protected] H.D. REUTER, P H D Siebengebirgsallee 24, D-50939 Köln, Germany. E-mail: [email protected] M. SCHACHTER, MD Department of Clinical Pharmacology, National Heart and Lung Institute, Imperial College, St. Mary’s Hospital, London, W2 1NY, UK. E-mail: [email protected] PATRICK SCHMID Basel Center for HIV Research, Division of Infectious Diseases, University Hospital, Basel, Switzerland. S.A. SCHUG, MD, FANZCA, FFPMANZCA Department of Pharmacology, University of Western Australia and Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected] R.P. SEQUEIRA, P H 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] N.H. SHEAR, MD, FRCPC Drug Safety Clinic, Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, ON M4N 3M5, Canada. E-mail: [email protected] D.A. SICA, MD 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, USA. E-mail: [email protected] A. STANLEY, P H D, MRP HARM S Birmingham Oncology Centre, St Chad’s Unit, City Hospital, Dudley Road, Birmingham B18 7QH, UK. P.F.W. STRENGERS, MD Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. S. SWAMINATHAN, MD Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail: [email protected] W.G. VAN AKEN, MD Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected]

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G.B. VAN DER VOET, P H D, ERT Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Chemistry, Pharmacy and Toxicology, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] P.J.J. VAN GENDEREN, MD, P H D Harbour Hospital, Department of Internal Medicine, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail: [email protected] R. VERHAEGHE, MD University of Leuven, Center for Vascular and Molecular Biology, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] PIETRO L. VERNAZZA Basel Center for HIV Research, Division of Infectious Diseases, University Hospital, Basel, Switzerland. E-mail: [email protected] T. VIAL, MD Centre Antipoison – Centre de Pharmacovigilance, 162 avenue Lacassagne, 69424 Lyon cedex 03, France. E-mail: [email protected] P.J.M. VOSSEBELD, P H D Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] Dr. G.M. WALSH, MS C , P H D School of Medicine, Institute of Medical Sciences Building, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: [email protected] T.J. WALSH, MD Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20891, USA. E-mail: [email protected] E.J. WONG, MD Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Boston, MA 02115, USA. E-mail: [email protected] GAVIN WONG, MBC H B, MRCP(UK) Drug Safety Clinic, Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, ON M4N 3M5, Canada. E-mail: [email protected] Y. YOUNG, MBBS, MRCP(UK), FRCA Department of Anaesthesia, Level 14, Support Building, Auckland City Hospital, Private Bag 92024, Auckland, New Zealand. E-mail: [email protected] O. ZUZAN, MD Royal Liverpool University Hospital, Department of Anaesthesia, Prescot Street, Liverpool, L7 8XP, UK. E-mail: [email protected]

Contents Contributors Special reviews

v xv

Cumulative index of special reviews, Annuals 14–27

xvii

Table of Essays, Annuals 1–27

xxiii

How to use this book Essay: Classifying adverse drug reactions in the 21st century J.K. Aronson 1. Central nervous system stimulants and drugs that suppress appetite R.P. Sequeira

xxv xxvii 1

2. Antidepressant drugs P.J. Cowen

14

3. Lithium D.L. Dunner

23

4. Drugs of abuse J.K. Patel, T.E. Ralston, and E. Wong

28

5. Hypnosedatives and anxiolytics S. Curran and S. Musa

52

6. Antipsychotic drugs A. Carvajal, L.H.M. Arias, and N. Jimeno

59

7. Antiepileptic drugs A. Gil-Nagel

86

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

106

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

118

10. General anesthetics and therapeutic gases Y. Young

139

11. Local anesthetics S.A. Schug, P. Flisberg, S.A. Jackson, and D.J. O’Connor

145

12. Neuromuscular blocking agents and skeletal muscle relaxants O. Zuzan and M. Leuwer

155

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

160

14. Dermatological drugs, topical agents, and cosmetics S.R. Knowles, G. Wong, and N.H. Shear

168

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15. Antihistamines (H1 receptor antagonists) G.M. Walsh

177

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

184

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

196

18. Beta-adrenoceptor antagonists and antianginal drugs A.P. Maggioni, M.G. Franzosi, and R. Latini

217

19. Drugs acting on the cerebral and peripheral circulations R. Verhaeghe

223

20. Antihypertensive drugs P. Joubert

226

21. Diuretics D.A. Sica

233

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

244

23. Metal antagonists R.H.B. Meyboom

254

24. Antiseptic drugs and disinfectants P. Magee

261

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

265

26. Miscellaneous antibacterial drugs A. Imhof

274

27. Antifungal drugs A.H. Groll, H. Kolve, and T.J. Walsh

294

28. Antiprotozoal drugs J. Buser and K. Fattinger

315

29. Antiviral drugs P.L. Vernazza and P. Schmid

326

30. Drugs used in tuberculosis and leprosy S. Swaminathan

342

31. Antihelminthic drugs P.J.J. van Genderen

346

32. Vaccines S. Dittmann

356

33. Blood, blood components, plasma, and plasma products P.J.M. Vossebeld, P.F.W. Strengers, and W.G. van Aken

369

34. Formulations used in nutrition M.C. Allwood and G. Hardy

383

35. Drugs affecting blood coagulation, fibrinolysis, and hemostasis D.M. Keeling and J.K. Aronson

391

Contents

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36. Gastrointestinal drugs S. Dar and H.R. Dalton

401

37. Drugs that act on the immune system: cytokines and monoclonal antibodies T. Vial, J. Descotes, F. Braun, and M. Behrend

415

38. Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs F. Braun and M. Behrend

450

39. Corticotrophins, corticosteroids, and prostaglandins J. Costa and M. Farré

471

40. Sex hormones and related compounds, including hormonal contraceptives M.N.G. Dukes

480

41. Thyroid hormones and antithyroid drugs J.A. Franklyn

505

42. Insulin, glucagon, and oral hypoglycemic drugs H.M.J. Krans

509

43. Miscellaneous hormones R. Page

528

44. Drugs that affect lipid metabolism I. Aursnes

534

45. Cytostatic drugs H.P. Lipp, J.T. Hartmann, and A. Stanley

538

46. Radiological contrast agents S.K. Morcos

552

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

568

48. Treatments used in complementary and alternative medicine E. Ernst

573

49. Miscellaneous drugs and materials, medical devices, and techniques N.H. Choulis and J.K. Aronson

587

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

602

Index of drugs

616

Index of adverse effects

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Special reviews

Overdose with antidepressant drugs Antipsychotic drugs and new-onset diabetes mellitus Risperidone and stroke in patients with dementia Do NSAIDs inhibit the cardioprotective effects of acetylsalicylic acid? NSAIDs and the risk of intracerebral hemorrhage Dyspepsia and NSAIDs Risk of necrotizing fasciitis due to Group A Streptococcus pyogenes in patients taking NSAIDs NSAIDs and the risk of acute renal insufficiency with ACE inhibitors Interaction of aspirin with ACE inhibitors Suxamethonium and postoperative myalgia Treating asthma during pregnancy Choice of antihypertensive drugs in patients with diabetes and hypertension Uses of mannitol Prudent future use of antibiotics Immunologic reactions to penicillins: cross-reactivity with cephalosporins Drug interactions with antifungal azoles Metabolic complications and antiretroviral therapy Pharmacogenetics: genetic susceptibility, drug metabolism, and adverse effects The safety of thiomersal-containing vaccines MMR vaccine and autism Glucocorticoid-induced osteoporosis and fractures Contraindications to metformin Combinations of hypoglycemic drugs Vinca alkaloids Contrast medium-induced nephrotoxicity Nephrotoxicity of gadolinium salts and their use in patients with impaired renal function Safety issues involving herbal medicines: kava as a case study Errors in drug administration

14 60 76 118 119 120 121 122 124 155 186 226 236 265 267 299 329 342 357 363 473 515 521 538 556 561 579 587

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Cumulative index of special reviews, Annuals 14–27 Index of drugs Note: the format 27.109 refers to SEDA-27, p. 109. ACE inhibitors angioedema, 22.225 cough, 19.211 indications, 24.233 Acetylsalicylic acid, 21.100 benefit to harm balance in preventing strokes and heart attacks, 27.109 co-medication, 26.423 gastrointestinal effects, 17.95, 18.90 Reye’s syndrome, 15.85 rhinosinusitis/asthma, 17.94 Aerosols, delivery, 27.172 Albumin, human, anaphylaxis, 14.296 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 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 15.268, 17.305 ototoxicity, 14.222, 18.268 and ribostamycin, 15.270 Amiodarone, dysrhythmias, 25.211 respiratory toxicity, 15.168 thyroid disease, 27.192 Amphotericin, liposomal, 17.319 nephrotoxicity, 14.229, 27.276 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 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 bone loss, 27.74 comparison, 25.78 death, 23.83 overdosage, 22.84 psychiatric effects, 22.82, 27.72 Antiestrogens, genotoxicity and tumorigenicity, 27.429 Antifungal drugs drug interactions (azoles), 24.318 Pneumocystis jiroveci (carinii) pneumonia, 18.289 Antihistamines cardiovascular adverse effects, 17.196, 22.176, 25.183, 26.180 drowsiness/sedation, 21.170, 23.171, 26.182 Antihypertensive drugs, 19.209 fixed-dose combinations, 22.224 individualizing therapy, 17.246 Antimalarial drugs, 14.237, 17.325, 20.257 adjunctive treatments, 24.330 prophylaxis, 23.304 Antimicrobial drugs allergic reactions, 23.251 coagulation disorders, 18.258 colitis, 17.303 future use, 27.242 male fertility, 16.262 new, with adjuvants, 17.296 the pill and pregnancy, 24, 274 policies and politics, 16.273 prescribing, 15.254 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 Antioxidant vitamins, 20.363 Antiprotozoal drugs African trypanosomiasis, 18.293 toxoplasmosis, 20.262

xvii

xviii

Cumulative index of special reviews, Annuals 14–27

Antipsychotic drugs comparisons of different types 25.53, 27.50 use in conditions other than schizophrenia, 27.49 weight gain, 26.56 Antituberculosis drugs, 16.341 liver damage, 25.363, 26.339 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, see Acetylsalicylic acid Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Avoparcin, lessons from, 27.242 Azoles, see antifungal drugs

contact allergy, 16.150, 19.151 ingredient labeling 22.159 COX2 inhibitors, 24.115, 25.126, 26.116

Baclofen, withdrawal syndrome, 26.152 Bambuterol, cardiac failure, 23.181 Benzodiazepines, depression, 17.43 brain damage, 14.36 Beta2 -adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 Beta-adrenoceptor antagonists, sexual function, 15.188 Beta-carotene, see also Vitamin A alcohol, vitamin A, interaction, 24.442 tumorigenicity, 25.454 Beta-lactam antibiotics, immediate hypersensitivity reactions, 14.211 pregnancy, 25.280 Botulinum toxin A, use in primary axillary hyperhidrosis, 27.161 Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carotenoids, tumorigenicity, 25.454 Ceftriaxone, 15.258 Charcoal, activated, in digitalis overdose, 24.201 Chloramphenicol, children, 15.267 Chloroquine, 15.286 Chondroprotective agents, 14.439 Chymopapain, 14.264 Ciclosporin, urinary system, 19.348 Clozapine, 15.50 agranulocytosis, 22.1359 Complementary and alternative therapies, indirect risks, 27.521 esophagus, adverse effects on, 14.442 Co-trimoxazole, hypersensitivity reactions, 20.264 Cocaine cardiovascular effects, 18.5 prenatal exposure and perinatal effects, 27.1 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151 Contrast media adverse effects, 24.525 anaphylactoid and allergic reactions, 20.422 delayed reactions, 26.513 in magnetic resonance imaging, 20.419 renal damage, 27.500 Corticosteroids, see Glucocorticoids Cosmetics

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, compared with other drugs in heart failure in sinus rhythm, 14.141 compared with other drugs in chronic uncomplicated atrial fibrillation, 14.144 in heart failure in sinus rhythm, 18.196 Diuretics diabetes mellitus, electrolyte abnormalities, and the ALLHAT trial, 27.219 renal cell carcinoma, 23.225 renal insufficiency, 25.250 Dofetilide, 26.208 Dopamine receptor agonists, sleep disorders, 26.160, 27.149 Ecstasy, see MDMA EDTA, pseudothrombocytopenia, 21.250 Endothelin receptor antagonists, in hypertension, 26.233 Enzyme inhibitors, 15.337 Erythromycin, versus the new macrolides, 21.269 Erythropoietin, pure red cell aplasia, 27.348 status and safety, 16.400 Etoposide, 27.477 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 Fertility drugs malignant melanoma, 26.434 ovarian cancer, 24.474 Flecainide, in supraventricular dysrhythmias, 21.200 Fluoroquinolones, 18.271 Fluorouracil, adverse effects, 23.476 Folic acid, dietary supplementation, 19.369 safety aspects, 27.407 Formoterol, tolerance, 24.187 Fragrances, contact allergy, 20.149 General anesthetics, see Anesthetics Germanium, 16.545 Glucocorticoids bone, 16.447, 22.182, 25.195 contact allergy, 15.139, 21.158 effective dose and therapeutic ratio, 23.175 and growth, 14.335 inhaled, growth inhibition, 26.186 inhaled, risks in children, 27.174

xix

Cumulative index of special reviews, Annuals 14–27 inhaled, systemic availability, 24.185, 26.187 musculoskeletal adverse effects, 21.417 osteoporosis and osteonecrosis, 19.377, 20.374 preterm infants, 17.445 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501 insulin resistance, 24.504 malignancy, 23.468 Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Heroin, see diamorphine Histamine (H2 ) receptor antagonists, 15.393 HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530 Hormones, sex, tumors, 22.465 5-HT, see serotonin Hypnotics, 20.30 avoiding adverse effects, 21.37 Hypoglycemic drugs, combinations of, 27.458 Immunization adverse effects, 24.364 and autoimmune disease, 27.336 bioterrorism, 25.378, 26.354 multiple, 27.334 surveillance after, 15.340, 22.333, 23.335, 24.364, 25.376, 26.353, 27.334 Immunotherapy, in leishmaniasis, 15.299 Indometacin, fetal and neonatal complications, 18.102 Insulin human, and hypoglycemia, 15.452 modes of administration, 26.464 resistance, and growth hormone, 24.504 synthetic analogs, 24.489 Interleukin-2, 14.325 Irinotecan, 27.477 Isoniazid, prophylactic, toxicity, 24.352

Macrolides, drug interactions, 14.220 intestinal motility, 18.269 Malaria vaccines, 22.306 MAO inhibitors, 17.361 MDMA cognitive effects, 26.32 deaths, 24.32 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 Mibefradil, drug interactions, 23.210 Midazolam, 15.112 Midodrine, 26.159 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387 Crohn’s disease, 23.350, 25.387 Morphine, managing adverse effects, 26.98 Muscle relaxants emergency medicine, 20.133 eyes, 21.145 hypersensitivity reactions, 27.138 intensive care, 19.140

Kava kava, liver damage, 27.518 Ketorolac, risk of adverse effects, 17.110

Niacin, extended-release, 16.440 Non-depolarizing neuromuscular blockers, 15.127 residual paralysis, 27.139 NSAIDs blood pressure, 19.92, 27.102 children, 19.96 current controversies, 17.102 COX2 inhibitors, 24.115, 25.126, 26.116 gastrointestinal adverse effects, 14.79, 17.95, 18.90, 18.99, 20.86, 21.96, 22.108, 23.114 gastrointestinal damage, role of Helicobacter pylori, 27.105 gastrointestinal toxicity, prevention, 19.93 inflammatory bowel disease, 25.131 nephrotoxicity, 18.100, 20.89, 24.120, 26.111 topical, 18.163

Lamotrigine, skin rashes, 20.62, 24.88 Leukotriene receptor antagonists, Churg–Strauss syndrome, 24.183, 27.177 Lipid-lowering drugs, 15.479 Lithium adverse effects, prevention and treatment, 17.28 beneficial uses other than in bipolar disorder, 27.19 interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 18.25 mortality, 19.14 urinary system, 14.18, 19.16 Local anesthetics, see Anesthetics Lorenzo’s oil, 27.475 Lyme disease vaccine, autoimmune disease, 24.366

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 and breast cancer, 15.426 formulations, 24.472 third-generation, 25.484, 26.442 venous thromboembolism, 23.442

xx

Cumulative index of special reviews, Annuals 14–27

Paclitaxel, adverse effects, 21.463 Pancreatic enzyme supplements, fibrosing colonopathy, 20.322 Paracetamol liver damage, 17.98, 18.94 overdose, 23.117 Parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Penicillins, acute desensitization, 23.252 Peritoneal dialysis fluids, effects on peritoneum, 22.381 Phentermine, cardiac valvulopathies, 24.4 Platinum compounds, 26.490 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 Propofol, infusion syndrome, 26.135 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 PUVA, malignant melanoma, 22.166 Pyrazinamide, in latent pulmonary tuberculosis, 27.323

Somatostatin, 15.468 Statins, see HMG Co-A reductase inhibitors Steroids, see glucocorticoids Sumatriptan, 17.171 Suramin, patients with prostate cancer, 20.283

Quinidine, versus quinine, 15.295 Quinine, versus quinidine, 15.295 Ribostamycin, and aminoglycosides, 15.270 Rocuronium, allergic reactions, 26.150 Rotashield, intussusception, 23.354 Salmeterol, tolerance, 24.187 Sex hormones, tumors, 22.465 Serotonin receptor antagonists, 15.391 selective serotonin reuptake inhibitors, drug interactions, 22.13 Smallpox vaccination, 27.339

Teniposide, 27.477 Tetracyclines adverse effects, 26.268 comparative toxicity, 22.268 and metalloproteinases, 26.266 in pregnancy, 25.280 in rheumatology, 23.255 Theophylline, asthma, 17.2, 18.1, 18.2 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 Topiramate, cognitive effects, 26.81 Topoisomerase inhibitors, 27.477 Topotecan, 27.477 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 L-tryptophan, eosinophilia-myalgia syndrome, 15.514 Vaccines, poliomyelitis, 22.352 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78, 24.95, 25.98, 26.82 Valproate, polycystic ovary syndrome, 26.81 Vancomycin., lessons from, 27.242 Vitamin A, 17.436 alcohol, beta-carotene, interaction, 24.442 hypervitaminosis, 15.411 in pregnancy, 21.405 Vitamin B6 , debate, 23.420 Vitamin E, co-medication, 26.423 Vitamin K cancer, 23.424 skin reactions, 25.461 Vitamins, in old age, 22.431 rhinosinusitis, acetylsalicylic acid, 17.94

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, 26.180 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 cardiotoxicity, propofol, 26.135 dysrhythmias, antihistamines, 22.176 dysrhythmias, amiodarone, 25.211 hypertension, NSAIDs, 19.92, 27.102 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 amiodarone, 15.168 asthma, acetylsalicylic acid, 17.94 asthma, fenoterol, 23.182 asthma deaths, beta2 -adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 Churg–Strauss syndrome, leukotriene receptor antagonists, 24.183, 27.177 cough, ACE inhibitors, 19.211

Cumulative index of special reviews, Annuals 14–27

xxi

primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2, 25.5 therapeutic effects, 24.278 Nervous system brain damage, benzodiazepines, 14.36 demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness/sedation, antihistamines, 21.170, 23.171, 26.182 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 seizures, antibiotics, 18.261 sleep disorders, dopamine receptor agonists, 26.160, 27.149 tardive dyskinesia, 14.47, 20.38 tardive syndromes, 17.54 transient symptoms, intrathecal anesthetics, 25.152 Neuromuscular residual paralysis, neuromuscular blocking drugs, 27.139 Sensory systems eye effects, muscle relaxants, 21.145 ototoxicity, aminoglycosides, 14.222, 18.268 visual field defects, vigabatrin, 21.78, 24.95, 25.98, 26.82 Psychiatric antiepileptic drugs, 22.82, 27.72 autism, MMR/measles immunization, 23.350, 25.387 cognitive effects, MDMA, 26.32 cognitive effects, topiramate, 26.78 depression, benzodiazepines, 17.43 psychosis and abnormal behavior, vigabatrin, 18.71 Endocrine diabetes mellitus, diuretics, 27.219 insulin resistance, growth hormone, 24.504 insulin resistance, HIV-protease inhibitors, 22.317 ovarian hyperstimulation syndrome, valproate, 26.477 polycystic ovary syndrome, valproate, 26.81 thyroid disease, amiodarone, 27.192 Metabolism hypoglycemia, insulin, 15.452 lactic acidosis, metformin, 23.459 metabolic acidosis, propofol, 26.135 lipodystrophy, HIV-protease inhibitors, 22.317 polyvinylpyrrolidone storage disease, 22.522 weight gain, antipsychotic drugs, 26.56 Electroyte balance electrolyte abnormalities, diuretics, 27.219 Hematologic agranulocytosis, clozapine, 22.59 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 eosinophilia-myalgia syndrome, tryptophan, 15.514

pseudothrombocytopenia, EDTA, 21.250 pure red cell aplasia, erythropoietin, 27.348 Gastrointestinal bleeding, acetylsalicylic acid, 17.95, 18.90 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 ulceration, bleeding and perforation, NSAIDs, 14.79, 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114, 27.105 Liver hepatotoxicity, alcohol/vitamin A/beta-carotene, 24.442 hepatotoxicity, antituberculosis drugs, 25.363, 26.339 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, kava kava, 27.518 hepatotoxicity, paracetamol, 17.98, 18.94 Reye’s syndrome, acetylsalicylic acid, 15.85 Urinary tract cystitis, tiaprofenic acid, 18.106 nephrotoxicity, aminoglycosides, 15.268, 17.305 nephrotoxicity, amphotericin, 14.229, 27.276 nephrotoxicity, analgesics, 21.98 nephrotoxicity, anesthetics, halogenated, 20.106 nephrotoxicity, ciclosporin, 19.348 nephrotoxicity, contrast media, 27.500 nephrotoxicity, lithium, 14.18, 19.16 nephrotoxicity, NSAIDs, 18.100, 20.89, 24.120, 26.111 renal cell carcinoma, diuretics, 23.225 renal insufficiency, diuretics, 25.250 Skin contact allergy, 23.160 contact allergy, glucocorticoids, 15.139 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 loss, antiepileptic drugs, 27.74 bone mineral density, glucocorticoids, 25.195 eosinophilia-myalgia syndrome, tryptophan, 15.514 growth in children, inhaled glucocorticoids, 26.186 growth in children, oral glucocorticoids, 14.335 osteoporosis and osteonecrosis, glucocorticoids, 16.447, 19.377, 20.374, 21.417, 22,182 rhabdomyolysis, propofol, 26.135 Sexual function and beta-adrenoceptor antagonists, 15.188 Immunologic allergic reactions, antibiotics, 23.251 allergic reactions, rocuronium, 26.150 anaphylaxis, human albumin, 14.296

xxii

Cumulative index of special reviews, Annuals 14–27

angioedema, ACE inhibitors, 22.225 autoimmune disease, immunizations, 27.336 autoimmune disease, Lyme disease vaccine, 24.366 cocamidopropylbetaine, 19.151 contrast agents, 20.422 cosmetics, 16.150, 19.151 co-trimoxazole, 20.264 desensitization, penicillin, 23.252 Euxyl K 400, 16.150 fragrances, 20.149 glucocorticoids, 21.158 hypersensitivity reactions, beta-lactam antibiotics, 14.211 hypersensitivity reactions, muscle relaxants, 27.138 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 Drug withdrawal baclofen, 26.152 Genotoxicity antiestrogens, 27.429 Tumorigenicity alcohol/vitamin A/beta-carotene, 24.442 antiestrogens, 27.429 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474, 26.434 growth hormone, 23.468 omeprazole, 16.423 oral contraceptives, 15.426 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424

Fertility fertility, male, antibiotics, 16.262 Pregnancy affective disorders in, 21.17 antibiotics and the pill, 24.274 beta-lactams, 25.280 cocaine, 27.1 opioids, 24.102 tetracyclines, 25.280 vitamin A, 21.405 Teratogenicity tretinoin, topical, 18.164 Fetotoxicity cocaine, 20.24, 27.1 indometacin, 18.102 Susceptibility factors children, inhaled glucocorticoids 27.174 children, NSAIDs, 19.96 intensive care, muscle relaxants, 19.140 neonatal complications, indometacin, 18.102 ocular drugs, 22.507 old age, vitamins, 22.431 preterm infants, beta-lactam antibiotics, 21.258 Drug administration delivery of aerosols, 27.172 dosage regimens, aminoglycosides, 23.264 formulations, oral contraceptives, 24.472 inhaled glucocorticoids, 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 macrolides, 14.220 mibefradil, 23.210 specific serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Methods ethnopharmacology, 14.429 onchocerciasis, treatment, 14.261 post-marketing surveillance, 14.210, 15.266, 24.274

Table of Essays, Annuals 1–27 SEDA

Author

Country

Title

The Netherlands Germany USA The Netherlands UK

The moments of truth Drug monitoring: why care? Wanted and unwanted drug effects: the need for perspective The van der Kroef syndrome Adverse reactions to drugs—the information lag

Hungary Canada Denmark UK Denmark Denmark Switzerland UK Denmark

Science vs practice and/or practice vs science Adverse reactions: some pitfalls and postulates The seven pillars of foolishness Let’s get our act together Integrated medicine, safer medicine and “AIDS” Hark, hark, the fictitious dogs do bark Both sides of the fence On our side of the fence The great cholesterol carousel

15 16 17 18

M.N.G. Dukes K.H. Kimbel L. Lasagna M.N.G. Dukes J.P. Griffin, P.F. D’Arcy I. Bayer E. Napke M.N.G. Dukes W.H.W. Inman S. Van Hauen M.N.G. Dukes M.C. Cone C. Medawar M.N.G. Dukes, E. Helsing P. Tyrer M.N.G. Dukes M.N.G. Dukes R.D. Mann

UK Denmark Denmark UK

19

A. Herxheimer

UK

20

E. Ernst

UK

21

H. Jick

USA

22

UK

24

J.K. Aronson, R.E. Ferner K.Y. HartiganGo, J.Q. Wong I. Palmlund

The nocebo effect—poorly known but getting stronger Good enough for Iganga? The mists of tomorrow Databases, privacy, and confidentiality—the effect of proposed legislation on pharmacoepidemiology and drug safety monitoring Side effects: freedom of information and the communication of doubt Complementary/alternative medicine: what should we do about it? Thirty years of the Boston Collaborative Drug Surveillance Program in relation to principles and methods of drug safety research Errors in prescribing, preparing, and giving medicines: definition, classification, and prevention Inclusion of therapeutic failures as adverse drug reactions

25 26 26 27 27

L. Marks D.J. Finney L.L. Iversen J.K. Aronson H. Jick

UK UK UK UK USA

1 2 3 4 5 6 7 8 9 10 11 12 13 14

23

Philippines UK

Secrecy hiding harm: case histories from the past that inform the future The pill: untangling the adverse effects of a drug From thalidomide to pharmacovigilance: a personal account How safe is cannabis? Louis Lewin—Meyler’s predecessor The General Practice Research Database

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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 2002. During the production of this Annual, some more recent papers have also been included; older literature has also been cited when it is relevant. 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. Some confirmatory reports are also described. 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 the Special Reviews that were published in SEDA-14 to SEDA-27 and a list of the Special Reviews that appear 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 is 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 or as a combination product. DRUG NAMES Drugs are usually called by their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a fixed combina-

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How to use this book

tion 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. SYSTEM OF REFERENCES References in the text are tagged using the following system, which was introduced in SEDA-24: 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 1–27 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 ESSAY

Classifying adverse drug reactions in the 21st century Jeffrey K. Aronson 1. Introduction Any good classification system should begin by considering the components of the system that needs to be classified. An adverse drug reaction has the following components: 1. A drug. 2. A patient. 3. Drug + patient → adverse reaction. The next step is to consider what features of these components best define them: 1. The dose of the drug determines its effects. 2. The susceptibility of the patient to the effects of the drug determines whether the individual suffers the adverse reaction. 3. The time-course of the adverse reaction describes how it occurs. This is illustrated in Figure 1. This approach yields the system of classification of adverse drug reactions called DoTS, based on Dose, Time-course, and Susceptibility (1).

Fig. 1. The components of an adverse effect whose characteristics lead to the DoTS classification.

2. Dose-relatedness of adverse drug reactions The earliest attempts to classify adverse drug reactions were based on their dose-relatedness, and it was generally hypothesized that some reactions were dose-related and predictable and that some were not (2–12) (Table 1). However, it is a pharmacological tenet that everything is related to dose via the dose–response curve, or more accurately to concentration via the concentration–effect curve. This applies even to effects that are produced by immunological actions, which are often mistakenly regarded as being non-dose-related. Examples of doserelated immunological reactions include hay fever in response to pollen (13); the immunogenic response to hepatitis B vaccine (14); desensitization by the use of increasing doses of antigen (for example, cephalosporins) (15); and type IV hypersensitivity skin reactions (16). This suggests that rather than classifying adverse drug reactions as being either dose-related or non-dose-related it would be more logical to classify them according to the relative positions of the dose–response curve for harm (the adverse reaction) and the dose–response curve for benefit. There are three cases. 1. Hypersusceptibility reactions. Here the dose– response curve for harm is far to the left of the dose–response curve for benefit; hypersusceptibility adverse reactions therefore occur at doses below those that are normally beneficial (Figure 2a). Penicillin allergy is an example. 2. Collateral reactions. Here the dose–response curve for harm is in a region that is bounded by a curve that is just to the left of the dose–response curve for benefit and one that

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Jeffrey K. Aronson Table 1. Classifications of adverse drug reactions based on dose-relatedness and time-course

Authors Haber, 1924 (2)

Dose-related classification

Time-related classification

Haber’s Law: the severity of a reaction is a function of concentration and the duration of exposure

Wayne, 1958 (3)

Distinguishes predictable and unpredictable effects

Lasagna, 1964 (4)

Distinguishes predictable and unpredictable effects

Levine, 1973 (5)

Distinguishes dose-related and nondose-related reactions

Distinguishes acute, subacute, and chronic toxic reactions

Wade and Beeley, 1976 (6)

Distinguish dose-related and non-doserelated effects

Distinguish long-term and teratogenic effects

Rawlins and Thompson, 1977 (7)

Distinguish dose-related and non-doserelated effects (types A and B)

Grahame-Smith and Aronson, 1984 (8)

Classify types A and B as dose-related and non-dose-related reactions

Add two time-related categories: longterm and delayed

Hoigné et al., 1990 (9)

Distinguish acute, subacute, and latent allergic reactions

Park et al., 1992 (10)

Label Grahame-Smith & Aronson’s categories types C (long-term) and D (delayed)

Laurence and Bennett, 1992 (11)

Split type C into two types, type C (continuous) and type E (end of use)

Ferner and Mann, 1997 (12)

Distinguish five patterns of time course

Aronson and Ferner, 2003 (1)

Distinguish three types of dose related adverse reactions: hypersusceptibility reactions, collateral reactions, toxic reactions

is just to the right; collateral adverse reactions therefore occur at doses within the range of those that are normally beneficial (Figure 2b). They can occur (i) through a pharmacological effect that is distinct from that involved in the beneficial effect (for example an anticholinergic effect of a tricyclic antidepressant) or (ii) through the same pharmacological effect as that associated with the beneficial effect, but in a different tissue (for example colour vision disturbance due to sildenafil). 3. Toxic reactions. Here the harm occurs through the same mechanism as benefit (i.e. is on the same dose–response curve) but at doses that are above those that are normally beneficial (Figure 2c). An example is bleeding due to warfarin. [Sometimes a toxic reaction occurs through some other pharmacological effect at a very high concentration, i.e. when the curve for harm is far to the right

Distinguish time-dependent and timeindependent reactions

of the curve for benefit; however, that can be regarded as a toxicological reaction that will occur only in overdose.] Finally, the dose-relatedness of an adverse reaction will also be affected by the relative shapes of the dose–response curves for benefit and harm, specifically their steepness and maximal efficacy; however, each reaction will be some variant of one of these three types.

3. Time-courses of adverse drug reactions Adverse drug reactions can be either timedependent or time-independent. 3.1. TIME-INDEPENDENT ADVERSE DRUG REACTIONS Time-independent reactions are generally toxic reactions and they occur when the actual con-

Classifying adverse drug reactions in the 21st century

xxix

(a)

(b)

(c) Fig. 2. Dose-relatedness of adverse drug reactions. (a) Hypersusceptibility reactions; (b) collateral reactions; (c) toxic reactions.

xxx

Jeffrey K. Aronson Table 2. Time-related classification of adverse drug reactions

Type of reaction

Example(s)

Time independent Due to a change in dose or concentration (pharmaceutical effects)

Toxicity due to increased systemic availability

Due to a change in dose or concentration (pharmacokinetic effects)

Digitalis toxicity due to renal insufficiency

Occurs without a change in dose or concentration (pharmacodynamic effects)

Digitalis toxicity due to hypokalemia

Time dependent Rapid (due to rapid administration)

Red man syndrome (vancomycin) Hypertension (digitalis) Hypotension (iodipamide)

First dose [of a course]

Hypotension (α1 adrenoceptor antagonists and angiotensin converting enzyme inhibitors) Type I hypersensitivity reactions

Early (abates with repeated exposure)

Adverse reactions that involve tolerance (for example nitrateinduced headache)

Intermediate (risk maximum during the first few weeks or months)

Venous thromboembolism (antipsychotic drugs)

Late (risk increases with time)

Osteoporosis (glucocorticoids) Tardive dyskinesia (dopamine receptor antagonists) Retinopathy (chloroquine) Tissue phospholipid deposition (amiodarone) Withdrawal syndromes: opiates, benzodiazepines, hypertension (clonidine and methyldopa), myocardial infarction (betablockers)

Delayed

Carcinogenesis (ciclosporin, diethylstilbestrol) Teratogenesis (thalidomide)

Hypersensitivity reactions types II, III, and IV

There are six types of time-dependent reactions. Examples of each of these types are given in Table 2.

• First-dose reactions occur only after the first dose of a course. • Early reactions occur soon after the first administration but wear off with time (i.e. are subject to tolerance). • Intermediate reactions occur within the first few weeks or months of administration but not thereafter; those who are susceptible will suffer the reaction and those who are not will not (healthy survivors). • Late reactions occur late in the course of administration, the risk increasing with time; this group includes withdrawal reactions. • Delayed reactions are seen at some distant time after the initial exposure, even if the drug is withdrawn before the reaction appears.

• Rapid reactions occur when a drug is given too quickly.

We do not currently know what proportions of all adverse reactions fall into these differ-

centration of the drug increases or the effective concentration falls, for whatever reason. An example is digoxin toxicity, which can occur for pharmaceutical reasons (for example administration of the wrong tablets), pharmacokinetic reasons (for example renal insufficiency), or pharmacodynamic reasons (for example hypokalemia). In the first two cases the concentration at the site of action increases and in the last the dose–response curve is shifted to the left. 3.2. TIME-DEPENDENT ADVERSE DRUG REACTIONS

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Classifying adverse drug reactions in the 21st century Table 3. Sources of altered susceptibility to adverse drug reactions Source of susceptibility (mnemonic GASPED)

Examples

Genetic

Porphyria Suxamethonium sensitivity Malignant hyperthermia CYP isozyme polymorphisms

Age

Neonates, for example chloramphenicol Elderly people, for example hypnotics

Sex

Alcohol intoxication Mefloquine, neuropsychiatric effects Angiotensin converting enzyme inhibitors, cough Lupus-like syndrome

Physiology altered

Phenytoin in pregnancy

Exogenous factors

Drug interactions Interactions with food, for example grapefruit juice with drugs cleared by CYP3A4

Disease

Renal insufficiency, for example lithium Hepatic cirrhosis, for example morphine

ent categories, although it is my impression that most time-dependent reactions are of the intermediate type.

More than one susceptibility factor can be present in an individual.

4. Susceptibility factors in adverse drug reactions

5. Examples of the DoTS classification in the Side Effects of Drugs Annuals

The risk of an adverse drug reaction differs among members of an exposed population. For some reactions some individuals are susceptible, others are not—for example hemolysis due to oxidizing agents in people with glucose-6phosphate dehydrogenase (G6PD) deficiency. In other cases susceptibility follows a continuous distribution—for example, increasing susceptibility with increasing impairment of renal function. Although reasons for hypersusceptibility may be unknown, several types are recognized (Table 3). These include: • • • •

genetic variation; age; sex; physiological variation (for example pregnancy, body weight); • exogenous factors (for example drugs and food); • diseases (for example renal or hepatic impairment).

A few examples of the DoTS system can be found in this volume of the Side Effects of Drugs Annual: • diabetes mellitus due to antipsychotic drugs (Chapter 6); • visual field loss from vigabatrin (Chapter 7) • sleep attacks from dopamine receptor agonists (Chapter 13) • osteoporosis from glucocorticoids (Chapter 16) • renal damage from gadolinium salts (Chapter 46). I hope that in future volumes it will be possible to classify more adverse reactions in this way.

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6. Uses of the DoTS classification The DoTS classification should provide important insights for drug development and regulation, for pharmacovigilance, for monitoring patients, and for the prevention, diagnosis, and treatment of adverse drug reactions. Here I shall give just one example of its potential application—in drug regulation. Drugs are often removed from the market after initial licensing, because of adverse reactions. However, not all individuals are necessarily susceptible to the adverse reaction of a drug, and those who have benefited from it may legitimately demand that the drug should be made available for them. For example, in the UK in 2004, products containing kava kava were removed from the market because of worldwide reports of liver damage in a relatively small number of patients. A group of users challenged this ruling in the High Court. They claimed that kava was no more likely to cause liver damage than diazepam, that those who did develop liver damage had identifiable susceptibility factors, and that those who wanted to continue using it had benefited from it for several years. An outright ban, they claimed, was unnecessary— a change in the labelling would have been sufficient. However, their petition was rejected (17). The DoTS classification helps us analyse this type of problem. Let us just consider susceptibility. There are three possible scenarios: 1. the nature of the susceptibility to the adverse reaction is identifiable; 2. the nature of the susceptibility to the adverse reaction is not identifiable but the adverse effect can be monitored; 3. the nature of the susceptibility to the adverse reaction is not identifiable and the adverse effect cannot be monitored. 6.1. SUSCEPTIBILITY IDENTIFIABLE If the nature of the susceptibility to the adverse reaction is identifiable, a suitable regulatory strategy would be to restrict the use of the drug to those without the susceptibility. An example of this is the recent reintroduction of thalidomide for the treatment of erythema nodosum leprosum (18). A system known as STEPS (System for Thalidomide Education and Prescribing Safety) has been instituted to

Jeffrey K. Aronson

ensure that the drug is not given to the susceptible population, women of child-bearing age (19). 6.2. SUSCEPTIBILITY NOT IDENTIFIABLE BUT ADVERSE EFFECT CAN BE MONITORED Even if the nature of the susceptibility to the adverse reaction is not identifiable, if it can be monitored a regulatory strategy is available that would allow the drug to continue to be used. In such a case careful monitoring would allow the drug to be withdrawn at the first sign of the adverse effect. An example of this is the reintroduction of clozapine for the treatment of schizophrenia in conjunction with a monitoring scheme, after it had been found to cause agranulocytosis (20). An extra consideration in this case is that the adverse effect is most likely in the first 24 weeks of treatment, i.e. it is of an intermediate time-course; this implies that monitoring should be intense during the period of maximum likelihood, after which vigilance can be relaxed. 6.3. SUSCEPTIBILITY NOT IDENTIFIABLE AND ADVERSE EFFECT CANNOT BE MONITORED In such a case, if the benefit to harm balance is considered to be unfavorable the drug should be withdrawn. However, there may be an argument for allowing such a drug to continue to be marketed, albeit with restrictions. For example, the FDA withdrew the licence for alosetron after it had been discovered to cause ischemic colitis. However, patients with irritable bowel syndrome who felt that they had benefited from the drug complained, and the drug was again made available, on the understanding that the patients who wanted to use it took the risk themselves (21). The criteria for prescription of alosetron in the USA are (22): • the patient is a woman; • she has severe diarrhea-predominant irritable bowel syndrome, with continuous symptoms lasting more than 6 months; • other treatments have failed; • there are no contraindications to alosetron, particularly certain structural diseases of the gut; • the prescriber registers with the manufacturer to give the drug;

Classifying adverse drug reactions in the 21st century

• the prescriber educates the patient about the drug and she signs a patient-physician agreement. These scenarios illustrate how a consideration of susceptibility factors in adverse drug

xxxiii reactions can guide regulatory decision making. Adding in considerations of dose-relatedness and the time-course of the reaction can give added guidance.

REFERENCES 1. Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. Br Med J 2003; 327: 1222–5. 2. Haber F. Zur Geschichte des Gaskrieges. In: Fuenf Vortaege aus den Jahren 1920–1923. Berlin: Springer, 1924: 76–94. 3. Wayne EJ. Problems of toxicity in clinical medicine. In: Walpole AL, Spinks A, editors. The Evaluation of Drug Toxicity. London: Churchill, 1958: 1–11. 4. Lasagna L. The diseases drugs cause. Perspect Biol Med 1964; 19: 457–70. 5. Levine RR. Factors modifying the effects of drugs in individuals. In: Pharmacology. Drug Actions and Reactions. Boston: Little, Brown, 1973: 261–91. 6. Wade OL, Beeley L. Adverse Reactions to Drugs. 2nd edition. London: William Heinemann, 1976. 7. Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, editor. Textbook of Adverse Drug Reactions. Oxford: Oxford University Press, 1977: 10. 8. Grahame-Smith DG, Aronson JK. Adverse drug reactions. In: Oxford Textbook of Clinical Pharmacology and Drug Therapy. Oxford: Oxford University Press, 1984: 132–57. 9. Hoigné R, Jaeger MD, Wymann R, Egli A, Muller U, Hess T, Galeazzi R, Maibach R, Kunzi UP. Time pattern of allergic reactions to drugs. Agents Actions Suppl 1990; 29: 39–58. 10. Park BK, Pirmohamed M, Kitteringham NR. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol 1992; 34: 377–95. 11. Laurence DR, Bennett PN. Clinical Pharmacology. Edinburgh: Churchill Livingstone 1992: 121– 2.

12. Ferner R, Mann RD. Drug safety and pharmacovigilance. In: Page C, Curtis MJ, Sutter MC, Walker MJA, Hoffman BB, editors. Integrated Pharmacology. 1st edition. London: Mosby, 1997: 83–90. 13. Frenz DA. Interpreting atmospheric pollen counts for use in clinical allergy: allergic symptomology. Ann Allergy Asthma Immunol 2001; 86: 150–7. 14. Troisi CL, Heiberg DA, Hollinger FB. Normal immune response to hepatitis B vaccine in patients with Down’s syndrome. A basis for immunization guidelines. J Am Med Assoc 1985; 254: 3196–9. 15. Kelkar PS, Li JT. Cephalosporin allergy. New Engl J Med 2001; 345: 804–9. 16. Friedmann PS, Moss C, Shuster S, Simpson JM. Quantitative relationships between sensitising dose of DNCB and reactivity in normal subjects. Clin Exp Immunol 1983; 53: 709–15. 17. Bale J. Kava calm hits a storm. http://www. timesonline.co.uk/article/0„8125-956510,00.html. 18. Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 1996; 35: 969–79. 19. Pharmion. Programmes for Patients Taking Thalidomide. http://www.pharmion.com/ corporateweb/home.nsf/Content/ ProgrammesForPatientsTakingThalidomide. 20. Bastani B, Alphs LD, Meltzer HY. Development of the Clozaril Patient Management System. Psychopharmacology (Berl) 1989; 99 Suppl: S122– 5. 21. Traynor K. Alosetron use drops dramatically with risk management. Am J Health Syst Pharm 2004; 61: 1210–12. 22. Shen B, Soffer EE. Use of alosetron is limited because of its adverse effects. Cleveland Clin J Med 2003; 70: 64–5.

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Central nervous system stimulants and drugs that suppress appetite

METHYLXANTHINES

(SED-14, 1; SEDA-25, 1; SEDA-26, 1; SEDA-27, 1)

Caffeine Nervous system Caffeine has been reported to worsen seizures. • A 49-year-old man with a 36-year history of mixed seizure disorder, well controlled with phenytoin and primidone, developed a sharp increase in seizure frequency attributed to the consumption of caffeinated beverages (1A ). Anticonvulsant drug compliance had been maintained with blood concentrations in the target ranges, there had been no changes in sleep or stress, and no concurrent illness or medications. Self-rechallenge with caffeinated beverage was associated with increased seizure frequency.

The authors emphasized the need for taking a careful dietary history. Neuromuscular Susceptibility to malignant hyperthermia is diagnosed by the in vitro halothane-caffeine contracture test (2S ). 31 Phosphorus magnetic resonance spectroscopy has also been described for evaluating the metabolic abnormality in the skeletal muscle in malignant hyperthermia (3c ). The basal balance of energyrelated phosphates in skeletal muscle was similar in both susceptible subjects (n = 10) and non-susceptible subjects (n = 7). However, intramuscular injection of caffeine impaired this balance (4c ). This non-invasive study has confirmed that the pathophysiological defect in malignant hyperthermia is uncontrolled calcium release from the sarcoplasmic reticulum, due to a mutation in ryanodine receptors. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

Pregnancy In a population-based case-control study a high caffeine intake during pregnancy was a risk factor for fetal growth retardation (5C ). Caffeine intake among mothers of smallfor-gestational-age infants (56 boys, 56 girls) was compared with intake among 747 mothers of normal infants (368 boys, 379 girls). Food records for 3 days were obtained in the second and third trimesters, and caffeine intake from coffee, tea, soft drinks, and chocolate was estimated and classified as low or high. Mothers of small-for-dates infants had a significantly higher mean intake of caffeine in the third trimester than the mothers of the normal infants; the risk of being small for dates was nearly double if the mother had a high caffeine intake in the third trimester (OR = 1.8; 95% CI = 1.2, 2.5). The increased risk was in boys (OR = 2.8; 95% CI = 1.5, 5.2) and not in girls (OR = 1.2; 95% CI = 0.7, 2.1). The increased risk in boys persisted after adjustment for cigarette smoking alone, or for smoking and various other risk factors combined. The authors proposed a cause-and-effect relation between high caffeine intake in the third trimester of pregnancy and the risk of being small-for-dates, in particular if the fetus was male, based on a dose–effect relation. These findings are consistent with the results of two meta-analyses (6M , 7M ). Slow metabolism of caffeine during pregnancy and the absence of several enzyme systems involved in caffeine metabolism in the fetus may play an important role (8E ). Nevertheless, the reason for the differential effect of caffeine intake on the growth of male and female fetuses is uncertain. Earlier conclusions that caffeine consumption over 300 mg/day during pregnancy approximately doubles the risk of miscarriage (9C – 11C ) have been supported by the results of a recent study (12C ).

1

2 The policy implications of these results are that pregnant women may be able to lower their risk of miscarriage by reducing coffee intake during early pregnancy. Drug interactions Hormone replacement therapy A protective effect of caffeine against the onset of Parkinson’s disease may be reversed in women who use hormone replacement therapy (HRT). The effects of HRT and caffeine have been estimated in an analysis of the records of over 77 000 women who had been followed up for 18 years as part of the US Nurses Health Study (13C ). Overall, the risk of Parkinson’s disease was similar in women who had used postmenopausal HRT and those who had never done so. However, the use of HRT reduced the risk of the disease in women with a low caffeine consumption (RR = 0.39; 95% CI = 0.13, 1.17). High caffeine consumption and HRT increased the risk of Parkinson’s disease (RR = 2.4; CI = 0.75, 7.86). Women who used HRT and who drank six or more cups of coffee per day were four times more likely to develop Parkinson’s disease. Caffeine metabolism is markedly inhibited by estrogens (14c ). Menthol In a randomized, double-blind, placebo-controlled, two-way crossover study in 11 healthy women, the kinetics and effects of a single oral dose of caffeine 200 mg in coffee taken together with a single oral dose of menthol 100 mg resulted in significant increase in caffeine tmax and a non-significant reduction in Cmax , and no effect on tlag . These finding suggest that menthol slows the rate of caffeine absorption (15c ).

Theophylline Nervous system The incidence rate of convulsions in a large Japanese pediatric population was 0.24% (127/54 066) in asthmatic patients taking theophylline versus 0.36% (27/7568) in asthmatic patients not taking theophylline (16R ). The difference between these two groups was not significant. Of eight patients who developed convulsions related to theophylline, three were infants; the mean serum theophylline concentration at the time

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of the convulsion was 17 µg/ml and they were taking several other medications. The rate of recurrent convulsions after readministration of theophylline was higher in patients with epilepsy than in patients with febrile convulsions. Thus, the incidence of convulsions in children was not affected by the use of theophylline for asthma. Based on the low frequency of convulsions, the authors suggested that theophylline is safe, but that special care must be taken in infants under 1 year old, in children who have fever, during concomitant oral and rectal administration, and in children who are taking other medications, including macrolides and antihistamines.

STIMULANT DRUGS

(SED-14, 12; SEDA-25, 2; SEDA-26, 3; SEDA-27, 1)

Cocaine Patients with brain death due to acute intoxication of drugs, including cocaine, can be organ donors. Satisfactory outcomes of graft functions were achieved in orthotopic liver transplants (17c , 18c ), kidney transplants (18c ), and lung transplants (19c ). The use of grafts from donors with brain death due to cocaine overdosage may be a valid option to expand the donor pool and help maximize the availability of scarce donor organs. Cardiovascular As cocaine use has become more widespread, the number of cocaine-related cardiovascular events has increased (20R ). During the hour after cocaine is used, the risk of myocardial infarction is 24 times the baseline risk (21C ). Cocaine users have a lifetime risk of non-fatal myocardial infarction that is seven times the risk in non-users, and cocaine use accounts for up to 25% of cases of acute myocardial infarction in patients aged 18–45 years (22C ). In 2000, there were 175 000 cocainerelated visits to emergency departments in the USA (23S ), with chest discomfort in 40% of the patients (24c ), 57% of whom were admitted to the hospital and had an admission lasting an average of 3 days (25c ), involving huge costs (26c ). Based on a retrospective study of 344 patients with cocaine-associated chest pain, it has

Central nervous system stimulants and drugs that suppress appetite

been suggested that patients who do not have evidence of ischemia or cardiovascular complications over 9–12 hours in a chest-pain observation unit have a very low risk of death or myocardial infarction during the 30 days after discharge (27c ). Nevertheless, patients with cocaine-associated chest pain should be evaluated for potential acute coronary syndromes; those who do not have recurrent symptoms, increased concentrations of markers of myocardial necrosis, or dysrhythmias can be safely discharged after 9–12 hours of observation. A protocol of this sort should incorporate strategies for treating substance abuse, since there is an increased likelihood of non-fatal myocardial infarction in patients who continue to use cocaine. In a randomized, controlled trial in 36 patients with cocaine-associated chest pain, the early use of lorazepam together with glyceryl trinitrate was more efficacious than glyceryl trinitrate alone in relieving the chest pain (28C ). These findings contrast with those of an earlier study in which there was no evidence of additional benefit from diazepam in managing cocaine-related chest pain (29C ). However, the Advanced Cardiovascular Life Support (ACLS) guidelines state that in cocaine-associated acute coronary syndromes a nitrate should be firstline therapy together with a benzodiazepine (30S ). Ear, nose, and throat Most surgeons in the UK use local anesthesia with cocaine for nasal operations because of the superior operative field it provides and because they consider it to be safe, even with adrenaline. The incidence of adverse reactions to cocaine is reportedly low, and serious complications are less common than with general anesthesia. These conclusions were based on a postal survey of all British Associations of Otolaryngologists and Head and Neck Surgeons. Only 11% of surgeons had experienced cocaine toxicity in their patients, and there had been only one recorded death (31c ). Any sino-nasal inflammatory condition that involves the midline structures, that is characterized by symptoms such as nasal obstruction and crusting, and that persists or remains refractory to treatment may be the first manifestation of substance abuse, particularly of cocaine. From January 1991 to September 2001, 25 patients with cocaine-induced midline destructive lesions were observed at the Department of

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Otorhinolaryngology of the University of Brescia (32c ). There was septal perforation in all 25, and 16 also had partial destruction of the inferior turbinate. There was hard palate resorption in six patients and 14 were positive for antineutrophil cytoplasmic antibodies (ANCA). The need to consider substance abuse in the differential diagnosis of destructive lesions of the nasal cavity, even in the presence of antineutrophilic cytoplasmic antibodies, has been emphasized. There was constant progression of the ulceronecrotic process in 17 patients, and in three patients who stopped cocaine use the mucosa slowly normalized. Management consisted of periodic debridement of necrotic tissue and crusts, local and systemic antimicrobial drug therapy based on culture results, the use of saline douches for moistening the nasal mucosa, and surgical correction in severe cases. Nervous system Analysis of intracranial hematomas for detecting drugs with short halflives in individuals who survive several hours after intracranial bleeding has been recommended for establishing the cause of death. Cocaine metabolites were found in an intracerebral hematoma in a patient who apparently died due to cocaine (33c ). The hematoma contained ethanol 0.05% w/v and benzoylecgonine 0.43 mg/l. A presynaptic protein, α-synuclein, which has been implicated as a possible causative agent in the pathogenesis of Parkinson’s disease, was raised in midbrain dopamine neurons in post-mortem brains of chronic cocaine abusers. Although the overexpression of αsynuclein may occur as a protective response to changes in dopamine turnover and increased oxidative stress resulting from cocaine abuse, the authors speculated that it may also put cocaine abusers at increased risk of the motor abnormalities of Parkinson’s disease (34rC ). The issue of cocaine-induced dopamine neurotoxicity has not been resolved (35c ). Sexual function Three patients developed priapism after taking cocaine or non-prescription weight loss formulations containing ephedrine (36A ). Intracavernous injection of phenylephrine and irrigation with heparinized saline, followed by an Al-Ghorab shunt procedure, was effective.

4 Pregnancy Considering the increased prevalence of recreational cocaine abuse among young women (37rc ), the diverse clinical manifestations of acute cocaine intake combined with physiological changes of pregnancy and the pathophysiology of co-existing pregnancyspecific diseases can result in life-threatening complications during anesthesia. When regional anesthesia is selected, combative behaviour, altered pain perception, and ephedrine-resistant hypotension can occur. Cardiac dysrhythmias, hypertension, and myocardial ischemia can occur during general anesthesia. Individualizing anesthesia management in patients presenting with diverse clinical manifestations of acute cocaine intake is important. • A 26-year-old woman with a history of multiple substance abuse required emergency caesarean section at 30 weeks of gestation as a result of crack cocaine-induced placental abruption and fetal distress (38c ). Her admission blood pressure was 145/95 mmHg, heart rate 95/minute and respiratory rate 20/minute. The fetal heart rate was 130/minute and non-reactive, with late and variable decelerations and no response to maternal oxygen administration. Spinal block with bupivacaine, fentanyl, and morphine was performed with the patient in a sitting position. No maternal or neonatal postoperative complications were reported.

Fetotoxicity Prenatal exposure to cocaine can alter the typical developmental trajectory of functional asymmetries. Twenty infants who were prenatally exposed to cocaine performed a grasping task with their right hand for significantly shorter durations and were less likely to show a dominant hand preference at 1 month of age (39c ). It is unclear from this study whether the absence of side biases in motor functions seen in cocaine-exposed, 1-month-old infants continues beyond the neonatal period. Considering how much plasticity there is in infants’ brains, any early nervous system disorganization or damage may not predict later outcomes. Therefore, the possibility that absence of motor asymmetries seen in these infants may reflect a transient effect of prenatal exposure to cocaine must be considered.

Amphetamines Cardiovascular The frequency of acute coronary syndrome in patients who developed chest

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pain after using metamfetamine has been described. In 33 patients (25 men, 8 women, mean age 40 years) metamfetamine abuse was confirmed by urine screening. Acute coronary syndrome was diagnosed in nine patients. Three patients (two of whom had acute coronary syndrome) had cardiac dysrhythmias. The authors concluded that acute coronary syndrome is common in patients with chest pain after metamfetamine use, and that the frequency of other potentially life-threatening cardiac complications is not negligible. A normal electrocardiogram reduces the likelihood of acute coronary syndrome, but an abnormal electrocardiogram is not helpful in distinguishing patients with or without acute coronary syndrome (40C ). These conclusions were based on a small population that included hospitalized patients, not all of whom underwent non-invasive cardiac stress testing or coronary angiography. Thus the generalizality of these findings is limited. • A 44-year-old female metamfetamine abuser died unexpectedly due to right-sided infective endocarditis (41c ). • A 27-year-old man who had used intravenous amfetamine had an acute myocardial infarction (42c ).

The authors suggested that coronary angiography with an ergometrine provocation test might be necessary in patients who use amfetamine and who develop acute coronary syndrome. Psychiatric Two young women with metamfetamine abstinence developed mania after taking fluvoxamine, which was prescribed for persistent depressive symptoms (43A ). Both had abused methamphetamine for several years. Two weeks after starting to take fluvoxamine 100 mg/day and brotizolam 0.5 mg/day they became manic, with elevated mood, talkativeness, and increased activity. When fluvoxamine was withdrawn the manic state gradually abated and they were discharged from hospital 3 months after admission. It is not known whether a manic switch in metamfetamine users with depression is specific to fluvoxamine, or can occur with other SSRIs. Once metamfetamine psychosis has developed, patients in remission are liable to spontaneous relapse without again consuming metamfetamine (44c ). It has been postulated that a sensitization phenomenon induced by repeated

Central nervous system stimulants and drugs that suppress appetite

consumption of metamfetamine develops in the brain in patients with metamfetamine psychosis and is the neural basis for increased susceptibility to relapse (45C ). Deficits in attention and motor skills persisted after 1 year of abstinence from stimulant abuse in 50 twin pairs in which only one member had heavy stimulant abuse with cocaine and/or amphetamines (46C ). Stimulant abusers performed significantly worse on tests of motor skills and attention, and significantly better on one test of visual vigilance. These findings provide evidence of long-term residual effects of stimulant abuse. Drug abuse There was a high frequency of amfetamine abuse and withdrawal among patients from the Thai–Myanmar border area admitted to hospital with Plasmodium falciparum malaria (47c ). This co-morbidity can cause diagnostic confusion, alter malaria pathophysiology, and lead to drug interactions. Considering the potential neuropsychiatric adverse effects of mefloquine, an important component of current antimalarial treatment in South-east Asia, it should be avoided in patients who abuse amphetamines. Drug dependence Metamfetamine dependence was associated with impairment across a range of neurocognitive domains in users whose abstinence was continually monitored with urine screening (48C ). The authors compared 27 metamfetamine-dependent individuals who achieved abstinence for 5–14 days and 18 control subjects and evaluated neurocognitive measures sensitive to psychomotor speed, measures of verbal learning and memory, and executive systems measures sensitive to fluency. The differential performance across the test and control groups was not attributable to demographic factors, estimated premorbid IQ, or self-reported depression. It is unlikely that the observed neurocognitive deficits resulted from residual symptoms of withdrawal, because symptoms of metamfetamine withdrawal resolved to minimal levels by the fifth day of abstinence (49C ). Moreover, metamfetaminedependent individuals had poor test performances even after 12 months of abstinence, suggesting that impairment observed during the early phase of abstinence was relatively stable (50c ). It is possible that neurocognitive impairment from amphetamines is associated with

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worse functional outcomes, including poorer vocational functioning during the rehabilitation program, thus undermining the effectiveness of psychosocial treatment for metamfetamine dependence. Fetotoxicity The effects of prenatal metamfetamine exposure on fetal growth and drug withdrawal symptoms in infants born at term have been described (51C ). In 294 mother–infant pairs of methamphetamine-exposed and nonexposed pairs, withdrawal symptoms requiring pharmacological intervention were observed in 4% of methamphetamine-exposed infants. There was growth restriction in methamphetamine-exposed infants and a confounding effect of nicotine. There was also growth restriction in infants who had been exposed to metamfetamine during all three trimesters of pregnancy. Since this study included only infants seen at term, the effect of metamfetamine on premature delivery was not addressed. Since toxicology screens were not conducted on control infants, it is possible that some of the neonates in the control group had also been exposed to drugs. Susceptibility factors Genetic A genetic explanation for individual differences in the response of the brain to amphetamines has been suggested. There are numerous proteins involved in regulating synaptic dopamine activity; catechol-O-methyl transferase, which inactivates released dopamine, appears to play a unique role in regulating dopamine flux in the prefrontal cortex because of the low abundance and minimal role of dopamine transporters (52c , 53E , 54E ). Neuroimaging and genetic analysis in 27 healthy volunteers showed that individuals with the met/met catechol-Omethyl transferase genotype were at risk of an adverse response (related to prefrontal cortex information processing) to amfetamine (55cE ). In populations of European ancestry, individuals with met/met genotypes constitute about 15–20% of the population (56C ). The hDAT1 gene (SLC6A3) encodes the human dopamine transporter. A possible genetic influence of hDAT1 gene variants on the development of metamfetamine dependence or psychosis has been investigated. Analysis of four exonic polymorphisms of the hDAT gene – 242 C/T (exon 2), 1342 A/G (exon 9), 2319 G/A (3 UTR of exon 15), and VNTR

6 (3 UTR of exon 15) – in 124 Japanese patients with metamfetamine dependence or psychosis showed that the presence of nine or fewer repeat alleles in the hDAT1 gene is a strong risk factor for a worse prognosis of metamfetamine psychosis (57C ). Drug interactions In 20 healthy adults who received a placebo, triazolam 0.25 mg/70 kg, amfetamine sulfate 20 mg/70 kg, and a combination of triazolam and amfetamine in a doubleblind, crossover study the results supported the conclusion that triazolam-induced impairment of free recall is related to its sedative effects, whereas recognition, memory, and recall differ with respect to the contribution of sedation to the amnesic effect of triazolam (58c ). Thus, benzodiazepines have specific effects on memory that are not merely a by-product of their sedative effects, and the degree to which sedative effects contribute to their amnesic effects can vary as a function of the particular memory process being assessed. It is important to note that the generalizability of the conclusions of this study is limited by use of a single dose design for both drugs.

Methylphenidate Methylphenidate was safe in children with attention deficit hyperkinetic disorder (ADHD) and concomitant active seizures or electroencephalographic abnormalities (59c ). Patients aged 6–16 years with ADHD and active seizures (n = 57) or with ADHD and electroencephalographic abnormalities (n = 62) were included in this open trial. Seizure frequency, changes in ADHD symptoms, electroencephalographic findings, drug-related adverse effects, and parent reports were used for evaluating safety and efficacy. The study lasted 12 months, and patients were re-evaluated every 3 months. The epileptic children received both antiepileptic drugs and methylphenidate (0.3–1.0 mg/kg/day), and antiepileptic drug dosages were kept constant throughout the study. The results suggested that methylphenidate is safe and effective in children with ADHD and active seizures or electroencephalographic abnormalities. Concomitant administration of methylphenidate and antiepileptic drugs improves attention without adverse effects on seizure threshold or

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electroencephalographic findings. There were adverse effects of methylphenidate in only 26 patients: loss of appetite (n = 23), difficulty in falling asleep (n = 19), stomach ache (n = 14), headache (n = 14), nausea (n = 11), and motor tics (n = 2); none required withdrawal. Since almost a third of children with epilepsy can have ADHD, and since it is commonly believed that methylphenidate lowers the seizure threshold, these findings have considerable significance and support the results of earlier studies (60C , 61c , 62R ). Drug overdose The trend of increasing frequency of methylphenidate exposure reported to poison centers exactly parallels its increasing therapeutic use (63R ). Based on an evaluation of data reported to the American Association of Poison Control Centers in 1993–9 there were 12 917 exposures in all, increasing from 927 in 1993 to 2445 in 1999. Most of these children had no adverse effects (60%) or only minor effects (29%), and there were no deaths. The most common reasons were suicide attempts in adolescents and unintentional or therapeutic errors in children under 13 years. Adolescents were more likely to experience clinical toxicity, hospitalization, and more serious outcomes. In 33 subjects with major outcomes, tachycardia and hypertension, agitation/irritability, coma, hallucinations, and seizures were the most common adverse effects.

DRUGS THAT SUPPRESS APPETITE (SEDA-25, 5; SEDA-26, 6; SEDA-27, 4) Cardiovascular Six years after the withdrawal of fenfluramine, aortic regurgitation remains highly prevalent among patients with end-stage Chinese herb nephropathy due to Aristolochia fangchi (64C ). In a case-control echocardiographic study of 40 women with end-stage renal insufficiency due to Chinese herb nephropathy and 37 age-matched controls with end-stage renal disease due to nephropathy of other origin, there was a significantly higher rate of aortic regurgitation (72% versus 22%). A history of appetite suppressant medication

Central nervous system stimulants and drugs that suppress appetite

was the only determinant of aortic regurgitation. Higher cumulative doses of Chinese herbs, fenfluramine, dexfenfluramine, and amfebutamone were observed in patients with Chinese herb nephropathy and valvular regurgitation. This study suggests that aortic regurgitation persists long after withdrawal of appetite suppressants, contrasting with some reports that this adverse effect can resolve over time. A long duration of treatment and the high doses of appetite suppressants, as well as metabolic disturbances associated with renal insufficiency, may have altered the potential for reversal of the valvular lesions.

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The similarity between the histopathological lesion documented in patients treated with appetite suppressants and the valvular diseases associated with ergot-related drugs suggests a common pathophysiological mechanism and a central role for serotonin in the development of the disease. Further support for this hypothesis has emerged from a report of two patients who took pergolide in doses of more than 5 mg/day and who developed symptomatic heart failure due to restrictive valvular disease (68A ). An earlier report described strikingly similar features of pergolide-induced valvular heart disease (69c ). Fibrotic valvular heart disease has also been described with another ergot derivative, bromocriptine (70c ).

Amfepramone (diethylpropion) Susceptibility factors Genetic Amfepramone can trigger primary pulmonary hypertension in carriers of a mutation in the bone morphogenetic protein receptor type II (BMPR2) gene, suggesting a genetic susceptibility to appetite suppressants (65C ). • A 27-year-old woman with a BMPR2 gene mutation developed pulmonary arterial hypertension after a short course of amfebutamone.

Among 34 patients who used fenfluramine derivatives, four with BMPR2 mutations developed primary pulmonary hypertension (66c ). The distinction between primary pulmonary hypertension and pulmonary arterial hypertension secondary to the use of appetite-suppressants blurs, and favors a general model integrating genetic and environmental factors in the pathogenesis of the disease. Molecular genetic counselling should be useful for preventing such adverse effects, which are genetically determined among close relatives.

Benfluorex Cardiovascular Valvular heart disease has been attributed to the anorectic agent benfluorex (67c ). • A 50-year-old woman who had been taking benfluorex intermittently for 1 year developed severe fibrosis and regurgitation of the mitral, aortic, and tricuspid valves. Clinical, echocardiographic, and histopathological findings were analogous to those reported with fenfluramines.

Nitrosofenfluramine Liver N-nitrosofenfluramine, a fenfluramine derivative, has been detected in a Chinese herbal slimming product, “Be Petite” (71E ), and hepatotoxicity has been attributed to it (72c , 73R ). • Hepatotoxicity resembling chronic hepatitis due to ingestion of “Be Petite” occurred in a 52-yearold Japanese woman (74c ). A liver biopsy showed chronic hepatitis with portal inflammation consisting of lymphocytes and plasma cells and fibrosis. After withdrawal the liver function tests returned to normal after 8 weeks.

Phenylpropanolamine Cardiovascular Phenylpropanolamine-induced myocardial injury has been reported in a young woman using the recommended dose for weight control (75c ). • A 25-year-old woman with a negative medical history developed severe retrosternal chest tightness of sudden onset lasting for 30 minutes after taking phenylpropanolamine 25 mg bd for 3 days. She had never smoked and had no family history of heart disease. The electrocardiogram and cardiac markers were consistent with a non-Q wave myocardial infarct. She was treated with aspirin, intravenous glyceryl trinitrate, oral diltiazem, and intravenous eptifibatide and made a rapid recovery.

8 The author reviewed other cases of phenylpropanolamine-induced myocardial injury, all in younger women. It is not known why women are especially susceptible to this adverse effect of phenylpropanolamine (76c ).

Sibutramine Acting on new post-marketing surveillance data, the French health authorities have restricted the initial prescribing of sibutramine to community or hospital specialists in endocrinology, cardiology, and internal medicine, whereas repeat prescriptions can be written by general practitioners, and the drug can be dispensed provided it was initially prescribed less than a year before (77S ). This is in contrast with a communication from the European Agency for the Evaluation of Medicinal Products, which considered that the benefit to harm balance of sibutramine is favorable in the treatment of obesity (78S ). However, some consider that it is best not to prescribe sibutramine at all (79r ). Comparative studies The effectiveness of sibutramine alone and in combination with ethinylestradiol + cyproterone acetate on clinical and metabolic parameters in obese women with polycystic ovary syndrome has been evaluated in a prospective, randomized, controlled trial in 40 patients (80c ). Group 1 (n = 14) was treated with oral ethinylestradiol + cyproterone acetate (35 + 2 mg/day), group 2 (n = 12) with oral sibutramine (10 mg/day), and group 3 (n = 14) with the combination, all for 6 months. All were advised to take a diet of 1200 kcal/day. The authors concluded that sibutramine produced beneficial effects on cosmetic, hormonal, metabolic, and cardiovascular risk parameters. The findings of this preliminary study need to be confirmed by double-blind trials in larger numbers of patients. Placebo-controlled studies In a randomized, double-blind, parallel placebo-controlled study of sibutramine 15 mg/day for 12 weeks in 79 obese patients with binge-eating disorder in Brazil, there was a significant reduction in the number of days on which binge episodes occurred with sibutramine, associated with significant weight loss of 7.4 kg (81C ). Sibutramine

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was also associated with a greater reduction in Binge Eating Scale and Beck Depression Inventory scores. Dry mouth and constipation were more common with sibutramine than placebo. The need for comprehensive psychiatric evaluation and the risk of drug interactions with other psychotropic drugs (82c ) are very important considerations before starting sibutramine in patients with co-morbid psychiatric disorders. In terms of binge eating reduction and overall response, the findings from this study are consistent with those from previous randomized, placebo-controlled studies of other drugs currently used in binge eating and related disorders. It will be important to observe what happens with weight and behavioral outcomes over a much longer period and after withdrawal of sibutramine. Skin An unusual complication of erythema multiforme-like bullous lesions due to sibutramine has been reported (83c ). • A 19-year-old, Chinese woman taking sibutramine developed a fever, erosive stomatitis, and erythematous cutaneous eruptions on her trunk and limbs after a third dose of sibutramine. She had erosions and crusting over her lips and ulcers in the buccal mucosa and soft palate. Laboratory investigations were consistent with a drug eruption. She was treated with oral prednisolone, and improved by the fourth day.

This is the first report of a patient with a severe bullous eruption related to sibutramine. Susceptibility factors Genetic Genotyping for the G-protein β3 subunit gene (GNB3) C825T is predictive for identification of obese individuals who benefit from sibutramine, according to the authors of a study that included genotyping of 111 Caucasian subjects in a randomized, placebo-controlled trial (84CS ). The association of weight loss with GNB3 genotype was strong, suggesting a significant role of the gene in the regulation of body weight. It would be interesting to see whether the cardiovascular adverse effects of sibutramine are also related to genotypes of the GNB3 C82T polymorphism. Drug interactions Sibutramine is metabolized by CYP3A4 in the liver, generating two pharmacologically active metabolites (85C , 86R ); of these, N-di-desmethylsibutramine is considered to be a major metabolite (87E ).

Central nervous system stimulants and drugs that suppress appetite

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• An obese patient taking ciclosporin, azathioprine, prednisolone, and amlodipine after renal transplantation developed a significant increase in ciclosporin serum concentration after taking sibutramine 10 mg/day (88c ). After 1 week, the trough ciclosporin serum concentration increased from 79 to 152 µg/ml, requiring a 25% reduction in the daily dose.

Drug withdrawal In two patients taking donepezil, withdrawal symptoms developed (98c ). The symptoms, severe agitation, difficulty in concentrating and sleeping, and rapid mood changes, typically developed 5–6 days after withdrawal of donepezil and disappeared by around days 9–10.

The authors proposed a competitive interaction between sibutramine and ciclosporin for CYP3A4.

Drug interactions Maprotiline Neuroleptic malignant syndrome has been attributed to a combination of donepezil plus maprotiline.

DRUGS USED IN ALZHEIMER’S DISEASE (SED-14, 435; SEDA-25, 7;

• Concomitant treatment with donepezil and maprotiline in a 73-year-old patient with Alzheimer’s disease and stroke produced a syndrome resembling the neuroleptic malignant syndrome (99c ). The patient responded to withdrawal of maprotiline and donepezil and intravenous fluids, and did not require dantrolene.

SEDA-26, 7; SEDA-27, 7) The intensity of interest in therapies for Alzheimer’s disease has increased with each passing year (89R –91R ). A long-term comparison of galantamine and donepezil has shown that galantamine may have advantages in improving cognition and reducing the care-giver burden (92c ). In 20 patients with Alzheimer’s disease, SPET scanning showed that the response to donepezil is greater in patients with evidence of a more marked cholinesterase deficit (93c ).

Donepezil In an open study patients with Alzheimer’s disease and psychotic symptoms benefited from the addition of donepezil to neuroleptic drugs (94c ). Cardiovascular Soon after the start of donepezil treatment three patients with Alzheimer’s disease developed cardiac syncope (95A ). In two cases, a bradydysrhythmia was documented and pacemaker implantation was considered justified rather than donepezil withdrawal. Exaggeration of hypotension during donepezil treatment, due to interference with autonomic control, has been described (96c ). Nervous system Increased rates of hypnotic drug use among patients taking donepezil has been linked to sleep problems (97c ).

Since the patient had been taking maprotiline for almost 2 months before this episode, the authors suggested that both these drugs may cause an imbalance in acetylcholine/dopamine in the striatum. Neuromuscular blocking drugs The potential for interactions between donepezil and neuromuscular blocking agents has major implications for the anesthetic care of people taking donepezil (100r , 101r , 102). Prolonged paralysis resulting from an interaction of donepezil with suxamethonium has been reported (103c , 104c ). Risperidone An open comparison of donepezil and risperidone, alone or in combination, in 24 healthy men showed no significant pharmacokinetic differences (105c ). Adverse events such as headache, nervousness, and somnolence were minor and comparable in all groups. These results suggest that no clinically significant interactions occur between risperidone and donepezil at steady state. However, whether these conclusions can be extrapolated to the elderly patients with dementia, who may eliminate both donepezil and risperidone slowly, is uncertain. Monitoring therapy P300 , one of the cognitive event-related potentials of the cerebral cortex may serve as a marker for measuring the course of Alzheimer’s disease during treatment with donepezil. There was reduced

10 P300 latency associated with parallel improvement of ADAS-J Cog scores after administration of donepezil 5 mg/kg in 13 patients with

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Alzheimer’s disease (8 women and 5 men, aged 70–88 year) (106c ).

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symptoms in patients with dementia of the Alzheimer’s type. Clin Neuropharmacol 2003; 26: 88–92. 95. Bordier P, Garrigue S, Barold SS, Bressolles N, Lanusse S, Clementy J. Significance of syncope in patients with Alzheimer’s disease treated with cholinesterase inhibitors. Europace 2003; 5: 429– 31. 96. McLaren AT, Allen J, Murray A, Ballard CG, Kenny RA. Cardiovascular effects of donepezil in patients with dementia. Dement Geriatr Cogn Disord 2003; 15: 183–8. 97. Stahl SM, Markowitz JS, Gutterman EM, Papadopoulos G. Co-use of donepezil and hypnotics among Alzheimer’s disease patients living in the community. J Clin Psychiatry 2003; 64: 466–72. 98. Singh S, Dudley C. Discontinuation syndrome following donepezil cessation. Intl J Geriat Psychiatry 2003; 18: 282–4. 99. Ohkoshi N, Satoh D, Nishi M, Shoji S. Neuroleptic malignant-like syndrome due to donepezil and maprotiline. Neurology 2003; 60: 1051. 100. Heath ML. Donepezil, Alzheimer’s disease and suxamethonium. Anaesthesia 1997; 52: 1018. 101. Heath ML. Donepezil and succinylcholine. Anaesthesia 2003; 58: 202. 102. Walker C, Perks D. Do you know about donepezil and succinylcholine? Anaesthesia 2002; 57: 1041. 103. Crowe S, Collins L. Suxamethonium and donepezil: a cause of prolonged paralysis. Anaesthesiology 2003; 98: 574–5. 104. Morillo S, Ferrari DA, Lopez RTA. Interaction of donepezil and muscular blockers in Alzheimer’s disease. Rev Esp Anestesiol Reanim 2003; 50: 97– 100. 105. Zao Q, Xie C, Pesco-Koplowitz L, Jia X, Parier J-L. Pharmacokinetic and safety assessment of concurrent administration of risperidone and donepezil. J Clin Pharmacol 2003; 43: 180–6. 106. Katsada E, Sato K, Sawaki A, Dohi Y, Ueda R, Ojika K. Long term effects of donepezil on P300 auditory event-related potentials in patients with Alzheimer’s disease. J Geriat Psychiatry Neurol 2003, 16: 39–43.

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2

Antidepressant drugs

GENERAL Sexual function Most classes of antidepressant drugs are associated with sexual dysfunction of various kinds, including reduced desire and arousal, erectile difficulties, and ejaculatory and orgasmic inhibition. A literature review has shown that rates of sexual dysfunction of all kinds were highest with selective serotonin re-uptake inhibitors (SSRIs) and venlafaxine and least with amfebutamone (bupropion) and the reversible inhibitor of monoamine oxidase type A, moclobemide (1R ). Switching to amfebutamone or mirtazapine from SSRIs often enabled patients to obtain relief from sexual dysfunction. However, commonly recommended antidotes to SSRI-induced sexual dysfunction, such as Ginkgo biloba, serotonin (5-HT2 ) receptor antagonists, such as cyproheptadine, and amfebutamone augmentation were not supported by placebo-controlled trials. These data suggest that antidepressant-induced sexual dysfunction is more likely to be associated with agents that greatly potentiate 5-HT neurotransmission. This notion is supported by the results of a 6-week double-blind study of 24 men with premature ejaculation, in which paroxetine (20 mg/day) increased latency to ejaculation six-fold while mirtazapine (30 mg/day) had minimal effect (2C ). In a randomized, 8-week, double-blind, placebocontrolled study in 450 patients with major depression, fluoxetine (20–40 mg/day) significantly impaired sexual function, while the noradrenaline re-uptake inhibitor reboxetine had no effect (3C ). In a double-blind, placebo-controlled study in 90 patients with sexual dysfunction who were taking a variety of 5-HT re-uptake inhibitor antidepressants, sildenafil (50–100 mg) © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

14

produced improvement in all aspects of the sexual response in 54% of antidepressant-treated patients compared with a placebo response rate of 4.4% (NNT = 2) (4C ). This suggests that sildenafil is an effective treatment for antidepressant-induced sexual dysfunction. Tumorigenicity Studies in rats have suggested that both tricyclic antidepressants and selective serotonin re-uptake inhibitors (SSRIs) promote the growth of mammary tumors. Rates of antidepressant prescribing have increased over the last 20 years, and breast cancer remains a leading cause of mortality in women. Two recent non-systematic reviews (5R , 6M ) have examined the question of whether antidepressant treatment might increase the risk of breast cancer. A variety of studies have been conducted, including hospital- and population-based casecontrol studies and prospective cohort studies. Overall the evidence for an association between any use of antidepressant medication and breast cancer is weak and inconclusive. However, it is possible that sustained use of certain drugs, for example, the SSRI paroxetine, might be associated with an increased risk. Problems with the studies reviewed include defining what kind of antidepressant treatment regimen represents significant exposure, and the unknown nature of the time-course of any effect of antidepressants on the development of breast cancer. The increasing use of SSRIs, which are known to be associated with breast enlargement (SEDA-22, 12), suggests that further prospective studies are needed.

Overdose with antidepressant drugs Suicidal ideation of some kind almost invariably accompanies severe depression. Hence the relative toxicity of antidepressants in overdose can be important in determining treatment

Antidepressant drugs

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choice. It is accepted that SSRIs are less dangerous in overdose than tricyclic antidepressants, but there are fewer data on the toxicity of other antidepressants. The presentation and likely toxicity in overdose of several newer antidepressant drugs have been reviewed (7R ). Deaths in overdose have been most clearly associated with amfebutamone and venlafaxine. Amfebutamone overdose typically presents with neurological symptoms, including delirium, agitation, and seizures; however, cardiac dysrhythmias, with QT interval prolongation and cardiac arrest, have occurred (8c , 9c ). Venlafaxine overdose is also associated with seizures and cardiac dysrhythmias (4R ). Venlafaxine is a potent 5-HT re-uptake inhibitor, and signs of 5-HT toxicity (agitation, myoclonus, hyperthermia) are common. In a prospective cohort study of over 450 patients who had attempted suicide by antidepressant ingestion the risk of seizures after venlafaxine overdose (14%) was significantly greater than that of SSRIs (1.3%) and similar to that seen with dosulepin (11%) (10C ). Rates of 5-HT toxicity did not differ significantly between venlafaxine and SSRIs (29% versus 19%) but were greater than with tricyclic antidepressants (1.2%). Unlike SSRIs, venlafaxine was associated with significant prolongation of the QT interval; tricyclic antidepressants had a similar effect. Data on the consequences of overdose of other new antidepressant agents are limited, but current evidence suggests that reboxetine and mirtazapine have low toxicity in overdose (7R ). Reboxetine, as would be expected, presents with signs of noradrenergic overactivity, such as sweating, tachycardia, hypertension, and anxiety. The characteristic feature of mirtazapine overdose is sedation (7R ). Overdose of moclobemide by itself rarely appears to give rise to serious problems. This is in contrast to overdose with conventional monoamine oxidase inhibitors, which can cause fatal 5-HT toxicity. However, if patients take moclobemide together with serotonergic antidepressants, such as SSRIs or clomipramine, 5HT toxicity is common. 5-HT toxicity occurred in 11 of 21 patients who took overdoses of moclobemide and serotonergic agents but in only one of 33 patients who took moclobemide alone (11C ). Consistent with this, four patients died, presumably of 5-HT toxicity, after co-ingesting

3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and moclobemide (12c ). Overall the current data suggest that the safety advantage in overdose relative to tricyclic antidepressants enjoyed by SSRIs may extend to reboxetine and mirtazapine. Amfebutamone and venlafaxine are more toxic than SSRIs in overdose, but they are still likely to be safer than tricyclic antidepressants.

TRICYCLIC ANTIDEPRESSANTS (SED-14, 44; SEDA-25, 13; SEDA-26, 11; SEDA-27, 11) Musculoskeletal Elderly people are at increased risk of fractures, and a case-control study of patients admitted to hospital suggested that both tricyclic antidepressants and SSRIs increased the probability of hip fracture about 2.5 times (SEDA-22, 11). In a prospective study of 8127 women aged 65 years and older who were followed for 4.8 years, the risk of a first hip fracture was 4% and the risk in women taking antidepressants was increased 1.7 times (95% CI = 1.05, 2.07) (13C ). The relative risk among women taking tricyclic antidepressants (RR = 1.83; CI = 1.08, 3.09) was slightly higher than that for SSRIs, which had wider confidence intervals (RR = 1.54; CI = 0.62, 3.08). Depression as an independent variable did not increase the risk of hip fracture. This study has confirmed that women taking antidepressants are at increased risk of hip fracture and has suggested that the effects of SSRIs and tricyclic antidepressants are similar.

SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) (SED-14, 67; SEDA-25, 14; SEDA-26, 11; SEDA-27, 12) Nervous system SSRIs are often associated with sleep disturbances, particularly reduced sleep efficiency and altered sleep architecture. Paroxetine has been associated with sleepwalking (somnambulism) (14c ).

16 • A 61-year-old woman taking paroxetine 10 mg/day for depression had difficulty falling asleep, but there was no personal or family history of parasomnia. After 2 weeks the paroxetine was increased to 20 mg/day and 1 week later she was noted by her husband to be sleep-walking and trying at times to leave the house. When wakened she was confused and had no memory of the event. The paroxetine was withdrawn; the sleep-walking stopped and did not recur.

Other classes of antidepressant drugs can sometimes cause somnambulism, and it seems likely that paroxetine provoked this rare adverse effect. Sleep-walking is thought to be initiated during slow-wave sleep, after which partial arousals activate motor behaviors in the absence of full consciousness. The disrupting effects of antidepressants on sleep architecture might lead to somnambulism in pre-disposed individuals. Psychiatric Over the last decade there has been a debate as to whether SSRIs might increase the risk of suicide in certain individuals. Some patients can respond to SSRIs by becoming agitated and restless and developing symptoms that resemble akathisia. Case reports have suggested that adverse effects of this type could underlie an increased risk of selfharm and aggression. However, results from the placebo-controlled randomized trials carried out for regulatory purposes have not supported the proposal that SSRIs increase the risk of suicide of suicidal behavior. A review of the database of the Food and Drug Administration showed 77 suicides among 48 277 patients who had participated in placebocontrolled trials of antidepressants (15M ). The rate of suicide with SSRIs (0.59%; CI = 0.31, 0.87) was similar to that of other antidepressants (0.76%; CI = 0.49, 1.03) and placebo (0.45%; CI = 0.01, 0.89). While these data are reassuring, patients considered clinically at high risk of suicide were excluded from the trials and the patients received a greater degree of supervision than would occur in routine practice. In a re-analysis of antidepressant trial data there was an odds ratio for a suicidal act while taking SSRIs relative to placebo of 2.0 (CI = 1.2, 3.3), while the risk for completed suicide on SSRIs, although raised, had wide confidence intervals (RR = 3.1; CI = 0.4, 23.1) (16R ). One of the author’s arguments was that in previous analyses suicidal behaviors occurring during placebo wash-out have been misclassified

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as happening during placebo treatment. Separation of these two classes of event allows a pro-suicidal effect of SSRIs to be revealed. Overall the randomized studies suggest that the risk of suicide and suicidal behavior in patients taking placebo is numerically less than in patients taking active antidepressants. Since on clinical rating scales, antidepressant drugs usually reduce suicidal ideation more than placebo, this is a paradoxical observation. It might, however, reflect the old adage that the risk of suicide is greatest during the early stages of antidepressant treatment, when motor retardation has remitted but depressed mood and suicidal thinking persist. Such an effect might be exaggerated with modern antidepressants, which are more activating than tricyclic antidepressants. The need for caution in both clinical practice and trial evaluation is underlined by a warning from the Committee of Safety of Medicines that paroxetine is no more effective than placebo in the treatment of depression in adolescence, and may also be associated with a greater risk of self-harm and suicidal behavior (17S ). Gastrointestinal A previous case-control study linked SSRI treatment with gastrointestinal bleeding (SEDA-24, 15), and this has been confirmed in a cohort study in 26 005 antidepressant users (18C ). The risk of being hospitalized for upper gastrointestinal bleeding within 90 days of antidepressant prescription was increased in people taking SSRIs (OR = 3.6; CI = 2.7, 4.7). Combined use of SSRIs and aspirin increased the risk 5.2 times (CI = 3.2, 8.0), while combined use with an NSAID increased the risk 12 times (CI = 7.1, 20). There was a lower risk of gastrointestinal bleeding (OR = 2.3; CI = 1.5, 3.4) with antidepressants with less potency to inhibit 5-HT re-uptake (amitriptyline, dosulepin, imipramine), while non-serotonergic antidepressants (desipramine, nortriptyline, mianserin) did not increase the risk. These findings suggest that SSRIs should be used with caution in patients taking aspirin or NSAIDs. The risk of upper gastrointestinal bleeding with SSRIs used by themselves appears to be of the same order as that with aspirin. This observation is of interest, in view of a case-control study suggesting a lower risk of first myocardial infarction in patients taking SSRIs (OR = 0.59; CI = 0.39, 0.91) (19C ). This effect was not seen with non-SSRI antidepressants.

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Chapter 2

Liver Hepatitis has been reported in association with paroxetine and fluoxetine (SEDA-21, 12; SEDA-24, 15) and a case has now been associated with sertraline (20c ). • A 23-year-old woman taking sertraline (dose and length of time not stated) developed a mild pyrexia, right-sided abdominal pain, nausea, vomiting, and chills. She had a raised serum alanine transaminase activity but no other abnormality of liver function tests. A liver biopsy showed changes consistent with either a drug-induced reaction or autoimmune disease. Sertraline was withdrawn and prednisone 20 mg/day started. Four weeks later her alanine transaminase activity had fallen significantly, but she then restarted sertraline because of increasing depression. The alanine transaminase activity rose again, despite continuing prednisone, and only fell when sertraline was withdrawn.

While there have been other cases of hepatitis in association with sertraline this is the first case to have been confirmed by re-challenge. Reproductive system SSRIs can be associated with breast enlargement in women and gynecomastia has been reported in men. • Gynecomastia occurred in a 30-year-old man who had taken paroxetine 40 mg/day for 5 years (21c ). Over this time gynecomastia of the left breast became increasingly marked. There was no evidence of metabolic or hormonal abnormalities and plasma prolactin was within the reference range. Biopsy showed no evidence of malignancy. The gynecomastia was reduced by surgery and paroxetine was replaced with mirtazapine. At 2-year follow-up there was no evidence of recurrence. • A similar but more acute case of gynecomastia in association with fluoxetine has been reported in a 21 year old man (22c ). The gynecomastia resolved after fluoxetine withdrawal.

Fetotoxicity An increasing number of women take SSRIs during pregnancy and in the postnatal period. Some studies have suggested that SSRI treatment in pregnancy is not associated with an increased risk of malformations (SEDA-24, 15). However, neonates born to woman taking SSRIs can have a variety of symptoms, including jitteriness, hypoglycemia, hypothermia, and respiratory distress. • A boy (3.4 kg) was born by cesarean section, because of fetal distress, to a mother who had taken paroxetine (40 mg/day) and olanzapine (10 mg/day) until 48 hours before delivery (23c ). After delivery, the baby had increased tone and was hypoglycemic. The next day he was increasingly jittery, with profuse salivation. At 44 hours

17 there was no detectable paroxetine or olanzapine in the neonatal plasma and CSF concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were normal. The baby’s condition improved over the next few days, and 1 week after birth the only abnormality was slight jitteriness. At 6 months the baby was considered normal.

This infant’s symptoms were similar to those described in other neonates whose mothers took SSRIs shortly before delivery, although in this case a contributory effect from olanzapine was also possible. The authors made the point that it can be difficult to decide from the clinical presentation whether neonatal problems, such as those described above, represent SSRI withdrawal (5-HT deficiency) or SSRI toxicity (5HT excess). The fact that no paroxetine was detected in the infant’s plasma led them to conclude that SSRI withdrawal was responsible for the symptoms in this case. In a follow-up study in 20 infants born to mothers who had taken either fluoxetine (20– 40 mg/day) or citalopram (20–40 mg/day), the children of mothers who had taken SSRIs had raised scores in the first 4 days of life on scales rating symptoms of 5-HT excess, including tremor, rigidity, and restlessness (24C ). Children who had been exposed to SSRIs had lower concentrations of 5-HIAA in cord blood (consistent with persistent 5-HT reuptake blockade) and there was a significant negative correlation between the 5-HT symptom score and cord blood 5-HIAA. At 4 days citalopram and fluoxetine were detectable in plasma samples from the infants. By 2 weeks there was no significant difference in 5-HT symptom scores between exposed infants and controls. Weight gain over this time was similar in the two groups. These findings support the view that the neonatal syndrome associated with SSRI treatment of mothers around the time of delivery can sometimes be due to 5-HT toxicity rather than SSRI withdrawal. Lactation Mothers taking antidepressants often want to breast feed their babies. Generally SSRI treatment of nursing mothers is without an obvious acute effect on the infant (SEDA26, 14), although adverse effects in infants are occasionally reported (SEDA-25, 15). When blood and milk were sampled in 22 nursing women taking sertraline (25–200 mg/day), sertraline and its metabolite, desmethylsertraline,

18 were found in all the milk samples (25C ). The maximum concentration of sertraline and desmethylsertraline in the milk occurred 8– 9 hours after maternal ingestion of the daily dose of sertraline. Eleven infants had detectable desmethylsertraline; of these, four also had detectable sertraline. No adverse effects were noted in any of the children. The authors calculated that the infants had received on average about 0.5% of the maternal sertraline dose. These data confirm that the infants of nursing mothers taking SSRIs are likely to be exposed to low doses of antidepressants. While this rarely causes overt effects, the possibility of subtle long-term behavioral consequences cannot be excluded. In the case of sertraline it would be wise to discard breast milk accumulated 8–9 hours after dosing as this will reduce the daily dose that the infant receives. Drug interactions Alprazolam SSRIs and the benzodiazepine alprazolam are often used to treat panic disorder. Pharmacokinetic reactions between them could therefore be important. Alprazolam is metabolized by CYP3A4, which fluvoxamine inhibits (SEDA-22, 13). In 23 outpatients (11 men, 12 women, mean age 39 years) who took alprazolam both as monotherapy (mean dose 1.0 mg/day) and in combination with fluvoxamine (mean dose 34 mg/day), fluvoxamine increased plasma alprazolam concentrations by 58% (26C ). This was not associated with increased sleepiness, measured by a subjective rating scale, but objective measures of psychomotor function were not carried out and these could have been impaired by raised alprazolam concentrations. The effects of SSRIs on alprazolam pharmacokinetics have been studied in 21 healthy volunteers (age and sex not given) who were pre-treated with either fluoxetine or citalopram (20 mg/day for 21 days) (27C ). Fluoxetine increased the AUC of a single 1.0 mg dose of alprazolam by 32%; citalopram had no effect. These findings are consistent with previous reports that fluoxetine and its active metabolite, norfluoxetine, produce moderate inhibition of CYP3A4 while citalopram does not. Grapefruit juice Grapefruit juice is also a modest inhibitor of CYP3A4. Grapefruit juice (250 ml tds) for 5 days produced a 1.6-fold increase in the AUC of a single dose of fluvoxamine 75 mg in 10 healthy men (aged 19–30

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years) (28c ). Fluvoxamine is metabolized by CYP2D6 and CYP1A2, but this study suggests that there may also be a modest contribution from CYP3A4. Pethidine Pethidine plus an SSRI may have caused a 5-HT syndrome (29c ). • A 43-year-old man was premedicated for endoscopy with intravenous midazolam 2 mg and pethidine 50 mg). He immediately became agitated and restless. His blood pressure rose to 180/100 mmHg, he sweated, had widely dilated pupils, and had diarrhea. Over the next 90 minutes his condition remitted without specific treatment. He then reported that he had been taking fluoxetine (20 mg every other day), which he had stopped taken about 2 weeks before.

The symptoms described here resemble the 5-HT toxicity syndrome (SEDA-25, 16) and suggest that pethidine can provoke this reaction when combined with SSRIs, as it can with monoamine oxidase inhibitors. The report is also a useful reminder that the active metabolite of fluoxetine, norfluoxetine, has a half-life of about 1 week and would still have been present at the time of endoscopy, even though fluoxetine had been stopped 14 days before.

OTHER ANTIDEPRESSANTS Amfebutamone (bupropion) (SED-14, 60; SEDA-25, 17; SEDA-26, 15; SEDA-27, 14) Nervous system Somnambulism has been reported with amfebutamone (30c ). • A 35-year-old man took amfebutamone 150 mg bd as part of a smoking cessation program. After 14 days he stopped smoking, after which he noted some increase in mood and appetite. Three days later a friend reported that the patient had telephoned him at 1.00 am, about 2 hours after he had gone to sleep, but the patient had no memory of this. Over the next week he discovered evidence of several episodes of nocturnal eating but again had no recall of getting up at night to obtain food. He stopped taking amfebutamone and the sleepwalking episodes disappeared and did not recur.

Amfebutamone promotes slow wave sleep, the sleep stage during which somnambulism is

Antidepressant drugs

initiated. However, this case was complex, because of the possible interaction with nicotine withdrawal. Nicotine withdrawal is associated with increased appetite and weight gain, and sleep walking can be associated with nocturnal eating (31c ). Amfebutamone has been associated with extrapyramidal movement disorders (SEDA-27, 15) and ballismus has been reported (31c ). • A 42-year-old woman developed ballismus 4 days after increasing her dose of amfebutamone to 150 mg bd. She had an involuntary urge to move, gross flexion movements of the torso, and slapping movements of her arms. She had no previous history of movement disorders and was taking only occasional sumatriptan for migraine. Amfebutamone was withdrawn and she was given haloperidol and oxazepam. The movements abated.

It seems likely from this that the dopaminergic effects of amfebutamone can provoke movement disorders in therapeutic doses in some individuals. Immunologic Amfebutamone has been associated with a variety of hypersensitivity reactions, including urticaria and serum sickness (SEDA-25, 17). Further reactions in association with amfebutamone have been reported. • A 24-year-old man developed a fever and a generalized maculopapular rash after taking amfebutamone 150 mg bd for 3 weeks (32c ). Amfebutamone was withdrawn but he went on to develop angioedema, eosinophilia, and a systemic syndrome with hepatitis, myositis, and obstructive lung disease. His symptoms resolved over several weeks with a glucocorticoid.

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(SED-14, 63; SEDA-27, 16)

Nervous system Mirtazapine is a potent histamine H1 receptor antagonist and is perceived by patients as being sedative. While this may improve disturbed sleep, it also has implications for daytime psychomotor performance. The effect of mirtazapine (15 mg at night for 2 days, then 30 mg at night for 2 days) and paroxetine (20 mg in the morning for 5 days) has been studied in a placebo-controlled, crossover design in 12 healthy volunteers (10 women, 2 men, median age 26 years) (33C ). On the fifth

day the subjects undertook a battery of psychomotor tests. Mirtazapine significantly impaired several aspects of psychomotor performance and increased daytime sleepiness, while paroxetine did not. These results suggest that patients who take mirtazapine should be warned about its deleterious effects on psychomotor performance, particularly driving. It is likely that tolerance to this effect will occur, but the time course of adaptation is uncertain. Also uncertain is how far these results in healthy subjects can be extrapolated to depressed patients, many of whom will have performance deficits due to poor sleep, which could conceivably be helped by mirtazapine.

Trazodone

(SED-14, 64)

Teratogenicity The use of antidepressants in pregnancy is a difficult area, because the teratogenic effects of many antidepressants are not known. While tricyclic antidepressants and SSRIs are believed to present a low risk of fetal abnormality (SEDA-24, 15), the teratogenic potential of trazodone has been unclear. In 147 women who took either trazodone or nefazodone during the first trimester of pregnancy, the rate of major malformations in the trazodone/nefazodone group (1.6%) did not differ statistically from that in a control group (3.0%) (34C ). Similarly, there were no statistically significant differences in rates of spontaneous abortion or stillbirth or in birth weight in the babies of women who took trazodone or nefazodone. These findings are reassuring. However, as the authors pointed out, the study, while prospective, was not randomized. In addition they did not examine the effects of trazodone and nefazodone separately, and did not state how many women were taking each drug. While trazodone and nefazodone are pharmacologically similar, they are not identical, and nefazodone has recently been withdrawn in the UK because of a rare association with severe liver disease (SEDA-26, 16).

Venlafaxine

(SED-14, 66; SEDA-25, 18; SEDA-26, 16; SEDA-27, 16) Respiratory There has been a previous report linking venlafaxine to pneumonia associated

20 with eosinophilic infiltration, and SSRIs have been associated with drug-induced infiltrative lung disease. • A 21-year-old woman developed progressive dyspnea, a non-productive cough, weight loss, and syncope (35c ). She had been taking venlafaxine for depression for 2 months (75 mg/day for 1 month, then 37.5 mg/day). A chest X-ray showed diffuse reticulonodular opacities throughout both lung fields, and a CT scan showed numerous diffuse, ill-defined pulmonary nodules. Lung function tests showed a restrictive ventilatory defect, depression of gas transfer, and resting hypoxia. Histological examination showed a lymphocytic interstitial infiltrate. Venlafaxine was withdrawn and glucocorticoid treatment started. Her clinical condition improved rapidly over the next 2 weeks after which the glucocorticoid treatment was stopped. At 3 years she remained well.

It is difficult to be sure how far venlafaxine contributed to this presentation, but no other cause could be established and the patient improved quickly when venlafaxine was withdrawn. Venlafaxine is a potent 5-HT re-uptake inhibitor and 5-HT has been implicated in fibrotic reactions in a variety of tissues. Nervous system The 5-HT toxicity syndrome usually results from the combination of two drugs with potentiating effects on 5-HT neurotransmission. However, it can occasionally result from therapeutic doses of a conventional 5-HT re-uptake inhibitor antidepressant. • A 29-year-old woman developed anxiety, restlessness, shivering, diarrhea, nausea, and vomiting after taking venlafaxine 37.5 mg/day for 3 days (36c ). She also had ataxia and myoclonus. Her symptoms resolved after a few hours and treatment with prochlorperazine and lorazepam. Two weeks later she took fluoxetine 20 mg/day without adverse effects.

This case shows how sensitive some patients can be to even low doses of 5-HT potentiating drugs and also the rather puzzling fact that another drug, equally potent at facilitating 5-HT neurotransmission, can then be taken without apparent adverse consequences. Psychiatric Delusions of love (erotomania or De Clérambault’s syndrome) is a rare but striking disorder. • A 39-year-old woman with a history of treatmentresistant depression developed delusions that her

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medical attendants were in love with her on two separate occasions when taking venlafaxine in doses of 225 mg and more (37c ). There was no evidence of mania and no other psychotic symptoms. On both occasions the delusional beliefs subsided when venlafaxine was withdrawn. She was subsequently treated with another antidepressant and made a good recovery.

The absence of a history of psychosis and the re-emergence of delusional thinking when venlafaxine was prescribed again suggest that venlafaxine played a role in producing this psychotic state. At high doses venlafaxine potentiates dopamine activity, which could lead to psychotic reactions in predisposed individuals. Endocrine SSRIs can facilitate prolactin release and have been associated with galactorrhea (SEDA-26, 13). A similar effect would be expected with venlafaxine. • A 38-year-old woman developed galactorrhea on two separate occasions while taking venlafaxine 225 mg/day and 75 mg/day (38c ). On the first occasion prolactin concentrations were modestly raised but on the second they were not.

This report confirms that, like SSRIs, venlafaxine can cause galactorrhea and also suggests, as has been observed with other drugs, that the symptom of lactation is not necessarily closely linked to plasma prolactin concentrations. This suggests that other mechanisms could be involved in the production of druginduced galactorrhea. Drug abuse usual.

Misuse of antidepressants is un-

• A 38-year-old man without a previous history of substance misuse took up to 3600 mg of venlafaxine daily (about 10 times the maximum therapeutic dose) because it caused a subjective “high” (39c ). He maintained his high doses by obtaining illicit supplies of venlafaxine until a dose of 4050 mg produced acute central chest pain. He was then admitted to be treated for depression and substance misuse.

This patient developed features of drug dependence. Such reactions are unusual but might be related to the ability of venlafaxine to potentiate dopamine function at high doses. This pharmacological property characterizes many drugs that are misused for their euphoriant properties.

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21

REFERENCES 1. Labbate LA, Croft HA, Oleshansky MA. Antidepressant-related erectile dysfunction: management via avoidance, switching antidepressants, antidotes and adaptation. J Clin Psychiatry 2003; 64: 11–19. 2. Waldinger MD, Zwinderman AH, Olivier B. Antidepressants and ejaculation: a double-blind, randomised, fixed-dose study with mirtazapine and paroxetine. J Clin Psychopharmacol 2003; 23: 467– 70. 3. Clayton AH, Zajecka J, Ferguson JM, FilipiakReisner JK, Brown MT, Schwartz GE. Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder. Int Clin Psychopharmacol 2003; 18: 151–6. 4. Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S. Treatment of antidepressant-associated sexual dysfunction with sildenafil. J Am Med Assoc 2003; 289: 56–64. 5. Bahl S, Cotterchio M, Kreiger N. Use of antidepressant medications and the possible association with breast cancer risk. Psychother Psychosom 2003, 72: 185–94. 6. Lawlor DA, Juni P, Ebrahim S, Egger M. Systematic review of the epidemiologic and trial evidence of an association between antidepressant medication and breast cancer. J Clin Epidemiol 2003: 56: 155–63. 7. Buckley NA, Faunce TA. “Atypical” antidepressants in overdose. Clinical considerations with respect to safety. Drug Saf 2003; 26: 539–51. 8. Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Med J Aust 2003; 178: 61– 3. 9. Isbister GK, Balit CR. Bupropion overdose: QTc prolongation and its clinical significance. Ann Pharmacother 2003; 37: 999–1002. 10. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Assoc Phys 2003; 96: 369–74. 11. Isbister GK, Hackett LP, Dawson AH, Whyte IM, Smith AJ. Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol 2003; 56: 441–50. 12. Vuori E, Henry JA, Ojanpera I, Nieminen R, Savolainen T, Wahlsten P, Jantti M. Death following ingestion of MDMA (ecstasy) and moclobemide. Addiction. Soc Study Addiction Alcohol Other Drugs 2003; 98: 365–8. 13. Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A, Hanlon JT, Nevitt MC, Whooley MA. Central nervous system active medications and risk for fractures in older women. Arch Intern Med 2003; 163: 949–57. 14. Kawashima T, Yamada S. Paroxetine-induced somnambulism. J Clin Psychiatry 2003; 64: 483. 15. Khan A, Kahn S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepres-

sants and placebo: analysis of FDA reports. Am J Psychiatry 2003; 160: 790–2. 16. Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosom 2003; 72: 71–9. 17. Committee on Safety of Medicines 2003. Paroxetine (Seroxat). Safety in children and adolescents. SSRI and venlafaxine use in children. 2003 September; 29: 4. 18. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003; 163: 59–64. 19. Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003; 108: 32. 20. Persky S, Reinus JF. Sertraline hepatotoxicity. A case report and review of the literature on selective serotonin reuptake inhibitor hepatotoxicity. Dig Dis Sci 2003; 48: 939–44. 21. Damsa C, Sterck R, Schulz P. Case of gynecomastia during paroxetine therapy. J Clin Psychiatry 2003; 64: 971. 22. Boulenger A, Viseux V, Plantin-Eon I, Commegeille P, Plantin P. Gynaecomastia following treatment by fluoxetine. J Eur Acad Dermatol Venereol 2003; 17: 97–116. 23. Jaiswal S, Coombs RC, Isbister GK. Paroxetine withdrawal in a neonate with historical and laboratory confirmation. Eur J Pediatr 2003; 162: 723–4. 24. Laine Kari, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 2003; 60: 720–6. 25. Stowe, ZN, Hostetter AL, Owens MJ, Ritchie JC, Sternberg K, Cohen LS, Nemeroff CB. The pharmacokinetics of sertraline excretion into human breast milk: determinants of infant serum concentrations. J Clin Psychiatry 2003; 64: 73–80. 26. Suzuki Y, Shioiri T, Muratake T, Kawashima Y, Sato S, Hagiwara M, Inoue Y, Shimoda K, Someya T. Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles. Eur J Clin Pharmacol 2003; 58: 829–33. 27. Hall J, Naranjo CA, Sproule BA, Herrmann N. Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine. J Clin Psychopharmacol 2003; 23: 349– 57. 28. Hori H, Yoshimura R, Yeda N, Eto S, Shinkai K, Sakata S, Ohmori O, Terao T, Nakamura J. Grapefruit juice–fluvoxamine interaction. Is it risky or not? J Clin Psychopharmacol 2003; 23: 422–4. 29. Tissot TA. Probable meperidine-induced serotonin syndrome in a patient with a history of fluoxetine use. Anesthesiol (Phil) 2003; 98: 1511–12.

22 30. Khazaal Y, Krenz S, Zullino DF. Bupropioninduced somnambulism. Addict Biol 2003; 8: 359– 62. 31. De Graaf L, Admiraal P, Van Puijenbroek EP. Ballism associated with bupropion use. Ann Pharmacother 2003; 37: 302–3. 32. Bagshaw SM, Cload B, Gilmour J, Leung ST, Bowen TJ. Drug-induced rash with eosinophilia and systemic symptoms syndrome with bupropion administration. Ann Allergy Asthma Immunol 2003; 90: 572–5. 33. Ridout F, Meadows R, Johnsen S, Hindmarch I. A placebo controlled investigation in to the effects of paroxetine and mirtazapine on measures related to a car driving performance. Human Psychopharmacol 2003; 18: 261–9. 34. Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, Koren G. A multicentre prospective controlled study to determine the safety

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of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003; 48: 106–10. 35. Drent M, Singh S, Gorgels APM, Hansell DM, Bekers O, Nicholson AG, Van Suylen RJ, Du Bois RM. Drug-induced pneumonitis and heart failure simultaneously associated with venlafaxine. Am J Resp Crit Care 2003; 167: 958–61. 36. Pan JJ, Shen WW. Serotonin syndrome induced by low-dose venlafaxine. Ann Pharmacother 2003; 37: 209–11. 37. Adamou M, Hale AS. Erotomania induced by venlafaxine: a case study. Acta Psychiatr Scand 2003; 107: 314–17. 38. Sternbach H. Venlafaxine-induced galactorrhea. J Clin Psychopharmacol 2003; 23: 109. 39. Sattar SP, Grant KM, Bhatia SC. A case of venlafaxine abuse. New Engl J Med 2003; 248: 764–5.

David L. Dunner

3 Adverse effects of lithium have been reviewed, particularly in relation to drug interactions; for the most part, the reports discussed related to case reports or reviews of adverse effects and drug interactions of lithium that have long been associated with lithium (1R ). Therapeutic studies Guidelines for treating bipolar disorder, developed in a consensus meeting of experts, have been published by the British Association of Psychopharmacology (2S ). Lithium was recommended for many of the phases of bipolar disorder, often in combination with other treatments. Although the efficacy of lithium salts in the treatment of bipolar disorders, particularly in the prevention of recurrence of manic, hypomanic, mixed, and depressive episodes is well established, recent data suggest that it also has a prominent role in reducing the rate of suicide among patients with bipolar mood disorders. A meta-analysis showed a considerable reduction in the suicide rate in bipolar patients taking lithium carbonate compared with patients who were not taking lithium or patients who had stopped taking lithium (3M ), and this finding has been confirmed in an evaluation of patients who were being treated in two large health maintenance organizations between 1994 and 2001 (4C ). The subjects were patients with bipolar disorders taking maintenance lithium, divalproex, or carbamazepine. There was a significant reduction in the rate of suicidal behaviors among those taking lithium compared with those taking divalproex or carbamazepine. The suicide attempt rate resulting in hospitalization (events per 1000 patient years) was 4.2 with lithium, 10.5 with divalproex, and 15.5 with carbamazepine. The rate of suicide deaths per 1000 patient years was 0.7 with lithium, 1.7 with divalproex, and 1.0 with carbamazepine. © 2005 Published by Elsevier B.V. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

Lithium In a double-blind, placebo-controlled study, 175 manic or recently manic patients were stabilized over 8–16 weeks with lamotrigine 100–400 mg/day (n = 59), lithium in a dose sufficient to produce a serum concentration of 0.8–1.1 mmol/l (n = 46), or placebo and were then randomized to continued treatment (5C ). Both lamotrigine and lithium were superior to placebo in prolonging the time to the next episode of any mood disturbance. Lamotrigine, but not lithium, was superior to placebo in prolonging the time to a depressive episode. Lithium, but not lamotrigine, was superior to placebo in prolonging the time to a manic, hypomanic, or mixed episode. A similarly designed study in 463 bipolar I patients whose most recent episode was depression gave similar results (6C ). A combined analysis of the data from these two studies, involving over 1300 bipolar I patients, showed that in the 638 randomized patients lamotrigine and lithium were superior to placebo regarding time to intervention to the next mood episode (7C ). Beneficial effects have been reported in patients with schizophrenia (n = 10) and schizoaffective disorder (n = 10) who were treated with a combination of clozapine and lithium (8c ). When lithium (serum lithium concentration titrated to at least 0.5 mmol/l) was added to clozapine 100–800 mg/day there was a positive effect in the patients with treatment-resistant schizoaffective disorder, but not in the patients with schizophrenia. In a retrospective chart analysis of patients with depression, 23 took added lithium (9c ). There was improvement in 13 and 11 improved over 4 weeks. Patients who continued to take lithium continued to improve, compared with patients who stopped taking lithium. In five adolescents with somnolence from Kleine–Levin syndrome lithium (serum concentrations 0.6–0.9 mmol/l) reduced the frequency and severity of the somnolence, without severe adverse effects (10c ).

23

24 The addition of lithium to other drug therapy has been studied in 92 patients with treatmentresistant major depression taking nortriptyline (11C ). Non-responders to nortriptyline (n = 35) were randomized to added lithium or placebo; there was no significant difference. The addition of lithium in treating major depressive disorder in patients unresponsive to antidepressant drugs has been discussed, and it has been noted that about 50% of patients respond to lithium augmentation in 2–4 weeks (12r ), while others have pointed to the absence of controlled data for this treatment in bipolar depression, while nevertheless recommending its use (13r ). In summary, there are data that support the use of lithium augmentation for treatment-resistant unipolar major depression. However, the data are not robust and are based on only a few hundred patients. Placebocontrolled studies of lithium augmentation for treatment-resistant bipolar depression are lacking (14r ). Cardiovascular In 30 patients there were only minimal electrocardiographic changes during long-term treatment with lithium using the method of body surface electrocardiographic mapping (15c ). In contrast, a tricyclic antidepressant showed dose-related effects.

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David L. Dunner

The authors concluded that lithium alone can cause neuroleptic malignant syndrome, since no neuroleptic drugs had been co-administered in this case. Endocrine Of 15 patients who had taken long-term lithium and who had also had surgery for primary hyperparathyroidism, one had recurrent hyperparathyroidism 2 years after the first operation (18c ). The authors noted that in their experience hyperparathyroidism during lithium treatment was associated with a high incidence of parathyroid adenomas rather than parathyroid gland hyperplasia, and they suggested that lithium might selectively stimulate the growth of parathyroid adenomas in individuals who are susceptible to developing parathyroid adenomas. Furthermore, such adenomas were best treated by excision rather than subtotal parathyroidectomy. • A 63-year-old man taking long-term lithium for a schizoaffective disorder developed a dural sinus thrombosis and severe hypernatremia and died (19A ).

The authors suggested that the sequence of events was lithium-induced nephrogenic diabetes insipidus resulting in hypernatremia followed by the dural sinus thrombosis.

Nervous system There has been a report of ataxia and dysarthria/choreoathetosis in a patient taking lithium.

Urinary tract Polyuria, defined as a urine volume greater than 3 l/day, is a well-known effect of lithium.

• Ataxia and dysarthria/choreoathetosis occurred in a 76-year-old woman who was taking lithium and had a serum lithium concentration of 2.43 mmol/l (16A ). She underwent hemodialysis and the choreoathetotic movements disappeared. She also had repeated episodes of a tachydysrhythmia and atrial fibrillation, but returned to sinus rhythm after the lithium toxicity had resolved.

• A 33-year-old man who had taken multiple medications, including valproic acid and lithium carbonate, started to take olanzapine instead of haloperidol (20A ). Five days later he reported malaise, polyuria, and polydipsia. He had a raised blood glucose, an increased serum osmolality, ketonemia, and glycosuria.

The neuroleptic malignant syndrome has previously been reported in patients taking lithium plus a neuroleptic drug, but whether lithium alone can cause it is controversial (SEDA-23, 24). • A 45-year-old man took an intentional overdose of lithium (17A ). He was dialysed and stabilized, but on day 10 developed neuroleptic malignant syndrome. He died after developing acute renal insufficiency and acute respiratory distress syndrome.

The authors suggested that he had insulin resistance (probably due to olanzapine), which was exacerbated by valproic acid and lithium. In a follow-up study of 54 patients with lithium-induced renal insufficiency and 20 patients who had been referred for renal biopsy, the authors concluded that lithium-induced chronic renal disease is slowly progressive (21CR ). The rate of progression was related to the duration of lithium treatment, and lithiumrelated end-stage renal disease accounted for a small percentage (0.22%) of all cases of

Lithium

Chapter 3

end-stage renal disease in France. The authors strongly suggested that regular monitoring of creatinine clearance is important during longterm lithium management. Renal size and structure have been evaluated by MRI in 16 patients with renal insufficiency and nephropathy thought to be secondary to lithium (22c ). There were renal microcysts in all patients. All the patients had nephrogenic diabetes insipidus, in which antidiuretic hormone concentrations are raised, and there is evidence that antidiuretic hormone can stimulate the production of renal cysts, by an action mediated via cyclic AMP (23E ). Fetotoxicity Lithium can have fetotoxic effects (SEDA-27, 23), as illustrated by the following case. • A 36-year-old woman with bipolar disorder who had taken lithium for 17 years continued to take it and other medications during pregnancy (24A ). At 35 weeks she developed signs of lithium toxicity, with nausea, diarrhea, and a concentration of 1.25 mmol/l. She delivered a lethargic infant with poor muscle tone, who showed signs of respiratory distress and hypopnea. The infant’s lithium concentration was 3.58 mmol/l. The infant was treated and responded, but at day 6 the lithium concentration increased to 2.6 mmol/l after dropping to 2.4 mmol/l on day 4.

However, the authors identified a laboratory error, in that the blood tube for analysis for lithium contained lithium heparin rather than sodium heparin. When the infant’s serum lithium concentration was checked using a proper tube on day 6 it was 0.06 mmol/l, not 2.6 mmol/l, so the fetus may not after all have had lithium toxicity. Drug overdose There has been a 10-year review of lithium overdose in 304 patients (25R ). The circumstances were accidental ingestion, mistakes in the quantity of ingested tablets, raised lithium concentrations due to diuretic therapy, renal insufficiency or dehydration, and suicide attempts. About half the patients required management in an intensive care unit, 5% needed hemodialysis, 10% had cardiac disturbances or neurological complications, and 2% died. The authors concluded that modified-release formulations when taken in large amounts present the greatest danger. Of 56 patients with lithium toxicity, 42 had initially overdosed and they were compared

25 with those who had toxicity that was described as inadvertent and associated with volume depletion (26R ). The initial lithium concentration was lower in the cases of intentional overdose than in the cases of inadvertent intoxication (2.4 mmol/l versus 3.4 mmol/l). Hemodialysis for lithium toxicity was required in 9% of those who had taken an intentional overdose compared with 50% of those who had inadvertent intoxication. These findings were in contrast to the amount of lithium taken during the 24 hours before hospitalization, which was much higher in those who had taken an intentional overdose, because of the large inhibitory effect of dehydration on lithium excretion. Drug interactions COX-2 inhibitors There have been several reports of raised serum lithium concentrations and neurotoxic symptoms when COX-2 inhibitors (celecoxib and rofecoxib) were added to an otherwise stable lithium regimen (SEDA-27, 24). Serum lithium concentrations increased in 18 patients taking lithium who started to take a COX-2 inhibitor (rofecoxib or celecoxib) (27c ). The authors stressed the need for lithium monitoring when COX-2 inhibitors are used concomitantly. Neuroleptic drugs Neuroleptic malignant syndrome has again been reported in a patient taking lithium plus a neuroleptic drug. • A 30-year-old man developed neuroleptic malignant syndrome after taking risperidone and lithium carbonate for 1 week, having previously been taking olanzapine and divalproex (28A ).

Although the neuroleptic malignant syndrome has been reported in patients taking these atypical neuroleptic drugs, it is less common than in patients taking typical neuroleptic drugs, and lithium may have increased the risk in these cases, as has previously been suggested (SEDA-25, 22; SEDA-27, 24). Monitoring therapy In a comparison of lithium concentrations in erythrocytes and plasma during acute or chronic lithium intoxication (309 samples in 165 patients) good general correlation between erythrocyte and plasma lithium concentrations was confirmed (29c ). There were higher plasma lithium concentrations in acute intoxication and higher

26 erythrocyte lithium concentrations in chronic intoxication; the lithium erythrocyte:plasma

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concentration ratio was highest in those with chronic intoxication.

REFERENCES 1. Dunner DL. Drug interactions of lithium and other antimanic/mood-stabilizing medications. J Clin Psychiatry 2003; 64 Suppl 5; 38–43. 2. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: recommendation from the British Association of Psychopharmacology. J Psychopharmacol 2003; 17: 149–73. 3. Baldessarini RJ, Tondo L, Hennen J. Treating the suicidal patient with bipolar disorder: reducing suicide risk with lithium. Ann NY Acad Sci 2001; 932: 24–38. 4. Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. J Am Med Assoc 2003; 290: 1467–13. 5. Bowden CL, Calabrese JR, Sachs G, Yatham LM, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, De Vaugh-Geiss J. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003; 60: 392–400. 6. Calabrese JR, Bowden CL, Sachs G, Yatham LM, Behnke K, Mehtonen OP, Montgomery P, Ascher J, Paska W, De Vaugh Geiss J. Lamictal 605 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003; 64: 1013–24. 7. Goodwin GM, Bowden CL, Calabrese JR, Grunze H, Kasper S, White R, Greene P, Leadbetter R. A pooled analysis of two placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry 2004; 65: 432–41. 8. Small JG, Klapper MH, Malloy FW, Steadman TM. Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. J Clin Psychopharmacol 2003; 23: 223–8. 9. Morishita S, Arita S. Lithium augmentation of antidepressants in the treatment of protracted depression. Int Med J 2003; 10: 29–32. 10. Poppe M, Friebel D, Reuner U, Todt H, Koch R, Heubnerb G. The Kleine–Levin Syndrome – effects of treatment with lithium. Neuropediatrics 2003; 34: 113–19. 11. Nierenberg AA, Papakostas GI, Petersen J, Montoya HD, Worthington JJ, Tedlow J, Alpert JE, Fava M. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol 2003; 23: 92–5. 12. Bauer M, Adli M, Baethge C, Berghofer A, Sasse J, Heinz A, Bschor J. Lithium augmentation therapy in refractory depression: clinical evidence

and neurological mechanisms. Can J Psychiatry 2003; 48: 440–8. 13. Bschor T, Lewitzka U, Bauer M. Lithiumaugmentation zur Behandlung der bipolaren Depression. PsychoNeurology 2003; 29: 392–9. 14. Lee W, Cleare A. Lithium augmentation in treatment-refractory unipolar depression. Br J Psychiatry 2003; 182: 456–7. 15. Paclt I, Slavicek J, Dohnalova A, Kitzlerova E, Pisvejcova K. Electrocardiographic dose-dependent changes in prophylactic doses of dosulepine, lithium and citalopram. Physiol Res 2003; 52: 311– 17. 16. Stemper B, Thurauf N, Neundorfer B, Heckmann JG. Choreoathetosis related to lithium intoxication. Eur J Neurol 2003; 10: 743–4. 17. Gill J, Singh H, Nugent K. Acute lithium intoxication and neuroleptic malignant syndrome. Pharmacotherapy 2003; 23: 811–15. 18. Awad SS, Miskulin J, Thompson N. Parathyroid adenomas versus four-gland hyperplasia as the cause of primary hyperparathyroidism in patients with prolonged lithium therapy. World J Surg 2003; 27: 486–8. 19. Kamijo Y, Soma K, Hamanaka S, Nagai T, Kurihara K. Dural sinus thrombosis with severe hypernatremia developing in a patient on long-term lithium therapy. J Toxicol Clin Toxicol 2003; 41: 359–62. 20. Chen PS, Yang YK, Yeh TL, Lo YC, Wang YT. Nonketotic hyperosmolar syndrome from olanzapine, lithium, and valproic acid cotreatment. Ann Pharmacother 2003; 37: 919–20. 21. Presne C, Fakhouri F, Noel L-H, Stengel B, Even C, Kreis H, Mignon F, Grunfeld J-P. Lithiuminduced nephropathy: rate of progression and prognostic factors. Kidney Int 2003; 64: 585–92. 22. Farres MT, Ronco P, Saadoun D, Remy P, Vincent F, Khalil A, Le Blanche AF. Chronic lithium nephropathy: MR imaging for diagnosis. Radiology 2003; 229: 570–4. 23. Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nature Med 2003; 9: 1323–6. 24. Malzacher A, Engler H, Drack G, Kind C. Lethargy in a newborn: lithium toxicity or lab error? J Perinat Med 2003; 31: 340–2. 25. De Haro L, Roelandt J, Pommier P, Prost N, Arditti J, Hayek-Lanthois M, Valli M. Circconstances d’intoxication par sels de lithium: experience du centre antipoison de Marseille sur 10 ans. Ann Fr Anesth Reanim 2003; 22: 514–19. 26. Tuohy K, Shemin D. Acute lithium intoxication. Dial Transplant 2003; 32: 478–81.

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27. Phelan KM, Mosholder AD, Lu S. Lithium interaction with cyclooxygenase 2 inhibitors refocoxib and celecoxib and other nonsteroidal antiinflammatory drugs. J Clin Psychiatry 2003; 64: 1328–34. 28. Bourgeois JA, Kahn DR. Neuroleptic malignant syndrome following administration of risperidone and lithium. J Clin Psychopharmacol 2003; 23: 315–17.

27 29. Camus M, Hennere G, Baron G, Peytavin G, Massias L, Mentre F, Farinotti R. Comparison of lithium concentrations in red blood cells and plasma in samples collected for TDM, acute toxicity, or acute-or-chronic toxicity. Eur J Clin Pharmacol 2003; 59: 583–7.

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong

4 Drug interactions The combination of opiates and cocaine in drug overdose deaths has been examined retrospectively in a review of all accidental drug overdoses that resulted in death in New York City from 1990 to 1998 (1c ). There were 7451 accidental overdose deaths, of which opiates played a role in 71%, cocaine in 70%, and alcohol in 40%; one of these drugs was identified in 98% of all overdose deaths. As evidence of higher polydrug mortality, 58% of the deaths were caused by more than one drug. The most common combination was opiates plus cocaine, which caused a peak death rate in 1994 of 44 per million person-years, compared with rates of 21 and 31 deaths per million person-years for opiates and cocaine alone respectively. Although it was retrospective, this study has elaborated and highlighted the dangers of polydrug abuse and has shown that the risk of overdose is significantly increased when opiates and cocaine are used together. There have been two new reports of the fatal combination of metamfetamine with morphine (2A ). • A 43-year-old man was found dead in bed after injecting metamfetamine and morphine the night before. An autopsy showed mild edema of the brain and lungs, fatty liver, and active HCV hepatitis. The postmortem findings suggested hyperthermia. The blood metamfetamine concentration was 550 ng/ml, and the blood morphine concentration was 760 ng/ml. • A 21-year-old man was found dead in bed after injecting metamfetamine and morphine the previous evening. He had severe edema of the brain and lungs, swollen tonsils, and enlarged deep cervical lymph nodes. The postmortem findings suggested hyperthermia. The blood metamfetamine concentration was 2640 ng/ml, and the blood morphine concentration was 500 ng/ml.

In both cases, the blood metamfetamine concentration was less than the lethal concentration of 4.5 µg/ml. Morphine concentrations © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

28

Drugs of abuse were higher than the non-toxic concentration of 0.3 µg/ml. It is unlikely that morphine was the cause of death, because it would have caused hypothermia instead of hyperthermia. It is more likely that morphine interacted with metamfetamine, increasing the hyperthermic effect that is typical of metamfetamine overdose. This would explain why hyperthermia caused death, despite a non-lethal blood concentration of metamfetamine.

AMPHETAMINES

(SED-14, 100; SEDA-25, 34; SEDA-26, 30; SEDA-27, 29) Note on spelling In International Non-proprietary Names the digraph -ph- is usually replaced by -f-, although usage is not consistent, and -ph- is used at the beginnings of some drug names (for example, compare fenfluramine and phentermine) or when a name that begins with a ph- is modified by a prefix (for example, chlorphentermine). For the amphetamines we have used the following spellings: amfetamine, benzfetamine, dexamfetamine, metamfetamine (methylamphetamine), and methylenedioxymetamfetamine (ecstasy), since these are the rINNs; however, for the general term of the group of drugs we have used the more common spelling amphetamines.

Amfetamine

(SEDA-25, 34;

SEDA-26, 30) Cardiovascular An uncommon presentation of amfetamine-related acute myocardial infarction due to coronary artery spasm has been reported (3A ). • A 24-year-old man developed an acute myocardial infarction involving the anterior and inferior

Drugs of abuse

Chapter 4

walls within 3 hours of taking intravenous amfetamine. A coronary angiogram showed plaques in the mid-portion of the left anterior descending artery, which developed spasm after the administration of intracoronary ergonovine. He was discharged after treatment with verapamil, isosorbide mononitrate, and aspirin. He subsequently developed early morning chest tightness 2 weeks, 1 month, 2 months, and 9 months after discharge. On each occasion he left against medical advice.

These findings suggest that coronary artery plaques played a role in endothelial dysfunction resulting from amfetamine use, and that induction of coronary artery spasm, a finding not reported before, was the likely mechanism of amfetamine-related acute myocardial infarction.

Metamfetamine Metamfetamine has been abused for more than 80 years. It is easily synthesized in home laboratories and has a low street price, more prolonged effects, and a high potential for abuse/dependency. It is therefore not surprising that there has been a worldwide surge in its use in recent years. It is often sold as “crank”, “speed”, “shabu”, “meth”, “chalk”, “crystal”, “glass”, or “ice.” Cardiovascular A retrospective chart review was conducted to explore metamfetamine-associated acute coronary syndromes in patients who presented to the emergency room at a University Center between 1994 and 1996 (4A ). There were 36 admissions, three of which were repeat patients. Nine of these patients had acute coronary syndrome. Of these, one had an acute anterior Q wave myocardial infarction with cardiac arrest, seven had non-Q wave myocardial infarctions, and one had unstable angina. There were potentially life-threatening cardiac complications in three subjects (8%). The authors suggested that acute coronary syndromes and life-threatening complications associated with the use of metamfetamine are not uncommon, as evidenced by their experience in this study. Nervous system Subcortical hemorrhage after metamfetamine abuse has been reported (5A ).

29 • A 32-year-old woman was found comatose with left hemiplegia. A brain CT scan showed a subcortical hemorrhage in the right parietal lobe with a midline shift of more than 10 mm. Cerebral angiography did not show any vascular anomalies. A craniotomy was performed immediately to remove the hematoma. The serum metamfetamine concentration was very high at 120 ng/ml. She admitted using intravenous metamfetamine before she became unconscious. She was discharged 40 days later with a residual left hemiparesis.

The authors strongly recommended testing for drugs in young, non-hypertensive patients with angiographically negative intracranial hemorrhage. Electroencephalographic abnormalities were examined in 11 recently abstinent metamfetamine abusers and 11 non-drug-using controls (6c ). The metamfetamine-dependent subjects were hospitalized for 4 days to ensure abstinence during the study. The abstinent metamfetamine users had increased power in their electroencephalograms for lower frequency bands, with robust effects in all regions. This effect did not appear to be due to drowsiness. There was also a higher rate of generalized electroencephalographic slowing than in controls. Two of the 11 controls and seven of the 11 metamfetamine abusers had abnormal electroencephalograms. The authors contended that the patterns seen here are indicative of the development of an encephalopathy, suggesting that the neurotoxic effects of metamfetamine may contribute to electroencephalographic abnormalities. The authors suggested that these abnormalities may be associated with other cognitive dysfunction. Psychological, psychiatric The toxic effects of methamfetamine on brain neurotransmitters have been investigated (7c ). Loss of the dopamine transporter in the brain due to metamfetamine abuse was studied, in order to determine its correlation with psychiatric symptoms, in 11 abstinent metamfetamine abusers and nine healthy controls. In the metamfetamine group, the mean duration of use was 4.8 years, and the mean length of abstinence was 5.6 months. Dopamine transporter density was measured by analysing PET scans of the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala. Dopamine transporter density was significantly lower in metamfetamine abusers in all three regions. The reductions in dopamine transporter

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densities in the orbitofrontal and dorsolateral prefrontal cortices were significantly associated with the duration of metamfetamine use and with the severity of persistent psychiatric symptoms. The association of metamfetamine dependence and cognitive function in the initial stages of abstinence has been examined in 27 metamfetamine-dependent subjects and 18 non-drug using controls (8c ). The subjects were required to stop using metamfetamine and to produce a negative urine sample on the day of cognitive testing with a standard neurocognitive battery. Metamfetamine-dependent subjects had significantly impaired measures of attention, verbal learning and memory, and fluency-based measures of executive function compared with control subjects. These results suggest that metamfetamine abuse may be associated with cognitive impairment across a number of domains. The authors claimed this to be the first evidence that metamfetamine dependence is associated with a broad range of cognitive deficits, the degree of which is substantial and greater than in cocaine dependence. However, causality cannot be inferred, owing to the study design and the sample size, and it is possible that withdrawal symptoms were related to poor performance in those using metamfetamine. Death Metamfetamine-related deaths have been reported (9A ). • A 22-year-old man was found dead in a field. At autopsy, all organs were severely congested. Concentrations of metamfetamine in the heart, urine, and stomach were 0.8, 17, and 6.2 µg/ml respectively. Immunohistochemical tests on skeletal muscle showed lower than normal immunoreactivity of myoglobin, and 70-kDa heat shock protein was positive in the kidney. Because the concentration of metamfetamine in the blood was not lethal, acute intoxication was not deemed to have been the cause of death. Rather, based on the immunohistochemical findings, it was suggested that the patient had died of hyperthermia and metabolic acidosis. The patient’s muscular hyperactivity had led to hyperthermia and metabolic acidosis. • An 18-year-old woman died after taking a single dose of oral metamfetamine. The autopsy showed severe congestion and edema in the lungs. The metamfetamine concentration in blood from the heart was 17 µg/ml and metamfetamine was also found in the urine and stomach contents. This patient also had reduced concentrations of myoglobin in skeletal muscle, but there was no evidence of

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong 70-kDa heat shock protein in the kidney, in contrast to the previous case. As the concentration of metamfetamine in the patient’s heart was above the lethal concentration, she was reported to have died of acute metamfetamine intoxication.

The authors proposed that immunohistochemical staining can be useful in the diagnosis of metamfetamine poisoning. An unexpected death due to right-sided infective endocarditis has been reported in a metamfetamine abuser (10A ). • A 44-year-old female metamfetamine abuser was brought to hospital after losing consciousness. She had a low blood pressure, anuria, a high fever, and a significant increase in white blood cell count. She had many scars from previous intravenous injections and old scars of cuts from previous suicide attempts. She died 6 hours later. The postmortem metamfetamine blood concentration was 0.6 µg/ml. An autopsy showed mycotic emboli in the pulmonary artery and primary infective endocarditis in the tricuspid valve. The emboli had also been disseminated to other organs in the body. There was no evidence of acute infection at the sites of scars or intravenous injections. She was said to have died from septicemic shock due to right-sided infective endocarditis.

According to the authors, right-sided infective endocarditis, often a consequence of intravenous drug abuse, is rare and has a better prognosis than left-sided infective endocarditis. Among drug-abusers, the injected particulate matter can damage the tricuspid valve through continuous bombardment of the endothelial surface. The authors recommended a high degree of suspicion of drug abuse in right-sided infective endocarditis, even when an injection site is not visible. Fetotoxicity The effects of in utero exposure to metamfetamine on fetal growth and withdrawal symptoms have been studied (11c ). Consenting pregnant women with a positive urine toxicology screen were interviewed and followed until delivery. A control group of unexposed infants was obtained through newborn logbooks during the same time. A total of 294 mothers took part in the study, 134 in the exposed group and 160 in the unexposed group. There were no significant differences found between exposed and unexposed infants for any of the outcome measures. The percentage of infants who were small for gestational age was higher in the exposed group, but this did not

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reach significance. However, there were significant differences in the metamfetamine-exposed group. For instance, infants who were exposed to metamfetamine during all three trimesters had reduced weight and head circumference compared with infants who were exposed for only a portion of the pregnancy. Another important finding was that concurrent use of metamfetamine and nicotine resulted in significantly reduced growth parameters compared with infants who were exposed to metamfetamine alone. These results suggest that the frequency of metamfetamine use and its combination with nicotine could negatively affect the growth of a developing fetus. Withdrawal symptoms requiring pharmacological intervention were observed in 4% of metamfetamineexposed infants. Genotoxicity The genetic toxicity of metamfetamine in human abusers has been studied (12cE ). Previous research has suggested that amfetamine can act as a mutagen, so the researchers sought to understand the genotoxicity of metamfetamine. In order to obtain samples for analysis, they recruited 76 current metamfetamine abusers from a treatment facility. The control group comprised 98 healthy volunteers. Blood samples were taken from all participants, added to cultures, and incubated for 72 hours. Assays were then run for sister chromatid exchange and micronucleus, indicators of genotoxicity. The results suggested that metamfetamine abuse significantly increases the incidence of sister chromatid exchange and micronucleus compared with healthy controls. In addition, the amount of metamfetamine consumption correlated positively with the degree of increase. These results suggest that metamfetamine is a genotoxic agent whose effects are dose-related. The authors speculated that long-term metamfetamine abuse produces high concentrations of reactive oxygen species, which in turn consume natural antioxidants and scavengers in the body. This reduction could make a person more vulnerable to genotoxicity.

Methylenedioxymetamfetamine (MDMA, ecstasy) MDMA, commonly known by names such as “ecstasy“, “XTC”, “E”, or “Love Drug”, was

31 synthesized in 1914 for use in chemical warfare, but has more recently become a popular drug of abuse among young people, especially at “raves”. It is relatively easy to obtain and is erroneously regarded as a safe drug. The toxic effects of ecstasy have been reported in seven individuals who took it in a nightclub and developed varying degrees of MDMA toxicity (13A ). Three collapsed in or around the nightclub and arrived in an ambulance. Four came in themselves. • A 20-year-old man collapsed at the nightclub. He had tachycardia, hypotension, hyperglycemia, hyperthermia, and significant hyperkalemia. He was ventilated but died 1 hour later. • A 22-year-old man collapsed after falling 15 feet through a glass roof into a stairwell. He was comatose and had hypoglycemia, tachycardia, hypotension, hyperthermia, raised liver enzymes, significantly raised creatine kinase activity, and hyperkalemia. Although he was treated vigorously, metabolic acidosis persisted. He developed significant myoglobinuria and his creatine kinase activity peaked at 215 000 IU/l. His liver, kidney, respiratory, and cardiovascular function started to fail and he died 58 hours after admission. • An 18-year-old man was found collapsed outside the nightclub. He had taken five ecstasy tablets and some “powder” that was later confirmed as ecstasy. He was vomiting and agitated, had a tachycardia and hyperthermia, and needed mechanical ventilation. He later developed rhabdomyolysis and renal impairment with raised liver enzymes. He went on to develop pneumonia and a urinary tract infection. He was discharged after 32 days with a mildly ataxic gait and dysphonia secondary to vocal cord damage. • A 23-year-old man took two tablets of ecstasy and developed a tachycardia and a fever, which responded to treatment. • An 18-year-old man took four tablets of ecstasy and became anxious but showed no clinical signs of MDMA toxicity. • An 18-year-old woman took two tablets and had no clinical signs of toxicity except a tachycardia. • A 17-year-old man took one ecstasy tablet and was well without any symptoms.

No other drugs were detected in the serum samples from any of these patients. Detailed analyses of the tablets obtained from the patients showed ecstasy and no contaminants. The authors commented on the unpredictable nature of toxicity with ecstasy, especially when death can occur with one tablet in some cases, while others survive even after they have consumed large quantities. In this series there was no correlation between the amount of ecstasy taken and the resulting serum MDMA concentration

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in most patients. However, high serum concentrations correlated with the severity of symptoms, including death. The local news headlines prominently implied that “poisoned” ecstasy had led to death when in fact there was no contamination. The authors suggested that such headlines lead people to believe erroneously that ecstasy use is safe except when it is contaminated. Cardiovascular Atrial fibrillation after use of ecstasy has been reported (14A ). • A 17-year-old previously healthy man had a generalized tonic–clonic seizure. He denied drug abuse, but his urine drug screen was positive for ecstasy. He had an irregular heart rhythm with a normal blood pressure. An electrocardiogram showed atrial fibrillation with a ventricular rate of 102/minute. His routine laboratory investigations, a brain CT scan, and an electroencephalogram were normal. There were no underlying cardiac lesions. He was stabilized with medical treatment and was doing well 6 months later.

Since atrial fibrillation is unusual in young people, the authors speculated that ecstasy may have contributed in this case even though this adverse effect has not been reported before. Nervous system Parkinsonism associated with ecstasy use has been reported (15A ). • A 38-year-old man developed Parkinsonism that progressed to Hoehn and Yahr stage 5 within 4 years of onset. Treatment with ropinirole resulted in further deterioration, levodopa was not tolerated, and subthalamic nucleus stimulation provided only partial relief. The patient reluctantly reported heavy use of ecstasy through most of his twenties and thirties. He had a family history of Parkinsonism, but other investigations to determine the underlying cause, such as urine copper and heavy metals, were non-contributory.

The authors cautioned against making a strong link between ecstasy use and parkinsonian symptoms, because there are other potential toxins that could have caused it and the use of ecstasy may have been coincidental. Impaired cerebral blood flow after ecstasy intoxication has been reported (16A ). • A 19-year-old woman had a grand mal seizure 4 hours after taking 10 ecstasy tablets and developed coma, hyperthermia, tachycardia, tachypnea, raised liver enzymes, and renal insufficiency. After wakening, she reported hallucinations, helplessness, panic attacks, and amnesia, though she was

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong oriented. Her brain CT and MRI scans were normal. Her urine toxicology screen was positive for ecstasy and opiates. A SPECT study 20 days after intoxication showed reduced non-homogeneous supratentorial tracer uptake bilaterally, suggesting hypoperfusion. Electroencephalography showed diffuse slowing and occasionally generalized sharp waves. After treatment with valproic acid, she had slight amnesia, her neuropsychological deficits disappeared, and the SPECT scan normalized 29 days later, followed by normalization of the electroencephalogram.

The authors thought that the abnormal SPECT scan was best explained by reduced cerebral blood flow due to vasoconstriction, which could have been due to ecstasy-induced reduction in serotonin. Two cases of non-aneurysmal subarachnoid hemorrhage associated with ecstasy have been reported (17A ). • A 29-year-old woman had a sudden severe occipital headache and photophobia with nausea and vomiting. She had marked nuchal rigidity. Her head CT scan was normal, but the CSF was bloodstained with spectrophotometric evidence of xanthochromia. Cerebral angiography showed beading of vessels in the posterior circulation. However, MRI/MRA did not show any abnormality and the ESR was normal. The patient admitted to having used ecstasy for the first time. Cerebral angiography 2 months later showed that the abnormalities had completely resolved. • A 24-year-old man smoked marijuana and then consumed one and a half ecstasy tablets at a party, and several hours later had a sudden severe retroorbital headache and felt unwell. Shortly later, he had a generalized tonic–clonic seizure, after which he was alert and oriented with an unremarkable neurological examination. He then had another seizure and a brain CT scan showed a subarachnoid hemorrhage, localized to several parasaggital sulci towards the vertex. Cerebral angiography showed focal beading of peripheral branches to the right anterior cerebral cortex, consistent with arteritis.

In both cases, angiography suggested vasculitis, when there was subarachnoid hemorrhage in the absence of a vascular malformation, probably associated with the use of ecstasy. The authors recommended that an accurate drug history is essential in any young person with a subarachnoid hemorrhage. The precise etiology of ecstasy-associated subarachnoid hemorrhage is not known. Psychological In 430 regular ecstasy users, a semi-structured interview was administered

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to evaluate the psychological effects of different patterns of ecstasy use in men and women (18c ). Factor analysis established three main categories of acute effects of ecstasy – namely positive and negative effects on mental health and physical effects. In terms of subacute effects, 83% reported low mood and 80% reported impaired concentration between ecstasytaking sessions. Susceptibility factors influencing these effects included age, sex, extent of ecstasy use, and concomitant use of cocaine or amfetamine. Specifically, the individuals who had mid-week lows were older than those who did not, and in men length of use was also a significant factor. Women who reported impaired concentration between ecstasy-taking sessions were older than those who did not. Surprisingly, men who had mid-week lows consumed ecstasy less often. This may be because they were aware, based on their previous experience, that higher consumption leads to an increase in midweek symptoms. The most common long-term effects included tolerance to ecstasy (59%), impaired ability to concentrate (38%), depression (37%), and feeling more open towards people (31%). In terms of what might persuade abusers to stop using ecstasy, their most prominent concern was the drug’s long-term effects on mental health. Those who took cocaine with ecstasy had higher scores on the negative effect factor. In one study, investigators used a working memory task and functional magnetic resonance imaging (f MRI) to investigate cerebral activation in 11 previously heavy but currently abstinent ecstasy users and two equal-sized groups of moderate users and non-users (19c ). Surprisingly, there were no significant group differences in working memory and no differences in cortical activation patterns for a conservative level of significance. However, ecstasy users had stronger activation in the right parietal cortex than controls. Furthermore, heavy users had a weaker blood oxygenation level-dependent (BOLD) response than moderate users and controls. Although these results suggest subtly altered brain functioning associated with prior use of ecstasy, the authors cautioned that an alternative interpretation of the group differences must be considered. The ecstasy users in this study had also used other amphetamines and cannabis, further confounding the data. A meta-analysis of 10 studies that met a priori inclusion/exclusion criteria evaluated the

33 possible functional neurotoxic effects of ecstasy use in humans on verbal short-term memory, verbal long-term memory, processing speed, and percent errors (attention) (20M ). The mean effect sizes were significant. Ecstasy users had poorer verbal short-term memory and long-term memory, reacted more slowly, and made more errors. However, the meta-regressions of effect sizes against total lifetime ecstasy consumption were not significant, and the effect sizes for long-term memory became insignificant, suggesting that ecstasy does not impair long-term memory. Although the conclusions were based on a very low number of studies, the results supported the idea that chronic ecstasy use impairs short-term memory. There was no support for a link between lifetime ecstasy consumption and functional neurotoxicity. The author suggested that there may be a stepwise relation rather than a continuous one. Moreover, it is possible that the damage threshold is reached after the first few doses of ecstasy, so that lifetime use does not matter. Furthermore, apparent neurotoxic effects of ecstasy may actually be due to the effects of concomitant drugs used, such as alcohol. In an analysis of the nature of cognitive deficits in ecstasy users, 60 currently abstinent ecstasy users and 30 non-users were given memory tests (21c ). Heavy ecstasy users (n = 30; lifetime dose at least 80 ecstasy tablets) had poorer memory than both non-users and moderate users (n = 30). However, there were no group differences in central executive function, working memory, planning ability, and cognitive impulsivity between ecstasy users and controls. Poorer memory was associated with a heavier pattern of ecstasy use. Poor memory performance did not predict poor working memory, planning ability, central executive control, or high cognitive impulsivity. Thus, the authors concluded that primary memory dysfunction in heavy ecstasy users (lifetime consumption of about 500 ecstasy tablets) may be related to a particularly high vulnerability of the hippocampus to the neurotoxic effects of ecstasy. Hippocampal dysfunction after the use of ecstasy may be a susceptibility factor for earlier onset and/or more severe age-related memory impairment in later years. Psychiatric Ten heavy ecstasy users and 10 age-matched controls underwent single-pulse

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transcranial magnetic stimulation (TMS) of the occipital cortex to evaluate the hypothesis that use of ecstasy can increase excitability in the visual cortex, which can result in visual hallucinations (22c ). Transcranial magnetic stimulation can elicit conscious subjective light sensations (phosphenes) in the absence of visual stimuli. The minimum intensity that evokes phosphenes, also known as the phosphene threshold, is thought to be a useful measure of cortical excitability. The phosphene threshold was significantly reduced in ecstasy users compared with controls and correlated negatively with the frequency of ecstasy consumption but not the duration of ecstasy use. The phosphene threshold of subjects with hallucinations was lower than that of subjects without hallucinations. However, the presence of hallucinations correlated directly with the frequency of ecstasy use. The authors suggested that this may represent neurotoxicity of ecstasy linked to massive serotonin release, followed by serotonin depletion in this cortical area. Although alterations in serotonergic systems after the use of ecstasy have been documented, it is unclear whether these neurotoxic effects are reversible. In 117 subjects who underwent PET studies using a serotonin transporter (SERT) ligand, 30 subjects were actual ecstasy users, 29 were former ecstasy users, 29 were drug-naïve controls, and 29 were using drugs other than ecstasy. The distribution volume ratios in ecstasy users were significantly reduced in the mesencephalon and the thalamus (23c ). The distribution volume ratio in former ecstasy users was very close to that in drug-naïve controls in all brain regions. The distribution volume ratio in poly-drug users was slightly higher than that in the naïve group. The authors therefore concluded that ecstasy causes protracted but fully reversible alterations in the serotonin transporter. However, this does not imply full reversibility of the neurotoxic effects. Two cases of ecstasy abuse with unusual neuropsychiatric complications have been reported (24AR ). • A 24-year-old man had perinatal asphyxia and subsequently a slight delay in psychomotor development. At age 3–4 years, he had problems in school because of ADHD and had difficulty with relationships, persisting into adulthood. From age 21 he abused ecstasy and marijuana. He suffered a “horror trip” with a panic attack after

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong using LSD at age 23. Although he abstained from LSD, he used more ecstasy and cannabis. Three months later, he developed a psychosis. He was anxious and paranoid and reported bizarre delusions and auditory and visual hallucinations. He had a normal brain CT scan and no medical, neurological, or laboratory abnormalities. Electroencephalography showed normal basal activity, with paroxysmal discharges in both temporal regions but no evidence of seizures. The diagnosis was paranoid schizophrenia and he was treated with antipsychotic drugs, with progressive improvement over 6 weeks. After discharge, he stopped taking his medications and resumed sporadic ecstasy and cannabis abuse. Drug intake was often followed by short-lasting prepsychotic decompensation with increased impulsivity and hyperactivity. However, he recovered after such episodes within 2–3 days without any antipsychotic medication. • A 23-year-old woman who had been heroin dependent for several years and was taking methadone maintenance and who had abused cannabis and benzodiazepine in the past, used ecstasy for the first time and within 3 hours developed a wide range of sympathomimetic symptoms, including tachycardia, tremor, mydriasis, and headache. She felt extremely anxious, had psychomotor agitation, and was incoherent in thinking and disoriented in time and place. Her urine drug screen was positive for benzodiazepines, cannabis, and ecstasy. Electroencephalography suggested temporal lobe epilepsy with a normal CT scan. She then had two series of four and five complex-partial seizures, two with secondary tonic-clonic generalization. Although her psychotic symptoms persisted for a while, even with treatment, her seizures responded well to anticonvulsant drugs (phenobarbital 100 mg/day, clonazepam 3 mg/day, and diazepam as required) and her electroencephalogram normalized.

While acknowledging that only a minority of ecstasy users develop psychosis and even fewer develop seizures, the authors argued that symptoms suggestive of toxic psychosis were present in both cases and that the electroencephalographic abnormalities showed seizure activity. They suggested that individuals with potential genetic vulnerability to psychosis and seizures may be at higher risk when they use ecstasy, especially in combination with cannabis. Nutrition In a study of plasma concentrations of 33 amino acids, 159 subjects were recruited, of whom 107 were ecstasy users (25c ). The subjects were grouped according to cumulative lifetime use: under 100 tablets (n = 34), 100– 499 tablets (n = 42), 500–2500 tablets (n = 30), abstinent subjects (n = 11), and never users (n = 41). All were ecstasy free for at least 3

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days, as verified by toxicological analysis. In 49% of the users, the time to the last use of ecstasy was 1 month or less. There were significant reductions in the serum concentrations of phosphoserine, glutamate, citrulline, methionine, tyrosine, and histidine. Based on findings from other studies, the authors speculated that the reductions in serine and methionine may underlie psychosis associated with the use of ecstasy. Reduced glutamate may also add to the burden of psychiatric symptoms in ecstasy users. Electrolyte balance Hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported (SEDA-23, 36; SEDA-25, 37). • A previously healthy 18-year-old woman had an altered mental state after using ecstasy, followed by excessive thirst and consumption of a lot of water within a few hours (26A ). She became anxious, remorseful, and mildly agitated, with visual hallucinations. She vomited several times, became lethargic and unresponsive, and had pronounced bruxism. Her pupils were dilated with a sluggish response, she was hypothermic, and she had a serum sodium concentration of 124 mmol/l; serum and urine osmolalities suggested SIADH and serum ADH concentration was inappropriately high. A urine drug screen was only positive for amphetamines. She was given isotonic saline, and her sodium concentration fell further to 114 mmol/l. She was given hypertonic saline and recovered completely after medical treatment.

The combination of SIADH and excessive fluid intake after the use of ecstasy played a significant role in causing water intoxication, which was worsened by isotonic saline in the early stages of treatment. The authors reviewed the literature, and found that 17 of the reported 18 cases were young women aged 15–30 and the majority admitted taking only one tablet along with large quantities of fluid. The interval between the consumption of ecstasy and the onset of symptoms was 4–24 hours, with serum sodium concentrations of 101–130 mmol/l. There were three deaths and all were women. Hyperthermia was extremely rare (one case). Initial treatment appears to have played an important role in reducing mortality. When treatment other than hypertonic saline was used initially, there was a higher risk of death. The authors strongly recommended a high degree of suspicion of water intoxication and aggressive treatment with hypertonic saline instead of diuretics and water restriction.

35 Mouth Oral complications of topical application of ecstasy have not been described previously (27A ). • A 15-year-old boy developed an atraumatic painful swelling of the upper lip, fever, and malaise. He had good oral hygiene and no pathological periodontal pockets, but there was a swelling of the maxillary labial vestibule in relation to the upper central incisors. Both maxillary central incisors had grade II mobility and were tender to percussion. The dentoalveolar abscess was incised and drained and culture yielded commensal oral flora. His white cell count was normal with raised eosinophils; the ESR was slightly raised at 23 mm/hour and he had a mild rise in hepatic enzymes. He had used ecstasy 1 day before the onset of symptoms and had stored the drug in the upper anterior labial vestibule adjacent to the site of periodontal destruction. He denied previous use of ecstasy or other recreational drugs.

The authors diagnosed local drug-induced necrotizing gingivitis and said that although similar lesions have been reported with local cocaine, none has been reported with ecstasy. Urinary tract Transient proximal tubular renal injury following ecstasy has been reported (28A ). • An 18-year-old woman presented with new onset seizures and polydipsia. She had a hyponatremia of 117 mmol/l, polyuria for several hours, renal glycosuria with urine glucose of over 55 mmol/l, a blood glucose of 6.6 mmol/l, and solute diuresis. She had low tubular reabsorption of phosphorus, with an appropriate transtubular potassium gradient of 3.0 and a serum potassium of 3.7 mmol/l. After medical treatment and gradual correction of her hyponatremia, her tubular reabsorption of phosphorus normalized and her glycosuria resolved. An extensive drug screen was positive for ecstasy.

The authors thought that this was the first report of acute transient proximal tubular injury with ecstasy. In contrast to SIADH, there was a high urine output in the presence of hyponatremia and solute diuresis. Urinary retention has been reported (29A ). • A 17-year-old male developed abdominal pain and urinary retention after taking ecstasy the previous evening. He had a tachycardia, mydriasis, and a tender suprapubic mass, which resolved with catheterization. He was discharged the next day.

The authors suggested that ecstasy had caused release of noradrenaline, which had caused urinary retention through alpha-adrenoceptor stimulation.

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Death Deaths related to ecstasy either alone or in combination with other drugs have been reported from England and Wales using the National Programme on Substance Abuse Deaths (np-SAD) database (30c ). This database receives information about all drug-related deaths from coroners. A total of 202 ecstasy related deaths occurred in the period from 1996 to 2002. There was a steady increase in the number of deaths each year. The male to female ratio was 4 : 1 and 75% of the victims were under 29 years. In 17% of cases, ecstasy was the sole drug implicated in death, and in the other cases a number of other drugs (mainly alcohol, cocaine, amfetamine, and opiates) were found. Based on toxicology reports, MDMA accounted for 86% of the cases and 3,4-methylenedioxyamfetamine (MDA) for 13% of the cases. There was one death each associated with 3,4-methylenedioxy-N -ethylamfetamine (MDEA) and paramethoxyamfetamine (PMA). The authors reported that this was the largest sample of ecstasy-related deaths on record, with a death-rate of 3.4 per month; 31% of the subjects were living independently and 25% were with parents; 47% were employed and 10% were students; 49% died at home and 39% in hospitals. The most frequent verdict by the coroner was accident/misadventure at 49%. The authors commented on the possible reasons for the increase in the number of deaths from ecstasy. Specifically, the UK has possibly the greatest availability of ecstasy among all European Union countries. Unfortunately, with increased use and supply, the purchase price of ecstasy tablets has fallen significantly over the years to nearly half its original price. Moreover, it is not uncommon for more lethal forms of amphetamines to be passed off as ecstasy. With increased publicity and awareness, coroners may have improved and thereby increased their reporting of such deaths. There is a particular concern that deaths from ecstasy tend to occur in younger individuals. The authors speculated that multiple compounds were probably consumed, in order to boost the effects of the single compound or to overcome its untoward effects. In such cases, death possibly occurred from the cumulative effects of all the drugs used. Drug interactions There have been four deaths after interactions of moclobemide, a monoamine oxidase A inhibitor, with ecstasy (31A ).

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong • An 18-year-old woman took an unknown quantity of ecstasy and the next day became confused and had seizures, loss of consciousness, and respiratory arrest. At autopsy, no cause of death was found. There were no specific findings on histology except visceral hyperemia. MDMA, moclobemide, and some alcohol were found in the blood. There was no history of mental illness or evidence of prescription drugs. • A 23-year-old man was found dead in his apartment, having previously been confused. At autopsy there was no clear cause of death. His urine was positive for amphetamines, opiates, moclobemide, dextromethorphan, cyclizine, oxazepam, diazepam, and temazepam. The coroner concluded that the death was from a combination of ecstasy and moclobemide, with a possible contribution from dextromethorphan. • An 18-year-old man with a long history of amfetamine abuse became confused, was rolling about on the ground, and then collapsed and died. He had ecstasy and moclobemide in his possession. Autopsy did not show a clear cause of death. His urine was positive for amphetamines and marijuana. Histology showed congestion in the brain, liver, kidney, and lungs and signs of aspiration. The cause of death was recorded as accidental poisoning from moclobemide and ecstasy. • A 19-year-old man took 10 ecstasy tablets and became unconscious, had problems breathing, and later died. At autopsy, his lungs were edematous and there was general visceral congestion. His blood contained MDMA, MDA, cannabis, and moclobemide. The cause of death was recorded as having been due to the combination of moclobemide and ecstasy.

The authors suggested that the serotonin syndrome possibly occurred as a result of the combination of moclobemide and ecstasy, although it was not clear why the combination had been used.

CANNABINOIDS

(SED-14, 95; SEDA-25, 43; SEDA-26, 36; SEDA-27, 32) Cardiovascular Coronary no-flow and ventricular tachycardia after habitual marijuana use has been reported (32A ).

• A 34-year-old man developed palpitation, shortness of breath, and chest pain. He had smoked a quarter to a half an ounce of marijuana per week and had taken it 3 hours before the incident. He had ventricular tachycardia at a rate of 200/minute with a right bundle branch block pattern. Electrical cardioversion restored sinus rhythm. Angiography showed a significant reduction in left anterior descending coronary artery flow rate, which was

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normalized by intra-arterial verapamil 200 micrograms.

The authors thought that marijuana may have enhanced triggered activity in the Purkinje fibers along with a reduction in coronary blood flow, perhaps through coronary spasm. Postural syncope after marijuana use has been studied in 29 marijuana-experienced volunteers, using transcranial Doppler to measure cerebral blood velocity in the middle cerebral artery in response to postural changes (33C ). They were required to abstain from marijuana and other drugs for 2 weeks before the assessment, as confirmed by urine drug screening. They were then given marijuana, tetrahydrocannabinol, or placebo and lying and standing measurements were made. When marijuana or tetrahydrocannabinol was administered, 48% reported a dizziness rating of three or four and had significant falls in standing cerebral blood velocity, mean arterial blood pressure, and systolic blood pressure. Eight subjects were so dizzy that they had to be supported. The authors suggested that marijuana interferes with the protective mechanisms that maintain standing blood pressure and cerebral blood velocity. All but one of the subjects who took marijuana or tetrahydrocannabinol reported some degree of dizziness. Women tended to be dizzier. As the postural dizziness was significant and unrelated to plasma concentrations of tetrahydrocannabinol or other indices, the authors raised concerns about marijuana use in those who are medically compromised or elderly. Psychological The effect of regular marijuana use on binocular depth perception has been examined using the Binocular Depth Inversion Illusion (BDII) to identify individuals with an impairment of “top down” processing in perceptual networks in 10 regular users of marijuana and 10 healthy, non-cannabis-using controls (34c ). The subjects had consumed marijuana at least every other day for a full year. The results suggested that regular marijuana users had significantly higher scores on the BDII, which implies subtle neurocognitive impairment that affects the sensory system involved in correcting ambiguous perceptions. The authors proposed that these impairments are similar to those seen in individuals with schizophrenia, and that cannabis use could be an independent risk factor for the development of schizophrenia.

37 Immunologic The effects of cannabinoids on the immune system have been examined in two separate studies. In the first of these the effects of oral cannabinoids on immune functioning were studied in 16 patients with multiple sclerosis in a crossover study of dronabinol, Cannabis sativa plant extract, or placebo for 4 weeks (35C ). There was a modest increase in pro-inflammatory cytokine tumor necrosis factor alfa during cannabis plant extract treatment in all the subjects. Those with high adverse event scores (n = 7) had significant increases in pro-inflammatory plasma cytokine IL-12p40 while taking the plant extract; this was not the case with tetrahydrocannabinol. Other cytokines were not affected. Tumor necrosis factor alfa and IL-12p40 are known to worsen the course of multiple sclerosis (36c ). These results are interesting because they suggest immunoactivation by cannabinoids in patients with multiple sclerosis, rather than immunosuppression, as previously reported with the plant extract (37c ). More studies are needed, because these pro-inflammatory effects could have negative influence on the course of the disease. Nervous system It has previously been reported that long-term marijuana altered the electroencephalogram during abstinence (38C ). In 29 individuals who met DSM-III R criteria for marijuana dependence or abuse and 21 drug-free controls, electroencephalograms were recorded for 3 minutes (39c ). Marijuana abusers had significantly lower log power for the theta and alpha1 bands during abstinence compared with controls. The authors also observed increased cerebrovascular resistance using transcranial Doppler sonography in an overlapping sample of marijuana abusers. They proposed that this combination of electroencephalographic findings and changes in cerebral blood flow may explain cognitive deficits reported in chronic marijuana users. Fetotoxicity The consequences of prenatal exposure to marijuana have previously been reported (SEDA-25, 44). In another report the same group examined the effects of prenatal marijuana exposure on cognitive functioning in 145 children aged 13–16 years (40c ). The age breakdown was 45 13-year-olds, 36 14year-olds, 51 15-year-olds, and 13 16-year-olds. These groups were further classified by maternal marijuana use: less than six joints per

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week (n = 120) and six or more joints per week (n = 25). A standard neurocognitive test battery was administered, and two of the tests differed significantly between non-users/light users and heavy users. On the Abstract Designs test the children of heavy users had significantly slower response times. Children in the heavy user group also scored significantly lower on the Peabody Spelling test. These results suggest a dose-related effect of prenatal marijuana exposure on cognition. The two tests that differed across groups depend, to a lesser degree, on cognitive manipulation or comprehension and, to a greater degree, on visual memory, analysis, and integration. Unlike cigarette exposure, marijuana does not seem to affect overall intelligence. It is therefore possible that heavy marijuana use during pregnancy causes subtle deficits in visual analysis. Susceptibility factors HIV infection The use of cannabinoids has been studied in 62 patients with HIV-1 infection (41C ). Cannabinoids and HIV are of interest because there is the chance of an interaction between tetrahydrocannabinol and antiretroviral therapy. Tetrahydrocannabinol inhibits the metabolism of other drugs (42c , 43c ) and cannabinoids are broken down by the same cytochrome P-450 enzymes that metabolize HIV protease inhibitors. The subjects were randomly assigned to marijuana, dronabinol (synthetic delta-9-tetrahydrocannabinol), or placebo, given three times a day, 1 hour before meals. The amounts of HIV RNA in the blood did not increase significantly over the course of the study and there were no significant effects on CD4+ or CD8+ cell counts. However, there was significant weight gain in both cannabinoid groups compared with placebo. Although this study was of very short duration, the results suggested that either oral or smoked marijuana may be safe for individuals with HIV-1.

COCAINE (SED-14, 106; SEDA-25, 40; SEDA-26, 27; SEDA-27, 33) Hospital visits related to cocaine use have been increasing over the past 10 years and the cost of cocaine-related hospitalization in the USA is now more than $80 million a year.

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong

Cardiovascular The incidence of acute myocardial infarction in cocaine-associated chest pain is small but significant (44R ). The electrocardiogram has a higher false-positive rate in these patients. A normal electrocardiogram reduces the likelihood of myocardial injury but does not exclude it. Cocaine use may account for up to 25% of acute myocardial infarctions among patients aged 18–45 years. The safety of a 12-hour observation period in a chest pain unit followed by discharge in individuals with cocaineassociated chest discomfort who are at low risk of cardiovascular events has been evaluated in 302 consecutive patients aged 18 years or older (66% men, 70% black, 84% tobacco users) who developed chest pain within 1 week of cocaine use or who tested positive for cocaine (45c ). Cocaine use was self-reported by 247 of the 302 subjects and the rest had urine positive for cocaine; 203 had used crack cocaine, 51 reported snorting, and 10 had used it intravenously. Of the 247 who reported cocaine use, 237 (96%) said they had used it in the week before presentation and 169 (68%) within 24 hours before presentation. Follow-up information was obtained for 300 subjects. There were no deaths from cardiovascular causes. Four patients had a non-fatal myocardial infarction during the 30-day period; all four had continued to use cocaine. Of the 42 who were directly admitted to hospital, 20 had acute coronary syndrome. The authors suggested that in this group of subjects, observation for 9–12 hours with follow-up is appropriate. Fiberoptic bronchoscopy is often done after intratracheal injection of 2.5% cocaine solution and lidocaine spray. Acute myocardial infarction after fiberoptic bronchoscopy with intratracheal cocaine has been reported (46A ). • A 73-year-old man with a history of breathlessness, cough, and weight loss had some ill-defined peripheral shadow in the upper zones of a chest X-ray. He had fiberoptic bronchoscopy with cocaine and lidocaine and 5 minutes later became distressed, with dyspnea, chest pain, and tachycardia. Electrocardiography showed an evolving anterior myocardial infarction. Coronary angiography showed a stenosis of less than 25% in the proximal left anterior descending artery with coronary artery spasm. He made an uneventful recovery.

The authors suggested that the principal cardiac effects of cocaine can be attributed

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to or are mediated by the following mechanisms: increased myocardial oxygen demand due to an acute rise in systemic blood pressure and heart rate; coronary vasoconstriction caused by alpha-adrenergic effects and calcium-dependent direct vasoconstriction; and promotion of arteriosclerosis and endothelial dysfunction, which predisposes to vasoconstriction and thrombosis. The hypothesis that cocaine users have increased coronary microvascular resistance, even in the absence of recent myocardial infarction, coronary artery disease, or spasm, has been assessed in 59 consecutive cocaine users without acute or recent myocardial infarction or angiographically significant epicardial stenosis or spasm (47c ). Microvascular resistance was significantly increased by 26–54% in cocaine users. There was an abnormally high resistance in the left anterior descending artery in 61% of the patients, in the left circumflex artery in 69%, and in the right coronary artery in 47%. Increased microvascular resistance may explain many important cardiovascular effects of cocaine and has therapeutic implications. For example, slow coronary filling in diagnostic tests may suggest the possibility of cocaine use in patients in whom it was not otherwise suspected. There was increased microvascular resistance in the coronary bed even after the acute effects of a dose of cocaine would have worn off, suggesting that cocaine may have long-lasting effects on coronary microvasculature. This implies that medical therapy of vasoconstriction should be continued for extended periods. Moreover, heightened microvascular resistance in cocaine users may explain the development of chest pain and myocardial ischemia in patients who do not have epicardial stenosis due to coronary artery disease or spasm. The authors suggested that in the absence of coronary artery disease, the small vessel effects of cocaine may be more important. As the process is diffuse rather than confined to one vascular territory, electrocardiographic findings may not be localizing. In another report of cocaine-associated chest pain, the authors studied the incidence and predictors of underlying significant coronary disease in 90 patients with and without myocardial infarction (48c ). Patients with 50% or more stenosis of coronary arteries or major branches or bypass graft were included and 50% of them

39 had significant disease: one-vessel disease in 32%, two-vessel disease in 10%, three-vessel disease in 6%, and significant graft stenosis in 3%. There was significant disease in 77% of patients with myocardial infarction or a raised troponin I concentration, compared with 35% of patients without myonecrosis. Predictors of significant coronary disease included myocardial damage, a prior history of coronary disease, and a raised cholesterol level. Only seven of the 39 patients without myonecrosis or a history of coronary disease had significant angiographic disease. The authors concluded that significant disease is found in most patients with cocaineassociated myocardial damage. In contrast, only a minority of those without myonecrosis have significant coronary disease. Spontaneous acute coronary dissection after cocaine abuse has been reported (49A ). • A 34-year-old woman developed chest pain suggestive of acute coronary syndrome, having inhaled cocaine 30 minutes before. Her blood pressure was 180/100 mmHg and an electrocardiogram showed sinus rhythm with anterolateral ischemia, ST segment depression, and T wave inversion. An echocardiogram showed a large hypokinetic area, including the middle and apical segments of the anterior septum and the anterior and lateral walls, and mild reduction in the left ventricular ejection fraction (45%). Troponin I and creatine kinase were slightly raised but the MB fraction was normal. Unstable angina was diagnosed but despite full medical therapy, the chest pain and ischemic changes did not resolve. Immediate catheterization showed a dissection flap within the left main trunk extending to the proximal portion of the descending anterior and circumflex arteries. There was no atherosclerosis in the coronary vessels. The flap resulted in a 90% stenosis of the proximal left anterior descending artery. Urgent coronary artery bypass surgery was successful.

Spontaneous coronary artery dissection is an unusual cause of acute coronary syndrome. Only three other cases secondary to cocaine use have been described. Aortic thrombus and renal infarction has been reported in a patient who used nasal cocaine (50AR ). • A 52-year-old woman with a history of hypertension for 15 years developed acute left flank pain, nausea, and vomiting. On a previous similar occasion 2 weeks before she had a trace of proteinuria and microscopic hematuria. A contrast-enhanced CT scan of the abdomen had not shown stones, hydronephrosis, or morphological abnormalities. She

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had no rash. Her urine contained cocaine. Creatine kinase and lactate dehydrogenase activities were raised and there was a leukocytosis. A second abdominal CT scan with contrast showed a segmental infarct of the left kidney. A transesophageal echocardiogram showed a 2 × 2 cm mobile mass, consistent with a thrombus, attached to the aortic arch, distal to the left subclavian artery. There was no evidence of atherosclerosis. She was given anticoagulants and aggressive fluid therapy for rhabdomyolysis.

The authors speculated that cocaine may have caused aortic inflammation by assuming that cocaine-related increased sympathetic tone along with possible cocaine-related aortic inflammation (similar to reported cases of cocaine-related vascular injury) may have led to enhance aggregation of platelets at the inflamed area, which would act as a nidus to form a thrombus. The thrombus resolved with anticoagulation within 13 days and similar results have been reported before (51A ). The patient had very high creatine kinase activity, suggesting rhabdomyolysis, which could have been caused by intense cocaine-related vasoconstriction. Respiratory Pneumomediastinum and bilateral pneumothorax have again been attributed to cocaine (52A ). • A 22-year-old previously healthy man presented with acute sore throat awakening him from sleep. He had palpable crepitation due to extensive cervical subcutaneous emphysema. A chest X-ray showed a pneumomediastinum and bilateral apical pneumothoraces. CT scan did not show any underlying lung disease. Bronchoscopy was unremarkable except for a swollen nasal mucosa and acute bronchitis. Bronchoalveolar lavage was normal without evidence of infection. The patient reported repeated cocaine consumption. No tube drainage was necessary and the air collections resolved spontaneously within days.

Crack, the heat stable form of cocaine, when smoked and followed by deep inhalation plus a Valsalva maneuver to increase uptake, and cough triggered by the sniffed substance can cause pulmonary barotrauma. The increased intra-alveolar pressure can cause alveolar rupture, with consequent air dissection through the peribronchial connective tissue in the mediastinum, pleural space, pericardium, peritoneum, or subcutaneous soft tissues. Empyema-like eosinophilic pleural effusion following the use of smoked crack cocaine has been reported (53A ).

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong • A 33-year-old man developed a fever of 104◦ F, sweats, and a productive cough 1 week after using crack cocaine. He had diffuse wheezes at the lung apices and apical infiltrates and pleural effusions on CT scan. He had a raised white cell count at 18 × 109 /l with 45% eosinophils. He was negative for acid-fast bacilli, HIV, and fungi. There was no history of travel or exposure to ill contacts or other medications. Pus-like pleural fluid 500 ml, drained from a left pneumothorax, was an exudate with large number of white cells with 80% eosinophils. Cultures of blood, sputum, bronchoalveolar lavage fluid, and pleural fluid were negative for bacteria and fungi. The bronchoalveolar lavage fluid contained many eosinophils and transbronchial biopsy showed an acute inflammatory infiltrate, with many eosinophils, edema, and no fibrosis, consistent with eosinophilic pneumonitis. The symptoms improved after chest drainage and glucocorticoid treatment. His illness resolved 1 month after discharge.

The authors speculated that a leak mediator, vascular endothelial growth factor, present in eosinophils, and cytokines implicated in the effects of cocaine and eosinophil activation may have contributed to the pleural effusion. They found the highest concentration of vascular endothelial growth factor ever reported at 20 ng/ml and increased pleural concentrations of IL-5, IL-6, and IL-8, suggesting potential roles for these cytokines in eosinophilic lung disease due to cocaine. They recommended that a pleural effusion that appears grossly to be pus in the setting of cocaine abuse should not be drained until an eosinophil predominant effusion is ruled out. If infection is excluded, an eosinophilic empyema in the setting of inhaled cocaine abuse should be treated with glucocorticoids and may not require drainage. Ear, nose, and throat All reports of cocaineinduced midline destructive lesions have been reviewed, and retrospective data involving 25 cases have been reported (54Ac ). All but three subjects admitted to cocaine abuse during the initial evaluation. There were 15 men and 10 women with a mean age of 36 years (range 22–66 years) and they had abused cocaine for 2–30 years, at a dose of 1–180 g/week. At rhinoscopy, all had necrotizing ulcerative lesions, extensive crusting, and septal perforation. The destructive process extended to the inferior (68%), middle (44%), and superior turbinates (16%). There were hard and/or soft palate perforations in six patients (24%); the lateral wall of the nose was entirely reabsorbed in five.

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The lesions caused both dysphagia and nasal reflux. In two subjects there was ulceration at the base of the columella at diagnosis. During follow up, two patients developed a nasocutaneous fistula. At diagnosis or during follow-up, none had any laboratory finding suggestive of a systemic disease, but 22 had nasal swabs positive for Staphylococcus aureus. Fungi were not grown. During the course of disease, two patients with severe diffuse destructive lesions had acute orbital symptoms and signs (diplopia, pain, and proptosis), caused by infection. One patient had a secretory otitis media. All had septal erosion. In 15 there was altered olfaction. The authors speculated that the possible mechanism included either direct damage to the neuroepithelium from cocaine or its adulterants or obstruction of the olfactory cleft by inflammation and edema of the nasal mucosa. Vascular abnormalities mimicking vasculitis were present in 23 subjects. The authors observed a constant progression of the ulcerative process in 17 patients. Three subjects who stopped using cocaine had slow normalization of the mucosa. The authors suggested that any sinonasal inflammatory condition involving the midline structures characterized by symptoms such as nasal obstruction and crusting that persists or remains refractory to treatment may be the first manifestation of a potentially lethal drug addiction. Nervous system Cocaine has been associated with significant reductions in cerebral blood flow, thought to be secondary to its vasoconstrictor effects (55c ). In 13 chronic cocaine abusing men (mean age 38, range 28–45) and 10 healthy aged-matched male subjects, cerebrovascular pathology was assessed with functional magnetic resonance imaging (f MRI) to compare the abnormal blood oxygenation level dependent (BOLD) responses to photic visual stimulation. Cocaine abusers had a significantly enhanced positive BOLD response to photic stimulation compared with controls. The authors proposed that the enhanced activation in the cocaine abusers could have resulted from low resting cerebral blood flow secondary to increased vasoconstriction and/or from low oxidative metabolism during activation. Alternatively, the larger signal intensity in the cocaine abusers could have resulted from inefficient neuronal processing, as has been reported in other conditions of cerebral pathology.

41 Alpha-synuclein is a presynaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson’s disease. In a study of postmortem neuropathological specimens from cocaine users (n = 21) and age-matched drug-free controls (n = 13), the concentrations of alpha-synuclein in dopaminecontaining cells of the substantia nigra and ventral tegmental area were increased threefold in chronic cocaine users compared with controls with changes in the expression of alpha-synuclein mRNA (56c ). Although alphasynuclein is prominent in the hippocampus, there was no increase in this area. Alphasynuclein concentrations were increased in the ventral tegmental but not the substantia nigra area in victims of excited cocaine delirium who had paranoia, marked agitation, and hyperthermia before death. The authors speculated that increased alpha-synuclein may be a protective response to changes in dopamine and increased oxidative stress resulting from cocaine abuse. On the other hand, this accumulation of alphasynuclein with long-term cocaine abuse may put addicts at increased risk of the motor abnormalities of Parkinson’s disease. Endocrine The association of cocaine withdrawal with hypothalamic-pituitary-adrenal axis dysregulation has previously been reported and may be important in understanding vulnerability to stress response and relapse (57c ). The hypothesis that withdrawn cocaine-dependent patients would have higher cerebrospinal fluid concentrations of corticotropin-releasing hormone than healthy controls has been tested in 29 cocaine-dependent men (mean age 40 years) who were abstinent for a minimum of 8 days (mean 29 days) and 66 healthy controls. The subjects were 21 African Americans, two Hispanics, and six Caucasians. There were no significant differences in cerebrospinal fluid concentrations of corticotropin-releasing hormone between the subjects and the controls. There was no correlation between the number of days of cocaine withdrawal and the corticotropin-releasing hormone concentrations. This negative study reflected the fact that the hypothalamic-pituitary-adrenal axis in cocaine abstinence is no longer dysregulated. Cocaine and nicotine share many similarities, including a strong potential for addiction. In a comparison of the acute effects of cocaine

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and cigarette smoking on luteinizing hormone, testosterone, and prolactin, 24 men who met criteria for cocaine abuse or nicotine dependence were given intravenous cocaine (0.4 mg/kg) or placebo cocaine, or smoked a low-nicotine or high-nicotine cigarette (58c ). Placebo-cocaine and low-nicotine cigarette smoking did not change luteinizing hormone, testosterone, or prolactin. Luteinizing hormone increased significantly after both intravenous cocaine and high-nicotine cigarette smoking and correlated significantly with increases in cocaine and nicotine plasma concentrations. However, highnicotine cigarette smoking stimulated significantly greater increases in luteinizing hormone release than intravenous cocaine. On the other hand, testosterone concentrations did not change significantly after either cocaine or high-nicotine cigarette smoking. Prolactin concentrations fell significantly and remained below baseline after intravenous cocaine. However, after high-nicotine cigarette smoking, prolactin increased to hyperprolactinemic concentrations within 6 minutes and remained significantly above baseline for 42 minutes. The increases in luteinizing hormone were temporally related to behavioral and physiological measures of sexual arousal. The authors commented that the rapid increases in luteinizing hormone and reports of subjective high after both intravenous cocaine and high-nicotine cigarette smoking illustrate the similarities between these drugs and they suggested a possible contribution of luteinizing hormone to their abuse-related effects. Hematologic Erythrocytosis has been implicated as one of the factors underlying cocaineassociated cardiac complications. In a prospective study, differences in mean hemoglobin concentration, hematocrit, and reticulocyte count were measured in 79 consecutive cocaineexposed and cocaine-unexposed patients who developed chest pain (59c ). The authors hypothesized that the contribution of the bone marrow to cocaine-induced erythrocytosis is negligible. Acute cocaine exposure was of less than 3 hours duration. Hemoglobin and hematocrit levels were significantly higher in cocaineusing subjects than in controls (13.5 versus 12.6 g/dl and 40% versus 38%). There was no corresponding increase in reticulocyte count, suggesting that the bone marrow does not contribute to transient erythrocytosis. Men with

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong

chest pain were more likely to be exposed to cocaine then women. Moreover, all relative increases in hemoglobin concentration in the cocaine-exposed group were attributable to sex. Amongst other variables, only a history of diabetes mellitus was significantly associated with an increased reticulocyte count. The authors therefore concluded that acute cocaine exposure is not associated with erythrocytosis in younger patients with chest pain. Musculoskeletal Non-traumatic rhabdomyolysis is often secondary to alcohol, cocaine, amphetamines, heroin, etc., and is characterized by laboratory features that reflect the release of muscle cell contents into the plasma. Early detection can prevent progression to acute renal insufficiency (60AR ). • A 37-year-old man sustained multiple fractures without loss of consciousness after an assault. He had a history of smoking crack cocaine and drinking alcohol. He was afebrile and had stable vital signs. His urine analysis was positive for cocaine and blood, thought to be secondary to trauma from a Foley catheter. His temperature rose to 101◦ F and surgery was postponed. He subsequently developed uremia with a creatinine concentration of 389 µmol/l, a raised uric acid, and a creatine kinase activity of 3055 IU/l, with an MB isoenzyme activity of 12 ng/ml (reference range 0 to 6); serum phosphorus and magnesium were also increased. Ultrasonography of the kidneys was normal and he did not have HIV. His fever resolved spontaneously and his renal function recovered.

After an extensive literature search, the authors reported that the main pathophysiological mechanism underlying cocaine associated rhabdomyolysis is unknown. They suggested that cocaine blocks the reuptake of noradrenaline and dopamine, resulting in increased sympathetic activity. This, coupled with potent vasoconstriction by the cocaine metabolite benzoylecgonine, can lead to skeletal muscle ischemia and injury and result in rhabdomyolysis. Death About 1–2% of people in Western countries are regular consumers of cocaine and 10% are sporadic users. This proportion increases considerably in the age groups in which organ donors are most often found. Cocaine use is often associated with death, creating opportunities for organ donation (61A ). • A 30-year-old woman with a history of bronchial asthma and cocaine abuse had a cardiorespiratory

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arrest preceded by sudden dyspnea 1 hour after cocaine inhalation. Direct laryngoscopy showed edema of the glottis. After extended cardiopulmonary resuscitation, she went into a deep coma with dilated non-reactive pupils. Toxicological analysis showed cocaine and amphetamines in her urine. She was brain dead 11 hours later and her organs were used for transplantation. Her liver was given to a 14-year-old boy with acute hepatocellular failure caused by isoniazid; 5 years later he had normal liver function. Her kidneys were given to a 52-year-old woman and a 56-year-old man, both with polycystic kidney disease; in both cases renal function was normal after 5 years.

The grafts took in all three cases. Myoglobinuric acute renal insufficiency in the donor did not affect immediate, short-term, or longterm graft function. In their review of the literature, the authors found one report of eight transplants from three donors. There were no effects attributable to cocaine in any of the recipients in the immediate post-transplantation period. They concluded that organ donation is safe after brain death caused by cocaine toxicity, probably because of the characteristics of the cocaine, such as a short half life. Fetotoxicity There are 100 000 crack cocaine babies born each year in the USA, and an increasing number of anomalies are being linked to maternal cocaine abuse (62R ). Double aortic arch anomaly has been linked to maternal cocaine abuse (63A ). • A girl born to a cocaine-abusing mother had cocaine withdrawal symptoms and at 2 months developed respiratory dysfunction and died. At autopsy, the heart and lung were normal, but there was a double aortic arch anomaly of right persistent dominant arch type. The aorta encircled the trachea and esophagus. The right common carotid, right vertebral, and right subclavian arteries arose from the right aortic arch and the left carotid and left subclavian arteries originated from the left aortic arch.

Cocaine may directly affect the fetal cardiovascular system or do so by increasing the concentrations of circulating catecholamines and activating the sympathetic nervous system. Amelia and humeral “bifurcation” due to humeroradial synostosis are both very rare limb abnormalities and occur in less than 1 in 50 000 births. A new case has been reported (64A ). • A 29-year-old Canadian Aboriginal woman, who had used cocaine intermittently during the first 8 weeks of pregnancy, gave birth to a boy at

43 38 weeks. Amniocentesis was normal and labor was unremarkable. The boy’s left arm was absent and he had right-sided phocomelia with a threefingered hand. Radiography showed hypoplasia of the left clavicle and scapula, and absence of the left pedicle at T5. There was ulnar aplasia, with a short radius fused to the humerus on the right side. The family history was unremarkable.

This was one of the most severely affected children reported. In most cases the defect is unilateral. When both arms are involved, oligodactyly is often asymmetrical. Such cocaine related defects have also been reported in animal models (65E –67E ). • A 23-year-old woman who was taking methadone 34 mg/day and lorazepam 4 mg/day admitted to irregular alcohol abuse of up to 3 liters of beer per day and regular intravenous use of cocaine and heroin over the previous 3 months at dosages and frequencies that could not be accurately ascertained (68A ). She was positive for hepatitis B and C. At 12 weeks her urine contained cocaine, cannabis, codeine, and morphine. At 17 weeks, ultrasonography showed ahydramnios, and color Doppler confirmed bilateral renal agenesis. After termination an autopsy confirmed the renal findings but also showed a right upper limb reduction defect and single umbilical artery. The right arm skeleton consisted of a round rudiment of the humerus and a near normal ulna, with no evidence of a radius. The hand lacked the thumb and two fingers.

The authors reviewed the literature and reported that cocaine abuse in pregnancy results in congenital defects in 15–20% of cases, primarily involving the brain, heart, genitourinary tract, and limbs. They reported that at their hospital, since 1996, 35 cases of cocaine abuse in pregnancy had been identified. From this group another four cases of congenital defects, including talipes, optic nerve atrophy, acromelia of the left hand and right fingers, and an isolated single umbilical artery, were identified. The overall defect rate at their center was 14%. They quoted other human and animal studies suggesting an increased risk of vascular disruption defects after in utero cocaine exposure and supported this by the findings from their case of a single umbilical artery. They further suggested that some of the findings are similar to the teratogenic effects of thalidomide, a well-known inhibitor of angiogenesis, supporting the notion that these findings are due to cocaine-induced vascular disruption syndrome in pregnancy.

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The development of motor asymmetries was assessed in 20 infants who were exposed to cocaine prenatally and 23 infants who were not (69c ). Asymmetries in stepping, grasping, and head orientation were assessed at 1 month of age. As expected, based on the findings of previous research on high-risk infants, infants who were exposed to cocaine prenatally preformed a grasping task with their right hand for significantly shorter durations than the control infants, who were more likely to have a side bias for head orientation and stepping. There was a dose-response relation between maternal substance use during pregnancy and motor asymmetries in the infants. These findings suggest that prenatal exposure to cocaine alters the typical developmental trajectory of functional asymmetries and may have important implications for long-term developmental outcomes. However, longer term studies with larger samples are needed to explore these issues. In one study, drug-exposed infants did not differ from non-exposed infants on Neonatal Behavioral Assessment Scale (NBAS) clusters or on birth characteristics (70c ). Infants (n = 137) born to three groups of low-income mothers – cocaine and poly-drug-using mothers in a treatment group (n = 76), users in a treatment rejecter group (n = 18), and non-users (n = 43) – were examined at 2 days and 2–4 weeks. The motor cluster improved and regulation of state worsened from the first to the second examination. There were no interactions of group by time. Regression analyses found no competing variables to explain the group differences. Power analysis showed that sample size was sufficient to have detected differences. The literature on prenatal cocaine exposure on infants is mired with contradictory perspectives, ranging from detrimental findings to the absence of any effects. The studies done thus far suffer from methodological problems or confounding variables, such as the use of other drugs and nicotine and nutritional status, making it harder to generalize. The Miami Prenatal Cocaine Study is a prospective study starting at birth. The effect of prenatal cocaine exposure on language functioning in 476 full-term African-American infants has been evaluated longitudinally at six times, from 4 months to 3 years of age (71c ). The children were categorized as cocaineexposed (n = 253) or non-cocaine exposed

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong

(n = 223) by maternal self report and bioassays using maternal/infant urine and meconium. The Bayley Scale of Infant Development was administered at 4, 8, 12, 18, and 24 months and the Clinical Evaluation of Language Fundamentals-Preschool at 36 months; 464 children received at least one language assessment. In longitudinal analyses, using Generalized Estimating Equations, cocaineexposed children had lower overall language skills than non-cocaine-exposed children. The findings were stable after evaluation of potential confounding effects, including exposure to other prenatal substances and sociodemographic factors. Preliminary evidence also suggested possible mediation through an intermediary effect involving cocaine-associated defects in fetal growth. Cocaine-exposed-children scored on an average 15% of a standard deviation lower on measures of global language ability. These results were strongest at 18 and 36 months. There was no relation between head circumference and language function, suggesting that language development was affected by a more generalized defect, perhaps associated with low birth weight and related susceptibility factors, as opposed to a specific defect resulting from smaller head circumference. The major limitation of this study was the lack of inclusion of infants with major congenital malformations or HIV or other infections. The authors hypothesized that this phenomenon may be underpinned by impairment of neurobehavioral arousal and attention processes that are essential to processing linguistic cues and information, disruption of specific parent–child interactions critical to language development as a result of parental drug use, and the effect of negative social environments typically associated with parental use of cocaine and other drugs.

OPIOID ANALGESICS (SED-14, 198; SEDA-25, 37; SEDA-27, 38)

Buprenorphine Drug overdose A high-dosage formulation of buprenorphine is used to treat opioid dependency. Buprenorphine abuse has been explored

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as part of a larger retrospective study of opioid overdose (72c ). In Helsinki, from January 1995 to April 2002, of 308 cases of opioid overdose, 12 were due to buprenorphine (one was excluded because the patient’s Glasgow Coma Score was too high). Three did not require naloxone and the others required 0.2–0.8 mg of naloxone to reverse the effects. One patient did not respond to naloxone and had to be intubated. None of the patients died. Most of the patients in this study had used crushed buprenorphine tablets intravenously but one had been given buprenorphine intravenously by his friends to reverse respiratory depression caused by heroin overdose, a practice with the potential to cause more complications.

Diamorphine (heroin) Respiratory Heroin insufflation has been identified as a trigger for asthma (73Ac ). Of 23 patients aged 50 years and younger who were admitted to Cook County Hospital during 6 months with a primary diagnosis of asthma exacerbation, 13 reported heroin use and identified it as an asthma trigger, four reported heroin use but did not associate it with asthma exacerbation, and six had no recent history of heroin use. The patients with heroin-triggered symptoms stated that asthma exacerbation had not occurred on first use but had developed over time. Five of the seven patients whose asthma developed in adulthood reported that their heroin use had predated their asthma. The same group of researchers then conducted a retrospective case-control study of all asthma admissions in patients under 50 over a period of 2 years. The charts of patients admitted with diabetic ketoacidosis during the same period were used as controls. Drug histories and urine drug screens were used to identify heroin users. Of 104 admissions (84 patients), 38 acknowledged a history of heroin use and 34 returned a urine drug screen that was positive for opiates. Both a history of heroin use and a positive urine drug screen were significantly more common in those with asthma than in those with diabetic ketoacidosis. These two studies taken together suggest that heroin insufflation commonly triggers asthma, and that heroin use is more prevalent in patients with asthma. It is possible that heroin

45 causes bronchospasm or pulmonary mast cell degranulation; alternatively, since heroin becomes a trigger over a long period of time, allergic sensitization could be involved. Another possibility is that the cutting agents and contaminants in street heroin act as irritants to the airways. Nervous system The term “chasing the dragon” originated in East Asia, where typically heroin powder is placed on aluminum foil and heated from beneath with a lighter or matches, causing heroin to liquefy into a reddish brown blob (heroin pyrolysate), which moves around on the foil and emits a white vapor (SEDA24, 40). The blob or “dragon” is “chased” with the lighter and the vapor is sucked through a straw or pipe. This method of administration avoids the negative consequences of intravenous use. It is also known as “Chinese blowing”. This became a popular method of heroin administration when the drug was cheap but impure. The first cases of leukoencephalopathy due to inhalation of heroin pyrolysate were described in the Netherlands in 1982. The condition has three stages, progressing from cerebellar signs and motor restlessness to pyramidal and pseudobulbar signs and, in a minority of patients (about 25%), to a terminal stage characterized by spasms, hypotonic paresis, and ultimately death. Symmetrical spongiform degeneration occurs, particularly in the cerebral and cerebellar white matter and in corticospinal and solitary tracts. Involvement of the cerebellum and the posterior limb of the internal capsule, with sparing of the anterior limb, appear to be characteristic, helping to distinguish this condition from other causes of leukoencephalopathy. Neuroimaging techniques contribute significantly to the management of such patients, as is evident from recent cases. • A 16-year-old man was found at home drowsy 36 hours after smoking heroin for the first time (74A ). He had a gaze paresis and sensorimotor hemiplegia on the left side. A CT scan showed bilateral hypodense lesions in the globus pallidus. An MRI scan 5 days later showed symmetrical hyperintense signals in the T2 weighted images, along with a massive diffusion disorder in the diffusion weighted images. This was predominantly in the deep white matter of the parieto-occipital cortex. There were also bilateral hyperintense T2 signals in the ventral globi pallidorum. MR spectroscopy suggested combined hypoxic and mitochondrial

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damage, resulting in axonal injury without demyelination. He was discharged 1 month later with no hemiplegia. A follow-up MRI scan 6 months later showed improvement. There were no signs of brain atrophy.

According to the authors, this is the first reported MRI follow-up study of acute leukoencephalopathy after a single inhaled dose of heroin. It most likely involved a complex mechanism triggered by heroin, causing mitochondrial and hypoxic injury limited to specific areas of the white matter of the brain. • A 21-year-old man became unconscious after smoking heroin at a rave party and developed an aspiration pneumonia, bilateral pyramidal signs, and spastic paresis (75A ). He was given clonidine and midazolam, but continued to have daily episodes of stretching spasms, hyperventilation, profuse sweating, pyrexia, and mydriasis. He was given coenzyme Q 300 mg qds on day 14. A CT scan showed diffuse hypodensities in the white matter indicative of spongiform leukoencephalopathy. On day 30, he began to improve and an MRI scan showed diffuse abnormal lesions in the white matter. He gradually recovered and an MRI scan on day 59 showed less extensive lesions. At 7 months he had regained all functions but had a residual gait ataxia. A follow-up MRI scan showed recovery of the white matter, but some necrosis.

The mechanism of heroin-induced spongiform leukoencephalopathy is not known and the disease is not reproducible in animals. Suspicions have been raised about potential contaminants, such as strychnine, caffeine, phenacetin, quinine, and procaine. This man started inhaling heroin 2 weeks before the onset of the disease, but he used it in large amounts, raising the possibility that the severity of the disease is dose-related. In the two cases discussed above, the onset was abrupt, which is not usual. Antioxidant therapy, such as the use of coenzyme Q, is supported by its efficacy in previous cases and also because mitochondrial swelling has been reported in patients with such lesions. The authors stressed that there was a favorable outcome with prolonged and supportive care and the use of coenzyme Q, especially in a patient who developed stretching spasms, a feature that has been associated with a very high mortality rate. Symmetrical deep cerebellar lesions have been associated with heroin smoking (76A ). • A 40-year-old man presented to the emergency room after smoking heroin on 2 consecutive days.

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong He complained of unsteadiness and clumsiness. While speaking to a nurse, his condition dramatically worsened, and he became severely ataxic, dysarthric, and clumsy and was unable to stand. An MRI scan showed symmetric bilateral “Cshaped” lesions in the white matter and dentate nuclei of the cerebellum. The diagnosis was toxic leukoencephalopathy secondary to inhaled heroin. Six months later, his cerebellar dysfunction was unchanged.

Because of clustering of cases, it was thought that an additive in the heroin had brought on the symptoms. Elsewhere a cluster of five cases of toxic leukoencephalopathy over a span of 5 weeks after inhalation of heroin vapor has been reported, with details of three (77A ). • A 27-year-old man was found at home in a low state of consciousness after smoking heroin. He developed aphasia and spastic quadriparesis. A CT scan showed symmetrical white matter hypodensity in the cerebellum and symmetrical white matter hypoattenuation in the posterior limb of the internal capsule and optic radiations. An MRI scan showed white matter hypointensity in the cerebellum, with sparing of the cortex and dentate nuclei. There were also hyperintensities in the medial lemnisci and spinothalamic tracts. He died after a seizure 6 weeks later. An autopsy showed spongiform degeneration of the white matter that coincided with the MRI scans. • A 39-year-old man developed bradykinesia and ataxia after smoking heroin. A brain MRI scan showed symmetrically increased signals in the white matter of the cerebellum, the peduncles, and the pons, with sparing of the dentate nuclei. There were abnormal signals in the posterior limb of the internal capsule and optic radiations. The signal abnormalities in this patient were not as pronounced as the previous one, who ultimately died. This patient was also taking methadone in a maintenance program. • A 32-year-old man in a methadone program developed dysarthria, bradykinesia, and ataxia after smoking heroin. CT scans showed symmetric hypodensities in the cerebellum with sparing of the dentate nuclei. There were abnormal signals in the internal capsule and optic radiations, although not as extensive as in those who died.

These cases were typical of toxic leukoencephalopathy secondary to heroin inhalation. Moreover, they had symptoms involving both cerebellum and non-cerebellar structures. Another form of brain injury, progressive myelopathy, has been reported after inhalation of heroin vapor (78A ). • A 46-year-old man chronically abused heroin through inhalation and developed a gait disorder

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with paresthesia of the legs, incontinence, and impotence. MRI scans showed bilateral subcortical lesions and bilateral signal abnormalities in the corticospinal tract and posterior columns. Motor evoked potentials were slow, with prolonged F wave latency, which is evidence of peripheral nerve disease. Multivitamins and high doses of prednisone did not produce benefit.

This condition was diagnosed as progressive myelopathy affecting only the corticospinal tract and posterior columns, the characteristics of which differ from acute leukoencephalopathy significantly, although both are serious consequences of heroin inhalation. Progressive myelopathy has been reported after heroin insufflation but never after inhalation of vapors. The authors favored an immune mechanism. Special senses Seven cases of acute strabismus related to opiate abuse in Switzerland between 1993 and 2001 have been reported (79A ). In five cases the symptoms coincided with heroin withdrawal and acute esotropia occurred a few days after heroin was stopped. The other two patients developed acute exotropia that was related to opiate abuse. All the symptoms disappeared spontaneously. It is likely that changes in the blood opioid concentration disrupted the oculomotor system and affected binocular vision, although the exact mechanism underlying this phenomenon is not known. Drug overdose One of the complications of opiate overdose is pulmonary edema. In a retrospective chart review (80c ) of patients with heroin overdose between July 1996 and July 1999 at a Medical Center, 13 of 125 charts indicated the presence of non-cardiogenic pulmonary edema and all the patients were men. The mean field respiratory rate for individuals with non-cardiogenic pulmonary edema was 5.9 compared to 9.7 in those without. All the patients with non-cardiogenic pulmonary edema and 68% without received naloxone. The mean duration of heroin use was less in patients with non-cardiogenic pulmonary edema (2.9 years) than in patients without (14 years). The results of this chart review are limited, but it seems that in a small percentage of cases, heroin overdose results in non-cardiogenic pulmonary edema. These individuals typically have a respiratory rate close to six and need naloxone. The authors postulated that there may be a higher risk of non-cardiogenic pulmonary edema in men who are relatively inexperienced heroin users.

Methadone Cardiovascular Opioids block the cardiac human ether-a-go-go-related gene (HERG) potassium current in susceptible patients without any apparent heart disease and can thus prolong the QT interval (81r ). Two cases of QTc interval prolongation and torsade de pointes have been reported in patients taking methadone (82Ar ). • A patient was found unconscious with plasma concentrations of bromazepam 277 µg/ml and methadone 3500 µg/ml, both of which were above the toxic threshold. The QTc interval was 688 ms. After initial improvement, torsade de pointes occurred and the patient was treated with DC shock 200 J, isoprenaline, magnesium, and potassium. The QTc interval improved to 440 ms after 3 days. • The second patient was admitted to the hospital in a comatose state. Sinus bradycardia was present with a QTc interval of 736 ms. The plasma concentration of methadone was 1740 µg/ml. Ventricular bigeminy was followed by torsade de pointes. The patient was treated with DC shock 200 J, lidocaine, and magnesium. By the fifth day after the episode, the QTc interval had improved to 502 ms.

This potentially life-threatening dysrhythmia has been reported previously in association with methadone and is probably underrecognized in this population. The authors did not provide details about the sex of the patients and reasons why methadone concentrations were high. Following reports similar to those mentioned above, changes in the QTc interval were studied in 132 heroin-dependent patients as they were starting treatment with methadone (83A ). After baseline electrocardiography methadone 30–150 mg/day was given and a second electrocardiogram was obtained 2 months later. Across all doses of methadone, the QTc interval increased significantly by a mean of 11 ms over the first 2 months of treatment. No episodes of torsade de pointes were reported. Male sex and methadone doses over 110 mg/day were associated with the greatest prolongation. The average follow-up QTc interval was 428 ms. Clinical significance is generally attributed to an increase in QTc interval of 40 ms or greater or a value above 500 ms. None of these patients had an increase that was above this threshold. While these results were statistically significant, the authors were not sure of their clinical significance. The synthetic opioid levacetylmethadol, a metabolite of methadone, can also cause torsade

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de pointes, and its use requires electrocardiographic screening before treatment and during titration (81r ). Nervous system Coprolalia is a typical symptom of Tourette’s syndrome that can take on a malignant quality in response to pharmacological agents. Malignant coprolalia in association with heroin abuse has been reported (84A ). • A 37-year-old woman developed Tourette’s syndrome at 9 years of age, with motor and phonic tics. At 25 she began to smoke heroin weekly. After 3 months, her motor tics became uncontrollable and she began to have coprolalia for the first time at a rate of about 10 words per minute. Heroin was withdrawn over 6 months but her motor tics and coprolalia did not improve, despite various drug treatments. Six months later she smoked heroin again and was readmitted with violent motor tics and constant coprolalia. She was sedated and her condition improved slightly, after which she was given sulpiride 600 mg/day and clonazepam 4 mg/day. She made a partial recovery with inadequate control of motor tics.

Since the mechanisms that underlie heroin abuse and Tourette’s syndrome overlap, specifically involving dopaminergic innervation, it is likely that this condition was caused by the effects of heroin in the ventral tegmental area and its projections.

Jayendra K. Patel, Timothy E. Ralston, and Eileen Wong

Drug abuse Since its first use as a treatment for opioid dependence, methadone has been the subject of much debate. Since it is itself an opioid, there is a potential for abuse. In one study all unexpected deaths positive for methadone in the Strathclyde Police region of Scotland from 1991 to 2001 were identified and were classified as being “methadone-only”, “methadonerelated”, or “not methadone-related” (85c ). Of 352 cases, 82 were considered not methadonerelated; the other 270 were thought to be caused by methadone alone or in combination with other drugs. Of these drug-related deaths, methadone was identified as the sole cause in 56, while methadone in combination with other drugs was responsible for 140 deaths. The other 74 cases were positive for methadone, but the concentration was not high enough to be considered contributory. When methadoneonly deaths and methadone-related deaths were compared, there was a significant difference in blood methadone concentrations, which were higher on average in methadone-only cases (800 versus 400 ng/ml). This does not mean that methadone is unsafe, but rather that its use in methadone maintenance programs needs to be closely monitored.

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49 amino acids in ecstasy users. Neuro Endocrinol Lett 2003; 24: 348–9. 26. Budisavljevic MN, Stewart L, Sahn SA, Ploth DW. Hyponatremia associated with 3,4methylenedioxymethylamphetamine (“ecstasy”) abuse. Am J Med Sci 2003; 326: 89–93. 27. Brazier WJ, Dhariwal DK, Patton DW, Bishop K. Ecstasy related periodontitis and mucosal ulceration – a case report. Br Dent J 2003; 194: 197–9. 28. Kwon C, Zaritsky A, Dharnidharka VR. Transient proximal tubular renal injury following ecstasy ingestion. Pediatr Nephrol 2003; 18: 820–2. 29. Inman DS, Greene D. The agony and the ecstasy: acute urinary retention after MDMA abuse. BJU Int 2003; 91: 123. 30. Schifano F, Oyefeso A, Corkery J, Cobain K, Jambert-Gray R, Martinotti G, Ghodse AH. Death rates from ecstasy (MDMA, MDA) and polydrug use in England and Wales 1996–2002. Hum Psychopharmacol 2003; 18: 519–24. 31. Vuori E, Henry JA, Ojanpera I, Nieminen R, Savolainen T, Wahlsten P, Jantti M. Death following ingestion of MDMA (ecstasy) and moclobemide. Addiction 2003; 98: 365–8. 32. Rezkalla SH, Sharma P, Kloner RA. Coronary no-flow and ventricular tachycardia associated with habitual marijuana use. Ann Emerg Med 2003; 42: 365–9. 33. Mathew RJ, Wilson WH, Davis R. Postural syncope after marijuana: a transcranial Doppler study of the hemodynamics. Pharmacol Biochem Behav 2003; 75: 309–18. 34. Semple DM, Ramsden F, McIntosh AM. Reduced binocular depth inversion in regular cannabis users. Pharmacol Biochem Behav 2003; 75: 789– 93. 35. Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, Nagelkerken L, Polman CH. Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. J Neuroimmunol 2003; 137: 140–3. 36. Huang YM, Liu X, Steffensen K, Sanna A, Arru G, Fois ML, Rosati G, Sotgiu S, Link H. Immunological heterogeneity of multiple sclerosis in Sardinia and Sweden. Mult Scler 2005; 11: 16–23. 37. Van Boxel-Dezaire AH, Hoff SC, Van Ooosten BW, Verweij CL, Drager AM, Ader HJ, Van Houwelingen JC, Barkhof F, Polman CH, Nagelkerken L. Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis. Ann Neurol 1999; 45: 695–703. 38. Struve FA, Straumanis JJ, Patrick G, Leavitt J, Manno JE, Manno BR. Topographic quantitative EEG sequelae of chronic marihuana use: a replication using medically and psychiatrically screened normal subjects. Drug Alcohol Depend 1999; 56: 167–79. 39. Herning RI, Better W, Tate K, Cadet JL. EEG deficits in chronic marijuana abusers during monitored abstinence: preliminary findings. Ann N Y Acad Sci 2003; 993: 75–8; discussion 79–81. 40. Fried PA, Watkinson B, Gray R. Differential effects on cognitive functioning in 13- to 16-year-olds

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prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 2003; 25: 427–36. 41. Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambelan M. Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. Ann Intern Med 2003; 139: 258–66. 42. Benowitz NL, Nguyen TL, Jones RT, Herning RI, Bachman J. Metabolic and psychophysiologic studies of cannabidiol-hexobarbital interaction. Clin Pharmacol Ther 1980; 28: 115–20. 43. Benowitz NL, Jones RT. Effects of delta9-tetrahydrocannabinol on drug distribution and metabolism. Antipyrine, pentobarbital, and ethanol. Clin Pharmacol Ther 1977; 22: 259–68. 44. Carley S, Ali B. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Acute myocardial infarction in cocaine induced chest pain presenting as an emergency. Emerg Med J 2003; 20: 174–5. 45. Weber JE, Shofer FS, Larkin GL, Kalaria AS, Hollander JE. Validation of a brief observation period for patients with cocaine-associated chest pain. New Engl J Med 2003; 348: 510–17. 46. Osula S, Stockton P, Abdelaziz MM, Walshaw MJ. Intratracheal cocaine induced myocardial infarction: an unusual complication of fibreoptic bronchoscopy. Thorax 2003; 58: 733–4. 47. Kelly RF, Sompalli V, Sattar P, Khankari K. Increased TIMI frame counts in cocaine users: a case for increased microvascular resistance in the absence of epicardial coronary disease or spasm. Clin Cardiol 2003; 26: 319–22. 48. Kontos MC, Jesse RL, Tatum JL, Ornato J. Coronary angiographic findings in patients with cocaine-associated chest pain. J Emerg Med 2003; 24: 9–13. 49. Bizzarri F, Mondillo S, Guerrini F, Barbati R, Frati G, Davoli G. Spontaneous acute coronary dissection after cocaine abuse in a young woman. Can J Cardiol 2003; 19: 297–9. 50. Mochizuki Y, Zhang M, Golestaneh L, Thananart S, Coco M. Acute aortic thrombosis and renal infarction in acute cocaine intoxication: a case report and review of literature. Clin Nephrol 2003; 60: 130–3. 51. Stollberger C, Kopsa W, Finsterer J. Resolution of an aortic thrombus under anticoagulant therapy. Eur J Cardiothorac Surg 2001; 20: 880–2. 52. Maeder M, Ullmer E. Pneumomediastinum and bilateral pneumothorax as a complication of cocaine smoking. Respiration 2003; 70: 407. 53. Strong DH, Westcott JY, Biller JA, Morrison JL, Effros RM, Maloney J. Eosinophilic “empyema” associated with crack cocaine use. Thorax 2003; 58: 823–4. 54. Trimarchi M, Nicolai P, Lombardi D, Facchetti F, Morassi ML, Maroldi R, Gregorini G, Specks U. Sinonasal osteocartilaginous necrosis in cocaine abusers: experience in 25 patients. Am J Rhinol 2003; 17: 33–43.

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51 inhalation toxicity: “chasing the dragon”. Am J Roentgenol 2003; 180: 847–50. 78. Nyffeler T, Stabba A, Sturzenegger M. Progressive myelopathy with selective involvement of the lateral and posterior columns after inhalation of heroin vapour. J Neurol 2003; 250: 496–8. 79. Sutter FK, Landau K. Heroin and strabismus. Swiss Med Wkly 2003; 133: 293–4. 80. Sterrett C, Brownfield J, Korn CS, Hollinger M, Henderson SO. Patterns of presentation in heroin overdose resulting in pulmonary edema. Am J Emerg Med 2003; 21: 32–4. 81. Krantz MJ, Mehler PS. Synthetic opioids and QT prolongation. Arch Intern Med 2003; 163: 1615; author reply 1615. 82. De Bels D, Staroukine M, Devriendt J. Torsades de pointes due to methadone. Ann Intern Med 2003; 139: E156. 83. Martell BA, Arnsten JH, Ray B, Gourevitch MN. The impact of methadone induction on cardiac conduction in opiate users. Ann Intern Med 2003; 139: 154–5. 84. Berthier ML, Campos VM, Kulisevsky J, Valero JA. Heroin and malignant coprolalia in Tourette’s syndrome. J Neuropsychiatry Clin Neurosci 2003; 15: 116–17. 85. Seymour A, Black M, Jay J, Cooper G, Weir C, Oliver J. The role of methadone in drug-related deaths in the west of Scotland. Addiction 2003; 98: 995–1002.

Stephen Curran and Shabir Musa

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AZASPIRONES

(SED-14, 133; SEDA-26, 49; SEDA-27, 43)

Buspirone Buspirone (40 mg/day for 4 weeks) has been used as an alternative treatment in eight psychiatric outpatients with attention deficit disorder (1c ). The results suggested that buspirone might be useful in attention deficit disorders, reducing hyperactive behavior and enabling greater attention with few adverse effects. There were no clinically significant changes in blood pressure. There was mild transient tiredness, which lasted about 2 weeks. In one case, there was an initial trend toward a reduced appetite, but that generally stabilized. Headaches and stomach aches occurred in two patients during the first 2 weeks and one of them continued to have mild episodes.

BENZODIAZEPINES (SED-14, 122; SEDA-25, 47; SEDA-26, 46; SEDA-27, 43) Drug dependence In 1048 consecutive patients attending 20 primary care health centers in the Canary Islands, who had taken benzodiazepines for 1 month or more, 47% developed dependence (2c ). Benzodiazepine dependence was more prevalent among women who were middle-aged, separated, of low educational background, unemployed, or housewives. Benzodiazepine dependence was closely related only to three of the variables considered: the dose, the duration of use, and the concomitant use of antidepressants. © 2005 Published by Elsevier B.V. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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Alprazolam Alprazolam 0.25 mg or 1 mg has been evaluated in 47 otherwise healthy subjects, selected for a moderate to high degree of anxiety before oral surgery in a three-arm, parallel design, double-blind, randomized, placebo-controlled study (3C ). There were 27 adverse events in the interval between dosing and surgery: 2, 10, and 15 events each with placebo, alprazolam 0.25 mg, and alprazolam 1 mg respectively. The most common events were drowsiness with placebo and drowsiness, dizziness, lightheadedness, and nausea with alprazolam. There were also single reports of trembling, feeling cold, anxiety, panic attacks, a desire to smoke, increased appetite, sleepiness, and dry mouth with alprazolam. There were no serious adverse events and no subject withdrew from the study because of adverse events. Drug interactions SSRIs The effects of coadministration of fluvoxamine on plasma concentrations of alprazolam have been studied in 23 Japanese outpatients (4c ). All patients were taking fluvoxamine (25–100 mg/day) either before or after monotherapy with alprazolam (0.4–1.6 mg/day). Co-administration with fluvoxamine produced on average a 58% increase in plasma alprazolam concentrations. However, there were wide variations in the plasma concentrations of alprazolam. The interaction was attributed to the CYP2C19 genotype. A within-subject, double-blind, placebocontrolled, parallel design has been used to measure the effects of citalopram (20 mg/day) and fluoxetine (20 mg/day) on the pharmacokinetics and pharmacodynamics of alprazolam (1 mg/day) (5C ). Fluoxetine significantly impaired the metabolism of a single oral dose of alprazolam 1 mg, leading to prolongation of the half-life and an increased AUC, whereas citalopram did not. Neither SSRI significantly affected the pharmacodynamic effects of alprazolam. This experiment suggests differential

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effects of citalopram and fluoxetine on alprazolam kinetics.

Clobazam In an open study 25 patients with new-onset focal and primary generalized epilepsy were treated with clobazam at a single centre (6c ). After a mean follow-up of 16 months (range 7–24), 16 patients were seizure free, while five had more than a 50% reduction in seizure frequency. Sedation was the most common adverse event, reported by four patients; however, it was always mild and did not require withdrawal of clobazam. Other adverse effects, reported in one patient each, were weight gain, ataxia, loss of short-term memory, and breakthrough seizures.

• A 49-year-old man with severe mental retardation was given clonazepam 2 mg/day to treat aggression, self-injurious behavior, property destruction, and screaming, which got worse instead of better (8A ). When clonazepam was withdrawn, the behavior improved.

Drug interactions A fatal drug interaction was caused by the ingestion of oxycodone and clonazepam. • A 38-year-old white woman was found dead (9A ). She had physical evidence of previous drug abuse and positive hepatitis B and C serology. Her plasma clonazepam concentration was 1.41 µg/ml and her plasma oxycodone concentration was 0.60 µg/ml.

Postmortem findings suggested severe nervous system and respiratory depression produced by high concentrations of clonazepam and oxycodone, including collapsed lungs, aspirated mucus, and heart failure.

Clonazepam Diazepam In a randomized, double-blind, placebo-controlled, three-arm study in 60 patients with panic disorder, paroxetine alone (40 mg/day) was compared with paroxetine co-administered with clonazepam (2 mg/day) followed either by a tapered benzodiazepine withdrawal phase or continuing combination treatment (7C ). The outcomes in the three groups were similar. Most of the patients had at least one adverse effect: 68% of patients given paroxetine alone, 85% of those given the two drugs, and 94% of those given the two drugs followed by withdrawal. The most common adverse effects of combined treatment were sedation, sexual dysfunction, and jitteriness; jitteriness and gastrointestinal symptoms were most common with monotherapy. Sedation and sleep disturbances were the most common adverse effects that made patients withdraw from the study. Psychiatric Behavioral adverse events associated with clonazepam include agitation, aggression, hyperactivity, irritability, property destruction, and temper tantrums. These adverse effects can be inadvertently confused with other behavioral or psychiatric conditions, especially if exacerbation of existing challenging behavior occurs.

Teratogenicity To study the possible teratogenicity of short-term (about 3 weeks) oral diazepam during pregnancy, a matched casepopulation control pair analysis was conducted in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (10C ). The investigators compared the “total” (maternal self-reported plus medically recorded) and “medically recorded” diazepam treatments, and compared cases and controls from 1980 to 1996. Among 38 101 neonates without any congenital abnormality 4130 (11%) were exposed to diazepam, compared with 2746 (12%) of 22 865 neonates or fetuses with congenital abnormalities, and 97 (12%) of 812 neonates or fetuses with Down’s syndrome. Based on maternal self-reported and medically recorded information, the matched case-population control pair analysis showed a higher rate of limb deficiencies, rectal-anal atresia/stenosis, cardiovascular malformations, and multiple congenital abnormalities after diazepam use during the second and third months of gestation. However, the evaluation of only medically recorded diazepam use did not show a higher use of diazepam in any congenital abnormality group. The authors suggested that

54 the higher occurrence of diazepam treatment among cases in the primary analysis may have been due to a lower proportion of mothers who recalled having take diazepam during their pregnancy in the population control group, i.e. a recall bias. They concluded that short-term diazepam treatment in usual therapeutic doses during pregnancy did not cause detectable teratogenicity. Drug interactions Neurological abnormalities have been attributed to phenytoin toxicity caused by an interaction with diazepam (11A ). • A 44-year-old man with a long-standing seizure disorder developed headache, nystagmus, diplopia, and ataxia. His antiepileptic drug regimen of phenytoin, phenobarbital, and lamotrigine had been unchanged for almost 5 months. Two days before admission he had been given amoxicillin and diazepam. The serum phenytoin concentration was 148 µmol/l, having been 32 µmol/l 2 weeks before. Both phenytoin and diazepam were withdrawn, and his symptoms resolved.

Lorazepam Nervous system In a placebo-controlled, double-blind, parallel-group comparison of single oral doses of lorazepam (2 mg) and flunitrazepam (1.2 mg), 36 young, healthy subjects completed a test battery before and after treatment including classic behavioral tests and visual and auditory event-related potentials (12C ). Differences in the impairment profile between equipotent doses of lorazepam and flunitrazepam suggested that lorazepam causes atypical central visual processing changes.

Midazolam In a randomized trial of intramuscular midazolam 15 mg (n = 151) or intramuscular haloperidol 10 mg plus promethazine 50 mg (n = 150) in agitated patients in three psychiatric emergency rooms, both treatments were effective (13C ). Midazolam was more rapidly sedating than haloperidol + promethazine, reducing the time people were exposed to aggression. One important adverse event occurred in each group;

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a patient given midazolam had transient respiratory depression, and one given haloperidol + promethazine had a generalized tonic–clonic seizure. In a 1-year retrospective survey of the use of intramuscular midazolam in a 30-bed acute inpatient general adult unit in Sydney, Australia, 212 doses of intramuscular midazolam were given, predominantly 5 mg (48%) or 10 mg (50%) (14c ). An antipsychotic drug was coadministered in 2.4%. Adverse effects were documented in eight episodes (3.8%), seven cases of excess sedation and one of urinary incontinence. None of the adverse effects required medical intervention. Nervous system Forty anxious day-case patients undergoing extraction of third molar teeth under local anesthesia with sedation, were studied in a randomized, double-blind, controlled trial (15C ). A target-controlled infusion of propofol was compared with patient-controlled propofol for sedation, combined with a small dose of intravenous midazolam (0.03 mg/kg) to improve amnesia. Five patients became oversedated in the target-controlled group compared with none in the patient-controlled group. Psychological In a placebo-controlled study of the effects of midazolam 0.5 mg/kg as a premedicant in 40 children aged 4–6 years having myringotomy, midazolam caused significant amnesia on a cued recall task (16C ). In addition, free recall for post-drug events was also impaired by midazolam, suggesting that benzodiazepine-induced amnesia occurs even for highly salient information. Drug interactions Pharmacokinetic and pharmacodynamic interactions of midazolam with fluoxetine, fluvoxamine, nefazodone, and ketoconazole have been investigated in 40 healthy subjects (17C ). The mean AUC of midazolam was increased 772% by ketoconazole and 444% by nefazodone. However, fluoxetine and fluvoxamine had no significant effects. Nefazodone and ketoconazole caused significant increases in midazolam-related cognitive impairment, reflecting changed midazolam clearance. Midazolam is metabolized by CYP3A4, as is atorvastatin. In a matched-pair study the effects of long-term atorvastatin on the pharmacokinetics of midazolam 0.15 mg/kg intravenously as a single dose were studied in 14

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patients undergoing general anesthesia for elective surgery (18c ). Atorvastatin significantly reduced the clearance of midazolam by 33% and increased the AUC by 40%.

Quazepam Nervous system The hangover effects of night-time administration of triazolam 0.25 mg, flunitrazepam 1 mg, and quazepam 15 mg were compared in 15 healthy subjects, who were given one of the three hypnotics at each session in a single-blind, crossover fashion (19c ). There were no significant between-drug differences in relation to psychomotor performance. Subjective hangover effects in the morning were prominent with flunitrazepam and quazepam relative to triazolam, whereas objective indices suggested a marked hangover effect of quazepam compared with the other two compounds. Drug interactions The effects of itraconazole 100 mg/day for 14 days on the pharmacokinetics of a single oral dose of quazepam 20 mg and its two active metabolites have been studied in 10 healthy men in a double-blind, randomized, placebo-controlled crossover study (20C ). Itraconazole did not change the pharmacokinetics of quazepam but significantly reduced the peak plasma concentration and AUC of 2oxoquazepam and N-desalkyl-2-oxoquazepam. Itraconazole did not affect psychomotor function. The results suggested that CYP3A4 is partly involved in the metabolism of quazepam.

Temazepam The incidence of adverse effects of temazepam and whether the addition of cognitive therapy was associated with a reduction in drug and fewer adverse effects have been studied in 60 patients aged 55 years or older (mean 65) with chronic and primary insomnia (21C ). They were randomized to placebo (n = 20), temazepam (mean dose 20 mg/day) (n = 20), or temazepam plus cognitive therapy (n = 20). Adverse effects were infrequent: placebo (11%), temazepam 7.8%, and temazepam plus cognitive therapy

8.3%. The adverse events were mild and reduced in severity over the course of treatment. The patients who received cognitive therapy used less temazepam with about the same incidence of adverse effects. Cardiovascular The effect of hypnotics during spaceflight on the high incidence of postflight orthostatic hypotension has been studied in astronauts who took no treatment (n = 20), temazepam 15 or 30 mg (n = 9), or zolpidem 5 or 10 mg (n = 8) (22c ). Temazepam and zolpidem were only taken the night before landing. On the day of landing, systolic pressure fell significantly and heart rate increased significantly in the temazepam group, but not in the control group or in the zolpidem group. Temazepam may aggravate orthostatic hypotension after spaceflight, when astronauts are hemodynamically compromised. It should not be the initial choice as a sleeping aid for astronauts; zolpidem may be a better choice. Nervous system In a double-blind, randomized, placebo-controlled, crossover study of the comparative pharmacodynamics of single doses of temazepam (15 and 30 mg), diphenhydramine (50 and 75 mg), and valerian (400 and 800 mg) in 14 healthy elderly volunteers, temazepam had dose-dependent effects on sedation and psychomotor ability with a distinct time course (23C ). Temazepam 30 mg and both doses of diphenhydramine elicited significantly greater sedation than placebo, and temazepam had the greatest effect. There were no differences in sedation scores between 50 and 75 mg of diphenhydramine. Psychomotor impairment was evident after diphenhydramine 75 mg compared with placebo on the manual tracking test; this was less than the impairment with temazepam 30 mg but similar to that with temazepam 15 mg. There was no psychomotor impairment with diphenhydramine 50 mg. Valerian was not different from placebo on any measure of psychomotor performance or sedation.

Triazolam Nervous system In a study of the effects of d-amfetamine (20 mg/70 kg) on the sedative and memory-impairing effects of triazolam

56 (0.25 mg/70 kg) in 20 healthy adults, the results suggested that benzodiazepines have specific effects on memory that are not merely a byproduct of their sedative effects, and that the degree to which sedative effects contribute to the amnestic effects may vary as a function of the particular memory process being assessed (24C ). In addition to enhancing the understanding of the mechanisms underlying benzodiazepine-induced amnesia, these results may also contribute to better understanding of the complex relation between specific memory processes and level of arousal. Drug overdose A case of triazolam overdose has been reported (25A ). • A 57-year-old man was found dead in a bamboo thicket. His blood and urine contained triazolam and hydroxytriazolam. Blood concentrations of triazolam and unbound hydroxytriazolam were 62– 251 and 10-66 ng/ml respectively. There was a substantial amount of triazolam in his bile.

This man probably died of postural asphyxia caused by triazolam poisoning.

OTHER HYPNOTICS AND SEDATIVES Pregabalin Pregabalin is a novel compound being developed for the treatment of several types of anxiety disorders. In a double-blind, fixed-dose, parallel-group, placebo- and active-controlled, multicenter, 4-week study, 271 patients with generalized anxiety disorder were randomized to pregabalin 50 mg tds (n = 70), pregabalin 200 mg tds (n = 66), placebo (n = 67), or lorazepam 2 mg tds (n = 68), followed by a 1-week double-blind taper (26C ). The adjusted mean change scores on the Hamilton Anxiety Scale were significantly improved by pregabalin 200 mg tds, and the most common adverse events were somnolence and dizziness, which were usually mild or moderate in intensity and were often transient.

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Zaleplon (SEDA-24, 49; SEDA-25, 50; SEDA-26, 49; SEDA-27, 46) Drug overdose An overdose of zaleplon can cause psychomotor impairment. • A 20-year-old man became unsteady on his feet after a road traffic accident (27A ). He had slow movements and reactions, poor co-ordination, lack of balance, and poor attention. He admitted to having inhaled three crushed zaleplon 10 mg tablets and ingesting three zaleplon 10 mg tablets. His blood zaleplon concentration was 0.13 µg/ml.

Blood concentrations consistent with doses exceeding therapeutic concentrations of zaleplon can impair level of consciousness and driving ability.

Zolpidem (SED-14, 132; SEDA-24, 50; SEDA-25, 50; SEDA-26, 50) Of 53 patients with insomnia randomly given zolpidem 10 mg or zaleplon 10 mg on 2 consecutive nights, 62% preferred zolpidem and 38% preferred zaleplon (28c ). The quality of sleep (for example the ease of getting to sleep) was significantly more improved after zolpidem. Insomniac patients tended to prefer zolpidem to zaleplon on both nocturnal and diurnal assessments. Seven adverse events occurred during the study, three of them with zolpidem (sluggish tongue, impaired concentration, leg complaints) and four with zaleplon (cephalalgia requiring an analgesic, abdominal fullness, headache, vertigo). All the adverse events were mild or moderate in intensity. Nervous system Zolpidem 5 mg, zopiclone 3.75 mg, lormetazepam 1 mg, or placebo were given at night to 48 healthy volunteers aged 65 years or over (29C ). The study included four treatment periods separated by wash-out periods of at least 1 week. The results suggested that compared with placebo, the active drugs increased body sway; however, this effect disappeared after 5 hours with zolpidem, while it disappeared only after 8 hours with lormetazepam and zopiclone. None of the three drugs affected attention. In learning tasks, there was impaired memory with lormetazepam relative to both zolpidem and placebo. Zolpidem had no significant effect on memory.

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Psychiatric Visual hallucinations have been attributed to zolpidem. • A 50-year-old woman, who had taken one conjugated estrogen tablet daily for hormone replacement therapy and tricalcium phosphate twice daily for osteoporosis, took zolpidem 10 mg for insomnia and paracetamol 500 mg for a headache at bedtime (30A ). She began to have visual hallucinations within 20 minutes, lasting for about 30 minutes, and then her vision returned to normal. She only partially recalled the event. She had never taken zolpidem before and had not had any such disturbances in the past.

57 Drug interactions An interaction of zolpidem with valproic acid has been reported. • A 47-year-old white man with a history of bipolar disorder, who was taking citalopram 40 mg/day and zolpidem 5 mg at bedtime, developed manic symptoms and was given valproic acid (31A ). Soon after this, he had episodes of somnambulism, which stopped when valproic acid was withdrawn. On rechallenge with valproic acid, the somnambulism returned.

This appears to be the first report in which the interaction of valproic acid with zolpidem led to somnambulism.

REFERENCES 1. Niederhofer H. An open trial of buspirone in the treatment of attention-deficit disorder. Hum Psychopharmacol Clin Exp 2003; 18: 489–92. 2. De las Cuevas C, Sanz E, De la Fuente J. Benzodiazepines: more “behavioural” addiction than dependence. Psychopharmacology 2003; 167: 297– 303. 3. Wolf DL, Desjardins PJ, Black PM, Francom SR, Mohanlal RW, Fleishaker JC. Anticipatory anxiety in moderately to highly-anxious oral surgery patients as a screening model for anxiolytics: evaluation of alprazolam. J Clin Psychopharmacol 2003; 23: 51–7. 4. Suzuki Y, Shioiri T, Muratake T, Kawashima Y, Sato S, Hagiwara M, Inoue Y, Shimoda K, Someya T. Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles. Eur J Clin Pharmacol 2003; 58, 829–33. 5. Hall J, Naranjo CA, Sproule BA, Herrmann N. Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine. J Clin Psychopharmacol 2003; 23: 349– 57. 6. Mehndiratta MM, Krishnamurthy M, Rajesh KN, Singh G. Clobazam monotherapy in drug naive adult patients with epilepsy. Seizure 2003; 12: 226– 8. 7. Pollack MH, Simon NM, Worthington JJ, Doyle AL, Peters P, Toshkov F, Otto MW. Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol 2003; 17: 276–82. 8. Kalachnik JE, Hanzel TE, Sevenich R, Harder SR. Brief report: clonazepam behavioral side effects with an individual with mental retardation. J Autism Development Dis 2003; 33: 349–54. 9. Burrows DL, Hagardorn AN, Harlan GC, Wallen EDB, Ferslew KE. A fatal drug interaction between oxycodone and clonazepam. J Forensic Sci 2003; 48: 683–6.

10. Czeizel AE, Erös E, Rockenbauer M, Sorensen HT, Olsen J. Short-term oral diazepam treatment during pregnancy. A population-based teratological case-control study. Clin Drug Invest 2003; 23: 451– 62. 11. Murphy A, Wilbur K. Phenytoin-diazepam interaction. Ann Pharmacother 2003; 37: 659–63. 12. Pompéia S, Manzano GM, Galduroz JCF, Tufik S, Bueno OFA. Lorazepam induces an atypical dissociation of visual and auditory event-related potentials. J Psychopharmacol 2003; 17: 31–40. 13. Huf G, Coutinho ESF, Adams CE, Borges RVS, Ferreira MAV, Silva FJF, Pereira AJCR, Abreu FM, Lugao SM, Santos MPCP, Gewandsznajder M, Mercadante VRP, Lange Jr W, Dias CI. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. Br Med J 2003; 327: 708–11. 14. Bradley N, Malesu RR. The use of intramuscular midazolam in an acute psychiatric unit. Aust NZ J Psychiatry 2003; 37: 111–12. 15. Burns R, McCrae AF, Tiplady B. A comparison of target-controlled with patient-controlled administration of propofol combined with midazolam for sedation during dental surgery. Anaesthesia 2003; 58: 170–6. 16. Buffett-Jerrott SE, Stewart SH, Finley GA, Loughlan HL. Effects of benzodiazepines on explicit memory in a paediatric surgery setting. Psychopharmacology 2003; 168: 377–86. 17. Lam YWF, Alfaro CL, Ereshefsky L, Miller M. Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol 2003; 43: 1274–82. 18. McDonnell CG, Harte S, O’Driscoll J, O’Loughlin C, Van Pelt FD, Shorten GD. The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam. Anaesthesia 2003; 58: 899–904.

58 19. Takahashi T, Okajima Y, Otsubo T, Shinoda J, Mimura M, Nakagome K, Kamijima K. Comparison of hangover effects among triazolam, flunitrazepam and quazepam in healthy subjects: a preliminary report. Psychiatry Clin Neurosci 2003; 57: 303–9. 20. Kato K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Kanno M, Otani K. Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug. Ther Drug Monit 2003; 25: 473–7. 21. Morin CM, Bastien, CH, Brink D, Brown TR. Adverse effects of temazepam in older adults with chronic insomnia. Hum Psychopharmacol Clin Exp 2003; 18: 75–82. 22. Shi SJ, Garcia KM, Keck, JV. Temazepam, but not zolpidem, causes orthostatic hypotension in astronauts after spaceflight. J Cardiovasc Pharmacol 2003; 41: 31–9. 23. Glass JR, Sproule BA, Herrmann N, Streiner D, Busto UE. Acute pharmacological effects of temazepam, diphenhydramine, and valerian in healthy elderly subjects. J Clin Psychopharmacol 2003; 23: 260–8. 24. Mintzer MZ, Griffiths RR. Triazolamamphetamine interaction; dissociation of effects on memory versus arousal. J Psychopharmacol 2003; 17: 17–29. 25. Moriya F, Hashimoto Y. A case of fatal triazolam overdose. Legal Med 2003; 5: 591–5.

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26. Feltner DE, Crockatt JG, Dubovsky SJ, Cohn CK, Shrivastava RK, Targum SD, Liu-Dumaw M, Carter CM, Pande AC. A randomized, doubleblind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003; 23: 240–9. 27. Stillwell ME. Zaleplon and driving impairment. J Forensic Sci 2003; 48: 677–9. 28. Allain, H, Bentué-Ferrer D, Le Breton S, Polard E, Gandon J-M. The preference of insomnia patients between a single dose of zolpidem 10 mg versus zaleplon 10 mg. Hum Psychopharmacol Clin Exp 2003; 1: 369–74. 29. Allain H, Bentué-Ferrer D, Tarral A, Gandon J-M. Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomised, cross-over, doubleblind study versus placebo. Eur J Clin Pharmacol 2003; 59: 179–88. 30. Huang, C-L, Chang, C-J, Hung C-F, Lin H-Y. Zolpidem-induced distortion in visual perception. Ann Pharmacother 2003; 37: 683–6. 31. Sattar SP, Ramaswamy S, Bhatia SC, Petty F. Somnambulism due to probable interaction of valproic acid and zolpidem. Ann Pharmacother 2003; 37: 1429–33.

Alfonso Carvajal, Luis H. Martín Arias, and Natalia Jimeno

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Antipsychotic drugs

GENERAL Comparative studies The impact of new antipsychotic drugs on the pattern of antipsychotic drug use has been studied in Spain (1C ). The use of antipsychotic drugs rose by 146% from 1990 to 2001; the atypical antipsychotic drugs accounted for 49% of the total consumption of antipsychotic drugs in 2001 and 90% of the costs. There is a similar pattern worldwide. This is surprising, since there is no clear evidence that atypical antipsychotic drugs are more effective or better tolerated than conventional antipsychotic drugs (SEDA-25, 53). Moreover, a recent meta-analysis of typical and atypical antipsychotic drugs (31 studies, 2320 participants) showed that optimum doses of low-potency conventional antipsychotic drugs might not induce more extrapyramidal signs than newer drugs (2M ); mean doses less than 600 mg/day of chlorpromazine equivalents had no higher risk of extrapyramidal signs than newer antipsychotic drugs. Cardiovascular QT interval prolongation remains a focus of attention (SEDA-24, 54; SEDA-25, 56; SEDA-26, 54; SEDA-27, 52). Conflicting results have been found in two crossover studies with regard to haloperidolinduced QT interval prolongation. In the first study, QT interval prolongation was associated with sulpiride but not haloperidol (3c ). Eight schizophrenic patients who had been free of medication for at least 2 weeks took sulpiride 15 mg/kg for 2 weeks and then haloperidol 0.25 mg/kg for another 2 weeks. QTc intervals during sulpiride treatment were significantly prolonged by 5.1% and 8.5% compared with haloperidol and no treatment. Conversely, in the second study there was a statistically longer mean QTc interval with haloperidol (422 ms) © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

than placebo (408 ms) 10 hours after haloperidol or placebo administration (4C ). The subjects of this study were 16 healthy volunteers who randomly took haloperidol (a single dose of 10 mg) or placebo during the first study period (4 days) and the alternative during the second period (4 days). Despite a statistically significant longer mean half-life of haloperidol (19 versus 13 hours) in poor metabolizers of CYP2D6 than in extensive metabolizers, this exposure change did not translate into marked changes in the QTc interval. Nervous system Neuroleptic malignant syndrome is a potentially fatal adverse effect of neuroleptic drugs (SEDA-20, 41). A casecontrol study in a psychiatric institution has shown an association between different susceptibility factors and the appearance of neuroleptic malignant syndrome (5C ). In a multivariate analysis of 15 patients who developed the reaction (cases) and 45 patients who did not (controls), increasing doses of neuroleptic drugs were significantly associated with an increased risk of neuroleptic malignant syndrome (OR = 44), which is in accordance with the results of other case-control studies (SEDA-22, 52). Intramuscular administration, but not environmental higher temperatures, was also a significant risk factor (OR = 36). There were no deaths. Caution is recommended in the use of intramuscular neuroleptic drugs and the use of rapidly increasing high doses, particularly in mentally retarded or agitated patients. Precautionary measures seem to reduce the risk of definite neuroleptic malignant syndrome in schizophrenia in-patients treated with typical neuroleptic drugs, according to the results of a study in which a group of consecutive drug-free in-patients with schizophrenia, who received various typical antipsychotic drugs for 28 days, were compared with a historical group of 192 similarly treated patients but in whom such precautionary measures were not adopted (6c ); the study group had a significantly lower incidence

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of definite neuroleptic malignant syndrome (1/657 versus 4/192). The protocol of measures included strict monitoring of signs that often precede neuroleptic malignant syndrome (i.e. altered level of consciousness, raised serum creatine kinase activity, white blood cell count, and body temperature, and altered autonomic function).

behavioral disturbances; of those, 24 were taking antipsychotic drugs and eight of the 24 developed extrapyramidal adverse effects; the effects were severe in five cases and in one case resulted in impaired consciousness. A therapeutic role for nefazodone 100 mg bd has been suggested in the treatment of antipsychotic drug-induced extrapyramidal signs, based on the results of a placebo-controlled, Akathisia and violence A review of several randomized study in 49 patients (10c ). There case reports and three studies relating to akathisia were no differences in akathisia or tardive dyskand violence has been published (7R ). Three inesia between the two groups. However; it cases involved homicidal behavior and two sui- should be noted that nefazodone has been withcidal behavior linked to haloperidol-induced drawn in most countries owing to the risk of severe liver damage. akathisia. • A 29-year-old man with a sociopathic personality and transvestism was treated with haloperidol after developing psychotic symptoms; he developed violent behavior, which consisted of assaulting his dog. • A 47-year-old man with bipolar disorder had haloperidol-induced akathisia thought to be associated with an attack on an emergency room staff member and subsequent destruction of ward property after he had been admitted as an in-patient.

Endocrine Hyperprolactinemia Three women, aged 61, 53, and 21 years, developed delusions of pregnancy while taking risperidone; their blood prolactin concentrations were 49, 78, and 52 ng/ml, respectively (reference range 2–26) (11A ).

Among 16 patients with no history of violence, there were significantly more violent episodes during haloperidol use than during placebo or chlorpromazine. Also, in a series of patients admitted to hospital (n = 313), there were higher scores for akathisia in the violent group. There was also a non-significant increase in akathisia among 31 physically aggressive schizophrenics compared with 31 nonaggressive ones. The authors concluded that clinicians need to differentiate between akathisia manifesting as violence and generalized psychotic agitation. From the forensic point of view, aggression associated with neuroleptic drug-induced akathisia is relevant when considering a criminal defendant’s mental state at the time of an alleged crime. Patients with catatonic schizophrenia are highly vulnerable to negative symptoms related to antipsychotic drugs, according to the results of a study in 1528 schizophrenic patients, of whom 51 had catatonic schizophrenia (8c ). Similarly, patients with frontotemporal lobar degeneration, commonly associated with behavioral disturbances, may be particularly sensitive to extrapyramidal adverse effects. This was observed in 100 patients with such degeneration (9c ). In 61 patients there were significant

Antipsychotic drugs and new-onset diabetes mellitus DoTS classification: Reaction: Diabetes mellitus due to antipsychotic drugs Dose-relation: collateral reaction Time-course: intermediate Susceptibility factors: male sex, African-American origin Antipsychotic drugs, particularly atypical ones, have been associated with adverse effects on glucose regulation, including diabetes (SEDA27, 53), and new-onset diabetes mellitus in such patients is of particular concern, owing to the associated cardiovascular morbidity and the difficulty in managing diabetes in psychiatric patients. Soon after the first neuroleptic drugs were used, associations with weight gain and diabetes were reported (12A , 13A ). Nevertheless, even before antipsychotic drugs appeared, diabetes was observed to be more common in patients with schizophrenia (14c ). The rate of diabetes in patients with schizophrenia has been estimated at 6.2–8.7% (15C ) and at 0.8% in the general population in the USA (16C ).

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Recently, the Food and Drug Administration (FDA) has asked all manufacturers of atypical antipsychotic drugs to add the following warning statement describing the increased risk of hyperglycemia and diabetes in patients taking these medications (17S ): “Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic drugs including . . . [a long list]. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotic drugs. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotic drugs are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotic drugs should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotic drugs should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotic drugs should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotic drugs should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug”. Whether diabetes is associated, and to what extent, with a particular antipsychotic drug or a particular type of antipsychotic drug is a matter of debate; since the two most commonly used atypical antipsychotic drugs are risperidone

and olanzapine, comparison of these two drugs has been a recent focus of attention. There are more case reports for clozapine and olanzapine, but the studies discussed below have reached conflicting results; further information from clinical trials is needed. Observational studies Claims data for the period January 1996 to December 1997 were analysed for patients with mood disorders in two large US health plans (18C ). In all, 849 patients had been exposed to risperidone, 656 to olanzapine, 785 to high-potency conventional antipsychotic drugs, and 302 to low-potency conventional drugs; 2644 were untreated. Adjusted odds ratios of newly reported type 2 diabetes in patients who took risperidone or high-potency conventional antipsychotic drugs were not significantly different from those in untreated patients at 12 months; on the contrary, patients who took olanzapine or low-potency conventional antipsychotic drugs had a significantly higher risk of type 2 diabetes compared with untreated patients; the 12-month adjusted odds ratios compared with untreated patients were 4.3 (95% CI = 2.1, 8.8) in those who took olanzapine and 4.9 (95% CI = 1.9, 13) in those who took low-potency conventional antipsychotic drugs. Olanzapine had significantly positive diabetic effects, based on both duration of treatment and dosage. All patients had been exposed to antipsychotic drugs for more than 60 days; because there was less awareness of the diabetic effects of atypical antipsychotic drugs during that period, the use of these data reduced the possibility of selection bias. Additionally, three other epidemiological studies have identified a higher risk of diabetes associated with olanzapine (1C , 15C , 19C ). The first of these studies included out-patients with schizophrenia treated over 4 months in 1999 (15C ). When patients who had taken atypical drugs (n = 22 648) were compared with those who had taken typical antipsychotic drugs (n = 15 984), the adjusted odds ratio of new diagnoses of diabetes was 1.09 (CI = 1.03, 1.15); and was even higher in patients under 40 years of age (OR = 1.63; CI = 1.23, 2.16; n = 3076 and n = 1105). The odds ratios for individual atypical drugs were: • quetiapine 1.31 (1.11, 1.55; n = 955);

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• clozapine 1.25 (1.07, 1.46; n = 1207); • olanzapine 1.11 (1.04, 1.18; n = 10 970); • risperidone 1.05 (0.98, 1.12; n = 9903). In a nested case-control study using information from the UK General Practice Research Database 451 patients with diabetes out of 19 637 patients treated for schizophrenia were matched with 2696 controls (19C ). There was a significantly increased risk of diabetes in patients taking olanzapine compared with nonusers of antipsychotic drugs (adjusted OR = 5.8; 95% CI = 2, 17) and compared with those taking conventional antipsychotic drugs (adjusted OR = 4.2, 95% CI = 1.5–12); there was a non-significantly increased risk in those taking risperidone compared with non-users of antipsychotic drugs (adjusted OR = 2.2, 95% CI = 0.9, 5.2) and compared with those taking conventional antipsychotic drugs (adjusted OR = 1.6; 95% CI = 0.7, 3.8). In a comparison of olanzapine and risperidone, 319 patients out of 19 153 who were given a prescription for olanzapine between 1 January 1997 and 31 December 1999 developed diabetes, compared with 217 who were given a prescription for risperidone (n = 14 793) (20C ). Proportional hazards analysis showed a 20% increased risk of diabetes with olanzapine relative to risperidone (RR = 1.20; CI = 1.00, 1.43). Finally, a retrospective cohort study carried out with a database that included information from different care plans (16C ) showed that the incidence of diabetes mellitus in patients taking any conventional antipsychotic drug was 84 per 1000 patient-years (crude incidence 307 in 19 782) compared with 67 per 1000 patientyears (crude incidence 641 in 38 969) in patients taking any atypical antipsychotic drugs; the estimated incidence in the reference general population was 15.7 per 1000 patients-years (crude incidence 45 513 in 5 816 473). Cox proportional hazards regression, adjusted for age, sex, and duration of antipsychotic drug exposure, showed that the risk of diabetes mellitus was significantly higher for whatever antipsychotic drug than in the general population but not different between the conventional and atypical antipsychotic drugs (HR = 0.97; 95% CI = 0.84, 1.11). The hazard ratios for individual atypical antipsychotic drugs compared with haloperidol were:

• • • •

clozapine 1.31 (95% CI, 0.60–2.86); risperidone 1.23 (95% CI, 1.01–1.50); olanzapine 1.09 (95% CI = 0.86, 1.37); quetiapine 0.67 (95% CI, 0.46–0.97).

The data cut-off point for this study was 31 August 2000. Only incident cases of diabetes mellitus that resulted in intervention with antidiabetic drugs were selected and only patients taking antipsychotic drug monotherapy were included; the average duration of antipsychotic drug treatment was not long (68–137 days). One of the main flaws of this study was the possibility of selection bias, since certain patient attributes that influence treatment selection might also affect the likelihood of diabetes mellitus. Weight gain due to atypical antipsychotic drugs has been addressed in a cross-sectional study of the weight at the time of a single visit compared with that recorded in the clinical chart (21C ). The proportion of patients with clinically relevant weight gain (≥7% increase versus initial weight) was higher with olanzapine (46%; n = 228) than with risperidone (31%; n = 232) or haloperidol (22%; n = 130); no patient had clinically relevant weight gain while taking quetiapine (n = 43). The risk of weight gain was higher in women (OR = 4.4), overweight patients (OR = 3.0) and patients with at least 1 year of treatment (OR = 6.3) in the olanzapine group; these risk factors are not entirely coincidental with other findings (SEDA-26, 56). In a recent open non-randomized study of the frequency of undiagnosed impaired fasting glucose and diabetes mellitus in 168 patients taking clozapine, 47 patients were discarded because a fasting plasma glucose was not successfully obtained (n = 20) or because they were identified as diabetic before the fasting plasma glucose screening (n = 27) (22c ). Of 121 patients not previously diagnosed as diabetic, 93 had normal fasting blood sugar concentrations (below 6 mmol/l or 110 mg/dl), and two had a raised plasma glucose concentration (fasting plasma glucose over 6 mmol/l), including seven with type 2 diabetes. Patients with hyperglycemia were significantly older and more commonly had concurrent bipolar affective disorder.

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Randomized studies In a randomized doubleblind study, in-patients with schizophrenia were assessed for fasting glucose, cholesterol, and weight gain after 14 weeks of treatment with clozapine (n = 28), haloperidol (n = 25), olanzapine (n = 26), or risperidone (n = 22) (23C ). There was a statistically significant increase in mean blood glucose concentrations only in the olanzapine group; 14 out of 101 patients (14%) developed raised blood glucose concentrations (over 7 mmol/l or 125 mg/dl) at some time during the study: six while taking clozapine, one haloperidol, four olanzapine, and three risperidone. Similarly, there was a significant increase in cholesterol concentration in the olanzapine group. The largest weight gain was also observed with olanzapine (mean change 7.3 kg), followed by clozapine (4.8 kg) and risperidone (2.4 kg); there was minimal weight gain with haloperidol (0.9 kg). ANCOVA showed no main effect or treatment interaction for the relation between change in blood glucose and weight gain at end-point; however, there was a significant main effect for the association between change in cholesterol and weight gain in the four groups. The rate of hyperglycemia (14%) in this study was about twice the rate of diabetes reported in a large survey of the US population (6–8%) (24C ) and somewhat higher than the current prevalence rate of 10% found in extensive samples of patients with schizophrenia (25C ). Susceptibility factors and clinical features Most of the patients who develop diabetes while taking antipsychotic drugs do so in under 6 months; men are at greater risk, and AfricanAmericans are more susceptible than other ethnic groups (26R ). Weight gain can be present or not; in a retrospective series of 76 patients who developed diabetes while taking olanzapine or risperidone, the increase in fasting blood glucose concentration in patients taking olanzapine did not correlate with changes in weight (27C ). Diabetic ketoacidosis is a common presentation of diabetes in patients taking atypical antipsychotic drugs. In 126 patients taking atypical antipsychotic drugs, new-onset, acute, marked glucose intolerance developed in 11 (8.7%) after treatment with clozapine, olanzapine, or quetiapine (28c ). Of these, six patients required insulin (four only transiently) and five

63 developed diabetic ketoacidosis. The mean and median times to the onset of diabetic ketoacidosis after the start of treatment with an atypical antipsychotic drug were 81 and 33 days respectively. In 45 patients, 19 who presented with ketoacidosis were significantly younger, more often women, and less overweight at baseline than 26 patients who developed diabetes without ketoacidosis (29c ). Death due to olanzapine-induced hyperglycemia has been reported (SEDA-27, 61). Mechanisms There has been some discussion about whether antipsychotic drug-induced hyperglycemia and diabetes are associated with weight gain (SEDA-25, 65; SEDA-26, 62; SEDA-27, 61). Clozapine and olanzapine have a high propensity to cause both weight gain and diabetes (SEDA-26, 56); however, there have been cases in which diabetes appeared or worsened in the absence of weight gain or even with weight loss (30A , 31R ). Both weight gain and diabetes seem to be effects that occur simultaneously, rather than diabetes being an indirect effect of weight gain. Other mechanisms have therefore been suggested (SEDA-21, 67). Ten patients with schizophrenia taking olanzapine 7.5–20 mg/day were compared with 10 healthy volunteers with regard to body weight, fat mass, and insulin resistance over 8 weeks (32C ). Fasting serum glucose and insulin increased significantly in the olanzapine group, as did weight gain. The index for insulin resistance increased only in the olanzapine group, whereas beta-cell function did not change significantly. Consistent with this, it has been observed that some antipsychotic drugs inhibit glucose transport into PC12 cells in culture and increase cellular concentrations of glucose, which would in turn cause a homeostatic increase in insulin release. The hormone leptin is synthesized by adipocytes and is important in controlling body weight; plasma leptin concentrations correlate with fat mass and insulin resistance. Plasma leptin concentrations are raised, regardless of weight, in patients taking clozapine (33c ). These observations suggest that insulin resistance might be responsible for the development of diabetes during treatment with atypical antipsychotic drugs, but it may not be the only factor, since the rapid development of diabetes in many of these patients suggests a direct and possibly toxic effect of antipsychotic drugs.

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Management The relation between the metabolic syndrome and antipsychotic drug therapy has been reviewed (34R –36R ). In most patients, diabetes improves or resolves after withdrawing antipsychotic drugs or switching to less diabetogenic drugs. Simple interventions, such as changes in diet and exercise, are recommended for patients with schizophrenia or bipolar disease taking antipsychotic drugs. Patients who develop conditions such as hyperlipidemia or diabetes mellitus often respond to routine treatment. However, managing diabetes in patients with schizophrenia is complicated by their lack of insight, loss of initiative, and cognitive deficits, which are central features of the illness. For patients with type 2 diabetes, the major risk is accelerated coronary heart disease and stroke, greatly aggravated by smoking, which is common in patients with schizophrenia. In addition to considerations of the diabetogenic potential of each agent, the presence of susceptibility factors, such as obesity, sedentary lifestyle, and a family history of type 2 diabetes, should be taken into account in the selection of a suitable regimen. It is sensible to monitor fasting plasma glucose concentrations, glycosylated hemoglobin, and fasting cholesterol and triglycerides in order to anticipate hyperglycemia and hyperlipidemia. Given the serious implications for morbidity and mortality attributable to diabetes and raised cholesterol, clinicians need to be aware of these risk factors when treating patients with chronic schizophrenia. Sexual function Sexual dysfunction associated with antipsychotic drugs has been reviewed (37R ). The authors concluded that sexual dysfunction is common in patients with schizophrenia, but often not reported to doctors nor explored, and may be an unrecognized cause of non-adherence to treatment.

controls. Five cases and three controls had been previously exposed to antipsychotic drugs for 48-252 months; the adjusted OR was 5.4 (95% CI = 1.1, 26). The authors hypothesized that hyperprolactinemia, which usually reduces the pulsatile secretion of follicle-stimulating and luteinizing hormones, inhibits gonadal function and might stimulate mitotic activity in the endometrium. Susceptibility factors Genetic In a prospective study the prevalence of poor CYP2D6 metabolizers was significantly higher in those who developed extrapyramidal adverse events (39c ). However, in a retrospective case-control study, CYP2D6 genotype was not associated with tardive dyskinesia (40C ). Patients with tardive dyskinesia (50 cases) were compared with 59 controls. Genotyping identified the functional allele CYP2D6*1, the known major defective alleles CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, and gene duplication; there was no statistical differences in the proportion of the different functional categories between the cases and the controls. In a study funded by Eli Lilly, the marketing authorization holder of olanzapine, claims data for schizophrenic patients taking olanzapine (n = 1875), risperidone (n = 982), or haloperidol (n = 726) between January 1997 and August 1998 were retrieved to determine the role of ethnicity in predicting adherence to antipsychotic drugs (41c ). After controlling for other factors, African-Americans and MexicanAmericans were significantly less adherent to therapy than white patients; for all ethnicities, olanzapine was associated with 23 more adherent days than risperidone and 55 more adherent days than haloperidol.

INDIVIDUAL DRUGS Tumorigenicity Little information is available on the relation between antipsychotic drug use and cancers of any type or in any site, although an increase in markers of genotoxicity has been described (SEDA-23, 57). In a recent case-control study there was an association between the use of antipsychotic drugs and endometrial cancer (38C ). Premenopausal women with histologically confirmed endometrial cancer (41 cases) were compared with 123

Chlorpromazine Sexual function Priapism has often been reported in connection with the use of different antipsychotic drugs, including chlorpromazine (42A ). • A 30-year-old man with schizophrenia developed priapism for 8 hours after taking chlorpromazine

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for 3 years. He was taking no other medications and there were no other pathological findings; a complete blood count and sickle cell screen were normal. Aspiration of blood from the corpora cavernosa, followed by saline irrigation led to complete detumescence.

Clozapine (SED-14, 140; SEDA-25, 60; SEDA-26, 59; SEDA-27, 55) There have been further attempts to establish the role of clozapine in the treatment of resistant schizophrenia, and clinical predictors of the response to clozapine in partly treatment-refractory out-patients have previously been examined (SEDA-27, 55). Since clozapine may be the gold standard and the last resort in the treatment of refractory schizophrenia, the aim of a recent review was to discover whether a trial with clozapine is adequate (43R ). The results favored an approach of increasing the clozapine plasma concentration in treatment-refractory schizophrenic patients who do not respond to an initial lowto-medium dose, that some patients, especially young male smokers, will need dosages over 900 mg/day, and that the addition of lowdose fluvoxamine while closely monitoring clozapine concentrations can help to reduce the large number of tablets required, since fluvoxamine increases the clozapine plasma concentration 2- to 3-fold, maximally 5-fold, and reduces N-desmethylclozapine concentrations; the combination can lead to non-linear kinetics of clozapine. Observational studies The aim of a new study was to evaluate the long-term efficacy of clozapine in patients with treatment-resistant schizophrenia (n = 34), schizoaffective disorder, bipolar type (n = 30), or bipolar disorder with psychotic features (n = 37), who were treated with clozapine in flexible doses over 48 months (44C ). After this time, Global Assessment of Functioning scores were improved in all three groups, with significantly greater improvement in the bipolar disorder group compared with the others; however, 54 patients withdrew during the study, five because of adverse effects (sedation, sleep cycle inversion, weight gain, and leukopenia).

65 Changes in regional cerebral blood flow induced by clozapine or haloperidol have been compared using positron emission tomography (PET) with radiolabelled water (H2 15 O), first after withdrawal of all psychotropic drugs (n = 6), then after treatment with therapeutic doses of haloperidol (n = 5) or clozapine (n = 5) (45c ). Cerebral blood flow increased in the ventral striatum and fell in the hippocampus and ventrolateral frontal cortex. The authors suggested that these changes might mediate a common component of the antipsychotic action of both drugs; however, the increase in cerebral blood flow in the dorsal striatum caused by haloperidol could well be associated with its prominent motor adverse effects, whereas the increased cerebral blood flow in the anterior cingulate or dorsolateral frontal cortex may mediate the probably superior antipsychotic action of clozapine. Cardiovascular Clozapine has been associated with venous thromboembolism (SEDA-25, 61; SEDA-26, 59; SEDA-27, 56), and the mortality rate associated with pulmonary embolism has been estimated to be about 28 times higher than in the general population of similar age and sex; it is not clear whether pulmonary embolism can be attributed to clozapine or some characteristics of its users (SEDA-27, 56). • A 58-year-old white deaf man, with a history of pulmonary embolism, two first-degree relatives with a history of stroke and myocardial infarction, and one first-degree relative who died suddenly, developed a new episode of pulmonary embolism shortly after clozapine was begun (46A ).

The authors pointed out that this case suggests that susceptibility factors, such as a previous history of pulmonary embolism or venous thrombosis or a strong family history, could be viewed as relative contraindications to treatment with clozapine; however, in an invited comment it was pointed out that in this case it was not mentioned whether the patient was immobile or not, because a crucial risk factor for thrombosis in psychiatric patients is reduced physical activity (47r ). In another case venous thromboembolism occurred on two occasions in a 22-year-old man taking clozapine (48A ). Resolution of the first episode was most probably due to treatment with anticoagulants, and the authors thought

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that withdrawal of anticoagulants could be regarded as equivalent to reintroduction of clozapine. They suggested that, although the interval between the withdrawal of anticoagulant therapy and the second episode was long (26 months), the sequence of events suggested a causal relation between clozapine and venous thromboembolism. Since selenium is an essential antioxidant, and its deficiency has been implicated in myocarditis and cardiomyopathy, the aim of an observational study was to measure plasma and erythrocyte selenium concentrations in random venous blood samples from four groups: patients with mood disorders (n = 36), patients with schizophrenia taking clozapine (n = 54), patients with schizophrenia not taking clozapine (n = 41), and healthy controls (n = 56) (49C ). Selenium concentrations in plasma and erythrocytes were significantly lower in the patients taking clozapine compared with all the others. Thus, low selenium concentrations in patients taking clozapine may be important in the pathogenesis of life-threatening cardiac adverse effects associated with clozapine. Nervous system Neuroleptic malignant syndrome has occasionally been associated with clozapine, although the presentation can be different from that associated with traditional antipsychotic drugs; for example, the patient may not develop rigidity or a rise in creatine kinase activity (SEDA-25, 62). • A 22-year-old man developed atypical neuroleptic malignant syndrome while taking clozapine (50A ). He vomited and was sweating and agitated but afebrile, with mild hypertension (maximum 156/96 mmHg) and a tachycardia, with marked increases in white blood cell count (32 × 109 /l), neutrophils (25 × 109 /l), and creatine kinase (1442 IU/l); a similar syndrome occurred while he was taking haloperidol.

The use of clozapine to treat psychosis related to Parkinson’s disease has previously been discussed (SEDA-24, 63). Now, 32 patients with Parkinson disease and psychosis (mean age 73 years; mean disease duration 12.3 years) have been followed for 5 years in a non-randomized, open study (51c ). Nineteen patients (eight with dementia) continued to take clozapine (mean dose 50 mg/day) and 13 stopped taking it; the average duration of treatment in those in whom medication was

stopped was 8.5 (range 1–24) months; the reasons for withdrawal were: symptoms improved and did nor return after weaning off clozapine (n = 9), somnolence (n = 3), and personal reasons (n = 1). There was no correlation between age, sex, duration and severity of disease, the presence of dementia, and the response to clozapine. Also, the Parkinsonian Psychosis Rating Scale scoring did not influence clozapine response. Metabolism Weight gain has been commonly associated with clozapine (SEDA-27, 56). • The 22-year-old son of healthy parents, with a lifelong history of galactosemia, developed weight gain while taking an effective dose of clozapine (52A ).

Because patients with galactosemia need to avoid weight loss as a result of restrictive dietary measures, the authors suggested that this is an interesting example of weight gain as a positive side effect of clozapine, not necessarily associated with increased appetite and higher caloric intake. Hematologic The problem of agranulocytosis caused by clozapine has been extensively discussed and studied (SEDA-26, 59; SEDA-27, 57). The underlying mechanism of agranulocytosis is unknown, but hemopoietic cytokines, such as granulocyte colonystimulation factor (G-CSF), are likely to be involved (SEDA-25, 62). • Increased apoptosis of neutrophils has been reported in a 45-year-old woman with clozapineinduced agranulocytosis (53A ). Withdrawal of clozapine and treatment with granulocyte colonystimulating factor led to normalization of the blood neutrophil count within 3 weeks.

The authors suggested that enhanced apoptosis of blood neutrophils during the acute phase of clozapine-induced agranulocytosis could have resulted from enhanced expression of the pro-apoptotic proteins Bax and Bilk and from a reduction in the anti-apoptotic proteins BCI-XL mRNA. The time-course of the fall and recovery of the neutrophils, as well as the release pattern of endogenous G-CSF, resembled those of chemotherapy-induced neutropenia. The kinetics of CD 34-positive cells mimic those of cytotoxic progenitor cell mobilization,

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for example after cytostatic drug administration. They suggested that clozapine-mediated inhibition of release of G-CSF or granulocyte– macrophage colony-stimulation factor (GMCSF) is involved in clozapine-induced agranulocytosis. Patients with severe neutropenia secondary to clozapine are at a high risk of recurrent neutropenia and more importantly agranulocytosis, if they are re-exposed to clozapine. In a recent cohort study, based on a prospective drug exposure database, the effectiveness of centralized routine monitoring of blood counts was evaluated in 1500 patients taking clozapine between March 2001 and December 2001 (54c ). Seven patients developed severe neutropenia while taking clozapine (neutrophil counts below 1.5 × 109 /l). The mean time to withdrawal of therapy was 1.6 days (maximum 6 days), and neutrophil counts recovered to normal in all cases after 6.4 days (maximum 13 days). Based on an estimate of 500 patient-years of exposure, the frequency of severe neutropenia was one case per 71 patient-years of therapy or 1.4% per annum. Pancreas Pancreatitis is an uncommon adverse effect of clozapine, although occasional cases have been reported, and monitoring serum amylase activity during slow increases in the dosage of clozapine has been recommended (SEDA-24, 64). • A 17-year-old man took clozapine in a dose that was gradually increased to 175 mg/day, and 23 days after the start of treatment developed mild epigastric pain (55A ). He had raised pancreas amylase (140 U/l) and lipase (463 U/l) activities, and four days later developed increasing pain in both shoulders and a large pericardial effusion.

Death The causes of sudden unexpected death in psychiatric patients are often unknown; however, sudden cardiac death has been associated with clozapine (SEDA-26, 59). On the other hand, suicide is a common cause of death among patients with schizophrenia. In a recent report, the authors claimed that in cases of sudden unexpected death, toxic post-mortem drug concentrations can lead to erroneous conclusions and reported a case of supposed postmortem redistribution of clozapine (56A ). • A 22-year-old obese woman was found unresponsive after taking clozapine for about 6 weeks, in

67 an eventual dose of 350 mg/day. Resuscitation was unsuccessful, and an autopsy about 8 hours later showed no clozapine in her stomach, but a clozapine concentration in cardiac blood of 4500 ng/ml; a concentration over 1300 ng/ml is considered toxic. The coroner expressed concern over the possibility of suicide, but the authors of the report suspected that suicide was very unlikely, since there were no overt signs of toxicity and the staff reported no change in behavior.

Pregnancy All antipsychotic drugs cross the placenta and reach the fetus in potentially significant amounts; however, clozapine caused no serious complications or developmental abnormalities during pregnancy in two cases (SED14, 152). Case reports have shown no congenital anomalies with clozapine in animals or humans (57R ). • A 22-year-old woman took clozapine 75 mg/day throughout pregnancy (58A ). Her pregnancy was not detected until the end of the first trimester. She and her husband were counselled on the possible risk to the fetus, but decided to continue taking clozapine. She was brought to the hospital in labor with vaginal leaking at 9 months and 9 days of gestation. Ultrasound examination confirmed a fetus of 32 weeks gestation, with intrauterine growth retardation, oligohydramnios, and absence of fetal heart sounds. She delivered a macerated still-born boy weighing 2.2 kg with no gross congenital anomalies.

Although it is not clear whether clozapine, the disease process, poor nutrition, lack of antenatal care, or a combination of all these factors, contributed to the outcome of this pregnancy. The authors suggested that one should be cautious about using clozapine during pregnancy. Lactation Neonatal safety may be compromised during breast feeding by a woman taking clozapine (57R ). The authors also pointed out that the available data suggest that neonates are at risk during breast-feeding by a mother who is taking lithium, are at moderate risk from lamotrigine and clozapine, and are probably at little risk from valproate or carbamazepine; the risks from most other new anticonvulsants and atypical antipsychotic drugs are currently undetermined. Susceptibility factors Age Since the adverse effects of clozapine may be more common in children than adults, perhaps reflecting developmental pharmacokinetic differences, clozapine and its metabolites, norclozapine and

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clozapine-N-oxide, have been studied in six youths aged 9–16 years, with childhood onset schizophrenia (59c ). Dose-normalized concentrations of clozapine did not vary with age and were similar to reported adult values. Clinical improvement in five patients correlated with serum clozapine concentrations, and clinical response and total number of common adverse effects (sialorrhea, n = 5; tachycardia, n = 4; sedation, n = 1; enuresis, n = 1) correlated with norclozapine concentrations. One child had a reduced neutrophil count (1.1 × 109 /l) and another child had increased hepatic transaminases. Drug formulations Since the patent for Clozaril® (Novartis) expired in 1998, three manufacturers of generic clozapine have submitted abbreviated new drug applications to the FDA for review and approval to market generic clozapine. In a recent review, the authors suggested that until further studies have been conducted, patients who are refractory to treatment and stabilized on Clozaril® should not be switched to a generic formulation; on the other hand, if a patient is stabilized on Clozaril® and not refractory to treatment, then cautious switching to a generic formulation may be reasonable; finally, initiating a generic formulation in a clozapine-naïve individual would be appropriate (60r ). There has been an open, nonblinded out-patient study in 20 patients with schizophrenia to ascertain the effects of switching from branded to generic clozapine; at the end-point, there were no significant differences in the total Positive and Negative Syndrome Scale (PANSS), the positive symptom subscale, the negative symptom subscale, or the general psychopathology subscale, or the Beck Anxiety Inventory (BAI), and there were no clinically significant changes in any measure; these results are consistent with data that suggest bioequivalence of these products (61c ). Drug overdose Persistence of serum concentrations after clozapine overdose, whose halflife is normally about 12 hours, has previously been reported (SEDA-25, 63). • A 20-year-old woman presented 6 hours after taking clozapine 3500 mg (62A ). She had unexpectedly prolonged tachycardia and somnolence, and recovered only after the serum clozapine concentration began to fall after a 4-day plateau.

Drug interactions Lithium The combination of clozapine and lithium has been studied in a randomized controlled trial in 10 patients with schizophrenia and 10 with a schizoaffective disorder taking clozapine with either lithium or placebo for 4 weeks (63C ). The combination was well tolerated, except for reversible neurotoxic reactions in two patients with schizophrenia, and safety measures showed no significant variations. The authors concluded that the lithium added to clozapine appears to afford potential benefit in schizoaffective disorders without harmful effects; for schizophrenia, however, it did not afford improvement but posed a risk of lithium toxicity. Omeprazole Clozapine is mainly metabolized by CYP1A2, which is induced by the proton pump inhibitor omeprazole. In two patients comedication with omeprazole and clozapine was associated with reduced plasma concentrations of clozapine of 42% and 45% (64A ). Monitoring therapy The range of serum concentrations that corresponds to toxicity is unclear, and in three patients taking clozapine, a high serum concentration was interpreted as showing that they had a significant risk of toxicity, although the patients appeared to be well, with no signs of toxicity or evidence of adverse effects. It has therefore been suggested (62A ) that serum concentration monitoring of clozapine should be used only in specific circumstances: • a poor clinical response to routine doses; • signs of toxicity or adverse events that could be linked to the serum concentration, such as seizures; • the use of concurrent medications that interact with CYP isozymes, in particular CYP1A2; • a change in the usual consumption of nicotine or caffeine; • suspected or known liver disease; • concerns about non-compliance. However, serum concentrations should be interpreted with caution in view of significant intra-individual variation (65AR ). In contrast, other authors have stated that serum concentration monitoring is recommended during maintenance treatment with clozapine, in the light of a retrospective, open,

Antipsychotic drugs

non-randomized study in 86 patients, in which 404 serum concentrations were measured (66c ). Eight cases of intoxication were identified, and the conclusions were that the risk of toxicity is increased at serum concentrations over 750 ng/ml, while the risk of relapse is low at serum concentrations over 250 ng/ml, irrespective of concurrent psychotropic drugs, although intoxication was defined only according to the reason for the request for serum concentrations assay, as outlined in the request form. • Serum concentrations of clozapine were measured 29 times in a 24-year-old woman who took clozapine for 3 years (67A ). Relapses occurred repeatedly at low serum concentrations of 48, 109, and 138 ng/ml, because of non-adherence by the patient during out-patient treatment, and also because the dose was lowered too hastily after partial response during in-patient treatment. However, intoxication was evident at a serum concentration of clozapine of 1158 ng/ml during a trial with a dose of 800 mg/day.

Droperidol

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(SEDA-24, 66; SEDA-27, 58)

With regard to the benefit to harm balance of the use of droperidol as an antiemetic, it has been suggested that the acceptable risk for antiemetic drug administration be established and that prospective data be collected to establish the risk associated not only with the administration of droperidol but also with other commonly used antiemetics (68r ). However, according to the FDA (69S ), a causal relation between the drug and an adverse effect need not be established, and reasonable evidence of an association requires including a warning in the drug labelling. Placebo-controlled studies In a randomized, double-blind, dose-ranging study in 305 adults receiving droperidol 0.1, 2.75, 5.5, and 8.25 mg for the acute treatment of migraine, the number of patients who achieved a pain-free response at 2 hours after treatment was significantly greater than with placebo for droperidol 2.75, 5.5, and 8.25 mg (70C ). The most frequent adverse events were akathisia and weakness, and adverse events were dose related. Anorexia, anxiety, somnolence, tremor, and confusion were also reported. No patient had QT interval prolongation.

Cardiovascular In late 2001 the FDA decided to introduce a “black box” warning regarding the use of droperidol because of its potential cardiac effects (QT prolongation leading to torsade de pointes and death). This decision, based mainly on post-marketing surveillance (MedWatch program and other relevant sources), has produced several reactions. The authors of a review (71r ) of three clinical studies, one published abstract, and seven case reports, as well as MedWatch reports, stressed the following points: there are several risk factors for dysrhythmias, including underlying illnesses, other drug exposures, different clinical settings (including surgery, emergencies, and psychiatry), and high doses of the drug (up to 100 mg intramuscularly). Long and widespread clinical use is also mentioned. They found no convincing evidence of a causal relation between droperidol and serious cardiac events. Others reached the same conclusion after reviewing 10 cases, reported in the FDA database, that were possibly related to the administration of droperidol in doses of 1.25 or less (72r ). Pancreas Droperidol is used as an adjunct in conscious sedation for endoscopic procedures. In one study, basal biliary sphincter pressures measured in 35 patients before and after droperidol were 56 and 48 mmHg; the basal pancreatic sphincter pressures measured in 22 patients before and after droperidol were 92 and 67 mmHg (73c ). However, in another study basal pressures of the biliary sphincter and of the pancreatic sphincter were not significantly altered by droperidol (74c ).

Haloperidol Drug interactions In a study of the interindividual variation in serum haloperidol concentrations, Japanese patients taking concomitant antiparkinsonian drugs (n = 145) had a mean haloperidol concentration:dose ratio that was 25% higher than in patients who were not taking antiparkinsonian drugs (n = 95) (75c ).

Loxapine

(SEDA-26, 61)

After 6 and 12 weeks of treatment with loxapine, patients with schizophrenia (n = 24; aged

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18–70 years) showed both lymphocyte D2 -like and 5-HT2A platelet receptor binding downregulation, which suggests that both receptors are involved in the mechanism of action of the drug, as well as its possible extrapyramidal adverse effects (76c ).

Olanzapine

(SEDA-25, 64; SEDA-26, 61;

SEDA-27, 59) Observational studies Data from 904 patients with schizophrenia have been collected in a prospective, comparative, non-randomized, open, observational study funded by Eli Lilly (77c ). In all, 483 patients took olanzapine and 421 took typical antipsychotic drugs. Somnolence was reported in 3.3% of cases in the olanzapine group and in 2.9% in the typical antipsychotic drug group; weight gain was more common in the olanzapine group than in the typical antipsychotic group (1.7% versus 0.2%), although there was no systematic recording of weights and participating clinicians reported weight changes as adverse events when they deemed it appropriate. The incidence of extrapyramidal symptoms was significantly lower in the olanzapine group, and the incidences of dystonia, hypertonia, hypokinesia, tremor, akathisia, and dyskinesia with olanzapine were also significantly lower; the open and non-randomized design of this study limited its conclusions. In a retrospective study in 499 in-patients with schizophrenia or schizoaffective disorder (78C ); 259 subjects were taking olanzapine and 240 risperidone. Treatment was considered effective in most cases (74% with olanzapine and 78% with risperidone). There were adverse effects in 19% of the patients taking olanzapine and 22% of those taking risperidone; they were mainly somnolence (n = 15 and n = 17 respectively) and extrapyramidal symptoms (n = 9 and n = 6 respectively); there were also three cases of weight gain with olanzapine. The efficacy of olanzapine monotherapy for the acute hypomania or mania has also been studied in a consecutive series of 15 patients entering an open, uncontrolled, 8-week trial of olanzapine monotherapy (79c ). Most of the patients had significant reductions in mania rating and more limited improvement in depression

rating, but more reported adverse events, consistent with other studies. The most commonly reported adverse effects were moderate to severe dry mouth (80%), weight gain (77%), mild dizziness (60%), edema (53%), mild to moderate drowsiness (53%), and constipation (47%). The efficacy and safety of olanzapine in particular disorders or particular groups of patients have been previously studied (SEDA-24, 67), and new studies have been published. For example, in a 4-week open trial, 94 elderly psychiatric in-patients (aged 65 years or older) were treated with a mean daily dose of olanzapine of 10 mg (range 2.2–20). The most common adverse effects were somnolence (18%), dizziness (18%), and weakness of the legs or bradykinesia (16%); body weight and fasting triglyceride and glucose concentrations were significantly increased (80c ). In a review of the charts of 98 oncology patients who were given olanzapine, 28 took it specifically for prevention of delayed emesis (81c ). The authors claimed that olanzapine was well tolerated and might reduce the incidence of delayed emesis in patients receiving emetogenic chemotherapy. In 18 patients with trichotillomania given olanzapine (maximum dose 10 mg/day) in a 3month open study the most common adverse effects were sedation and weight gain (82c ). The authors claimed that olanzapine may be effective monotherapy for trichotillomania. Three patients with chronic pain were successfully treated with olanzapine as an adjunct therapy; two had fatigue associated with olanzapine (83A ). Two patients with refractory panic attacks (84c ) and five patients with long-lasting and untreatable nightmares and insomnia (85c ) benefited from olanzapine with no adverse effects after several months of treatment. In a recent non-randomized, open study in 37 patients (21 women, 16 men) with essential tremor, the most common movement disorder, olanzapine significantly reduced the median tremor score from 3.3 to 1.1 (86c ); seven of the patients reported adverse effects such as sedation, which disappeared in about 7 days, and three complained of weight gain. Comparative studies Although mania has been associated with olanzapine (SEDA-24, 68; SEDA-25, 68; SEDA-26, 62), it has also

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been used in the treatment of acute mania. In a 12-week, double-blind, double-dummy, randomized trial, 120 patients with bipolar disorder type I hospitalized for an acute manic episode were randomly assigned to either sodium valproate (n = 63) or olanzapine (n = 57) and were followed in hospital for up to 21 days (87C ). Valproate and olanzapine had similar short-term effects on clinical or health-related quality of life outcomes in bipolar disorder; adverse effects that occurred in a higher percentage of olanzapine-treated than valproatetreated patients included somnolence (47% versus 29%), weight gain (25% versus 10%), rhinitis (14% versus 3%), edema (14% versus 0%), and slurred speech (7% versus 0%); no adverse events occurred significantly more often with valproate. In a recent pooled analysis, three previously published trials have been reviewed to compare the efficacy, safety, and tolerability of oral-loaded valproate with standard-titration valproate, lithium, olanzapine, or placebo in patients with acute mania associated with bipolar I disorder (88M ). Valproate loading was as well tolerated as the other active treatment or better tolerated, as measured by adverse events and changes in laboratory parameters, and was of better efficacy than placebo; however, there were no efficacy differences between valproate loading and olanzapine. Placebo-controlled studies Promoted by EliLilly, the market authorization holder of olanzapine, three randomized, double-blind, placeboand active medication-controlled trials in agitated patients have been reanalyzed looking for a calming effect (89M ); the studies were conducted in patients with schizophrenia (n = 311), bipolar mania (n = 201), or dementia (n = 206) to compare intramuscular olanzapine with intramuscular haloperidol, lorazepam, or placebo. There were no significant betweengroup differences in Agitation-Calmness Evaluation Scale scores. The incidence of adverse events was not significantly more reduced with olanzapine versus comparators; haloperidoltreated patients with schizophrenia had more acute dystonias and akathisia than olanzapinetreated patients, but no parkinsonism, and no treatment-related adverse effect had an incidence of 10% or more among olanzapinetreated patients, although one had two serious adverse effects, overdose and psychosis.

71 Cardiovascular Olanzapine causes prolongation of the QT interval (SEDA-25, 64; SEDA26, 61; SEDA-27, 59). • A 66-year-old woman taking chlorpromazine and quetiapine had QTc interval prolongation, which improved when these drugs were withdrawn (90A ). However, prolongation later recurred while she was taking high-dosage olanzapine (60 mg/day), which had not occurred with a smaller dosage (40 mg/day). • QTc prolongation occurred in a 28-year-old woman while she was taking olanzapine 40 mg/day; after olanzapine withdrawal, the QTc interval returned to normal (91A ).

An episode of asystole (at which time olanzapine was withdrawn), followed 6 days later by a brain stem stroke, occurred during a double-blind parallel study for 2 weeks in 39 demented patients with agitation (mean age 83 years) (92c ); olanzapine (n = 20, mean daily dose 6.65 mg, modal dose 10 mg) or risperidone (n = 19, mean daily dose 1.47 mg, modal dose 2 mg) were given once a day at bedtime. Subclinical cases of increased blood pressure related to olanzapine have previously been reported (SEDA-25, 64). • A 29-year-old man developed transient rises in systolic and diastolic blood pressures (160/90; previous blood pressure 130/84 mmHg) with raised transaminases and dependent pitting edema of both feet (93A ).

Peripheral edema might be more frequent than expected in patients taking olanzapine. In a recent open, non-randomized study in 49 subjects taking olanzapine, 28 reported edema, which was severe in five (94c ). There were no significant differences regarding sex, dose of olanzapine or duration of treatment, concomitant diagnoses, or other psychotropic drugs, but there was a tendency toward greater frequency of thyroid abnormalities and older age in those with edema, in whom there was a positive correlation between age and severity. Nervous system Olanzapine has occasionally been seen to improve pre-existing tardive cervical dystonia (SEDA-27, 59). However, two patients developed acute dystonias while taking the lowest therapeutic dose of olanzapine (5 mg/day) (95A ). Neuroleptic malignant syndrome associated with olanzapine has previously been reported

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(SEDA-25, 64; SEDA-26, 62; SEDA-27, 60), and two further cases have been reported. • A 16-year-old boy developed fever, generalized rigidity, leukocytosis, and increased serum transaminase and creatine kinase activities while taking olanzapine and lithium; when both drugs were withdrawn, his fever and rigidity subsided and the biochemical tests returned to normal, without any complications (96A ). • A 75-year-old man developed typical neuroleptic malignant syndrome while taking olanzapine; he had previously had haloperidol-associated neuroleptic malignant syndrome (97A ).

The incidence of seizures with olanzapine, which has been estimated at 0.9% of treated patients, is probably comparable to that with other antipsychotic drugs (SEDA-27, 60). • A 32-year-old woman with genetically confirmed Huntington’s disease of 6 year’s duration, who was treated with increasing doses of olanzapine and responded well to 30 mg/day, had a seizure (98A ).

The author pointed out that seizures are common in juvenile-onset Huntington’s disease but rare in adult-onset Huntington’s disease. Metabolism Significant weight gain occurs more often with olanzapine than with haloperidol or risperidone (SEDA-24, 69; SEDA-25, 65; SEDA-26, 57; SEDA-27, 61); on the other hand, histamine H2 receptor antagonists, like nizatidine, can control appetite in overweight patients, as has previously been observed in a patient taking olanzapine (SEDA-25, 65). In a recent double-blind trial, the efficacy of nizatidine in limiting weight gain has been evaluated in 175 patients with schizophrenia and related disorders who took olanzapine 5–20 mg, nizatidine 150 mg or 300 mg, or placebo for up to 16 weeks (99C ). There was significantly less weight gain on average at weeks 3 and 4 with olanzapine plus nizatidine 300 mg compared with olanzapine plus placebo, but the difference was not statistically significant at 16 weeks. Hematologic Olanzapine is relatively free of hematological adverse effects, although cases of neutropenia have been reported (SEDA-24, 69; SEDA- 25, 65; SEDA-26, 62). • Neutropenia occurred in a 21-year-old man taking olanzapine 20 mg/day, haloperidol 10 mg/day, and lorazepam 2 mg/day (100A ). The white cell count was 2.6 × 109 /l, with a 22% differential neutrophil count.

The authors stated that, in spite of decades of experience with haloperidol, an associated literature search has revealed only very rare instances of hemotoxicity, and since lorazepam is not known to cause leukopenia, olanzapine may have been the more likely offender; the simultaneous effect of both antipsychotic drugs, olanzapine and haloperidol, is unknown. Gastrointestinal Olanzapine-induced fecal incontinence has been reported, purportedly for the first time (101A ). • A 65-year-old man who had primary insomnia for 20 years, was given olanzapine 2.5 mg/day at night-time because of lack of response to various anxiolytics; he developed fecal incontinence during the 20 days of olanzapine treatment in combination with two anxiolytic drugs. The frequency of incontinence varied from 1 to 3 times a day, and withdrawal of olanzapine resulted in complete recovery.

Liver Initial trials and other observational studies with olanzapine detected transient rises in liver transaminases (SEDA-23, 65). Several other cases have further illustrated this. • There were significantly raised transaminases, up to 5 times the reference range, in a 37-year-old woman taking olanzapine 10 mg/day and in a 62year-old woman taking 15 mg/day (102Ar ). • A 29-year-old man had raised transaminases, pitting edema of both feet, and transient rises in systolic and diastolic blood pressures after taking olanzapine 20 mg/day; 14 days after olanzapine withdrawal, the transaminases returned to baseline, the edema cleared completely, and the blood pressure returned to normal (93A ). • Olanzapine caused increased transaminases in a 38-year-old man with hereditary coproporphyria; the enzyme changes were not associated with symptoms or evidence of either acute liver failure or exacerbation of his porphyria (103A ).

Olanzapine-induced acute hepatitis has been reported, supposedly for the first time (104A ). • A 78-year-old woman with no history of liver disease, alcohol intake, intravenous drug use, or blood transfusions, took olanzapine 10 mg/day; her only other medications were calcium + vitamin D, multivitamins, and occasional paracetamol. After 13 days she developed symptoms of acute hepatitis with abnormal liver function tests; hepatobiliary ultrasonography showed several gallstones without dilatation of the biliary ducts or changes of acute cholecystitis. The plasma paracetamol concentration was less than 7 µmol/l, and serological tests for hepatitis A, B, and C viruses, cytomegalovirus, Epstein–Barr virus, and antimitochondrial and antinuclear antibodies were negative.

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Body temperature Antipsychotic drugs can cause a reduction in body temperature, and several cases of hypothermia, defined as a body temperature lower than 35◦ C, have been reported (SEDA-26, 58). Now hypothermia related to olanzapine has been published (105A ). • A 54-year-old man with end-stage renal disease on hemodialysis took olanzapine 2.5 mg/day for 21 days because of night-time delirium, including visual hallucinations and abnormal behaviors; the delirium disappeared completely and his body temperature returned to normal. However, the delirium reappeared 7 days later and he took olanzapine again for 10 days; his body temperature suddenly fell to below 34◦ C after the first dose.

Susceptibility factors Genetic Gilbert’s syndrome has been reported to increase susceptibility to the adverse effects of olanzapine. • A 19-year-old man with Gilbert’s syndrome took olanzapine 2.5 mg/day for 2 days, then increased the dosage to 5 mg/day on day 3 (106A ). On the day 4, because of a suicide attempt and extreme agitation, the patient was admitted to a psychiatric center. He was given oral olanzapine 10 mg and lorazepam 5 mg. On day 6, he was conscious but did not respond to verbal stimuli, and his symptoms of mutism persisted over the next few days. Communication was only possible by monosyllables on day 8. On day 10 he was bradypsychic, oriented, and able to articulate short sentences with great effort. Speech returned to normal on day 12. He described his experience as a sensation of not being able to find the words in his head. He had not previously had speech alterations, nor did they occur later.

Since mutism with olanzapine has been reported in cases of overdose, and detoxification of bilirubin by conjugation with glucuronic acid, the pathway olanzapine uses, is altered in Gilbert’s syndrome, which affects 10% of the population, the authors claimed that we should keep in mind idiopathic unconjugated hyperbilirubinemia when prescribing olanzapine. Smoking Plasma concentrations of olanzapine are lower in smokers than in non-smokers, mainly because of induction of cytochrome CYP1A2 (SEDA-27, 62). In addition, in a recent study it has been investigated whether the smoking-inducible cytochrome CYP1A2 and the polymorphic CYP2D6 play significant roles in the metabolism of olanzapine and its clinical effects at steady-state; caffeine and debrisoquine were used as measures of CYP1A2 and

CYP2D6 respectively (107c ). Psychiatric patients, smokers (n = 8) and non-smokers (n = 9), took oral olanzapine for 15 days. The mean urinary caffeine indexes of non-smokers and smokers indicated that smoking had induced a six-fold higher activity of CYP1A2; likewise, the dose-corrected plasma olanzapine concentration was about five-fold lower in smokers than in non-smokers. The authors suggested that a simple caffeine test might assist in individualization of the dosage of olanzapine. There have been reports that selective serotonin reuptake inhibitors, which inhibit CYP1A2, increase plasma olanzapine concentrations (SEDA-24, 71; SEDA-26, 63). In a recent open add-on trial, 21 patients with obsessive-compulsive disorder unresponsive to treatment with paroxetine 60 mg/day for at least 12 weeks, took additional olanzapine 10 mg/day (108c ). Steady-state plasma concentrations of paroxetine were not changed, and 7 patients were rated as responders at final evaluation. Sedation (n = 12), weight gain up to 3 kg (n = 8), dry mouth (n = 6), and constipation (n = 3) were the most frequent adverse effects.

Prochlorperazine Liver Phenothiazines can cause cholestatic jaundice. • Cholestasis occurred in a woman with alpha1 antitrypsin deficiency (phenotype PiZZ) who had taken prochlorperazine 5–10 mg qds for 27 months (109A ). She developed jaundice and ascites. Liver biopsy confirmed diffuse advanced chronic cholestasis, moderate portal and periportal inflammation, and bridging necrosis. Her liver function tests normalized within days of withdrawal of prochlorperazine.

Promazine Drug overdose Minimal myocardial damage after promazine overdose has been reported, purportedly for the first time (110A ). • A 31-year-old woman with a borderline personality disorder took 15 ml of promazine hydrochloride (total 600 mg), 25 capsules of OptalidonTM (butalbital 1250 mg, propyphenazone 3125 mg, caffeine 500 mg), and 20 capsules of flurazepam (total

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600 mg). Her electrocardiogram showed T wave inversion in V3–V6, with no significant changes in ST segments or QRS duration and no dysrhythmias. Transthoracic echocardiography showed hypokinesis of the distal segments of the anterior and lateral segments and of the apex of the left ventricle; there was mild reduction of global systolic function, with an ejection fraction of 54%. Creatine kinase and myocardial band releases peaked at 36 hours, reaching maximum values of 469 U/l and 10 µg/l respectively. Her electrocardiogram, recorded every 12 hours, began to normalize within 2 days and was definitely normal after 5 days.

Because she also took a large dose of caffeine, a combined effect cannot be excluded.

Risperidone

(SEDA-25, 67; SEDA-26, 63; SEDA-27, 62)

Observational studies A prospective open study of the effects of risperidone (mean dose 1.8 mg/day) has been carried out in 21 sites across Canada in 108 patients (mean age 44 years) with bipolar I disorder, with manic or mixed episodes (111c ). The usual mood stabilizers and antidepressants, but no other antipsychotic drugs or newer generation anticonvulsants, were permitted during the 12-week study. There were significant reductions in manic and depressive symptoms, as measured by conventional scales (Young Mania Rating Scale). The antimanic effect was observed from week 1 on: mean baseline score 28 (n = 107); mean change from baseline on week 1, −11 (n = 103); week 3, −18 (n = 92); week 12, −23 (n = 77). There were 15 serious unspecified adverse events in nine patients, resulting in five dropouts; adverse events that occurred in at least 10% of the patients included headache (24%), depression (15%), fatigue (13%), nausea (12%), constipation (10%), and diarrhea (10%); 27% developed at least one of the following extrapyramidal symptoms: dyskinesia, dystonia, hyperkinesia, involuntary muscle contractions, and tremor; none developed tardive dyskinesia. At week 12 there was weight gain of 2.4 kg among completers; and 21 had a weight gain of at least 7% during the study. Risperidone has also been used in combination with topiramate in a Spanish multicenter study in 58 patients (28 men and 30 women;

mean age 41 years) with bipolar I disorder, with manic but not mixed episodes (112c ). Risperidone (mean dose 2.7 mg/day) and topiramate (mean dose 236 mg/day) were started with a maximum 48-hour time difference; risperidone was used for acute manic symptoms and topiramate for longer-term stabilization and prevention of relapse. The incidence of any adverse event was 64%, mostly somnolence, paresthesia, dizziness, tremor, weight loss (n = 27; mean change −1.1 kg), extrapyramidal disorders, gastrointestinal effects, and cognitive disturbances. One patient developed tardive dyskinesia during the study and there were five dropouts because of adverse effects; adverse effects that required withdrawal of risperidone but not topiramate were amenorrhea (n = 3) and sexual dysfunction (n = 1). In 21 Turkish children and adolescents with conduct disorder (17 boys and 4 girls; mean age 11 years), the mean dose of risperidone at the 8-week endpoint was 1.27 mg/day (113c ). There were significant improvements in several symptoms, including inattention and hyperactivity/impulsivity. There was mild and transient sedation at the beginning of the study in all patients, and a mean increase in sleep duration of 0.9 hours (range 0–3 hours). There were no extrapyramidal symptoms or other severe adverse events. Several symptoms of dementia can be improved by risperidone. In 18 patients with Alzheimer’s disease (no sex or age data reported), delusions of theft, hallucinations, and agitation/aggression improved significantly after 12 weeks of treatment (114c ). The modal optimal dosage was 1 mg/day, the same already suggested for this pathology (SEDA-26, 64). There were mild extrapyramidal symptoms at some point during the trial in one patient. Comparative studies Several adverse events, including one death (no further information provided), have been described with risperidone in a study in which elderly patients with schizophrenia (mean age 70 years) were randomly assigned to risperidone (n = 32) or olanzapine (n = 34) for 4 weeks (115c ). Placebo-controlled studies Other special groups in which risperidone has been used include schizotypal personality disorder, posttraumatic stress disorder, conduct disorder,

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Tourette syndrome, and dementia (SEDA-25, 68; SEDA-26, 64; SEDA-27, 62). In a 9-week double-blind, randomized, placebo-controlled study, subjects were assigned to either risperidone (n = 14, 13 men and 1 woman; mean age 42 years; dose titrated upwards up to 2 mg/day) or to placebo (n = 9, 6 men and 3 women; mean age 39 years) (116c ). Adverse effects were reported in seven subjects who took risperidone, including dry mouth, tiredness, weakness, reduced sexual arousal and delayed ejaculation, and a mild dystonic reaction. However, five placebo-treated subjects also reported adverse effects, which might have been due to the strong tendency of these patients to become somatically preoccupied. There were no group differences in dropout rates due to adverse effects. Patients with post-traumatic stress disorder may also benefit from risperidone. In a randomized study in 40 male Vietnam combat veterans, 37 completed at least 1 week of treatment, of whom 19 took risperidone and 18 took placebo; their mean ages were 51 and 54 years respectively (117c ). The dose of risperidone was individually adjusted (maximum 6 mg/day); the mean dose at endpoint was 2.5 mg/day. Risperidone was generally well tolerated; adverse effects included only mild akathisia in one patient taking 3 mg/day and gastrointestinal effects in one patient taking 4 mg/day; no patient withdrew because of adverse effects. Irritable aggression and intrusive thoughts in post-traumatic stress disorder are reduced by low-dose risperidone as adjunctive therapy, according to the results of a double-blind, randomized trial in 16 male combat veterans, who took either risperidone (n = 7; mean age 49 years) or placebo (n = 8; mean age 54 years) for 6 weeks; one subject taking risperidone dropped out because of urinary retention (118c ). Concurrent antidepressant medication and anxiolytic drugs were allowed in both groups. Risperidone also appears to be safe and effective in the short-term treatment of tics in children or adults with Tourette syndrome, according to the results of a randomized, doubleblind study in 34 subjects (mean age 20, range 6–62 years), of whom 26 were children (25 boys and 1 girl; mean age 11, range 6–18 years) (119c ). After 8 weeks of treatment (mean dose 2.5 mg/day; maximum 4 mg/day for adults and

75 3 mg/day for children), those who took risperidone had significant improvements in tic severity, as evidenced by a 32% drop in the Yale Global Tic Severity Scale total score. Furthermore, 12 children randomized to risperidone had a 36% reduction in tic symptoms compared with an 11% reduction in the 14 children who took placebo. The most frequent adverse effects with risperidone were: increased appetite (n = 7), fatigue (n = 6), sedation (n = 3), foggy thinking (n = 2), blurred vision (n = 2). In and acute social phobia (which might be also diagnosed as panic attack) (n = 2); the last of these was managed by dosage reduction in one subject but required treatment withdrawal in the other. Two men had sexual adverse effects (either erectile difficulties or reduced libido); both improved with dosage reduction. There was a mean weight gain of 2.8 kg. In a multicenter, randomized, double-blind, 12-week trial in Australia and New Zealand, 384 patients with dementia, mainly Alzheimer’s disease, were initially enrolled and received at least one dose of risperidone (n = 167; 71% women; mean age 83 years; modal dose 0.99 mg/day) or placebo (n = 170; 72% women; mean age 83 years) (120C ). Clinical improvement in aggression and psychotic symptoms was evidenced by means of specific scales; 45 subjects taking risperidone and 56 taking placebo did not complete the trial, mainly because of insufficient responses and adverse effects. In the whole sample there was a high prevalence and variety of adverse events (94% of those taking risperidone and 92% of those taking placebo), mainly injuries, falls, somnolence, and urinary tract infections; however, only the last two were more common in those taking risperidone than in those taking placebo. A total of 39 patients taking risperidone (23%) and 36 (21%) taking placebo had at least one severe adverse effect, including cerebrovascular events (9% with risperidone, n = 15; 1.8% with placebo, n = 3). Ten patients (3.6% with risperidone, n = 6; 2.4% with placebo, n = 4) died during the course of the trial, pneumonia and stroke being the most frequent causes (three due to pneumonia and two to stroke in the risperidone group; one due to pneumonia in the placebo group). Nevertheless, the investigators considered that relations between risperidone and adverse events that led to death were doubtful or non-existent.

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Cardiovascular Acute massive pulmonary thromboembolism has been attributed to risperidone in two patients (121c ): • a 64-year-old woman taking bromperidol chronically, who also took risperidone (last dose 6 mg) for 40 days before the event; • a 48-year-old woman who took risperidone for 6 days (last dose 2 mg).

The first patient died and the second survived. In the same series from a Japanese Emergency Center, seven patients (two men and five women, aged 23–70) who took chlorpromazine, levomepromazine, or propericiazine also had thromboembolic disorders; none of them had any known risk factor for thrombotic disease. Suggested mechanisms are: reduced movement at night as a consequence of the sedative effect of neuroleptic drugs (symptoms developed in all cases in the early morning); an effect of anticardiolipin antibodies, which can occur in some patients taking phenothiazines; or increased 5HT2A -induced platelet aggregation. The debate about the need to restrict drug therapy in relation to the risk of cardiovascular events is open, and some authors have already expressed agreement (122r ) or disagreement about it (123r ), as well as pointing to the need for individual patient meta-analyses and significant changes to clinical trial methods in order to better assess the effectiveness, in contrast to the efficacy, of risperidone and other drugs in dementia (124r ). Nervous system Neuroleptic malignant syndrome has been attributed to risperidone (125A ). • A 30-year-old man with a history of bipolar disorder had substantial weight gain with olanzapine and was switched to risperidone (dose unknown) and lithium carbonate (450 mg bd). A few days later he developed confusion, mild muscle rigidity, a raised temperature, and increased creatine kinase activity. The medications were withdrawn and he responded to supportive therapy.

Risperidone and stroke in patients with dementia Stroke is a matter of increasing concern with some antipsychotic drugs, and the Canadian

Medicine Agency has recently issued a warning that there is a risk of stroke with risperidone (126S ). Particular attention has been devoted to the possibility of risperidone-induced stroke in patients with dementia, and it is important to remember, as the company itself, Janssen Pharmaceuticals, stated in a letter of April 2003, that risperidone is not approved for the treatment of this condition (127S ). Based on data from four placebo-controlled trials (n = 1230), the company also warned about cerebrovascular adverse events, including stroke, in elderly patients with dementia: “Cerebrovascular adverse events (e.g. stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73–97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. [Risperidone] has not been shown to be safe or effective in the treatment of patients with dementia-related psychosis”. The higher risk of stroke with risperidone or olanzapine compared with placebo has been addressed by the World Health Organization (128S ), the European Agency for the Evaluation of Medicinal Products (EMEA), and other national agencies, which have also warned of this possible association (129S –131S ). Furthermore, the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK has recommended avoiding risperidone and olanzapine in elderly patients with dementia (132S ). In the UK, the Committee on Safety of Medicines (CSM) has also advised in a message of 9 March 2004 that there is clear evidence of an increased risk of stroke in elderly patients with dementia who take risperidone or olanzapine (133S ): “. . . the magnitude of this risk is sufficient to outweigh likely benefits in the treatment of behavioral disturbances associated with dementia and is a cause for concern in any patient with a high baseline risk of stroke”. Surprisingly, there was no statistically significant increased risk of stroke with either risperidone or olanzapine in a retrospective population-based study of 11 400 patients over the age of 66 years, in which three cohorts were identified: users of typical antipsychotic drugs (n = 1015), risperidone (n = 6964), or

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olanzapine (n = 3421) (134C ). During 13 318 person-years of follow-up, there were 92 admissions for stroke, distributed as follows: typical antipsychotic drug users (n = 10), risperidone users (n = 58), and olanzapine users (n = 24); the crude stroke rate per 1000 person-years did not differ significantly among the patients taking typical antipsychotic drugs (5.7), risperidone (7.8), or olanzapine (5.7). Relative to typical antipsychotic drug users, model-based estimates adjusted for covariates showed risk ratios for stroke of 1.1 (95% CI = 0.5, 2.3) with olanzapine and 1.4 (95% CI = 0.7, 2.8) with risperidone. Relative to olanzapine, users of risperidone were not at significantly increased risk of stroke-related hospital admission (adjusted risk ratio = 1.3, 95% CI = 0.8, 2.2). Finally, the authors of this report suggested that the possibility of a type II error to detect small differences in stroke-related outcomes between groups could not be excluded; assuming that the relative risk of stroke in risperidone-treated patients was 1.4, this would translate into about two extra strokes per 1000 person-years. Once more, experimental and observational studies have not yielded consistent results. Further studies to assess the specific risks of atypical antipsychotic drugs in elderly patients with dementia are required. Psychological Psychomotor performance and cognitive function have been explored in a double-blind, randomized, four-way, crossover trial in 12 healthy volunteers (six men, six women), aged 66–77 years (mean age 69), who took single doses of risperidone 0.25 or 0.5 mg, lorazepam 1 mg, or placebo (135c ). Compared with placebo, those who took risperidone had minor impairment of motor activity (reduced finger tapping at 6 hours after dosing in both the 0.25 and 0.5 mg groups), postural instability (displacement from the center of gravity at 3 hours after dosing), and impaired information processing (impaired digit symbol substitution at 2.5 hours after dosing in the 0.25 mg group). There were no significant effects on speed of reaction, vigilance and sustained attention, working and long-term memory, cortical arousal, or electroencephalography. The same study showed detrimental effects of lorazepam on cognitive function and cortical arousal.

77 Endocrine Galactorrhea has been reported in relation to risperidone (SEDA-25, 69; SEDA26, 65; SEDA-27, 63), and four new cases have been published (136A ). It is suggested that this condition can occur after many weeks of risperidone treatment, with small dosages (2–4 mg/day), and at times even after drug withdrawal. Hyperprolactinemia can occur with risperidone (SEDA-25, 70). In a recent study, the prevalence of hyperprolactinemia among women taking risperidone was 88% (n = 42) versus 48% (n = 105) in those taking conventional antipsychotic drugs; 48% of these women of reproductive age taking risperidone had abnormal menstrual cycles (137c ). In the whole sample (147 women and 255 men) there were trends towards low concentrations of reproductive hormones associated with rises in prolactin; patients taking concomitant medications known to increase prolactin had been excluded. Raised prolactin concentrations were also observed in 13 (9 women and 4 men) of 20 patients (13 women and 7 men; mean age 36 years) (138c ). In pre-menopausal women there was a good correlation between prolactin concentrations and age, but there was no clear correlation between duration of treatment, dose, prolactin concentration, and prolactin-related adverse effects. In 41 schizophrenia patients who took either risperidone (11 men, 9 women; mean dose 4 mg/day) or perospirone (10 men, 11 women; mean dose 24 mg/day) for at least 4 weeks, prolactin concentrations increased only in those taking risperidone (5.3-fold in women and 4.2fold in men) (139c ). Hyperprolactinemia was found after about 30 months in 12 premenopausal women with schizophrenia or schizoaffective disorder (aged 15–55 years) taking risperidone but not in those taking olanzapine (n = 14) (140c ). Prolactin concentrations were significantly higher in the first group than in the second (123 ng/ml versus 26 ng/ml). Risperidone-induced hyperprolactinemia has been reported to resolve with quetiapine, a low-potency dopamine D2 receptor antagonist (141A ). Metabolism Weight gain, a well-known adverse effect of risperidone, particularly common in children (SEDA-25, 70), has been studied in 146 Chinese patients with schizophrenia

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(85 men and 61 women; mean age 33 years) who took risperidone in a maximum dose of 6 mg/day (142c ). Mean body weight rose gradually from 61 kg at baseline to 62 kg on day 14, 63 kg on day 28, and 64 kg on day 42; the mean dose at 6 weeks was 4.3 mg/day. Weight gain was associated with a lower baseline body weight, younger age, undifferentiated subtype, a higher dosage of risperidone, and treatment response (for positive, negative, and cognitive symptoms and social functioning). However, a possible ethnic difference might contribute to the marked weight increase found in these Chinese patients, since non-white patients reported more weight gain than white patients. Musculoskeletal In premenopausal women with schizophrenia or schizoaffective disorder aged 15–55 years, there was a significantly lower speed of sound transmission in the radius and the phalanges of the hand in patients taking risperidone (n = 12) compared with those taking olanzapine (n = 14) (140c ). Furthermore, the speed of sound in bone in this group correlated inversely with urinary deoxypyridinoline excretion, indicating a high bone turnover rate in this subset of patients, which is usually considered a risk factor for fragility fracture, independent of bone mineral density. Hyperprolactinemia is considered to be a risk factor for osteoporosis and those taking risperidone had significantly higher prolactin concentrations than those taking olanzapine (123 ng/ml versus 26 ng/ml) (see also Endocrine above). The relative risks for fragility fracture in the women taking risperidone compared with those taking olanzapine were 1.78 and 1.23 (speed of sound in bone measured at the phalanges and the radius respectively). Sexual function Priapism (SEDA-25, 70; SEDA-27, 64) has again been reported in patients taking risperidone. • A 32-year-old man who had taken flupentixol (up to 3 mg/day) over 5 years was switched to risperidone 4 mg/day because of recurrent psychotic episodes, and 2 months later, in view of a partial response, the dose was increased to 5 mg/day (143A ). He developed a persistent, painful penile erection 2 weeks later and was treated; a second episode occurred on the next day, and episodes of rigid erection that subsided without surgical intervention were detected during the next 4 days. The results of investigations, a complete hemogram, a sickling test, a penile Doppler study, and a penile biopsy, were all normal.

• A 26-year-old man who had taken risperidone 3 mg/day and sodium valproate 1500 mg/day for 1 year developed a persistent erection, dysuria, and urinary incontinence, which did not respond to irrigation of the corpora cavernosa on two occasions and required surgical treatment (144A ). Prolonged priapism also resulted in penile fibrosis, associated with a high risk of permanent erectile dysfunction.

Ejaculation dysfunction (SEDA-26, 65) has again been reported in a patient taking risperidone. • A 17-year-old man, with a history of paranoid schizophrenia and irregular abuse of cannabis and alcohol, took risperidone (145A ). Starting at 0.5 mg/day, the dose was titrated up to 4 mg/day over 3 weeks. In a few weeks, he stopped taking risperidone because of a recurrent inability to ejaculate, despite normal libido, erection, and sense of orgasm; he also had difficulty in urinating. These effects disappeared after drug withdrawal. However, risperidone was restarted because of relapse of schizophrenia, and the ejaculatory disturbance recurred within a few days.

Risperidone may have caused retrograde ejaculation by altering sympathetic tone and allowing semen to pass retrogradely into the bladder during ejaculation. Drug interactions Two cases of serotonin syndrome (SEDA-27, 64) associated with combined therapy of risperidone and selective serotonin-reuptake inhibitors in elderly patients have been described. • A 78-year-old woman with hypertension, angina, diabetes, depression, and dementia took venlafaxine 37.5 mg bd for depression and risperidone 0.25 mg at bedtime for agitation for more than 1 year, as well as isosorbide dinitrate, lisinopril, and glibenclamide (146A ). Because of periods of extreme agitation, her medication was changed to paroxetine 20 mg and risperidone 0.5 mg at bedtime. Her agitation worsened, and after 3 days the dose of risperidone was increased to 0.5 mg bd. Two days later she did not respond to verbal or tactile stimuli and developed a tremor, dizziness, and muscle incoordination. The risperidone and paroxetine were withdrawn and her agitation was managed with low doses of lorazepam. She recovered and 6 months later was stable, taking paroxetine 40 mg/day and risperidone 0.25 mg at bedtime.

Possible interactions between donepezil and risperidone, which are both metabolized by CYP2D6 and CYP3A4, have been studied (SEDA-26, 65; 147c ). Of 24 healthy men (mean age 40 years) who were assigned to risperi-

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done 1 mg/day, donepezil 5 mg/day, or both, 20 reported at least one adverse event, mostly headache, nervousness, or somnolence. However, measures of pharmacokinetics showed no interaction.

Ziprasidone

(SEDA-25, 71;

SEDA-27, 66) Observational studies Ziprasidone is apparently well tolerated, with a limited potential to cause extrapyramidal adverse effects or weight gain (148r ). Out-patients who partly respond to conventional antipsychotic drugs, risperidone, or olanzapine may have improved control of psychotic symptoms after switching to ziprasidone, according to the results of a re-analysis of 6-week, multicenter, randomized, open, parallel-group studies in patients with schizophrenia who had previously taken conventional antipsychotic drugs (n = 108), olanzapine (n = 104), or risperidone (n = 58); these results have been published in two different journals (149r , 150r ). Cardiovascular Ziprasidone is probably the only antipsychotic drug not to be unequivocally associated with weight gain, which might result in a relatively reduced effect on cardiac mortality compared with some other antipsychotic drugs. However, reports of cardiovascular adverse events led the FDA to include a “black box” warning in the official labelling of the product (SEDA-27, 66). Furthermore, in a warning letter the FDA stated that the manufacturers, Pfizer Inc, had promoted the product in a misleading manner, because they had minimized the greater capacity of ziprasidone to cause QT prolongation, as well as its potential to cause torsade de pointes and sudden death (151S ). The Indications and Usage section of the manufacturers’ approved product labelling stated that ziprasidone has a “greater capacity to prolong the QT/QTc interval compared with several other antipsychotic drugs” and that this effect “is associated in some other drugs with the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. Whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known.” Although torsade

79 de pointes was not observed in pre-marketing studies, experience is too limited to rule out an increased risk. Furthermore, the FDA has received several spontaneous reports of QT interval prolongation greater than 500 ms, all suggestive of a potential risk of this dysrhythmia. There are also reports of sudden death of unknown cause, which could have been due to unrecognized torsade de pointes. The question of the effect of ziprasidone on the QTc interval has been analysed in an extensive review (152R ). It is generally accepted that 440 ms is the upper limit of normality, and the authors concluded that ziprasidone clearly prolongs the QTc interval, but that the clinical consequences of this effect are uncertain, and that so far no direct association with torsade de pointes, sudden death, or increased cardiac mortality has been observed. However, they provided recommendations about its use. 1. Before starting treatment, conditions that might predispose to a higher risk of QTc interval prolongation or torsade de pointes (either cardiac, metabolic, or others) should be ruled out; a careful medical history is recommended. 2. In people with stress, shock, and extreme or prolonged physical exertion already taking ziprasidone, therapy can be continued, but electrocardiographic monitoring is advised when episodes are severe or prolonged. 3. Although no special precautions are suggested when ziprasidone is co-prescribed with metabolic inhibitors, drugs that do not inhibit hepatic enzymes should be preferred. 4. Ziprasidone should be avoided in the following cases: a. When there is evidence of long QT syndrome, a history of myocardial infarction or ischemic heart disease, and persistent or recurrent bradycardia; a cardiologist should be consulted if uncertain. b. In conditions often associated with electrolyte disturbance, including anorexia or bulimia; electrolyte disturbance should be always ruled out by means of a blood sample, and low concentrations of calcium, potassium, or magnesium should be corrected before treatment. c. In patients taking other drugs that prolong the QT interval, including certain antidysrhythmic drugs, antidepressants,

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antihistamines, antimicrobial drugs, and others; if co-prescription is unavoidable, electrocardiographic monitoring by a specialist is advised. d. In patients taking thioridazine, droperidol, sertindole, or pimozide; these drugs should be always withdrawn before starting ziprasidone. e. In patients taking other antipsychotic drugs; this is permissible only when cross-tapering and excessive doses of antipsychotic drugs should not be used in combination. Nervous system Four cases of ziprasidoneinduced mania (SEDA-27, 66) have recently been described (153A ). In all cases, the symptoms occurred within 7 days of the start of ziprasidone therapy and improved substantially when the drug dosage was lowered or the drug was withdrawn. • An association between mania and ziprasidone has been suggested in a 20-year-old man taking 160 mg at bedtime who suddenly had increased energy, elated mood, and agitation (154A ). The symptoms resolved after 48 hours when ziprasidone was substituted by olanzapine.

Sexual function to ziprasidone.

Priapism has been attributed

• A 32-year-old patient with schizophrenia taking ziprasidone 40 mg bd developed several spontaneous involuntary erections, which lasted about 20–30 minutes and did not resolve with ejaculation (155A ). No physical or laboratory abnormalities were found.

A possible explanation of this event would be that novel antipsychotic drugs are antagonists at alpha-1-adrenoceptors with very high affinities. Drug overdose Various reports of overdose of ziprasidone have been published. • A 17-year-old man with a 5-year history of severe depression took 120 tablets of ziprasidone 20 mg (2400 mg), 15–20 tablets of bupropion SR 150 mg (2250–3000 mg), 15 tablets of clonazepam 0.5 mg, and 4 tablets of lorazepam 0.5 mg (156A ). He was somnolent but responded to vocal commands. Over the next 45 minutes he became lethargic and was intubated. The initial electrocardiogram 1 hour after ingestion was normal, with a QTc interval of less than 440 ms, but 2.5 hours after ingestion he developed a widened QRS interval (200 ms), which resolved with intravenous lidocaine 75 mg. A subsequent 12-lead electrocardiogram showed a QTc interval of 480 ms and a QRS interval of 120 ms. He was alkalinized to maintain a pH of 7.45–7.50. The QTc interval varied from 420 to 480 ms. About 40 hours after ingestion, the QTc interval finally stabilized at around 440 ms. • In a 37-year-old female, the ingestion of 1200 mg of ziprasidone was associated with a QTc interval of 459 ms (157A ). • In a 17-month-old girl who was given ziprasidone 400 mg, the QTc interval was 480 ms (157A ). • In a 50-year-old woman, 1760 mg of ziprasidone and 1000 of quetiapine caused an increase in the QTc interval to 638 ms (157A ).

All the last three patients had somnolence, which resolved completely in a few days.

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71. Kao LW, Kirk MA, Evers SJ, Rosenfeld SH. Droperidol, QT prolongation, and sudden death: what is the evidence? Ann Emerg Med 2003; 41: 546–58. 72. Habib AS, Gan TJ. Food and drug administration black box warning on the perioperative use of droperidol: a review of the cases. Anesth Analg 2003; 96: 1377–9. 73. Wilcox CM, Linder J. Prospective evaluation of droperidol on sphincter of Oddi motility. Gastrointest Endosc 2003; 58: 483–7. 74. Fogel EL, Sherman S, Bucksot L, Shelly L, Lehman GA. Effects of droperidol on the pancreatic and biliary sphincters. Gastrointest Endosc 2003; 58: 488–92. 75. Yukawa E, Ichimaru R, Maki T, Matsunaga K, Anai M, Yukawa M, Higuchi S, Goto Y. Interindividual variation of serum haloperidol concentrations in Japanese patients – clinical considerations on steady-state serum level-dose ratios. J Clin Pharmacol Ther 2003; 28: 97–101. 76. Singh AN, Barlas C, Saeedi H, Mishra RK. Effect of loxapine on peripheral dopamine-like and serotonin receptors in patients with schizophrenia. J Psychiatry Neurosci 2003; 28: 39–47. 77. Alvarez E, Bobes J, Gómez J-C, Sacristán JA, Cañas F, Carrasco JL, Gascón J, Gibert J, Gutiérrez M; EUROPA Study Group. Safety of olanzapine versus conventional antipsychotics in the treatment of patients with acute schizophrenia. A naturalistic study. Eur Neuropsychopharmacol 2003; 13: 39– 48. 78. Taylor DM, Wright T, Libretto SE, for the Risperidone Olanzapine Drug Outcomes Studies on Schizophrenia (RODOS) UK Investigator Group. Risperidone compared with olanzapine in a naturalistic clinical study: a cost analysis. J Clin Psychiatry 2003; 64: 589–97. 79. Dennehy EB, Doyle K, Suppes T. The efficacy of olanzapine monotherapy for acute hypomania or mania in an outpatient setting. Int Clin Psychopharmacol 2003; 18: 143: 5. 80. Hwang JP, Yang CH, Lee TW, Tsai SJ. The efficacy and safety of olanzapine for the treatment of geriatric psychosis. J Clin Psychopharmacol 2003; 23: 113–18. 81. Passik SD, Kirsh KL, Theobald DE, Dickerson P, Trowbridge R, Gray D, Beaver M, Comparet J, Brown J. A retrospective chart review of the use of olanzapine for the prevention of delayed emesis in cancer patients. J Pain Symptom Manage 2003; 25: 485–9. 82. Stewart RS, Nejtek VA. An open-label, flexibledose study of olanzapine in the treatment of trichotillomania. J Clin Psychiatry 2003; 64: 49–52. 83. Gorski ED, Willis KC. Report of three case studies with olanzapine for chronic pain. J Pain 2003; 4: 166–8. 84. Khaldi S, Kornreich C, Dan B, Pelc I. Usefulness of olanzapine in refractory panic attacks. J Clin Psychopharmacol 2003; 23: 100–1. 85. Jakovljevi´c M, Šagud M, Mihaljevi´c-Peleš A. Olanzapine in the treatment-resistant, combatrelated PTSD – a series of case reports. Acta Psychiatr Scand 2003; 107: 394–6.

83 86. Yetimalar Y, Irtman G, Gürgör N, Ba¸so˘glu M. Olanzapine efficacy in the treatment of essential tremor. Eur J Neurol 2003; 10: 79–82. 87. Revicki DA, Paramore LC, Sommerville KW, Swann AC, Zajecka JM. Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes. J Clin Psychiatry 2003; 64: 288–94. 88. Hirschfeld RMA, Baker JD, Wozniak P, Tracy K, Sommerville KW. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry 2003; 64: 841–6. 89. Battaglia J, Lindborg SR, Alaka K, Meehan K, Wright P. Calming versus sedative effects of intramuscular olanzapine in agitated patients. Am J Emerg Med 2003; 21: 192–8. 90. Gurovich I, Vempaty A, Lippmann S. QTc prolongation: chlorpromazine and high-dosage olanzapine. Can J Psychiatry 2003; 48: 348. 91. Dineen S, Withrow K, Voronovitch L, Munshi F, Nawbary MW, Lippmann S. QTc prolongation and high-dose olanzapine. Psychosomatics 2003; 44: 174–5. 92. Fontaine CS, Hynan LS, Koch K, Martin-Cook K, Svetlik D, Weiner MF. A double-blind comparison of olanzapine versus risperidone in the acute treatment of dementia-related behavioral disturbances in extended care facilities. J Clin Psychiatry 2003; 64: 726–30. 93. Farooque R. Uncommon side effects associated with olanzapine. Pharmacopsychiatry 2003; 36: 83. 94. Ng B, Postlethwaite A, Rollnik J. Peripheral oedema in patients taking olanzapine. Int Clin Psychopharmacol 2003; 18: 57–9. 95. Alevizos B, Papageorgiou C, Christodoulou GN. Acute dystonia caused by low dosage of olanzapine. J Neuropsychiatry Clin Neurosci 2003; 15: 241. 96. Berry N, Pradhan S, Sagar R, Gupta SK. Neuroleptic malignant syndrome in an adolescent receiving olanzapine-lithium combination therapy. Pharmacotherapy 2003; 23: 255–9. 97. Goveas JS, Hermida A. Olanzapine induced “typical” neuroleptic malignant syndrome. J Clin Psychopharmacol 2003; 23: 101–2. 98. Bonelli RM. Olanzapine-associated seizure. Ann Pharmacother 2003; 37: 149–50. 99. Cavazzoni P, Tanaka Y, Roychowdhury SM, Breier A, Allison DB. Nizatidine for prevention of weight gain olanzapine: a double-blind placebocontrolled trial. Eur Neuropsychopharmacol 2003; 13: 81–5. 100. Abdullah N, Voronovitch L, Taylor S, Lippmann S. Olanzapine and haloperidol: potential for neutropenia? Psychosomatics 2003; 44: 83–4. 101. Mendhekar DN, Srivastav PK, Sarin SK, Jiloha RC. A case report of olanzapine-induced fecal incontinence. J Clin Psychiatry 2003; 64: 339. 102. Kolpe M, Ravasia S. Effect of olanzapine on the liver transaminases. Can J Psychiatry 2003; 48: 210.

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103. Horgan P, Jones H. Olanzapine use in acute porphyria. Int J Psychiatry Clin Pract 2003; 7: 67– 9. 104. Jadallah KA, Limauro DI, Colatrella AM. Acute hepatocellular-cholestatic liver injury after olanzapine therapy. Ann Intern Med 2003; 138: 357–8. 105. Fukunishi I, Sato Y, Kino K, Shirai T, Kitaoka T. Hypothermia in a hemodialysis patient treated with olanzapine monotherapy. J Clin Psychopharmacol 2003; 23: 314. 106. Dueñas-Laita A, Pérez-Castrillón JL, Herreros-Fernández V. Olanzapine toxicity in unconjugated hyperbilirubinaemia (Gilbert’s syndrome). Br J Psychiatry 2003; 182: 267. 107. Carrillo JA, Herráiz AG, Ramos SA, Gervasini G, Vizcaíno S, Benítez J. Role of the smokinginduced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23: 119–27. 108. D’Amico G, Cedro C, Muscatello MR, Pandolfo G, Di Rosa AE, Zoccali R, La Torre D, D’Arrigo C, Spina E. Olanzapine augmentation of paroxetine-refractory obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 619–23. 109. Mindikoglu A, Anantharaju A, Hartman G, Li S, Villanueva J, Thiel D. Prochlorperazine induced cholestasis in a patient with alpha 1 antitrypsin deficiency. Hepato-Gastroenterology 2003; 50: 1338– 40. 110. Garroni A, Palloshi A, Fragasso G, Margonato A. Minimal myocardial damage after tricyclic neuroleptic overdose. Pharmacopsychiatry 2003; 36: 33–4. 111. Yatham LN, Binder C, Riccardelli R, Leblanc J, Connolly M, Kusumakar V, on behalf of the RIS-CAN 25 Study Group. Risperidone in acute and continuation treatment of mania. Int Clin Psychopharmacol 2003; 18: 227–35. 112. Vieta E, Goikolea JM, Olivares JM, GonzálezPinto A, Rodríguez A, Colom F, Comes M, Torrent C, Sánchez-Moreno J. 1-year follow-up of patients treated with risperidone and topiramate for a manic episode. J Clin Psychiatry 2003; 64: 834–9. 113. Ercan ES, Kutlu A, Cikoglu S, Veznedaroglu B, Erermis S, Varan A. Risperidone in children and adolescents with conduct disorder: a single-center, open-label study. Curr Ther Res 2003; 64: 55–64. 114. Shigenobu K, Ikeda M, Fukuhara R, Komori K, Tanabe H. A structured, open trial of risperidone therapy for delusions of theft in Alzheimer Disease. Am J Geriatr Psychiatry 2003; 11: 256–7. 115. Ritchie CW, Chiu E, Harrigan S, Hall K, Hassett A, Macfarlane S, Mastwyk M, O’Connor DW, Opie J, Ames D. The impact upon extra-pyramidal side effects, clinical symptoms and quality of life of a switch from conventional to atypical antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia. Int J Geriatr Psychiatry 2003; 18: 432–40. 116. Koenigsberg HW, Reynolds D, Goodman M, New AS, Mitropoulou V, Trestman RL, Silverman J, Siever LJ. Risperidone in the treatment of schizo-

typal personality disorder. J Clin Psychiatry 2003; 64: 628–34. 117. Hamner MB, Faldowski RA, Ulmer HG, Frueh BC, Huber MG, Arana GW. Adjunctive risperidone treatment in post-traumatic stress disorder: a preliminary controlled trial of effects on comorbid psychotic symptoms. Int Clin Psychopharmacol 2003; 18: 1–8. 118. Monnelly EP, Ciraulo DA, Knapp C, Keane T. Low-dose risperidone as adjunctive therapy for irritable aggression in posttraumatic stress disorder. J Clin Psychopharmacol 2003; 23: 193–6. 119. Scahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology 2003; 60: 1130–5. 120. Brodaty H, Ames D, Snowdon J, Woodward M, Kirwan J, Clarnette R, Lee E, Lyons B, Grossman F. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003; 64: 134–43. 121. Kamijo Y, Soma K, Nagai T, Kurihara K, Ohwada T. Acute massive pulmonary thromboembolism associated with risperidone and conventional phenothiazines. Circ J 2003; 67: 46–8. 122. Qureshi N. Atypical antipsychotics and dementia: some reflections! http://bmj.bmjjournals. com/cgi/eletters/328/7450/1262-b. 123. Mowat D, Fowlie D, MacEwan T. CSM warning on atypical antipsychotics and stroke may be detrimental for dementia. http://bmj.bmjjournals. com/cgi/eletters/328/7450/1262-b. 124. Schneider L, Dagerman K. Meta-analysis of atypical antipsychotics for dementia patients: balancing efficacy and adverse events. http://ipa. confex.com/ipa/11congress/techprogram/ paper_4201.htm. 125. Bourgeois JA, Kahn DR. Neuroleptic malignant syndrome following administration of risperidone and lithium. J Clin Psychopharmacol 2003; 23: 315–17. 126. Health Canada. http://www.hc-sc-gc.ca. 127. Janssen Pharmaceutica Inc. 2003 safety alert–Risperdal. http://www.fda.gov/medwatch/ SAFETY/2003/risperdal.htm. 128. World Health Organization. Regulatory matters–olanzapine, risperidone. WHO Pharm Newslett 2004; 2: 1–2. 129. EMEA Public Statement, EMEA/CPMP/856/ 04 Final, 9 March 2004. http://www.emea.eu.int. 130. Agemed. Agencia Española de Medicamentos y Productos Sanitarios. Nota informativa sobre olanzapina y risperidona. http://www.agemed. es/documentos/notasPrensa/csmh/2004/ cont_olanzapina.htm. 131. Wooltorton E. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. Can Med Assoc J 2002; 167: 1269–70. 132. Medicines and Healthcare products Regulatory Agency (MHRA). Atypical antipsychotic drugs: questions and answers, 9 March 2004. http:// www.mca.gov.uk/aboutagency/regframework/com/ csmhome.htm.

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133. Committee on Safety of Medicines. Atypical antipsychotic drugs and stroke. http://www.mca. gov.uk/aboutagency/regframework/com/csmhome. htm. 134. Hermann N, Mamdani M, Lanctôt KL. Atypical antipsychotics and risk of cerebrovascular accidents. Am J Psychiatry 2004; 161: 1113–15. 135. Allain H, Tessier C, Bentué-Ferrer D, Tarral A, Le Breton S, Gandon HM, Bouhours P. Effects of risperidone on psychometric and cognitive functions. Psychopharmacology 2003; 165: 419–29. 136. Gupta SC, Jagadheesan K, Basu S, Paul SE. Risperidone-induced galactorrhoea: a case series. Can J Psychiatry 48: 130–1. 137. Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone. Psychoneuroendocrinology 2003; 28: 55–68. 138. Brunelleschi S, Zeppegno P, Risso F, Cattaneo CI, Torre E. Risperidone-associated hyperprolactinemia: evaluation in twenty psychiatric outpatients. Pharmacol Res 2003; 48: 405–9. 139. Togo T, Iseki E, Shoji M, Oyama I, Kase A, Uchikado H, Katsuse O, Kosaka K. Prolactin levels in schizophrenic patients receiving perospirone in comparison to risperidone. J Pharmacol Sci 2003; 91: 259–62. 140. Becker D, Liver O, Mester R, Rapoport M, Weizman A, Weiss M. Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients. J Clin Psychiatry 2003; 64: 761–6. 141. Kunwar AR, Megna JL. Resolution of risperidone-induced hyperprolactinemia with substitution of quetiapine. Ann Pharmacother 2003; 37: 206–8. 142. Lane H-Y, Chang Y-C, Cheng Y-C, Liu G-C, Lin X-R, Chang W-H. Effects of patient demographics, risperidone dosage, and clinical outcome on body weight in acutely exacerbated schizophrenia. J Clin Psychiatry 2003; 64: 316–20. 143. Relan P, Gupta N, Mattoo S. A case of risperidone-induced priapism. J Clin Psychiatry 2003; 64: 482–3. 144. Bourgeois JA, Mundh H. Priapism associated with risperidone: a case report. J Clin Psychiatry 2003; 64: 218–19.

85 145. Holtmann M, Gerstner S, Schmidt MH. Risperidone-associated ejaculatory and urinary dysfunction in male adolescents. J Child Adolesc Psychopharmacol 2003; 13: 107–9. 146. Karki SD, Masood GR. Combination risperidone and SSRI-induced serotonin syndrome. Ann Pharmacother 2003; 37: 388–90. 147. Zhao Q, Xie C, Pesco-Koplowitz L, Jia X, Parier J-L. Pharmacokinetic and safety assessments of concurrent administration of risperidone and donepezil. J Clin Pharmacol 2003; 43: 180–6. 148. Editorial. Ziprasidone: zealous in the treatment of schizophrenia and schizoaffective disorder. Drug Ther Perspect 2003; 19: 1–4. 149. Weiden PJ, Simpson GM, Potkin SG, O’Sullivan RL. Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia. J Clin Psychiatry 2003; 64: 580–8. 150. Weiden PJ, Daniel DG, Simpson G, Romano SJ. Improvement in indices of health status in outpatients with schizophrenia switched to ziprasidone. J Clin Psychopharmacol 2003; 23: 595–600. 151. FDA warning letter. Pfizer Inc. Geodon (ziprasidone HCI). http://www.pharmcast.com/ WarningLetters/Yr2002/. 152. Taylor D. Ziprasidone in the management of schizophrenia. The QT interval issue in context. CNS Drugs 2003; 17: 423–30. 153. Baldassano CF, Ballas C, Datto SM, Kim D, Littman L, O’Reardon J, Rynn MA. Ziprasidoneassociated mania: a case series and review of the mechanism. Bipolar Disord 2003; 3: 72–5. 154. Nolan BP, Schulte JJ. Mania associated with initiation of ziprasidone. J Clin Psychiatry 2003; 64: 336. 155. Reeves RR, Kimble R. Prolonged erections associated with ziprasidone treatment: a case report. J Clin Psychiatry 2003; 64: 97–8. 156. Biswas AK, Zabrocki LA, Mayes KL, MorrisKukoski CL. Cardiotoxicity associated with intentional ziprasidone and bupropion overdose. J Toxicol Clin Toxicol 2003; 41: 79–82. 157. Bryant SM, Zilberstein J, Cumpston KL, Magdziarz DD, Costerisan D. A case series of ziprasidone overdoses. Vet Hum Toxicol 2003; 45: 81–2.

Antonio Gil-Nagel

7

Antiepileptic drugs

GENERAL TOPICS

(SED-14, 164; SEDA-25, 78; SEDA-26, 70; SEDA-27, 72)

Comparisons of drugs Monotherapy is the preferred treatment for epilepsy and is effective in most cases. The selection of a drug for initial therapy is based on several factors, such as efficacy for the suspected type of epilepsy, safety, and tolerability. In patients with new-onset epilepsy the motivation to tolerate mild adverse effects is usually very poor compared with patients with medically refractory epilepsy. The results from add-on trials in patients with medically resistant focal epilepsy cannot be extrapolated to new-onset epilepsy and other epilepsy syndromes, because of significant differences in the severity of the disease and the mechanism of the epilepsy. In a review of randomized trials of new antiepileptic drugs in monotherapy, gabapentin, lamotrigine, oxcarbazepine, and topiramate usually had higher retention rates than carbamazepine, phenytoin, and valproic acid, because of fewer adverse effects; in general, efficacy was similar (1R ). In another review of antiepileptic drugs in new-onset epilepsy the authors concluded than none of the newer drugs (felbamate, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, oxcarbazepine, vigabatrin, and zonisamide) have superior efficacy compared with classic antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid). However, some of the newer drugs have good tolerability, resulting in better overall effectiveness in the case of lamotrigine over carbamazepine, and oxcarbazepine over phenytoin, whereas vigabatrin and remacemide (which is not yet licensed for epilepsy) had less efficacy than carbamazepine (2R ). © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

86

Psychological The most common adverse effects of antiepileptic drugs are central nervous system effects, such as sedation, dizziness, and cognitive impairment. Several factors affect cognition, including the cause of the epilepsy, the effect of seizures, and the antiepileptic medication, including the rate of titration, the dosage, the number of drugs taken, co-medications, and individual sensitivity. Experimental design flaws in assessing the cognitive adverse effects of antiepileptic drugs have been identified in a Medline review, cross-referencing terms related to cognition and anticonvulsants (3R ). The authors observed that there is incomplete information about newer antiepileptic drugs, but some of them may have favorable cognitive profiles. In a comparison of the adverse cognitive effects and sedation caused by topiramate, lamotrigine, and phenobarbital, phenobarbital had 0.6–4.8 times the efficacy of topiramate and 1.1–10 times the efficacy of lamotrigine (4M ). Sedation rates were similar with topiramate and phenobarbital but were 2–4 times worse than with lamotrigine. The estimated monthly cost of treatment with phenobarbital was $10, compared with $177 for topiramate and $137 for lamotrigine. In this systematic review only studies on medically refractory focal epilepsy were included; this provides only a partial view of these drugs, since phenobarbital, lamotrigine, and topiramate differ in efficacy among different epilepsy syndromes (primary generalized epilepsy, Lennox–Gastaut syndrome) and in less severe forms of epilepsy. In addition, other adverse effects and drug interactions, which also differ among the three drugs, were not considered. Metabolism The effect of antiepileptic drugs on body weight has been reviewed (5R ). Valproic acid, carbamazepine, gabapentin, and vigabatrin are associated with weight gain. The mechanisms have not been identified. Increased secretion of insulin and proinsulin,

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increased appetite for carbohydrates, reduced energy expenditure, reduced leptin concentrations, and reduced beta-oxidation of fatty acids because of carnitine deficiency are proposed mechanisms for valproic acid. Carbamazepineinduced weight gain can arise from edema secondary to increased antidiuretic hormone secretion or from increased appetite and food consumption. Weight gain associated with vigabatrin and gabapentin could be related to GABAergic properties, which can increase carbohydrate consumption and reduce energy expenditure. Topiramate, felbamate, and zonisamide are associated with weight loss. In animals topiramate reduced food intake, but also reduced energy disposition in the absence of reduced intake. In addition, topiramate increased lipoprotein lipase activity in adipose tissue, possibly reflecting enhanced regulatory thermogenesis. In humans and animals topiramate reduces leptin concentrations. With felbamate weight loss is almost always associated with anorexia. There is little information on the mechanism of weight loss with zonisamide. Skin Pseudolymphoma, a rare complication of antiepileptic drugs, can be associated with extensive skin lesions, hepatitis, and neutropenia. Its course can be fatal and it can be difficult to differentiate from other lymphomas, including mycosis fungoides. However, a retrospective review of eight cases of antiepileptic druginduced pseudolymphoma showed significant differences from mycosis fungoides (6c ). The causative agents were carbamazepine (n = 4), phenytoin (n = 2), phenobarbital (n = 1) and valproic acid (n = 1). The duration from the start of treatment to the skin eruption was 3– 24 weeks (mean 7 weeks). All the patients had generalized maculopapular eruptions, in one case accompanied by vesiculopustular lesions. The most frequent accompanying symptoms were facial edema, fever, lymphadenopathy, and hepatomegaly. Laboratory findings included leukocytosis, atypical lymphocytes, predominance of either white cell subtype, and increased liver enzymes. In both mycosis fungoides and pseudolymphoma skin histology showed epidermotrophism of atypical lymphocytes and Pautrier’s microabscess structures. However, there were differences as well, such as spongiosis, necrotic keratinocytes, and

87 eosinophil infiltration in the epidermis, and in the dermis papillary dermal edema, extravasated erythrocytes, larger lymphocytes than in the epidermis, and infiltration of various inflammatory cells, which were found only in pseudolymphoma. Genotypic analysis showed rearrangement of the T cell receptor gamma gene in one of the eight cases. All the patients improved within 2–9 weeks of withdrawal of the causative agent plus therapy with systemic and topical glucocorticoids. Hypersensitivity skin reactions to antiepileptic drugs are often difficult to differentiate from cutaneous symptoms caused by viral infections. This is especially difficult in children during the early phase of the reaction, when decisions about continuing or stopping the antiepileptic drug have to be made. To address this issue eight children with drug-induced skin reactions, 10 children with virus-induced skin reactions, diagnosed on the basis of clinical evolution and positive viral serology, and a control group of children without skin reactions matched for drug therapy have been compared (7c ). Drugs that induced skin reactions in this study included carbamazepine (n = 4), phenytoin (n = 2), lamotrigine (n = 1), and cefuroxime (n = 1). There were significant differences in lymphocyte subpopulations in the expression of the activation marker CD69, and the homing receptor cutaneous lymphocyte-associated antigen (CLA), and in cytokine mRNA profiles. In a follow-up study of 10 patients with drug-induced skin reactions (eight due to carbamazepine and two to lamotrigine) there were seven mild to severe reactions, one case of toxic epidermal necrolysis, one of Stevens–Johnson syndrome, and one hypersensitivity syndrome (8A ). All the severe skin reactions were induced by carbamazepine. All the patients were taking monotherapy at recommended daily doses. The drug was withdrawn abruptly in five patients, and in two cases was substituted by a new antiepileptic drug. Because these cases were observed before reports of treatment with intravenous immunoglobulin were published, some patients were treated with glucocorticoids, although the authors acknowledged that there is no evidence of benefit from such treatment (9A ). In a follow-up period of 5–7 years no new skin reactions occurred. • A woman developed an anticonvulsant hypersensitivity syndrome while taking phenytoin and lamot-

88 rigine for several years (10A ). Prednisolone produced improvement, but caused Cushing’s syndrome, and exfoliative dermatitis reappeared after withdrawal, even 1 year after her antiepileptic drugs had been stopped.

The authors suspected Sézary syndrome (erythrodermic mycosis fungoides) secondary to phenytoin, but a skin biopsy was not consistent with this diagnosis. Ciclosporin 4 mg/kg and topical clobetasol propionate relieved the symptoms. • A child with lamotrigine-induced toxic epidermal necrolysis did not improve after treatment with dexamethasone for 48 hours, after which a single high dose of intravenous immunoglobulin (2 g/kg) was given (11A ). Analysis of immunological changes in peripheral blood and in the serum of the blisters showed reduced expression of apoptotic markers.

In the description of this case it is not clear whether the disease was affected by intravenous immunoglobulin, since new blisters developed 30 days after treatment. Reproductive function Polycystic ovary syndrome, hypothalamic amenorrhea, premature menopause, and hyperprolactinemia are more common in women with epilepsy than in women in general. These effects may be related to the epilepsy itself or to the effect of antiepileptic drugs (12R ). Phenytoin is associated with raised serum sex hormone-binding globulin concentrations, and low concentrations of dehydroepiandrosterone sulfate. Raised sex hormone-binding globulin leads to reduced bioactivity of estradiol and testosterone. Phenobarbital reduces serum concentrations of estradiol. Carbamazepine also increases serum concentrations of sex hormone-binding globulin and reduces dehydroepiandrosterone concentrations. Valproic acid is associated with a high prevalence of menstrual disorders, obesity, hyperandrogenism, and polycystic ovary syndrome. The pathogenesis of valproic acid-induced reproductive endocrine disorders is unclear. Obesity, hyperinsulinemia, and low serum insulin-like growth factor-binding protein 1 are involved in the development of polycystic ovary syndrome and hyperandrogenism, but the exact mechanisms are not known and other factors cannot be excluded. Serum insulin-like growth

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Antonio Gil-Nagel

factor-binding protein 1 is an important regulator of insulin-like growth factor I, a stimulator of ovarian androgen synthesis. However, there seem to be other primary initiating factors. Teratogenicity Malformations in the general population occur in 2–3% pregnancies. In infants exposed in utero to antiepileptic drugs, the combined estimates of malformation yields a 4–6% risk. In a review of the risk of neural tube defects, the prevalence of spina bifida aperta is reported to be 1–2% with valproic acid and 0.5% with carbamazepine (13R ). Additional susceptibility factors for this complication include a previous pregnancy with a neural tube defect, maternal insulin-dependent diabetes mellitus, nutritional deficiencies, occupational exposures, and a high weight before pregnancy. The protective value of folic acid before conception for women in the general population is widely accepted. However, it is not clear whether folic acid protects against teratogenicity in woman taking antiepileptic drugs. Nevertheless, folic acid supplementation is recommended; although the dose has not been determined, it should probably be more than the 400 micrograms/day recommended by the Centre for Disease Control and Prevention, especially for woman who do not metabolize folate effectively. In addition, women who take antiepileptic drugs should have prenatal diagnostic ultrasound to rule out neural tube defects.

Carbamazepine

(SED-14, 172; SEDA-24, 84; SEDA-25, 81; SEDA-26, 72; SEDA-27, 76) Cardiovascular Autopsy in an 11-year-old boy who had been taking carbamazepine for almost 7 years showed diffuse coronary artery disease and a reduced coronary artery lumen diameter by as much as 40% (14A ). The authors considered that coronary artery disease could have been caused by carbamazepine-induced dyslipidemia; however, serum lipid testing had not been performed, and there had been two cases of sudden death in young maternal age relatives, suggesting other mechanisms in the

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pathogenesis of occlusive arterial disease in this patient. Hypertension has been attributed to carbamazepine.

• A 32-year-old woman was successfully treated with hemodialysis after carbamazepine overdose (21A ). The carbamazepine serum concentration fell by more than 50% and consciousness returned within 2 hours.

• A 68-year-old man with epilepsy and well controlled hypertension had a marked increase in arterial pressure and a transient neurological deficit after starting to take carbamazepine (15A ). His blood pressure normalized when the dose of carbamazepine was reduced or discontinued, but because this was the only antiepileptic drug that controlled his seizures it had to be used again, resulting in hypertension each time the dose was increased.

Gabapentin

Although uncontrolled hypertension in this patient could have been a direct adverse effect of carbamazepine, it is more likely that carbamazepine increased the clearance of antihypertensive drugs (atenolol, felodipine, ramipril, and irbesartan) by inducing oxidative enzymes.

• An 83-year-old man with end-stage renal disease had mental status deterioration and coma 4 hours after receiving a single dose of gabapentin (22A ). Co-medication included carbamazepine. Flumazenil and hemodialysis returned his mental state to normal.

Immunologic Some virus infections, such as those caused by human herpesvirus have been reported as being precipitating factors for druginduced hypersensitivity syndrome (16c , 17c ). • A 14-year-old boy had carbamazepine-induced hypersensitivity syndrome associated with hypogammaglobulinemia (18A ). He had increased serum concentrations of IgG but not IgM to 6.

These findings suggest that there was reactivation of human herpesvirus 6 in relation to carbamazepine-induced hypersensitivity syndrome. • A 9-year-old boy has a progressive fall in IgG, IgM, and IgA concentrations over 4 years of treatment with carbamazepine (19A ). He was studied when he developed recurrent enterocolitis and otitis media, when immunological investigation showed falls in the concentrations of IgG2 and IgG4. Withdrawal of carbamazepine and substitution with zonisamide did not normalize the immunoglobulin concentrations. • In a 13-year-old girl carbamazepine-induced pemphigus was associated with selective IgA deficiency and did not resolve despite 9 months of immunosuppressive therapy (azathioprine and prednisolone), but regressed within 24 hours of carbamazepine withdrawal (20A ).

Drug overdose There is little information on the management of carbamazepine overdose, but most reports suggest the use of gut decontamination with charcoal, hemoperfusion, and plasma exchange as the main therapeutic approaches.

(SED-14, 188; SEDA-25, 84; SEDA-26, 73; SEDA-27, 77)

Nervous system gabapentin.

Coma has been attributed to

However, the attribution in this case was doubtful. Before dialysis his gabapentin serum concentration was relatively low (4.6 µg/ml), and the authors did not state the serum concentration of carbamazepine, which had been begun at a dose of only 200 mg bd a few days before, a starting dose that can be considered high for an elderly person with systemic disease. Therefore, no conclusive information can be obtained from the analysis of this case, and coma could have been the effect of carbamazepine, gabapentin, or a combination of the two. Neuromuscular A 64-year-old woman with myasthenia gravis had worse weakness when she took gabapentin for postherpetic pain (23A ). Sexual function Anorgasmia during treatment with gabapentin, and a withdrawal syndrome (sweating, tremors, and abdominal pain) when the drug was withdrawn was reported in a 35-year-old woman with bipolar disorder (24A ). Drug overdose In a multicenter prospective observational study by three poison centers, 20 cases in which gabapentin was the only intoxicating agent were identified in patients aged 11 months to 83 years (25c ). Most of the gabapentin exposures were “acute-on-chronic” (65%), suggesting that it involved the patient’s own medication. Twelve patients were symptomatic; seven were managed at home, eight

90 were treated in hospital and discharged, and five were admitted for psychiatric care. The mean doses ingested by symptomatic and asymptomatic patients were not significantly different. All 12 symptomatic patients developed drowsiness, lethargy, or dizziness. Other symptoms included mild tachycardia (n = 2), hypotension (n = 2), nausea and vomiting (n = 2), and ataxia (n = 1). The clinical effects developed within 5 hours, with a median onset of 2 hours, and always resolved within 24 hours. Gastrointestinal decontamination with activated charcoal was performed in nine patients.

Lamotrigine

(SED-14, 188; SEDA-25, 85; SEDA-26, 74; SEDA-27, 77)

Nervous system An 8-year-old boy taking lamotrigine developed tremor, chorea, ataxia, and abnormal eye movements (altered pursuit and vertical movements associated with eyelid twitching), and a 7-year-old boy developed altered vertical eye movements (26A ). They recovered after lamotrigine withdrawal. Psychiatric Lamotrigine caused hypomania in a 23-year-old woman with major depression and no history of bipolar illness; it resolved 2 weeks after withdrawal (27A ). Skin Lamotrigine-induced skin reactions are assumed to have an immune cause. However, this has not been conclusively demonstrated, and other factors may also play a role. In order to characterize the role of T cells in lamotrigine hypersensitivity, a lymphocyte transformation test was performed on four patients 24 months after hypersensitivity reactions and compared with four controls taking lamotrigine without adverse effects (28c ). The lymphocytes of three of the four lamotrigine hypersensitive patients proliferated when stimulated with lamotrigine. T cell clones generated from one of these patients were studied in order to characterize the nature of T cell involvement. Most of the clones were CD4+, with occasional CD8+ cells. All the clones expressed the alpha-beta T cell receptor; several V-beta 5.1+ or 9+ T cell clones were generated, findings that suggest that polymorphisms in T cell receptor genes might act as determinants of susceptibility.

Chapter 7

Antonio Gil-Nagel

Drug interactions The benefit to harm balance of the co-administration of valproic acid and lamotrigine has been assessed in 28 children aged 4–16 years (mean 8 years) (29c ). Most of the children (n = 26) had a history of refractory epilepsy. Follow-up ranged from 6 months to 4 years (mean 1.8 years). Six children were seizure-free while taking this combination, while 18 were responders (with a greater than 50% reduction in seizure frequency). All the patients had previously used valproate and/or lamotrigine, but not both drugs simultaneously. Adverse events included tremor in six patients and urinary incontinence and ataxia in one. Tremor required a dosage reduction in one patient. Skin rashes occurred in two patients; both had a previous history of hypersensitivity to antiepileptic drugs. Rash was an early adverse reaction, presenting within the first 3–4 weeks of treatment, whereas other adverse events occurred later. Seven patients stopped taking valproate + lamotrigine for a variety of reasons: one had status epilepticus, in one efficacy was lost after a seizure-free period of 3 months, and two patients had skin rashes, including one in whom a second attempt to introduce the drug was also associated with a skin reaction. Valproic acid competitively inhibits lamotrigine glucuronidation, reducing its clearance and increasing its plasma concentration by about 50% (30c ). Because of this the dose of lamotrigine should be reduced by a half when valproic acid is added. Three patients taking oral lamotrigine developed signs of neurotoxicity when they received intravenous valproic acid for status epilepticus (31A ). In one patient the dose of lamotrigine was unchanged when intravenous valproic was added, while two patients had the dose of lamotrigine reduced by 25% and 50%. Despite this, all three developed signs of toxicity and their plasma lamotrigine concentrations increased 3–7 times compared with baseline. Valproic acid inhibits lamotrigine glucuronidation within 1 hour of administration; however, these three patients developed adverse effects at 4–14 days after adding valproic acid. Because of this the authors concluded that another mechanism may be involved.

Antiepileptic drugs

Chapter 7

Levetiracetam (SED-14, 190; SEDA-25, 88; SEDA-26, 75; SEDA-27, 79) Observational studies Adverse events have been recorded in an analysis of data from 1422 patients with refractory epilepsy treated with levetiracetam during the development of the drug (32C ). Adverse events were classified according to the Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART). The most common adverse events were accidental injury (28%), infection (27%), headache (26%), somnolence (23%), weakness (23%), and dizziness (19%). However, a detailed analysis of the nature of adverse effects and a comparison with the placebo group showed that accidental injury was more frequent in patients taking placebo than in those taking levetiracetam, and for the term “infection” most investigators reported common cold, therefore a relationship with levetiracetam is very unlikely. Cognitive and nervous system adverse events included headache (367 patients, 26%), somnolence (327, 23%), dizziness (269, 19%), depression (152, 11%), nervousness (115, 8.1%), insomnia (105, 7.4%), tremor (102, 7.2%), diplopia (74, 5.2%), amnesia (76, 5.3%), anxiety (86, 6.0%), ataxia (89, 6.3%), abnormal thoughts (67, 4.7%), confusion (56, 3.9%), and stupor, delusions, and hallucinations (each less than 1%). Behavioral adverse events included hostility (55, 3.9%), emotional lability (54, 3.8%), personality disorder (34, 2.4%), agitation (27, 1.9%), and sleep disorder (18, 1.3%). Euphoria, apathy, psychosis, paranoid reactions, depersonalization, antisocial reactions, manic reactions, neurosis, and psychotic depression were uncommon adverse events, each occurring in under 1% of patients. Other adverse events included weakness (321, 23%), pain (230, 16%), abdominal pain (142, 10%), diarrhea (146, 10%), nausea (129, 9.1%), skin rashes (125, 8.8%), back pain (124, 8.7%), anorexia (79, 5.6%), constipation (76, 5.3%), and dyspepsia (76, 5.3%). Since no information was provided about the rate of adverse reactions reported in placebo groups, it is not possible to obtain adequate estimates of the rate of adverse effects that can be attributed to levetiracetam itself. The efficacy and safety of levetiracetam as add-on therapy have been explored in a series of open studies. In a multicenter community-based

91 study 1030 patients with inadequately controlled partial seizures had levetiracetam added to their antiepileptic drug regimens (33C ). The initial dose was 500 mg bd, increased by 500 mg bd at the end of the second and fourth week to a maximum dose of 1500 mg bd, unless the patient had been seizure-free during the preceding 2 weeks; the dose was kept stable for the next 12 weeks. During the last 6 weeks of the study 67% (500/750) had at least a 50% reduction in the frequency of partial seizures, 52% (393/750) had at least a 75% reduction, and 42% (316/750) were seizure-free. Overall, 38% reported at least one drug-related adverse event. The most common were somnolence (13%), weakness (8.3%), dizziness (7.2%), and headache (5.9%). These adverse events were predominantly of mild-to-moderate intensity, and only 6% (62/1030) stopped taking the study drug because of them. In addition, severe incontinence in a 46-year-old man, confusion in a 34-year-old woman, and ataxia in a 45-year-old woman were serious adverse reactions that were considered possibly or probably related to levetiracetam. In each case the symptoms resolved completely after levetiracetam was withdrawn. Levetiracetam did not affect body weight: a similar number of patients had increased or reduced body weight (defined as a weight change of 7%), and there was no change in the mean weight from baseline to the final visit. There was a low rate of behavioral adverse events, including hostility (1.7%), emotional instability (1.7%), depression (1.5%), agitation (1.2%), anxiety (1.2%), and depersonalization (0.1%). In a subgroup analysis of 78 patients aged 65 years or older (range 65–100 years), 77% had a 50% or greater reduction in seizure frequency, and levetiracetam was in general well tolerated. In this subgroup of patients somnolence (17%) and dizziness (9.0%) were also the most commonly reported adverse events, and their incidence did not differ markedly from the rest of the study population. In a retrospective analysis of 119 patients with either partial or primary generalized epilepsy studied for 1 year, levetiracetam was used as add-on therapy (34c ). After 6 months 32% and at 1 year 26% of the patients were seizurefree. There were 21 withdrawals by 6 months and 27 by 1 year. Adverse events that led to withdrawal of levetiracetam were tiredness (n = 4), ataxia (n = 4), aggression (n = 4), insomnia (n = 4), depression (n = 2), and nausea

92 (n = 2); some patients had more than one adverse reaction, and overall 14 patients withdrew as a result. Tolerable adverse effects in patients who continued to take levetiracetam included: tiredness (n = 22), ataxia (n = 2), weight gain (n = 2), and poor memory, aggression, insomnia, and nausea (n = 1 each). In a retrospective study levetiracetam was used as adjunctive therapy in patients with partial epilepsy in whom epilepsy surgery had failed (n = 21), and non-surgical patients (n = 61) (35c ). The responder rate in patients whose seizures were not controlled with surgery was 76% (16/21); 10 patients (48%) were seizurefree and six (29%) had an over 50% reduction in seizure frequency. These figures were significantly lower in the non-surgical group: 34% (21/61) responder rate; nine patients (15%) seizure free, and 12 (20%) with an over 50% reduction in seizure frequency. In both groups the most common adverse effects were fatigue, somnolence, and dizziness. In the surgical group levetiracetam was withdrawn in two patients because of increased seizure frequency, and in four patients because of intolerable adverse effects: severe fatigue in one and in three a delayed psychotic syndrome that developed after 4–9 months. This psychotic reaction had not previously been present in any of the affected patients. The symptoms included psychotic thoughts, behavioral symptoms, insomnia, and personality changes, all of which resolved after withdrawal of levetiracetam. Since epilepsy surgery itself has not been associated with psychosis, while levetiracetam causes psychotic symptoms in a small proportion of patients within the first week of treatment, the authors considered that surgery or other factors may change the adverse effects profile of levetiracetam. In the non-surgical group 11 patients withdrew because of increased seizure frequency (n = 7, 12%), and intolerable adverse effects (n = 5, 8.2%); these adverse effects were those usually associated with the drug: fatigue, somnolence, headache, and dizziness. In an open multicenter study for 10–16 weeks levetiracetam was used in 219 patients with resistant focal and generalized epilepsy with at least two concomitant antiepileptic drugs (36c ). Doses were individualized at 1000– 3000 mg/day. Adverse events were classified according to COSTART, blood and urine laboratory tests were performed every 2 weeks, and

Chapter 7

Antonio Gil-Nagel

12-lead electrocardiography was conducted at the beginning and the end of the study. There were adverse events in 196 of 219 patients (89%). The frequency of adverse events was not dose-related, but was higher early in the study: 82% of the patients reported adverse events during up-titration, 66% during the evaluation phase, and 23% during down-titration. The nature of the adverse events did not differ from previous studies. Behavioral adverse events were severe in seven patients (3.1%), and were thought to be probably related to levetiracetam in one, possibly related in three, and unlikely to be related in three. These seven patients had symptoms of hostility (n = 3) and suicidal depression, nervousness, personality disorder, and psychosis (n = 1 each). All recovered after levetiracetam was withdrawn. There were no important changes in physical findings, laboratory measures, or electrocardiography during the study. In an open study in 21 children with highly refractory partial and generalized epilepsy, levetiracetam was added to the previous antiepileptic drug therapy in a dosage of 10 mg/kg/day given in two equal doses for the first week; the dose was then increased every four days in 10 mg/kg increments, depending on the clinical response, up to a maximum of 60 mg/kg/day (37c ). The final dosage was 17–60 (median 37) mg/kg/day. There was a more than 50% reduction in seizure frequency in 10 children and three became seizure free. Four patients reported adverse effects: two had somnolence, one of whom required withdrawal of levetiracetam, one had headache (n = 1), and one had behavioral problems and required withdrawal of levetiracetam. All four were taking a high dose of levetiracetam (over 40 mg/kg/day). In a retrospective chart review study 13 patients with newly diagnosed epilepsy in whom levetiracetam was used in monotherapy were identified (38c ). Levetiracetam was chosen as the first drug because of liver disease (n = 3) or because of its favorable pharmacokinetic and adverse effects profile (n = 10). Of the 13 patients, 11 continued to take levetiracetam monotherapy for at least 6 months; six of them were seizure free and five had an over 50% reduction in seizure frequency. Three patients reported irritability within 2 weeks, two stopped taking levetiracetam but the third continued to take it and the adverse effects disappeared after 1 month.

Antiepileptic drugs

Chapter 7

Nervous system In a prospective, uncontrolled evaluation of the tolerability and efficacy of levetiracetam as add-on therapy in 122 patients (78 adults and 44 children) with intractable epilepsy (39c ) the authors draw attention to a paradoxical increase in seizure frequency (over 25% compared with seizure frequency at baseline), observed in 14 of the adults and 19 of the children; three adults and four children developed status epilepticus. None of the children had status epilepticus before. Four adults developed a greater tendency for generalization of their partial seizures. Half of the children with seizure aggravation had a good initial response (over 50% reduction in seizure frequency). Irritability and aggression were only seen in adults with mental retardation (n = 3). The authors interpreted these results with caution: as the patients were recruited from a referral center there was a selection bias against severe, very difficult-totreat epilepsy; in addition there was no control group. However, almost all antiepileptic drugs have sometimes been associated with a paradoxical increase in seizures, and the evidence comes from isolated reports, as well as data obtained from randomized, placebo-controlled, add-on trials in patients with uncontrolled partial seizures. The authors suggested that by using a lower initial dose and slower dosage escalation than recommended by the manufacturers a paradoxical effect might be avoided. Psychiatric The prevalence and clinical features of psychiatric adverse events in patients taking levetiracetam for a mean duration of 8.3 months have been investigated prospectively in 517 patients, 50% with symptomatic partial epilepsy, 27% with cryptogenic partial epilepsy, 8.7% with idiopathic generalized epilepsy, 6.8% undetermined, and 5% with other syndromes (Lennox–Gastaut syndrome, West syndrome, and symptomatic generalized epilepsy) (40c ). There were psychiatric adverse events in 53 patients (10%): 19 (3.5%) developed aggressive behavior, 13 (2.5%) affective disorders, 12 (2.3%) emotional lability, 6 (1.2%) psychosis, and 3 (0.6%) other behavioral abnormalities, such as agitation, anger, or hostile behavior, and personality changes: four (0.7%) reported suicidal ideation. There was a significant association with a history of febrile seizures, status epilepticus, and a previous psychiatric history. In contrast, lamotrigine

93 co-therapy had a protective effect, while the levetiracetam titration regimen had no effect on the occurrence of psychiatric adverse events. Psychiatric adverse events and seizure exacerbation in patients taking levetiracetam have been reviewed, including randomized clinical trials in which levetiracetam was used in combination with other antiepileptic drugs, withdrawal to monotherapy studies, long-term extension studies, and postmarketing surveillance of adverse events in programs such as MEDWATCH (41M ). In contrast to previous reviews of safety data, the frequency of adverse events in patients taking levetiracetam was compared with those taking placebo in controlled trials: 15% of patients taking levetiracetam discontinued therapy or had their dosage reduced because of adverse events, compared with 12% of those who took placebo. The adverse events most commonly associated with withdrawal or dosage reduction were somnolence (4.4% versus 1.6% with placebo), convulsions (3.0% versus 3.4%), dizziness (1.4% versus 0%), weakness (1.3% versus 0.7%), and rashes (0% versus 1.1%). Most adverse events were mild or moderate in intensity. Overall, 113 patients (15%) taking levetiracetam and 49 (11%) of those who took placebo had severe adverse events. Seizure exacerbation in placebo-controlled trials (defined as a greater than 25% increase in seizure frequency) occurred in 14% of patients taking levetiracetam, compared with 26% of those taking placebo; seizure aggravation in these studies could therefore have represented spontaneous fluctuation in seizure frequency. The authors cited the Postmarketing Antiepileptic Drug Survey (42c ), a prospective registry that polls information from 16 epilepsy centers, behavioral adverse events were reported in 288 patients taking levetiracetam, and led to withdrawal in 27 patients (8.5%). Behavioral adverse events included depression (n = 14, 4.9%), anxiety (n = 8, 2.8%), aggression (n = 5, 1.7%), irritability (n = 4, 1.4%), mood swings (n = 3, 1.0%) and unspecified behavioral changes (n = 5, 1.7%). There was a previous history of psychiatric disease, behavioral problems, or mental retardation in 51% of patients with behavioral adverse events, compared with 50% of all the patients taking levetiracetam. As the authors observed, it is difficult to ascertain from this information how much levetiracetam contributes to behavioral and psychiatric symptoms, since these can

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Chapter 7

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be related to the epilepsy, the direct effect of seizures, drug interactions, or fluctuations in seizure frequency.

because the patients who participated had already tolerated oxcarbazepine during the previous double-blind study.

Drug dosage regimens In an open study the long-term efficacy and safety of levetiracetam were analysed in 98 patients taking two titration regimens (43c ). The first 35 patients were given levetiracetam in a starting dose of 500 mg bd with weekly increments of 500 mg bd (fast titration). The other 63 patients started with a dose of 250 mg bd with weekly increments of 250 mg bd (slow titration). The frequency of tiredness, any other adverse reactions, and withdrawal of levetiracetam did not differ significantly between the two groups. In 19 patients treatment was withdrawn because of adverse effects and/or lack of efficacy. Behavioral adverse effects, mainly irritability, were reported by five patients during the first 12 weeks, and by seven after the first 12 weeks. This led to withdrawal in four patients, three of whom had a prior history of behavioral problems and mental retardation. One patient, also with mental retardation and a prior history of aggressive behavior, had a psychotic reaction. His seizures had not improved with levetiracetam and the episode resolved after withdrawal.

Nervous system The relation of adverse events to concentrations of the major metabolite of oxcarbazepine, a monohydroxy derivative, is controversial; in one study there was a correlation between nervous system adverse events and raised plasma concentrations of the metabolite, while in another study there was no such correlation (45R ). Nutrition In children taking carbamazepine and oxcarbazepine monotherapy there were no changes in serum concentrations of unbound and total carnitine (46c ).

Oxcarbazepine

Electrolyte balance Hyponatremia (plasma sodium concentration below 125 mmol/l) has been associated with carbamazepine and oxcarbazepine, particularly in adults. However, hyponatremia does not appear to be so common during treatment of children with oxcarbazepine; in 2026 patients taking oxcarbazepine, hyponatremia was not seen in those aged under 6 years, was present in 0.4% of children aged up to 17 years, and in 3.8% of patients aged 18 to 64 years. However, some reports have suggested that there is an increased risk of hyponatremia in small children with infections, and these patients should be monitored at such times.

After a multicenter, randomized, double-blind, study in patients with medically refractory partial epilepsy, an open study of efficacy, tolerability, and safety during the first 48 weeks of treatment was performed in 76 patients, of whom 55 completed the study (44C ). The responder rate (an over 50% reduction in seizure frequency) was 46%, and five patients (6.6%) were seizure free. Most of the adverse events were mild to moderate in intensity, and tended to be transient. However, 13% of the patients withdrew because of adverse events. The six most common adverse events were dizziness, headache, fatigue, diplopia, nausea, and rash; these were more common in patients taking polytherapy than in those taking oxcarbazepine monotherapy. The authors suggested that tolerability data in this study had an inherent bias,

Liver There were abnormal liver enzymes (alkaline phosphatase, aspartate transaminase, and alanine transaminase) in five of 92 children taking oxcarbazepine, nearly a quarter of that observed in those taking phenytoin (18 of 92 patients). Oxcarbazepine was used as monotherapy in 42 children, mean age 12 years, with newly diagnosed focal or generalized epilepsy in an open non-randomized, multicenter study; 35 were seizure free at 6 months (47c ). Two patients stopped taking the drug because of intolerable adverse effects (headache and leukopenia). Serum concentrations of cholesterol and low-density lipoprotein were in the reference ranges in all patients at the start of the study, but increased significantly after 6 months of oxcarbazepine therapy. Concentrations of triglycerides and high-density lipoprotein were unaffected. In addition to the

(SED-14, 190; SEDA-25, 90; SEDA-26, 76; SEDA-27, 79)

Antiepileptic drugs

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Chapter 7

usual adverse effects, there was weight gain in five patients, aggression in four, rash in one, and a slight rise in liver enzymes in one. Skin In a comprehensive review of the use of oxcarbazepine in children with epilepsy the authors concluded that oxcarbazepine is better tolerated than phenytoin and carbamazepine as monotherapy (45R ). The adverse effect profile was similar to that reported in previous articles, and the authors estimated that rashes, which occurred in 5% of children taking oxcarbazepine, are less frequent than with carbamazepine. As with other antiepileptic drugs, there is a higher rate of adverse events when oxcarbazepine is used as adjunctive therapy compared with monotherapy, leading to its withdrawal in about 10% of children taking other antiepileptic drugs. In some randomized studies the occurrence of rash was similar among patients taking oxcarbazepine and placebo, perhaps because patients and physicians were more ready to attribute minor skin reactions to oxcarbazepine (45R ).

Phenobarbital Fetotoxicity In a secondary analysis of double-blind trials of the effects of phenobarbital and repeated antenatal glucocorticoid use on intelligence, achievement, behavior, and head circumference in children aged 7 years there were no adverse events related to antenatal exposure to phenobarbital (48C ).

Phenytoin and fosphenytoin

age, or the mean dose of phenytoin, but there were correlations with the duration of epilepsy and the duration of treatment with phenytoin. However, a multiple correlation analysis and backward stepwise multiple regression analysis, including all variables, showed that only the duration of treatment was significantly associated with cerebellar atrophy. There was no information about whether there were abnormal cerebellar or neuropsychological tests. • A patient with antecedent perinatal asphyxia developed phenytoin toxicity, which was attributed to cerebellar atrophy, documented by MRI scanning at the time (50A ).

However, this report does not allow such a conclusion, since brain MRI was not performed before the event, no new persistent neurological deficit was detected after normalization of the serum phenytoin concentration, and other potential causes of cerebellar atrophy, such as perinatal asphyxia, were present. • A 5-year-old girl developed a severe dyskinesia after taking phenytoin for 2 months for generalized tonic–clonic seizures (51A ). The serum phenytoin concentration was 40 µmol/l. This complication occurred while she had a concomitant urinary tract infection. The dyskinesia slowly improved and resolved within 2 weeks after phenytoin withdrawal and treatment with biperiden lactate 4–5 mg/day.

Skin toin.

Exfoliation has been attributed to pheny-

• A 47-year-old woman had disseminated exfoliative skin lesions and fever associated with cholestatic hepatitis after phenytoin was introduced for seizure prevention after surgery for glioblastoma multiforme (52A ). Her laboratory tests and clinical condition normalized 5 days after phenytoin was withdrawn.

(SED-14, 180; SEDA-25, 90; SEDA-26, 76; SEDA-27, 80)

Body temperature Hypothermia has been attributed to phenytoin.

Nervous system Cerebellar atrophy was found using MRI scanning in 20 of 56 patients who took phenytoin for over 2 months (49c ). Patients with a prior history of status epilepticus, severe head trauma, or meningitis were excluded, since these disorders can cause cerebellar atrophy. Cerebellar atrophy was not related to frequency of generalized seizures,

• Hypothermia occurred in a 38-year-old patient with mental retardation when serum phenytoin concentrations had increased to toxic concentrations after prolonged therapy in association with phenobarbital, baclofen, and paroxetine (53A ). Other causes of hypothermia were excluded and the temperature normalized when the phenytoin concentration was allowed to fall. She continued to take a lower dose without further adverse events.

96 Drug formulations Because of its poor water solubility, non-linear pharmacokinetics, and narrow therapeutic window, non-equivalence after generic substitution of phenytoin is highly likely. In a randomized, crossover, assessorblind study of the bioequivalence of a single oral dose of 200 mg of four phenytoin formulations (three generic and the reference standard) in 12 healthy Indian volunteers the three generic brands failed to remain within the prescribed limits of 80–120% for untransformed data, and 80–125% for log transformed data (54c ). Based on these results, switching phenytoin brands could have significant implications, such as adverse effects or poor seizure control in a previously stable patient. Drug administration route In a prospective study of the use of intravenous phenytoin in 22 children who received 100 doses over 10 months, six had one or more adverse events, including extravasation of the drug, hypotension, and cardiac dysrhythmias (55c ). In two patients the adverse event was considered to have been related to rapid infusion of phenytoin or the subsequent saline flush. Although these events were potentially serious, all resolved spontaneously. Management of adverse drug reactions Severe phenytoin toxicity in a 45-year-old patient was successfully treated with MARS (Molecular Adsorbents Recirculating System), a bloodpurification system based on albumin dialysis, and including a charcoal filter (56A ). Drug interactions Three cases of delayed phenytoin toxicity due to fluoropyrimidines (5fluorouracil or capecitabine) were attributed to competitive inhibition with the clearance of phenytoin by CYP2C9 or reduced synthesis of this isozyme by fluorouracil (57A ). • A 41-year-old woman had severe life threatening phenytoin intoxication after receiving a single intravenous dose of 15 mg/kg for severe seizures (58A ). She developed coma, a low respiratory rate, hypotension, and bradycardia, and had to be intubated and treated with vasopressors. Because impaired metabolism of phenytoin was suspected, she was screened for genetic polymorphism of CYP2C9 and was found to be heterozygous for the CYP2C9*3 allele. Other family members were also screened for CYP2C9 polymorphism, but only her brother, who had an episode of liver toxicity while taking phenytoin, was heterozygous for the CYP2C9*3 allele.

Chapter 7

Sultiame

Antonio Gil-Nagel

(SED-14, 187)

Urinary tract The rate of crystalluria in patients with epilepsy who took various antiepileptic drugs for more than 1 month has been studied retrospectively (59c ). The drugs were carbamazepine (492 urinary samples), valproic acid (n = 248), phenobarbital (n = 79), zonisamide (n = 49) and sultiame (n = 31). The frequency and degree of crystalluria were high among patients taking sultiame (29%) and zonisamide (45%), compared with the other drugs (range 7.1% to 15%) and controls (14%). Serum concentrations of sultiame were higher in patients with crystalluria than in those without, while age, sex, and duration of treatment were not different. The risk of crystalluria was also higher in patients with a urine pH of 8.0 and over.

Topiramate (SED-14; 191; SEDA-25, 780; SEDA-27, 81) In a randomized, concentration-controlled study of topiramate in refractory epilepsy (60C ) 65 patients were randomized to three specified plasma concentrations: low (2 µg/ml), medium (10.5 µg/ml), and high (19 µg/ml). Topiramate was titrated to the specified plasma concentration over a period of 8 weeks, followed by 12 weeks of observation. Patients assigned to the medium plasma concentration had the best seizure control, while patients with medium and high plasma concentrations had more adverse events. Most of the adverse events were psychiatric disorders or disorders of the central and peripheral nervous systems. Diplopia was not concentration-related, but the frequency of abnormal vision increased with increasing concentration. Adverse events were classified according to the World Health Organization Adverse Reaction Terminology (WHOART). In this adverse event classification system “rash” includes heat bumps and flushing, terms that were commonly reported and accounted for the majority of an otherwise surprising 22% incidence of “rash” observed in this study. All the adverse events were mild, and did not require withdrawal of topiramate. Fatigue and somnolence were also concentration-related, while nausea was not. Renal calculi were found in

Antiepileptic drugs

Chapter 7

two patients, both at a medium concentration. Weight loss occurred across the three groups and appeared to be concentration-related, with a median of 2.4% in the low group, 3.0% in the median group, and 5.2% in the high group. One patient, assigned to the low plasma concentration group, died during the trial; he had an initial good response to topiramate, followed by a series of secondarily generalized tonic–clonic seizures; the cause of death was thought to be aspiration during a seizures. Four patients were hospitalized because of adverse events possibly related to topiramate. One patient in the medium group had extreme vertigo, massive thrombophlebitis in the right leg, and significant weight loss during treatment with topiramate plus phenobarbital; because of weight loss (15 kg), the dose of topiramate was reduced by 33% and he continued treatment without further adverse effects. One patient in the low group had a psychosis; topiramate was withdrawn and the symptoms resolved. One patient in the medium group had vertigo, which resolved without a change in dose. One patient in the medium group had a renal stone, which was treated without changing the dose of topiramate. There was increased seizure frequency in three patients, two in the low and one in the medium group; topiramate was withdrawn in one of these patients in the low group and left unchanged in the other two. Two dosages of topiramate, 25–50 mg/day (n = 125) or 200–500 mg/day (n = 127), in monotherapy in patients aged over 3 years with epilepsy diagnosed during the previous 2 years have been compared in a randomized, double-blind study (61C ). The incidence of adverse effects was comparable between the two groups, with the exception of a higher incidence of paresthesia in the high-dose group. The incidences of paresthesia, dizziness, and weight loss were lower in children than in adults. There was no significant difference in the frequency of weight loss in the two groups: 12 of the patients in the low-dose group and 19 in the high-dose group. Serious adverse events thought to be related to topiramate were very uncommon, and included generalized tonic– clonic seizures, renal calculi, and psychosis. The most common treatment-limiting adverse events were related to the nervous system. They included somnolence, headache, psychomotor slowing, anorexia, paresthesia, mood problems,

97 and nervousness. The adverse events that most often required dosage adjustments were paresthesia, somnolence, dizziness, headache, and confusion. Renal calculi were reported in three patients. Nervous system Worsening of headache in patients receiving topiramate for migraine prophylaxis has been reported in an observational study (62c ). One patient had a reduced cerebrospinal fluid opening pressure at lumbar puncture. This finding suggests that in some patients headache related to topiramate may be related to a low cerebrospinal fluid pressure. Sensory systems There have been three reports of acute myopia and bilateral angleclosure glaucoma and the manufacturers have recommended withdrawal of topiramate and an ophthalmological opinion when patients taking the drug develop abrupt loss of visual acuity or ocular pain (63AS ). These adverse effects are usually seen in the first month of topiramate treatment and the mechanisms are not known, although it is suspected that they are related to osmotic changes in the aqueous humors caused by inhibition of carbonic anhydrase. • Angle-closure glaucoma associated with ciliary body detachment has been reported in two patients aged 42 and 44 years taking topiramate (64A ). They started taking topiramate 2 and 10 days before the onset of ocular symptoms, were not taking any other medications known to cause glaucoma, and recovered after topiramate was withdrawn.

Psychological The cognitive adverse effects of topiramate have been studied in 62 patients taking carbamazepine who had add-on therapy with either topiramate, valproic acid, or placebo in a multicenter, randomized, doubleblind study (65C ). A neuropsychological test battery was administered before the start of treatment with topiramate, valproic acid, or placebo, at the end of an 8-week titration period, and at the end of a 12-week maintenance period. Slightly more patients taking topiramate dropped out of the study; 62 patients completed the study: 27 in the topiramate group, 25 at the valproic acid group, and 10 on placebo. At the end of maintenance therapy, the effects of topiramate and valproic acid were comparable, except for two variables, the Symbol

98 Digit Modalities Test and the Controlled Oral Word Association Test, in which topiramate had greater negative effects than valproic acid. The statistical differences were due in large part to a small subset of patients who were more negatively affected by topiramate. Cognitive adverse effects of topiramate compared with valproic acid were greater at the end of titration than at the end of maintenance. Changes in neuropsychological testing have been investigated in two groups of patients: 22 patients who were taking topiramate in addition to other antiepileptic drugs, in whom topiramate was withdrawn during hospitalization, and 16 patients before and after using topiramate (66c ). Since each group used a different order of testing, this open design allowed comparison of the same patient on and off the drug, without respect to which condition was tested first. Topiramate was associated with impairment of fluency, attention/concentration, processing speed, language skills, and perception; working memory was affected but not retention. Of 431 consecutive patients taking topiramate, 31 (7.2%) developed word-finding difficulties (67c ). This adverse event was not associated with a rapid titration schedule, but it correlated with the presence of simple partial seizures and left temporal epileptiform activity on the electroencephalogram, suggesting that there is a subgroup of patients with a specific susceptibility. A significant improvement in neuropsychological functions associated with the frontal lobe after withdrawal of topiramate in epilepsy patients was reported in an open controlled study (68c ). The results suggested that verbal fluency and working memory were very sensitive to topiramate. Improvement in this function was observed after withdrawal of topiramate but not in the control group. Psychiatric The prevalence of psychiatric adverse events in relation to topiramate has been studied in 431 consecutive patients (69C ). There were psychiatric adverse events in 103 patients (24%), including affective disorder in 46 (11%), psychotic disorder in 16 (3.7%), aggressive behavior in 24 (5.6%), and other behavioral abnormalities (agitation, anger/hostility, and anxiety) in 17 (3.9%). Psychiatric disorders were more prevalent with a high starting dose, rapid titration, a family history of a psychiatric disorder, a family history of epilepsy, a personal

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history of febrile seizures, and the presence of tonic–atonic seizures. The seizure frequency before starting topiramate and lamotrigine coadministration protected against psychiatric adverse events. • A 41-year-old woman with a diagnosis of bipolar disorder developed severe suicidality when topiramate was added to her previous treatment (carbamazepine and levothyroxine) for mood stabilization (70A ).

Urinary tract Acute renal insufficiency has been attributed to topiramate. • Acute renal insufficiency occurred in a 19-yearold man 10 days after he started to take topiramate (71A ). He had poorly controlled epilepsy, treated with carbamazepine and topiramate 50 mg bd. For several days before developing renal insufficiency he had frequent complex partial and secondarily generalized tonic–clonic seizures, and his carbamazepine serum concentration had fallen to 1.4 µg/ml for unknown reasons.

In this scenario rhabdomyolysis should have been considered as a potential cause of acute renal insufficiency. Unfortunately there was no information on serum creatine kinase activity and so the relation between the acute renal insufficiency and the use of topiramate can be questioned. Body temperature Reduced sweating and hyperthermia induced by topiramate were investigated in a pilot study in 13 patients aged 1–37 years compared with 14 age-matched controls (72c ). They were questioned about sweating and heat intolerance and had a pilocarpine iontophoresis sweat test. Nine patients taking topiramate had reduced sweating; eight were below 16 years of age. This effect is thought to be related to inhibition of carbonic anhydrase by topiramate, a mechanism of action that topiramate shares with zonisamide, another drug known to cause reduced sweating. • Reduced sweating occurred in a 32-year-old man taking topiramate (73A ). Cardiovascular autonomic function and peripheral thermoregulatory mechanisms were normal, suggesting that the effect was exerted directly on the sweat glands, and therefore was probably related to inhibition of carbonic anhydrase.

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Susceptibility factors Age The use of topiramate as add-on therapy has been investigated in an open study in 207 children under 12 years with refractory epilepsy (74c ). The most frequent adverse effects were moderate behavioral and gastrointestinal disorders. Adverse events led to topiramate withdrawal in 28 children (14%), and to dosage reduction in 10 (5%). Children under 4 years of age have better tolerability than children aged 4–12 years: six (15%) of 41 children in the younger group had at least one adverse event, compared with 89 (54%) of 166 in the older group. Adverse events were not related to the dosage of topiramate, and only one child had urolithiasis. In an open study the charts of 28 infants under 24 months who had been treated with topiramate were reviewed (75c ). Topiramate was prescribed as add-on therapy in 25 cases and as monotherapy in three. Adverse events occurred in five patients: anorexia and weight loss in two (topiramate was withdrawn in one case), seizure aggravation in one (withdrawn), irritability in one, and drowsiness in one. Three patients were treated with a ketogenic diet while taking topiramate and none had a metabolic acidosis.

Valproate sodium and semisodium (SED-14, 182; SEDA-25, 95; SEDA-26, 80; SEDA-27, 82) Cardiovascular The effect on the blood pressure of intravenous valproate sodium at larger doses and more rapid rates of infusions than recommended in the original labelling has been investigated in a randomized study (76C ). The original labelling recommended that valproate sodium injection be administered over 60 minutes, at rates up to 20 mg/min, and, for adjunctive therapy, that doses exceeding 250 mg be given in divided doses. In this study 112 adults and children with epilepsy (age range 13 months to 79 years) were randomized in a 2 : 1 ratio to receive up to 15 mg/kg of valproate sodium at 3.0 or 1.5 mg/kg/minute. Up to four doses were allowed within 24 hours to achieve target plasma concentrations. There were no significant differences in blood pressures among the two groups of patients.

99 Nervous system Various nervous system effects of valproate have been reported. • Valproate was associated with acute akinesia and marked cognitive impairment in a 62-year-old woman taking the drug for mood disorder (77A ). • Reversible impaired consciousness and brain atrophy was identified in a CT scan of a 5-year-old girl taking long-term valproic acid (78A ). Her mental status normalized 12 hours after withdrawal of valproic acid, and serial CT scans showed progressive improvement of cerebral atrophy, reaching normality within 2 months.

Metabolism The incidence of weight gain in young patients taking valproic acid has been investigated in a series of reports. In a review of 43 patients aged 10–17 years there was a mild to moderate increase in body mass index in 25 and a fall in 16; however, the weight loss tended to be modest (79c ). Six patients moved up to a potentially overweight or overweight category. Two factors tended to predict an increase in body mass index: normal cognitive status and primary generalized epilepsy. In an open study of the effects of lamotrigine and valproic acid monotherapy on weight in 38 adolescents (18 taking lamotrigine, 20 taking valproic acid) with epilepsy treated over 8 months, (80c ) weight gain and increased body mass index were greater in patients who took valproic acid than in those who took lamotrigine. In contrast, in a retrospective analysis of 58 children there was no weight gain (81r ). The relationship of hyperammonemia to valproic acid-associated encephalopathies has been questioned after a study of ammonia concentrations in 55 asymptomatic patients taking valproic acid showed that 29 had ammonia concentrations above the reference range, the highest being 140 µmol/l (82r ). Hematologic Neutropenia has been attributed to valproic acid. • A 56-year-old woman taking phenytoin, vancomycin, ceftriaxone, and metronidazole developed a fever, thought to be due to phenytoin (83A ). The phenytoin was withdrawn and she was given valproic acid instead. After 2 days her absolute neutrophil count fell progressively to a minimum of 47 × 106 /l. Ceftriaxone was substituted by levofloxacin after 3 days and valproic acid was withdrawn after 4 days. The absolute neutrophil count started to improve 2 days after the withdrawal of valproic acid and returned to normal within another 24 hours.

100 Although the authors dismissed other drugs as the cause of this severe neutropenia, the complexity of the therapy and the frequent drug changes make interpretation difficult. Based only on the time sequence of drugs used and the evolution of the absolute neutrophil count, it is not possible to exclude an effect of other drugs. Pancreas A review of published reports and four further reports of children with valproic acid-induced acute pancreatitis, in one case fatal, led to the conclusion that this adverse event should be considered seriously in any patient taking valproic acid who presents with abdominal symptoms, fatigue, or apathy, regardless of the age of the patient and the duration of valproic acid treatment (84R ). Serum lipase, and less so amylase, is valuable. Abdominal imaging, with ultrasound or CT, and laparoscopy should be considered to detect the presence of hemorrhagic pancreatitis. Sexual function The effect of valproic acid on sexual development in adolescents aged 8– 16 years has been studied in 38 patients with epilepsy (23 girls, 15 boys) and 25 controls (15 girls, 10 boys) (85c ). There were no differences in sexual development and no cases of hirsutism or polycystic ovaries. There were increases in weight, relative weight, and body mass index in patients with epilepsy treated with valproic acid, compared with controls, but the differences were not statistically significant. Compared with controls testosterone concentrations were raised in girls with epilepsy taking valproic acid, and this was statistically significant but not related to the duration of valproic acid therapy or the dose. In boys testosterone concentrations were not different between those taking valproic acid and controls. Reproductive system The question of whether the association of valproic acid with reproductive endocrine abnormalities occurs in women with bipolar disorder or is unique to women with epilepsy has been explored in 45 women aged 18–40 years, 15 with bipolar disorder taking lithium monotherapy, 15 with bipolar disorder taking valproic acid in combination with lithium, and 15 with idiopathic generalized epilepsy taking valproic acid monotherapy (86c ). Valproic acid was associated with

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menstrual abnormalities and increased total testosterone concentrations in patients with both bipolar disorder and epilepsy, although women with bipolar disorder did not have clinical features of hyperandrogenism (menstrual abnormalities, hirsutism, and truncal obesity), as women with epilepsy often did. There were similar results in a study of 18 women with bipolar disorder taking valproic acid and 20 taking lithium (87c ). An open analysis of 163 women taking valproic acid for different types of epilepsy showed an association with polycystic ovaries, hyperandrogenism, obesity, and menstrual abnormalities (88c ). Immunologic Anticonvulsant hypersensitivity syndrome has been attributed to valproic acid. • A 36-year-old man had a drug hypersensitivity syndrome with carbamazepine (89A ). The carbamazepine was withdrawn, and 2 weeks later he was given valproic acid. He immediately developed a widespread exanthematous rash. • A 2-year-old girl with a history of foot-and-mouth disease, enterovirus 71 infection, and Staphylococcus aureus pneumonia, developed a fever, encephalopathy, toxic hepatitis, and an exanthem 17 days after starting to take valproic acid for new-onset myoclonic jerks (90A ). A liver biopsy showed microvesicular steatosis and findings consistent with toxic hepatitis; a skin biopsy was consistent with lichenoid dermatitis or a lichenoid drug eruption. Despite withdrawal of valproic acid, administration of intravenous glucocorticoids, and blood exchange therapy she died as a result of complications of hepatorenal syndrome, hepatic encephalopathy, Pseudomonas septicemia, and multiorgan failure.

The authors concluded that this case combined hepatotoxicity and anticonvulsant hypersensitivity syndrome, both related to valproic acid. Interference with diagnostic tests An interaction of platelets with EDTA in the presence of valproic acid can cause false thrombocytopenia (91A ). The false results are secondary to platelet clumping and failure of automatic analysers to count platelet clumps correctly. Heparin anticoagulated blood and non-automated counting can avoid the error.

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Vigabatrin (SED-14, 192; SEDA-25, 98; SEDA-26, 82; SEDA-27, 83) Sensory systems DoTS classification: Reaction: visual field loss from vigabatrin Dose relation: Collateral reaction Time course: Late Susceptibility factors: More common in adults A follow-up study of 22 patients with vigabatrin-induced visual field loss did not show improvement or worsening in the evolution of peripheral vision, electro-oculography, and flash electroretinography after vigabatrin had been withdrawn for 37–47 months (92c ). However, there was a slight increase in visual field loss in patients who continued to take vigabatrin. In a retrospective analysis of digitally enhanced photographs of the ocular fundus, kinetic visual field maps, and treatment parameters in 26 patients taking vigabatrin, 12 had minor or questionable defects and 14 had more advanced defects (93c ). There was evidence of subtle diffuse atrophy of the retinal nerve fiber layer in 21 patients. The severity of atrophy correlated with visual field defects and cumulative vigabatrin dose. The occurrence of optic atrophy in this study supports the irreversible nature of vigabatrin-induced visual toxicity. In an observational study of six patients who had taken vigabatrin for at least 3 years, foveal cone electroretinography amplitudes were at or below the lower limit of normal, and darkadapted perimetry showed abnormal rod-derived visual fields (94A ). Hearing loss has also been attributed to vigabatrin. • Reversible sensorineural hearing loss occurred in a 14-year-old boy who had taken vigabatrin for about 3 years (95A ). He also had peripheral visual field loss. Ten days after withdrawal of vigabatrin his hearing loss almost completely recovered.

Zonisamide

(SED-14, 193; SEDA-25, 100; SEDA-26, 84; SEDA-27, 83)

Nervous system Restless legs syndrome has been attributed to zonisamide.

101 • A 27-year-old woman with myoclonic and generalized tonic–clonic seizures that had been resistant to valproic acid and lamotrigine, but were controlled with high doses of zonisamide developed restless legs (96A ). Because zonisamide was effective she preferred to continue taking it, but obtained some improvement in her restless legs syndrome when the dosage of zonisamide was reduced.

Psychiatric Complex visual hallucinations occurred in three patients taking zonisamide for different syndromes and types of seizures (Landau–Kleffner syndrome in a 7-year-old girl, myoclonic and generalized tonic seizures in a 21-year-old woman, and partial epilepsy in a 13-year-old girl) (97A ). None of the patients had visual hallucinations before zonisamide was started, and the symptoms resolved after withdrawal. • A 5-year-old girl presented behavioral problems after her seizures had been controlled with zonisamide (98A ). This was interpreted as a case of forced normalization, and her behavioral difficulties disappeared when zonisamide was withdrawn and her seizures reappeared.

Urinary tract The incidence of urolithiasis induced by antiepileptic drugs has been studied in 927 epilepsy patients taking antiepileptic drugs, 122 patients with epilepsy not taking antiepileptic drugs, and 657 controls (59c ). The patients with epilepsy taking antiepileptic drugs included 492 taking carbamazepine, 248 taking valproic acid, 79 taking phenobarbital, 49 taking zonisamide, 31 taking sultiame, and 28 taking phenytoin; all had taken monotherapy for more than 1 month. The frequency of crystalluria was 45% with zonisamide, and 29% with sultiame, compared with 14% among controls. The other antiepileptic drugs did not increase the frequency of crystalluria. Zonisamide-induced crystalluria occurred only in men, was more common in patients with urine pH of 8.0 and over, and was not related to blood concentrations of the drug or the duration of treatment. Body temperature Six cases of reduced sweating and fever in children taking zonisamide have been identified in a review of reports to the Food and Drug Administration’s Adverse Event Reporting System (99c ). All were under 18 years of age. The calculated reporting rate was 13 cases per 10 000 child-years of exposure, about 10 times the rate in Japan.

102 Drug overdose In a case of fatal acute zonisamide overdose, generalized tonic clonic seizures and cardiopulmonary arrest occurred during transfer to the hospital (100A ). The dose of

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zonisamide was calculated to be 4.8 g, but it was not possible to determine the time elapsed since ingestion.

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103 43. Ben-Menachem E, Gilland E. Efficacy and tolerability of levetiracetam during 1-year follow-up in patients with refractory epilepsy. Seizure 2003; 12: 131–5. 44. Beydoun A, Sachdeo RC, Kutluay E, McCague K, D’Souza J. Sustained efficacy and long-term safety of oxcarbazepine: one-year open-label extension of a study in refractory partial epilepsy. Epilepsia 2003; 44: 1160–5. 45. Bang L, Goa K. Oxcarbazepine: a review of its use in children with epilepsy. Paediatr Drugs 2003; 5: 557–73. 46. Kurul S, Dirik E, Iscan A. Serum carnitine levels during oxcarbazepine and carbamazepine monotherapies in children with epilepsy. J Child Neurol 2003; 18: 552–4. 47. Serdaroglu G, Kurul S, Tutuncuoglu S, Dirik E, Sarioglu B. Oxcarbazepine in the treatment of childhood epilepsy. Pediatr Neurol 2003; 28: 37– 41. 48. Thorp JA, O’Connor M, Belden B, Etzenhouser J, Hoffman EL, Jones PG. Effects of phenobarbital and multiple-dose corticosteroids on developmental outcome at age 7 years. Obstet Gynecol 2003; 101: 363-73. 49. De Marcos FA, Ghizoni E, Kobayashi E, Li LM, Cendes F. Cerebellar volume and long-term use of phenytoin. Seizure 2003; 12: 312–15. 50. Zuin DR, Neme R, Porta L, Vera J, Lopez OL. Atrofia cerebelosa aguda por intoxicacion con difenilhidantoina producto de interaccion medicamentosa. Rev Neurol 2003; 36: 195–6. 51. Caksen H, Odabas D, Anlar O. Use of biperiden hydrochloride in a child with severe dyskinesia induced by phenytoin. J Child Neurol 2003; 18: 494–6. 52. Altuntas Y, Ozturk B, Erdem L, Gunes G, Karul S, Ucak S, Sengul A. Phenytoin-induced toxic cholestatic hepatitis in a patient with skin lesions: case report. South Med J 2003; 96: 201–3. 53. Newberger DS, Blyth SA. Hypothermia and phenytoin toxicity. Clin Neuropharmacol 2003; 26: 172–3. 54. Gogtay NJ, Dalvi SS, Mhatre RB, Kirodian BG, Gupta AH, Jadhav SP, Kshirsagar NA. A randomized, crossover, assessor-blind study of the bioequivalence of a single oral dose of 200 mg of four formulations of phenytoin sodium in healthy, normal Indian volunteers. Ther Drug Monit 2003; 25: 215–20. 55. Appleton RE, Gill A. Adverse events associated with intravenous phenytoin in children: a prospective study. Seizure 2003; 12: 369–72. 56. Sen S, Ratnaraj N, Davies NA, Mookerjee RP, Cooper CE, Patsalos PN, Williams R, Jalan R. Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS). Epilepsia 2003; 44: 265–7. 57. Brickell K, Porter D, Thompson P. Phenytoin toxicity due to fluoropyrimidines (5FU/ capecitabine): three case reports. Br J Cancer 2003; 89: 615–16. 58. Citerio G, Nobili A, Airoldi L, Pastorelli R, Patruno A. Severe intoxication after phenytoin in-

104 fusion: a preventable pharmacogenetic adverse reaction. Neurology 2003; 60: 1395–6. 59. Go T. Effect of antiepileptic drug monotherapy on crystalluria in children and young adults. J Neurol 2003; 250: 1251–2. 60. Christensen J, Andreasen F, Poulsen JH, Dam M. Randomized, concentration-controlled trial of topiramate in refractory focal epilepsy. Neurology 2003; 61: 1210–18. 61. Gilliam FG, Veloso F, Bomhof MA, Gazda SK, Biton V, Ter Bruggen JP, Neto W, Bailey C, Pledger G, Wu SC. A dose-comparison trial of topiramate as monotherapy in recently diagnosed partial epilepsy. Neurology 2003; 60: 196–202. 62. Rozen TD. Worsening of headaches on topiramate? A low cerebrospinal fluid pressure syndrome? Headache 2003; 43: 819–20. 63. Anonymous. Myopia and glaucoma with topiramate. Prescrire Int 2003; 12: 61. 64. Medeiros FA, Zhang XY, Bernd AS, Weinreb RN. Angle-closure glaucoma associated with ciliary body detachment in patients using topiramate. Arch Ophthalmol 2003; 121: 282–5. 65. Meador KJ, Loring DW, Hulihan JF, Kamin M, Karim R; CAPSS-027 Study Group. Differential cognitive and behavioral effects of topiramate and valproate. Neurology 2003; 60: 1483–8. 66. Lee S, Sziklas V, Andermann F, Farnham S, Risse G, Gustafson M, Gates J, Penovich P, AlAsmi A, Dubeau F, Jones-Gotman M. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia 2003; 44: 339–47. 67. Mula M, Trimble MR, Thompson P, Sander JW. Topiramate and word-finding difficulties in patients with epilepsy. Neurology 2003; 60: 1104–7. 68. Kockelmann E, Elger CE, Helmstaedter C. Significant improvement in frontal lobe associated neuropsychological functions after withdrawal of topiramate in epilepsy patients. Epilepsy Res 2003; 54: 171–8. 69. Mula M, Trimble MR, Lhatoo SD, Sander JW. Topiramate and psychiatric adverse events in patients with epilepsy. Epilepsia 2003; 44: 659–63. 70. Litman LC. Sexual sadism with lust-murder proclivities in a female? Can J Psychiatry 2003; 48: 127. 71. Ferriols Lisart R, Heras Javierre A, Sanz Munoz M, Ibanez Benages E, Alos Alminana M. Fallo renal agudo probablemente asociado a topiramato. Farm Hosp 2003; 27: 105–8. 72. Ben-Zeev B, Watemberg N, Arten A, Brand N, Yahav Y, Efrati O, Topper L, Blatt I. Oligohydrosis and hyperthermia: pilot study of a novel topiramate adverse effect. J Child Neurol 2003; 18: 254–7. 73. De Carolis P, Magnifico F, Pierangeli G, Rinaldi R, Galeotti M, Cevoli S, Cortelli P. Transient hypohidrosis induced by topiramate. Epilepsia 2003; 44: 974–6. 74. Mikaeloff Y, De Saint-Martin A, Mancini J, Peudenier S, Pedespan JM, Vallee L, Motte J, Bourgeois M, Arzimanoglou A, Dulac O, Chiron C. Topiramate: efficacy and tolerability in children according to epilepsy syndromes. Epilepsy Res 2003; 53: 225–32.

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75. Watemberg N, Goldberg-Stern H, Ben-Zeev B, Berger I, Straussberg R, Kivity S, Kramer U, Brand N, Lerman-Sagie T. Clinical experience with openlabel topiramate use in infants younger than 2 years of age. J Child Neurol 2003; 18: 258–62. 76. Ramsay RE, Cantrell D, Collins SD, Walch JK, Naritoku DK, Cloyd JC, Sommerville K. Safety and tolerance of rapidly infused Depacon. A randomized trial in subjects with epilepsy. Epilepsy Res 2003; 52: 189–201. 77. Reif A, Hamelbeck B, Pfuhlmann B. Acute akinetic crisis with marked cognitive impairment due to valproate treatment. Int J Geriatr Psychiatry 2003; 18: 356–7. 78. Yamanouchi H, Ota T, Imataka G, Nakagawa E, Eguchi M. Reversible altered consciousness with brain atrophy caused by valproic acid. Pediatr Neurol 2003; 28: 382–4. 79. Wirrell EC. Valproic acid-associated weight gain in older children and teens with epilepsy. Pediatr Neurol 2003; 28: 126–9. 80. Biton V, Levisohn P, Hoyler S, Vuong A, Hammer AE. Lamotrigine versus valproate monotherapy-associated weight change in adolescents with epilepsy: results from a post hoc analysis of a randomized, double-blind clinical trial. J Child Neurol 2003; 18: 133–9. 81. Bosnak M, Dikici B, Haspolat K, Dagli A, Dikici S. Do epileptic children treated with valproate have a risk of excessive weight gain? J Child Neurol 2003; 18: 306. 82. Murphy JV. Valproate-induced hyperammonemic encephalopathy. Epilepsia 2003; 44: 268. 83. Vesta KS, Medina PJ. Valproic acid-induced neutropenia. Ann Pharmacother 2003; 37: 819–21. 84. Grauso-Eby NL, Goldfarb O, Feldman-Winter LB, McAbee GN. Acute pancreatitis in children from valproic acid: case series and review. Pediatr Neurol 2003; 28: 145–8. 85. Balaguer Martinez JV, Lopez Garcia MJ, Andres Celma M, Contell Villagrasa A, Castello Pomares ML. Efectos del acido valproico sobre el desarrollo sexual. An Pediatr (Barc) 2003; 58: 443– 8. 86. Akdeniz F, Taneli F, Noyan A, Yuncu Z, Vahip S. Valproate-associated reproductive and metabolic abnormalities: are epileptic women at greater risk than bipolar women? Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 115–21. 87. McIntyre RS, Mancini DA, McCann S, Srinivasan J, Kennedy SH. Valproate, bipolar disorder and polycystic ovarian syndrome. Bipolar Disord 2003; 5: 28–35. 88. Otoom S, Nusier M, Hasan M, Hadidi H, Samawi R, Younes AM, Darweesh M, Boulatova NR. Association of polycystic ovaries with the use of valproic acid in Jordanian epileptic patients. Clin Drug Invest 2003; 23: 527–32. 89. Arevalo-Lorido JC, Carretero-Gomez J, BureoDacal JC, Montero-Leal C, Bureo-Dacal P. Antiepileptic drug hypersensitivity syndrome in a patient treated with valproate. Br J Clin Pharmacol 2003; 55: 415–16.

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90. Huang YL, Hong HS, Wang ZW, Kuo TT. Fatal sodium valproate-induced hypersensitivity syndrome with lichenoid dermatitis and fulminant hepatitis. J Am Acad Dermatol 2003; 49: 316–19. 91. Yoshikawa H. EDTA-dependent pseudothrombocytopenia induced by valproic acid. Neurology 2003; 61: 579–80. 92. Hardus P, Verduin W, Berendschot T, Postma G, Stilma J, Van Veelen C. Vigabatrin: long term follow-up of electrophysiology and visual field examinations. Acta Ophthalmol Scand 2003; 81: 459– 65. 93. Frisen L, Malmgren K. Characterization of vigabatrin-associated optic atrophy. Acta Ophthalmol Scand 2003; 81: 466–73. 94. Banin E, Shalev RS, Obolensky A, Neis R, Chowers I, Gross-Tsur V. Retinal function abnormalities in patients treated with vigabatrin. Arch Ophthalmol 2003; 121: 811–16. 95. Papadeas E, Polychronopoulos P, Papathanasopoulos P, Frimas C, Pharmakakis N, Paschalis C.

105 Sensorineural hearing loss: a reversible effect of vigabatrin. Neurology 2003; 61: 1020–1. 96. Chen JT, Garcia PA, Alldredge BK. Zonisamide-induced restless legs syndrome. Neurology 2003; 60: 147. 97. Akman CI, Goodkin HP, Rogers DP, Riviello Jr JJ. Visual hallucinations associated with zonisamide. Pharmacotherapy 2003; 23: 93–6. 98. Hirose M, Yokoyama H, Haginoya K, Iinuma K. [A five-year-old girl with epilepsy showing forced normalization due to zonisamide] No To Hattatsu 2003; 35: 259–63. 99. Knudsen JF, Thambi LR, Kapcala LP, Racoosin JA. Oligohydrosis and fever in pediatric patients treated with zonisamide. Pediatr Neurol 2003; 28: 184–9. 100. Sztajnkrycer MD, Huang EE, Bond GR. Acute zonisamide overdose: a death revisited. Vet Hum Toxicol 2003; 45: 154–6.

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8

Opioid analgesics and narcotic antagonists

Opioid therapy and chronic non-cancer pain has been reviewed by the Canadian Pain Society in a consensus document that states that there is no recorded risk in the medical literature of direct permanent organ damage (including cognitive and psychomotor deficits) due to the appropriate therapeutic use of opioids and that problems are more often due to concurrent use of sedatives, such as benzodiazepines (1M , 2c ). Respiratory depression caused by opioid analgesics occurs largely in opioid-naïve patients and is short-lived. Constipation is a common initial adverse effect and is usually more difficult to treat than to prevent. It is therefore important to manage constipation prophylactically, using a stepped approach involving adequate dietary fiber, stool softeners, osmotic agents, and if necessary intermittent stimulant laxatives. Nausea is also a common adverse effect and usually resolves with continued use within days. Patients with a history of addiction should not necessarily be denied a trial of opioid therapy but will require more careful prescribing, closer follow up, and joint clinics between chronic pain and addiction specialists (3M , 4M ).

OPIOID RECEPTOR AGONISTS Dextromethorphan

(SED-14, 212; SEDA-25, 111; SEDA-26, 90; SEDA-27, 88) Comparative studies In a double-blind, randomized study dextromethorphan and intrathecal morphine were used for analgesia after cesarean section under spinal anesthetic in 120 patients in six groups (5c ). The groups had differing mixtures of intrathecal morphine (0.05 mg, © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

106

0.1 mg, 0.2 mg) and dextromethorphan (60 mg) or placebo. The results suggested that the addition of dextromethorphan reduced postoperative pain and reduced the doses of morphine. The combination reduced the incidence of nausea, vomiting, and pruritus. Skin A multifocal fixed drug eruption has been attributed to dextromethorphan. • A 64-year-old healthy Japanese woman developed fingertip- to egg-sized erythematous patches surrounded by peripheral pigmentation on the buttocks, back, and thighs after taking an antitussive formulation containing dextromethorphan (6A ). Histopathological examination confirmed the diagnosis. The lesions were reproduced 2 hours after an oral challenge test with dextromethorphan 15 mg.

Drug dosage regimen The effects of dextromethorphan on postoperative pain and other parameters have been investigated in a doubleblind, randomized study in 60 patients undergoing surgery for bone malignancies (7c ). They received either placebo (n = 30) or dextromethorphan 90 mg preoperatively and 2 days postoperatively (n = 30). Those given dextromethorphan had 50% less postoperative pain, required 30–50% less epidural analgesia, and demanded fewer rescue drugs than their placebo counterparts. Those given dextromethorphan were 40– 60% less sedated and reported 50% fewer overall adverse effects. The authors recommended that this dextromethorphan protocol is promising and safe for patients with severe orthopedic and oncological disease without affecting the time to discharge.

Diamorphine (heroin)

(SED-14, 214; SEDA-25, 112; SEDA-26, 91; SEDA-27, 89) In two separate open, randomized, controlled but unblinded trials, 549 patients were divided

Opioid analgesics and narcotic antagonists

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into five treatment groups. In the first study there were 375 patients in three groups: • methadone alone for 12 months (controls); • methadone plus inhaled heroin for 12 months; • methadone alone for 6 months followed by methadone plus inhaled heroin for 6 months. In the second study there were 174 patients in two similar experimental groups in whom injectable rather than inhaled heroin was used (8C ). A response to treatment was defined as at least a 40% improvement in physical, mental, or social domains of quality of life, if not accompanied by a substantial (over 20%) increase in the use of another illicit drug, such as cocaine or amphetamines. After 12 months those who took methadone and heroin (smoked or injected) had significantly better outcomes. The incidences of adverse effects (constipation and drowsiness) were similar in all the groups. However, owing to the limitations of the study and the complex nature of drug dependence, the therapeutic outcomes could not be justifiably and solely attributed to the specific drug(s). Nervous system Various neurological complications after inhalation of heroin have again been reported. • A 46-year-old man with a 26-year history of heroin abuse developed a slowly progressive gait disorder with paresthesia in the legs after he had bought heroin from a different illicit heroin dealer (9A ). After another few weeks he developed urinary incontinence and impotence. Neurological examination, an MRI scan of the brain and neck, and evoked potentials confirmed a progressive myelopathy affecting only the corticospinal tracts and posterior columns as a result of inhalation of heroin vapor. Prolonged multivitamin supplementation and subsequent high-dose prednisone for 10 days did not improve the symptoms. • Four patients developed acute toxic spongiform leukoencephalopathy after inhaling heroin vapor (10A , 11A ). One died and the other three were discharged with residual neurological symptoms.

Infection risk Injection of heroin can cause local infection. • A 32-year-old man with pyomyositis developed abdominal pain and vomiting, fresh rectal bleeding, hematuria, and a swelling on his lower back (12A ). Two weeks before, he had accidentally given himself an extravascular injection of heroin into his left groin. A CT scan showed a large

107 left sided gluteal abscess communicating through the left sacroiliac joint with the retroperitoneal space. He needed catheterization and multiple open drainage of the abscess and was discharged after 2 months.

Withdrawal effects Opioid withdrawal symptoms should be included as part of the differential diagnosis in young people with restless legs syndrome. • Restless legs syndrome was a feature of opioid withdrawal on days 3–4 in two heroin-dependent individuals (13A ). They were treated with levodopa and clonidine.

Drug administration route Intranasal The pharmacokinetic profile of intranasal diamorphine has been studied in adults. Diamorphine is rapidly absorbed as a dry powder and has similar pharmacokinetic properties to intramuscular diamorphine, with similar physiological responses (for example reduced pupil diameter, respiration, and temperature) and behavioral measures (for example euphoria, sedation, and dysphoria). Intranasal diamorphine has been evaluated in a multicenter, randomized, controlled trial as an alternative to intramuscular morphine in 404 patients aged 3–16 years with suspected limb fractures (i.e. in acute pain of moderate to severe intensity) (14c ). They were randomized to either intramuscular morphine sulfate 0.2 mg/kg (n = 200) or intranasal diamorphine hydrochloride 0.1 mg/kg (n = 204). Intranasal diamorphine was significantly better tolerated: 80% had no obvious discomfort compared with only 9% of those given morphine. There were no serious adverse effects of diamorphine, but the lack of blinding may have introduced bias. The intranasal route of administration is also not without problems when abused. Some nonfatal complications include neurological, acute myelopathy, oculogyric crisis and generalized dystonia, hypersensitivity reactions, pneumonitis, pemphigus, and pancreatitis (14c ). Drug overdose Strategies for preventing heroin overdose have been discussed (15R ). Heroin overdose is a leading cause of morbidity and mortality among active heroin injectors. Education, family support groups, and motivational interviews after overdose have been proposed as complementary strategies to reduce morbidity and mortality. The author concluded that

108 methadone maintenance is the most effective method of reducing mortality from overdose, and that home treatment with naloxone by a significant other is a possible future strategy. However, the use of naloxone is regarded as controversial by some health professionals.

Fentanyl

(SED-14, 213; SEDA-25, 113; SEDA-26, 92; SEDA-27, 90) Observational studies In a small open study, in which patients using transdermal fentanyl were switched to an intravenous infusion of fentanyl for acute cancer-related pain relief, there was no excessive sedation or opioid adverse effects (16c ).

Placebo-controlled studies In a double-blind, randomized, placebo-controlled study 29 boys undergoing day-case penile surgery were allocated to either intravenous fentanyl 1 microgram/kg intraoperatively or intravenous saline (17c ). Pain and opioid-related adverse effects were monitored for the first 24 hours after surgery. The authors concluded that intraoperative intravenous fentanyl is associated with an increased incidence of nausea and vomiting, without any significant contribution to postoperative pain relief. Respiratory Intravenous fentanyl is associated with coughing in 28–45% of patients. Coughing due to fentanyl may not always be benign and brief; it can sometimes be explosive, requiring immediate intervention on the operating table. Coughing occurs because fentanyl constricts the tracheal smooth muscle, stimulating the irritant receptors. Other possible factors are release of histamine, leukotrienes, interleukins, and other inflammatory mediators from mast cells. In 200 patients scheduled for elective laparoscopic cholecystectomy under general anesthesia and given intravenous fentanyl 2 micrograms/kg, pretreatment with salbutamol, beclomethasone, or sodium cromoglicate by aerosol before the fentanyl bolus reduced the incidence of cough (18c ). Drug withdrawal In a prospective interventional cohort study in 19 neonates who received fentanyl by continuous infusion for a minimum

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of 24 hours, those who received fentanyl in a total dose of at least 415 micrograms/kg or as an infusion for more than 8 days were at risk of developing opioid withdrawal symptoms on stopping fentanyl (19c ). Having identified patients who are at risk of developing withdrawal symptoms, one needs to be able to monitor withdrawal signs and symptoms adequately and objectively, reduce the dose of fentanyl gradually, or even use methadone. Drug administration route Transdermal The rate of absorption of fentanyl by transdermal administration can be increased by increasing the local temperature. • A 42-year-old woman with cervical carcinoma had a fentanyl patch delivering 100 micrograms/hour applied to her chest and at the same time started using a heated pad on her abdomen (20A ). Two hours later she developed pinpoint pupils and shallow respiration, which was reversed with intravenous naloxone hydrochloride 0.4 mg. The heating pad had covered the fentanyl patch and had presumably increased the rate of absorption of the drug. • A 57-year-old woman developed opioid toxicity after thick blankets were used during surgery because her nasopharyngeal temperature was low, inadvertently covering her fentanyl patch (20A ). Naloxone was used to reverse opioid toxicity.

These two cases highlight the need to inform patients that fever and even participation in outdoor activities in hot climates and in hot tubs/saunas can cause an increase in fentanyl absorption, with a risk of opioid toxicity.

Methadone

(SED-14, 214; SEDA-25, 115; SEDA-26, 94; SEDA-27, 91)

Cardiovascular QT interval prolongation and torsade de pointes can occur after intravenous or high-dose methadone. There is a linear relation between QT interval prolongation and the dose of methadone (21C ). It is prudent to avoid concomitant use of other drugs that prolong the QT interval. This is of significance in individuals infected with HIV, who might have not only viral cardiomyopathies or autonomic neuropathies but also be taking macrolides, quinolones, clindamycin, trimethoprim, fluconazole, pentamidine, and other drugs that are closely associated with torsade de pointes and other cardiac dysrhythmias (22A ).

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Several case have been described in which methadone in a dose of more than 300 mg/day was associated with an increased risk of cardiac dysrhythmias, especially if prescribed with other drugs that inhibit CYP3A4 (23A ). Death There have been two retrospective studies of drug-related deaths, investigating the role of methadone. In one, there were 605 deaths from 1989 to 2000 registered in Cologne (24C ) and in the other 398 deaths from 1997 to 2001 registered in Bonn (25C ). The most common agents in drug-related deaths were combinations of substances, especially opioids (morphine or heroin), benzodiazepines, antidepressants, and alcohol. Methadone played a minor role, and most methadone-related deaths occurred in individuals who were not participating in a methadone maintenance programme. The rate of methadone-related deaths has risen, but not significantly when other variables are taken into account. Similar conclusions were reached in another extensive retrospective study of all drug-related deaths between 1992 and 2002 in Minnesota (26C ). Drug dosage regimens As methadone is being increasingly used for analgesia in chronic pain, investigators are looking at how to make conversion from other opioids to methadone pain-free and effective in a short period of time without producing toxicity. In a prospective study 10 consecutive patients with cancer taking oral morphine successfully converted to methadone using a fixed ratio of 5 : 1. There were significant improvements in pain intensity and adverse effects over an average of 1–2 days, because methadone rapidly achieved a stable concentration in the first 2 days of conversion as morphine was rapidly withdrawn (27c ). In a similar study methadone in 1/12 of the total daily dose of morphine, up to a maximum of 30 mg/day, achieved good pain control 7 days after conversion (28c ). Drug interactions In 20 HIV-infected patients starting therapy with ropinavir + ritonavir while taking part in a methadone maintenance programme, there were no opioid withdrawal symptoms over 28 days (29c ). The interaction of methadone with fluvoxamine, an SSRI that inhibits CYP3A4 has been used to achieve higher and more effective serum methadone concentrations in three

patients (30c ). Fluvoxamine should not be withdrawn suddenly in such cases, since it can precipitate an acute opioid withdrawal syndrome. Equally, the introduction of fluvoxamine should be slow and gradual, giving time to monitor for potential oversedation or intoxication with methadone. Methadone is a substrate of both CYP3A4 and P glycoprotein. Caution should be taken when patients on methadone maintenance treatment take St John’s wort, which induces CYP3A4 and P glycoprotein. Four patients taking both methadone and St John’s wort had a median reduction in methadone concentration of 47%; two also had opioid withdrawal symptoms (31c ).

Hydromorphone

(SEDA-24, 106;

SEDA-26, 94) Observational studies The efficacy of hydromorphone in 43 studies in acute and chronic pain published between 1966 and 2000 has been reviewed (32M ). There was little difference between hydromorphone and other opioids in terms of analgesic efficacy, adverse effects, and patient preference. However, most of the studies were of poor quality, low statistical power, and non-standardized, making it difficult to determine real differences between interventions.

Morphine

(SED-14, 215; SEDA-25, 115; SEDA-26, 97; SEDA-27, 92)

Observational studies In a prospective nonrandomized comparison of epidural analgesia and intravenous morphine after major surgery in 2696 patients, epidural morphine was used in 1670 patients and intravenous morphine in 1026 patients (33C ). The epidural group had overall less pain both at rest and during mobilization, but also more dosage adjustment and pruritus. Those given intravenous morphine had significantly more opioid adverse effects, such as respiratory depression. Sedation and hallucinations or confusion were also significantly more common after intravenous morphine.

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Comparative studies There has been a prospective, randomized, double-blind comparison of the adverse effects of morphine (n = 250) and piritramide 1.5 mg (n = 250) with a lockout period of 10 minutes both by patient-controlled analgesia and in patients undergoing abdominal orthopedic or obstetric surgery (34C ). On postoperative day 1 there were no significant differences in the overall incidences of vomiting (15% with morphine and 19% with piritramide) or nausea (27% versus 30%). Even though the pain scores and adverse effects profiles did not differ between the groups or between day 1 and day 4, the patients still thought that morphine was the better analgesic. The authors suggested that consumption of specific opioids during patient-controlled analgesia may not only depend on analgesic potency and requirements for analgesia but also on euphoric effects or adverse effects.

later produced the same symptoms. The episodes of allodynia resolved spontaneously after about 24 hours.

Placebo-controlled studies The effectiveness of epidural local anesthetics, morphine, or placebo in postoperative pain relief after lumbar disc and other spinal operations has been reviewed (35M ). The authors suggested that epidural morphine (3–5 mg) rather than intrathecal morphine at the end of surgery significantly reduces postoperative pain with no major adverse effects and should be a routine procedure. Epidural administration of glucocorticoids does not increase effectiveness when combined with epidural morphine. Nervous system Allodynia in the dermatomes close to the level of injury has been reported in a patient with spinal cord injury who was given a single relatively small dose of intrathecal morphine (36A ). • A 66-year-old man with a T8 complete paraplegia after an accident 12 years before was admitted for a trial of intrathecal morphine and clonidine in an attempt to relieve his neuropathic pain, after repeated splanchnic and sympathetic blocks, transcutaneous electrical nerve stimulation, fentanyl, and other medications had produced only transient effects. He received morphine 0.5 mg, which did not relieve his pain but 2 hours later caused mechanical allodynia in a band over dermatomes T6 and T7. The allodynia was a painful sensation after light touch with clothes or sheets. He also had drowsiness, nystagmus, and severe pruritus 30 minutes after the injection. Naloxone 50 micrograms/hour relieved the pruritus but not the allodynia. Another dose of morphine 2 days

A.H. Ghodse and A.M. Baldacchino

Susceptibility factors Genetic UGT2B7 (UDP-glucuronosyltransferase 2B7) is the predominant enzyme responsible for the glucuronidation of morphine to M6G (morphine-6-glucuronide) and M3G (morphine-3-glucuronide). The analgesic properties of morphine are enhanced by M6G and reduced by M3G. Mutations in the UGT2B7 gene may therefore have pharmacological, toxicological, and physiological significance. A genetic polymorphism of UGT2B7 has been reported in two patients with cancer pain who had different responses to morphine (37A ). • A 78-year-old man who was extremely sensitive to the adverse effects of morphine had a rare ATTGAT2C sequence and reference alleles at almost all SNPs. • A 46-year-old woman who needed more than 2000 mg of morphine a day and still complained of mild to moderate pain had a predominant GCCAGC1G sequence.

Both genotype–phenotype studies in large groups of patients and controls and in vitro studies are needed to establish and interpret results that can have clinical relevance to varying responses to morphine. Drug interactions Two deaths involving the concurrent abuse of metamfetamine and morphine have been reported (38A ). The blood concentrations of both drugs were sublethal, and synergism between morphine and metamfetamine, especially in causing hyperthermia, seemed to be the mechanism.

Oxycodone

(SED-14, 216; SEDA-24, 107; SEDA-25, 116; SEDA-26, 99; SEDA-27, 93) Death The involvement of oxycodone in drugrelated deaths has been reviewed in 1243 confirmed drug-related deaths in 23 states in the USA during August 1999 to January 2002 (39M ). Each case was evaluated to determine the role of oxycodone and especially the controlled-release formulation. Only 30 (3.3%)

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cases involved oxycodone as the single reported pharmacological agent, and of these 12 were linked to the controlled-release formulation (OxyContin® ). Of the other cases 96–97% were multiple drug deaths in which there was at least one other contributory drug in addition to oxycodone. The drugs that were most commonly combined with oxycodone were a benzodiazepine (40A ), alcohol, cocaine, other opioids (41c ), cannabinoids, or antidepressants. This highlights the increased risk of oxycodone abuse and its contribution to either drug-induced or drug-related deaths. Drug formulations Controlled-release oxycodone has been reviewed comprehensively in relation to its pharmacokinetics and pharmacodynamics, impact on health economics, addiction potential, and use in palliative care (42R ). In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 6-week study in 159 patients with moderate to severe pain due to diabetic neuropathy, controlledrelease oxycodone 10 mg was effective at a relatively low average daily dose (52 mg), which was 33% of the maximum dose allowed (43C ). The adverse effects were predictably opioid-related, but there were no significant differences between placebo and oxycodone in the number of patients who withdrew because of adverse events. In a randomized, double-blind, crossover comparison in 36 patients the mean dose of controlled-release oxycodone was 40 mg/day (44C ). Oxycodone was a significantly better analgesic than benzatropine, which was used as a comparator. The incidence of adverse effects was the same with the two treatments (n = 131 with oxycodone and n = 107 with benzatropine). Four patients had serious adverse effects, three with benzatropine. Only one patient who took oxycodone had a serious adverse reaction, severe opioid withdrawal symptoms during the washout period. These results contrast with those of similarly constructed studies 1 year before in patients with chronic cancer and non-cancer pain (SEDA-27, 93). Similarly, in a randomized, double-blind, placebo-controlled, parallelgroup comparison of oxycodone 10 mg plus paracetamol 325 mg and controlled-release oxycodone 20 mg in post-surgical acute pain,

111

the combination therapy was significantly better in four out of the five outcome measures of pain intensity and pain relief (45C ).

Pethidine (meperidine) (SED-14, 217; SEDA-25, 117; SEDA-26, 99; SEDA-27, 94) Nervous system Pethidine has been reported to cause an epileptic seizure (46A ). • A 55-year-old woman developed severe abdominal pain, vomiting, diarrhea, and dysuria. A provisional diagnosis of pyelonephritis was made, and she was given intravenous pethidine in gradually increasing doses until day 4 (cumulative dose 2125 mg), when she had a seizure lasting 1 minute. The pethidine was withdrawn and replaced with buprenorphine, with no further complications.

Drug interactions Serotonin syndrome has been reported in a patient taking fluoxetine and pethidine (47A ). • A 43-year-old man scheduled for endoscopic retrograde cholangiopancreatography to evaluate chronic recurrent episodes of pancreatitis was given pethidine 50 mg intravenously plus midazolam 2 mg. He immediately became agitated and restless, with widely dilated pupils, hyper-reflexia, increased heart rate and blood pressure, and diarrhea. He recovered after 20 minutes without treatment. He subsequently confirmed that he had been taking unspecified doses of fluoxetine irregularly but frequently.

The authors suggested that this presentation was due to serotonin syndrome, but offered no mechanistic explanation.

Remifentanil (SED-14, 217; SEDA-25, 118; SEDA-26, 99; SEDA-27, 94) The literature on remifentanil has been reviewed (48M ). In cardiac anesthesia, remifentanil provides better hemodynamic control intraoperatively and postoperatively than other opioids and is a good anesthetic agent together with propofol for total intravenous cardiac anesthesia. The recommended intraoperative infusion rate is 0.05–0.5 micrograms/kg/minute, changing to 0.05 micrograms/kg/minute to treat postoperative pain with a view to changing short-acting remifentanil to a longer-acting morphine derivative (49M ).

112 Comparative studies In a multicenter doubleblind randomized, dose-comparison study in 149 patients undergoing first-time elective coronary artery bypass grafting, the recommended remifentanil infusion rate was not more than 1 microgram/kg/minute without any adverse effects that necessitated withdrawal (50C ). Placebo-controlled studies The combined used of remifentanil plus propofol or midazolam can reduce the incidence of opioid-induced nausea and vomiting, but can also increase the rate and severity of respiratory depression. In a double-blind, randomized, placebo-controlled study, 40 patients undergoing extracorporeal shock-wave lithotripsy were given prophylactic dolasetron 12.5 mg before remifentanil (0.15 micrograms/kg/minute) (51c ). Dolasetron produced a significant reduction in the incidence of nausea and vomiting and significantly earlier discharge.

Tramadol

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patients in each of the three groups. However, at least 8% of the patients in each group recorded similar adverse events at entry into the study. On the basis of these results and patients’ opinions, once-daily tramadol 150 mg was the preferred treatment. Drug administration route Pethidine 100 mg produced better analgesia and significantly fewer adverse effects than intramuscular tramadol 100 mg in 49 full-term parturients in active labor in a randomized study (55c ). Drug overdose Fatal overdose of tramadol has been reported (56A ). • A 67-year-old man with painful rib fractures was given tramadol 100 mg qds and 8 days later developed acute liver failure as a result of fulminant hepatic necrosis. He had a cardiorespiratory arrest and died soon after admission. It transpired that he had taken 168 tablets of tramadol, each of 50 mg. Post-mortem toxicology confirmed a blood tramadol concentration of 3.7 micrograms/ml, 12 times higher than the usual target range (0.1–0.3 micrograms/ml).

(SED-14, 218; SEDA-25, 119; SEDA-26, 102; SEDA-27, 96) Susceptibility factors Genetic In 300 patients recovering from abdominal surgery recruited into a prospective study, the CYP2D6 poor metabolizer genotype had a negative impact on the response to tramadol analgesia postoperatively (52C ). Drug dosage regimens A double-blind, randomized, controlled study has been performed in 60 patients undergoing knee arthroplasty in order to identify the appropriate initial dose of tramadol PCA to minimize the incidence of opioid-related adverse effects (53c ). The patients received tramadol 1.25, 2.5, 3.75, or 5 mg/kg. The results suggested that a 2.5 mg/kg intraoperative loading dose of tramadol is optimal, since it provided the right balance of effective analgesia and minimal adverse effects. In a double-blind, randomized, crossover trial in 134 patients with moderate osteoarthritic pain tramadol 150 or 200 mg/day and normalrelease tramadol capsules 50 mg 8 hourly had similar therapeutic efficacy, adherence to therapy, and tolerability (54C ). Nausea, constipation, itching, drowsiness, dizziness, and headache were recorded by over 10% of the

PARTIAL OPIOID RECEPTOR AGONISTS Buprenorphine (SED-14, 220; SEDA-25, 120; SEDA-26, 104; SEDA-27, 97) Drug formulations In 151 patients with severe chronic pain of malignant or non-malignant origin in a double-blind, randomized, placebocontrolled study of the efficacy and tolerability of buprenorphine transdermal therapeutic system, three strengths of the formulation were prescribed, 35, 52.5, or 70 micrograms/hour (57C ). Overall, 23% of patients reported adverse events, with no significant differences between the treatment groups. There were local adverse reactions in 10–20% of patients and about 50% of the symptoms lasted under 24 hours. One patient had severe pruritus and a severe allergic rash with mild vesiculation; another reported moderate swelling, severe pruritus, and erythema. Both were receiving buprenorphine 52.5 micrograms/hour. Another patient, receiving 70 micrograms/hour,

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had severe nausea and vomiting with urinary retention. The authors concluded that buprenorphine transdermal therapeutic system is an effective analgesic medication for chronic moderate to severe pain, but there was also a marked placebo effect, which minimized any difference in response rate between buprenorphine and placebo. One should not underestimate the effect of placebo in studies in which patient expectation plays a prominent role, if pain is measured as remembered pain (as in the above study) rather than based on an assessment of current pain. In a similar study from the same research group 79% of patients receiving placebo or buprenorphine transdermal therapeutic system reported at least one adverse event during the study (58C ). Most of these events were mild or moderate and were typical of those that occur at the start of therapy with a strong opioid. A review of other double-blind, placebocontrolled trials has confirmed that most of the adverse effects of buprenorphine transdermal therapeutic system are transient and predictably opioid related. All the trials confirmed analgesic efficacy; patients reported that their analgesia was maintained for a mean duration of 4.7 months and that the patch was user-friendly (59c , 60c ). Sublingual buprenorphine is increasingly being used in the treatment of opioid dependence. In several double-blind, randomized, controlled studies buprenorphine has been compared with methadone (61C ), naltrexone and/or methadone (62c ), naloxone (63C ), or placebo (64C ) in opioid-dependent individuals who are treatment seekers. Most of the results have reiterated the importance of identifying a clear rationale for prescribing sublingual buprenorphine, of adequate psychosocial support, and of adequate dosage (a fixed dose of 12–16 mg of sublingual buprenorphine for 12 months) in order to maximize treatment outcomes in this challenging population. A combined buprenorphine/naloxone formulation was safe, well tolerated, and efficacious, reducing the use of illicit opioids and craving for opioids in dependent individuals (65M ). Low doses of buprenorphine (5–8 mg) did not have any additional benefits over methadone (66M ). Drug overdose The concomitant use of benzodiazepines and intravenous injections of dissolved buprenorphine tablets increases the risk

of serious overdose. In a retrospective study of opioid overdose in Helsinki between 1995 and 2002 there were 11 cases of overdose in which buprenorphine was involved (67c ). Buprenorphine had been used intravenously in seven cases and concomitant benzodiazepines in three, alcohol in four, and heroin in two.

OPIOID RECEPTOR ANTAGONISTS Naloxone

(SED-13, 179; SEDA-26, 104;

SEDA-27, 97) Susceptibility factors Age In a systematic review of nine trials that specifically studied the use of naloxone in treating neonates with respiratory depression due to transplacentally acquired opioids the infants who received naloxone had increased alveolar ventilation compared with control infants, but this was not considered clinically relevant (68M ). Since naloxone can interfere with the effects of endogenous opioids in neuroendocrine programming and subsequent behavior, its therapeutic role is not clear and there has been no large randomized trial that would justify its use in these cases.

Naltrexone

(SED-14, 200; SEDA-25, 121; SEDA-26, 104; SEDA-27, 97) Naltrexone has yet again been used to determine whether it provides an effective pharmacological adjunct to prevention of relapse in alcohol dependence. Naltrexone 50 mg/day has been studied in early problem drinkers (69C ) and in people with severe alcohol dependence (70c ), with or without cognitive behavioral therapy (71C , 72C ). In other studies naltrexone and acamprosate have been compared and combined (73C , 74c , 75C ). All of these studies have confirmed the efficacy of naltrexone in reducing drinking and also the risk of relapse into excessive alcohol consumption and dependence. However, these effects are not maintained after 8–10 weeks, unless psychosocial therapeutic techniques and support are also in place. The

114 combination of naltrexone and acamprosate together with behavioral interventions seems promising without causing unacceptable physical symptoms. More patients taking naltrexone plus acamprosate reported fatigue, reduced libido, and diarrhea compared with placebo. The preliminary data suggested that patients taking the combined medication had no more adverse reactions than the other groups, including the placebo-treated group (71c ). One needs to be cautious in patients with compromised liver function and liver function tests should be checked regularly for any 3- to 5-fold rise in liver enzymes when medication (naltrexone alone or in combination with acamprosate) needs to be withdrawn. Hepatitis status is also important, since one needs to determine if the patient is positive for hepatitis B and/or C due to previous high-risk behavior (for example poly-

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drug intravenous use) since this will further compromise liver function. Drug abuse Inappropriate use of naltrexone with heroin in an opioid-dependent individual has been reported (76A ). • A 39-year-old man took naltrexone 150 mg with an unknown quantity of smoked heroin. He was extremely agitated, disoriented, and sweating, with episodes of profuse projectile vomiting and diarrhea. His pupils were dilated but reactive to light, his heart rate was regular at 180/minute, and his respiration was 40/minute. He was given midazolam 20 mg and droperidol 15 mg but remained acutely confused and became increasingly violent. A lumbar puncture and a CT scan of the brain were normal. He became less agitated over the next 12 hours and took his own discharge.

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75. Johnston BA, O’Malley SS, Ciravlo DA, Roache JD, Chambers Ra, Sarid-Segal O, Couper D. Dose-ranging kinetics and behavioural pharmacology of naltrexone and acomprosate, both alone and combined, in alcohol-dependent subjects. J Clin Psychopharmacol 2003; 23: 281–93.

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76. Boyce SH, Armstrong PAR, Stevenson J. Effect of inappropriate naltrexone use in a heroin misuser. Emerg Med J 2003; 20: 381–2.

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Cardiovascular NSAIDs can cause or aggravate hypertension and can inhibit the effects of antihypertensive drugs (SEDA-27, 102). Postpartum patients may be at especial risk. The Australian Adverse Drug Reaction Advisory Committee recently received six reports of severe hypertension in women after postpartum administration of indometacin, ibuprofen, or diclofenac (1AS ). Four of the women had a history of pre-eclampsia and the other two had no prior history of hypertension. One of the women with pre-eclampsia died of a hypertensive crisis and intracranial hemorrhage. Only two were taking antihypertensive drugs at the time of the adverse event. The committee suggested that the severe hypertension in these cases may have been caused by the underlying condition, but that it is plausible that the administration of an NSAID had made a significant contribution. While waiting for more data on this potential risk, careful monitoring of the blood pressure in women with a history of pre-eclampsia or hypertension who are given an NSAID in post-partum is wise.

Do NSAIDs inhibit the cardioprotective effects of acetylsalicylic acid? Ibuprofen antagonizes the cardioprotective effects of aspirin in patients with cardiovascular disease (SEDA-26, 115; SEDA-27, 111). In one © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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study 7107 patients who were discharged after a first admission for cardiovascular disease, who were taking low-dose aspirin (less than 325 mg/day), and who survived for at least 1 month were studied (2C ). Compared with those who used aspirin alone, patients taking aspirin plus ibuprofen had increased risks of all-cause mortality [hazard ratio 1.93 (95% CI = 1.30, 2.87)] and cardiovascular mortality [1.73 (1.05, 2.84)]. The theoretical basis for this interaction came from experimental data (3C ), which suggest that ibuprofen may limit the cardioprotective effects of aspirin by competitively inhibiting aspirin binding to platelets. If this interaction were demonstrated with all NSAIDs its clinical relevance could be enormous, because NSAIDs are among the most frequently used drug. This issue has been examined in two studies. The first study was a subgroup analysis of the results of a randomized, double-blind, placebo-controlled study of aspirin (325 mg on alternate days) in 22 071 individuals participating in the Physicians Health Study (4C ). During a mean follow-up period of 5 years, there were 378 myocardial infarctions among the study participants, 139 of which occurred in those taking aspirin and 239 in those taking placebo (RR = 0.56; 95% CI = 0.45, 0.70). While intermittent NSAID use was not associated with an increased risk of myocardial infarction in either the aspirin or placebo group, the use of NSAIDs on more than 60 days/year in those taking aspirin was significantly associated with an increased risk of myocardial infarction. Compared with no NSAID use, the relative risks of myocardial infarction among participants randomized to receive aspirin were 1.21 (95% CI = 0.78, 1.87) for NSAID use on 1– 59 days/year and 2.86 (95% CI = 1.25, 6.25)

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for NSAID use on more than 60 days/year. In contrast, among those who took placebo, NSAID use did not significantly alter the risk of myocardial infarction. Thus, this post-hoc subgroup analysis from a large randomized trial showed a more than two-fold increase in the risk of a first myocardial infarction among participants taking aspirin who also take NSAIDs for more than 60 days/year. The second study gave contrasting results (5C ). Compared with aspirin alone the concomitant use of aspirin and ibuprofen did not increase the risk of death in elderly patients after myocardial infarction. The authors conducted a retrospective cohort study of 234 769 Medicare patients aged over 65 years) discharged from hospital after a myocardial infarction between 1994 and 1996, of whom 70 316 were taking aspirin at discharge; 66 739 took aspirin alone, 844 took aspirin + ibuprofen, and 2733 took aspirin + other NSAIDs. A total of 11 546 patients (17.5%) who took aspirin alone, 118 (14%) who took aspirin + ibuprofen, and 432 (16%) who took aspirin + other NSAIDs died within 1 year of discharge. Patients who took aspirin + ibuprofen had a comparable risk of death to those who took aspirin alone (hazard ratio 0.84; 95% CI = 0.7, 1.01) or aspirin + another NSAID (0.96; 0.86, 1.06). Thus, in this study in elderly patients discharged after myocardial infarction aspirin and ibuprofen did not adversely interact. These studies have been criticized for many different reasons: study design poor; population studied not representative of general population; bias in data collection; use of concomitant medications not addressed; only a small number of events measured (6r –9r ); the results must be interpreted with caution. Although an interaction of ibuprofen with aspirin is potentially clinically important, the current evidence is not sufficient to make definitive recommendations for or against the use of concomitant ibuprofen in patients who may need prophylactic aspirin. The place of aspirin in primary and secondary prevention of coronary artery disease is well established (10M ), while the evidence supporting the hypothesis that regular use of NSAIDs may negate the cardioprotective benefit of aspirin is not. While waiting for further research to clarify this issue aspirin avoidance in patients taking long-term NSAIDs, and vice versa, is probably not justified.

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NSAIDs and the risk of intracerebral hemorrhage The use of acetylsalicylic acid has been associated with an increased risk of intracerebral hemorrhage (11C , 12C ), but the effect of nonaspirin NSAIDs on the risk of intracerebral hemorrhage is unclear. This issue is particularly important, as NSAIDs are widely used and therefore even small risks of adverse effects, especially serious ones, may have considerable clinical and public health implications. Furthermore, most NSAIDs are prescribed for people over 65 years, often with other susceptibility factors (for example hypertension) for intracerebral hemorrhage or subarachnoid hemorrhage. Two recent studies have helped to clarify this issue. The first (13C ) is a population-based casecontrol study aimed at estimating the risk of intracerebral hemorrhage, subarachnoid hemorrhage, and ischemic stroke in users of NSAIDs versus non-users. The diagnosis was validated if the patient had clinical evidence of stroke, according to the World Health Organization definition, and appropriate neuroimaging or autopsy. The investigators compared the use of NSAIDs in 659 patients with intracerebral hemorrhage, 208 with subarachnoid hemorrhage, and 40 000 random controls using a nested case-control design. Compared with non-user, NSAID users did not have an increased risk of intracerebral hemorrhage or subarachnoid hemorrhage or a reduced risk of ischemic stroke. The adjusted odds ratio of stroke in current NSAIDs users compared with never users was 1.2 (95% CI = 0.9, 1.6) for intracerebral hemorrhage and 1.2 (0.7, 2.1) for subarachnoid hemorrhage. This study had several strengths: potential cases were identified from a long-standing population-based registry, neurologists who assessed the records were blinded to drug exposure information, drug exposure was assessed through a prescription database and was therefore not susceptible to recall bias, and the analysis was adjusted for many potential confounding medical conditions. The second study was a population-based case-control study of the risk of being hospitalized for intracerebral hemorrhage among users of non-aspirin NSAIDs (14C ). There were 912

120 cases and 9059 sex-matched and age-matched controls. The use of non-aspirin NSAIDs was not associated with a significant increase in the risk of hospital admission for intracerebral hemorrhage. There was no overall association between prescription of NSAIDs in the preceding 30, 60, or 90 days and the risk of intracerebral hemorrhage. The odds ratios ranged from 0.92 (95% CI = 0.70, 1.21) to 1.19 (0.81, 1.58). This absence of association was present in all subgroups analysed, including those with higher baseline risks of intracerebral hemorrhage, such as the elderly and patients with hypertension. The validity of these studies of the association between the use of NSAIDs and intracerebral hemorrhage depends on accurate identification of cases, including methods used to diagnose intracerebral hemorrhage and assessment of exposure to NSAIDs. Despite the potential limitations of case-control studies, the evidence provided by these two studies suggests that non-aspirin NSAIDs are unlikely to be a major contributor to the risk of intracerebral hemorrhage (15r ). Gastrointestinal Consecutive new patients with colitis (n = 105) were questioned about their recent use of NSAIDs and salicylates and compared with two groups of 105 age- and sex-matched controls taken from hospital inpatients and community cases attending the Accident and Emergency Department (16c ). Of the patients with colitis, 78 (74%) had taken NSAIDs or salicylates before or during the development of their disease. By comparison, significantly fewer of the community controls (20%; OR = 9.1; CI = 4.5, 22) and hospital inpatients (30%; OR = 6.2; CI = 3.2, 14) were using NSAIDs or salicylates. The authors concluded that in new patients with colitis there is a significantly high frequency of antecedent exposure to NSAIDs or salicylates, supporting the concept that these agents may be important in the pathogenesis of colitis.

Dyspepsia and NSAIDs Dyspepsia is common in patients taking NSAIDs and is the most common reason for discontinuation of therapy or for beginning symptomatic

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“gastroprotective” therapy. NSAIDs differ in their capability to cause dyspepsia, but despite the high prevalence, understanding of the relation between NSAID use and dyspepsia is scanty. Meta-analysis of randomized studies The risk of upper gastrointestinal damage by NSAIDs has been estimated in five meta-analyses (17M –21M ), but these reviews mainly focused on estimating the risk of severe ulcer complications (hemorrhage, perforation) rather than the dyspeptic syndrome caused by NSAIDs. In only one of them (17M ) was dyspepsia addressed, and it had two important limitations: first, the definition of dyspepsia was not specified and secondly, information was not provided about the effect of different NSAIDs or dosages, which can be important factors associated with dyspepsia. Interesting and more accurate information on this topic has come from a recent metaanalysis (22M ). The authors identified studies in which defined upper gastrointestinal outcomes were reported in patients who had used oral NSAIDs for more than 4 days. Unpublished data from the Food and Drug Administration (FDA) were also obtained from new drug application reviews for the most common NSAIDs used in the USA. The authors identified 55 randomized comparisons of NSAIDs with placebo; 86 randomized comparisons of NSAIDs versus NSAIDs; 23 large exposure trials; and 37 previously unpublished placebo-controlled trials (data from the FDA). Of the 55 NSAID versus placebo trials and the 37 FDA reviews, 48 studies (37 published and 11 from the FDA) reported data on dyspepsia, encompassing nearly 12 000 patients. The overall percentage of patients with dyspepsia in the NSAID treated group was 4.8% (95% CI = 3.8, 5.8) and the percentage in the placebo group was 2.3% (95 CI = 1.6, 3.1), with a significant risk ratio of 1.4 (95% CI = 1.1, 1.8). Meta-regression identified an increased risk of dyspepsia among users of specific NSAIDs (indometacin, meclofenamate, and piroxicam) (OR = 2.8), and for high dosages of other NSAIDs (OR = 3.1), but not for other NSAIDs in low dosage (OR = 1.1). The risk of dyspepsia varied according to the type of patient. The overall percentage of

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patients with NSAID-associated dyspepsia increased from 4.8% (12 000 patients in 48 studies) in the NSAID versus placebo studies to 7.1% (11 299 patients in 66 studies) in the NSAID versus NSAID comparisons, and to 11% (80 000 patients in 8 studies) in the large exposure studies. The percentage of patients who reported dyspepsia in the NSAID-treated arm of the NSAID versus placebo randomized trials may be lower in the general population because these studies tend to enrol healthier patients, who are least likely to have complications. The duration of NSAID use was not significantly associated with an increased percentage of patients reporting dyspepsia or with an increased risk of NSAID-associated dyspepsia, but only two studies lasted longer than 12 weeks. Thus, the risk of dyspepsia in patients taking long-term NSAIDs may be different from that reported in this meta-analysis. COX2 selective NSAIDs were not considered. In conclusion this meta-analysis suggests that the combination of a high dosage of any NSAID along with any dosage of indometacin, meclofenamate, or piroxicam increases the risk of dyspepsia by about three-fold. Other NSAIDs at lower dosages were not associated with an increased risk of dyspepsia. Are modified-release formulations of NSAIDs any better? Despite claims of better gastroduodenal tolerability and improved adherence, evidence that modified-release NSAIDs should be preferred to standard formulations is at best scanty (SEDA-9, 83). Standard and modified-release formulations of NSAIDs have been compared in a study from a practice database of 36 908 patients over 4 months who had an initial prescription for a standard NSAID formulation, most commonly ibuprofen (58%), and 4195 patients who received a prescription for a modified-release NSAID, most commonly diclofenac (73%) (23C ). The measures that were used to document better tolerability were: prescriptions of gastroprotective drugs, the need for gastrointestinal investigations, switching from the modifiedrelease formulation to a standard formulation. Patients who took modified-release formulations were more likely to receive concomitant gastroprotective agents, were more likely to need gastrointestinal investigations, and more commonly switched from modified-release to

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standard formulations than vice versa. Thus, it appears that modified-release NSAID formulations are no better tolerated than standard formulations. However, these conclusions must be interpreted with caution, as the possibility of confounding by indication could not be excluded.

Risk of necrotizing fasciitis due to Group A Streptococcus pyogenes in patients taking NSAIDs There have been sporadic case reports of a possible association between NSAIDs and necrotizing fasciitis due to Group A Streptococcus pyogenes (SEDA-12, 79; SEDA-22, 112). It has been suggested that NSAIDs may increase the risk of the infection, impede its timely recognition and management, and/or accelerate the course of infection, and these questions have been examined in a systematic review of case reports, retrospective studies, and prospective studies (24M ). To be included in the analysis documentation of invasive streptococcal infection and necrotizing fasciitis was required. To assess the relation between NSAID use and the development of necrotizing fasciitis, cases were analysed for the presence of risk factors for necrotizing fasciitis (co-morbidity), a putative portal of entry for Streptococcus pyogenes, the timing of NSAID use, the concomitant use of immunosuppressive agents, and the development of complications. Of eight patients with necrotizing fasciitis identified in the published case reports, only one had used an NSAID on a long-term basis (an elderly man with alcoholism and osteoarthritis), three had used 3 NSAIDs before the onset of symptoms suggestive of necrotizing fasciitis, and four had no identifiable susceptibility factors. There were 12 retrospective studies of necrotizing fasciitis including data on the use of NSAIDs. Of these, 10 were case series, often including duplicate publications, and two were case-control studies. There were detailed data on 31 patients. Of these 15 had no identifiable susceptibility factor, and in 22 NSAIDs had been started after the onset of symptoms. In the first case-control study of NSAID use in childhood Varicella infection there were only

122 three cases of necrotizing fasciitis and there was no significant association between NSAIDs and fasciitis. In the second case-control study of 16 children with necrotizing fasciitis, always in the setting of primary Varicella infection, the cases were more likely than controls to have taken ibuprofen before hospitalization, suggesting an association between the use of ibuprofen and necrotizing fasciitis. There were five prospective studies of the association between NSAIDs and necrotizing fasciitis, and three were conducted by the same group in Canada. These studies included a larger number of patients who had been exposed to NSAIDs, and there was no association between their use and necrotizing fasciitis. Thus, establishing an adverse effect of NSAIDs on the course of necrotizing fasciitis associated with Streptococcus pyogenes is difficult on the basis of the available data. However, some conclusions can be reached. First, published data show no evidence of necrotizing fasciitis in young healthy persons taking longterm NSAIDs and no evidence that NSAIDs adversely affect the severity of necrotizing fasciitis once it is established. Secondly, it is likely that some sign and symptoms (swelling, erythema, fever, and pain), which characterize the initial presentation of necrotizing fasciitis, may be attenuated by NSAIDs, thus delaying diagnosis and treatment. Thirdly, it is possible that NSAIDs could reduce host immunity by many different mechanisms (25M ); however, the evidence in humans that they adversely affect the outcome of infection is still lacking.

NSAIDs and the risk of acute renal insufficiency with ACE inhibitors Whenever renal blood flow is compromised the kidneys respond by releasing prostaglandins and angiotensin II. Angiotensin II has a vasoconstrictor effect on the renal efferent arterioles and prostaglandins have a vasodilator effect on the afferent arterioles; thus, both preserve glomerular filtration rate. Under conditions of renal hypoperfusion or renal impairment, the administration of a combination of NSAIDs with ACE inhibitors will interfere with these physiological compensatory mechanisms, and

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so cause acute impairment of renal function through a fall in glomerular filtration by combined renal blood flow changes: NSAIDs inhibit dilatation by renal prostaglandins and the vasoconstrictor effect on the efferent arterioles is inhibited by ACE inhibitors. It is not surprising, therefore, that various combinations of ACE inhibitors, diuretics, NSAIDs (including COX2 selective inhibitors) and angiotensin receptor antagonists have been implicated in a significant number of reports of drug-induced renal insufficiency. More specifically, the combined use of ACE inhibitors, diuretics, and NSAIDs has been implicated most often (26A ) in single cases or small series of cases of nephrotoxicity (27A –30A ), in spontaneous reports to pharmacovigilance agencies, or in epidemiological studies. In 2002, 28 of the 129 reports to the Australian Drug Reaction Advisory Committee (ADRAC) of acute renal insufficiency implicated one of the above-mentioned combinations (31A ). Most of the events reported to ADRAC related to elderly patients and appeared to be precipitated by mild stress (for example diarrhea, dehydration) in a patient taking the triple combination or by the addition of a third drug, usually an NSAID, to the stable use of the other two. If promptly recognized and the offending drug is withdrawn, the renal dysfunction can be reversible, but the fatality rate for ADRAC cases of renal insufficiency with the “triple whammy” was as high as 10%. More recently, a case-control study has shown an increased risk of hospitalization for renal insufficiency in patients taking ACE inhibitors who started using NSAIDs (32C ). The study included 144 users of ACE inhibitors aged over 40 years, who were admitted to hospital with renal insufficiency during treatment and 1189 controls without any hospital admission for renal problems during ACE inhibitor therapy. Of the 144 cases, 22% had taken an NSAID in the 90 days before hospital admission (adjusted OR = 2.2; 95% CI = 1.1, 4.5). The increased risk was most pronounced in patients aged over 70 years and in those who had received a larger number of prescriptions for an ACE inhibitor. Convincing evidence is now available that there is an increased risk of acute renal insufficiency in patients taking ACE-inhibitors with or without a diuretic who start using NSAIDs (including COX2 selective agents). The risk of this

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interaction seems to be underestimated and the syndrome under-recognized. NSAIDs should be avoided in these patients, especially if they are elderly and have predisposing factors to renal insufficiency. Tumorigenicity NSAIDs and aspirin are associated with a reduced risk of colon cancer. In rheumatoid arthritis the risk of colon cancer is reduced, but the risk of non-Hodgkin’s lymphoma is increased. The association between the use of NSAIDs and aspirin, a history of arthritis, and the risk of non-Hodgkin’s lymphoma has been evaluated in a prospective cohort of 27 290 postmenopausal women (33c ). During 7 years of follow-up, 131 cases of non-Hodgkin’s lymphoma were identified. Compared with women who did not use either aspirin or non-aspirin NSAIDs, there was an increased risk of non-Hodgkin’s lymphoma in women who used aspirin exclusively (RR = 1.71; 95% CI = 0.94, 3.13), non-aspirin NSAIDs exclusively (RR = 2.39; 95% CI = 1.18, 4.83), or both types of drugs (RR = 1.97; 95% CI = 1.06, 3.68). A diagnosis of rheumatoid arthritis (RR = 1.75; 95% CI = 1.09, 2.79), but not osteoarthritis (RR = 1.06; 95% CI = 0.67, 1.68), was associated with an increased risk of non-Hodgkin’s lymphoma, but the positive association between the use of aspirin and other NSAIDs and non-Hodgkin’s lymphoma was independent of a history of rheumatoid arthritis.

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(reductions of 6 and 4 mmHg in systolic and diastolic blood pressures respectively). As aspirin is given once a day for its cardioprotective effect, giving it in the evening could be of greater benefit if it also results in a reduction in blood pressure.

INDIVIDUAL DRUGS AND CLASSES

Respiratory Two studies have examined possible biochemical pathways in aspirin-induced asthma. In a study of the generation of 15hydroxyeicosatetraenoic acid (15-HETE) and other eicosanoids by peripheral blood leukocytes from aspirin-sensitive and aspirin-tolerant asthmatics incubation with aspirin 2, 20, or 200 µmol/l resulted in a dose-dependent increase in 15-HETE generation (mean change +85%, +189%, and +284% at each aspirin concentration respectively) only in aspirinsensitive patients (35E ). In a study of the cyclo-oxygenase pathways in airway fibroblasts from patients with aspirin-tolerant asthma (n = 9), and patients with aspirin-intolerant asthma (n = 7), patients with asthma had a low capacity for PGE2 production after stimulation (36E ). In non-asthmatic patients mean PGE2 production was 32 ng/ml (35 times basal production), in the patients with aspirin-tolerant asthma it was 16 ng/ml (16 times basal), and in the patients with aspirin-intolerant asthma it was only 5.3 ng/ml (4 times basal). These studies show biochemical differences in the effects of aspirin in patents with aspirin-induced asthma. That this is mediated by inhibition of cyclo-oxygenase type 1 is suggested by a study in 33 subjects with a typical history of aspirin-induced asthma, who tolerated the cyclo-oxygenase-2 selective celecoxib; there were no changes in lung function or in urinary excretion of leukotriene E4 (37c ).

Acetylsalicylic acid (aspirin) and related compounds (SED-14, 233;

Sensory systems Aspirin has been reported to cause damage to the semicircular canals.

SEDA-25, 132; SEA-26, 113; SEDA-27, 109)

• A 61-year-old man with a monoclonal gammopathy developed severe persistent bilateral vestibular dysfunction after taking a high dose of aspirin (5–6 g/day for 3 days) (38A ). His symptoms (unsteadiness, a broad-based gait, blurred vision, and apparent visual motion when he moved his head and when he walked) persisted for 9 months. Investigations showed a bilateral dynamic deficit of his horizontal semicircular canal.

Cardiovascular The effects of aspirin on blood pressure have been investigated in 100 untreated patients with mild hypertension who took aspirin on awakening or before bedtime (34c ). There was no change in blood pressure after dietary recommendations alone or when aspirin was given on awakening. However, there was a highly significant reduction in blood pressure in those who took aspirin before bedtime

Drug overdose Aspirin overdose in children can be particularly serious.

124 • A 5-year-old girl died after taking an aspirin overdose. Autopsy showed a pattern of necrosis resembling acute toxic myocarditis (39A ).

Drug interactions The combination of aspirin with clopidogrel can increase the risk of bleeding (40A ). A 76-year-old man with a history of myocardial infarction and unstable angina developed spontaneous hemarthrosis in his knee 2 weeks after starting to take clopidogrel 75 mg/day and aspirin 100 mg/day. He suddenly developed pain in the right knee while resting in bed. There was massive swelling, tenderness, and an intra-articular effusion; an X-ray showed osteoarthritis. Hemorrhagic fluid was aspirated. His coagulation status was normal. Treatment was withdrawn and recovery was uneventful.

Interaction of aspirin with ACE inhibitors Many large, prospective, randomized studies have shown that aspirin and ACE inhibitors reduce the risk of death and major adverse cardiovascular events in patients who have left ventricular dysfunction with or without congestive heart failure. Thus, both drugs are often taken concomitantly. Shortly after the first demonstration of the favorable effects of ACE inhibitors (41C ) a controversy arose about whether there is a risk of a negative interaction between ACE inhibitors and COX inhibitors, in particular aspirin. It is important to understand the theoretic basis for this potential interaction. ACE not only converts angiotensin I to angiotensin II, but it is also responsible for the degradations of kinins; thus, ACE inhibitors can increase bradykinin concentrations. Bradykinin, a potent vasodilator, activates endothelial β2 -kinin receptors, which promote the formation of vasodilatory prostaglandins through the action of phospholipase A2 and cyclo-oxygenase (COX). ACE inhibitors reduce arterial blood pressure by reducing angiotensin II production and increasing the vasodilators bradykinin, PGI2 , and PGE3 . Some investigators have suggested that aspirin (and other NSAIDs) blunt the blood pressure lowering effects of ACE inhibitors

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by inhibiting the production of vasodilatory prostaglandins. Others have suggested that aspirin causes reduced synthesis of renal PGE2 , which might augment unwanted ACE inhibitorinduced impairment of renal function, resulting in increased retention of sodium and water. Consequently, it has been postulated that the beneficial effects of ACE inhibitors might be reduced in patients taking concomitant aspirin. All of the studies of the clinical relevance of this possible interaction were post-hoc analyses or retrospective cohort studies of large trials of ACE inhibitors, and these studies have given different results. Some of them have shown possible interactions (41C , 42C ), while others have given conflicting results (43C , 44C ) or have not supported the hypothesis that aspirin has a negative effect on survival in patients taking ACE inhibitors (45C –47C , 48M ). More recently a systematic review and two retrospective studies have provided more information on this topic. The systematic review assessed the effects of ACE inhibitors in patients with or without aspirin use at baseline (49M ). Individual patient data were collected on 22 060 patients from six long-term, randomized, placebo-controlled studies of ACE inhibitors (50C –55C ) each of which included more than 1000 patients. The results from all of the trials, except SOLVD, did not suggest any significant differences between the proportional reductions in risk with ACE inhibitors in the presence or absence of aspirin for the major clinical outcomes (death; myocardial infarction and reinfarction; stroke; hospital admission for congestive heart failure; revascularization; and a combination of major vascular events) or in the risk of any of its individual components, except myocardial infarction. Overall ACE inhibitors significantly reduced the risk of the major clinical outcomes by 22% with clear reductions in risk among those taking aspirin at baseline (OR 0.80; 99% CI = 0.73, 0.88) and those who were not (OR 0.71; 99% CI = 0.62, 0.81). Considering the totality of evidence on all major vascular outcomes in these studies, there is only weak evidence of any reduction in the benefit of ACE inhibitor therapy when added to aspirin. On the other hand, there is strong evidence of clinically important benefits with respect to these major clinical outcomes with ACE inhibitors, irrespective of whether aspirin is used concomitantly.

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The authors of this meta-analysis concluded that at least some of the differences in the effects of ACE inhibitors on outcomes in SOLVD (23C ) among patients taking aspirin, compared with those who were not, might have suggested differences in the effects of ACE inhibitors in different types of patients rather than an interaction between ACE inhibitor and aspirin. Evidence that aspirin does not interact with ACE inhibitors has come from two retrospective studies. The first was a retrospective analysis of 755 stable patients with left ventricular systolic dysfunction and congestive heart failure, 92% of whom were taking ACE inhibitors (56C ). Compared with previous retrospective trials this study had some specific favorable features. It was a single-center study with the same kind of management used for all patients (including diagnostic procedures), all the patients had congestive heart failure related to left ventricular systolic dysfunction, and treatment (including aspirin and its dosage) was precisely recorded at entry. The mean dose of aspirin at entry was 183 mg/day and 74% of the patients took under 200 mg/day. Using a Cox regression model there were no interactions among aspirin, ACE inhibitors, and survival in the overall population or in subgroups of patient with ischemic or non-ischemic cardiomyopathies. Therefore, small doses of aspirin did not affect survival in patients with stable congestive heart failure taking ACE inhibitors. The importance of the dose of aspirin was confirmed in the second study, a retrospective analysis of 344 patients taking ACE inhibitors admitted to hospital for congestive heart failure, in whom information was available about aspirin therapy during a follow-up period of 37 months (57C ). Cox proportional hazards regression analysis showed that the combination of high dose aspirin (325 mg/day and over) with an ACE inhibitor was independently associated with the risk of death, but that the combination with low-dose aspirin (under 160 mg/day) was not. The results of these two studies must be interpreted with caution. Not only do they have the limitations common to cohort studies, including their retrospective nature and lack of randomization, but they were also small and biased by potential confounders related to patient characteristics.

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However, taken together, the evidence for a significant interaction between low-dose aspirin and ACE inhibitors in patient with congestive heart failure is probably negligible and all patients should receive low-dose aspirin together with full-dose ACE inhibition if both are needed.

ANILINE DERIVATIVES (SED-14, 240; SEDA-25, 132; SEDA-27, 110)

Paracetamol and combinations Susceptibility factors In patients who develop liver damage after moderate or even recommended doses of paracetamol, recent fasting or severe nutritional impairment have been described as possible susceptibility factors for hepatotoxicity (58A ).

PYRAZOLONE DERIVATIVES (SED-14, 260) Despite the availability of many analgesics that are at least as effective and more safe, some irrational combinations of old drugs are still available in some countries and can be responsible for severe adverse reactions, for example hepatitis (59A ), erythema multiforme (60A ), and acute renal insufficiency (61A ).

Propyphenazone combination (Saridon) Liver Hepatitis has been attributed to Saridon, which contains propyphenazone, phenacetin, and apronalide. • A 30-year-old women developed hepatitis with hepatic granulomata after taking long-term Saridon for headaches (59A ). The drug was withdrawn and within 10 weeks her liver enzymes had returned to normal.

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Phenazone

Dexketoprofen

Skin Erythema multiforme has been rarely reported with phenazone. In a 70-year-old man erythema multiforme occurred in association with a reticular exanthema after the use of phenazone in combination with epirizole (60A ).

Skin Dexketoprofen has been reported to cause photosensitivity. • A 27-year-old woman developed contact photosensitivity after applying topical dexketoprofen trometamol for joint pains (64A ). Photopatch testing for components of the gel was positive for ketoprofen trometamol only.

Dipyrone Diclofenac Pregnancy Adverse effects of dipyrone have been described in pregnancy. • A 21-year-old woman developed acute renal insufficiency during her 30th week of pregnancy (61A ). She had been taking dipyrone 1.5–3 g/day for 10 days for back pain. Laboratory investigations showed renal insufficiency, generalized edema and a skin rash. Ultrasound showed oligohydramios. Dipyrone was withdrawn and her rash disappeared, amniotic fluid production rose, and her laboratory values normalized. Delivery was uneventful.

ARYLALKANOIC ACID DERIVATIVES (SED-14, 268; SEDA-25, 133; SEDA-26, 115; SEDA-27, 115)

Aceclofenac Skin Stevens–Johnson syndrome has been attributed to aceclofenac (62A ). • A 75-year-old woman who took aceclofenac for 15 days for arthritis developed erythema of the face followed by multiple target lesions with central bullae on the neck, chest, back, and palmoplantar regions. The lesions became confluent and also involved mucous membranes. She was treated with glucocorticoids and within 4 weeks the lesions had cleared completely.

Respiratory Eosinophilic pneumonia has been attributed to oral diclofenac (SEDA-18, 103), but according the authors of a recent report it has never previously been described with long-term topical use (65A ). • A 62-year-old woman developed a chronic cough and bilateral infiltrates on the chest X-ray. She had been taking diclofenac emulgel for 10 years for osteoarthritis. Bronchoscopy showed eosinophilic alveolitis. After ruling out other possible causes, eosinophilic pneumonia was diagnosed. Diclofenac was withdrawn and oral glucocorticoids started. Within 7 days the bilateral pulmonary infiltrates on CT scan resolved.

Hematologic Diclofenac is one of the most frequently prescribed NSAIDs and has been implicated in immune hemolytic anemia and less often immune thrombocytopenia (SEDA16, 109). Occasionally, for unknown reasons, patients who develop either immune hemolysis or thrombocytopenia while taking diclofenac may simultaneously be sensitized to both erythrocytes and platelets.

Dexibuprofen

• Two patients developed antibodies against platelets and red blood cells while taking diclofenac (66A ). One developed severe hemolysis and significant thrombocytopenic purpura, and the other developed thrombocytopenia but no hemolysis. Standard serological tests for antibodies against platelets and erythrocytes were carried out in the presence and absence of diclofenac and its metabolites. Both patients had a positive direct antiglobulin test and drug-dependent and/or metabolitedependent antibodies against erythrocytes and platelets.

Dexibuprofen is the S (+) isomer of ibuprofen. Clinical experience is still inadequate to judge its safety profile, although there are claims that it is of comparable safety to celecoxib (63A ).

A recent systematic evaluation of 12 patients who had diclofenac-induced immune hemolysis has provided evidence that patients with diclofenac-induced immune hemolysis produce

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a broad spectrum of anti-diclofenac erythrocyte antibodies (67A ). The metabolite 4 -OHdiclofenac seems to be the most immunogenic metabolite. Nevertheless, all patients’ sera samples contain a mixture of antibodies that recognize several distinguishable epitopes, which consist of different drug metabolites and a target protein on the erythrocyte surface, which appears to be the Rh complex in many, but not all, cases. However, when serum samples were processed to detect platelet antibodies to diclofenac or diclofenac metabolites, none of the 12 patients gave positive results. Additional target proteins remain to be identified.

Ibuprofen Cardiovascular All NSAIDs can cause or aggravate hypertension and inhibit the effects of antihypertensive drugs (SEDA-22, 102; SEDA26, 116). Data from a randomized trial have suggested that ibuprofen significantly increases blood pressure in patients taking ACE inhibitors, but that celecoxib and nabumetone do not (68C ). Compared with placebo, ibuprofen was associated with significantly greater increases in both systolic and diastolic blood pressure, whereas blood pressure increases with nabumetone and celecoxib were not significantly different to placebo. In addition, the proportion of patients with systolic blood pressure increases of clinical concern was significantly greater in those taking ibuprofen (17%) than in those taking nabumetone (5.5%), celecoxib (4.6%), or placebo (1.1%). However, the results of this study must be confirmed in a larger population of hypertensive patients on the basis of relevant clinical outcomes. Nervous system Dementia has been attributed to ibuprofen. • A 76-year-old man became confused and lost in familiar places and had short-term memory loss after taking ibuprofen 600 mg tds for osteoarthritic pain for 2 weeks (69A ). These symptoms continued for 2 weeks until he stopped taking ibuprofen, when his mental symptoms resolved within 1 week. Six months later he started taking ibuprofen again and within 1 week had the same symptoms. He stopped taking ibuprofen and his mental status again returned to normal.

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Body temperature Ibuprofen is commonly prescribed for a raised temperature and is well tolerated in children. Adverse effects are not common, even in overdose. Nevertheless, there have been two case reports of profound and protracted hypothermia after a single dose of ibuprofen in a 7-year-old girl (70A ) and after four doses over 3 days in a 19-month-old child (71A ). Drug interactions Hyponatremic coma induced by the concomitant use of desmopressin and ibuprofen has been reported (72A ). • A 55-year-old woman with von Willebrand’s disease became comatose. A brain CT scan was normal and laboratory investigations showed hyponatremia (121 mmol/l) and a low plasma osmolality (247 mosm/kg) with normal sodium excretion and urine osmolality. A diagnosis of hyponatremic coma was made. She had taken desmopressin for hemostasis plus ibuprofen for analgesia 2 days before, after a dental intervention. She was treated with water restriction and recovered fully within 24 hours.

The fact that she had previously used desmopressin several times without developing hyponatremia suggests that the effect was due to the combination of ibuprofen with vasopressin. Water intoxication and severe hyponatremia, sometimes resulting in coma and seizures, is a severe, but rare, complication of desmopressin when given alone. On the other hand, NSAIDs inhibit prostaglandin synthesis, and renal medullary prostaglandins are important regulators of urinary dilution. By inhibiting prostaglandin synthesis, NSAIDs potentiate the effect of vasopressin on water reabsorption in the renal tubules, thereby enhancing water retention. Despite these renal effects of NSAIDs and their frequent use, hyponatremia as a result of water intoxication has rarely been described with NSAIDs used alone, suggesting that additional factors are needed in order to develop symptoms of water intoxication. Ginkgo biloba and NSAIDs both inhibit platelet aggregation, albeit by different mechanisms. • A fatal cerebral hemorrhage occurred in an elderly patient without susceptibility factors who was taking a Ginkgo biloba extract (40 mg bd for more than 2.5 years) and ibuprofen (600 mg/day for 4 weeks) for osteoarthritis (73A ). A CT scan showed massive intracerebral bleeding.

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Indometacin Drug interactions Major bleeding occurred during combined treatment with indometacin and low doses of acenocoumarol in a patient who was homozygous for the 2C9*3 variant of CYP2C9, which is responsible for low requirements of acenocoumarol and makes dosing difficult (74A ).

Lornoxicam Susceptibility factors Genetic Lornoxicam 8 mg bd for 2 weeks was well tolerated by subject with the Mediterranean form of G6PD deficiency (75C ).

Meloxicam Respiratory Meloxicam can be added to the long list of drugs that can cause eosinophilic pneumonia, albeit rarely. • A 23-year-old man developed pulmonary infiltrates in both lungs and an eosinophilia after taking meloxicam 7.5 mg/day for 4 days for shoulder pain (76A ).

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and toxic epidermal necrolysis associated with NSAIDs has been quantified in an analysis of three large data sources: first, an international case-control study of severe skin reactions (SCAR study); secondly, a population-based registry in Germany; thirdly, the spontaneous reporting system of the US Food and Drug Administration (FDA) (78C ). In the SCAR study the oxicams were associated with the greatest increase in risk of Stevens–Johnson syndrome and toxic epidermal necrolysis, with a selective risk of 34 (95% CI = 11, 105). When the risk for only recent use was compared with that for long term use (over 8 weeks), the relative risk of Stevens–Johnson syndrome and toxic epidermal necrolysis associated with oxicams was significantly increased. The German data registry confirmed these findings. The numbers of spontaneous reports of Stevens–Johnson syndrome and toxic epidermal necrolysis to the FDA were similar for piroxicam and other NSAIDs (diflunisal, etodolac, oxaprozin, sulindac). The authors concluded that the absolute risks of Stevens–Johnson syndrome and toxic epidermal necrolysis associated with NSAIDs are low. It should be remembered that isoxicam, an oxicam derivative, was withdrawn from the market following a higher than expected number of cases of Stevens–Johnson syndrome and toxic epidermal necrolysis (SEDA-10, 88).

Nitronaproxen Gastrointestinal Nitronaproxen is a naproxen derivative that might be better tolerated in the gut by virtue of nitric oxide donation. In a small, short term, crossover, endoscopic study in healthy volunteers, nitronaproxen caused less gastrointestinal damage than naproxen (77C ). However, no firm conclusions can be made and confirmation is required in large, prospective, comparative trials.

OXICAMS

(SED-14, 287; SEDA-24, 122; SEDA-27, 116) Skin The risk of the life-threatening adverse reactions such as Stevens–Johnson syndrome

SELECTIVE COX-2 INHIBITORS (SEDA-25, 122; SEDA-26, 116; SEDA-27, 111) Criticisms of outcome studies that support the safety of COX-2 inhibitors continue to appear. A number of flaws in both the design and analysis of these studies have been identified in a recent review (79M ), casting doubts on the available evidence of the safety profile of coxibs. Cardiovascular Selective COX-2 inhibitors have been increasingly used instead of conventional NSAIDs because of claims of less gastrotoxicity. However, the cardiovascular safety of COX-2 inhibitors (celecoxib and rofecoxib) has been questioned, because of evidence that they

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increase the risk of arterial thrombosis (SEDA26, 116; SEDA-27, 102). The theory behind this effect is that selective COX-2 inhibitors promote atherothrombosis by inhibiting the formation, via COX-2 isoenzymes in macrovascular endothelial cells, of prostacyclin (PGI 2 ), which is a potent vasodilator and inhibitor of smooth muscle cell proliferation and platelet aggregation. Moreover, coxibs do not inhibit the formation, via COX-1 in platelets, of thromboxane A2 , which facilitates vasoconstriction, platelet activation, and smooth muscle cell proliferation, thus disrupting the normal homeostatic balance and promoting a prothrombotic state. These theoretical concerns have been supported by the result of some studies, in which there was an increased risk of myocardial infarction with COX-2 selective inhibitors compared with the non-selective NSAIDs. There is evidence from experimental and clinical studies that COX-2 may be atherogenic and thrombogenic and that selective COX-2 inhibitors may actually reduce, rather than cause, atherothrombotic vascular events (80M ). Some evidence supporting this hypothesis comes from laboratory and clinical studies. A recent randomized trial suggested that simvastatin reduces inflammation and suppresses the expression of COX-2 and prostaglandin E synthase in plaque macrophages, and this effect may in turn contribute to plaque stabilization by inhibition of metalloproteinase-induced plaque rupture (81C ). Inhibition of COX-2 by celecoxib compared with placebo improved endothelium-dependent vasodilatation and reduced oxidative stress in men with severe coronary artery disease (82C ). The NSAIDs in Unstable Angina Treatment2 (NUT-2) pilot study, which compared meloxicam (15 mg/day until 30 days after discharge) with aspirin plus heparin in 120 patients who had a non-ST segment elevation acute coronary syndrome, showed that patients who took meloxicam had a significant reduction in the primary composite outcome of recurrent angina, myocardial infarction, or death during their stay in the coronary care unit (83C ): the relative risk reduction was 61% (95% CI = 23, 80). Larger trials are required to confirm the findings of this pilot study. Psychiatric Psychiatric effects have been previously reported with celecoxib (SEDA-26,

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123), and may represent a class effect of the COX-2 inhibitors, according to the Australian Adverse Reactions Advisory Committee (ADRAC), which has received 142 reports of acute neuropsychiatric reactions attributed to celecoxib and 49 to rofecoxib (84S ). The most common reactions associated with celecoxib were: confusion (n = 23) somnolence (n = 22), and insomnia (n = 21), while those associated with rofecoxib were confusion (n = 18) and hallucinations (n = 11). In many cases the onset of the reaction occurred within 24 hours of the first dose of the drug. Sensory systems There is evidence that celecoxib and rofecoxib can be associated with visual impairment (85A ), and visual disturbances associated with standard or COX-2 selective NSAIDs may be more frequent than previously thought and may be under-recognized. There have been two cases of more severe visual disturbances, one of temporary blindness related to celecoxib, and one that suggested a visual field defect related to rofecoxib. There have also been another five less specific reports of blurred or abnormal vision. One patient who had blurred vision while taking celecoxib had similar symptoms many years before while taking indometacin. Four of seven patients had an onset time of visual impairment of 1 week or less. One patient regularly had problems for a few hours after each dose. All the patients recovered rapidly (within one or two days of withdrawal), which suggests the absence of vascular embolism or thrombosis. A likely mechanism for the visual impairment is inhibition of the synthesis of prostaglandins and other related compounds that control retinal blood flow. As these adverse reactions have also been reported with conventional NSAIDs, it is likely that inhibition of either COX-1 or COX-2 alters the cyclo-oxygenase pathway and in turn alters regulation of retinal blood flow, with potential changes in vision. Musculoskeletal There have been few human studies of the effects of NSAIDs on fracture healing. The results of a recent retrospective study suggested that NSAID therapy delays fracture healing (86C ). Overall 20 of 29 NSAID users in a comparable patient population had non-union of femoral fractures compared with 12 of 70 patients who did not took any NSAIDs.

130 In an experimental study this NSAID-induced delay in fracture healing was attributable to inhibition of COX-2, since absent COX-2 gene function prevented normal fracture healing in animals (87E ). Although it is difficult to extrapolate from animal studies to humans the available data suggest caution in the long term use of NSAIDs, including COX-2 selective inhibitors, after bone fractures or certain orthopedic procedures until prospective human clinical studies show otherwise. Susceptibility factors Children Despite the abundance of studies on coxibs in adults, there is a dearth of published data on their use in children (88M ). One study showed that ibuprofen was better than rofecoxib but equally well tolerated in patients undergoing tonsillectomy when added to paracetamol (89C ). Children had faster drug clearance of celecoxib and a shorter half-life than adults in a single-dose pharmacokinetic study (90C ). While the coxibs appear, at least in the short term, safe and effective in adults, more investigations are needed before widespread use in children can be recommended.

Celecoxib Gastrointestinal With extensive use of COX2 inhibitors, gastrointestinal adverse reactions similar to those observed with non-selective NSAID are being increasingly observed. • An 87-year-old man developed severe esophagitis with a chronic peptic esophageal stricture and had dysphagia and odynophagia. He had taken celecoxib for 5 months (200–400 mg/day) and endoscopy showed severe desquamative esophagitis. Celecoxib was withdrawn and he was given esomeprazole. His symptoms improved and 3 months later the esophageal mucosa had completely healing (91A ).

Inhibition of COX-2 in the large bowel can worsen inflammatory bowel disease and collagenous colitis has been reported. • An 80-year-old woman who had taken celecoxib 100 mg bd for 18 months developed a collagenous colitis, with watery diarrhea, with multiple non-bloody stools each day, and crampy lower abdominal pain (92A ). Colonoscopy showed diffuse

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erythema, hyperemia, and multiple linear ulcers. Ulcer biopsies were consistent with collagenous colitis. Celecoxib was withdrawn, she was given mesalazine, and the diarrhea resolved.

Urinary tract COX-2 inhibitors have a nephrotoxic potential similar to that of non-selective NSAIDs (SEDA-25, 129). • A 61-year-old woman with rheumatoid arthritis developed renal papillary necrosis after taken celecoxib (200 mg bd) for about 6 months. The drug history and clinical findings suggested celecoxib as the most likely cause (93A ). • A 59-year-old man with type 2 diabetes mellitus developed acute allergic interstitial nephritis associated with minimal change disease after taking celecoxib (100–200 mg/day) for 1 year. The laboratory abnormalities lasted for several months after withdrawal of celecoxib and normalized only after treatment with prednisone (94A ). • A 78-year-old woman developed membranous glomerulopathy after taking celecoxib (200 mg bd) for 7 months. She developed orbital and leg edema and proteinuria in the nephrotic range. Renal biopsy was consistent with membranous glomerulopathy. Celecoxib was withdrawn and she recovered rapidly and completely (95A ). • A 71-year-old man developed nausea and weakness 9 months after starting to take celecoxib (100 mg bd). Tests showed acute interstitial nephritis. Celecoxib was withdrawn and he was given prednisone for 4 weeks; the serum creatinine returned to normal 1 month later (95A ).

Skin A fixed drug eruption has been attributed to celecoxib. • A 57-year-old woman developed a fixed drug eruption while taking celecoxib (200 mg/day for 10 days) for osteoarthritis (96A ). She developed an eruption or the abdomen and forearm. Both lesions subsided spontaneously but recurred on rechallenge.

Immunologic Drug-induced lupus-like syndrome has been associated with celecoxib (97A ). • A 68-year-old woman started to take celecoxib (200 mg/day) and 2 weeks later developed generalized joint pains and a micropapular skin rash associated with a malar rash. Celecoxib was withdrawn and she was given oral antihistamines and glucocorticoids, with complete resolution of the reaction within 5 days. Skin prick and patch tests with celecoxib were negative. She underwent an oral rechallenge test with increasing doses of celecoxib up to 200 mg/day over 3 days. The rash and polyarthralgia recurred. She had a weakly positive titer of antinuclear antibodies and a skin biopsy that was characteristic of lupus erythematosus. She

Anti-inflammatory and antipyretic analgesics and drugs used in gout also had a predisposing HLA-DR4 subtype. Antihistone antibodies and serial antinuclear antibodies were negative. She remained asymptomatic for 1 year of follow up.

Although the product labelling of celecoxib (Celebrex) contains a warning that patient allergic to “sulfa” drugs should avoid using this COX-2 inhibitor, which contain a sulfonamide substituent, there is evidence that cross-reactivity between sulfonamide antimicrobials and celecoxib is low (98C ). However, further investigations are required to confirm this, in view of a case report that suggested cross-reactivity of celecoxib with sulfamethoxazole (99A ). Drug interactions An interaction of rofecoxib with lithium has been described (SEDA27, 113) and two reports document the same type of interaction with celecoxib (100A , 101A ). Recovery was uneventful. The proposed mechanism was a celecoxib-induced reduction in renal function, causing increased serum lithium concentrations.

Etoricoxib Gastrointestinal Two randomized, doubleblind, placebo-controlled and non-selective NSAID-controlled studies have documented the upper gastrointestinal tract tolerability of etoricoxib (102C ). In the first study, fecal blood loss was measured daily in 62 healthy volunteers taking etoricoxib (120 mg/day), ibuprofen (800 mg tds), or placebo; etoricoxib caused less fecal blood loss than placebo or ibuprofen. In the second study, the incidence of endoscopically detectable gastric/duodenal ulcers was measured in 742 patients with osteoarthritis or rheumatoid arthritis taking etoricoxib (120 mg/day), naproxen (500 mg bd), or placebo over 12 weeks. Etoricoxib caused significantly fewer ulcers and erosions than naproxen. However, there was a higher incidence of ulcers in patients taking etoricoxib relative to placebo. The real benefit to harm balance of this derivative is still unknown.

Rofecoxib Rofecoxib has been withdrawn by its manufacturers, Merck, because of its adverse cardiovascular effects during long-term therapy.

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Observational studies The results of a postmarketing Prescription Event Monitoring study have better defined the safety profile of rofecoxib as used in general practice in England (103C ). Questionnaires requesting clinical event data were sent to prescribing physicians between February and November 2000. They identified 15 268 patients, mean age 62 years, 67% women. The commonest indication was osteoarthritis (24%). Dyspepsia and nausea were the most frequently reported adverse events. During treatment or within 1 month of withdrawal, 110 serious gastrointestinal events were reported, including 76 upper gastrointestinal tract bleeds/peptic ulcers and one perforated colon. Other events were: thromboembolism (n = 101), acute renal insufficiency (n = 3), Stevens–Johnson syndrome (n = 1), severe anaphylaxis (n = 1), and angioedema (n = 1). Cardiovascular Hypertensive patients taking rofecoxib are more likely to require an increase in their antihypertensive drug dosages (104C ) than those taking celecoxib: OR = 1.68 (95% CI = 1.09, 2.6). Nervous system Aseptic meningitis has been attributed to rofecoxib. • A 28-year-old woman with a history of Sjögren’s syndrome who had aseptic meningitis from two different non-selective NSAIDs (naproxen and ibuprofen) had similar symptoms 2 years later, after taking rofecoxib 25 mg/day for 1 week for joint pain. She improved significantly 2 days after rofecoxib was withdrawn (105A ).

Hematologic Thrombocytopenia has been attributed to rofecoxib. • A 66-year-old man took rofecoxib 12.5 mg/day for 5 days before stopping because of purpura; 3 days later he developed a disseminated petechial rash and epistaxis (106A ). His platelet count was 1 × 109 /l. Rofecoxib was withdrawn but he required treatment with prednisone, immunoglobulin, and plasmapheresis owing to the severity of the hemorrhagic event. The platelet count slowly returned to normal.

Gastrointestinal Rofecoxib has been studied in patients with inflammatory bowel disease and an associated peripheral arthropathy and/or arthritis in an uncontrolled study in 32 patients, of whom 26 took 25 mg/day and six took 12.5 mg/day (107c ). Three patients had to

132 be withdrawn because of gastrointestinal complaints. There was no exacerbation of the inflammatory bowel disease and in 32 patients the arthralgia was thought to have responded. In a small phase II study rofecoxib did not increase the antitumor activity of chemotherapy in the treatment of metastatic colorectal cancer, and resulted in increased gastrointestinal toxicity (108C ). Urinary tract The pattern of nephrotoxicity of rofecoxib is similar to that with non-selective NSAIDs. There have been reports of acute renal insufficiency (109A , 110A ) and acute interstitial nephritis (111A ). Skin Two women developed neutrophilic dermatosis (Sweet’s syndrome) while taking rofecoxib. • A 31-year-old woman with Crohn’s disease started to take rofecoxib 50 mg/day for joint pain and 1 week later developed multiple tender erythematous nodules on her legs (112A ). Some had central pustules and some were ulcerated. She stopped taking rofecoxib. Biopsy of a nodule showed infiltration of neutrophils into the surrounding derma and a central area of abscess formation. Ten days later her lesions were less indurated and the ulcerated lesion had stopped draining and 5 weeks later her lesions had resolved. • A 30-year-old woman with rheumatoid arthritis started to develop multiple tender subcutaneous nodules over both her legs within 2 weeks of starting to take rofecoxib (50 mg/day) for joint pain (112A ). After 1 month the lesions had progressed to focal areas of ulceration with purulent drainage. A biopsy showed neutrophilic dermatitis, consistent with pyoderma gangrenosum. Rofecoxib was withdrawn and her lesions resolved in 4 weeks.

Non-selective NSAIDs have been reported to exacerbate psoriasis. • A 46-year-old woman developed severe psoriasis 5 days after starting to take rofecoxib 25 mg/day for a neck strain. She had a similar reaction while taking diclofenac. In both cases remission did not occur until several months after withdrawal (113A ).

This report, and others involving non-selective NSAIDs, adds strength to the likelihood of an association between all types of NSAIDs and exacerbation of psoriasis. Severe cutaneous vasculitis has been described in two patients taking rofecoxib (114A , 115A ).

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Valdecoxib The benefit to harm balance of valdecoxib is still unknown. Recently a “Dear Health Care Professional” letter containing important safety information about valdecoxib was issued by Pharmacia Canada Inc and Pfizer Canada Inc, following discussions with Health Canada. Valdecoxib has been withdrawn by its manufacturers because of an increased risk of cardiovascular events after coronary artery bypass surgery and reports of potentially fatal skin reactions. Skin Toxic epidermal necrolysis has been attributed to valdecoxib (116A ). • A 55-year-old woman developed toxic epidermal necrolysis while taking valdecoxib (dosage not stated) for knee pain. She had previously had an allergic reaction to a sulfonamide antibacterial cream. Eight days after starting to take valdecoxib, she developed a diffuse erythematous rash and fever. Valdecoxib was withdrawn, but her reaction worsened and she was transferred to a burns unit with lesions consistent with toxic epidermal necrolysis, with complete skin and hair loss, and received wound care for 12 days. At 5 months follow-up she still had leg pain and complete hair loss.

Valdecoxib has been associated with rare cases of serious skin reactions and of hypersensitivity reactions in patients with or without a history of allergic reactions to sulfonamides and should not be given to patients with such a history (117S ).

OTHER COMPOUNDS Nimesulide Hematologic Thrombocytopenia with oligohydramios occurred during pregnancy with premature labor in a woman taking nimesulide (118A ). Liver There have been several reports of hepatotoxicity of nimesulide either published or submitted as spontaneous reports to various national pharmacovigilance agencies (SEDA-26, 112). Concern about its benefit to harm balance has prompted its withdrawal from the market in some countries.

Anti-inflammatory and antipyretic analgesics and drugs used in gout

From estimates of patient exposure and data from spontaneous reports received from the Spanish pharmacovigilance system (119r ), nimesulide was associated with a higher risk of hepatotoxicity than other NSAIDs. However, these data were in contrast to those from an epidemiological study conducted in Italy, one of the countries with the highest prevalence of nimesulide prescription (120C ). The study was a retrospective cohort and nested case-control study in 400 000 individuals from the Umbria region admitted to hospital for acute non-viral hepatitis and who had received at least one prescription for an NSAID between 1997 and 2001. Nimesulide was the most commonly prescribed NSAID, with 551 000 prescriptions. Of the 176 cases of hepatotoxicity included in the final analysis, 42 occurred during current use of the NSAID, giving an increased risk of hepatotoxicity compared with past use of an NSAID (RR = 1.4; 95% CI = 1, 2.1). This ratio was increased among elderly patients. In current users of nimesulide the RRs for all hepatopathies and more severe liver injury were 1.3 (0.7, 2.3) and 1.9 (1.1, 3.8) respectively. Fulminant hepatitis was not observed. This study has therefore confirmed that hepatotoxicity is a rare class effect of NSAIDs. Despite the fact that data from spontaneous reports suggest an increased risk of hepatic injury with nimesulide, this retrospective study showed that the risk of liver injury in patients taking nimesulide and other NSAIDs is small. Following a Community-wide review of nimesulide, the CPMP concluded that it has a favourable benefit to harm balance and that marketing authorization should be maintained (121S ). However, the CPMP recommended that systemic use of nimesulide be restricted to the treatment of acute pain. Patients using nimesulide must be monitored for possible hepatotoxicity and the drug should be withdrawn if laboratory or clinical findings suggest liver toxicity. Liver failure requiring liver transplant in patients taking nimesulide has also been associated with hemolytic anemia (122A ).

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DRUGS USED IN THE TREATMENT OF GOUT (SED-14, 310; SEDA-25, 135; SEDA-26, 125; SEDA-27, 125)

Allopurinol Hematologic Allopurinol has been blamed for a variety of hematological adverse effects. • Pure red cell aplasia occurred in a 79-year-old man taking allopurinol (dosage not stated) (123A ). The anemia promptly resolved after withdrawal, strongly supporting a drug effect.

Immunologic Allopurinol-induced hypersensitivity reactions are characterized by a variety of manifestations. Two reports suggest that reactivation of infection with herpesvirus 6 (124A ) or Epstein–Barr virus (125A ) may contribute in some way to the development of allopurinol hypersensitivity reactions and its clinical course. A similar report has already been described (SEDA-23, 122).

Colchicine Musculoskeletal Colchicine-induced myopathy with associated myotonia has rarely been reported (126A ). Colchicine myopathy with or without neuropathy can occur more often than has previously been thought, especially in elderly patients with chronic renal insufficiency taking long-term low doses of colchicine (SEDA-12, 94). Acute rhabdomyolysis can occur (see also Drug interactions below). Drug dosage regimens It has been suggested that the dosages of colchicine recommended by the British National Formulary in patients with gout should be revised; lower doses are probably better tolerated and equally efficacious (127S ). Drug interactions The combination of colchicine with other myotoxic drugs (for example statins and gemfibrozil) can cause acute rhabdomyolysis. This potential interaction has clinical relevance, as these classes of drugs are often prescribed together for patients with renal insufficiency. In two cases simvastatin (128A )

134 and atorvastatin (129A ) were blamed and in the third, gemfibrozil (130A ) was thought to have contributed to colchicine-induced rhabdomyolysis. The rhabdomyolysis that occurs when simvastatin is combined with colchicine may be due to inhibition of CYP3A4.

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While these single case reports require confirmation, and although the interaction is probably rare, it would be wise to avoid such combinations if possible, or to monitor susceptible patients carefully.

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General anesthetics and therapeutic gases

ANESTHETIC VAPORS (SED-14, 318; SEDA-25, 139; SEDA-26, 132; SEDA-27, 119)

Sevoflurane Cardiovascular Sudden death in infants is associated with prolongation of the QTc interval to 440 ms or longer, and sevoflurane prolongs the QTc in adults. In a prospective randomized trial the QTc interval was measured in pre-, peri-, and post-operative electrocardiograms in 36 infants aged 1–6 months scheduled for inguinal or umbilical hernia repair (1c ). Anesthesia was by either sevoflurane or halothane. There was prolongation of the QTc interval during sevoflurane anesthesia (mean 473 ms) and 60 minutes after emerging from anesthesia (433 ms) compared with infants who received halothane. The JTc interval was analogously affected. The authors suggested that despite sevoflurane’s shorter halflife, electrocardiographic monitoring until the QTc interval has returned to preanesthetic values may increase safety after sevoflurane anesthesia. Life-threatening dysrhythmias during anesthesia have been reported in patients with increased QT dispersion (the difference between the longest and shortest QT intervals in any of the 12 leads of the electrocardiogram). The effects of sevoflurane on QT dispersion have been compared with those of halothane in 50 children aged 5–15 years in a blind randomized study (2C ). Neither sevoflurane nor halothane caused a significant increase in QT dispersion compared with baseline. © 2005 Published by Elsevier B.V. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

Severe bradycardia has been described after sevoflurane induction for adeno-tonsillectomy in three children aged 42, 26, and 5 months with trisomy 21 (3A ). Two had normal electrocardiography and echocardiography. The third had a complete AV canal repaired early in life, and had first degree heart block but normal echocardiography. Severe bradycardia (40–44/minute from a baseline of 110–130) and hypotension occurred on induction of anesthesia. Two children responded to atropine and glycopyrrolate, but the third required adrenaline for resuscitation. The authors suggested that children with trisomy 21 should be premedicated with an anticholinergic agent either orally or intramuscularly. Nervous system Sevoflurane often causes postoperative delirium and agitation in children, and this can be severe. Rapid emergence has been proposed as a possible mechanism. This has been assessed in a randomized, prospective study in 53 infants and children, all of whom received sevoflurane as the sole anesthetic for induction and then either sevoflurane or propofol for maintenance (4c ). Either a caudal epidural block was performed before surgery with 0.25% bupivacaine or intravenous fentanyl 2 micrograms/kg was used for analgesia. The times to extubation and recovery were similar between the two groups, but emergence agitation was significantly more common with sevoflurane than with propofol (23% versus 3.7%). There was no relation between analgesic technique and agitation. Gastrointestinal About 2 million day-case anesthetics are given annually in England, and anesthetic practice varies widely, because of a large and contradictory evidence base for the optimal anesthetic in day surgery. In a randomized controlled trial in 1063 adults and 322 children sevoflurane, when used for induction

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140 and maintenance, was more costly and associated with higher rates of postoperative nausea and vomiting than anesthetic regimens using propofol for induction of anesthesia (5C ). Genogenicity Sevoflurane can cause toxicity (for example nephrotoxicity) from either inorganic fluoride ions or the haloalkene degradation product Compound A. Fluoride ions are produced by metabolism of sevoflurane and can reach high concentrations after prolonged anesthesia. Compound A is produced in carbon dioxide absorbers (soda lime and barium hydroxide lime in particular) and is nephrotoxic in rats but not in humans. Compound A induces sister chromatid exchanges in Chinese hamster ovary cells in vitro as a marker for possible genotoxicity. The formation of sister chromatid exchanges in mitogen-stimulated T lymphocytes of 40 children undergoing sevoflurane anesthesia for minor operations has been investigated (6c ). Anesthesia was induced and maintained with sevoflurane in oxygen and nitrous oxide at a fresh gas flow rate of 3 l/minute in a circle system, using soda lime as the carbon dioxide absorbent. Blood samples were drawn immediately before induction and after the end of anesthesia. The average duration of anesthesia was 50 minutes. There was no difference in the rate of sister chromatid exchanges after sevoflurane anesthesia and so no evidence of a genotoxic effect.

Trichloroethylene Nervous system A population-based study of 143 people who had been exposed to long-term low concentrations of trichloroethylene because of a contaminated water supply showed significant neurobehavioral deficits (7C ). Carcinogenicity The carcinogenicity of trichloroethylene has been evaluated in a consecutive case-control study in 134 patients with renal cell cancers and 401 controls (8c ). There was a significant excess risk with occupational exposure to trichloroethylene (for example, for metal degreasing OR = 5.57; 95% CI = 2.33, 13.32).

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NITROUS OXIDE (SED-14, 325; SEDA-25, 142; SEDA-26, 134; SEDA-27, 120) Sensory systems Nitrous oxide is 34 times more soluble than nitrogen in enclosed body cavity gas spaces and enters such spaces rapidly, causing expansion and a rise in pressure. Vitreoretinal surgery often involves intraocular gases to replace vitreous humor, in order to tamponade the neuroretina to the retinal pigment epithelium. Various long-acting inert gases, such as sulfur hexafluoride (SF6 ) or perfluoropropane, can be used as intraocular tamponading agents. These gases can persist in the eye for up to 3 months after surgery, and during this time further anesthesia using nitrous oxide will cause the intraocular gas bubble to expand, increasing intraocular pressure. • A 71-year-old man with glaucoma developed a left retinal detachment, which was treated with vitrectomy and retinal cryotherapy (9A ). He subsequently underwent general anesthesia with oxygen in nitrous oxide for 2 hours, and had intense pain and complete loss of vision in the left eye while recovering from the anesthetic. He had no light perception in the left eye, the pupil was mid-dilated and non-reactive, and the intraocular pressure was 31 mmHg. The vitreous cavity was 50% full of gas and the retinal vasculature was attenuated. Three months later he still had no light perception and the optic disc was pale. • A 66-year-old man had a vitrectomy and peeling of an epiretinal membrane in the right eye (10A ). Perioperatively, the eye was filled with 20% sulfur hexafluoride gas to tamponade retinal breaks. Five days later he underwent prostatectomy under general anesthesia using nitrous oxide. Postoperatively the eye had no light perception as a result of ischemic retinopathy.

It has been suggested that all such patients should have warning bracelets detailing the presence of intraocular gas and that nitrous oxide be avoided until it has been shown that the gas bubble has been absorbed.

XENON

(SEDA-27, 120)

Xenon is receiving renewed interest, because it has many characteristics of the ideal anesthetic and has analgesic properties. In addition to its lack of effects on the cardiovascular system (most other anesthetics are negative inotropes),

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xenon has low solubility, enabling faster induction of anesthesia and faster emergence. The development of closed rebreathing systems has led to further interest, as otherwise its high cost limits its use. In a prospective randomized study in 21 patients following thoracic surgery xenon sedation (delivered via a closed circuit) was compared with a standard regimen of propofol plus alfentanil (11c ). Xenon sedation was very well tolerated and was not associated with any adverse physiological effects. In addition, there was extremely rapid recovery. In a multicenter randomized study in 224 patients the hypothesis that xenon anesthesia would be associated with faster recovery than an established isoflurane based regimen, and be as effective and safe, was tested (12C ). Patients who received xenon recovered much faster, and there were no more adverse effects than with the standard regimen.

INTRAVENOUS AGENTS MISCELLANEOUS NON-BARBITURATE ANESTHETICS Dexmedetomidine The alpha2 -adrenoceptor agonist dexmedetomidine has potent sedative and analgesic-sparing properties. In therapeutic doses it does not cause respiratory depression, making it attractive for infusion sedation. However, it causes reduced sympathetic outflow, which might cause untoward hemodynamic upset but might also have beneficial β-adrenoceptor antagonist-like action in patients undergoing cardiovascular surgery. Dexmedetomidine has been compared with propofol in a prospective randomized open trial in 295 patients undergoing coronary artery surgery (13C ). Mean times to weaning and extubation were similar in the two groups, but fewer patients given dexmedetomidine remained on the ventilator beyond 8 hours postoperatively. The use of morphine was significantly less in those who were given dexmedetomidine, only 28% of whom required morphine while being

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ventilated compared with 69% of propofoltreated patients (the latter also required four times the mean dose of morphine than the former). No patients who received dexmedetomidine had ventricular tachycardia, whereas 5% of propofol patients did. Significantly fewer patients who were given dexmedetomidine required β-adrenoceptor antagonists, antiemetics, non-steroidal anti-inflammatory drugs, adrenaline, and high-dose diuretics. Mean blood pressure fell by 3 mmHg relative to baseline in patients who were given dexmedetomidine and rose by 9 mmHg in those who were given propofol.

Etomidate

(SED-14, 329; SEDA-26, 135;

SEDA-27, 121) Nervous system Myoclonus is common with etomidate, and can cause severe problems. Methods for preventing myoclonus have been assessed in two prospective placebo-controlled studies from the same group. In the first they assessed the effect of midazolam pre-treatment in 60 patients (14C ). Midazolam 0.15 mg/kg 90 seconds before induction of anesthesia with etomidate 0.3 mg/kg was significantly better than placebo in reducing the incidence of myoclonus. In the second study they assessed the effect of sufentanil 0.3 micrograms/kg pretreatment in 40 patients; sufentanil abolished myoclonus completely (15C ).

Ketamine (SED-14, 329; SEDA-25, 143; SEDA-26, 135; SEDA-27, 120) Cardiovascular Subanesthetic low-dose ketamine is being used increasingly often for day-case surgery, acute pain, and chronic pain. Angina pectoris has been reported. • Subcutaneous low-dose ketamine precipitated angina in an elderly man with metastatic bladder cancer and venous gangrene of a leg, in whom antianginal medication had been withdrawn (16A ).

Psychiatric Ketamine often causes emergence delirium and disturbing dreaming. Benzodiazepines are often co-administered to attempt to manage this. The optimal dose of

142 diazepam to add to ketamine–fentanyl field anesthesia has been assessed in a randomized double-blind study in 400 patients from Vanuatu; the optimal dose was 0.1 mg/kg (17C ).

Propofol

(SED-14, 330; SEDA-25, 144; SEDA-26, 135; SEDA-27, 121)

Observational studies Gastrointestinal endoscopy is one of the most common invasive procedures (for example, about 500 000 procedures per year in Australasia). Propofol is a short-acting intravenous anesthetic with a rapid onset of action, a short half-life, and very favourable recovery characteristics, making it particularly suitable for day procedures. However, the use of propofol by non-anesthetists has been controversial because of the perceived risks of its smaller therapeutic ratio. The incidence of adverse events related to the use of propofol has been examined in three prospective audits of nurse-administered endoscopy sedation regimens that primarily used propofol. In the first study, adverse events were assessed in 300 patients over 3 months in a unit that already had experience with 8000 patients (18C ). The patients were carefully monitored with clinical observation, pulse oximetry, automated sphygmomanometry, and sidestream capnography via a nasal cannula sampling device. All received supplementary oxygen at 2 l/minute. There were no episodes of apnea, and assisted ventilation was not necessary. There were short periods of hypoxemia (defined as an oxygen saturation below 90%) in 11 patients. Three patients required an increase in supplementary oxygen to 4 l/minute. Hypotension (defined as a mean arterial pressure below 50 mmHg) occurred briefly in 22 patients. Two patients required a 500 ml infusion of isotonic saline. The authors concluded that propofol may be safely administered by non-anesthetists who are familiar with its pharmacological properties and use. In the second publication, nurses trained by an anesthesiologist gave propofol to 9152 patients in a private ambulatory setting (19C ). There were seven cases of airway or ventilation problems (three of prolonged apnea, three of laryngospasm, and one case of aspiration

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requiring hospitalization), all with upper endoscopy. Five patients required face-mask ventilation, but none required tracheal intubation. Monitoring did not include capnography. The third study examined 1435 elderly patients aged 70–85 years and 351 aged over 85 years who received propofol sedation over 17 months (20C ). Four patients (0.3%) required airway manipulations and two required facemask ventilation. There was bradycardia requiring atropine in four patients (0.3%), and a heart rate below 50/minute in 72 patients (5.7%). There was hypoxemia (SaO2 below 90%) in 52 patients (4.7%) and hypotension (systolic pressure below 90 mmHg) in 162 (11%). Capnography was not used routinely. The authors concluded that nurse-administered propofol in elderly patients is as safe as in younger ones. The safety and efficacy of propofol sedation by an emergency physician (a non-anesthetist) for painful procedures (mostly fractures and joint dislocation reductions) in 393 children has been examined (21C ). The children also received morphine 0.1 mg/kg and/or fentanyl 1–2 micrograms/kg. There was hypoxemia in 19 (5%), 11 (3%) needed airway manipulation, and three (0.8%) required face-mask ventilation. Hypotension was very common (92%) but only required treatment with intravenous fluid boluses in two children (0.67%). Comparative studies Acute withdrawal syndromes, including agitation and prolonged weaning, are common after long-term sedation with midazolam. It has been proposed that the sequential use of propofol following midazolam may have advantages over midazolam alone, reducing adverse effects while preserving the potential benefits (“co-sedation”). A midazolam– propofol sequence has been compared with midazolam alone for sedation for long-term mechanical ventilation in a prospective, randomized trial in 26 patients (22c ). The time from stopping sedation to tracheal extubation was significantly shorter in the midazolam–propofol group (1.3 hours) than in the midazolam group (4.0 hours). Agitation occurred in only 8% of the midazolam–propofol group, but in 54% of the midazolam group. Respiratory Propofol is often the induction agent of choice in people with asthma, as it causes bronchodilatation.

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Chapter 10

• A 45-year-old woman with sick building syndrome developed bronchospasm after induction of anesthesia with propofol (23A ). She had taken oral aminophylline and inhaled fluticasone for 6 years and had a raised eosinophil count (17%). She received methylprednisolone 80 mg and aminophylline 125 mg preoperatively, but still went on to develop bronchospasm that eventually responded to sevoflurane. Four weeks later, she underwent intradermal skin tests that were negative for propofol, vecuronium, and other anesthetic drugs. Drug lymphocyte stimulation tests were weakly positive for propofol.

Bronchial hyper-reactivity associated with sick building syndrome is thought to be due to volatile organic compounds such as formaldehyde, toluene, and xylene. Nervous system Mutism has been attributed to propofol total intravenous anesthesia. • A 56-year-old otherwise well woman underwent femoral fracture surgery, awoke, and was extubated after obeying commands and opening her eyes spontaneously, but was unable to speak (24A ). Clinical examination, blood tests, and a CT scan were otherwise unremarkable. There was no evidence of cerebral infarction on repeat imaging. She made a spontaneous recovery after 11 days.

Pain on injection is a sometimes severe adverse effect of propofol, and many agents have been tried to prevent it. The effects of remifentanil on the incidence and severity of pain after propofol injection have been compared with those of lidocaine in a double-blind, randomized, placebo-controlled study in 155 patients (25C ). Pretreatment with intravenous remifentanil infusion 0.25 micrograms/kg/minute significantly reduced the pain after propofol injection. Lidocaine 40 mg achieved the same effect. Granisetron and lidocaine have been compared in patients being given propofol in a double-blind, randomized, placebo-controlled study in 150 patients (26C ). Granisetron 2 mg

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intravenously was as effective as lidocaine 40 mg intravenously with 120 seconds of venous occlusion at preventing propofol injection pain, and significantly better than placebo. Metabolism Propofol infusion syndrome has been discussed at length in previous annuals (SEDA-26, 135; SEDA-27, 121). It is a syndrome of cardiac failure (bradycardia, hypotension, low cardiac output), metabolic acidosis, and rhabdomyolysis, first described in children receiving high-dose propofol infusions for more than 48 hours. Short-term infusions are thought to be safe. • Severe lactic acidosis occurred in a 7-year-old child with osteogenesis imperfecta during shortterm (150 minutes) propofol infusion anesthesia (mean infusion rate 13.5 mg/kg/hour) (27A ). The peak arterial lactate concentration occurred 160 minutes after withdrawal of propofol (lactate 9.2 mmol/l, bicarbonate 16 mmol/l, base deficit 8.3 mmol/l). The hyperlactatemia settled within 18 hours.

The authors suggested that the combination of a prolonged preoperative fast and a high dose of propofol had contributed to the lactic acidosis. Osteogenesis imperfecta is also associated with malignant hyperthermia, but the temperature was not raised in this case. Genotoxicity Propofol negatively affects very early development (first cell to blastocyst stage) in the mouse embryo. Cytogenetic assay systems based on the detection of sister chromatid exchanges in peripheral blood T lymphocytes have been widely advocated as a sensitive screening method for assessing genotoxic potential. The formation of sister chromatid exchanges in mitogen-stimulated T lymphocytes from 40 children undergoing propofol infusion anesthesia for minor operations has been investigated (28c ). There was no evidence to support propofol-induced genotoxicity.

REFERENCES 1. Loeckinger A, Kleinsasser A, Maier S, Furtner B, Keller C, Kuehbacher G, Lindner KH. Sustained prolongation of the QTc interval after anesthesia with sevoflurane in infants during the first

6 months of life. Anesthesiology 2003; 98: 639– 42. 2. Gurkan Y, Canatay H, Agacdiken A, Ural E, Toker K. Effects of halothane and sevoflurane

144 on QT dispersion in paediatric patients. Paediatr Anaesth 2003; 13: 223–7. 3. Roodman S, Bothwell M, Tobias JD. Bradycardia with sevoflurane induction with patients with trisomy 21. Paediatr Anaesth 2003; 13: 538–40. 4. Cohen IT, Finkel JC, Hannallah RS, Hummer KC, Patel KM. Rapid emergence does not explain agitation following sevoflurane anaesthesia in infants and children: a comparision with propofol. Paediatr Anaesth 2003; 13: 63–7. 5. Elliott RA, Payne K, Moore JK, Harper NJN, St Leger AS, Moore EW, Thoms GM, Pollard BJ, McHugh GA, Bennett J, Lawrence G, Kerr J, Davies LM. Clinical and economic choices in anaesthesia for day surgery: a prospective randomised controlled trial. Anaesthesia 2003; 58: 412–21. 6. Krause T, Scholz J, Jansen L, Boettcher H, Koch C, Wappler F, Schulte am Esch J. Sevoflurane anaesthesia does not induce the formation of sister chromatid exchanges in peripheral blood lymphocytes of children. Br J Anaesth 2003; 90: 233–5. 7. Reif JS, Burch JB, Nuckols JR, Metzger L, Ellington D, Anger WK. Neurobehavioral effects of exposure to trichloroethylene through a municipal water supply. Environ Res 2003; 93: 248–58. 8. Bruning T, Pesch B, Wiesenhutter B, Rabstein S, Lammert M, Baumuller A, Bolt HM. Renal cell cancer risk and occupational exposure to trichloroethylene: results of a consecutive casecontrol study in Arnsberg, Germany. Am J Ind Med 2003; 43: 274–85. 9. Yang YF, Herbert L, Ruschen H, Cooling RJ. Nitrous oxide anaesthesia in the presence of intraocular gas can cause irreversible blindness. Br Med J 2002; 325: 532–3. 10. Astrom S, Kjellgren D, Monestam E, Backlund U. Nitrous oxide anaesthesia and intravitreal gas tamponade. Acta Anaesthesiol Scand 2003; 47: 361–2. 11. Bedi A, Murray JM, Dingley J, Stevenson MA, Fee JPH. Use of xenon as a sedative for patients requiring critical care. Crit Care Med 2003; 31: 2470–7. 12. Rossaint R, Reyle-Hahn M, Schulte am Esch J, Scholz J, Scherpereel P, Vallet B, Giunta F, Del Turco M, Erdmann W, Tenbrick R, Hammerle AF, Nagele P. Multicenter comparision of the efficacy and safety of xenon and isoflurane in patients undergoing elective surgery. Anesthesiology 2000; 98: 6–13. 13. Herr DL, Sum-Ping STJ, England M. ICU sedation after coronary artery bypass graft surgery: dexmedetomidine-based versus propofol-based sedation regimens. J Cardiothorac Vasc Anesth 2003; 17: 576–84. 14. Schwarzkopf KRG, Hueter L, Simon M, Fritz HG. Midazolam pre-treatment reduces etomidateinduced myoclonic movements. Anaesth Intensive Care 2003; 31: 18–20.

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15. Hueter L, Schwarzkopf KRG, Simon M, Bredle D, Fritz HG. Pretreatment with sufentanil reduces myoclonus after etomidate. Acta Anaesthesiol Scand 2003; 47: 482–4. 16. Ward J, Standage C. Angina pain precipitated by continuous subcutaneous infusion of ketamine. J Pain Symptom Manage 2003; 25: 6–7. 17. Grace RF. The effect of variable dose diazepam on dreaming and emergence phenomena in 400 cases of ketamine-fentanyl anaesthesia. Anaesthesia 2003; 58: 904–10. 18. Külling D, Rothenbuhler R, Inauen W. Safety of nonanesthetist sedation with propofol for outpatient colonoscopy and esophagogastroduodenoscopy. Endoscopy 2003; 35: 679–82. 19. Walker JA, McIntyre RD, Schleinitz PF, Jacobson KN, Haulk AA, Adesman P, Tolleson S, Parent R, Donnelly R, Rex DK. Nurse-administered propofol sedation without anesthesia specialists in 9152 endoscopic cases in an ambulatory surgery center. Am J Gastroenterol 2003; 98: 1744–50. 20. Heuss LT, Schnieper P, Drewe J, Pfilmin E, Beglinger C. Conscious sedation with propofol in elderly patients: a prospective evaluation. Aliment Pharmacol Ther 2003; 17: 1493–501. 21. Bassett KE, Anderson JL, Pribble CG, Guenther EG. Propofol for procedural sedation in children in the emergency department. Ann Emerg Med 2003; 42: 773–82. 22. Saito M, Terao Y, Fukusaki M, Makita T, Shibata O, Sumikawa K. Sequential use of midazolam and propofol for long-term sedation in postoperative mechanically ventilated patients. Anesth Analg 2003; 96: 834–8. 23. Hattori J, Fujimura N, Kanaya N, Okazaki K, Namiki A. Bronchospasm induced by propofol in a patient with sick house syndrome. Anesth Analg 2003; 96: 163–4. 24. Kati I, Demirel CB, Anlar O, Huseyinoglu UA, Silay E, Elcicek K. An unusual complication of total intravenous anesthesia: mutism. Anesth Analg 2003; 96: 168–70. 25. Roehm KD, Piper SN, Maleck WH, Boldt J. Prevention of propofol-induced injection pain by remifentanil: a placebo-controlled comparison with lidocaine. Anaesthesia 2003; 58: 165–70. 26. Dubey PK, Prasad SS. Pain on injection with propofol: the effect of granisetron pre-treatment. Clin J Pain 2003; 19: 121–4. 27. Kill C, Leonhardt A, Wulf H. Lactic acidosis after short-term infusion of propofol for anaesthesia in a child with osteogenesis imperfecta. Paediatr Anaesth 2003; 13: 823–6. 28. Krause TKW, Jansen L, Scholz J, Boettcher H, Wappler F, Burmeister M-A, Schulte am Esch J. Propofol anaesthesia in children does not induce the formation of sister chromatid exchanges in lymphocytes. Mutation Res 2003; 542: 59–64.

Stephan A. Schug, Per Flisberg, Simon A. Jackson, and Dominic J. O’Connor

11

Local anesthetics

GENERAL TOPICS

EFFECTS RELATED TO MODES OF USE

Immunologic The extreme rarity of allergic reactions to local anesthetics has again been confirmed in a study of 236 patients with suspected hypersensitivity to local anesthetics referred to an allergy clinic for intradermal testing and subcutaneous challenge; none tested positive (1c ). This paper was accompanied by a useful editorial outlining the role of the allergologist in assessing reactions to local anesthetics (2r ). • A 35-year-old pregnant woman with a history of multiple allergies to local anesthetics underwent provocative challenge testing with preservativefree bupivacaine at 38 weeks gestation (3A ). The procedure was performed with full monitoring in the labor suite. There was no evidence of a reaction. She subsequently went on to have a cesarean section with preservative-free bupivacaine and fentanyl, with excellent analgesia throughout labor, delivery, and repair of her first-degree tear.

Nevertheless, reservations regarding skin testing during pregnancy were expressed in correspondence following this publication, on the grounds that fetal well-being may be greatly endangered during such procedures (4r ). In response, the authors of the initial case report pointed out that according to the American Academy of Allergy, Asthma, and Immunology, “patients who are pregnant . . . should be tested only if the results are contemplated to have substantial and immediate therapeutic implications”. They suggested that the provision of regional anesthesia using local anesthetics for labor has substantial and immediate therapeutic implications for the parturient sufficient to justify their approach (6r ).

© 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

Airway anesthesia Nervous system way anesthesia.

Seizures can occur after air-

• A 70-year-old man was given lidocaine 1200 mg to anesthetize the airway before bronchoscopy and 5 minutes later had a tonic–clonic seizure lasting 2 minutes before self termination (6A ). There were no long-term harm sequelae. The lidocaine concentration 30 minutes later was 33 µmol/l and may have been as high as 40 µmol/l during the procedure.

Lidocaine is potentially toxic at concentrations over 30 µmol/l. The authors stressed that local anesthetics should be used sparingly in airway anesthesia.

Brachial plexus anesthesia Cardiovascular Cardiovascular adverse effects of brachial plexus anesthesia have been reported. • A 34-year-old man undergoing acromioplasty of the right shoulder had a sudden cardiac arrest after an interscalene brachial plexus block with a mixture of ropivacaine 150 mg and lidocaine 360 mg (7A ). After successful resuscitation, severe hypotension persisted, necessitating the use of an adrenaline infusion. The patient developed pulmonary edema and was mechanically ventilated for 22 hours. He eventually made a good recovery.

A similar report with the use of a combination of lidocaine and levobupivacaine has been published (8A ). Tachycardia was the only cardiovascular symptom, while seizures were easily treatable. Both reports are in line with the improved cardiovascular safety reported with enantiomer-specific local anesthetics as discussed below.

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146 Ear, nose, throat Vocal cord paralysis can occur when local anesthesia is used after previous damage. • A 71-year-old patient with unrecognized preexisting left vocal cord paralysis developed severe stridor and airway compromise after right-sided subclavian plexus block (9A ). The paralysis was the consequence of partial glossectomy and neck dissection 18 months earlier for squamous cell carcinoma of the tongue.

The authors recommended evaluation of vocal cord function before brachial plexus block in patients with previous surgery or radiotherapy to the neck.

Caudal, epidural, and spinal anesthesia Caudal anesthesia Caudal anesthesia is commonly used for children undergoing operations below the diaphragm. Bupivacaine has for a long time been the most common local anesthetic in use. However, the long-acting aminoamide ropivacaine is reported to have a better safety profile than bupivacaine; being a single enantiomer it carries less risk of nervous system and cardiovascular toxicity. The authors of a review article concluded that, based on current evidence, ropivacaine 0.2% is the optimal concentration for pediatric caudal block (10R ). The levorotatory enantiomer of bupivacaine, levobupivacaine, is being more widely used. Like ropivacaine it has a wider margin of safety for cardiovascular and central nervous system effects. In an open study the efficacy and safety of caudal levobupivacaine 0.25% (2 mg/kg) was studied in 49 children under 2 years of age undergoing subumbilical surgery (11c ). In 90% there was adequate analgesia. One patient had an adverse event, a mild rash, which was possibly related to levobupivacaine. Neuromuscular In a controlled, randomized study in 60 children undergoing subumbilical surgery three different concentrations of levobupivacaine were used for caudal anesthesia (12C ). The caudal block was performed with

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levobupivacaine 0.125%, 0.2%, or 0.25% (total volume 1 ml/kg). The 0.125% solution was associated with significantly less early motor blockade but also a significantly shorter duration of postoperative analgesia.

Epidural anesthesia Comparative studies Analgesia after major surgery has been evaluated in a prospective study in 2696 patients, who received either epidural or intravenous analgesia for postoperative pain relief (13c ). Epidural analgesia consisted of bupivacaine 0.25% with morphine 0.05 mg/ml and was used in 1670 patients. Intravenous analgesia with morphine 1 mg/ml was used in 1026 patients. The patients with epidural analgesia had better pain relief both at rest and during mobilization compared with intravenous analgesia. However, orthostatic dysregulation in 6%, pruritus in 4.4%, and technical problems in 6.2% were more frequent with epidural analgesia. In comparison, intravenous morphine analgesia had a higher frequency of opioid related adverse effects, such as sedation/hallucinations/nightmares/confusion in 2.5% and respiratory depression in 1.2%. This study used background infusion plus patientcontrolled analgesia in both groups, which might have affected the adverse effects in the intravenous group; perhaps another choice of epidural solution would have caused less hypotension. Cardiovascular Prolongation of the QT interval can predispose to dysrhythmias with local anesthetics. • Intraoperative cardiac arrest occurred in a 9-yearold child with Pfeiffer syndrome (craniosynostosis, mild syndactyly of hands and feet, and dysmorphic facial features) undergoing reversal of a colostomy (14A ). All previous anesthetics had been uneventful. The child received an epidural catheter at the L3/4 interspace. A test dose of 2 ml of lidocaine 1% with adrenaline 1 : 200 000 was administered and aspiration for spinal fluid was negative. One minute after the first dose of bupivacaine 0.25% 3 ml with adrenaline 1 : 200 000 he developed cardiac dysrhythmias and 3 minutes later, and before surgical incision, ventricular fibrillation. After chest compression, 100% oxygen, adrenaline, and sodium bicarbonate, sinus rhythm returned. Blood was aspirated from the epidural catheter. Postoperative investigation showed a long QT syndrome.

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Prolongation of the QT interval predisposes to ventricular dysrhythmias and can be triggered by adrenaline. In this case the authors concluded that accidental intravascular injection of bupivacaine and adrenaline may have triggered the dysrhythmia. Brugada syndrome, right bundle branch block and raised ST segments, can cause sudden cardiac death, potentially hastened by class I antidysrhythmic drugs. Intravenous sodium channel blockers such as local anesthetics can therefore unmask Brugada syndrome. • A 77-year-old man with no previous symptoms of ischemic heart disease underwent elective gastrectomy for carcinoma of the stomach (15A ). Preoperative electrocardiography showed partial right bundle branch block. An epidural catheter was inserted at interspace T9/10 before induction. Aspiration of the catheter was negative for blood and cerebrospinal fluid. Bupivacaine 0.25% 10 ml was given in 2 ml increments, and an infusion of 0.125% bupivacaine and fentanyl 2.5 µg/ml was begun at 8 ml/hour. The operation was uneventful. Three epidural bolus doses were given postoperatively over 11 hours, consisting of 0.125% bupivacaine with fentanyl 2.5 µg/ml, 8 ml, 5 ml, and 5 ml. After the last dose, his systolic blood pressure fell to 80 mmHg. An electrocardiogram showed right bundle branch block with new convex-curved ST segment elevation in V1–V3. Acute myocardial infarction was ruled out and a diagnosis of Brugada syndrome was made. Bupivacaine was withdrawn after a total infusion time of 17 hours (total dose of bupivacaine 443 mg). The patient made a complete and uneventful recovery.

This is the first reported case of Brugada syndrome unmasked by bupivacaine. Cocaine was the only local anesthetic to show this before. As Class Ib drugs such as lidocaine do not induce the characteristic electrocardiographic changes, the authors suggested that bupivacaine causes greater inhibition of the rapid phase of depolarization in Purkinje fibers and ventricular muscle, and remains bound to sodium channels for longer than lidocaine. Nervous system Horner’s syndrome has previously been reported as a complication of epidural analgesia, more commonly in parturients than in other patients. It seems that even a dilute solution, such as 0.04% bupivacaine, can cause Horner’s syndrome through high cephalad spread (16A ). • A 32-year-old woman in labor had an epidural catheter inserted at L3/4. A test dose of total 5 ml

lidocaine 1.5% with adrenaline 1 : 200 000 was followed by 15 ml of 0.04% bupivacaine with fentanyl (1.66 micrograms/ml) with the patient in the left lateral position. An infusion of the same mixture at 15 ml/hour was started. After 1 hour she developed miosis, conjunctival injection, and ptosis of the left eye. The upper sensory level was T3/T2. The epidural infusion was stopped for 1 hour and restarted at 12 ml/hour. The signs of Horner’s syndrome resolved completely after 2 hours.

Sensory systems Hearing loss after epidural block has been reported again (17A ). • A 30-year-old woman with a body mass index of 54 received an epidural catheter at the L3/4 interspace during labor. The procedure was uneventful. A test dose of 3 ml lidocaine 2% was administered. The first top-up dose consisted of 10 ml plain bupivacaine 0.25%. The sensory level was T10 bilaterally after 15 minutes. With the first top-up and every subsequent top-up dose (bupivacaine 0.1% with fentanyl 2 micrograms/ml) she complained of bilateral hearing loss, disappearing spontaneously after 30–60 seconds. After 10 hours a cesarean section was performed. Anesthesia was achieved with two injections of 10 ml of bupivacaine 0.5%. Transient deafness occurred with each top-up dose. The postoperative period was uneventful.

Transient hearing loss after epidural block occurs because the perilymph in the inner ear is in continuity with the cerebrospinal fluid and any pressure wave in the epidural space is conducted to affect the inner ear (18r ).

Intrathecal (spinal) anesthesia Comparative studies Hyperbaric ropivacaine 0.5% and hyperbaric bupivacaine 0.5% for spinal anesthesia, 3 ml of either, have been compared in 40 randomized patients undergoing lower-abdominal, perineal, or lower-limb surgery (19c ). The onset time with bupivacaine was significantly faster than with ropivacaine. The mean duration of sensory block was significantly longer with bupivacaine. The patients given ropivacaine mobilized and passed urine significantly faster than those who received bupivacaine. There was also more hypotension with bupivacaine. The authors concluded that ropivacaine 15 mg in glucose 50 mg/ml provides reliable spinal anesthesia with less hypotension than bupivacaine.

148 Nervous system The frequency of transient neurological symptoms and neurological complications after spinal anesthesia with lidocaine compared with other local anesthetics has been reviewed (20M ). Lidocaine causes transient neurological symptoms in one in seven patients receiving spinal anesthesia and the relative risk is about seven times higher for lidocaine than for bupivacaine, prilocaine, and procaine. While the latter anesthetics are associated with a lower risk of transient neurological symptoms, their longer duration or lower quality of anesthesia may limit their suitability for ambulatory surgery. Neurological defects and arachnoiditis after neuroaxial anesthesia have been reviewed (21R ). Arachnoiditis in the context of epidural anesthesia can be caused by epidural abscess, traumatic puncture, local anesthetics, detergents, and other substances unintentionally injected into the spinal canal. Severe burning pain in the lower back and legs and dysesthesia and numbness in a non-dermatomal distribution suggest direct injury to the spinal cord. Patients with these symptoms should be thoroughly examined by a neurologist, followed by an MRI scan of the affected area. The author suggested that immediate administration of glucocorticoids and NSAIDs should be considered, to prevent inflammation, which might develop into arachnoiditis. Combined spinal–epidural analgesia for labor has a well-established safety record. However, there have been reports of unusual complications including, in one case, aphonia and aphagia (22A ). • A 21-year-old otherwise healthy woman at 37 weeks gestation, with no drug allergies and no previous anesthesia, received combined spinal– epidural analgesia in the sitting position at vertebral interspace L2/3. There were no technical problems and there was free flow of cerebrospinal fluid. She was given fentanyl 10 micrograms combined with 1 ml of bupivacaine 2.5 mg/ml, and an epidural catheter was inserted to 5 cm. No blood or spinal fluid was aspirated. She reported pain relief after 2 minutes. About 4 minutes after the subarachnoid injection her voice became weak and she then lost the ability to talk and swallow. She was alert and conscious and had normal vital signs; no treatment was given and she became able talk and swallow again after 20 minutes. Uneventful epidural analgesia was later used for labor and delivery.

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The authors speculated that there had been extensive cephalad spread of fentanyl in the subarachnoid space, since there has been one previous report of dysphagia after the administration of fentanyl combined with bupivacaine using combined spinal–epidural analgesia in conjunction with labor analgesia. Seven patients with chronic pain receiving intrathecal analgesics and/or local anesthetics were screened for catheter associated masses (23c ). Three of the seven had intraspinal masses; two were asymptomatic. Patients with intraspinal masses were significantly younger and were receiving significantly higher doses of morphine than the patients without masses; it is unclear whether local anesthetics contribute to this complication. The authors concluded that patients receiving long-term intrathecal analgesia should undergo periodic radiographic surveillance to look for catheter-associated masses and to allow intervention before neurological deficits occur. Spinal myoclonus can develop as a result of stimulation of the spinal cord, which can be caused by spinal cord compression, tumors, vascular myelopathy, infections, demyelinating diseases, trauma, and paraneoplastic syndromes, but also by medications such as contrast media, local anesthetics, and analgesics. Segmental spinal myoclonus after spinal bupivacaine has been described (24A ). • A 56-year-old woman underwent surgery for bilateral leg varices; she received 3 ml of 0.5% hyperbaric bupivacaine at the L4/5 interspace. Two hours postoperatively she started to have bilateral rhythmic myoclonic movements of the legs. The frequency gradually increased and reached a maximum after 30 minutes then disappeared after another 30 minutes without any neurological sequelae.

Dental anesthesia Nervous system Paresthesia associated with the use of local anesthetics as part of dental care is infrequent, although its incidence has increased over the last 30 years. Prolonged dysesthesia has been reported in seven cases of inferior alveolar nerve block injection, all associated with articaine (25A ). The author recommended a widespread survey of the relation between prolonged dysesthesia and

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particular local anesthetic choices to clarify this apparent adverse effect. In fact, such a review was published in 2003 (26R ). The use of articaine, and to a lesser extent prilocaine, for lingual and inferior alveolar nerve blocks is associated with a higher incidence of paresthesia in these nerves compared with lidocaine, bupivacaine, or mepivacaine. This raises doubts about the suitability of articaine and prilocaine for local anesthesia in dentistry. The incidence of paresthesia associated with the use of these agents should be considered when selecting a local anesthetic for anesthesia of the mandible and associated structures.

Femoral block Infection risk Psoas abscess complicating femoral nerve block has been reported (27A ). • A 35-year-old woman was admitted for arthroscopic arthrolysis of the knee. A femoral catheter was placed before induction of general anesthesia under strict aseptic conditions. The catheter was connected via a 0.2 µm bacterial filter to an infusion device containing ropivacaine. The catheter remained in place for 4 days with no sign of infection at the site of insertion. On the fifth day she complained of lower quadrant abdominal pain and developed a fever and a raised leukocyte count. A pelvic scan showed a psoas abscess, which was drained under CT guidance. The aspirate contained Staphylococcus aureus. After antibiotic therapy the abscess resolved completely.

The authors conclude that the abscess had probably resulted from catheter colonization at a superficial site that had spread to the psoas space.

Intravenous regional anesthesia Tumescent anesthesia is an infiltration technique now widely used in cosmetic surgery. It involves the infiltration of a relatively large volume of a solution containing lidocaine, adrenaline, sodium bicarbonate, and isotonic saline into the subdermal fat plane. There have been previous descriptions of severe and even fatal complications.

Plasma lidocaine concentrations and symptoms of local anesthetic toxicity have been reported in five oriental patients after tumescent local anesthesia (28c ). The patients received lidocaine in total doses of 20–35 mg/kg. The plasma lidocaine concentration 3 hours later did not exceed the toxic concentration of 5 µg/ml and was significantly lower at 8 hours. Sensory systems Patients should be given clear instructions to protect themselves from injury after local anesthesia, as emphasized in a recent case report (29A ). • A 38-year-old woman had liposuction of the inner and outer thighs using tumescent local anesthesia and intravenous sedation. The treated areas were infiltrated with isotonic saline containing lidocaine 0.1%, 1 : 1000 adrenaline, and 10 ml of sodium bicarbonate 8.4%. The procedure took 2.5 hours and the patient was discharged 2 hours later. At home she fell asleep with a lighted cigarette in her hand. The cigarette burned through her clothes to cause a full thickness burn on her upper thigh. She did not discover the burn until the following day. The burn was painless and was treated conservatively.

Lumbar plexus block Nervous system Phantom limb pain immediately after lumbar plexus block has been described (30A ). • A 72-year-old woman with a left below-knee amputation and intermittent phantom limb pain, had a lumbar plexus block via a posterior lumbar approach before anesthesia and 30 ml of levobupivacaine 0.5% was injected after successful identification of the lumbar plexus with a nerve stimulator needle. Within 5 minutes, she had phantom limb pain in the distribution of the sciatic nerve similar to previous episodes but more severe. A sciatic nerve block was performed with 15 ml of levobupivacaine 0.5% with complete resolution of the pain within 5 minutes.

This report demonstrates unmasking of phantom limb pain in a sciatic distribution after lumbar plexus block not dissimilar from previous reports with spinal anesthesia. The authors concluded that neighboring peripheral nerves may play an inhibitory role in phantom limb pain.

150

Ocular anesthesia Death Misplacement or migration of a catheter can lead to unwanted effects, as illustrated by a recent case (31A ). • A 38-year-old woman was given 3 ml of bupivacaine 0.5% by her sister through an orbital catheter for analgesia at home around 7 hours after ambulatory surgery. She stopped breathing and could not be resuscitated. Autopsy showed that the catheter had migrated into the subarachnoid space through the superior orbital fissure, probably facilitated by deficiency of collagen II in this patient, who had Stickler syndrome.

The authors recommended that orbital indwelling catheters should be used for analgesia only in hospital. Reports of apnea and seizures with retrobulbar anesthesia continue to appear (32A ). Sub-Tenon anesthesia is regarded as being safer than retrobulbar anesthesia in regard to the risk of optic nerve injury. However, the first case report of optic neuropathy secondary to sub-Tenon anesthesia has now been published (33A ).

Paravertebral block An interesting case is described where a catheter was inadvertently placed in the subdural space during intended cannulation of the paravertebral space (34A ). • After induction of anesthesia a 49-year-old woman, scheduled for thoracotomy, was placed in the left lateral position in order to perform a right paravertebral block. After loss of resistance to air with a 16-gauge Tuohy needle, an epidural catheter was threaded 3 cm into what was thought to be the paravertebral space. Aspiration was negative and 3 ml of bupivacaine 0.5% with adrenaline 1 : 200 000 was injected as a test dose. After 10 minutes without hemodynamic compromise a further 12 ml of 0.5% bupivacaine was injected down the catheter. However, 15 minutes later the patient developed bradycardia (48/minute) and hypotension (70/40 mmHg) and required intravenous fluid 500 ml, ephedrine 30 mg, and noradrenaline to maintain arterial pressure. The noradrenaline infusion was tapered over the next 60 minutes. When she was extubated at the end of surgery over 3 hours later there was no motor or sensory block. Contrast medium injected down the catheter and subsequent X-rays and CT scans showed that the catheter was in the subdural space.

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While total dural puncture and total spinal anesthesia have been reported after attempted paravertebral block, this is the first reported case of subdural catheter placement. The authors acknowledged that the diagnosis of a misplaced catheter was masked by the general anesthesia.

Urethral anesthesia Drug formulations Plain aqueous gel and 2% lidocaine hydrochloride gel (InstagelTM ) have been compared in 100 men attending for flexible cystoscopy in a double-blind study (35C ). They were randomized to receive either 11 ml of plain aqueous gel or 11 ml of 2% lidocaine gel intraurethrally and scored discomfort with a visual analogue scale. There was significantly less urethral discomfort in the patients who received the plain gel. The authors believed that the increased discomfort associated with lidocaine gel may have been due to excipients. They concluded that there is little rationale in using lidocaine gel for cystoscopy using finecaliber flexible instruments. Competence with the cystoscope and good lubrication are essential for patient comfort during simple urethral instrumentation.

INDIVIDUAL COMPOUNDS Benzocaine

(SED-14, 351; SEDA-25, 155; SEDA-26, 144)

Hematologic Methemoglobinemia continues to be reported after the use of benzocaine, in the setting of transesophageal echocardiography (36A , 37A ), percutaneous gastrostomy tube placement (38A ), and fiberoptic intubation (39A ). There were no deaths and all the patients recovered fully when treated with methylene blue 1–2 mg/kg.

Bupivacaine

(SED-14, 351; SEDA-25, 156; SEDA-27, 131) Cardiovascular The effect of a lipid emulsion infusion on bupivacaine-induced cardiac

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toxicity has been studied in dogs (40E ). Bupivacaine 10 mg/kg was given intravenously over 10 minutes to fasted dogs under general anesthesia. Resuscitation included 10 minutes of internal cardiac massage followed by either saline or 20% lipid infusion, as a 4 mg/kg bolus followed by a continuous infusion of 0.5 ml/kg/minute for 10 minutes. Electrocardiography, arterial blood pressure, myocardial pH, and myocardial PO2 were continuously monitored. All six lipid treated dogs survived after 10 minutes of cardiac massage, but there were no survivors among the six dogs who were given saline. Hemodynamics, PO2 , and myocardial pH were also improved in the treatment group. This study supports the need for further investigation of lipid-based resuscitation to treat bupivacaine toxicity in order to determine the optimum dosage regimen. Conduction disturbances have been attributed to bupivacaine. • A 60-year-old woman with pre-existing heart failure awaiting surgery for a fractured humerus was accidentally given a mixture of bupivacaine 75 mg and clonidine 15 micrograms intravenously (41A ). She developed a nodal rhythm with extreme bradycardia, severe shock, and convulsions. Seizures were controlled with thiopental, and suxamethonium and adrenaline partially restored the blood pressure to 50/30 mmHg and the heart rate to 60/minute (nodal rhythm). After clonidine 75 micrograms intravenously, her blood pressure rose to 90/70 mmHg and her heart rate to 70/minute. Her cardiac rhythm reverted to sinus rhythm with first degree atrioventricular block.

The authors concluded that clonidine had reversed bupivacaine-induced conduction disturbances. Cardiopulmonary bypass has been used to successfully treat bupivacaine-induced cardiovascular collapse (42A ). • A 39-year-old woman (72 kg, 165 cm) with congenital clubfoot presented for total right ankle arthroplasty. She had no history of syncope, seizures, coronary artery disease, or congenital heart disease. After induction of anesthesia she received a popliteal nerve block with 30 ml of 0.5% bupivacaine using a nerve stimulator device. Communication was maintained with the patient throughout the injection, and she denied any neurological symptoms suggestive of intravascular injection. About 30 seconds after the block, she had a generalized tonic–clonic seizure and soon afterwards developed ventricular fibrillation. Advanced cardiac life support was begun. She was

given adrenaline 2 mg and bretylium 1000 mg intravenously, as well as six attempts at electrical defibrillation. Bupivacaine cardiotoxicity because of inadvertent intravascular injection was suspected and cardiopulmonary bypass was begun and continued for 30 minutes. She was extubated on the second postoperative day and discharged home on postoperative day 10 with no neurological sequelae.

The prolonged duration of cardiac support needed after refractory drug-induced cardiotoxicity may make cardiopulmonary bypass, although invasive, the best option for successful resuscitation of such patients. Notwithstanding the practical and technical limitations of staff and equipment availability, the authors argued that cardiopulmonary bypass should become first-line therapy after unsuccessful basic resuscitation in such cases.

Levobupivacaine

(SEDA-26, 146;

SEDA-27, 133) Nervous system There have been two reports of generalized tonic–clonic seizures in patients who have received levobupivacaine for lumbar plexus block in elective orthopedic surgery (43A ). • A 71-year-old woman presented for elective total knee arthroplasty under combined lumbar plexus and sciatic nerve block. After midazolam and fentanyl sedation a lumbar plexus block was performed with 30 ml of levobupivacaine 0.5% and adrenaline 2.5 micrograms/ml. Slow injection of levobupivacaine with repeated negative aspiration of blood was performed over 90 seconds. She had a tonic–clonic seizure within 1 minute of injection. She was given thiopental, midazolam, and suxamethonium and was intubated and ventilated. There were no cardiovascular problems, surgery was completed, and she made a full recovery. Postoperatively she had sensory and motor blockade in the distribution of the lumbar plexus. • A 66-year-old man scheduled for total hip arthroplasty under general anesthesia had a lumbar plexus block performed after sedation with midazolam and fentanyl. He was in the lateral position and received 35 ml of levobupivacaine 0.5% with adrenaline 2 micrograms/ml over 90 seconds with aspiration every 5 ml. Immediately after the end of the injection he had a tonic–clonic seizure, which was terminated by intravenous thiopental 75 mg. There were no further adverse events and he underwent the planned procedure under general anesthesia and had an unremarkable postoperative course. Postoperatively he had a motor and sensory block in the distribution of the lumbar plexus.

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In a similar report tonic–clonic seizures after interscalene brachial plexus block have been described (44A ).

Ropivacaine

• A 27-year-old woman was given 30 ml of levobupivacaine for shoulder surgery, with no evidence of blood or CSF aspiration at any time during the injection. Her seizure activity ended after 2 minutes and after the administration of midazolam 2 mg. She remained cardiovascularly stable throughout the procedure with no electrocardiographic disturbance. Despite signs of pulmonary edema postoperatively, she made a full recovery and was discharged the following morning.

Cardiovascular The first cases of cardiac arrest due to ropivacaine toxicity have been reported; three related to the administration of ropivacaine for lower limb block.

Although it is well known that tonic–clonic seizures can occur as a result of toxic effects of other local anesthetics, including bupivacaine and ropivacaine, these are the first reports of seizures after levobupivacaine. The authors concluded that in view of the rapid onset of seizure activity there was probably inadvertent intravascular injection of local anesthetic in all three cases. This was despite slow injection, careful attention to aspiration, and the addition of adrenaline as a marker of intravascular injection. None of the patients developed any dysrhythmias or cardiovascular changes attributable to local anesthetic toxicity. These case reports are in line with previous descriptions of toxic effects of single enantiomers of local anesthetics, in which nervous system manifestations are predominant and cardiovascular collapse is rare. In a volunteer study ropivacaine and levobupivacaine had similar nervous system and cardiovascular effects after deliberate intravenous infusion (45C ).

Lidocaine

(SED-14, 349; SEDA-26, 146;

SEDA-27, 133) Cardiovascular There have been two reports of lidocaine-induced vasospasm after intraarterial injection to overcome constriction of a brachial artery after vascular surgical repair and after digital nerve block for hand surgery (46A ). While this sounds paradoxical, the authors pointed out that local anesthetics regulate vascular tension in a biphasic manner, and that lower concentrations cause vasoconstriction. Immunologic Delayed-type hypersensitivity to lidocaine is rare; of 1883 patients patch tested for suspected contact type IV sensitivity, only four had positive reactions (47c ).

(SED-14, 353; SEDA-25, 156; SEDA-26, 147; SEDA-27, 134)

• A 76-year-old woman underwent foot osteotomy under combined femoral and sciatic nerve block (48A ). A femoral nerve block using 20 ml of mepivacaine 1.5% with 1 : 400 000 adrenaline was followed by sciatic nerve block with 32 ml of ropivacaine 0.5% and 1 : 400 000 adrenaline. The injection was stopped as the patient became less responsive, developed twitching of the hand and face, and had a tonic–clonic seizure, which was terminated with intravenous propofol. She was intubated, developed a bradycardia with wide QRS complexes, and subsequently developed ventricular fibrillation. She was given adrenaline and sinus rhythm returned. She made a complete recovery and was discharged on the next day. The total ropivacaine concentration was 3.2 µg/ml, the unbound ropivacaine concentration 0.5 µg/ml, and the mepivacaine concentration 0.22 µg/ml 5 minutes after the injection. • A 66-year-old woman was admitted for foot surgery and underwent sciatic nerve block with 25 ml of ropivacaine 0.75% (49A ). The block was deemed inadequate for surgery and a further 15 ml of ropivacaine 0.75% was used to block the tibial and peroneal nerves at the ankle, resulting in a total ropivacaine dose of 300 mg (6.7 mg/kg). After 1 hour she became agitated and confused and then unresponsive with abnormal oculogyric movements. An electrocardiogram showed wide QRS complexes with worsening bradycardia, despite treatment with atropine and ephedrine. She then had an asystolic cardiac arrest and cardiopulmonary resuscitation was started. More ephedrine was given intravenously. Sinus rhythm was rapidly restored and return of cardiac output was accompanied by return of spontaneous respiration. The ropivacaine concentration was 1.88 µg/ml 70 minutes after the adverse event. She made a full recovery. • A 66-year-old man scheduled for hip arthroplasty received a lumbar plexus block with 25 ml of ropivacaine 0.75% (total dose 187.5 mg, 1.88 mg/kg) (50A ). Two minutes after the injection he had a tonic–clonic seizure, for which diazepam was given. He became asystolic and cardiopulmonary resuscitation was begun. After 5 minutes of cardiopulmonary resuscitation and intravenous adrenaline, cardiac activity was restored. An electrocardiogram showed sinus bradycardia with wide QRS complexes, but this normalized after a further 10 minutes. He was extubated 2 hours later and made a full recovery. The ropivacaine concentration 55 minutes after the episode was 5.61 µg/ml.

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In two of these cases the onset of adverse effects was within moments of injection of ropivacaine; the authors concluded that inadvertent intravascular injection was likely to have occurred, despite negative aspiration of blood. In the other case there was a delay of 1 hour between nerve block and cardiac arrest, implying ropivacaine toxicity due to absorption, and the authors acknowledged that the dose of ropivacaine had been excessive. While cardiac arrest after administration of other local anesthetic agents, such as bupivacaine, is often reported, these are the first cases associated with the use of ropivacaine. In the first case a combination of mepivacaine and ropivacaine was used; however, it is reasonable to conclude that cardiac arrest was due to inadvertent intravascular administration of ropivacaine, as ropivacaine concentrations were high after the episode.

153 On all three occasions cardiac arrest was immediately preceded by loss of consciousness and a seizure or seizure-like activity. All cases were also associated with bradycardia and wide QRS complexes. On all three occasions cardiac massage was rapidly successful and sinus rhythm was restored without defibrillation or antidysrhythmic drugs. These findings are in stark contrast to cardiac arrest associated with bupivacaine toxicity, which is particularly refractory to treatment and often requires prolonged resuscitation. This suggests that cardiac arrest in the context of ropivacaine toxicity may not only be less likely than with equal doses of bupivacaine, but also more easily treated. Ropivacaine also had significantly less myotoxic potential than bupivacaine in minipigs, when it was injected through femoral nerve catheters (51E ).

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154 20. Zaric D, Christiansen C, Pace NL, Punjasawadwong Y. Transient neurologic symptoms (TNS) following spinal anaesthesia with lidocaine versus other local anaesthetics. Cochrane Database Syst Rev 2003; 2: CD003006. 21. Aldrete JA. Neurologic deficits and arachnoiditis following neuroaxial anesthesia. Acta Anaesthesiol Scand 2003; 47: 3–12. 22. Kuczkowski KM, Goldsworthy M. Transient aphonia and aphagia in a parturient after induction of combined spinal–epidural labor analgesia with subarachnoid fentanyl and bupivacaine. Acta Anaesthesiol Belg 2003; 54: 165–6. 23. McMillan MR, Doud T, Nugent W. Catheterassociated masses in patients receiving intrathecal analgesic therapy. Anesth Analg 2003; 96: 186–90. 24. Celik Y, Bekir Demirel C, Karaca S, Kose Y. Transient segmental spinal myoclonus due to spinal anaesthesia with bupivacaine. J Postgrad Med 2003; 49: 286. 25. Pedlar J. Prolonged paraesthesia following inferior alveolar nerve block using articaine. Br J Oral Maxillofac Surg 2003; 41: 202. 26. Dower Jr JS. A review of paresthesia in association with administration of local anesthesia. Dent Today 2003; 22: 64–9. 27. Oba H. Large-volume tumescent anesthesia for extensive liposuction in oriental patients: lidocaine toxicity and its safe dose level. Plast Reconstr Surg 2003; 111: 945–6. 28. Grose DJ. Cigarette burn after tumescent anesthesia and intravenous sedation: a case report. Dermatol Surg 2003; 29: 433–5. 29. Garg S, Piva A, Sanchez RN, Sadun AA. Death associated with an indwelling orbital catheter. Ophthal Plast Reconstr Surg 2003; 19: 398–400. 30. Moorthy SS, Zaffer R, Rodriguez S, Ksiazek S, Yee RD. Apnea and seizures following retrobulbar local anesthetic injection. J Clin Anesth 2003; 15: 267–70. 31. Kim SK, Andreoli CM, Rizzo 3rd JF, Golden MA, Bradbury MJ. Optic neuropathy secondary to sub-Tenon anesthetic injection in cataract surgery. Arch Ophthalmol 2003; 121: 907–9. 32. Martin G, Grant SA, Macleod DB, Breslin DS, Brewer RP. Severe phantom leg pain in an amputee after lumbar plexus block. Reg Anesth Pain Med 2003; 28: 475–8. 33. Adam F, Jaziri S, Chauvin M. Psoas abscess complicating femoral nerve block catheter. Anesthesiology 2003; 99: 230–1. 34. Garutti I, Hervias M, Barrio JM, Fortea F, De La Torre J. Subdural spread of local anesthetic agent following thoracic paravertebral block and cannulation. Anesthesiology 2003; 98: 1005–7. 35. Ho KJ, Thompson TJ, O’Brien A, Young MR, McCleane G. Lignocaine gel: does it cause urethral pain rather than prevent it? Eur Urol 2003; 43: 194– 6. 36. Vidyarthi V, Manda R, Ahmed A, Khosla S, Lubell DL. Severe methemoglobinemia after trans-

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esophageal echocardiography. Am J Ther 2003; 10: 225–7. 37. Aepfelbacher FC, Breen P, Manning WJ. Methemoglobinemia and topical pharyngeal anesthesia. New Engl J Med 2003; 348: 85–6. 38. Patel PB, Logan GW, Karnad AB, Byrd Jr RP, Roy TM. Acquired methemoglobinemia: a rare but serious complication. Tenn Med 2003; 96: 373–6. 39. Rinehart RS, Norman D. Suspected methemoglobinemia following awake intubation: one possible effect of benzocaine topical anesthesia— a case report. AANA J 2003; 71: 117–18. 40. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198–202. 41. Favier JC, Da Conceicao M, Fassassi M, Allanic L, Steiner T, Pitti R. Successful resuscitation of serious bupivacaine intoxication in a patient with pre-existing heart failure. Can J Anaesth 2003; 50: 62–6. 42. Soltesz EG, van Pelt F, Byrne JG. Emergent cardiopulmonary bypass for bupivacaine cardiotoxicity. J Cardiothorac Vasc Anesth 2003; 17: 357–8. 43. Breslin DS, Martin G, Macleod DB, D’Ercole F, Grant SA. Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: a report of two cases. Reg Anesth Pain Med 2003; 28: 144–7. 44. Crews JC, Rothman TE. Seizure after levobupivacaine for interscalene brachial plexus block. Anesth Analg 2003; 96: 1188–90. 45. Stewart J, Kellett N, Castro D. The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg 2003; 97: 412–16. 46. Azma T, Okida M. Does lidocaine provoke clinically significant vasospasm? Acta Anaesthesiol Scand 2003; 47: 1174–5. 47. Mackley CL, Marks Jr JG, Anderson BE. Delayed-type hypersensitivity to lidocaine. Arch Dermatol 2003; 139: 343–6. 48. Klein SM, Pierce T, Rubin Y, Nielsen KC, Steele SM. Successful resuscitation after ropivacaine-induced ventricular fibrillation. Anesth Analg 2003; 97: 901–3. 49. Chazalon P, Tourtier JP, Villevielle T, Giraud D, Saissy JM, Mion G, Benhamou D. Ropivacaineinduced cardiac arrest after peripheral nerve block: successful resuscitation. Anesthesiology 2003; 99: 1449–51. 50. Huet O, Eyrolle LJ, Mazoit JX, Ozier YM. Cardiac arrest after injection of ropivacaine for posterior lumbar plexus blockade. Anesthesiology 2003; 99: 1451–3. 51. Zink W, Seif C, Bohl JRE, Hacke N, Braun PM, Sinner B, Martin E, Fink RH, Graf BM. The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades. Anesth Analg 2003; 97: 1173–9.

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Neuromuscular blocking agents and skeletal muscle relaxants

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14, 371; SEDA-25, 160; SEDA-26, 150; SEDA-27, 139)

Cisatracurium Neuromuscular Another example of flaccid paralysis after long-term use of a nondepolarizing muscle relaxant has been published, in this instance related to cisatracurium (1A ). While prolonged paralysis after the use of cisatracurium in intensive care had been described before (2A ), the authors of the recent report provided additional information related to the pathophysiology of neuromuscular function in their patient. Based on some previous studies, paralysis after neuromuscular blockers and glucocorticoids was thought to represent an intramuscular problem. However, electrophysiological studies in this case yielded a diagnosis of axonal neuropathy. This points to a critical illness polyneuropathy rather than an effect of cisatracurium.

Mivacurium Respiratory Triggered by requests for a medico-legal consultation for bronchospasm, the authors of a recent paper queried the Food and Drug Administration MedWatch database to assess whether adverse events leading to bronchospasm or asthma occurred more often © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

with mivacurium than with other muscle relaxants (3c ). Bronchospasm constituted 22% of the events with mivacurium, 14% with atracurium, 11% with vecuronium, 7.6% with rocuronium, and 2.0% with pancuronium. These figures emphasize the recommendation of the manufacturers that caution be taken when giving mivacurium to “patients with clinically significant cardiovascular disease and patients with any history suggesting a greater sensitivity to the release of histamine or related mediators”.

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14, 361; SEDA-24, 158; SEDA-25, 161; SEDA-26, 151)

Suxamethonium Suxamethonium and postoperative myalgia Generalized postoperative muscle pain associated with suxamethonium is a common problem that became apparent immediately after its introduction in the early 1950s (4c ). On average, 50% of the patients who receive suxamethonium during induction of anesthesia will complain of postoperative myalgia, which normally lasts 2 to 3 days (5R ). Mechanism The underlying mechanism is not well understood. Initially, suxamethonium was thought to cause direct muscle damage (6c ). However, no correlation was found between pain and biochemical changes that were assumed to represent muscle cell damage (7c ,

155

156 8c ). Subsequently, it was believed that generalized suxamethonium-induced fasciculation and asynchronous contraction of adjacent muscle fibers might result in damage to muscle fibers, causing pain (9c ). Fasciculation is thought to be mediated via presynaptic acetylcholine receptors (10c ). But the severity of fasciculation does not seem to correspond to the frequency or intensity of postoperative myalgia (11c –18c ). Serum potassium concentrations were higher in patients who developed myalgia (19c ) than in those who did not, but the implication of this is not clear. Intracellular lactic acid accumulation has also been considered but never substantiated (20r ). It has also been hypothesized that serotonin release (21c ) or calcium influx (19c ) might play a role. Some have suggested an inflammatory component (8c , 14c , 22c –24c ). However, the authors of a recent study were unable to show any effect of dexamethasone or to establish a relation between myalgia and post-suxamethonium increases in serum interleukin-6 concentrations, and therefore suggested that there was no evidence of an inflammatory origin (25c ). Prevention Many drugs and techniques have been investigated for the prevention of postsuxamethonium myalgia, with variable results. It has recently been reported that patients who received a high dose (3.5 mg/kg) of propofol for induction of anesthesia had a significantly lower incidence of myalgia (29%) than patients who were given either a standard dose of propofol 2 mg/kg (61%) or thiopental 5 mg/kg (63%) (18c ). Continuous propofol administration had previously been shown to be effective in preventing myalgia (26c ), while studies using a single dose had produced conflicting results (27c , 28c ). A very low incidence of post-suxamethonium myalgia was achieved when lidocaine 1.5 mg/kg and a small dose of atracurium (0.05 mg/kg) were combined (29c ). This pre-treatment can therefore be considered the approach of choice, but the patient needs to be closely observed for signs of partial curarization before injection of the induction agent, and the dose of suxamethonium needs to be increased to 1.5 mg/kg.

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Drug dosage regimens The short duration of action of suxamethonium is regarded as one of its big advantages over other muscle relaxants, as return of spontaneous ventilation can be expected within a few minutes in cases of failed intubation. Recently, the optimal dose in this respect has received some attention. In one study, a dose of 0.56 mg/kg was found to result in acceptable intubation conditions in 95% of the patients (30c ), while the authors of another paper reported that the duration of action shortened significantly when the dose was reduced to 0.6 mg/kg (31c ). However, as highlighted in an accompanying editorial (32r ), this does not apply to all patients, and even with such a low dose the duration of action was still as long as 11 minutes in some individuals. The reduced dose is not intrinsically safer but is associated with a higher incidence of unacceptable intubation conditions. Therefore, we agree with Donati, who concluded in his editorial that the traditional dose of 1 mg/kg is not a bad choice after all. Drug interactions Alkylating agents As suxamethonium is normally metabolized by plasma cholinesterase, only a small proportion of the injected dose reaches the neuromuscular junction. When plasma cholinesterase activity is significantly reduced a larger proportion of suxamethonium enters the neuromuscular junction, resulting in prolonged neuromuscular blockade. A variety of drugs and medical conditions are associated with this problem, and another example has recently been described (33A ). • A 65-year-old man became severely depressed after his first dose of chemotherapy for non-Hodgkin lymphoma. He was given venlafaxine, olanzapine, and lithium, but his depression worsened and electroconvulsive therapy was started. After three uneventful treatment sessions he allowed chemotherapy to be restarted with cyclophosphamide, doxorubicin, vincristine, and prednisolone. After the fourth electroconvulsive treatment, he had apnea for 45 minutes after thiopental 200 mg and suxamethonium 40 mg. Using a peripheral nerve stimulator, four equal twitch responses to train-offour stimulation were observed after 30 minutes. He recovered fully. A blood sample taken during the episode showed a dibucaine number of 73 (reference range 76–83), a fluoride number of 53 (56–65), a K002/0683 number of 86 (93–98), and a plasma cholinesterase activity of 339 units/l (600– 1400).

Neuromuscular blocking agents and skeletal muscle relaxants

Referring to previous reports the authors suggested that cyclophosphamide-induced inhibition of plasma cholinesterase might have caused prolonged neuromuscular blockade after suxamethonium. Indeed, it has long been known that nitrogen mustards and related agents, such as cyclophosphamide, chlorambucil, triethylmelamine, and thiophosphoramide, can prolong the action of suxamethonium, which probably reduce plasma cholinesterase activity by alkylation of the enzyme (SED 14, 368). On the other hand, suxamethonium has been used in a patient taking cyclophosphamide without any evidence of prolonged action (34A ). If it is indicated, suxamethonium can be used in these patients, but neuromuscular transmission should be monitored.

SKELETAL MUSCLE RELAXANTS (SED-14, 390; SEDA-24, 159; SEDA-25, 163; SEDA-26, 152; SEDA-27, 141)

Baclofen In 16 patients with non-acid duodenogastroesophageal reflux (or duodenal reflux) baclofen improved reflux and symptoms (35c ). The dose of baclofen was 5 mg tds, increasing by 5 mg every fourth day to a dose of 20 mg tds. Four patients reported adverse effects of nausea or drowsiness. Nervous system Baclofen is a GABA receptor agonist and can therefore produce nervous system suppression, especially in cases of overdose. However, some concern has been raised that baclofen might be associated with newonset seizures in children (36A ). Among 35 children with cerebral palsy aged 1–10 years, five developed new-onset seizures within 1– 2.5 months after baclofen was started or the

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dose was increased (dosage range 0.36–1.5 mg/kg/day). While the authors admitted that young children with cerebral palsy have a significant risk of developing seizures independent of other factors, they still felt that there might be an association with baclofen. Indeed, studies in animals have suggested that baclofen may have proconvulsive properties (37E ), and three clinical papers have linked baclofen to convulsions. In one of these, two patients with tonic–clonic seizures among 14 adolescents with baclofen intoxication were described (38A ). There were also cases of seizures in three adults with traumatic brain injury who were treated with intrathecal baclofen and in a patient with multiple sclerosis (39A , 40A ). We conclude that baclofen has some proconvulsive properties, which rarely result in clinically important effects. In most of the reported cases baclofen was continued with concomitant antiepileptic medication.

Tizanidine Drug interactions Fluvoxamine, a selective serotonin reuptake inhibitor, has recently been reported to have significant interactions with tizanidine (41c ). In healthy volunteers who took fluvoxamine 100 mg/day for 4 days, peak plasma concentrations of tizanidine after a single dose of 4 mg were 12 times higher than those observed previously in the same individuals without fluvoxamine. At the same time, the half-life increased from 1.5 to 4.3 hours. This was accompanied by a low arterial blood pressure, cognitive impairment, and drowsiness. The underlying mechanism seemed to be inhibition by fluvoxamine of tizanidine metabolism, by CYP1A2 in particular. The authors suggested that these two drugs should not be used together.

REFERENCES 1. Fodale V, Pratico C, Girlanda P, Baradello A, Lucanto T, Rodolico C, Nicolosi C, Rovere V, Santamaria LB, Dattola R. Acute motor axonal polyneuropathy after a cisatracurium infusion and

concomitant corticosteroid therapy. Br J Anaesth 2004; 92: 289–93. 2. Davis NA, Rodgers JE, Gonzalez ER, Fowler AA. Prolonged weakness after cisatracurium in-

158 fusion: a case report. Crit Care Med 1998; 26: 1290–2. 3. Bishop MJ, JT OD, Salemi JR. Mivacurium and bronchospasm. Anesth Analg 2003; 97: 484–5. 4. Churchill-Davidson HC. Suxamethonium (succinylcholine) chloride and muscle pains. Br Med J 1954; 4853: 74–5. 5. Wong SF, Chung F. Succinylcholine-associated postoperative myalgia. Anaesthesia 2000; 55: 144– 52. 6. Tammisto T, Airaksinen M. Increase of creatine kinase activity in serum as a sign of muscular injury caused by intermittently administered suxamethonium during halothane anaesthesia. Br J Anaesth 1966; 38: 510–15. 7. Laurence AS. Myalgia and biochemical changes following intermittent suxamethonium administration. Effects of alcuronium, lignocaine, midazolam and suxamethonium pretreatments on serum myoglobin, creatinine kinase and myalgia. Anaesthesia 1987; 42: 503–10. 8. McLoughlin C, Elliott P, McCarthy G, Mirakhur RK. Muscle pains and biochemical changes following suxamethonium administration after six pretreatment regimens. Anaesthesia 1992; 47: 202–6. 9. Waters DJ, Mapleson WW. Suxamethonium pains: hypothesis and observation. Anaesthesia 1971; 26: 127–41. 10. Bowman WC. Prejunctional and postjunctional cholinoceptors at the neuromuscular junction. Anesth Analg 1980; 59: 935–43. 11. Ferres CJ, Mirakhur RK, Craig HJ, Browne ES, Clarke RS. Pretreatment with vecuronium as a prophylactic against post-suxamethonium muscle pain. Br J Anaesth 1983; 55: 735–41. 12. O’Sullivan E, Williams N, Calvey T. Differential effects of neuromuscular blocking agents on suxamethonium-induced fasciculations and myalgia. Br J Anaesth 1988; 60: 367–71. 13. Lee TL, Aw TC. Prevention of succinylcholineinduced myalgia with lidocaine pretreatment. J Anesth 1991; 5: 239–46. 14. Leeson-Payne CG, Nicoll JM, Hobbs GJ. Use of ketorolac in the prevention of suxamethonium myalgia. Br J Anaesth 1994; 73: 788–90. 15. Nigrovic V, Wierda JM. Post-succinylcholine muscle pain and smoking. Can J Anaesth 1994; 41: 453–4. 16. Findlay GP, Spittal MJ. Rocuronium pretreatment reduces suxamethonium-induced myalgia: comparison with vecuronium. Br J Anaesth 1996; 76: 526–9. 17. Harvey SC, Roland P, Bailey MK, Tomlin MK, Williams A. A randomized, doubleblind comparison of rocuronium, d-tubocurarine, and “mini-dose” succinylcholine for preventing succinylcholine-induced muscle fasciculations. Anesth Analg 1998; 87: 719–22. 18. Kararmaz A, Kaya S, Turhanoglu S, Ozyilmaz MA. Effects of high-dose propofol on succinylcholine-induced fasciculations and myalgia. Acta Anaesthesiol Scand 2003; 47: 180–4. 19. Collier CB. Suxamethonium pains and early electrolyte changes. Anaesthesia 1978; 33: 454–61.

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20. König W. Über Beschwerden nach Anwendung von Succinylcholin. Anaesthesist 1956; 5: 50. 21. Kaniaris P, Galanopoulou T, Varonos D. Effects of succinylcholine on plasma 5-HT levels. Anesth Analg 1973; 52: 425–7. 22. Naguib M, Farag H, Magbagbeola JA. Effect of pre-treatment with lysine acetyl salicylate on suxamethonium-induced myalgia. Br J Anaesth 1987; 59: 606–10. 23. McLoughlin C, Nesbitt GA, Howe JP. Suxamethonium induced myalgia and the effect of pre-operative administration of oral aspirin. A comparison with a standard treatment and an untreated group. Anaesthesia 1988; 43: 565–7. 24. Kahraman S, Ercan S, Aypar U, Erdem K. Effect of preoperative i.m. administration of diclofenac on suxamethonium-induced myalgia. Br J Anaesth 1993; 71: 238–41. 25. Schreiber JU, Mencke T, Biedler A, Furst O, Kleinschmidt S, Buchinger H, Fuchs-Buder T. Postoperative myalgia after succinylcholine: no evidence for an inflammatory origin. Anesth Analg 2003; 96: 1640–4. 26. Manataki AD, Arnaoutoglou HM, Tefa LK, Glatzounis GK, Papadopoulos GS. Continuous propofol administration for suxamethoniuminduced postoperative myalgia. Anaesthesia 1999; 54: 419–22. 27. Maddineni VR, Mirakhur RK, Cooper AR. Myalgia and biochemical changes following suxamethonium after induction of anaesthesia with thiopentone or propofol. Anaesthesia 1993; 48: 626–8. 28. McClymont C. A comparison of the effect of propofol or thiopentone on the incidence and severity of suxamethonium-induced myalgia. Anaesth Intensive Care 1994; 22: 147–9. 29. Raman SK, San WM. Fasciculations, myalgia and biochemical changes following succinylcholine with atracurium and lidocaine pretreatment. Can J Anaesth 1997; 44: 498–502. 30. Naguib M, Samarkandi A, Riad W, Alharby SW. Optimal dose of succinylcholine revisited. Anesthesiology 2003; 99: 1045–9. 31. Kopman AF, Zhaku B, Lai KS. The “intubating dose” of succinylcholine: the effect of decreasing doses on recovery time. Anesthesiology 2003; 99: 1050–4. 32. Donati F. The right dose of succinylcholine. Anesthesiology 2003; 99: 1037–8. 33. Norris JC. Prolonged succinylcholine apnoea resulting from acquired deficiency of plasma cholinesterase. Anaesthesia 2003; 58: 1137. 34. Dillman JB. Safe use of succinylcholine during repeated anesthetics in a patient treated with cyclophosphamide. Anesth Analg 1987; 66: 351–3. 35. Koek GH, Sifrim D, Lerut T, Janssens J, Tack J. Effect of the GABAB agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut 2003; 52: 1397–402. 36. Hansel DE, Hansel CR, Shindle MK, Reinhardt EM, Madden L, Levey EB, Johnston MV, Hoon Jr AH. Oral baclofen in cerebral palsy: possible

Neuromuscular blocking agents and skeletal muscle relaxants seizure potentiation? Pediatr Neurol 2003; 29: 203– 6. 37. Burgard EC, Sarvey JM. Long-lasting potentiation and epileptiform activity produced by GABAB receptor activation in the dentate gyrus of rat hippocampal slice. J Neurosci 1991; 11: 1198–209. 38. Perry HE, Wright RO, Shannon MW, Woolf AD. Baclofen overdose: drug experimentation in a group of adolescents. Pediatrics 1998; 101: 1045–8. 39. Kofler M, Kronenberg MF, Rifici C, Saltuari L, Bauer G. Epileptic seizures associated with in-

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trathecal baclofen application. Neurology 1994; 44: 25–7. 40. Zak R, Solomon G, Petito F, Labar D. Baclofeninduced generalized nonconvulsive status epilepticus. Ann Neurol 1994; 36: 113–4. 41. Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther 2004; 75: 331–41.

Michael Schachter

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Drugs that affect autonomic functions or the extrapyramidal system

DRUGS THAT STIMULATE BOTH ALPHA- AND BETA-ADRENOCEPTORS (SED-14, 414; SEDA-25, 166; SEDA-26, 156; SEDA-27, 145)

Adrenaline Cardiovascular Adrenaline has retained, and no doubt will retain, its pre-eminent role in the management of life-threatening anaphylaxis. But it should not need to be noted that it is a dangerous drug. Immunologists from Bristol have described two cases in which it was used in non-critical circumstances and caused severe adverse effects, including myocardial ischemia and dysrhythmias (1A ). • A 64-year-old man was given an EpiPen to treat episodes of benign angioedema affecting the face and tongue, although he never considered the reaction to be life-threatening, and on two occasions was treated in an accident and emergency department with intramuscular adrenaline (doses not specified). On one occasion he developed chest pain and electrocardiographic signs of ischemia, which had not occurred before. The EpiPen was withdrawn and his angioedema was prevented by regular antihistamine administration. • A 40-year-old woman developed angioedema after taking pseudoephedrine and diphenhydramine for sinusitis. Her breathing was not compromised and she was not hypotensive but she was given 1ml of 1 in 1000 adrenaline intravenously, with subsequent ventricular tachycardia requiring cardiopulmonary resuscitation. Despite this an EpiPen was dispensed, though later withdrawn. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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The authors commented that adrenaline could and should have been avoided in both cases. In response to this report immunologists from Melbourne commented that in the first case it was difficult to be sure that angioedema of the tongue was really benign, while in the second adrenaline should not have been given intravenously and certainly not in such a high dose (2r ). They therefore counselled against excessive caution in the use of adrenaline, provided the dose and route of administration are correct. Adrenaline is widely used in topical anesthesia, when of course systemic administration is not intended. • A 19-year-old woman was given subcutaneous 0.25% bupivacaine with 1 : 100 000 adrenaline during arthroscopic knee surgery (3A ). Dilute adrenaline (calculated to be 0.3 µg/ml) was also used to irrigate the joint space during the procedure. There was sudden onset of hypertension and tachycardia (240/150 mmHg, heart rate 150/minute) and esmolol was immediately administered, but this was followed by acute pulmonary edema. She was treated with furosemide and hydrocortisone, but required mechanical ventilation. She recovered within 24 hours, with no evidence of ischemic myocardial damage.

The authors noted that in over 50 patients in whom dilute adrenaline irrigation was used for orthopedic procedures there were no cardiopulmonary complications (4c ). The authors could not be sure why this almost fatal complication occurred on this occasion, but they warned others of the possibility and emphasized the importance of accurate calculation of adrenaline concentrations (although there is no evidence of error in this case). Adrenaline is also used as an adjunct to interscalene block during shoulder surgery,

Drugs that affect autonomic functions or the extrapyramidal system

which is often performed with the patient in a sitting position. Up to 28% of patients develop hypotension, bradycardia, or both. In a prospective study intended to determine the role of adrenaline in these reactions in nonarthroscopic shoulder surgery 55 patients were given a scalene block with 0.5% bupivacaine and 2.5% lidocaine, together with 1 : 200 000 adrenaline, while a matched group of 55 patients had the same local anesthetics without the adrenaline (5c ). The incidence of hypotension or bradycardia was 28% in the adrenaline group but only 11% in the control group. Overall, however, the adrenaline-treated patients had higher intraoperative heart rates and blood pressures. Understandably, the authors argued against the use adrenaline in this setting. Long QT syndrome has been described as the mechanism of adrenaline-induced cardiac arrest (6A ). • A 9-year-old boy with multiple congenital abnormalities was given epidural anesthesia containing 0.25% bupivacaine and 1 : 200 000 adrenaline before closure of a colostomy. This led within a few minutes to ventricular tachycardia and then two episodes of ventricular fibrillation. There was full recovery after cardiopulmonary resuscitation, without the need for cardioversion. It was then found that the epidural catheter had in fact entered a vein. Subsequent electrocardiograms showed consistent prolongation of the QTc interval and the patient was therefore clearly at increased risk.

The main point of this case is the potential danger of accidental intravenous adrenaline injection even at very high dilutions.

Ephedrine The use of ephedrine alone or ephedrine plus caffeine is associated with an increased risk of psychiatric, autonomic, gastrointestinal, and cardiovascular symptoms (7M ). The hazard associated with use of over-thecounter nutritional supplements by athletes has been illustrated (8c ). • A 24-year-old, previously healthy, male university athlete developed a severe right-sided headache and collapsed with left-sided weakness while sprinting (9R ). Earlier that morning he had taken at least five tablets of Xenadrine, each of which contained ephedrine 34 mg, pseudoephedrine 24 mg,

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methylephedrine 6 mg, and caffeine 363 mg. He was not taking any other medications and had no history of trauma. His blood pressure was 137/87 mmHg and his heart rate 58/minute. Imaging showed moderate vasospasm in the right middle cerebral artery. He was treated with milrinone and heparin, and after 6 days was discharged to a rehabilitation center taking prophylactic aspirin.

This report illustrates the serious potential consumption of nutritional supplements containing ephedrine by the public and in particular by athletes. Ephedra contains ephedrine and is often used under the name Ma Huang in traditional Chinese medicine. In the West it has been promoted as an aid to weight loss but has been banned in several countries because of serious safety concerns. The relative risk of an adverse reaction to Ephedra was more than 100 times higher than with other popular herbal medicines (10R ). Ephedra self-medication has been associated with many adverse effects, including myocardial infarction (11A ), psychoses (12A , 13A ), and liver damage (14A ).

DRUGS THAT PREDOMINANTLY STIMULATE ALPHA1 -ADRENOCEPTORS (SED-14, 417; SEDA-25, 167; SEDA-26, 157; SEDA-27, 147)

Phenylpropanolamine Nervous system Phenylpropanolamine has now disappeared in many countries, as noted in previous editions of the Annual, but it still causes problems. In a study of the relation between phenylpropanolamine ingestion and intracranial haemorrhage between 1991 and 2000 the authors identified 177 patients, of whom 119 had an intracerebral haemorrhage and the remaining 58 had a subarachnoid haemorrhage (15C ). They were matched for age, sex, and place of residence with 996 individuals. Of the patients 73 (41%) had ingested phenylpropanolamine in the preceding year and in 10 (5.7%) there was a possible temporal relation between the drug and the clinical event, phenylpropanolamine having been taken in the 24

162 hours before the hemorrhage. The overall exposure to phenylpropanolamine was very similar in the control group (42%), none of whom had a hemorrhage. Clearly the risk from phenylpropanolamine is low, considering the large numbers of individuals who take it, but nevertheless the study again supports the proposition that the risk does exist.

DRUGS THAT ACT ON DOPAMINE RECEPTORS (SED-14, 421; SEDA-25, 168; SEDA-26, 159; SEDA-27, 148)

Levodopa and dopamine receptor agonists The many adverse effects of the dopamine agonists in current use, notably levodopa, have been reviewed (16R ). However, the authors pointed out that the therapeutic options in this disease are still far better than in most chronic degenerative neurological diseases, such as motor neuron disease and Alzheimer’s disease, but did not provide new solutions. The risks of adverse effects of ropinirole and pramipexole in Parkinson’s disease have been compared in a systematic review of 13 randomized clinical trials including over 263 patients (17M ). The authors concluded that the risks of dizziness, nausea, and hypotension were not significantly different when either drug was compared with levodopa. However, when compared with placebo there was much greater likelihood of hypotension with ropinirole (RR = 6.46, CI = 1.47, 28) than with pramipexole (RR = 1.65; CI = 0.88, 3.08). When compared with placebo, there was a higher risk of hallucinations with pramipexole (RR = 5.2; CI = 1.97, 14) than with ropinirole (RR = 2.8; CI = 0.55, 14), but the reverse was true with regard to somnolence, for which the risk was higher with ropinirole (RR = 5.7; CI = 2.34, 14) than with pramipexole (RR = 2.0; CI = 2.17, 3.16). Not surprisingly, there was a substantial overlap in the confidence intervals for all these comparisons. The authors noted that there has been no direct comparison of the efficacy or adverse effects of these two drugs.

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Nervous system Dopamine receptor agonists can cause sleep attacks. DoTS classification: Reaction: sleep attacks from dopamine receptor agonists Dose relation: collateral Time course: time-independent Susceptibility factors: not known In a review of dopamine receptor agonists and sleep attacks in Parkinsonian patients the authors concluded that sleep attacks can occur with any dopamine receptor agonist (18R ). Apart from this relatively uncommon phenomenon they noted that somnolence and excessive daytime sleepiness is also a complication of treatment with these drugs and with levodopa. The problem usually emerges during dose escalation, but can also occur in patients taking stable doses of medication. The authors emphasized that patients and their carers should be warned about this adverse reaction and particularly about its implications for driving. In a survey of sleep attacks in Parkinson’s disease, 6000 patients were sent preliminary questionnaires, and 2952 (mean age 69 years, 61% men) responded (19C ). A more detailed structured questionnaire was sent to the initial respondents, and on the basis of this 177 patients were identified who had sudden, unexpected, and irresistible sleep attacks. Of these the great majority (133) had relatively high scores (that is, greater than 10) on the Epworth Sleepiness Scale (ESS). Of the remainder, who had ESS scores of 10 or less, 31 had sleep attacks without any warning signs. Nevertheless, the mean ESS was much higher in patients who had sleep attacks compared with those who did not (mean 14 versus 6.3). All the dopamine receptor agonists were associated with sleep attacks, but levodopa monotherapy carried the lowest risk (2.9% of those treated); those who took monotherapy with any directlyacting dopamine receptor agonist had a risk of 5.3%, and the figure was 7.3% among those taking levodopa plus a dopamine receptor agonist. Co-administration of selegiline, entacapone, or amantadine did not appear to influence these events. Apart from high ESS scores and the use of dopamine receptor agonists, the main risk factor for sleep attacks was duration of disease: every year increased the risk of attacks by about 5%. This work again emphasized that dopaminergic drugs all increase sleepiness.

Drugs that affect autonomic functions or the extrapyramidal system

Sleepiness has been described in detail in two patients who were studied using 72-hour polysomnography (20c ). One patient was an 81-year-old man who had Parkinson’s disease for 11 years, and the other was a 74-yearold woman with disease duration of 7 years. Both were taking levodopa/benserazide (cobeneldopa) and both complained of excessive daytime sleepiness. Neither had cognitive impairment. On the second morning of a 4-day study period each received placebo or cobeneldopa (100/25 mg). After administration of the active drug both patients slept for 40– 49 minutes, beginning at about the time of peak levodopa plasma concentrations. This was accompanied by reductions in blood pressure and heart rate, with respective falls of 35 mmHg and 14 mmHg in mean pressure and 10 and 14 beats per minute in heart rate. Reaction times deteriorated 30–60 minutes after dosing and were impaired for up to 2 hours. Brief sleep episodes (7 and 13 minutes) occurred after placebo administration. Piribedil is a dopamine receptor agonist that has been used for over 20 years in the treatment of Parkinson’s disease but has received comparatively little attention. However, its pharmacology is unusual, in that it is an agonist at D3 as well as D receptors. Very few cases of sleep attacks have been described in association with piribedil. • Three patients among 50 newly given piribedil developed sleep attacks (21A ). All were men, aged 51, 53, and 63 years and all were given piribedil 100 mg/day within weeks of the initial diagnosis. In each case sleep attacks started within a few days of starting the drug, never having occurred with other antiparkinsonian therapy. Two of the patients were taking levodopa/carbidopa (co-careldopa, levodopa doses 600 mg and 300 mg/day) but the third was levodopa-naïve.

The author noted that two of the patients preferred to continue taking piribedil, at a lower dose. Sensory systems Apparent loss or severe distortion of colour vision has been associated with pramipexole (22A ). • A 72-year-old man with a 5-year history of Parkinson’s disease noticed that within 2 weeks of starting to take pramipexole 0.54 mg/day black appeared violet and white appeared yellow. Six

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months later his parkinsonian symptoms deteriorated and the dose of pramipexole was increased to 2.1 mg/day. Within a week he complained of total loss of colour vision. The dose was reduced and the drug was then withdrawn. Colour perception rapidly returned to normal. He had also had impaired colour vision while taking digitoxin a couple of years before.

The authors speculated that pramipexole may interact with GABA transmission in the retina, as the drug has structural similarities to compounds that block synaptic GABA reuptake. They suggested that this may be the first report of complete loss of colour vision due to any antiparkinsonian drug. It may be that patients taking this drug should be monitored specifically for this problem. Psychological, psychiatric In seven patients with Parkinson’s disease (age 55–66, 5 men), none of whom was demented, intravenous infusion of levodopa produced some reduction in self-reported learning performance and a reduction in activation of the ipsilateral occipital association area (23c ). The authors suggested that levodopa may have some hitherto undetected but subtle effects on cognitive performance. Complex behavioral changes can apparently be caused by medication in Parkinson’s disease. High-dose dopamine receptor agonist therapy has been associated with excessive gambling, which can be regarded as pathological (24C ). In a review of the records of 1884 patients, of whom 529 were taking pramipexole, 421 ropinirole, and 331 pergolide there were nine patients (7 men, 2 women) whose gambling behavior had led to financial hardship, in two cases with losses in excess of $60 000. None of these patients was taking levodopa alone and eight were taking pramipexole. The mean age of the affected patients was 57 years and the mean duration of their illness was 12 years. None was demented, but it is noteworthy that four had a previous history of depression and one of panic attacks. Overall the incidence of gambling behavior in the whole patient population was 0.5% (surely not 0.05% as stated) and 1.5% in those taking pramipexole, although as the authors pointed out this is close to some estimates of this problem in the general population, so a causal association was by no means established and the striking preponderance of one drug may have been coincidental.

164 Nutrition There has been enormous interest in the last decade in the possible role of the amino acid homocysteine as a risk factor in cardiovascular disease. Although it is still unclear whether homocysteine has a pathogenic role, or is possibly just a marker for atherosclerotic disease, it is nevertheless accepted that raised plasma concentrations of homocysteine are best avoided. It had been suggested that patients with Parkinson’s disease have raised homocysteine concentrations, but a group of American neurologists appear to have shown that it is levodopa that is responsible for this rather than the disease itself (25C ). They measured homocysteine concentrations in 235 patients with Parkinson’s disease, of whom 201 were taking levodopa and 34 were not. The groups were different in several other respects: age (73 versus 65 years in the levodopa-treated patients compared with untreated patients), sex (61% versus 50% male), and duration of illness (8.9 versus 4.8 years). Leaving this aside for the moment, there was clear difference in plasma homocysteine concentrations between the two groups: a mean of 16 µmol/l in the levodopatreated group against 12 µmol/l in the controls. Concentrations of co-factors of homocysteine metabolism (folic acid, vitamin B12 , and methylmalonate) were not significantly different in the two groups. Furthermore, the patients with the highest homocysteine concentrations had a higher prevalence of coronary artery disease (relative risk 1.75 for the highest quartile of homocysteine concentrations). The argument for the involvement of levodopa is plausible but was not conclusively proved by this study. Apart from the above discrepancies between the groups it is surprising that there was no mention of plasma creatinine concentrations, which are likely to be higher in the older, levodopatreated, patients and which correlate strongly with concentrations of homocysteine, reflecting reduced homocysteine clearance with diminished renal function. However, a smaller study from Boston has provided broad support for the above conclusions (26c ). In this study there were 20 patients with Parkinson’s disease who took levodopa compared with 20 controls, although again there was lack of concordance of important parameters: age (64 years in the levodopa-treated group versus 60 years in the controls), sex (50% versus 65% men), and duration of disease (79

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versus 17 months). The homocysteine concentrations were again higher in those who took levodopa (12 versus 8.8 µmol/l), but the absolute concentrations were different in the two papers, and the analytical techniques were not the same: a fluorescence immunoassay technique in the first paper and an HPLC-based method in the second, drawing attention to one of the difficulties in interpreting homocysteinerelated research. However, the author’s main conclusion in the second paper concerned the relation of homocysteine concentrations with those of folate, vitamin B12 , and pyridoxal phosphate. The authors found that homocysteine concentrations correlated negatively with concentrations of these vitamins in the treated but not in the control group. They therefore suggested, very reasonably, that patients taking levodopa should receive supplements of the relevant vitamins as a matter of routine. This would be safe, cheap, and potentially beneficial, even while attempts to define the role of homocysteine continue. Susceptibility factors Genetic Inevitably there has been increasing interest in the issue of genetic susceptibility to both the beneficial and harmful effects of levodopa. In a retrospective study of 183 German patients (mean age 67 years, 107 men) the possible role of polymorphisms of dopamine receptors of the dopamine transporter DAT in predicting the adverse effects of levodopa, including dyskinesias, psychotic reactions, and “on–off” phenomena, was studied (27c ). The results suggested that genetic variations of dopamine D2, D3, and D4 receptors do not influence the occurrence of levodopa-induced adverse effects, but that the nine copy allele 40-bp VNTR of the DAT is strongly predictive of all three types of adverse events.

OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY (SED-14, 424; SEDA-25, 171; SEDA-26, 162; SEDA-27, 151)

Selegiline Drug interactions Possible interactions of selegiline with sympathomimetic medications,

Drugs that affect autonomic functions or the extrapyramidal system

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mostly bought over the counter, have been reviewed (28M ). Several case reports were identified which support the possibility of significant and dangerous interactions.

as a direct consequence of enhancement of dopaminergic activity produced by entacapone.

• A 57-year-old man taking selegiline 10 mg/day and ephedrine 32 mg/day had a hypertensive crisis with a blood pressure of 300/150 mmHg and a tachycardia of 110/minute. Plasma concentrations of noradrenaline were raised but not urinary concentrations of vanillylmandelic acid, suggesting inhibition of noradrenaline metabolism. The patient was also taking maprotiline 75 mg daily, which may also have contributed to catecholamine excess. • Acutely raised blood pressure was also reported in a patient taking selegiline 20 mg/day with a tyramine-rich diet, resembling the “cheese reaction”, which selegiline is supposed not to cause.

DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM

Interactions between selegiline and the selective serotonin reuptake-blocking antidepressants, such as fluoxetine, have been reported, with occurrence of the serotonin syndrome (tachycardia, confusion, tremor, and hyperreflexia). The cough suppressant dextromethorphan also has serotonin reuptake inhibiting properties, but no interaction with selegiline has so far been reported. Nevertheless, it would seem sensible to advise patients taking this drug to avoid over-the-counter cold remedies where the potential for harmful interactions exists, although the actual risk is obviously low.

Catechol-O-methyl transferase inhibitors Nervous system Sleep attacks have been attributed to entacapone. • A 74-year-old man with Parkinson’s disease who had been treated with levodopa for about 10 years (29A ). Entacapone, in an unspecified dose, was added to his medication to minimize end-of-dose effects. Within a week he started to have sleep attacks, initially up to four times a week but then less often: motor benefits were modest. After 3 weeks the entacapone was withdrawn for 1 week and the attacks ceased. On rechallenge they started again. The patient noted a general increase in daytime somnolence, but the sleep attacks occurred without warning and could not be resisted.

Although this is the first report of its kind, this phenomenon is not altogether surprising,

(SED-14, 436; SEDA-25, 172; SEDA-26, 164; SEDA-27, 152)

Anticholinergic drugs Psychological Short-term memory loss has been attributed to tolterodine. • A 46-year-old woman took tolterodine 4 mg/day for stress incontinence (30A ). Her urinary symptoms were successfully controlled, but she complained of deteriorating short-term memory, so that she had to keep notes to remind herself of simple tasks. In fact the deterioration had started some 2 years earlier, but had become more noticeable during the 3 months of treatment with tolterodine. Psychometric testing showed quite severe impairment of verbal learning, although other aspects of memory seemed unimpaired. One month after stopping the drug her verbal learning had improved very significantly: she was now above the 75th percentile in the Hopkins Verbal Learning Test, having been at the 1st percentile at the initial test (albeit with different material).

This patient probably had some memory deficit before drug administration, but this appears to have been very modest. She had an exceptionally strong family history of dementia, Alzheimer’s disease having affected her mother, several maternal aunts and uncles, and her maternal grandmother. It is therefore possible that this apparent sensitivity to anticholinergic drugs may have ominous implications for this particular patient. However, the authors also pointed out that she might have a genetic polymorphism causing a deficiency of the CYP2D6 isoenzyme that metabolizes tolterodine, a trait that is found in about 7% of the population. Of course both circumstances can co-exist. Salivary glands The efficacy and safety of anticholinergic drugs have been reviewed in an analysis of data from 32 trials, in which anticholinergic drugs were compared with placebo (31M ). In terms of efficacy the authors concluded that the apparent improvement in symptoms, while significant, was generally small. On

166 the other hand there was a clear increase in the incidence of dry mouth, with a relative risk of 2.56 compared with placebo. The authors noted

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that none of the studies provided information on long-term outcomes.

REFERENCES 1. Johnston SL, Unsworth J, Gompels MM. Adrenaline given outside the context of life threatening allergic reactions. Br Med J 2003; 326: 589– 90. 2. Douglass JA, O’Hehir RE. Adrenaline and nonlife threatening allergic reactions. Br Med J 2003; 327: 226–7. 3. Mazzocca AD, Meneghini RM, Chhablani R, Badrinath SK, Cole BJ, Bush-Joseph CA. Epinephrine-induced pulmonary edema during arthroscopic knee surgery. J Bone Joint Surg 2003; 85A: 913–15. 4. Jensen KH, Werther K, Stryger V, Schultz K, Falkenberg B. Arthroscopic shoulder surgery with epinephrine saline irrigation. Arthroscopy 2001; 17: 578–81. 5. Sia S, Sarro F, Lepri A, Bartoli M. The effect of exogenous epinephrine on the incidence of hypotensive/bradycardic events during shoulder surgery in the sitting position during interscalene block. Anesth Analg 2003; 97: 583–8. 6. Cucchiaro G, Rhodes LA. Unusual presentation of long QT syndrome. Br J Anaesth 2003; 90: 804– 7. 7. Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica, Suttorp MJ, Rhodes SL, Jungvig L, Gagne J. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance. A meta-analysis. J Am Med Assoc 2003; 289: 1537–45. 8. Foxford RJ, Sahlas DJ, Wingfied KA. Vasospasm-induced stroke in a varsity athlete secondary to ephedrine ingestion. J Sports Med 2003; 13: 183–5. 9. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system effects associated with dietary supplements containing Ephedra alkaloids. New Engl J Med 2000; 343: 1833–38. 10. Bent S, Tiedt TN, Odden MC, Shlipak MG. The relative safety of Ephedra compared with other herbal products. Ann Intern Med 2003; 138: 468– 71. 11. Enders JM, Dobesh PP, Ellison JN. Acute myocardial infarction induced by ephedrine alkaloids. Pharmacotherapy 2003; 23: 1645–51. 12. Boerth JM, Caley CF. Possible case of mania associated with Ma-Huang. Pharmacotherapy 2003; 23: 380–3. 13. Walton R, Manos GH. Psychosis related to Ephedra-containing herbal supplement use. South Med J 2003; 96: 718–20. 14. Bajaj J, Knox JF, Komorowski PAC, Saeian K. The irony of herbal hepatitis. Ma-Huang-induced hepatotoxicity associated with compound heterozy-

gosity for hereditary hemochromatosis. Dig Dis Sci 2003; 48: 1925–8. 15. Arauz A, Velásquez L, Cantú C, Nader J, López M, Murillo L, Aburto Y. Phenylpropanolamine and intracranial hemorrhage risk in a Mexican population. Cerebrovasc Dis 2003; 15: 210–14. 16. Rascol O, Payoux P, Ory F, Ferreira JJ, BrefelCourbon C, Montastruc J-L. Limitations of current Parkinson’s disease therapy. Ann Neurol 2003; 53 Suppl 3: S3–15. 17. Etminan M, Gill S, Samii A. Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson’s disease. A metaanalysis. Drug Saf 2003; 26: 439–44. 18. Parkinson’s disease. What is currently known? CNS Drugs 17: 593–600. 19. Paus S, Brecht HM, Köster J, Seeger G, Klockgether T, Wüllner U. Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson’s disease. Mov Disord 2003; 18: 659–67. 20. Contin M, Provini F, Martinelli P, Riva R, Albani F, Vetrugno R, Lombardi C, Montagna P, Baruzzi A. Excessive daytime sleepiness and levodopa in Parkinson’s disease: polygraphic, placebocontrolled monitoring. Clin Neuropharmacol 2003; 26: 115–18. 21. Tan EK. Piribedil-induced sleep attacks in Parkinson’s disease. Fundam Clin Pharmacol 2003; 17: 117–19. 22. Müller T, Przuntek H, Kuhlmann A. Loss of colour vision during long-term treatment with pramipexole. J Neurol 2003; 250: 101–2. 23. Feigin A, Ghilardi MF, Carbon M, Edwards C, Fukuda M, Dhawan V, Margouleff C, Ghez C, Eidelberg D. Effects of levodopa on motor sequence learning in Parkinson’s disease. Neurology 2003; 60: 1744–9. 24. Driver-Dunkley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003; 61: 422–3. 25. Rogers JD, Sanchez-Saffon A, Frol AB, DiazArrastia R. Elevated plasma homocysteine levels in patients treated with levodopa. Association with vascular disease. Arch Neurol 2003; 60: 59–64. 26. Miller JW, Selhub J, Nadeau MR, Thomas CA, Feldman RG, Wolf PA. Effect of L-dopa on plasma homocysteine in PD patients. Relationship to Bvitamin status. Neurology 2003; 60: 1125–9. 27. Kaiser R, Hofer A, Grapengiesser A, Gasser T, Kupsch A, Roots I, Brockenmöller J. L-dopainduced adverse effects in PD and dopamine transporter gene polymorphism. Neurology 2003; 60: 1750–5.

Drugs that affect autonomic functions or the extrapyramidal system 28. Jacob JE, Wagner ML, Sage JI. Safety of selegiline with cold medications. Ann Pharmacother 2003; 37: 438–41. 29. Santens P. Sleep attacks in Parkinson’s disease induced by entacapone, a COMT-inhibitor. Fundam Clin Pharmacol 2003; 17: 121–3.

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30. Womack KB, Heilman KM. Tolterodine and memory. Arch Neurol 2003; 60: 771–3. 31. Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. Br Med J 2003; 326: 811–14.

Sandra R. Knowles, Gavin Wong, and Neil H. Shear

14

Dermatological drugs, topical agents, and cosmetics

Alefacept

Botulinum toxin A (SEDA-27, 24, 160; SEDA-27, 161)

Alefacept is a recombinant human lymphocyte function-associated antigen-3 (LFA-3)/IgG1 fusion protein that inhibits a co-stimulatory pathway of T cell activation and proliferation implicated in the pathogenesis of psoriasis. Studies of the efficacy and safety of alefacept treatment in patients with psoriasis have been reviewed (1R –3R ). The pooled results of randomized controlled trials show that alefacept is generally well tolerated (1289 evaluable patients; 876 received alefacept, 413 received placebo). The type and frequency of adverse events were similar in the two groups. The most common adverse effect was chills, which occurred in 13% of alefacept-treated patients during the first course of treatment, starting within 24 hours of treatment and limited to one or two treatments. In phase III trials there were reductions in CD4+ T cell counts to under 250 × 106 /l in 10% and 5% of patients treated with alefacept once weekly for 12 weeks by the intravenous (7.5 mg) and intramuscular (15 mg) routes respectively. Opportunistic infections have not been reported, and there has been no evidence of an increased risk of infections or malignancies. Immunologic Alefacept was minimally immunogenic; 1–4% of alefacept-treated patients developed anti-alefacept antibodies in phase III studies (1R –3R ). Antibody titers were low, were not associated with hypersensitivity reactions, and did not alter the efficacy of alefacept.

© 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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Botulinum toxin A is used for a variety of dermatologic procedures, including cosmetic indications (for example lateral orbital wrinkles, lower eyelid wrinkles, nasolabial lines, and horizontal forehead rhytides) and in the treatment of hyperhidrosis. In general, botulinum toxin is well-tolerated, although transient adverse effects occasionally occur, including temporary bruising, discomfort, incomplete muscle paralysis, headache, or spread beyond the intended site of application (4C , 5A , 6R ). Patients sometimes have transient brow or eyelid drooping (ptosis) and asymmetry of facial expression. The US FDA has raised objections that the web advertising and the printed product information for botulinum A toxin (Botox) as posted by the manufacturers, Allergan, has insufficient information on adverse effects and that this could result in patients being treated with the product for cosmetic purposes (7S ). The FDA is of the opinion that advertisements for the product are misleading because they falsely identify the product as a cosmetic treatment, fail to reveal material facts about the use of the product, and minimize the risk information presented. The advertising does not make it clear that more than four in 10 people treated with the product suffer some form of adverse effect, the most common being headache and nausea. The product has also been linked with respiratory infection and flu-like syndrome as well as temporary drooping of the eyelids. Neuromuscular Transient thumb-index pinch weakness lasting 1–4 weeks occurred in four of eight patients who received botulinum toxin for palmar hyperhidrosis (8C ).

Dermatological drugs, topical agents, and cosmetics

Chapter 14

Sensory systems Systemic effects of botulinum toxin injection are uncommon, but taste disturbance has been reported (9A ).

Diphenylcyclopropenone

• A 44-year-old woman who received botulinum toxin A injections for her glabellar frown and lateral orbital lines developed a metallic taste about 1 day after the injection, lasting for 2 weeks. Rechallenge on three separate occasions reproduced the adverse effect.

Sweat glands There was an increase in nonaxillary sweating in 4.3% of 207 patients who received botulinum toxin for axillary hyperhidrosis (10c ). Musculoskeletal In predisposed individuals, botulinum toxin injected into the pretarsal orbicularis of the lower lid can weaken the muscular pumping action, resulting in localized lymphedema and a transient “festoon”. • A 56-year-old man who underwent treatment of infraorbital and lateral canthal rhytides developed festoon formation 2–3 days after the injection (11A ). The patient had a history of a face lift, forehead lift, and four-eyelid blepharoplasty.

Caution is advised in injecting the infraorbital area in patients who have had significant previous surgery under the eye or if the patient has a great deal of redundant skin under the eye.

169

Topical immunotherapy with various contact allergens, such as diphenylcyclopropenone (DPCP), has been used in the treatment of chronic severe alopecia areata. Diphenylcyclopropenone is a potent contact sensitizer, with response rates of 4–85%. Adverse effects include erythema at the site of application, headache, lymph node enlargement, and changes in pigmentation. Severe dermatitis, which can develop into blistering reactions, is often managed successfully with topical glucocorticoids (13A ).

Finasteride Oral finasteride 1 mg/day has been used as an effective treatment for male androgenetic alopecia. Finasteride inhibits 5-alpha reductase, thereby inhibiting the conversion of testosterone to dihydrotestosterone, which is implicated in alopecia in some men. Finasteride 1 mg/day is generally well tolerated; the most common adverse events include reduced libido, reduced ejaculate volume, and gynecomastia. Painful bilateral gynecomastia occurred in two men who took finasteride 1 mg/day (14A ).

Glucocorticoids Calcipotriol Skin Calcipotriol is usually well-tolerated, although it can cause local irritation with redness, especially on the face and scalp, in up to 30% of patients. A high number of Malassezia yeasts are found in skin areas where skin irritation with calcipotriol is most commonly seen. Itraconazole is active against various moulds and yeasts, including Malassezia, and has been reported to be effective in reducing skin irritation due to calcipotriol. In 137 patients with scalp psoriasis taking calcipotriol who were randomized to either placebo or itraconazole, 13 (19%) who took itraconazole had local skin irritation, compared with 33 (47%) who took placebo (12C ).

Topical glucocorticoids are used for a variety of skin disorders, including atopic dermatitis, lichen planus, psoriasis, and bullous dermatoses. They have a number of different effects, including anti-inflammatory properties and antiproliferative and atrophic effects. Endocrine There is evidence that topical glucocorticoids can cause systemic adverse effects similar to those observed with systemic glucocorticoids, for example suppression of the hypothalamic-pituitary-adrenal axis, iatrogenic Cushing’s syndrome, and growth retardation in infants and children. However, in most cases in which systemic adverse effects occur, misuse of a product can be blamed. For example, a 4-month-old boy developed iatrogenic Cushing’s syndrome, which occurred when his

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mother used excessive amounts of clobetasol 17-propionate and hydrocortisone 17-butyrate cream for 2 months to treat a diaper rash (15A ).

with topical antibiotics was ineffective and treatment was switched to a topical basic fibroblast growth (bFGF) product, leading to rapid improvement in 2 weeks (19A ).

• An 18-year-old woman presented with a pruritic eczematous eruption that developed after topically applying an ointment containing hydrocortisone acetate, neomycin sulfate, and Centella asiatica (16A ). She was positive to all three ingredients of the ointment.

Glycyrrhizinic acid Immunologic Hypersensitivity to glycyrrhizinic acid has not previously been reported. • A 40-year-old woman developed erythema and micropapules following topical application of an alternative herbal treatment for androgenetic alopecia. The hair restorer consisted mainly of Ruscus auleatus, glycyrrhizic acid, and Serenoa serrulata. Patch testing was positive to glycyrrhizic acid (17A ).

Hydroxyurea Hydroxyurea inhibits ribonucleotide reductase and so affects DNA synthesis, DNA repair, and gene regulation. Its approved uses include squamous cell carcinoma of the head and neck, metastatic melanoma, and gastrointestinal melanoma. Non-approved indications include pyoderma gangrenosum, psoriasis, and hypereosinophilic syndrome. Hematologic The most common adverse effects of hydroxyurea are various hematological effects, such as anemia, leukopenia, and thrombocytopenia. Two patients treated with largedose hydroxyurea (4 g every 4 hours) developed acute tumor lysis syndrome (18A ). Skin Painful leg ulcers occur in about 9% of patients treated with hydroxyurea. Susceptibility factors include the duration of treatment and higher cumulative doses. This adverse effect is often resistant to treatment. • A 42-year-old man with chronic myelogenous leukemia had taken oral hydroxyurea 2 g/day for over 3 years. He developed foot ulcers and the dose of hydroxyurea was reduced to 1 g/day. Therapy

Minoxidil

(see also Chapter 20)

Cardiovascular In a 1-year observational study of more than 3 million subject-days of exposure to topical minoxidil solution, patients who use topical minoxidil were no more likely to have major medical events resulting in hospitalization or death than control subjects who had never been exposed to topical minoxidil. In addition, there was no difference in the rates of cardiovascular events between the two groups (20c ). Endocrine Pseudoacromegaly has been reported in a patient who had taken large oral doses of minoxidil for about 10 years (21A ). There have been no reports of pseudoacromegaly associated with topical minoxidil. Skin Allergic contact dermatitis has been reported in about 1–3% of patients who use topical minoxidil solution. • A 24-year-old woman developed allergic contact dermatitis while taking minoxidil and again while taking Serenoa repens (saw palmetto) solution for androgenic alopecia (22A ).

In many cases, propylene glycol is the causative allergen, but not always. • In a 40-year-old woman with a history of scalp desquamative dermatitis 1 week after starting 5% minoxidil solution, patch tests showed that minoxidil itself was the inciting agent (23A ).

Hair Excess facial hair has been reported as an adverse event when minoxidil is used either systemically or topically. A review of minoxidil topical solution clinical trials revealed that approximately 4% of women noted hypertrichosis/facial hair. Excessive hair growth was reported primarily on the face (including cheeks, chin, forehead, upper lip, sideburns and around the eyes), but also on the neck, chest, back and extremities. However, post-marketing data showed a lower occurrence (0.5%) of hypertrichosis/facial hair than in the clinical trials.

Dermatological drugs, topical agents, and cosmetics

Chapter 14

A dose-related pattern of response was noted. The hypertrichotic effect of minoxidil is reversible, and does not necessarily require discontinuation of therapy (24R ).

Phototherapy

Pregnancy There was no indication of increased risk of adverse pregnancy outcomes in women who used topical minoxidil during their pregnancy. However, it should be noted that this study was not designed to determine whether subjects continued to use topical minoxidil solution after they became pregnant (20c ). In contrast to the apparent safety of minoxidil in pregnancy, a case report describes a 28-year-old pregnant woman who applied daily minoxidil 2% to her scalp because of hair loss. A routine ultrasound test at the 22nd gestational week showed significant brain, heart and vascular malformations of the fetus; pregnancy was interrupted. The most evident pathological event was formation of abnormal vessels (25A ).

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Psoralen plus long-wave UV-A (PUVA) and bexarotene therapy have been used as an adjunct in patients with advanced cutaneous T cell lymphomas. One of five patients developed two in-situ melanomas after 14 months of PUVA treatment. The addition of PUVA resulted in neutropenia in another patient, which required a reduction in the doses of bexarotene, interferon, and PUVA. Another patient had a PUVA burn, which necessitated transient withdrawal of therapy (28A ).

VITAMIN A RETINOIDS (SED-14, 449; SEDA-25, 179; SEDA-27, 159; for vitamin A carotenoids see Chapter 38)

Acitretin Neomycin Neomycin is a common sensitizing agent; about 30% of patients with stasis ulcers, 15% of patients with chronic otitis externa, and 5% of patients with other chronic eczematous conditions have been sensitized to topical neomycin (26R ). • An 18-year-old woman presented with a pruritic eczematous eruption that developed after topically applying an ointment containing hydrocortisone acetate, neomycin sulfate and Centella asiatica. She was positive to all three ingredients of the ointment (16A ).

MOISTURIZERS Skin Contact allergy was documented in a 64-year-old man who had been applying an expired moisturizer for 2 weeks (27A ). Patch testing confirmed positive reactions to the expired Sorbolene cream, which contained cetylstearyl alcohol, triethanolamine, imidazolidinyl urea, and methylparabens cream. Individual excipients and non-expired Sorbolene cream did not elicit the same reaction.

There are substantial data regarding the use of broadband UVB and PUVA in combination with oral retinoids. Lower doses of retinoids can be used when they are combined with phototherapy, resulting in fewer mucocutaneous adverse effects such as cheilitis and hair loss. In patients who received acitretin in combination with narrowband UVB, common adverse effects were raised cholesterol (50% of patients) raised triglycerides (38%), burning (18%), abnormal liver function tests (8%), cheilitis (13%), and hair loss (5%) (29c ). Musculoskeletal Although osteoporosis has been previously identified as an adverse effect of long-term etretinate, there has been little research into the risk of osteoporosis with acitretin, the active metabolite of etretinate. In an observational study in 30 patients who had taken acitretin for a minimum of 9 months the dose of acitretin (whether measured as daily or overall dose) and the length of treatment were not associated with bone mineral loss (30c ).

Adapalene Adapalene is a topical retinoid that has increased stability in conditions of sunlight and

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oxygen exposure. After topical application of adapalene 0.1% gel once daily for 12 weeks, no adapalene was detected in patients’ plasma, suggesting minimal systemic absorption (31R ). Irritation profile studies have also shown that adapalene 0.1% gel has better tolerability than 0.025% tretinoin gel. Nevertheless, other studies have shown more severe erythema, burning, and dryness with adapalene than with tretinoin (32R ).

right bundle branch block with sinus tachycardia and urinary retention. They suggested that electrocardiography should be performed in patients with systemic illnesses who are taking oral isotretinoin.

Isotretinoin Isotretinoin is associated with a number of different adverse reactions, including ocular effects, bone effects (rarely premature epiphyseal closure), abnormal liver function tests in 10% of patients, pseudotumor cerebri, mucocutaneous effects, myalgias, reversible hair loss, and increased triglyceride and cholesterol concentrations (32R ). Cardiovascular Electrocardiographic changes have been attributed to isotretinoin (33A ). • An 18-year-old Caucasian man had been taking isotretinoin 1 mg/kg/day for severe acne for 3 months. He developed a fever, headache, rigidity of the neck and limbs, masseter twitch, and diffuse myalgia mainly localized to the buttocks and the lumbar region. He had a fever (38◦ C), a sinus tachycardia (140/minute) that did not correlate with the fever, and urinary retention. Renal stones and urinary tract infection were excluded. His liver enzymes were increased four-fold. An electrocardiogram showed sinus tachycardia with right branch bundle block. Electromyography showed a diffuse myopathy, but a muscle biopsy was not specific. A pulmonary CT scan showed interstitial pneumonitis with a small amount of encysted pleural effusion. A whole body bone scan showed dense radioactive areas at the upper wedge of the scapula and at vertebrae T4 to T7. There was hyperostosis in the vertebrosternal joint areas. All other laboratory tests were normal or negative. Isotretinoin was withdrawn and all the symptoms and signs disappeared after 3 weeks. Reintroduction 10 days later of isotretinoin 0.5 mg/kg/day for 1 week caused myalgia and right bundle branch block, but without sinus tachycardia. Withdrawal again produced resolution.

The authors recognized that all the adverse effects of isotretinoin noted in this case have been reported before, except the combination of

Sensory systems Ocular problems associated with isotretinoin are extensive and can include abnormal meibum secretion or atrophy of the Meibomian glands, blepharoconjunctivitis, corneal opacities, poor adaptation to darkness, contact lens intolerance, reduced visual acuity, increased tear osmolarity, myopia, dry eyes, and photophobia (34r ). Psychiatric Isotretinoin is the most important agent in the treatment of severe, recalcitrant, nodulcystic acne refractory to conventional antimicrobial therapies. Since 1982, according to the FDA, isotretinoin has been linked to over 400 cases of psychiatric illness, including depression, suicidal ideation, suicide attempts, and completed suicide (35r ). In the light of questionable psychiatric safety, evidence examining the link between isotretinoin and psychiatric illness in adolescents and young adults has been assessed (36M ). The data sources were primary literature located via MEDLINE (1966–2002). The key terms were isotretinoin, depression, psychosis, suicide, and adolescents. The authors concluded that although there may be a causal relation between isotretinoin and psychiatric illness in adolescents and young adults, this is not demonstrated by the literature. They identified some limitations in the available evidence, including the low numbers of adolescents in published studies, as well as methodological errors in many of the studies analysed. In addition, it is clear that acne alone can predispose patients to psychiatric illness, and that therefore isotretinoin is not the only contributing factor. Metabolism Although the incidence of hyperlipidemia has been reported as high as 50%, a recent review of 30 patients who had received three or more courses of isotretinoin showed no significant change in cholesterol or triglyceride concentrations (37c ). Skin Acute febrile neutrophilic dermatosis, or Sweet’s syndrome, is characterized by sudden onset of fever, neutrophilia, painful erythematous plaques, and a dermal infiltrate of mature

Dermatological drugs, topical agents, and cosmetics

neutrophils, with or without the involvement of other organs. Two patients developed Sweet’s syndrome after using isotretinoin (38A ). • A 7-year-old boy, who was receiving carboplatin, etoposide, vincristine, interferon alfa-2a, and isotretinoin for a retroperitoneal neuroblastoma, developed Sweet’s syndrome; • An 18-year-old girl with a cerebellar medulloblastoma, who received interferon alfa, isotretinoin, and low-dose cytarabine, developed Sweet’s syndrome.

Teratogenicity The teratogenic effects of isotretinoin include ocular malformations (34r ). • Congenital restrictive external ophthalmoplegia and gustatory epiphora have been reported in an infant whose mother had used isotretinoin for acne during the first 9 weeks of her pregnancy (39A ).

Tretinoin (all-trans retinoic acid) Nervous system Pseudotumor cerebri induced by tretinoin has again been reported (40A ). • A 30-year-old man with acute promyelocytic leukemia reported headaches and diplopia within 2 weeks of starting to take tretinoin. His visual acuity was 20/15 OU, his blood pressure was 120/92 mmHg, and there was a left abducens palsy. The fundus was abnormal, with disc edema, hemorrhages, and circumferential folds temporal to the disc in the left eye. A brain MRI scan showed no abnormalities. Lumbar pressure showed an increased opening pressure, but the cerebrospinal fluid showed no cells, no hypoglycorrhachia, and a normal protein concentration. Tretinoin was withdrawn and replaced with arsenic trioxide, daunorubicin, and cytosine. Over the next 6 weeks his headache, papilledema, and abducens palsy resolved.

In this patient papilledema was secondary to pseudotumor cerebri induced by tretinoin. Hematologic Tretinoin induces complete remission in most patients with acute promyelocytic leukemia. Thrombotic complications associated with leukocytosis are uncommon but recognized (41A ). • A 44-year-old man with acute promyelocytic leukemia was given tretinoin and 14 days later suddenly developed dyspnea and chest pain. There

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were no abnormal findings on electrocardiography, chest radiography, or CT imaging. Perfusion scintigraphy of the lungs showed a distinct reduction in uptake in areas S6 and S10 in the left lung, a finding suggesting pulmonary embolism, although there were no other signs of thrombosis. However, thrombotic complications of tretinoin were suspected because of an accompanying leukocytosis. Tretinoin was withdrawn, and heparin 20 U/kg/hour and dexamethasone 0.5 mg/kg/day were given, resulting in remission of dyspnea and chest pain. To reduce the leukocyte count cytarabine (for 3 days) and daunorubicin (for 2 days) were begun on day 18. On day 21, tretinoin was restarted because the leukocyte count had fallen to 5.7 × 109 /l. On day 24, he complained of headache with fever and developed confusion and disorientation, with a leukocytosis and microangiopathic hemolysis. The diagnosis was thrombotic thrombocytopenia purpura. Tretinoin was again withdrawn and he was given an infusion of plasma (15 U/day). His hematology, coagulation, and serum chemistry normalized within 10 days. After the administration of tretinoin again, from day 38, the leukocyte count remained below 5 × 109 /l and there were no more thrombotic complications. He achieved complete remission on day 61.

The authors suggested that this was the first report of thrombotic thrombocytopenic purpura as a complication of tretinoin therapy. In this case, both pulmonary embolism and thrombotic thrombocytopenic purpura occurred in association with a leukocytosis and the authors considered that these events were not directly due to tretinoin itself, but were mediated by the leukocytosis. Skin Genital ulceration is a unique adverse effect of tretinoin in patients with acute promyelocytic leukemia. Four cases have been described in patients taking tretinoin (45 mg/ m2 /day), two of whom were women (42A ). Genital ulcers and fever appeared at 17–32 days of therapy; they healed in three patients while the fourth developed Fournier’s gangrene and underwent left orchidectomy. Healing was achieved by either local or intravenous glucocorticoids. Intravenous dexamethasone enabled continuing therapy with tretinoin in one patient, while treatment was withdrawn in the others. The authors recommended that if glucocorticoids cannot control progression of genital ulcers or concomitant fever, tretinoin should be withdrawn to avoid Fournier’s gangrene or retinoic acid syndrome. Two evaluations of the efficacy and safety of topical formulations of tretinoin have been

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published. In the first report (43M ), involving two clinical studies of the efficacy and safety of long term tretinoin cream (0.02%) for the treatment of photodamage, the authors concluded that long term use is relatively safe. The cutaneous adverse effects (erythema, peeling, burning/stinging), although common, were mild and well tolerated. The second report concerned a study in 21 patients of all-trans retinol gel (10%) used, in combination with other agents, for bleaching hyperpigmentation skin lesions (44c ). The treatment lasted more than 10 weeks. The authors concluded that all-trans retinol gel is as effective as 0.1% tretinoin gel.

The authors also suggested that the dramatic response to glucocorticoid treatment was relevant to the diagnosis.

Immunological Vasculitis has been reported in a patient taking tretinoin (45A ). • A 26-year-old man with acute promyelocytic leukemia was given chemotherapy tretinoin and idarubicin. On day 13 he developed a fever, headache, wrist pain, and ecchymoses in the periorbital regions followed by hyperemic and indurated skin lesions varying in size from 1 to 3 cm on the limbs. All cultures and serological tests were negative for micro-organisms. A skin biopsy suggested a vasculitis. He was given methylprednisolone and the fever subsided in 24 hours. The skin lesions abated and disappeared. Tretinoin was restarted after 7 days. The fever recurred but disappeared again within 2 days. Treatment was completed and he remained in remission while taking maintenance therapy.

The fever in this case suggested retinoic acid syndrome, but there were no other manifestations. Rather, the skin lesions suggested vasculitis, especially in the absence of infection and non-responsiveness to antimicrobial agents.

Drug interactions Tretinoin is metabolized in the liver by cytochrome P450 and its metabolism can be inhibited by other drugs. One drug that has been reported to do this is fluconazole (46A ). • In a 4-year-old boy with acute promyelocytic leukemia chemotherapy comprised cytarabine, daunorubicin, and tretinoin (45 mg/m2 /day). He developed febrile neutropenia and was treated with meropenem on days 2–20 and amphotericin B on days 14–20. On day 20, fluconazole 100 mg/day for fungal prophylaxis was started. The following day he complained of headache and by day 27 had headache, vomiting, and papilledema. A CT scan was normal. The diagnosis was pseudotumor cerebri, and a lumbar puncture showed an opening pressure over 200 mmH2 O with normal CSF. Tretinoin was withdrawn and the symptoms resolved within 24 hours. It was restarted on day 30 at 75% of the previous dose, which resulted in recurrence of headache and vomiting within 2 days, and it was again withdrawn. It was restarted on day 35 at 30% of the dose, and by day 38 he had headache but only one episode was reported. On day 41 the fluconazole was withdrawn and within 24 hours he was much improved with complete resolution of symptoms and could tolerate a full dose of tretinoin without adverse events.

The authors suggested that patients, particularly children, who are taking tretinoin should be carefully monitored for adverse effects if other medications that affect the cytochrome P450 system are coadministered.

REFERENCES 1. Chagan L. Alefacept: a new therapy for psoriasis. Pharm J 2003; 28: 372–83. 2. Frampton J, Wagstaff A. Alefacept. Am J Clin Dermatol 2003; 4: 277–86. 3. Ormerod A. Alefacept. Curr Opin Invest Drugs 2003; 4: 608–13. 4. Carruthers A, Carruthers J, Cohen J. A prospective, double-blind, randomized, parallel-group, dose-ranging study of botulinum toxin type A in female subjects with horizontal forehead rhytides. Dermatol Surg 2003; 29: 461–7. 5. Park M, Ahn K, Jung D. Botulinum toxin type A treatment for contouring of the lower face. Dermatol Surg 2003; 29: 477–83.

6. Carruthers J, Weiss R, Narurkar V, Flynn T. Intense pulsed light and botulinum toxin type A for the aging face. Cosmetic Dermatol 2003; 16: 2–16. 7. Anonymous. Botulinum A. Patients misled over safety. WHO Pharm Newslett 2003; 4: 4. 8. Moreau M, Cauhepe C, Magues J, Senard J. A double-blind, randomized, comparative study of Dysport vs. Botox in primary palmar hyperhidrosis. Br J Dermatol 2003; 149: 1041–5. 9. Murray C, Solish N. Metallic taste: an unusual reaction to botulinum toxin A. Dermatol Surg 2003; 29: 562–3. 10. Naumann M, Lowe N, Kumar C, Hamm H. Botulinum toxin type A is a safe and effective treat-

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ment for axillary hyperhidrosis over 16 months. Arch Dermatol 2003; 139: 731–6. 11. Goldman M. Festoon formation after infraorbital botulinum A toxin: a case report. Dermatol Surg 2003; 29: 560–1. 12. Faergemann J, Diehl U, Bergfelt L, Brodd A, Edmar B, Hersle K, Lindemalm B, Nordin P, Ringdahl IR, Serup J. Scalp psoriasis: synergy between the Malassezia yeasts and skin irritation due to calcipotriol. Acta Dermatol Venereol 2003; 83: 438– 41. 13. Galadari I, Rubaie S, Alkaabi J, Galadari H. Dipihenylcyclopropenone (DPCP) in the treatment of chronic severe alopecia areata. Eur Ann Allergy Clin Immunol 2003; 35: 397–401. 14. Kim B, Kim Y, Ro B. Two cases of reversible bilateral painful gynecomastia induced by 1 mg oral finasteride (Propecia). Korean J Dermatol 2003; 41: 232–4. 15. Ermis B, Ors R, Tastekin A, Ozkan B. Cushing’s syndrome secondary to topical corticosteroids abuse. Clin Endocrinol 2003; 58: 795–7. 16. Oh C, Lee J. Contact allergy to various ingredients of topical medicaments. Contact Dermatitis 2003; 49: 49–50. 17. Cabrita S, Silva R, Correia M. Allergic contact dermatitis due to glycyrrhizic acid as an ingredient of a hair restorer. Contact Dermatitis 2003; 49: 46. 18. Seki J, Al-Omar H, Amato D, Sutton D. Acute tumor lysis syndrome secondary to hydroxyurea in acute myeloid leukemia. Ann Pharmacother 2003; 37: 675–8. 19. Aragane Y, Okamoto T, Yajima A, Isogai R, Kawada A, Tezuka T. Hydroxyurea-induced foot ulcer successfully treated with a topical basic fibroblast growth factor product. Br J Dermatol 2003; 148: 599–600. 20. Shapiro J. Safety of topical minoxidil solution: a one-year, prospective, observational study. J Cutan Med Surg 2003; 7: 322–9. 21. Nguyen K, Marks J. Pseudoacromegaly induced by the long-term use of minoxidil. J Am Acad Dermatol 2003; 48: 962–5. 22. Sinclair R, Mallair R, Tate B. Sensitization to saw palmetto and minoxidil in separate topical extemporaneous treatments for androgenetic alopecia. Aust J Dermatol 2002; 43: 311–12. 23. Carreno P, Martin E, Trabado A, Peral C, Timon S, Arbeiza FJ, Lopez RC. Allergic contact dermatitis due to minoxidil itself. Allergol Immunol Clin 2003; 18: 225–8. 24. Dawber R, Rundegren J. Hypertrichosis in females applying minoxidil topical solution and in normal controls. J Eur Acad Dermatol Venereol 2003; 17: 271–5. 25. Smorlesi C, Caldarella A, Caramelli L, Di Lollo S, Moroni F. Topically applied minoxidil may cause fetal malformation: a case report. Birth Defects Res 2003; 67: 997–1001. 26. Fisher AA. Contact Dermatitis. Philadelphia: Lea & Febiger, 1986: 195. 27. Lim A, Freeman S. Allergic contact dermatitis to an expired moisturiser. Aust J Dermatol 2003; 44: 291–5.

28. McGinnis K, Shapiro M, Vittorio C, Rook A, Junkins-Hopkins J. Psoralen plus long-wave UVA (PUVA) and bexarotene therapy. Arch Dermatol 2003; 139: 771–5. 29. Spuls P, Rozenblit M, Lebwohl M. Retrospective study of the efficacy of narrowband UVB and acitretin. J Dermatol Treat 2003; 14 Suppl 2: 17–20. 30. McMullen E, McCarron P, Irvine D, Dolan O, Allen G. Association between long-term acitretin therapy and osteoporosis: no evidence of increased risk. Clin Exp Dermatol 2003; 28: 307–9. 31. Krautheim A, Gollnick H. Transdermal penetration of topical drugs used in the treatment of acne. Clin Pharmacokinet 2003; 42: 1287–304. 32. Sardana K, Sehgal V. Retinoids: fascinating upand-coming scenario. J Dermatol 2003; 30: 355– 80. 33. Charalabopoulos K, Papalimneou V, Charalabopoulos A, Hatzis J. Two new adverse effects of isotretinoin. Br J Dermatol 2003; 148: 593. 34. Anonymous. Eye problems with isotretinoin. Préscrire Int 2003; 12: 64. 35. Wysowski DK, Pitts M, Beitz J. Depression and suicide in patients treated with isotretinoin. New Engl J Med 2001; 344: 460. 36. Enders SY, Enders JM. Isotretinoin and psychiatric illness in adolescents and young adults. Ann Pharmacother 2003; 37: 1124–7. 37. Baxter K, Ling T, Barth J, Cunliffe W. Retrospective survey of serum lipids in patients receiving more than three courses of isotretinoin. J Dermatol Treat 2003; 14: 216–18. 38. Gyorfy A, Kovacs T, Szegedi I, Olah E, Kiss C. Sweet syndrome associated with 13-cis-retinoic acid (isotretinoin) therapy. Med Pediatr Oncol 2003; 40: 135–8. 39. Guirgis MF, Wong AM, Tychsen L. Congenital restrictive external ophthalmoplegia and gustatory epiphora associated with fetal isotretinoin toxicity. Arch Ophthamol 2002; 120: 1094–5. 40. Colucciello M. Pseudotumor cerebri induced by all-trans retinoic acid treatment of acute promyelocytic leukaemia. Arch Ophthalmol 2003; 121: 1064–5. 41. Fujita H, Takemura S, Hyo R, Tanaki M, Hoharazawa H, Fujisawa S, Kanamori H, Ishigatsubo Y. Pulmonary embolism and thrombocytopenic purpura in acute promyelocytic leukaemia treated with all-trans retinoic acid. Leuk Lymph 2003; 44: 1627–9. 42. Fukuno K, Tsurumi H, Goto H, Oyama M, Tanabashi S, Moriwaki H. Genital ulcers during treatment with all-trans retinoic acid for acute promyelocytic leukemia. Leuk Lymph 2003; 44: 2009–13. 43. Nyirady J, Gisslen H, Lehmann, Liden S, Nordin P, Plewig G. Safety and efficacy of longterm use of tretinoin cream 0.02% for treatment of photodamage: review of clinical trials. Cosmetic Dermatol 2003; 16: 49–58. 44. Yoshimua K, Momosawa A, Aiba E, Sato K, Matsumoto D, Mitoma Y, Harii K, Aoyama T, Iga T. Clinical trial of bleaching treatment with 10% all-trans retinol gel. Dermatol Surg 2003; 29: 155– 60.

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45. Paydas S, Yavuz S, Disel U, Sahin B, Canbolat T, Tuncer I. Vasculitis associated with all trans retinoic acid (ATRA) in a case with acute promyelocytic leukemia. Leuk Lymph 2003; 44: 547–8.

46. Vanier KL, Mattiussi AJ, Johnston DL. Interaction of all-trans-retinoic acid with fluconazole in acute promyelocytic leukaemia. J Ped Hematol Oncol 2003; 25: 403–4.

Garry M. Walsh

15

Antihistamines (H1 receptor antagonists)

The incidence and prevalence of allergic diseases continues to rise worldwide, resulting in significant morbidity and loss of quality of life in affected individuals. Second-generation antihistamines are highly effective in the treatment of allergic diseases, including seasonal and perennial allergic rhinitis, urticaria, and atopic dermatitis (1R ). Antihistamines are a heterogeneous group of compounds, with markedly differing chemical structures, a spectrum of antihistaminic properties, half-lives, tissue distribution, and metabolism, and varying degrees of anti-inflammatory effects. Although they are among the most frequently prescribed and safest drugs in the world, the second-generation antihistamines are not free of adverse effects; they can be chosen or used inappropriately and can be the source of drug-related morbidity (2R ). The potential adverse effects that cause most concern include nervous system effects (3R ), cardiotoxic effects (4R ), and drug–drug interactions. Furthermore, certain foods, such as grapefruit juice, can alter the systemic availability of some antihistamines by interactions with enzymes such as cytochrome P450 or with active transport systems (1R ). First-generation antihistamines have a marked tendency to cross the blood–brain barrier, and their consequent well-documented sedative and anticholinergic effects, together with short half-lives, greatly limited their use in the treatment of allergic symptoms (1R ). However, firstgeneration drugs are still widely used, mainly as over-the-counter products often in combination with other drugs. This is a cause for concern as these drugs may cause significant daytime impairment, in particular their adverse effects on driving may be comparable to intoxication © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

with alcohol (5R ). Furthermore, first generation drugs have potential toxic effects if taken in doses higher than that recommended by the manufacturer. For example, seizures, hyperthermia, and rhabdomyolysis have been reported in severe cases of chlorphenamine ingestion (6C , 7C ). There is also a trend towards using secondgeneration antihistamines in long-term therapy, rather than confining them to the treatment of the short-term manifestations of allergic diseases (8R ). Therefore, a number of novel antihistamines have been developed that are either metabolites of active drugs or enantiomers. These newer compounds have enhanced potency, duration, and onset of action, and greater predictability and safety. They include fexofenadine (9R , 10R ), desloratadine (11R ), and levocetirizine (12R ), all of which appear to be effective in several allergic conditions. Recently, the term “third-generation antihistamines” has often been used, without being clearly defined, and a consensus group under the auspices of the British Society for Allergy & Clinical Immunology recently stated that none of the currently available second-generation drugs justifies the designation “third-generation” antihistamine (13R ).

Azelastine

(SED-14, 487)

Sensory systems In three studies topical azelastine was effective in the treatment of allergic conjunctivitis (14C –16C ). A minority of patients reported a bitter taste as the only significant adverse effect.

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Cetirizine

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(SED-14, 486; SEDA-22, 178;

SEDA-27, 166) Observational studies Allergic patients often titrate their antihistamine dosage upwards to obtain symptom relief. • A 46-year-old man tolerated cetirizine 50 mg/day for chronic idiopathic urticaria (17A ). He denied sedation or somnolence and had no difficulty in performing routine daily functions, including driving. He had tried other antihistamines, including fexofenadine, loratadine, and hydroxyzine without improvement in symptoms.

Susceptibility factors Age In addition to its ability to alleviate the symptoms of allergic disease, cetirizine, currently the most widely prescribed antihistamine in the world, has also been reported to have positive effects on quality of life outcomes (18C ). Furthermore it appears to be safe in very young children and infants. Indeed, it is the only prescription antihistamine approved in the USA for children of 6 months or older. The effects of cetirizine on central nervous system and cardiac effects in infants aged from 6–11 months have been reported in a prospective, randomized, parallelgroup, double-blind, placebo-controlled study (19C ). There were no differences in all-cause or treatment-related adverse events between cetirizine and placebo. There was no prolongation of the QTc interval with cetirizine compared with either baseline values or with placebo. A similar study showed that cetirizine was both safe and efficacious in children with allergic rhinitis with or without concomitant intermittent asthma (20C ).

Chlorphenamine (chlorpheniramine) Observational studies Chlorphenamine, used to treat allergic rhinitis in a 67-year-old woman, was reported to have a beneficial effect on her tendency to have chest pain as a result of panic attacks. The authors further reported that cardiological investigation showed that her heart was normal and that the psychotropic properties and antihistaminic effects of chlorphenamine benefited both her conditions (21A ).

Garry M. Walsh

Drug abuse Two cases have illustrated severe complications from abuse of Coricidin HBP (dextromethorphan hydrobromide 30 mg + chlorphenamine maleate 4 mg) by young women, who required prolonged hospitalization (22A ). • The first patient was considered for intubation for airway protection (respiratory rate 18/minute) as she was somnolent and confused with a fast heart rate (150/minute) with blood pressure of 170/100 mmHg. • The second patient had significant diffuse abdominal tenderness without rebound or guarding, and a distended bladder. Over the next 24 hours, she had increasing right upper quadrant abdominal pain and a palpable tender liver edge, leading to evaluation for a liver transplant. However, that was avoided as her clinical symptoms and laboratory abnormalities slowly improved over the next 60 hours.

The authors concluded that each ingredient in the Coricidin HBP products can result in significant toxicity when used in inappropriate doses. Drug interactions A serious interaction has been reported between opioid-based analgesia and chlorphenamine (23A ). • A young woman received fentanyl and bupivacaine lumbar epidural analgesia and anesthesia for labor pains and a cesarean section and then for postoperative pain relief. After the cesarean section she complained of itching, and was given chlorphenamine 10 mg intramuscularly. Within 35 minutes she became somnolent with a reduced respiratory rate. She responded quickly to assisted ventilation and naloxone 0.4 mg.

The authors questioned the rationale of using antihistamines to treat opioid-induced pruritus. They suggested that opioid antagonists, such as naloxone, partial opioid agonists, such as nalbuphine, or 5-HT3 receptor antagonists, such as ondansetron, should be used instead.

Cyclizine Nervous system A probable dystonic reaction followed a single dose of cyclizine 50 mg in a 34-year-old woman with a history of encephalitis after an emergency cesarean section (24A ).

Antihistamines (H1 receptor antagonists)

Desloratadine

Chapter 15

(SEDA-26, 181, 182;

SEDA-27, 167) Desloratadine is the primary metabolite of loratadine. It has a higher affinity for histamine H1 receptors and more potent antihistaminic activity than the parent compound. Several studies have proven its efficacy in allergic diseases, with particular positive effects on nasal congestion (25C , 26C ). Desloratadine is also effective in chronic idiopathic urticaria (27C ). The overall incidence of adverse effects is not significantly different to that of placebo (28R ). Nervous system It is not uncommon to see claims that some of the newer antihistamines are “non-sedating”. This is a misleading term; it is more correct to describe them as having minimal sedative effects when taken in their recommended doses. One problem is that most objective studies that support a so-called riskfree sedation profile for certain antihistamines are based on the use of non-allergic healthy volunteers (29R ). The issue is further complicated by evidence that individuals with symptoms of allergic rhinitis have reduced vigilance, with decrements in speed and efficiency across several cognitive domains (30C ). It is therefore of interest that the nervous system effects of desloratadine have been assessed in subjects with ragweed-induced allergic rhinitis (aged 18–60 years) who had predetermined severity of symptoms after challenge with ragweed pollen in an Environmental Exposure Unit (31C ). The subjects performed a comprehensive battery of repeatable, automated, neuropsychological tests before and 90 minutes after treatment with a randomized single dose of placebo, desloratadine 5 mg, or the positive control diphenhydramine 50 mg. Compared with placebo, both antihistamines alleviated the symptoms of rhinitis associated with exposure to ragweed pollen. As expected, diphenhydramine caused significant reductions in all vigilance parameters, while were no significant differences on any of the cognitive or subjective parameters between subjects treated with desloratadine and those given placebo. In another more conventional study in nine healthy volunteers, the effect of desloratadine 5 mg on psychomotor performance, daytime sleep latencies, subjective sleepiness, and memory was assessed in a placebo-controlled,

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double-blind, crossover study, with promethazine 25 mg as a positive control (32C ). The authors concluded that desloratadine has a favorable nervous system adverse effects profile and that it could prove suitable for allergic individuals who are involved in skilled activities, such as driving. Drug interactions The antifungal azoles are inhibitors of drug metabolism. • Severe hepatotoxicity has been reported in a woman with angioimmunoblastic T cell lymphoma after co-administration of desloratadine and fluconazole, given to treat chemotherapy-associated severe pruritus and fever respectively (33A ).

The authors concluded that second generation antihistamines should be avoided in patients taking antifungal azoles.

Diphenhydramine

(SED-14, 488; SEDA-22, 178; SEDA-27, 167)

Drug overdose The toxic effects of antihistamines in children are well known, and range from nervous system excitation to seizures, and in extreme cases death. Deaths in children are rare, but fatal diphenhydramine intoxication occurred in five infants aged 6–12 weeks as a result of intentional or inadvertent overdose by adult carers (34C ). Diphenhydramine is not recommended for use in children under 6 years of age. In the USA in recent years several regional poison centers have recognized a steady increase in teenage abuse of over-the-counter cough and cold products. • Rhabdomyolysis was associated with an unintentional overdose of diphenhydramine in a 23month-old boy (35A ). • Rhabdomyolysis and acute renal insufficiency were reported in a 21-year-old man who took an intentional overdose of ethanol and diphenhydramine (36A ).

Fexofenadine (SED-14, 488; SEDA-21, 177; SEDA-26, 181, 183; SEDA-27, 168) Fexofenadine, the active metabolite of terfenadine, is efficacious and well tolerated in

180 seasonal allergic rhinitis (37R , 38C ), with positive effects on nasal blockade (39C ) and chronic idiopathic urticaria (40R ). It is also safe in young children (41C ). Several antihistamines have been tested in aircrew, in an attempt to find a “recommended” antihistamine for safety critical workers. Psychological In 42 healthy naval aviation personnel in a double-blind, randomized, placebo-controlled, crossover study, subjective drowsiness, cognitive performance, and vigilance were measured after three treatments: fexofenadine 180 mg, diphenhydramine 50 mg as a positive control, or placebo. Diphenhydramine significantly impaired cognitive performance, while fexofenadine had similar effects on complex cognitive skills to placebo. The authors concluded that their findings provided additional support for the safe use of fexofenadine by aviation personnel (42C ). In a study of the effect of fexofenadine on driving and psychomotor behavior there were no differences between fexofenadine and placebo on reaction times, decision-making, or driver behavior (43C ). However, one criticism of this study was the failure to include a positive control, such as diphenhydramine. In a double-blind, placebo-controlled, crossover study of the acute effects of single doses of fexofenadine 120 mg, olopatadine 10 mg, and chlorphenamine 4 mg on cognitive and psychomotor performance in 11 healthy Japanese volunteers, both chlorphenamine and olopatadine reduced behavioral activity while fexofenadine was similar to placebo (44C ). In a randomized, double blind, six-way, crossover study of the cognitive effects of fexofenadine 180 mg, both alone and in combination with alcohol, fexofenadine had no disruptive effects on objective measures related to driving a car and aspects of psychomotor and cognitive function, even when combined with a dose of alcohol equivalent to 0.3 g/kg (45C ). The effect of fexofenadine on cognitive performance was assessed using the test of variables of attention (TOVA) in a double-blind, placebo-controlled, randomized, crossover design in 42 healthy subjects (46C ). Each subject rated their subjective feelings of drowsiness on a visual analogue scale and then completed four separate TOVA tests: at baseline and after the administration of placebo, diphenhydramine

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50 mg, or fexofenadine 180 mg. Diphenhydramine caused significant increases in omission errors and response time on the TOVA and increases in self-reported drowsiness compared with placebo, while fexofenadine had no significant effects. All of these findings suggest that fexofenadine has a favorable nervous system adverse effects profile. Drug interactions Potential drug–drug interactions continue to be a cause for concern with antihistamines. In a study of the interaction of fexofenadine with ketoconazole in relation to efflux transport proteins of the small intestine, such as P glycoprotein in eight normal volunteers there were no significant effects of acute co-administration or pretreatment with ketoconazole on the in vivo intestinal absorption of fexofenadine (47r ).

Levocetirizine

(SEDA-26, 182, 183;

SEDA-27, 169) Levocetirizine, the R enantiomer of cetirizine, has pharmacodynamically and pharmacokinetically favorable characteristics, including high systemic availability, a rapid onset of action, limited distribution, and a low degree of metabolism (48R ). It is safe and effective in allergic rhinitis and chronic urticaria with minimal untoward effects (9R ). Levocetirizine was highly effective in suppressing skin reactivity to histamine for 24 hours after a single dose in 18 healthy volunteers and its activity was consistent and long-lasting. No uncommon adverse events were reported and no subject withdrew from the study because of an adverse event (49C ). In another study levocetirizine was effective and well tolerated in relieving the symptoms of perennial allergic rhinitis, including nasal congestion (50C ). Cardiovascular To date, there have been no studies of potential cardiotoxic effects of levocetirizine. However, since cetirizine is free of such adverse effects (1R ), it is unlikely that levocetirizine would be any different in this regard. Psychological The effect of levocetirizine 5 mg/day on actual driving performance during normal traffic has been compared with the effect of the first-generation antihistamine

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diphenhydramine 50 mg/day in 48 healthy volunteers in a double-blind, placebo-controlled, randomized trial (51C ). Treatments were given on days 1, 2, 3, and 4, at 90 minutes before the start of a standardized driving test on days 1 and 4. In contrast to diphenhydramine, driving performance was not significantly affected by levocetirizine 5 mg/day. In a double-blind, placebo-controlled, randomized study (52C ) of levocetirizine 5 mg/day, diphenhydramine 50 mg/day, or placebo in 48 healthy volunteers (24 men and 24 women) levocetirizine did not impair performance or cause memory deficits after acute and subchronic administration while diphenhydramine significantly affected divided attention and tracking after acute administration (53C ). Levocetirizine had no deleterious effect on cognitive and psychometric functions compared with placebo, as assessed by a comprehensive battery of psychometric tests in healthy men.

Loratadine (SED-14, 488; SEDA-22, 178; SEDA-26, 182; SEDA-27, 169)

181

tis, asthma, and marked hypersensitivity to house-dust mites. The reaction produced a welldefined erythematous and edematous plaque in his right elbow. The rash resolved without treatment in 1 week (54A ). Drug interactions Torsade de pointes in association with prolongation of the QT interval is a feature of several antihistamines (SEDA-26, 180) and the risk is increased in drug interactions, such as with amiodarone. • A 73-year old woman taking long-term amiodarone for atrial fibrillation developed with syncope and multiple episodes of torsade de pointes after taking loratadine for a suspected allergic reaction (55A ). Her QT interval and QT dispersion returned to normal within 4 days of withdrawing loratadine.

The authors suggested that the QT interval should be monitored whenever loratadine is coadministered with drugs that can prolong the QT interval. However, it may be that loratadine is best avoided altogether in such cases.

Skin Loratadine caused a fixed drug reaction in an 8-year-old boy with perennial rhiniREFERENCES 1. Walsh GM, Annunziato L, Frossard N, Knol K, Levander S, Nicolas JM, Taglialatela M, Tharp MD, Tillement P, Timmerman H. New insights into the second generation antihistamines. Drugs 2001; 61: 207–36. 2. Casale TB, Blaiss MS, Gelfand E, Gilmore T, Harvey PD, Hindmarch I, Simons FE, Spangler DL, Szefler SJ, Terndrup TE, Waldman SA, Weiler J, Wong DF; Antihistamine Impairment Roundtable. First do no harm: managing antihistamine impairment in patients with allergic rhinitis. J Allergy Clin Immunol. 2003; 111: S835–42. 3. Meltzer EIO, Welch MJ. Adverse effects of H1 receptor antagonists in the central nervous system. In: Simons FER (editor). Histamine and H1 receptor antagonists in allergic disease. Clinical Allergy & Immunology Series. New York: Marcel Dekker Inc, 1996: 357–81. 4. Woolsey RL. Cardiac actions of antihistamines. Ann Rev Pharmacol Toxicol 1996; 36: 233–52. 5. O’Hanlon JF, Raemaekers JG. Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989–94. Allergy 1995; 50: 234–42.

6. Gunn VL, Taha SH, Leibelt EL, Serwint JR. Toxicity of over the counter cough and cold medications. Pediatrics 2001; 108: E52. 7. Wogoman H, Steinberg M, Jenkins AJ. Acute intoxication with guaifenesin, diphenhydramine and chlorpheniramine. Am J Med Pathol 1999; 20: 199– 202. 8. Walsh GM. Emerging safety issues regarding the long-term usage of H1 -receptor antagonists. Expert Opin Drug Saf 2003; 1: 225–35. 9. Sympson K, Jarvis B. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs 2000; 59: 301–21. 10. Kawashima M, Harada S, Tango T. Review of fexofenadine in the treatment of chronic idiopathic urticaria. Int J Dermatol 2002; 41: 701–6. 11. McCellan K, Jarvis B. Desloratadine. Drugs 2001; 61: 789–96. 12. Bloebaum RM, Grant JA. Levocetirizine: the allergist’s arsenal grows larger. Expert Opin Pharmacother 2004; 5: 1581–8. 13. Holgate ST, Canonica GW, Simons FER, Taglialatela M, Tharp M, Timmerman H, Yanai K. Consensus group on new-generation antihistamines

182 (CONGA): present status and recommendations. Clin Exp Allergy 2003; 33: 1305–24. 14. Nazarov O, Petzold U, Haase H, Nguyen DT, Ellers-Lenz B, Hermann R. Azelastine eye drops in the treatment of perennial allergic conjunctivitis. Arzneimittelforschung 2003; 53: 167–73. 15. Sodhi PK, Pandey RM, Ratan SK. Efficacy and safety of topical azelastine compared with topical mitomycin C in patients with allergic conjunctivitis. Cornea 2003; 22: 210–13. 16. Canonica GW, Ciprandi G, Petzold U, Kolb C, Ellers-Lenz B, Hermann R. Topical azelastine in perennial allergic conjunctivitis. Curr Med Res Opin 2003; 19: 321–9. 17. Nordness M, Zacharisen MC. High dose cetirizine: a case report. Cutis 2003; 71: 396. 18. Noonan MJ, Raphael GD, Nayak A, Greos L, Olufade AO, Leidy NK, Champan D, Kramer B. The health-related quality of life effects of oncedaily cetirizine HCl in patients with seasonal allergic rhinitis: a randomized double-blind, placebocontrolled trial. Clin Exp Allergy 2003; 33: 351–8. 19. Simons FE, Silas P, Portnoy JM, Catuogno J, Chapman D, Olufade AO. Safety of cetirizine in infants 6 to 11 months of age: a randomized, double-blind, placebo-controlled study. J Allergy Clin Immunol 2003; 111: 1244–8. 20. Segal AT, Meltzer EO, Lockey RF, Prenner BM, Mitchell DQ, Tinkelman DG, Hewlett Jr D, Chapman D, Kramer B. Once-daily cetirizine is safe and effective for children with allergic rhinitis with and without intermittent asthma. Pediatr Asthma Allergy Immunol 2003; 16: 265–74. 21. Hellbom E, Lundbeck H, Humble M. Panic disorder treated with the antihistamine chlorpheniramine. Ann Allergy Asthma Immunol 2003; 90: 361–2. 22. Kirages TJ, Sule HP, Mycyk MB. Severe manifestations of Coricidin intoxication. Am J Emerg Med 2003; 21: 473–5. 23. Anwari JS, Iqbal S. Antihistamines and potentiation of opioid induced sedation and respiratory depression. Anaesthesia 2003; 58: 494–5. 24. King H, Corry P, Wauchob T, Barclay P. Probable dystonic reaction after a single dose of cyclizine in a patient with a history of encephalitis. Anaesthesia 2003; 58: 257–60. 25. Simons FE, Prenner BM, Finn A Jr. Desloratadine Study Group. Efficacy and safety of desloratadine in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol 2003; 111: 617–22. 26. Horak F, Stubner P, Zieglmeyer R, Harris AG. Comparison of the effects of desloratadine 5-mg daily and placebo on nasal airflow and seasonal allergic rhinitis symptoms induced by grass pollen exposure. Allergy 2003; 58: 481–5. 27. Monroe E, Finn A, Patel P, Guerrero R, Ratner P, Bernstein D; Desloratadine Urticaria Study Group. Efficacy and safety of desloratadine 5 mg once daily in the treatment of chronic idiopathic urticaria: a double-blind, randomized, placebocontrolled trial. J Am Acad Dermatol 2003; 48: 535–41. 28. Murdoch D, Goa KL, Keam SJ. Desloratadine. Drugs 2003; 63: 2052–77.

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29. Meltzer EIO, Welch MJ. Adverse effects of H1 -receptor antagonists in the central nervous system. In: Simons FER (editor). Histamine and H1 receptor antagonists in allergic disease. Clin Allergy Immunol Series. New York: Marcel Dekker Inc, 1996: 357–81. 30. Wilken JA, Berkowitz R, Kane R. Decrements in vigilance and cognitive functioning associated with ragweed-induced allergic rhinitis. Ann Allergy Asthma Immunol 2002; 89: 372–80. 31. Wilken JA, Kane RL, Ellis AK, Rafeiro E, Briscoe MP, Sullivan CL, Day JH. A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis. Ann Allergy Asthma Immunol 2003; 91: 375–85. 32. Schottker B, Dosch A, Kraemer DM. Severe hepatotoxicity after application of desloratadine and fluconazole. Acta Haematol 2003; 110: 43–4. 33. Schottker B, Dosch A, Kraemer DM. Severe hepatotoxicity after application of desloratadine and fluconazole. Acta Haematol 2003; 110: 43–4. 34. Baker AM, Johnson DG, Levisky JA, Hearn WL, Moore KA, Levine B, Nelson SJ. Fatal diphenhydramine intoxication in infants. J Forensic Sci 2003; 48: 425–8. 35. Stucka KR, Mycyk MB, Leikin JB, Pallasch EM. Rhabdomyolysis associated with unintentional antihistamine overdose in a child. Pediatr Emerg Care 2003; 19: 25–6. 36. Haas C, Magram Y, Mishra A. Rhabdomyolysis and acute renal failure following an ethanol and diphenhydramine overdose. Ann Pharmacother 2003; 37: 538–42. 37. Sympson K, Jarvis B. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs 2000; 59: 301–21. 38. Hampel F, Ratner P, Mansfield L, Meeves S, Liao Y, Georges G. Fexofenadine hydrochloride, 180 mg, exhibits equivalent efficacy to cetirizine, 10 mg, with less drowsiness in patients with moderate-to-severe seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2003; 91: 354–61. 39. Wilson AM, Orr LC, Coutie WJR, Sims EJ, Lipworth BJ. A comparison of once daily fexofenadine versus the combination of montelukast plus loratadine on domiciliary nasal peak flow and symptoms in seasonal allergic rhinitis. Clin Exp Allergy 2002; 32: 126–32. 40. Kawashima M, Harada S, Tango T. Review of fexofenadine in the treatment of chronic idiopathic urticaria. Int J Dermatol 2002; 41: 701–6. 41. Simons FE, J Semus M, Goritz SS, Simons KJ. H1 -antihistaminic activity of cetirizine and fexofenadine in allergic children. Pediatr Allergy Immunol. 2003; 14: 207–11. 42. Bower EA, Moore JL, Moss M, Selby KA, Austin M, Meeves S. The effects of single-dose fexofenadine, diphenhydramine, and placebo on cognitive performance in flight personnel. Aviat Space Environ Med. 2003; 74: 145–52. 43. Potter PC, Schepers JM, Van Niekerk CH. The effects of fexofenadine on reaction time, decision-

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making, and driver behavior. Ann Allergy Asthma Immunol 2003; 91: 177–81. 44. Kamei H, Noda Y, Ishikawa K, Senzaki K, Muraoka I, Hasegawa Y, Hindmarch I, Nabeshima T. Comparative study of acute effects of single doses of fexofenadine, olopatadine, d-chlorpheniramine and placebo on psychomotor function in healthy volunteers. Hum Psychopharmacol 2003; 18: 611– 18. 45. Ridout F, Shamsi Z, Meadows R, Johnson S, Hindmarch I. A single-center, randomised, doubleblind, placebo-controlled, crossover investigation of the effects of fexofenadine hydrochloride 180 mg alone and with alcohol, with hydroxyzine hydrochloride 50 mg as a positive internal control, on aspects of cognitive and psychomotor function related to driving a car. Clin Ther 2003; 25: 1518–38. 46. Mansfield L, Mendoza C, Flores J, Meeves SG. Effects of fexofenadine, diphenhydramine, and placebo on performance of the test of variables of attention (TOVA). Ann Allergy Asthma Immunol. 2003; 90: 554–9. 47. Tannergren C, Knutson T, Knutson L, Lennernäs H. The effect of ketoconazole on the in vivo intestinal permeability of fexofenadine using a regional perfusion technique. Br J Clin Pharmacol 2003; 55: 182–90. 48. Tillement JP, Testa B, Bree F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1 receptor antagonists. Biochem Pharmacol 2003; 66: 1123–6. 49. Purohit A, Melac M, Pauli G, Frossard N. Twenty-four-hour activity and consistency of activ-

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ity of levocetirizine and desloratadine in the skin. Br J Clin Pharmacol 2003; 56: 388–94. 50. Potter PC; Study Group. Levocetirizine is effective for symptom relief including nasal congestion in adolescent and adult (PAR) sensitized to house dust mites. Allergy 2003; 58: 893–9. 51. Verster JC, De Weert AM, Bijtjes SI, Aarab M, Van Oosterwijck AW, Eijken EJ, Verbaten MN, Volkerts ER. Driving ability after acute and subchronic administration of levocetirizine and diphenhydramine: a randomized, double-blind, placebocontrolled trial. Psychopharmacol (Berl) 2003; 169: 84–90. 52. Verster JC, Volkerts ER, Van Oosterwijck AW, Aarab M, Bijtjes SI, De Weert AM, Eijken EJ, Verbaten MN. Acute and subchronic effects of levocetirizine and diphenhydramine on memory functioning, psychomotor performance, and mood. J Allergy Clin Immunol 2003; 111: 623–7. 53. Gandon JM, Allain H. Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers. Br J Clin Pharmacol 2002; 54: 51–8. 54. Pionetti CH, Kien MC, Alonso A. Fixed drug eruption due to loratadine. Allergol Immunopathol (Madr) 2003; 31: 291–3. 55. Atar S, Freedberg NA, Antonelli D, Rosenfeld T. Torsades de pointes and QT prolongation due to a combination of loratadine and amiodarone. Pacing Clin Electrophysiol 2003; 26: 785–6.

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Drugs acting on the respiratory tract

INHALED GLUCOCORTICOIDS (SED-14, 512; SEDA-26, 186; SEDA-27, 174) Fourteen asthmatic patients maintained on inhaled budesonide/formoterol (Symbicort™ ) 320/9 micrograms/day were randomized to additional budesonide/formoterol 1600/45 micrograms/day, additional formoterol 45 micrograms/day, or placebo in a crossover study (1c ). Changes in serum potassium concentration, pulse rate, blood pressure, QTc interval, blood glucose concentration, and plasma lactate concentration were significant in the 12 hours after high-dose budesonide/formoterol, but did not result in adverse effects. Systemic availability of inhaled glucocorticoids Systemic absorption of inhaled glucocorticoids can occur via the gut after swallowing and by pulmonary absorption. There is growing evidence that the latter is more significant in healthy than asthmatic individuals, owing to airway stenosis in the latter. The systemic availability of fluticasone, as assessed by mean AUC and Cmax , was significantly lower in patients with chronic obstructive airways disease than in healthy controls (2c ). Both the patients and the healthy volunteers received fluticasone 1000 micrograms/day for 7 days followed by a single intravenous dose of 1000 micrograms. Suppression of serum cortisol concentrations was greater in the controls than in the patients, whereas the pharmacokinetic of intravenous fluticasone were comparable. Sensory systems The relative risk of cataract has been retrospectively assessed using the British General Practice Research Database by © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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comparing 15 479 individuals exposed to inhaled glucocorticoids with 1479 matched controls in a case-control study (3C ). The corrected odds ratio for the association between exposure to inhaled glucocorticoids and cataract was significant for daily doses above 1600 micrograms (OR = 1.69, CI = 1.17, 2.43). The lowest effective dose of inhaled glucocorticoids should be used and the risk of cataract should be more widely appreciated. Endocrine Measurement of hypothalamicpituitary-adrenal axis function is a sensitive way of assessing the systemic effects of inhaled glucocorticoids. While suppression of adrenal gland function is associated with daily doses of fluticasone above 750 micrograms, the impact of concurrent moderate-dose fluticasone and oral steroids on adrenal response is unknown. Adult patients using intranasal steroids, low-dose fluticasone (440 micrograms/day), or high-dose fluticasone (880 micrograms/day) underwent a low-dose co-syntropin stimulation test to assess adrenal response before and 2 days after oral prednisone 60 mg/day (4c ). One of 31 control patients and one of 13 patients using moderate-dose fluticasone had suppressed adrenal gland function on the second day of oral prednisone, which normalized by the second week of treatment. However, 14 of 19 patients using high-dose fluticasone had suppressed adrenal gland function on day 2 with recovery in 10 of the 19 patients within 4 weeks. In conclusion, concurrent standarddose oral prednisone burst and moderate-dose fluticasone transiently suppress adrenal gland function, while concurrent high-dose fluticasone leads to prolonged impairment. Patients using high-dose fluticasone should be closely monitored. In another cross-sectional study, adrenal function was assessed in 50 asthmatic children

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and adolescents using high-dose inhaled fluticasone, by measuring early morning serum cortisol and tetracosactrin stimulation (5C ). The mean fluticasone daily dose was 925 µg for a mean duration of 2 years. In 36 patients with morning serum cortisol concentration less than 400 nmol/l a tetracosactrin stimulation test showed that six had a pathological response. Biochemical evidence of impaired adrenal gland function was thus found in 12% of the patients, suggesting that high-dose fluticasone can be associated with dose-dependent adrenocortical suppression. Adrenal function has been assessed by lowdose adrenocorticotropin (ACTH) stimulation in 12 adult asthmatic patients using inhaled beclomethasone (200–900 micrograms/day) before and after switching to inhaled fluticasone (200–600 micrograms/day) (6c ). Switching from beclomethasone to fluticasone led to a 40% reduction in corticosteroid dosage, improved lung function, and caused a significant rise in the adrenal gland response to ACTH. The reduced risk of adrenal gland suppression associated with fluticasone was most notably due to a lower overall dose of inhaled glucocorticoids. Endocrine effects of budesonide have been assessed in 29 asthmatic children aged 6 months to 3 years by measuring fasting plasma cortisol concentrations and performing an ACTH stimulation test in a double-blind, randomized, placebo-controlled study (7C ). The patients received budesonide either 2 mg followed by a stepwise reduction of 25% every second day or 0.5 mg/day or placebo for 8 days. Neither fasting nor 1-hour post-stimulation plasma cortisol concentrations differed in any group. The effect of inhaled triamcinolone on adrenal response has been assessed in 221 patients with chronic obstructive airway disease in a randomized placebo-controlled trial (8C ). The patients received either inhaled triamcinolone 1200 micrograms/day or placebo for 3 years. Basal cortisol concentrations were significantly lower with triamcinolone than placebo after 1 and 3 years. Cortisol concentrations were not suppressed at 30 minutes and 60 minutes after co-syntropin injection. The authors concluded that triamcinolone is safe in chronic obstructive airway disease patients at the tested dose with respect to adrenal gland response.

185 Musculoskeletal DoTS classification: Reaction: osteoporosis from glucocorticoids Dose relation: collateral reaction Time course: late Susceptibility factors: elderly patients, female sex (postmenopausal) Evidence of an association between inhaled glucocorticoids and impaired bone mineralization is still controversial. The safety of nebulized beclomethasone and budesonide has been assessed in 130 asthmatic children aged 6 months to 6 years in a randomized study (9C ). Adverse events were similar in patients who used beclomethasone 800 micrograms/day or budesonide 750 micrograms/day over 14 weeks. There was no influence on bone metabolism, as shown by a stable urinary deoxypyridinoline/urinary creatinine ratio, and the time course of patient height and weight were unaffected. Moderate-dose beclomethasone and budesonide appear to be safe in young children. Bone mineral density and growth have been analysed in 174 asthmatic children aged 6– 14 years, randomized to fluticasone 200 micrograms/day or nedocromil 8 mg/day over 2 years (10C ). Adjusted mean increase of lumbar spine and femoral neck bone mineral density (measured by dual-energy X-ray absorptiometry) and adjusted mean growth rates from baseline were similar in fluticasone and nedocromil treated patients after 2 years of treatment. Fluticasone is safe in children at a critical age of skeletal growth with the tested dose. However, the study was unblinded, oral steroids were used more often in the controls, and dietary calcium intake was not assessed. Bone mineral density has been assessed in 106 postmenopausal women exposed to inhaled glucocorticoids (predominantly budesonide) and compared with 674 postmenopausal women not exposed to glucocorticoids in a population-based, prospective cohort study (11C ). The mean duration of corticosteroid treatment was 8.2 years and the mean daily dose was 853 micrograms. The subjects were matched for known co-variates with effects on bone mineral density. There was no difference in age-adjusted bone mineral density between women who had been exposed to inhaled glucocorticoids and controls; nor was there any correlation between the dose of inhaled glucocorticoids and bone mineral density.

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Immunologic Inhaled glucocorticoids can cause allergic reactions, ranging from local (buccal) irritation to systemic contact dermatitis and anaphylaxis. Angioedema and urticaria that develop after a short period of inhaled glucocorticoids do not necessarily indicate type I allergy – type IV contact allergy has also been reported. • An asthmatic woman developed angioedema and dysphagia 3 hours after budesonide exposure (12A ). However, prick tests were negative, and patch testing was strongly positive for budesonide without cross-reactions with other major steroids. • A fluticasone-associated cutaneous allergic granulomatous vasculitis resembling Churg–Strauss syndrome has been reported in an asthmatic man shortly after exposure to combined fluticasone/salmeterol (13A ).

High-dose inhaled glucocorticoids can impair cellular immune responses (14C ). The association of inhaled glucocorticoids and anergy has been studied in a double-blind, randomized, placebo-controlled trial, to determine if a 28-day course of high-dose inhaled fluticasone can suppress delayed-type hypersensitivity in 45 steroid-naïve healthy volunteers (15C ). Delayed-type hypersensitivity was assessed by intradermal skin testing to a standard panel of antigens before and after 4 weeks of fluticasone 880 micrograms/day or placebo. Fluticasone had no effect on cellular immune responses. Infection risk Oropharyngeal candidiasis is a complication of inhaled glucocorticoids, with a prevalence of up to 30% (16C ). However, the prevalence of esophageal candidiasis is not known. In 49 patients using fluticasone (200– 1200 micrograms/day via a dry powder inhaler over a mean period of 13.3 weeks) and 700 control patients, upper gastrointestinal endoscopy showed that the prevalence of esophageal candidiasis was 37% with fluticasone and 0.3% in controls (17C ). Diabetes mellitus and high-dose fluticasone were associated with an increased risk of esophageal candidiasis. To assess the frequency of oral candidiasis associated with inhaled glucocorticoids, the amount of Candida spp. was assessed in oral swabs from 143 asthmatic patients using either inhaled fluticasone or beclomethasone, 11 asthmatic patients not using inhaled glucocorticoids, and 86 healthy volunteers (18C ). The mean dose of fluticasone was about 50% that

Markus Joerger, Katharina Hartmann, and Max Kuhn

of beclomethasone. The amount of oral Candida spp. was significantly higher in asthmatic patients who used inhaled glucocorticoids compared with those who did not and was also greater in patients who used fluticasone than in those who used beclomethasone. Gargling with amphotericin was effective in most asthmatic patients with candidiasis. Oral candidiasis was not associated with inappropriate corticosteroid flow rates.

Treating asthma during pregnancy A third of all asthmatic women have worse asthma at some time during pregnancy (19C ). While maternal use of oral glucocorticoids during the first trimester has been associated with reduced birth weight and an increased risk of pre-eclampsia and oral clefts (20M ), data about maternal use of inhaled glucocorticoids are more controversial. The US Food and Drug Administration (FDA) classifies inhaled glucocorticoids as pregnancy risk category C (adverse fetal effects described in animals, no controlled studies in women available), with the exception of budesonide, which is category B (positive animal data, but adequate and well controlled studies in humans failed to show a fetal risk). According to a recent review and position paper, beta2 -adrenoceptor agonists should be used as needed in pregnant women with mild intermittent asthma based on long-term safety data, and inhaled cromoglicate should be first-line therapy for pregnant women with mild persistent asthma, followed by inhaled budesonide if symptoms worsen (21R , 22R ). Continued treatment during pregnancy with the newer inhaled glucocorticoids can be considered in women who have a good response to these agents before pregnancy. Available data for the use of inhaled glucocorticoids during pregnancy are reassuring for beclomethasone and budesonide. In a surveillance study including more than 229 000 pregnant women, 395 mothers-to-be were exposed to beclomethasone during the first trimester with no subsequent evidence of beclomethasoneassociated congenital defects (23C ). Similarly, data from a Swedish Birth Registry showed no significant differences in congenital malformations in the offspring of 2014 mothers who used

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budesonide during early pregnancy compared with the general population (24C ). The rate of congenital malformations in the study population was 3.8% (CI = 2.9, 4.6), which was similar to the general population (3.5%). Four infants were born with orofacial clefts, which is also in agreement with the expected number in a general population. Although budesonideassociated teratogenic effects cannot be completely ruled out, the authors suggested that they are clinically insignificant. The safety of inhaled beclomethasone has been assessed during 45 pregnancies in 40 women with severe asthma who used beclomethasone at a mean daily dose of 336 micrograms (25c ). The prevalence of congenital malformations (one out of 45 live births) was within the normal range despite concurrent use of oral prednisone in 37 pregnancies and concurrent use of theophylline in all women. These data suggest that beclomethasone at recommended doses is safe in pregnancy. A retrospective observational cohort study assessed outcomes in 54 pregnant asthmatic women who used triamcinolone, beclomethasone, or oral theophylline (26c ). Birth weights did not differ between the groups, and triamcinolone was suggested to be at least as safe as beclomethasone during pregnancy. However, these results are preliminary and to our knowledge the final results have not yet been published. Data derived from the Swedish Medical Birth Register (years 1995–1998) on pregnancy outcomes in 2968 budesonide-exposed asthmatic women have been retrospectively compared with those in pregnant asthmatic women who were not exposed to asthma medications (27c ). The outcomes were similar between budesonide-exposed women and women without exposure to asthma medications. However, the authors pointed out that these results cannot be applied to other inhaled glucocorticoids, because their systemic effects vary owing to differences in potency and systemic availability. Preterm delivery and fetal growth, assessed by intrauterine growth retardation, have been prospectively studied in 873 pregnant women with asthma and compared with 13 333 women without asthma (28C ). Preterm delivery was significantly associated with the severity of asthma in univariate but not in multivariate analysis. The use of oral steroids and

theophylline, but not inhaled glucocorticoids, leukotriene antagonists, or beta2 -adrenoceptor agonists, significantly increased the risk of preterm delivery. There was no association for intrauterine growth retardation and the use of general or specific medications. For every increase in treatment step (according to the 2002 Global Initiative for Asthma Guidelines (29S )), there was an overall increased risk of preterm delivery of 32%. This increased risk, however, appeared to be restricted to the use of theophylline and oral steroids. In conclusion, assessment of the benefit: harm balance implies that inhaled glucocorticoids should be used if necessary to control asthma in pregnant women, as poorly controlled asthma threatens maternal and neonatal outcomes (30c ). Budesonide is to be preferred if treatment must be started during pregnancy or in the case of high-dose treatment schedules (22R ).

Drugs acting on the respiratory tract

Drug formulations A mandated worldwide phase-out of ozone-depleting chlorofluorocarbons has encouraged manufacturers to re-engineer pressurized metered-dose inhalers (MDIs) by applying new technologies. However, the properties of different MDIs may significantly affect the amount of drug that enters the lung (pulmonary availability). Drug plasma concentrations are the most direct surrogate marker for assessing the pulmonary availability of different inhalers, at least for drugs with high first-pass clearance, in which gastrointestinal availability is of minor importance. Furthermore, assessment of adrenal gland response provides an indirect measure of systemic availability. The effect of a single dose of budesonide 1000 micrograms from three different drypowder inhaler (DPI) formulations on urine and plasma cortisol concentrations has been studied in a randomized, placebo-controlled study in 13 healthy volunteers (31C ). Two new formulations of budesonide (Lactose and PassCal™ ) delivered from a Clickhaler™ were compared with Pulmicort™ from a Turbuhaler™ . Urinary cortisol concentrations with the PassCal Clickhaler™ and the Pulmicort Turbuhaler™ were significantly lower than with placebo, while the lactose budesonide Clickhaler™ produced a non-significant reduction in urinary cortisol concentrations compared with placebo.

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The authors concluded that the systemic availability of budesonide was similar for the lactose Clickhaler™ , the PassCal Clickhaler™ , and the standard comparator, the Pulmicort Turbuhaler™ . The mechanical aerosol generator MAGhaler™ is another chlorofluorocarbonfree inhalation device. Its efficacy and safety have been compared against a standard chlorofluorocarbon MDI in asthmatic patients in a double-blind, reference-controlled, randomized trial in 171 asthmatic patients who took beclomethasone 1000 micrograms/day for 12 weeks either via the MAGhaler™ or a conventional MDI (32C ). The equivalence of the two devices was confirmed on the basis of treatment efficacy, as assessed by the ratio of mean FEV1 in weeks 4 and 12, and treatment safety, as assessed by adverse events. Ease of administration favored the MAGhaler™ . The safety of inhaled flunisolide via an MDI containing a newer hydrofluoroalkane propellant has recently been reviewed (33R ). Hydrofluoroalkane propellants are not ozonedepleting and produce aerosols of smaller average particle size, which leads to an increase in lung deposition. A flunisolide hydrofluoroalkane formulation was compared with a flunisolide chlorofluorocarbon formulation, each at 340 micrograms bd and with placebo in 669 asthmatic patients in a randomized, doubleblind, placebo-controlled trial (34C ). There was no evidence of suppressed adrenal gland response after 12 weeks in any group, as assessed by intravenous co-syntropin stimulation. In randomized comparison of inhaled flunisolide hydrofluoroalkane 340 micrograms/day and beclomethasone chlorofluorocarbon 336 micrograms/day in 215 asthmatic patients, there was a significantly lower incidence of oral candidiasis in the flunisolide hydrofluoroalkane group, possibly because of reduced oropharyngeal drug deposition (33C ). The proportion of patients who used the flunisolide hydrofluoroalkane and who were not responsive to co-syntropin stimulation was similar at baseline and after 1 year on flunisolide (7.8% and 9.1% respectively). Flunisolide hydrofluoroalkane 340 micrograms/day had no adverse effects on linear growth and adrenal response in 152 asthmatic children compared with 39 children who used

Markus Joerger, Katharina Hartmann, and Max Kuhn

beclomethasone chlorofluorocarbon 336 micrograms/day and 44 children who used cromoglicate sodium 6400 micrograms/day (35C ). Finally, the safety of budesonide 200 micrograms bd via the metal Nebuchamber valved holding chamber has been compared with the same dose of budesonide via the polypropylene Aerochamber valved holding chamber in 30 children in a randomized crossover trial (36C ). The Nebuchamber device delivers a greater mass of aerosol to the mouth, owing to its non-electrostatic properties. However, adrenal gland response, as assessed by 24-hour urinary cortisol concentrations, was similar in the two groups, suggesting similar systemic availability.

BETA2 -ADRENOCEPTOR AGONISTS (SED-14, 500; SEDA-25, 192; SEDA-26, 190; SEDA-27, 179)

Formoterol

(SED-14, 506; SEDA-25, 194; SEDA-26, 191; SEDA-27, 179)

Formoterol is both a rapid and a long-acting beta2 -adrenoceptor agonist. A key issue is the safety of as-needed formoterol in addition to long-acting beta2 -adrenoceptor agonists in asthmatics on maintenance therapy. Formoterol 4.5 micrograms as reliever therapy has been compared with salbutamol 200 micrograms MDI in an large, open, real-life asthma study in 18 124 asthmatic children and adults, who were randomized to as-needed treatment for 6 months with either formoterol or salbutamol (37c ). Maintenance therapy included inhaled glucocorticoids in 76% of all patients, longacting beta2 -adrenoceptor agonists in 31%, and leukotriene receptor antagonists in 9%. While the time to first exacerbation was prolonged by formoterol, the overall incidence of adverse events was similar in the two treatment groups. Asthma-related adverse events were significantly less frequent with formoterol (12%) than salbutamol (14%). The authors concluded that formoterol as a reliever is as safe as salbutamol, that its use is associated with fewer asthma symptoms and exacerbations, and that maintenance use of inhaled glucocorticoids or long-acting beta2 -adrenoceptor agonists does not adversely affect the safety of reliever therapy.

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Drug formulations Airmax™ is a novel inhaler that uses the X-ACT™ technology to provide consistent dosing, independent of inspiratory flow-rate. The respirable dose of formoterol is twice as high with Airmax™ as with Aeroliser™ . Formoterol delivered from Airmax™ has been compared with formoterol from the single-dose dry-powder inhaler Foradil™ Aeroliser™ at a 1 : 2 dose ratio in 31 asthmatic patients (38c ). Formoterol delivered from Airmax™ provided similar bronchodilatory effects to formoterol from Aeroliser™ at double the dose. There were higher incidences of hypokalemia and hyperglycemia at the highest doses with Aeroliser™ (96 micrograms) than with Airmax™ (48 micrograms). Blood pressure and heart rate did not change significantly. These data are the first to suggest some safety advantage of Airmax™ over Aeroliser™ at equipotent doses of formoterol.

bpm with salbutamol and 2 bpm with levosalbutamol over the following 2 hours after drug inhalation. Patients without baseline tachycardia had a mean increase of heart rate of 4.4 bpm with salbutamol and 3.6 bpm with levosalbutamol. Short-term use of nebulized salbutamol and levosalbutamol was therefore associated with similar changes in heart rates in intensive care patients with or without baseline tachycardia.

Drugs acting on the respiratory tract

Levosalbutamol (levalbuterol) (SEDA-26, 191) Levosalbutamol is the R-enantiomer of racemic salbutamol (albuterol). Levosalbutamol 0.63 mg is equipotent to salbutamol 2.5 mg, but with a lower risk of adverse effects, except for the potassium-lowering effect (39c ). Cardiovascular Changes in heart rate before and after inhalation of nebulized salbutamol (2.5 mg) or levosalbutamol (0.63 mg) on days 1 and 3 have been retrospectively compared by chart review in 35 patients with acute airflow obstruction (40c ). On day 3, heart rate was increased by 2.7 bpm (CI = 0.02, 5.4) after inhalation of salbutamol compared with levosalbutamol. However, levosalbutamol did not provide clinical benefit with respect to drugassociated tachycardia. In a study of the effect of racemic nebulized salbutamol 2.5 mg and nebulized levosalbutamol 1.25 mg on heart rate in 20 intensive care patients with (n = 10) and without (n = 10) baseline tachycardia, the patients were randomized to receive at least two consecutive doses of salbutamol or levosalbutamol 4 hours apart (41C ). Patients with a baseline tachycardia had a mean increase in heart rate of 1.4

Electrolyte balance Equipotent doses of salbutamol (10 mg) and levosalbutamol (2.5 mg) have been compared for their potassium-lowering effect in nine healthy volunteers in a double-blind, randomized, placebo-controlled study (42C ). Serum potassium concentration was significantly lower at 30 minutes and 60 minutes after inhalation of salbutamol and levosalbutamol compared with placebo. Levosalbutamol and salbutamol were equivalent with respect to their potassium-lowering effects. Levosalbutamol caused fewer adverse effects, such as tremor, palpitation, tachycardia, and nervousness, than salbutamol.

Salbutamol

(SED-14, 502; SEDA-23, 185; SEDA-26, 191; SEDA-27, 179) Metabolism The pathophysiology of salbutamol-associated lactic acidosis is poorly understood and has partly been attributed to the production of lactate by overworked respiratory muscles. • A 39-year-old woman developed salbutamol-associated lactic acidosis (peak 7.8 mmol/l) during general anesthesia for planned thoracoscopic sympathectomy (43A ).

This suggests that the above mentioned mechanism is unlikely to have caused lactic acidosis in this patient. Rather, it may have resulted from beta2 -adrenoceptor activation, with subsequent excess glycogenolysis and lipolysis, production of pyruvate, and final conversion to lactate. Drug formulations The safety of Ventolin Evohaler™ , a salbutamol formulation with the hydrofluoroalkane propellant 134a, has been analysed during its introduction in a British

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prospective cohort study (44c ). Adverse events were compared before and after introducing Ventolin Evohaler™ in regular users of a salbutamol MDI (with a chlorofluorocarbon propellant) over five 3-month periods of observation between 1 October 1998 and 31 December 1999. Of the 10 472 subjects in the study, 8973 completed the observation period after transition to Ventolin Evohaler™ ; the overall exposure to Ventolin Evohaler™ was 53%. Major or minor adverse events were not more common when the five consecutive 3-month periods were compared, suggesting equal safety of Ventolin Evohaler™ and Ventolin MDI. However, the proportion of patients who were exposed to Ventolin Evohaler™ was below expectation, which may have biased the results.

Salmeterol

(SED-14, 506; SEDA-26, 192)

Cardiovascular Safety data have been pooled from seven randomized, double-blind, parallelgroup, multiple-dose studies, to study the cardiovascular safety of salmeterol 50 micrograms bd in chronic obstructive pulmonary disease in 2853 patients for a median of 24 weeks (45M ). The incidence of cardiovascular events (8%) was similar in the two groups. There were no episodes of sustained ventricular tachycardia or differences in heart rate, QT interval, or extra beats. The incidence of cardiovascular events increased with age, concurrent cardiovascular disease, and concurrent treatment with antidysrhythmic/bradycardic agents in both groups. In January 2003, the US Food and Drug Administration (FDA) announced the premature termination of a placebo-controlled evaluation of the risk of serious adverse effects of salmeterol (46S , 47C ). An interim analysis of 26 000 asthmatic patients showed an excess of serious asthma attacks and asthma deaths in patients using salmeterol. The difference was significant in the subgroup of patients who were not using inhaled glucocorticoids. The high proportion of patients who were not using inhaled glucocorticoids (53% of the study population) is remarkable and not in agreement with current guidelines. This might have biased the results.

Markus Joerger, Katharina Hartmann, and Max Kuhn

ANTICHOLINERGIC DRUGS (SED-14, 499; SEDA-24, 192; SEDA-26, 194; SEDA-27, 180)

Ipratropium bromide Death The association of ipratropium with premature death has been prospectively studied in outpatients with chronic obstructive pulmonary disease (n = 827) or asthma (n = 273) in a longitudinal cohort study (48C ). Ipratropium was used by 7.7% of the patients with chronic obstructive pulmonary disease and 8.1% of those with asthma. The 10-year mortality was 49% for patients with chronic obstructive pulmonary disease and 18% for patients with asthma. The relative risk for mortality of all causes was 1.6 (CI = 1.2, 2.1) in patients with chronic obstructive pulmonary disease using ipratropium and 2.4 (1.2, 5.0) in patients with asthma using ipratropium, after adjustment for FEV1 , smoking status, asthma medications, and the presence of cor pulmonale. Adjustment for severity of lung obstruction significantly reduced the relative risk of death. Therefore, disease severity as a confounding factor cannot be excluded, and based on these results an association between ipratropium and premature death should be interpreted with caution.

Tiotropium bromide The long-term effects of tiotropium have been compared with its short-term bronchodilatory response in patients with chronic obstructive pulmonary disease in a retrospective analysis of two randomized, placebo-controlled studies (49c ). Patients using tiotropium 18 micrograms/day were divided into good responders (n = 263) and poor responders (n = 255), depending on the presence or absence of shortterm improvements in FEV1 of at least 12% or at least 200 ml. The mean morning predose FEV1 improved significantly at 1 year in both the good responders (+212 ml) and the poor responders (+94 ml), compared with 328 controls. The proportion of patients who had adverse events was similar in all the groups. There was tiotropium-associated xerostomia in 16% of treated patients, but it led to withdrawal of treatment in under 1%. The authors

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concluded that long-term tiotropium is safe, irrespective of the fact that some patients are poor responders. The overall safety profiles of tiotropium and ipratropium are comparable, as are withdrawals due to adverse events, according to a recent review (50R ). While xerostomia was more frequent with tiotropium than with ipratropium in some trials (51C ), it was similar in others (52C ). Xerostomia was found in about 14% of tiotropium-treated patients with chronic obstructive pulmonary disease, with a usually mild course and often resolving with continued treatment (53R ). Other common adverse effects of tiotropium (affecting up to 10% of patients) are constipation, candidiasis, sinusitis, and pharyngitis. Uncommon adverse effects (affecting up to 1.0% of patients) are allergic reactions, urinary retention, and tachycardia. Isolated reported adverse effects are supraventricular tachycardia and atrial fibrillation. Data from two randomized, placebo-controlled studies have been pooled to compare tiotropium 18 micrograms/day via a HandiHaler with salmeterol 50 micrograms bd via an MDI over 6 months in 1207 patients with chronic obstructive pulmonary disease (54C ). Xerostomia was significantly more common with tiotropium (8.2%) than with salmeterol (1.7%) or placebo (2.3%), but only led to withdrawal of treatment in one patient using tiotropium.

• A 76-year-old man developed hepatocellular and cholestatic liver injury after taking montelukast 10 mg/day for 2 years and combined fluticasone/salmeterol for 4 years (59A ). A positive lymphocyte transformation test to montelukast, rapid improvement of the pathological findings after dechallenge, and the exclusion of other causes suggested montelukast-associated acute liver injury.

Drugs acting on the respiratory tract

LEUKOTRIENE MODIFIERS (SEDA-24, 184; SEDA-25, 197; SEDA-26, 193; SEDA-27, 177) Liver Liver damage has been reported with therapeutic doses of zafirlukast (55A , 56A ), but not with montelukast, except for one case of montelukast-associated cholestasis (57c ). However, two recent anecdotes have suggested that montelukast can cause liver damage. • A 42-year-old asthmatic man took montelukast 10 mg/day for 10 months before jaundice developed (58A ). A liver biopsy showed a pattern of mixed hepatocellular and cholestatic injury. Serum enzymes completely normalized within 4 months after withdrawal.

Both cases mimicked the well known zafirlukast-associated hepatotoxicity with respect to the long latency time to onset of jaundice and persistence of abnormal liver tests for several weeks after drug withdrawal. Skin Pemphigus has been attributed to montelukast (60A ). • An 8-year-old girl with a 2-year history of chronic asthmatic bronchitis developed pemphigus with eosinophilia after taking montelukast 5 mg/day for 5 months. The clinical, histopathological, and immunofluorescent findings were consistent with the diagnosis of pemphigus. Her symptoms subsided with oral prednisone within 2 months of stopping montelukast.

Immunologic The association of Churg– Strauss syndrome and the therapeutic use of leukotriene receptor antagonists was reviewed in SEDA-27 (p. 177). More case histories on the same topic have since been published. • Churg–Strauss syndrome with associated mononeuritis multiplex and peripheral neuropathy developed in a 68-year-old asthmatic patient 3 months after stopping prednisolone and starting montelukast (61A ). • A 57-year-old asthmatic man who had taken highdose fluticasone and salmeterol for more than 1 year and oral montelukast 10 mg/day for 9 months developed Churg–Strauss syndrome with a predominant necrotizing vasculitic rash (62A ). • A 7-year-old asthmatic girl developed Churg– Strauss syndrome while taking moderate doses of an unspecified inhaled corticosteroid and standard oral doses of montelukast for 15 months (63A ).

This is the first case report of leukotriene receptor antagonist-associated Churg–Strauss syndrome in a child. Accumulating evidence thus confirms the previous assessment that Churg–Strauss syndrome associated with leukotriene receptor antagonists is due to unmasking of subclinical Churg–Strauss syndrome when reducing corticosteroid doses.

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Pranlukast-associated Churg–Strauss syndrome may have an atypical course, as in a patient with isolated fulminant eosinophilic endomyocarditis (64A ).

Montelukast

(SEDA-24, 184; SEDA-26, 193; SEDA-27, 179) The activity and safety of montelukast have been assessed in 1214 patients with spring seasonal allergic rhinitis taking montelukast 10 mg (n = 522), loratadine 10 mg (n = 171), or placebo (n = 521) daily at bedtime for 2 weeks in a randomized, double-blind, placebocontrolled trial (65C ). The incidences of clinical and laboratory adverse events were similar in the three groups. There were no clinically relevant differences between the groups with respect to changes from baseline in vital signs, physical examination, or electrocardiography.

Drug administration route The efficacy and safety of intravenous montelukast has been assessed in asthmatic patients in a randomized, double-blind, controlled study (66C ). The patients received standard antiasthmatic therapy plus intravenous montelukast 7 mg (n = 67) or 14 mg (n = 68) or placebo (n = 66). Systemic glucocorticoids were used according to current guidelines. The patients who received intravenous montelukast had similar improvements in FEV1 over 2 hours after intravenous therapy, and the effects were greater than those of placebo. The safety profiles were similar in all groups.

Markus Joerger, Katharina Hartmann, and Max Kuhn

Pranlukast

(SEDA-26, 193)

The most frequent adverse effects of pranlukast are gastrointestinal, such as abdominal pain and diarrhea in up to 2% and liver injury in up to 0.5% of patients (67R ). In adults, long-term pranlukast was well tolerated, without significant changes in laboratory parameters (68c ). In children taking oral liquid pranlukast, there was nausea in 1.6% and increased liver enzymes in 0.9%, with an overall frequency of adverse events of 5.6% (67R ). Comparative trials of pranlukast with either zafirlukast or montelukast suggest similar safety profiles (67R ).

Zafirlukast

(SEDA-26, 194)

Urinary tract Zafirlukast has been reported to cause acute renal insufficiency (69A ). • Acute renal insufficiency and nephrotic syndrome developed in a 54-year-old asthmatic man who took zafirlukast for 6 weeks. The presentation was compatible with pre-vasculitic phase Churg– Strauss syndrome. Renal biopsy showed mild mesangial proliferation without any vasculitic signs, similar to that seen in non-steroidal antiinflammatory renal damage. Renal function normalized within 1 month after withdrawal of zafirlukast and the administration of intermittent highdose oral prednisolone.

A causal relation between zafirlukast and renal insufficiency, for example by interference with leukotriene homeostasis, could not be excluded.

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delivered as an extrafine aerosol in asthma patients. Ann Allergy Asthma Immunol 2001; 87: 405–11. 35. Boguniewicz M, GIllman S. Flunisolide HFA has no effect on growth in children with asthma. 3rd Triennial World Asthma Meeting, 15-7-2001. 36. Amirav I, Mansour Y, Tiosano T, Chamny S, Chirurg S, Oren S, Grossman Z, Kahana L, Kahan E, Newhouse MT. Safety of inhaled corticosteroids delivered by plastic and metal spacers. Arch Dis Child 2003; 88: 527–8. 37. Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A, Petermann W, Aubier M, Schwabe G, Bengtsson T. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J 2003; 22: 787–94. 38. Dubois EF, Roder E, Ifle RG. Bronchodilating effects of cumulative doses of formoterol from a novel multi-dose inhaler (Airmax). Respir Med 2003; 97: 71–4. 39. Handley DA, Tinkelman D, Noonan M, Rollins TE, Snider ME, Caron J. Dose–response evaluation of levalbuterol versus racemic albuterol in patients with asthma. J Asthma 2000; 37: 319–27. 40. Scott VL, Frazee LA. Retrospective comparison of nebulized levalbuterol and albuterol for adverse events in patients with acute airflow obstruction. Am J Ther 2003; 10: 341–7. 41. Lam S, Chen J. Changes in heart rate associated with nebulized racemic albuterol and levalbuterol in intensive care patients. Am J Health-Syst Pharm 2003; 60: 1971–5. 42. Pancu D, LaFlamme M, Evans E, Reed J. Levalbuterol is as effective as racemic albuterol in lowering serum potassium. J Emerg Med 2003; 25: 13–16. 43. Liem EB, Mnookin SC, Mahla ME. Albuterolinduced lactic acidosis. Anesthesiology 2003; 99: 505–6. 44. Craig-McFeely PM, Wilton LV, Soriano JB, Maier WC, Shakir SA. Prospective observational cohort safety study to monitor the introduction of a non-CFC formulation of salbutamol with HFA134a in England. Int J Clin Pharmacol Ther 2003; 41: 67–76. 45. Ferguson GT, Funck-Brentano C, Fischer T, Darken P, Reisner C. Cardiovascular safety of salmeterol in COPD. Chest 2003; 123: 1817–24. 46. FDA safety information. http://www.fda.gov/ medwatch/ SAFETY/2003/serevent.htm. Internet communication. Accessed 10 June 2004. 47. Excess mortality with salmeterol as singleagent therapy. Prescrire Int 2003; 12: 142. 48. Ringbaek T, Viskum K. Is there any association between inhaled ipratropium and mortality in patients with COPD and asthma? Respir Med 2003; 97: 264–72. 49. Tashkin D, Kesten S. Long-term treatment benefits with tiotropium in COPD patients with and without short-term bronchodilator responses. Chest 2003; 123: 1441–9. 50. Panning CA, DeBisschop M. Tiotropium: an inhaled, long-acting anticholinergic drug for chronic obstructive pulmonary disease. Pharmacotherapy 2003; 23: 183–9.

Markus Joerger, Katharina Hartmann, and Max Kuhn 51. Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, Cornelissen PJ. Improved health outcomes in patients with COPD during 1 year’s treatment with tiotropium. Eur Respir J 2002; 19: 209–16. 52. van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ. A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax 2000; 55: 289–94. 53. Tiotropium for chronic obstructive pulmonary disease. Drug Ther Bull 2003; 41: 15–16. 54. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003; 58: 399–404. 55. Actis GC, Morgando A, Lagget M, David E, Rizzetto M. Zafirlukast-related hepatitis: report of a further case. J Hepatol 2001; 35: 539–41. 56. Danese S, De Vitis I, Gasbarrini A. Severe liver injury associated with zafirlukast. Ann Intern Med 2001; 135: 930. 57. Sass DA, Chopra KB, Wu T. A case of montelukast-induced cholestatic jaundice. Am J Gastroenterol 2002; 97: S222. 58. Sass DA, Chopra KB, Wu T. A case of montelukast-induced hepatotoxicity. Am J Gastroenterol 2003; 98: 704–5. 59. Russmann S, Iselin HU, Meier D, Zimmermann A, Simon HU, Caduff P, Reichen J. Acute hepatitis associated with montelukast. J Hepatol 2003; 38: 694–5. 60. Cetkovska P, Pizinger K. Childhood pemphigus associated with montelukast administration. Clin Exp Dermatol 2003; 28: 328–9. 61. Michael AB, Murphy D. Montelukast-associated Churg-Strauss syndrome. Age Ageing 2003; 32: 551–2. 62. Tang MB, Yosipovitch G. Acute Churg–Strauss syndrome in an asthmatic patient receiving montelukast therapy. Arch Dermatol 2003; 139: 715– 18. 63. Turvey SE, Vargas SO, Phipatanakul W. Churg– Strauss syndrome in a 7-year-old receiving montelukast and inhaled corticosteroids. Ann Allergy Asthma Immunol 2003; 90: 274. 64. Hayashi S, Furuya S, Imamura H. Fulminant eosinophilic endomyocarditis in an asthmatic patient treated with pranlukast after corticosteroid withdrawal. Heart 2001; 86: E7. 65. van Adelsberg J, Philip G, LaForce CF, Weinstein SF, Menten J, Malice MP, Reiss TF. Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2003; 90: 214–22. 66. Camargo Jr CA, Smithline HA, Malice MP, Green SA, Reiss TF. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 2003; 167: 528–33. 67. Keam SJ, Lyseng-Williamson KA, Goa KL. Pranlukast: a review of its use in the management of asthma. Drugs 2003; 63: 991–1019.

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68. Obase Y, Shimoda T, Tomari S, Mitsuta K, Fukushima C, Kawano T, Matsuse H, Kohno S. Efficacy and safety of long-term treatment of asthmatic patients with pranlukast, a cysteinylleukotriene-receptor antagonist: four-year followup study. Ann Allergy Asthma Immunol 2001; 87: 43– 7.

69. Kumagai T, Hori Y, Kishida Y, Yakumaru K, Takahashi T, Itou T. Acute renal failure and nephrotic syndrome associated with zafirlukast therapy. Nephrol Dial Transplant 2003; 18: 2202– 3.

Drugs acting on the respiratory tract

J.K. Aronson

17

Positive inotropic drugs and drugs used in dysrhythmias

CARDIAC GLYCOSIDES (SED-14, 523; SEDA-25, 205; SEDA-26, 198; SEDA-27, 185) Cardiovascular Cardiac glycosides can occasionally cause atrial fibrillation or flutter. In Chung’s review of 726 patients, atrial fibrillation occurred in 1.7% and atrial flutter in 1.8% (1R ). In two patients with chronic atrial fibrillation taking digoxin, the administration of Fab fragments of antidigoxin antibodies for digoxin toxicity caused conversion to sinus rhythm, in one case maintained for 6 months before atrial fibrillation recurred and in the other case maintained for at least 15 days (2A ). In these cases digoxin may have caused atrial fibrillation, the adverse effect being reversed by the antibody. Among 8770 patients aged over 65 years with a new diagnosis of atrial fibrillation who had a previous myocardial infarction, there were 477 cases of bradydysrhythmias requiring a permanent pacemaker, and they were matched 1:4 with 1908 controls; the use of digoxin was associated with an increased risk of pacemaker insertion (OR = 1.78; 95% CI = 1.37, 2.31) (3C ). Drug overdose A case of combined toxicity with digoxin, metoprolol, and verapamil has been reported (4A ). • A 39-year-old man was found dead in his room, with a lot of empty packets of prescribed drugs nearby. The blood concentrations of digoxin, metoprolol, and verapamil were 3.2 ng/ml, 3.6 µg/ml, and 9.2 µg/ml respectively. The cause of death was given as cardiac failure, hypotension, and bradycardia, due to a mixed drug overdose of digoxin, metoprolol, and verapamil. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

196

The concentrations of the individual drugs were not high enough for any one drug to have caused death, and the authors speculated that the toxicity of verapamil is potentiated by interaction with metoprolol and digoxin. Susceptibility factors Sex Evidence of sex differences in the response to digoxin has been sought in two studies in Sweden (5c ), following the observation that in the DIG study women who were randomly assigned to digoxin had a significantly higher fatality rate than women who were randomly assigned to placebo (33% versus 29%), while the fatality rate was similar among men randomly assigned to digoxin or placebo (35% versus 37%) (SEDA-27, 186). In the first study, in which 363 women and 257 men were compared, the women were taking significantly smaller doses of digoxin (0.16 versus 0.18 mg/day), but had significantly higher trough steady-state serum digoxin concentrations, both unadjusted (1.48 versus 1.26 nmol/l) and adjusted for age, dose, and serum creatinine (1.54 versus 1.20 nmol/l); furthermore, significantly more women had serum digoxin concentrations above 2.5 nmol/l (OR = 4; 95% CI = 1.6, 10). In the second study the authors searched the Swedish national register of adverse drug reactions and found that there were significantly more reports of adverse reactions to digoxin in women (165 versus 112) and significantly more serious reactions (30 versus 9), despite similar numbers of prescriptions. These data support the suggestion that women may be more susceptible to the adverse effects of digoxin than men. Renal impairment Renal insufficiency reduces the clearance of digoxin and can cause toxicity, as has been reported in a 64-year-old with infective endocarditis, in whom digoxin toxicity was the mode of presentation (6A ).

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Table 1. The odds ratio of cardiac arrest according to renal function and digoxin therapy in patients with congestive heart failure (7c ) Creatinine (µmol/l)

Digoxin Cases (n)

Controls (n)

OR

95% CI

No digoxin Cases (n)

Controls (n)

OR

95% CI

<100 110–130 140–320

111 120 161

95 71 53

0.98 1.60 2.70

0.59, 1.64 0.94, 2.74 1.52, 4.82

66 54 61

58 41 44

1.00 1.02 1.12

– 0.55, 1.87 0.61, 2.08

The risk of primary cardiac arrest associated with digoxin therapy at three levels of renal function has been investigated in a case-control study (7c ). The results are shown in Table 1. After adjustment for other clinical characteristics, digoxin therapy for congestive heart failure was not associated with an increased risk of cardiac arrest among patients with normal renal function but was associated with a modest increase in risk among patients with mild renal impairment and a twofold increase in risk among patients with moderate renal impairment. Drug interactions P glycoprotein transports digoxin across intestinal and renal tubular epithelia, and inhibition of its activity by various inhibitors can increase serum digoxin concentrations by increasing its systemic availability and reducing its renal tubular secretion (8c ) (Table 2). Amiodarone See below under Amiodarone. Aprepitant Aprepitant, a selective neurokinin1 receptor antagonist is a substrate and a weak inhibitor of P glycoprotein. The effect of aprepitant on the pharmacokinetics of digoxin has been studied in a double-blind, randomized, placebo-controlled, crossover study in 12 healthy subjects (9C ). Each took oral digoxin 0.25 mg/day for 13 days and aprepitant 125 mg (or matching placebo) on day 7 and 80 mg (or matching placebo) on days 8–11. Aprepitant did not affect the pharmacokinetics of digoxin. Crataegus oxyacantha (hawthorn) contains flavonoids, and some flavonoids are substrates of P glycoprotein (10E ). The interaction of St John’s wort with digoxin (SEDA-24, 203) might be due to flavonoids, although St John’s wort contains many other types of compound that could also be responsible. The interaction

Table 2. Percentage changes in steady-state serum digoxin concentrations during co-administration of various inhibitors of P glycoprotein (8c ) P glycoprotein inhibitor

Increase in steady-state serum digoxin concentration (%)

Amiodarone Clarithromycin Ciclosporin Itraconazole Propafenone Quinidine Spironolactone Verapamil

70–100 100–150 10–80 35–80 35–60 100–200 0–20 40–80

between hawthorn (Crataegus extract 450 mg bd for 21 days) and digoxin 0.25 mg has been studied in a randomized crossover trial in eight healthy volunteers (11C ). Hawthorn extract had no effect on the pharmacokinetics of digoxin. Carvedilol In eight children (aged 2 weeks to 8 years) carvedilol reduced the oral clearance of digoxin by half; two of the children had digoxin toxicity (12c ). • A 12-year-old boy with dilated cardiomyopathy was treated with digoxin 250 micrograms in the morning and 125 micrograms in the evening. Carvedilol 0.07 mg/kg/day was begun, in an attempt to enhance ventricular performance. Within several days, he developed vomiting and anorexia; the serum digoxin concentration, which was usually 2–3 nmol/l, was 5.4 nmol/l. On withdrawal of digoxin, the serum concentration fell with a halflife of 72 hours (normal 12–36 hours); the serum creatinine was normal (42 µmol/l). Subsequently, digoxin was restarted at half the original dose.

The authors proposed that digoxin doses be reduced by at least 25% in children who also start to take carvedilol, with further adjustments as required after a new steady-state occurs, which can take up to 2 weeks, because of the reduced clearance.

198 Clarithromycin The macrolide antimicrobial drugs can reportedly interact with 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. However, there have been conflicting reports that clarithromycin can either reduce or increase the renal clearance of digoxin (SEDA-27, 186). In a double-blind, randomized, placebo-controlled, crossover study 12 healthy men took single oral doses of digoxin 0.75 mg with either placebo or clarithromycin 250 mg bd for 3 days (13C ). Three of the subjects also received single intravenous doses of digoxin 0.01 mg/kg with oral placebo or clarithromycin. Clarithromycin increased the AUC of oral digoxin 1.7-fold and reduced its non-glomerular renal clearance. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption phase of clarithromycin. The pharmacokinetics of intravenous digoxin were not affected by clarithromycin. The authors concluded that increased oral systemic availability and reduced non-glomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P glycoprotein. This interpretation has been supported by observations of increased steady-state plasma digoxin concentrations in patients taking clarithromycin 400 mg/day (1.4 versus 0.8 ng/ml) (8c ) (Table 2). Dipyridamole In a placebo-controlled study in 12 healthy volunteers dipyridamole 300 mg/day for 3 days altered the pharmacokinetics of a single oral dose of digoxin 0.5 mg, increasing its AUC by about 13% (14C ). This may have been due to reduced clearance of digoxin, since dipyridamole inhibits P glycoprotein. There was no difference in the effect of dipyridamole between subjects with the different MDR1 genotypes, TT and CC. Ritonavir Ritonavir is an inhibitor of P glycoprotein and might therefore be expected to interact with digoxin. • A 61-year-old woman taking digoxin 0.25 mg/day, coumadin, indinavir 800 mg tds, lamivudine 150 mg bd, and stavudine 40 mg bd developed nausea and vomiting 3 days after she started to take ritonavir 200 mg bd (15A ). Her serum digoxin concentration 5 hours after the last dose was 7.2 nmol/l.

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Polyethoxylated castor oil Polyethoxylated castor oil (Cremophor EL) inhibits P glycoprotein in vitro and in vivo. In a double-blind, randomized, placebo-controlled, crossover study in 12 healthy individuals a single oral dose of digoxin 0.5 mg in a hard gelatin capsule was given in combination with multiple doses of oral polyethoxylated castor oil (Cremophor RH40) 600 mg tds or placebo (16C ). Cremophor RH40 delayed and enhanced the absorption of digoxin in the first 5 hours after dosing: the lag time was prolonged from 0.36 to 0.53 hours; the Cmax rose by 22%, from 2.21 to 2.69 ng/ml; and the AUC0→5 increased by 22%. The authors concluded that Cremophor RH40 alters the pharmacokinetics of digoxin by inhibiting P glycoprotein and delaying the dissolution time of digoxin tablets. Teriparatide Teriparatide (recombinant human parathyroid hormone [1–34]) causes small transient increases in serum calcium concentration, and might therefore interact with digoxin. However, in 15 healthy subjects, teriparatide 20 micrograms on days 14 and 15 of steady-state digoxin therapy had no effects on the action of digoxin on systolic time intervals or heart rate compared with placebo (17C ). Voriconazole The effect of multiple-dose voriconazole on the steady-state pharmacokinetics of digoxin in healthy men has been studied in a double-blind, randomized, placebo-controlled study (18c ). All the subjects took oral digoxin for 22 days (0.5 mg bd on day 1, 0.25 mg bd on day 2, and 0.25 mg/day on days 3–22). On days 11–22 they were randomized to either voriconazole 200 mg bd or placebo. Voriconazole did not significantly alter the Cmax , Cmin , AUC, tmax , or clearance of digoxin at steady state. There were no significant differences in adverse events, all of which were classified as mild and transient. Management of digitalis toxicity The rapidity with which antidigoxin antibody Fab fragments can act in the treatment of digitalis toxicity has been illustrated in the case of a neonate who developed severe hyperkalemia (7.8 mmol/l) and an atrioventricular junctional tachycardia after the administration of several doses of digoxin for cardiac dysrhythmias (serum digoxin concentration 9.2 nmol/l)

Positive inotropic drugs and drugs used in dysrhythmias

(19A ). Within 1 minute of the administration of Digibind® the tachycardia converted to sinus rhythm and within 20 minutes the serum potassium concentration fell to within the reference range. The rate of reversal in this case was unusually fast. In another case an 89-year-old woman with bradycardia and hyperkalemia was treated with atropine, glucagon, insulin, and intravenous calcium chloride before it was realized that she had digoxin toxicity; antidigoxin antibody caused rapid resolution (20A ). Although calcium can potentiate the actions of cardiac glycosides, this patient did not seem to have suffered any adverse consequences as a result of its administration. It is not known whether antidigoxin antibody reduces mortality after digitalis poisoning; one randomized controlled study (21C ) was too small to detect an effect on mortality after self-poisoning with seeds of the yellow oleander. Another study that suggested that antibody reduced mortality after oleander poisoning was confounded by being retrospective and inferential, based on changes in death rates as antibody was introduced and reintroduced (22c ); furthermore, the change in mortality that was attributed to the use of antibody occurred at the same time as multiple-dose activated charcoal was introduced, and that has definitively been shown to reduce mortality (23C ). Interference with diagnostic tests Although spironolactone can interfere with digoxin radioimmunoassay, this was not found in a study of the AxSYM Digoxin II assay (24E ). However, the conclusion was based on a comparison with an Emit assay, and so systematic interference by both assays could have been missed. Furthermore, the dose of spironolactone was low (25 mg/day).

OTHER POSITIVE INOTROPIC DRUGS (SED-14, 532; SEDA-25, 208; SEDA-26, 201; SEDA-27, 188) The use of intravenous vasodilators, including amrinone and milrinone, in treating congestive heart failure has been reviewed (25R ).

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199

Hematologic Amrinone and milrinone can occasionally cause thrombocytopenia (SEDA23, 195). Whole blood platelet aggregation has been examined in 45 cardiac surgery patients who were randomly given milrinone 50 micrograms/kg plus 0.5 micrograms/kg/minute for 10 hours, amrinone 1.5 mg/kg plus 10 micrograms/kg/minute for 10 hours, or placebo after release of aortic cross-clamp (26C ). The mean postoperative platelet counts 3 days in those given milrinone and amrinone did not differ significantly from those given placebo. Although there were changes in platelet aggregation after surgery there were no significant differences in platelet aggregation or other hematological values among the three groups.

Milrinone Observational studies In a retrospective study of the effects of long-term combination therapy with intravenous milrinone and oral betablockers in 65 patients with severe congestive heart failure (New York Heart Association class IV and ejection fraction less than 25%) refractory to oral therapy, 51 successfully began betablocker therapy while receiving intravenous milrinone (27c ). The mean duration of milrinone treatment was 269 (range 14–1026) days and functional class improved from IV to II– III. In 24 patients beta-blocker up-titration was well tolerated and milrinone was stopped. During combination therapy 16 patients died; one died of sudden cardiac death (on day 116) and the other 15 died of progressive heart failure or other complications. Placebo-controlled studies In a double-blind, placebo-controlled study in 238 children after cardiac surgery, milrinone was used in a low dose (25 micrograms/kg bolus over 60 minutes followed by 0.25 micrograms/kg/minute by infusion for 35 hours) and a high dose (75 micrograms/kg bolus followed by 0.75 micrograms/kg/minute by infusion for 35 hours) (28C ). Low cardiac output syndrome developed in the first 36 hours after surgery in 26%, 18%, and 12% in those given placebo, low-dose milrinone, and high-dose milrinone respectively. High-dose milrinone significantly reduced the risk of low cardiac output syndrome compared

200 with placebo, with a relative risk reduction of 55%. There were two deaths, both after infusion of milrinone. Drug interactions In 30 adults randomly assigned to intravenous saline or milrinone (5 micrograms/kg/minute for 10 minutes followed by 0.5 micrograms/kg/minute) 30 minutes before anesthesia, the onset of neuromuscular block produced by vecuronium 0.1 mg/kg was significantly delayed by milrinone and recovery was significantly quicker (29c ). The mechanism of this effect is not known, but the authors suggested that milrinone blocks adenosine A1 receptors, increasing the release of acetylcholine in motor nerve endings, and might also make the neuromuscular junction more sensitive to the effects of acetylcholine.

Olprinone Comparative studies In 12 patients with mild stable asthma, intravenous olprinone 30 micrograms/minute was compared with aminophylline 2.25 mg/minute and the combination over 150 minutes (30c ). The mean maximal increases in FEV1 were 7.8% (95% CI = 2.4, 13), 17% (10, 24), 17% (11, 22), and 1% (−1.1, 3.1) during infusion of aminophylline, olprinone, aminophylline + olprinone, and saline respectively. Olprinone alone and in combination with aminophylline lowered diastolic blood pressure and increased heart rate.

Vesnarinone The anticancer effects of vesnarinone (SEDA25, 175) have been reviewed (31R ). It has immunomodulatory effects, including suppression of tumor necrosis factor-induced activation of NF-κB, NK cell activity, and endotoxininduced production of inflammatory cytokines, and altered expression of E selectin in endothelial cells, and it induces apoptosis and suppresses growth in a variety of in vitro cell lines.

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J.K. Aronson

DRUGS USED IN DYSRHYTHMIAS Management of atrial fibrillation In a metaanalysis of 91 randomized controlled trials of the effectiveness of antidysrhythmic drugs in promoting sinus rhythm in patients with atrial fibrillation followed for a median of 1 day (range 0.04–1096 days), the median proportion of patients in sinus rhythm at follow up was 55% (range 0–100%) of those who took active treatment and 32% (range 0–90%) of those who took placebo (32M ). Median survival was 99% (range 55–100%) and 99% (range 55–100%). Compared with placebo, the following drugs were associated with increased frequencies of sinus rhythm at follow-up: • class IA (disopyramide, procainamide, and quinidine; treatment difference 22%, 95% CI = 16, 27); • class IC (flecainide, pilsicainide, and propafenone; treatment difference 33%, 95% CI = 23, 43); • class III (amiodarone, dofetilide, and ibutilide; treatment difference 17%, 95% CI = 12, 23). Class IC drugs were associated with a higher frequency of sinus rhythm at follow-up than class IV drugs (treatment difference 43%; 95% CI = 12, 75). Adverse effects were not consistently reported in these studies and could not be analysed, but there was no significant difference in mortality between any drug classes. However, there is some doubt about whether conversion to sinus rhythm produces a better long-term outcome than rate control. Five randomized controlled comparisons of rhythm control versus rate control, mostly in patients with persistent atrial fibrillation (n = 5175 in all), have all suggested that there are no major differences in beneficial outcomes between the two strategies (33R –36R ), although there were fewer adverse drug reactions in patients randomized to rate control in three of the studies and in all the studies rate control was associated with fewer hospital admissions. The results are summarized in Table 3. Furthermore, in an analysis of cost-effectiveness, rate control plus warfarin was much cheaper than rhythm control in preventing thromboembolism, largely

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Table 3. Outcomes of five randomized comparisons of rhythm control and rate control in atrial fibrillation (34R ) PIAF

PAF2

AFFIRM

RACE

STAF

Number

252

141

4060

522

200

Mean duration (years)

1.0

1.3

3.5

2.3

1.7

Type of AF

Persistent

Paroxysmal with severe symptoms

Persistent or paroxysmal (2 : 1)

Persistent

Persistent

Rhythm control

Amiodarone, cardioversion

Amiodarone, flecainide, propafenone, sotalol

Amiodarone, propafenone, sotalol, cardioversion

Amiodarone, flecainide, propafenone, sotalol, cardioversion

Amiodarone, flecainide propafenone, cardioversion

Rate control

Digitalis, diltiazem, betablockers, ablation

Ablation

Digitalis, diltiazem, betablockers, verapamil, ablation

Digitalis, diltiazem, betablockers, verapamil, ablation

Digitalis, diltiazem, beta-blockers, verapamil, ablation

Warfarin

Continued

Discontinued in sinus rhythm

Discontinued in sinus rhythm

Discontinued in sinus rhythm

Discontinued in sinus rhythm

Outcome

No difference in symptoms or quality of life Rhythm control: better functional capacity Rate control: fewer adverse drug reactions

Rhythm control: less permanent AF Rate control less worsening heart failure

No difference in mortality, quality of life, or functional capacity Rate control: fewer adverse drug reactions

No overall difference or in quality of life Rate control: fewer adverse drug reactions

No overall difference

∗ PIAF = Pharmacological Intervention in Atrial Fibrillation (37C ); PAF2 = Paroxysmal Atrial Fibrillation 2 (38C ); AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management (39C ); RACE = Rate Control versus

Electrical Cardioversion for Persistent Atrial Fibrillation (40C ); STAF = Strategies of Treatment of Atrial Fibrillation (41C ).

because of the use of expensive modern antidysrhythmic drugs for rhythm control (42c ). Although these results suggest that rate control might be preferable to rhythm control, they do not give any information about patients in whom sinus rhythm is established permanently after pharmacological or physical conversion, since many of the patients in whom rhythm control is used as a strategy will actually have paroxysmal atrial fibrillation. Other trials are in progress (43S , 44S ). In a substudy of the AFFIRM study different antidysrhythmic drugs were compared, by randomly assigning the first drug treatment to amiodarone, sotalol, or a class I drug (45C ). At one year, in 222 patients randomized between

amiodarone and class I agents, 62% were successfully treated with amiodarone, compared with 23% taking class I agents. In 256 patients randomized between amiodarone and sotalol, 60% versus 38% were successfully treated. In 183 patients randomized between sotalol and class I agents, 34% versus 23% were successfully treated, although this portion of the substudy was stopped early when amiodarone was shown to be better than class I agents. Sinus rhythm was achieved in nearly 80% of patients at 1 year. There was only one case of torsade de pointes in this substudy (in a patient who had taken quinidine for more than 1 year). There were no cases of agranulocytosis or lupus syndrome induced by procainamide. However,

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Table 4. Adverse effects causing discontinuation of first antidysrhythmic drug within the first year (45C ) Adverse event

Amiodarone (n = 154)

Sotalol (n = 135)

Class I (n = 121)

Congestive heart failure Pulmonary events Gastrointestinal events Symptomatic bradycardia Prolonged QTc (>520 ms) Syncope Ocular effects Other

0

3

2

4

1

1

4

6

14

0

3

4

0

0

5

0 1 11

1 0 7

3 1 17

adverse effects that caused discontinuation of the antidysrhythmic drugs during the first year were frequent (Table 4), and occurred in 12% of patients taking amiodarone, 11% of those taking sotalol, and 28% of those taking class I agents. Among those who were randomized to amiodarone, pulmonary toxicity was diagnosed in two by 1 year, three by 2 years, and no additional patients by 3 years. Gastrointestinal adverse events were a common reason for stopping class I drugs. Comparative studies with other treatments The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT) was a multicenter randomized trial of atrioventricular junction ablation and pacing compared with pharmacological ventricular rate control in 99 patients, mean age 68 years, with mildly to moderately symptomatic permanent atrial fibrillation (46C ). At 12 months follow-up there was no significant difference in left ventricular ejection fraction or exercise duration on treadmill testing; however, the peak ventricular rate was lower in the ablation group during exercise (112 versus 153) as was a score of activities of daily life. The CAST qualityof-life questionnaire showed that patients who had ablation had fewer symptoms at 6 and 12 months, with a relative risk reduction in symptoms at 12 months of 18%. Global subjective semiquantitative measurement of quality of life using the “ladder of life” showed that ablation produced a 6% better quality of life at 6 months. There were no differences in adverse events between the two treatments.

J.K. Aronson

Cardiovascular Drug-induced and congenital prolongation of the QT interval have again been reviewed (47R –49R ). The major drugs that have been implicated in one way or another, including cardiac and non-cardiac drugs, are listed in Table 5. The mechanism of action of class I antidysrhythmic drugs has been studied in 14 patients with accessory pathways and orthodromic atrioventricular re-entrant tachycardia (50C ). The drugs were cibenzoline (n = 7), pilsicainide (n = 2), disopyramide (n = 2), and procainamide (n = 3). In four of six patients with a manifest accessory pathway, class I drugs induced unidirectional conduction block of the accessory pathway (anterograde conduction block associated with preserved retrograde conduction) and enhanced the induction of atrioventricular re-entrant tachycardia with atrial extrastimulation. In eight patients with a concealed accessory pathway, there was outward or inward expansion of the tachycardia induction zone in patients who had greater prolongation of the conduction time than the refractory period of the retrograde accessory pathway after class I drugs. During ventricular extrastimulation, induction of bundle branch re-entry after class I drugs initiated atrioventricular re-entrant tachycardia in all the patients. The authors concluded that the adverse effects of all class I drugs in patients with accessory pathways are mainly due to induction of unidirectional retrograde conduction in manifest accessory pathways and greater prolongation of retrograde conduction time in concealed accessory pathways than the refractory period, regardless of the subtype of drug. Monitoring therapy Of 36 patients receiving antidysrhythmic drugs for supraventricular or ventricular dysrhythmias, 12 were treated with flecainide, 12 with pilsicainide, and 12 with pirmenol (51C ). Signal-averaged electrocardiograms were recorded before starting therapy, 1 month later, and twice during subsequent therapy. All three drugs, but especially flecainide and pilsicainide, prolonged the filtered QRS and the duration of low-amplitude signals at the terminal portion of the QRS complex. Differences in the duration of the filtered QRS between recordings correlated significantly with differences in serum drug concentrations (r = 0.91 for flecainide, r = 0.70 for pilsicainide, and

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Table 5. Drugs that prolong the QT interval and/or might cause torsade de pointes (47R –49R ) Class

Drug

Class IA antidysrhythmic drugs

Ajmaline, aprindine, cibenzoline, disopyramide, pirmenol, procainamide, propafenone, quinidine Bretylium Flecainide Amiodarone, dofetilide, ibutilide, nifekalant, sotalol Bepridil, lidoflazine, prenylamine Isradipine, nicardipine Ciprofloxacin, clarithromycin, clindamycin, co-trimoxazole, erythromycin, grepafloxacin, levofloxacin, moxifloxacin, sparfloxacin, spiramycin, troleandomycin Amitriptyline, citalopram, clomipramine, desipramine, doxepin, fluoxetine, imipramine, maprotiline, nortriptyline, venlafaxine, zimeldine Felbamate, fosphenytoin Amphotericin, fluconazole, itraconazole, ketoconazole, miconazole Astemizole, azelastine, clemastine, diphenhydramine, ebastine, hydroxyzine, oxatomide, terfenadine Ketanserin Chloroquine, halofantrine, mefloquine, quinine Pentamidine Chlorpromazine, droperidol, fluphenazine, haloperidol, lithium, mesoridazine, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sultopride, thioridazine, timiperone, trifluoperazine, ziprasidone Foscarnet Arsenic trioxide, amsacrine, doxorubicin, tacrolimus, zorubicin

Class IB antidysrhythmic drugs Class IC antidysrhythmic drugs Class III antidysrhythmic drugs Class IV antidysrhythmic drugs Calcium channel blockers Antibacterial drugs Antidepressants Antiepileptic drugs Antifungal drugs Antihistamines Antihypertensive drugs Antimalarial drugs Antiprotozoal drugs Antipsychotic drugs Antiviral drugs Cytotoxic and immunosuppressant drugs Diuretics Histamine H2 receptor antagonists Hormones Miscellaneous drugs

Indapamide, triamterene Cimetidine, famotidine, ranitidine Octreotide, vasopressin Amantadine, aminophylline, budipine, chloral hydrate, cisapride, fenoxidil, ketanserin, prednisone, probucol, salbutamol, salmeterol, suxamethonium, terodiline, vincamine

r = 0.61 for pirmenol). There were no significant correlations between drug concentration and other parameters. The authors suggested that changes in the serum concentrations of flecainide, pilsicainide, and pirmenol can be estimated from changes in the duration of the filtered QRS on signal-averaged electrocardiograms and that periodic electrocardiographic monitoring in this way could substitute for drug concentration measurement.

Adenosine

(SED-14, 536; SEDA-25, 210; SEDA-26, 203; SEDA-27, 189) Observational studies In 44 patients with paroxysmal supraventricular tachycardia, adenosine terminated the tachycardia in 16 and revealed the type of tachycardia in 21; in three of six patients it contributed to the diagnosis of

broad-complex tachycardia; latent ventricular pre-excitation was induced in two of 12 patients (52c ). Subjective complaints after adenosine were common (at least one symptom in 50 of 62 patients), but all were transient. Comparative studies The perioperative antinociceptive and analgesic effects of intraoperative adenosine 50–500 micrograms/kg/minute have been compared with those of remifentanil 0.05–0.5 micrograms/kg/minute in 62 patients undergoing major surgical procedures in a randomized, double-blind study (53C ). Intraoperative inhibition of the cardiovascular responses to surgical stimulation was similar after adenosine and remifentanil, and both maintained excellent hemodynamic stability. However, there were striking postoperative differences: 1. initial pain score was significantly reduced by 60% by adenosine compared with remi-

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fentanil and it remained lower throughout the 48-hour recovery period; 2. postoperative morphine requirements during the first 0.25, 2, and 48 hours were consistently lower after adenosine than after remifentanil; 3. patients who received adenosine were significantly less sedated; 4. postoperative end-tidal and arterial carbon dioxide pressures were significantly higher after remifentanil.

and normal imaging (11% versus 1.5%). The authors concluded that patients with normal myocardial perfusion images in whom ST segment depression occurs during adenosine administration are at higher risk of future cardiac events than similar patients without electrocardiographic evidence of ischemia.

Placebo-controlled studies In 608 patients with ST-elevation acute myocardial infarction randomized to receive infusions of saline or adenosine 10 micrograms/kg/minute for 6 hours after the start of thrombolysis, there was a trend to reduced cardiovascular mortality with adenosine after 12 months, 9% versus 12% with placebo among all patients (OR = 0.71; 95% CI = 0.4, 1.2) and 8% versus 15% among patients with anterior myocardial infarction (OR = 0.53; 95% CI = 0.23, 1.24) (54C ). There were no adverse effects of adenosine. A much larger trial would be needed to confirm the trend to a beneficial effect on mortality after myocardial infarction.

• A 41-year-old man with a history of chronic alcohol abuse, bronchitis, hypertension, and an episode of tachydysrhythmia 10 years before, was given adenosine 6 mg for a supraventricular tachycardia, and 3–5 minutes later another 9 mg, which caused only a warm feeling. After a further 3–5 minutes he was given 12 mg and just over 8 minutes later had a tonic–clonic seizure with flushing of the skin. In addition, the supraventricular tachycardia degenerated into ventricular tachycardia.

Cardiovascular ST segment depression can occur during adenosine myocardial perfusion imaging and is an independent predictor of subsequent cardiac events and worse outcome, particularly in association with ischemic defects. In a retrospective analysis of 3231 patients undergoing adenosine myocardial perfusion imaging, 228 (7%) had ischemic electrocardiographic changes during adenosine infusion (55c ). Of these, 66 (29%, 2% of all patients) had normal imaging. An age- and sexmatched group of 200 patients with normal imaging without electrocardiographic changes served as controls. During a mean follow-up of 29 months, those who had electrocardiographic changes during imaging had significantly more adverse cardiac events than those in the control group (non-fatal myocardial infarction, 7.6% versus 0.5%; subsequent revascularization, 14% versus 2.5%). Although cardiac death alone did not differ between the two groups (3.0% versus 1.0%), cumulative survival free from cardiac death and non-fatal myocardial infarction was worse in patients with ST segment depression during adenosine infusion

Nervous system A tonic–clonic seizure lasting 5–10 seconds has been attributed to adenosine (56A ).

The authors thought that the adenosine had precipitated the seizure and that alcohol abuse had been a contributory factor. A seizure has been associated with adenosine in a previous case (SEDA-19, 191). However, in this case the association with adenosine was not clear, because the seizure did not occur until many minutes after the last injection and adenosine has a half-life of a few seconds. Furthermore, adenosine has been reported to be antiepileptic in animals (57E ).

Ajmaline and derivatives (SED-14, 537; SEDA-24, 206; SEDA-25, 211; SEDA-26, 204) Cardiovascular The diagnostic electrocardiographic pattern in Brugada syndrome can be absent and can be unmasked by sodium channel blockers, such as ajmaline. The risks of a standardized ajmaline challenge test have been studied in 158 patients, who were given intravenous ajmaline 10 mg every 2 minutes up to a target dose of 1 mg/kg (58c ). In 37 patients (23%) the typical coved ST pattern of the Brugada syndrome was unmasked. During the test, symptomatic ventricular tachycardia occurred in two patients. In all other patients, the drug challenge did not induce ventricular tachycardia

Positive inotropic drugs and drugs used in dysrhythmias

if the endpoints of the test were the administration of the target dose, QRS prolongation over 30%, the presence of the typical electrocardiogram, or the occurrence of ventricular extra beats. There was a positive response to ajmaline in two of 94 patients with a normal baseline electrocardiogram, who underwent evaluation solely for syncope of unknown origin.

Amiodarone

(SED-14, 537; SEDA-25, 211; SEDA-26, 204; SEDA-27, 189)

Observational studies The effects of additional intravenous amiodarone (300 mg in 1 hour followed by 15 mg/kg over 24 hours) have been studied in 45 patients with acute atrial fibrillation who were already taking oral amiodarone for maintenance of sinus rhythm (59c ). In 20 of 23 patients given amiodarone there was conversion to sinus rhythm, compared with 13 of 22 who were given placebo. There were no prodysrhythmic effects and the only adverse effect of intravenous amiodarone was thrombophlebitis in two patients. In 44 patients who underwent percutaneous balloon mitral commissurotomy for chronic persistent atrial fibrillation, with a procedural success rate of 100% and no immediate morbidity or mortality, amiodarone maintained sinus rhythm in eight patients compared with none in the control group (60c ). The adverse effects of amiodarone included bradycardia in two patients and shortness of breath in one; the last required drug withdrawal. Another patient developed long sinus pauses at 15 months and was treated with a permanent pacemaker without withdrawing amiodarone. Otherwise, there were no serious adverse effects or electrocardiographic abnormalities. Systematic reviews In a systematic review of the efficacy and safety of amiodarone for pharmacological cardioversion of recent-onset atrial fibrillation in 21 studies, amiodarone was efficacious in 34–69% with bolus-only regimens, and 55–95% with a bolus followed by an infusion (61M ). The highest 24-hour conversion rates occur with an intravenous regimen of 125 mg/hour until conversion or a maximum of 3 g and an oral regimen of 25–30 mg/kg given as a single loading dose (over 90% and over 85% respectively). Most con-

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versions occur by 6–8 hours after the start of therapy. Predictors of successful conversion are shorter duration of atrial fibrillation, smaller left atrial size, and higher amiodarone dose. Amiodarone is not superior to other antidysrhythmic drugs but is relatively safe in patients with structural heart disease and in those with depressed left ventricular function. No major prodysrhythmic events, such as sustained ventricular tachycardia, ventricular fibrillation, or torsade de pointes, were reported in these studies. There were minor cardiac effects: first-degree atrioventricular block, selflimited sinus bradycardia, hypotension, and non-sustained ventricular tachycardia. These adverse effects were more common after intravenous administration. Asymptomatic sinus bradycardia was reported in up to 10% of patients and hypotension in up to 18% of patients who received intravenous amiodarone. All the episodes of hypotension were transient and responded to saline volume expansion or inotropic support. Hypotension with intravenous amiodarone is reportedly due to the vehicle. Phlebitis at the amiodarone infusion site occurs up to 16% of patients. Other rare adverse effects were nausea, diarrhea, blurred vision, and allergic reactions. Gastrointestinal adverse effects were predominantly reported after oral administration. In another systematic review of the studies of the use of amiodarone in the treatment of atrial fibrillation, 21 studies met the eligibility criteria, including 10 of those covered in the systematic review mentioned above (62M ). Bradydysrhythmias and hypotension were the most commonly reported adverse effects. Death rates were reported in 18 studies; there were five deaths among 816 patients given amiodarone and five among 696 in comparison groups. However, information about adverse events in these randomized trials was inconsistently reported and too scanty to allow proper analysis. This stresses yet again the need for standard methods of reporting adverse events in clinical trials. Cardiovascular Amiodarone is superior to placebo for cardioversion of recent onset atrial fibrillation, and even though the onset of conversion is delayed compared with class IC drugs, efficacy is similar at 24 hours (63M ). However, among 8770 patients aged over 65

206 years with a new diagnosis of atrial fibrillation who had a previous myocardial infarction there were 477 cases of bradydysrhythmias requiring a permanent pacemaker and they were matched 1:4 with 1908 controls (3C ); the use of amiodarone was associated with an increased risk of pacemaker insertion (OR = 2.14; 95% CI = 1.30, 3.54). This effect was modified by sex, with a greater risk in women (OR = 3.86; 95% CI = 1.70, 8.75) than in men (OR = 1.52; 95% CI = 0.80, 2.89). During 409 trials of antidysrhythmic drugs to maintain sinus rhythm in patients with previous atrial fibrillation or atrial flutter amiodarone was used in 212 patients (52%), type 1C drugs in 127 (31%), sotalol in 37 (9.0%), and a type 1A drug in 33 (8.1%) (64c ). There were adverse events in 17 patients: three died, three had bradycardia that required permanent pacemaker implantation, and 11 had bradycardia requiring a reduction in drug dosage. Most of the events were due to bradycardia in patients who received amiodarone. There was a significant association between amiodaroneassociated bradycardia and female sex. The only event that occurred during the first 48 hours was an episode of bradycardia in a patient who received amiodarone and was managed as an out-patient. Amiodarone can occasionally cause torsade de pointes (65A ). • In an 84-year-old woman torsade de pointes occurred after oral amiodarone therapy for 4 days in the presence of multiple exacerbating factors, including hypokalemia and digoxin toxicity (66A ). Transient prolongation of the QT interval during bladder irrigation prompted the episode. When amiodarone was withdrawn, bladder irrigation did not induce torsade de pointes, despite hypokalemia and hypomagnesemia. • A 69-year-old woman with a history of coronary heart disease, myocardial infarction, and paroxysmal atrial fibrillation had an occipital stroke (67A ). She was given amiodarone 600 mg/day, beta-acetyldigoxin 0.1 mg/day, and bisoprolol 1.25 mg/day, and developed significant QT interval prolongation (maximum 700 ms; QTc 614 ms) and repetitive short-lasting torsade de pointes, which terminated spontaneously. Her serum electrolytes were normal and plasma concentrations of digoxin (1.8 ng/ml) and amiodarone (1.9 µg/ml) were within the usual target ranges.

In the first case the authors speculated that increased vagal tone during bladder irrigation was responsible for QT interval prolongation

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associated with bradycardia in the presence of amiodarone. In the second case the authors suggested that the dysrhythmia was due to the triple combination of amiodarone with a beta-blocker and digitalis in a patient with atrial fibrillation and structural heart disease; again it is possible that bradycardia played a part. In a retrospective study of 82 patients with an implanted pacemaker cardioverter defibrillator, those who were also taking amiodarone (for 24 consecutive months without interruption) had a significant three-fold increase in episodes of defibrillation compared with those who did not take amiodarone (68c ). This is an unexpected finding, for which the authors had no explanation. However, the finding was vitiated by the retrospective nature of the study. Intravenous amiodarone can cause hypotension in anesthetized patients undergoing cardiac surgery. In a prospective double-blind study, 30 patients undergoing coronary artery bypass graft surgery were randomly assigned to receive intravenous amiodarone or placebo (69C ). At 6 minutes, amiodarone reduced mean arterial pressure by 14 mmHg and placebo reduced it by 4 mmHg. The changes in mean arterial pressure and systolic and diastolic blood pressures between groups were statistically different for the first 15 minutes after drug administration. Hypotension required intervention in three of 15 patients given amiodarone and none of the 15 given placebo. The mean heart rate was 12/minute less after amiodarone, but pulmonary artery pressure, central venous pressure, mixed venous oxygen saturation, and fractional left ventricular area change were not different between the groups. The authors concluded that the hypotension that amiodarone caused during the first 15 minutes after administration was not accompanied by altered left ventricular function, suggesting that selective arterial vasodilatation was the primary cause. Respiratory Lung damage from amiodarone usually occurs after administration for several weeks or months. However, it can occur more quickly after lung resection (SEDA-19, 192). • A 73-year-old man underwent resection of the right middle lobe of lung for a squamous cell carcinoma (70A ). Postoperatively he developed atrial fibrillation and was given amiodarone 450 mg intravenously followed by 800 mg intravenously for 2 days, when sinus rhythm was restored. However,

Positive inotropic drugs and drugs used in dysrhythmias he then developed cough and fever, and a CT scan showed bilateral patchy infiltrates. After 20 days (total dose of amiodarone 9000 mg) he developed adult respiratory distress syndrome. Bronchoalveolar lavage showed eosinophils, mast cells, and foamy macrophages. Amiodarone was withdrawn and he was given intravenous methylprednisolone 200 mg/day followed by oral prednisolone. He recovered over 8 weeks.

The authors suggested that this man had amiodarone-induced pneumonitis, which occurred early because of pre-existing lung damage. Sensory systems Optic neuropathy is a rare adverse effect of amiodarone (SEDA-25, 181). In a retrospective study, three patients with amiodarone-induced optic neuropathy had mildly impaired vision, visual field defects, and bilateral optic disc swelling; on withdrawal of amiodarone, visual function and optic disc swelling slowly improved in all three (71A ). Endocrine Amiodarone-induced hyperthyroidism is of two types (SEDA-27, 192): type 1 occurs in those with latent disease and is due to the iodine that amiodarone contains; type 2 is due to a destructive thyroiditis in a previously normal gland. The distinction may be important, because type 1 typically responds to thionamides and perchlorate while type 2 responds to high-dose glucocorticoids. Colorflow Doppler sonography can be of use in distinguishing the two types, because type 1 is associated with increased vascularity and type 2 is not. In a retrospective study of 24 patients with amiodarone-induced hyperthyroidism in an iodine-replete environment, 13 had little or no vascularity, of whom seven were prednisolone-responsive; of 11 patients with increased vascularity, four responded to antithyroid drugs alone and only one of seven responded to prednisolone (72c ). Euthyroidism was achieved twice as rapidly in patients with low vascularity as in those with increased vascularity. Thus, responsiveness to prednisolone was not consistently predicted by lack of vascularity, but the presence of flow appeared to correlate with non-responsiveness to prednisolone. Of 26 fetuses with hydrops fetalis and supraventricular tachycardias, 25 received transplacental drug therapy; prenatal conversion occurred in 15 (73c ). Nine fetuses were converted to sinus rhythm using either flecainide (n =

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7) or amiodarone (n = 2) as first-line therapy, while digoxin either alone or in association with sotalol failed to restore sinus rhythm in all cases. After first-line therapy, supraventricular tachycardia persisted in 10 fetuses, nine of whom received amiodarone alone or in association with digoxin as second-line therapy, and five of whom converted to sinus rhythm. Of 11 neonates who received amiodarone in utero, two developed raised thyroid stimulating hormone concentrations on postnatal days 3–4; they received thyroid hormone and had normal outcomes. Amiodarone-induced thyrotoxicosis can be difficult to treat medically and sometimes requires a surgical approach. Two patients with cardiomyopathy and resistant dysrhythmias developed thyrotoxicosis while taking amiodarone (74Ar ). Despite medical therapy, they failed to improve. Both underwent total thyroidectomy without difficulty or complications. Most reported cases of amiodarone-induced thyrotoxicosis that have been treated surgically have been of type II, i.e. with no underlying thyroid disease. Liver A monitoring strategy has been devised for predicting liver damage in patients taking amiodarone (75C ). Liver function tests were monitored for over 2 years in 50 patients who were given a loading dose of amiodarone followed by an average maintenance dose of 300 mg/day. Only the serum transaminase activities changed significantly, and alanine transaminase activity showed the greatest discrimination between those taking a low dose of amiodarone and those taking a high dose. The authors proposed the following monitoring strategy: • establish baseline activities of transaminases, alkaline phosphatase, and lactate dehydrogenase before starting therapy, for future reference; • measure alanine transaminase activity after 1 month, to rule out hypersusceptibility reactions; • measure alanine transaminase activity at 3 and 6 months, to determine the maximum response to accumulated amiodarone; • measure alanine transaminase activity every 6 months thereafter, to screen for late effects; • further investigation of liver function should only be necessary if the alanine transaminase

208 activity rises to above three times to upper limit of the reference range or if other evidence of liver damage occurs. Amiodarone can occasionally cause cirrhosis that mimics alcohol damage (SEDA-18, 202), and another case has been reported (76A ). • A 79-year-old man who had taken amiodarone 200 mg/day for 33 months developed chronic liver disease. A liver biopsy showed established cirrhosis with extensive fibrosis, polymorphonuclear leukocyte infiltration, reduplicating bile ducts in nodules, and degenerating hepatocytes. Numerous investigations ruled out other causes of cirrhosis. Liver function deteriorated despite amiodarone withdrawal and he died 3 months later.

However, the authors did not mention intracellular deposition of phospholipids as a feature of this case and the attribution to amiodarone is not clear. Skin A 76-year-old woman who had taken amiodarone 200 mg/day for 4 years developed blue-gray discoloration of the skin of the face resembling cyanosis; amiodarone was withdrawn and substantial improvement occurred within 4 months (77A ). Drug interactions The time courses of the interactions of amiodarone with digoxin and warfarin have been compared (78C ). In 79 patients who had been taking fixed maintenance doses of warfarin (n = 77) and/or digoxin (n = 54), amiodarone reduced the clearance of S-warfarin within about the first 2 weeks of co-administration after which the interaction stabilized; there was only a small reduction in the clearance of R-warfarin. In contrast, the clearance of digoxin fell gradually with time, and did not become significantly reduced until about 6 weeks, during which time amiodarone and desethylamiodarone concentrations rose towards steady state; there was a good inverse correlation between amiodarone and desethylamiodarone concentrations and digoxin clearance. The authors concluded that relatively short-term monitoring of the effect of warfarin is required when amiodarone is coadministered, compared with long-term monitoring of digoxin. In therapeutic doses loratadine does not prolong the QT interval, but it can do so if its metabolism is inhibited (SEDA-26, 182).

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• A 73-year-old woman with hypertension and hyperlipidemia, who was taking amiodarone, cilazapril, pravastatin, and warfarin, was given loratadine 10 mg/day for an allergic reaction (79A ). She had a bout of syncope in association with a QTc interval of 688 ms. Rhythm monitoring showed episodes of long-short QT cycles preceded by short self-terminating bouts of torsade de pointes. Amiodarone and loratadine were withdrawn and over the next 4 days the QT interval returned to the reference range and she became asymptomatic.

The authors attributed QT interval prolongation in this case to a toxic effect of loratadine after inhibition by amiodarone of its metabolism by CYP3A4. They did not place much emphasis on a possible pharmacodynamic interaction between the two drugs, although that could also have contributed. One might expect the absorption of lipophilic drugs to be reduced by the lipase inhibitor orlistat. In a double-blind, placebo-controlled, randomized study in 32 healthy volunteers aged 18–65 years, body mass index 18–30 kg/m2 , orlistat significantly reduced the Cmax and AUC of amiodarone by about 25%; the Cmax and AUC of desethylamiodarone were also significantly reduced (80C ). However, orlistat did not affect the tmax or half-life of amiodarone. These results suggest that orlistat reduces the extent of absorption of amiodarone but not its rate of absorption. In parallel studies orlistat did not affect the pharmacokinetics of fluoxetine or simvastatin. Interference with diagnostic tests Ablation of the cavotricuspid isthmus generates a corridor of double potentials along the ablation line, and the double potential interval is shortened by isoprenaline. However, in 32 patients amiodarone prolonged the double potential interval, in both the presence and absence of isoprenaline, and this effect should be taken into account when assessing the completeness of this ablation procedure (81c ).

Bepridil

(SED-14, 541, 605; SEDA-27, 194) Comparative studies In a randomized study in 61 patients with symptomatic paroxysmal atrial fibrillation, bepridil 200 mg/day (n = 23) was compared with flecainide 100–200 mg/day

Positive inotropic drugs and drugs used in dysrhythmias

or pilsicainide 75–150 mg/day (n = 38) (82C ). Both bepridil and the class IC drugs effectively prevented paroxysmal atrial fibrillation (15/23 versus 24/38). In those who took the class IC drugs, the f–f interval on the surface electrocardiogram during atrial fibrillation before treatment was significantly longer in responders (114 ms) than in non-responders (68 ms). In contrast, in those who took bepridil the f–f interval was significantly shorter in responders (85 ms) than in non-responders (152 ms). In non-responders the class IC drugs prolonged the f–f interval from 78 ms to 128 ms whereas bepridil had no significant effect (109 versus 135 ms). Although bepridil has been primarily classified as a drug with class I and class IV properties (SEDA-13, 141), the authors suggested that these results marked it as acting primarily by a class III mechanism in paroxysmal atrial fibrillation. This is consistent with reports that bepridil inhibits a slow component of the cardiac delayed rectifier potassium current IKs in HEK293 cells (83E ). Respiratory Interstitial pneumonitis has been attributed to bepridil (84A ). • A 65-year-old man with paroxysmal atrial fibrillation took bepridil 150 mg/day and 2 weeks later developed a cough and fever which did not respond to antimicrobial drugs. He had fine crackles at the lung bases and severe hypoxia. An X-ray and a CT scan showed bilateral reticular shadows and microfibrosis, mainly in the lower lungs. Bepridil was withdrawn and he was given prednisolone, to which he responded.

Disopyramide

(SED-14, 543; SEDA-25, 217; SEDA-26, 208; SEDA-27, 195)

Monitoring therapy In 20 patients taking disopyramide 100–600 mg/day, there was no correlation between the dose and total or unbound plasma disopyramide concentrations (85c ). The unbound fraction of disopyramide in plasma was 0.25–0.57 and did not correlate with the plasma albumin concentration, but did correlate with the concentration of alpha1 -acid glycoprotein. In 16 of the 20 patients (four had adverse effects) there was a significant difference in plasma disopyramide concentrations in responders and nonresponders, but the overlap was large. However,

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the unbound concentration of disopyramide was above 0.8 µg/ml in responders and below 0.8 µg/ml in non-responders. There was no correlation between the unbound concentration of mono-N-dealkyldisopyramide and effectiveness. The authors suggested that plasma concentration of unbound disopyramide could be used as an index of efficacy.

Dofetilide

(SEDA-26, 208;

SEDA-27, 195) Management of adverse drug reactions In the USA there is a risk-management program for dofetilide, which restricts its distribution and requires education of prescribers. Charts for 47 patients taking dofetilide and 117 patients taking sotalol were reviewed (86c ). The recommended starting dose was prescribed significantly more often in the dofetilide group than in the sotalol group (79% versus 35%). Significantly more patients given dofetilide had baseline tests for serum potassium (100% versus 82%), magnesium (89% versus 38%), and creatinine (100% versus 82%), and electrocardiography (94% versus 67%). Significantly more patients given dofetilide had electrocardiography after the first dose (94% versus 43%) and subsequent doses (80% versus 3.5%). The authors concluded that there was better adherence to dosing and monitoring recommendations in those given dofetilide, which may have been attributable to the risk-management program. However, there was low usage of dofetilide during the study period, perhaps an unintended, negative consequence of the program.

Flecainide

(SED-14, 545; SEDA-25, 217; SEDA-26, 212; SEDA-27, 195)

Observational studies In a systematic review of trials of the use of a single oral loading dose of flecainide for cardioversion of recent-onset atrial fibrillation most of the trials used a single oral dose of 300 mg for loading (87M ). The success rate was 57–68% at 2–4 hours and 75–91% at 8 hours. Adverse effects were mild noncardiac adverse effects, reversible QRS complex widening, transient dysrhythmias, and left

210 ventricular decompensation. The transient dysrhythmias occurred chiefly at the time of conversion and included atrial flutter and sinus pauses; there were no life-threatening ventricular dysrhythmias or deaths. Cardiovascular Flecainide occasionally causes prolongation of the QT interval sufficiently to cause ventricular dysrhythmias. • A 68-year-old woman developed flecainide-induced syncope due to torsade de pointes, before the onset of which her QTc interval reached 680 ms without a change in the QRS duration (88A ). None of the usual triggers were found and she was taking no other drugs. • A baby developed a supraventricular tachycardia in utero at 38 weeks and was delivered by cesarean section (89A ). Flecainide 2 mg/kg was given postnatally and 48 hours later, after four doses had been given, a broad-complex tachycardia developed. Flecainide was withdrawn, but 4 hours later ventricular fibrillation developed. After resuscitation a re-entrant supraventricular tachycardia was treated with digoxin and amiodarone.

In the second case the serum flecainide concentration 24 hours after the last dose was 630 ng/ml, and since flecainide has a half-life of about 12 hours in children (90C ) this suggest that the flecainide concentration at the time of the ventricular fibrillation was probably quite high. Fetotoxicity The serum flecainide concentration at time of birth in a neonate whose mother had been given flecainide during pregnancy was 1030 ng/ml and there was a broad QRS complex, which resolved after 3 days (91A ). • A fetus was treated for a supraventricular tachycardia at 27 weeks of gestation by giving the mother first flecainide then amiodarone plus flecainide (92A ). The girl was born at 33 weeks by cesarean section and had poor cardiac contractility, a prolonged PR interval, a broad QRS complex, and a long QTc interval (532 ms).

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post-mortem blood and urine showed the presence of high concentrations of flecainide and its two major metabolites. The flecainide concentrations in blood and urine were 19 and 28 µg/ml respectively, and the metabolites were detected only in urine at the following concentrations: meta-O-dealkylated flecainide 9.4 µg/ml and meta-O-dealkylated flecainide lactam 8.6 µg/ml.

Lidocaine (lignocaine)

(SED-14, 546;

SEDA-25, 218; SEDA-27, 196) Drug interactions The effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of intravenous lidocaine and its two pharmacologically active metabolites, monoethylglycinexylidide and glycinexylidide has been studied in 10 healthy volunteers, 10 patients with hepatic cirrhosis Child’s class A, and 10 with hepatic cirrhosis class C, in a doubleblind, randomized, two-way, crossover study (94C ). Erythromycin caused statistically significant but small changes in the pharmacokinetics of lidocaine and monoethylglycinexylidide. In healthy subjects, lidocaine clearance fell from 9.93 to 8.15 ml/kg/minute (82%; 95% CI = 65, 98) and the half-life was prolonged from 2.23 to 2.80 hours (130%; 95% CI = 109, 151); the AUC of monoethylglycinexylidide rose to 129% (95% CI = 102, 156). There were quantitatively similar modifications in the two groups of patients with cirrhosis, but only in the patients with Child’s grade C liver cirrhosis were lidocaine pharmacokinetics significantly different than in the healthy subjects; clearance was approximately halved, steady-state volume of distribution was increased, and terminal halflife was more than doubled. The authors concluded that no dosage adjustment is needed in patients with moderate liver cirrhosis, but that the dose of lidocaine should be halved in patients with severe cirrhosis.

The authors attributed the cardiac abnormalities to flecainide toxicity.

Procainamide Drug overdose Another case of flecainide overdose has been reported (93A ). • A 15-year-old girl was found dead in bed a few days after a suicide attempt with benzodiazepines. At autopsy, no specific cause of death was identified. However, toxicological analysis of

(SED-14, 548; SEDA-24, 213; SEDA-26, 213; SEDA-27, 197) Immunologic The antiphospholipid antibody syndrome can cause widespread cutaneous necrosis, which has now been reported in a case attributed to procainamide (95A ).

Positive inotropic drugs and drugs used in dysrhythmias • A 51-year-old man developed multiple diffuse painful nodules, which coalesced, increased in size and number, ulcerated, and turned reddishblack. He had taken procainamide (Procan-SR) 500 mg qds for atrial tachydysrhythmias for 6 months. His other medications included fosinopril and glipizide. He had a normochromic, normocytic anemia, mild leukopenia, and thrombocytopenia. Cultures of the blood, urine, and skin were negative. Serology for auto-antibodies was negative, except for a low-titer of antinuclear antibody. The prothrombin time was 13 seconds and the activated partial thromboplastin time was prolonged to 57 seconds. A lupus anticoagulant was identified. Serology for anticardiolipin antibody was negative. A biopsy from the edge of the ulcer showed microthrombi in the dermal microvasculature with very minimal mononuclear inflammatory infiltration in the perivascular area. There was no leukocytoclastic vasculitis. Procainamide was withdrawn and high-dose intravenous methylprednisolone, heparin, and aspirin started. No further skin lesions developed and the ulcers healed.

Propafenone

(SED-14, 551; SEDA-25, 220; SEDA-26, 214; SEDA-24, 198)

Placebo-controlled studies In a randomized, double-blind, placebo-controlled study of a modified-release formulation of propafenone (propafenone SR) patients with a history of symptomatic atrial fibrillation who were in sinus rhythm were randomized to placebo or propafenone SR 225, 325, 425 or mg, all twice daily (96C ). In the primary efficacy analysis, propafenone SR significantly prolonged the time to first symptomatic recurrence of atrial dysrhythmia at all three doses compared with placebo. The median time to recurrence was 41 days with placebo, 112 days with propafenone 225 mg, 291 days with 325 mg, and over 300 days with 425 mg. The numbers of patients who reported at least one adverse event were 91 (72%) with placebo, 97 (77%) with propafenone 225 mg, 113 (84%) with propafenone 325 mg, and 113 (83%) with propafenone 425 mg. Adverse events that led to withdrawal occurred in 17 (14%), 16 (13%), 19 (14%), and 34 (25%) patients in each of the four groups respectively. In all of the propafenone treatment groups, the most commonly reported adverse events that also exceeded the percent reported by patients taking placebo by at least 5% were dizziness, dyspnea, taste disturbances, fatigue, and constipation. Propafenone

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increased the PR interval and QRS duration dose-relatedly but did not change the QTc interval. The average changes from baseline in PR interval were 1.0 ms with placebo, 9.1 ms with propafenone 225 mg, 12 ms with propafenone 325 mg, and 21 ms with propafenone 425 mg. The changes in QRS duration were −1.6 ms with placebo, 4.0 ms with propafenone 225 mg, 6.3 ms with propafenone 325 mg, and 6.3 ms with propafenone 425 mg. There were no deaths during treatment or within 30 days of withdrawal. There were no cases of ventricular tachycardia. Liver Propafenone can occasionally cause cholestatic hepatitis (SEDA-18, 207), and another two cases have been reported (97Ar ). • A 67-year-old woman who had taken glibenclamide 5 mg/day and enalapril 20 mg/day for 5 years became jaundiced 6 weeks after starting to take propafenone 450 mg/day. The liver function tests suggested an obstructive jaundice. Viral serology and autoantibodies were negative and gallstones and other obstructive lesions were ruled out by ultrasound. She recovered 15 days after withdrawal of propafenone. • A 69-year-old woman who had taken digitoxin 0.25 mg/day and enalapril 5 mg/day for 6 years became jaundiced 7 months after starting to take propafenone 300 mg/day. Viral serology was negative and obstruction was ruled out by ultrasound. All autoantibodies were negative except for an antinuclear factor titer of 1/160. A liver biopsy showed expanded portal tracts with an infiltrate of lymphocytes, monocytes, and macrophages and proliferation of bile ductules, sinusoidal dilatation, ballooning of hepatocytes, and bile thrombi. There were also some eosinophils among the hepatocytes. She recovered gradually after withdrawal of propafenone and her antinuclear factor titer returned to normal.

The occurrence of eosinophilia in most of the reported cases of cholestatic jaundice in patients taking propafenone suggests that it is a hypersensitivity reaction. Drug overdose Self-poisoning with propafenone is not uncommon and mortality is high (SEDA-26, 214). • A 16-year-old girl was discovered in her bedroom having tonic–clonic seizures and later had a cardiorespiratory arrest (98A ). She was thought to have taken an overdose of up to 9 g of propafenone. Despite vigorous resuscitation she died after 2.5 hours. Her plasma concentration of propafenone was 5.9 µg/ml, of 5-hydroxypropafenone 0.25 µg/ml, and of N-depropylpropafenone 0.38 µg/ml.

212 • A 13-year-old boy took about 3 g of propafenone and had a seizure, extreme bradycardia, cyanosis, and hypotension, followed by a cardiorespiratory arrest (99A ). He had hypokalemia, hypercalcemia, hyperphosphatemia, and hypermagnesemia. His electrocardiogram showed first-degree heart block with right bundle branch block and a prolonged QT interval. His plasma propafenone concentration on admission was 4.6 µg/ml and his 5hydroxypropafenone concentration was 17 µg/ml. He was resuscitated with cardiac massage, adrenaline, and sodium lactate and was given multiple doses of activated charcoal 25 g 4-hourly for 24 hours. • A 3-year-old boy unintentionally took one 300 mg tablet of propafenone (15 mg/kg); 3 hours later he had a seizure and became cyanosed and hypotensive followed by a cardiac arrest (100A ). His electrocardiogram showed irregular bradycardia with bundle branch block and a prolonged QT interval. His serum propafenone concentration was 1.8 µg/ml. He was resuscitated with cardiac massage, atropine, adrenaline, dobutamine, midazolam, and sodium bicarbonate and recovered within 15 hours.

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Quinidine (SED-14, 552; SEDA-25, 221; SEDA-26, 214; SEDA-24, 198) Drug interactions In a double-blind, randomized, crossover study 22 subjects took placebo, dextromethorphan hydrobromide 30 mg, dextromethorphan hydrobromide 60 mg, and dextromethorphan hydrobromide 30 mg preceded at 1 hour by quinidine hydrochloride 50 mg (101C ). Cough was elicited using citric acid. The intrinsic clearance of dextromethorphan estimated from a pharmacokinetic model was 59–1536 1/h, which overlapped with that extrapolated from in vitro data (12–261 1/h). Quinidine reduced the clearance of dextromethorphan with an estimated average Ki of 0.017 µmol/l, and prolonged its half-life more than three-fold to 58 hours; it also increased its rate of absorption, which the authors thought might be due to an increased rate of gastric emptying.

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fluoxetine, and simvastatin) in healthy volunteers. J Clin Pharmacol 2003; 43: 428–35. 81. Tada H, Ozaydin M, Chugh A, Scharf C, Oral H, Pelosi F Jr, Knight BP, Strickberger SA, Morady F. Effects of isoproterenol and amiodarone on the double potential interval after ablation of the cavotricuspid isthmus. J Cardiovasc Electrophysiol 2003; 14: 935–9. 82. Yoshida T, Niwano S, Inuo K, Saito J, Kojima J, Ikeda-Murakami K, Hara H, Izumi T. Evaluation of the effect of bepridil on paroxysmal atrial fibrillation: relationship between efficacy and the f–f interval in surface ECG recordings. Circ J 2003; 67: 11–15. 83. Yumoto Y, Horie M, Kubota T, Ninomiya T, Kobori A, Takenaka K, Takano M, Niwano S, Izumi T. Bepridil block of recombinant human cardiac IKs current shows a time-dependent unblock. J Cardiovasc Pharmacol 2004; 43: 178–82. 84. Gaku S, Naoshi K, Teruhiko A. A case of bepridil induced interstitial pneumonitis. Heart 2003; 89: 1415. 85. Ohkawa H, Watanabe M, Saito Y, Uchiwa H, Fujii S, Ino H, Yokogawa K, Miyamoto K-I. Evidence for the usefulness of unbound plasma concentration of disopyramide in individual antiarrhythmic therapy. Jpn J Clin Pharmacol Ther 2003; 34: 1–6. 86. Allen LaPointe NM, Chen A, Hammill B, DeLong E, Kramer JM, Califf RM. Evaluation of the dofetilide risk-management program. Am Heart J 2003; 146: 894–901. 87. Khan IA. Oral loading single dose flecainide for pharmacological cardioversion of recent-onset atrial fibrillation. Int J Cardiol 2003; 87: 121–8. 88. Thevenin J, Da Costa A, Roche F, Romeyer C, Messier M, Isaaz K. Flecainide induced ventricular tachycardia (torsades de pointes). PACE – Pacing Clin Electrophysiol 2003; 26: 1907–8. 89. Ackland F, Singh R, Thayyil S. Flecainide induced ventricular fibrillation in a neonate. Heart 2003; 89: 1261. 90. Perry JC, Garson Jr A. Flecainide acetate for treatment of tachyarrhythmias in children: review of world literature on efficacy, safety, and dosing. Am Heart J 1992; 124: 1614–21. 91. Rasheed A, Simpson J, Rosenthal E. Neonatal ECG changes caused by supratherapeutic flecainide following treatment for fetal supraventricular tachycardia. Heart 2003; 89: 470. 92. Hall CM, Platt MPW. Neonatal flecainide toxicity following supraventricular tachycardia treatment. Ann Pharmacother 2003; 37: 1343–4. 93. Benijts T, Borreyl D, Lambert WE, De Letter EA, Piette MHA, Van Peteghem C, De Leenheer AP. Analysis of flecainide and two metabolites in biological specimens by HPLC: Application to a fatal intoxication. J Anal Toxicol 2003; 27: 47–52. 94. Orlando R, Piccoli P, De Martin S, Padrini R, Palatini P. Effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function. Br J Clin Pharmacol 2003; 55: 86–93.

216 95. El-Rayes BF, Edelstein M. Unusual case of antiphospholipid antibody syndrome presenting with extensive cutaneous infarcts in a patient on longterm procainamide therapy. Am J Hematol 2003; 72: 154. 96. Pritchett ELC, Page RL, Carlson M, Undesser K, Fava G. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. Am J Cardiol 2003; 92: 941– 6. 97. Cocozzella D, Curciarello J, Corallini O, Olivera A, Alburquerque MM, Fraquelli E, Zamagna L, Olenchuck A, Cremona A. Propafenone hepatotoxicity. Report of two new cases. Dig Dis Sci 2003; 48: 354–7. 98. Palette C, Maroun N, Gaulier J-M, Priolet B, Lachatre G, Bedos J-P, Advenier C, Therond P. In-

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toxication fatale par la propafénone: à propos d’un cas documenté par des dosages danguins. Thérapie 2003; 58: 384–6. 99. Sadeg N, Richecoeur J, Dumontet M. Intoxication à la propafénone. Thérapie 2003; 58: 381–3. 100. Molia AC, Tholon J-P, Lamiable DL, Trenque TC. Unintentional pediatric overdose of propafenone. Ann Pharmacother 2003; 37: 1147–8. 101. Moghadamnia AA, Rostami-Hodjegan A, Abdul-Manap R, Wright CE, Morice AH, Tucker GT. Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs. dextrorphan using quinidine inhibition. Br J Clin Pharmacol 2003; 56: 57–67.

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18

Beta-adrenoceptor antagonists and antianginal drugs

BETA-ADRENOCEPTOR ANTAGONISTS (SED-13, 488; SEDA-25, 227; SEDA-26, 223; SEDA-27, 203) Sexual function Erectile dysfunction is often reported by patients with cardiovascular diseases, particularly when they are taking betaadrenoceptor antagonists. Patients with different newly diagnosed cardiovascular diseases and without erectile dysfunction were randomized to take atenolol 50 mg/day blindly (n = 32, group A), or atenolol 50 mg/day with information about the treatment but not its adverse effects (n = 32, group B), or atenolol 50 mg/day with information about both the kind of drug and the possible adverse effects (n = 32, group C) (1C ). Erectile dysfunction occurred in 3.1%, 16%, and 31% of the patients in groups A, B, and C respectively. All patients who reported erectile dysfunction were then randomized to sildenafil 50 mg or placebo, which were equally effective in reversing erectile dysfunction in all but one patient. This study confirms how knowledge of the adverse effects of beta blockers can cause erectile dysfunction. This suggests that the problem is predominantly psychological in origin.

Atenolol Fetotoxicity Atenolol-induced developmental toxicity has been reviewed, combining data from eight randomized clinical trials, three surveys, and one case series (2M ). The main indications for atenolol were pregnancy-induced © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

hypertension and pre-existing chronic hypertension. The most frequent prenatal adverse events were reduced placental weight, reduced birth weight, and intrauterine growth retardation. The most likely reasons for these effects were placental and fetal hemodynamic disturbances, characterized by a reduction in umbilical and fetal aortic blood flow, with or without reduced fetal heart rate. However, there were no increases in embryo-fetal deaths or congenital abnormalities. The effects of atenolol prenatal toxicity were similar to those reported in animal studies (rats and rabbits) suggesting that animal experiments can predict developmental toxicity caused by beta adrenoceptor antagonists.

Carvedilol There are concerns about the risks of starting beta-blockers in patients with heart failure, specifically those with severe impairment. The database of the COPERNICUS study, which tested the effects of carvedilol in patients with advanced heart failure, has been evaluated in order to assess the rates of death, hospitalizations, and permanent withdrawal of carvedilol in the first 8 weeks from the start of treatment (3C ). The patients allocated to carvedilol did not have any significant increase in cardiovascular risk compared with those randomized to placebo and carvedilol was associated with fewer deaths, hospitalizations, and drug withdrawals. These data suggest that in patients with advanced heart failure the benefit to harm balance in the first 2 months of treatment is similar to that observed during long-term therapy. These findings should encourage clinicians to use carvedilol in such patients.

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Metabolism Severe diabetes mellitus has been described in a patient with heart failure treated with carvedilol and furosemide (4c ). • A 37-year-old man with a dilated cardiomyopathy was given furosemide, spironolactone, and candesartan. After 1 year carvedilol was introduced in a maintenance dose of 10 mg/day. HbA1c was 5.1% at the beginning of carvedilol treatment. After 9 months of treatment, he started to feel extremely thirsty and lost 10 kg in 3 months. No viral infections or pancreatitis were detected. The HbA1c concentration increased to 17%, the blood glucose concentration was 31 mmol/l (557 mg/dl). Furosemide was withdrawn and the blood glucose concentration fell within a week to 8.9 mmol/l (160 mg/dl). Carvedilol was then replaced by metoprolol and after 2 further weeks the fasting blood glucose concentration fell to 5.9 mmol/l (106 mg/dl). The patient was stable thereafter.

The mechanisms of carvedilol-induced hyperglycemia are not known, although alphablockade in the pancreas could impair insulin secretion. In this case furosemide could have increased insulin resistance.

Sotalol Cardiovascular Four further cases of torsade de pointes have been reported in patients taking sotalol, prescribed for preventing atrial fibrillation episodes (5A ). All four were women and all had normal left ventricular function and QT intervals before treatment. The patients were taking no other drugs and the dosages were relatively low (80–240 mg/day). These cases confirm that there is a risk of torsade de pointes, even with low dosages of sotalol, normal QT intervals, and normal renal function before treatment. Close and careful follow-up of all patients treated with sotalol is therefore needed.

NITRATE DERIVATIVES (SED-14, 594; SEDA-25, 228; SEDA-26, 224; SEDA-27, 204) Nervous system Headache associated with nitrates may be less frequent in patients taking ACE inhibitors (12/762, 1.6%) than in those not taking ACE inhibitors (24/775, 3.2%) according to an analysis of a database of elderly patients (6M ).

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

Glyceryl trinitrate (nitroglycerin) Nervous system Glyceryl trinitrate has been associated with encephalopathy (7A ). • A 27-year-old woman developed pre-eclampsia at 35 weeks and after urgent cesarean section was given glyceryl trinitrate sublingually in an attempt to reduce her blood pressure, which was associated with intractable headache and which had not responded to urapidil and metoprolol. She lost her sight and 6 days later had a tonic–clonic seizure. Posterior reversible encephalopathy syndrome was diagnosed. The seizures did not recur in the absence of anticonvulsants, and her blood pressure was controlled with verapamil.

The vasodilatory action of glyceryl trinitrate may have aggravated the encephalopathy. Drug interactions Inhibitors of phosphodiesterase type 5 (PDE5), such as tadalafil, act synergistically with nitrates to cause falls in blood pressure, and nitrate use is contraindicated in patients taking such inhibitors. This hemodynamic interaction lasted 24 hours, and had 4 completely disappeared 8 hours after tadalafil treatment (8c ).

CALCIUM CHANNEL BLOCKERS (SED-14, 578; SEDA-25, 229, SEDA-26, 225, SEDA-27, 224) Skin The association of calcium channel blockers with photo-damage has been assessed in 82 patients with renal transplants (9c ). Most of the patients (90%) had photo-damaged skin (50% mild, 24% moderate, and 13% severe) and 53 (65%) had used a calcium channel blocker (49 nifedipine and four amlodipine). There were strong associations between calcium channel blockers and the grade of photodamage and the presence of telangiectasia, with a less marked association with solar elastosis. There was no convincing association between the grade of photo-damage and the duration of treatment. Tumorigenicity A population-based casecontrol study of 1982 women aged 65–79 years has contributed to the old controversy about the risk of cancer in patients taking calcium channel blockers (10C ). The responses of 975

Beta-adrenoceptor antagonists and antianginal drugs

women with invasive breast carcinoma were compared with the responses of 1007 women in a control group. Women who had ever used calcium channel blockers, beta-blockers, or ACE-inhibitors did not have an altered risk of breast carcinoma compared with women who had never used antihypertensive drugs. There was a modestly increased risk of breast carcinoma among users of immediate-release calcium channel blockers (OR = 1.5; 95% CI = 1.0, 2.1), thiazide diuretics (OR = 1.4; 95% CI = 1.1, 1.8), and potassium-sparing diuretics (OR = 1.6; 95% CI = 1.2, 2.1). No clear trends emerged from the analysis of the correlations between risk and duration of use. Drug overdose An overdose of a mixture of calcium channel blockers mimicked acute myocardial infarction (11A ). • A 42-year-old man developed shortness of breath, weakness, sweating, and left bundle branch block. Coronary angiography showed only non-obstructive lesions, ruling out acute closure of a coronary artery, and his left ventriculogram showed no wall motion abnormalities, but rather a markedly hyperdynamic left ventricle with an ejection fraction of 80%. Despite this, he subsequently developed profound bradycardia and hypotension, which were refractory to standard treatments, including pressor agents, calcium, and transvenous pacing. He gradually improved over several days and made a full recovery. After extubation he admitted to having taken “several” tablets each of long-acting verapamil, diltiazem, and nifedipine, of unclear dosages, and over an unclear period time, trying to self-medicate for symptoms he related to life-long paroxysmal supraventricular tachycardia.

This case highlights the fact that calcium channel blocker overdose must be considered in the differential diagnosis of patients who present with apparent acute myocardial infarction.

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re-administered because of worsening of hypertension, and gynecomastia reappeared.

Bepridil Respiratory A 65-year-old man with paroxysmal atrial fibrillation and an old myocardial infarction developed a cough and fever unresponsive to antibiotics 2 weeks after starting to take bepridil 150 mg/day (13A ). A chest Xray showed an interstitial pneumonia, which resolved only after withdrawal of bepridil and the use of high-dose prednisolone.

Diltiazem Skin Cutaneous reactions ranging from exanthems to severe adverse reactions have been reported in association with diltiazem. Four patients (one man and three women, mean age 60 years) who developed a maculopapular rash at 8–12 days after starting to take diltiazem underwent drug skin tests in order to determine the value of patch tests and cross-reactions among calcium channel blockers (14A ). In all cases patch tests were positive to diltiazem and there were no cross-reactions with nimodipine, nifedipine, nitrendipine, or nicardipine. There was a cross-reaction with diltiazem and verapamil in only one patient.

Lercanidipine Amlodipine Reproductive system Gynecomastia is not uncommon in men undergoing hemodialysis for end-stage renal disease. Two cases of gynecomastia have been reported in patients taking amlodipine 10 mg/day (12A ). In both cases the gynecomastia abated within a month or so of substituting amlodipine with an angiotensin receptor blocker. In one case, amlodipine was

Fluid balance Lercanidipine has been tested in the COHORT double-blind trial in 828 hypertensives aged over 59 years (15C ). Lacidipine and lercanidipine were associated with a lower incidence of edema than amlodipine. In another double-blind study in 92 postmenopausal hypertensive women, lercanidipine was associated with a smaller increase in leg volume and a lower incidence of leg edema than amlodipine (16C ).

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Nifedipine Immunologic Cutaneous lupus erythematosus has been associated with nifedipine (17A ). • Nifedipine-induced subacute cutaneous lupus erythematosus has been reported in a 48-year-old white woman who had taken nifedipine for essential hypertension for 4 years. She developed a papulosquamous annular eruption in sun-exposed areas during the summer. She had taken no other drugs. Serological tests (antinuclear and antihistone antibodies), histopathology, and immunological tests (granular IgM deposits at the dermoepidermal junction) confirmed the diagnosis. Nifedipine withdrawal led to rapid improvement, with almost complete resolution of the skin lesions in 1 month. Antinuclear and antihistone antibodies titers fell within 6 months.

Drug interactions Nine healthy men, aged 21–23 years, participated in a randomized, placebo-controlled, crossover study of the effects of 5 days pretreatment with nafcillin or placebo four times daily on the pharmacokinetics of an oral dose of nifedipine of 10 mg. Nafcillin markedly increased the clearance of nifedipine, suggesting that it is a potent enzyme inducer (18c ). A possible interaction of nifedipine with phenobarbital has been reported (19A ). • A 67-year-old man with hypertension and seizures taking nifedipine, digoxin, ticlopidine, paroxetine, and clorazepate dipotassium also took phenobarbital 100 mg/day for 2 months, after which the serum phenobarbital concentration 24 hours after the last dose of phenobarbital was almost twice as high as expected.

Since nifedipine and ticlopidine inhibit CYP2C9 and CYP2C19 respectively, both involved in phenobarbital metabolism, the authors suggested that phenobarbital concentrations should be monitored when these drugs are co-administered. Drug formulations Crushing an extendedrelease nifedipine tablet (nifedipine XL) can alter its release characteristics. • A 38-year-woman was treated for acute pulmonary edema and pneumonia and her medications were changed to oral hydralazine, labetalol, and nifedipine XL, crushed and administered through a nasogastric tube (20A ). She developed bradycardia, hypotension, and cardiac arrest. She was resuscitated, but died the next morning after worsening bradycardia with hypotension subsequent to a further dose of crushed labetalol and nifedipine XL.

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

The administration of crushed nifedipine XL resulted in severe hypotension and the concurrent administration of labetalol prevented a compensatory increase in heart rate. The release characteristics of oral modified-release formulations are destroyed when the formulation is crushed, resulting in rapid availability of the total dose, which can cause significant harm.

Nisoldipine In a double-blind study in African Americans with hypertension, extended-release nisoldipine and amlodipine were equally effective (21C ). The safety profiles were comparable: most of the adverse effects were mild and transient and common to all vasodilators (i.e. headache, dizziness, and edema); three of 92 patients taking nisoldipine five of 101 taking amlodipine withdrew because of adverse events.

Nitrendipine Skin Cutaneous lupus erythematosus has been attributed to nitrendipine (22A ). • A 66-year-old man developed widespread subacute cutaneous lupus erythematosus after taking nitrendipine 40 mg/day for hypertension for about 3 weeks. The skin lesions abated 2 weeks after drug withdrawal, and the immunological effects normalized within a few months. Nitrendipine was the only drug that the patient was taking at the time of the event.

Verapamil Cardiovascular Verapamil has been previously reported to cause severe cardiogenic shock. • A 37-year-old-man with rheumatoid disease developed rapid atrial fibrillation 4.5 years after aortic and mitral valve replacement and was given amiodarone 400 mg/day and verapamil 40 mg tds (23A ). Several months later amiodarone was withdrawn because of thyrotoxicosis and the dosage of verapamil was increased to 80 mg tds in order to slow his heart rate. About 3 hours after the third

Beta-adrenoceptor antagonists and antianginal drugs dose of verapamil, he developed severe bradycardia and cardiogenic shock, complicated by fulminant hepatic failure. His bradycardia was reversed by calcium and atropine and his blood pressure was maintained satisfactorily. However, he died from intracranial bleeding.

The authors suggested that the liver damage was probably caused by verapamil-induced cardiogenic shock and induced a vicious cycle of raised blood verapamil concentrations, which in turn aggravated the cardiogenic shock by cardiodepression, causing further liver damage. Thyrotoxicosis made his heart more susceptible to the effects of verapamil. Drug overdose Verapamil poisoning generally causes cardiac toxicity and often leads to death, as in the case of a 51-year-old man with a cardiomyopathy who took 7200 mg of sustained-release (SR) verapamil (24A ). Plasma verapamil and norverapamil concentrations on admission were 3–4 times higher than the highest therapeutic concentrations previously reported.

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Drug interactions Rhabdomyolysis has been associated with the co-administration of diltiazem with simvastatin or atorvastatin. • A 63-year-old white man taking ciclosporin after cardiac transplantation developed a fever and diffuse muscle pain (25A ). He had been taking several medications, including simvastatin, for more than 5 years, and verapamil had been started 4 weeks before for hypertension. A diagnosis of rhabdomyolysis was made and his medications were withdrawn. His creatine kinase activity reached a maximum of 24 028 units/l on day 4 and fell to normal in 2 weeks.

While rhabdomyolysis from statins is rare, the risk is increased when they are used in combination with agents that share similar metabolic pathways. Statins are metabolized by CYP3A4, which is inhibited by verapamil and ciclosporin; competitive interference with CYP3A4 can increase statin concentrations, and increase the risk of adverse events.

REFERENCES 1. Silvestri A, Galetta P, Cerquetani E, Marazzi G, Patrizi R, Fini M, Rosano GMC. Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and is reversed by placebo. Eur Heart J 2003; 24: 1928– 32. 2. Tabacova S, Kimmel CA, Wall K, Hansen D. Atenolol developmental toxicity: animal-to-human comparisons. Birth Defects Research (Part A) 2003; 67: 181–92. 3. Krum H, Roecker EB, Mohacsi P, Rouleau JL, Tendera M, Coats AJS, Katus HA, Fowler MB, Packer M, for the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effects of initiating carvedilol in patients with severe chronic heart failure. Results from the COPERNICUS Study. J Am Med Assoc 2003; 289: 712–18. 4. Kobayacawa N, Sawaki D, Otani Y, Sekita G, Fukushima K, Takeuchi H, Aoyagi T. A case of severe diabetes mellitus occurred during management of heart failure with carvedilol and furosemide. Cardiovasc Drugs Ther 2003; 17: 295. 5. Tan HH, Hsu LF, Kam RML, Chua T, Teo WS. A case series of sotalol-induced torsade de pointes in patients with atrial fibrillation. A tale with a twist. Ann Acad Med Singapore 2003; 32: 403–7. 6. Onder G, Pahor M, Gambassi G, Federici A, Savo A, Carbonin P, Bernabei R, on behalf of the

GIFA Study. Association between ACE inhibitors use and headache caused by nitrates among hypertensive patients: results from the Italian Group of Pharmacoepidemiology in the Elderly (GIFA). Cephalalgia 2003; 23: 901–6. 7. Finsterer J, Schlager T, Kopsa W, Wild E. Nitroglycerin-aggravated pre-eclamptic posterior reversible encephalopathy syndrome (PRES). Neurology 2003; 61: 715–16. 8. Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J, Jackson G. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol 2003; 42: 1855–60. 9. Cooper SM, Wojnarowska F. Photo-damage in Northern European renal transplant recipients is associated with use of calcium channel blockers. Clin Exp Dermatol 2003; 28: 588–91. 10. Li CI, Malone KE, Weiss NS, Boudreau DM, Cushing-Haugen KL, Daling JR. Relation between use of antihypertensive medications and risk of breast carcinoma among women ages 65–79 years. Cancer 2003; 98: 1504–13. 11. Henrikson CA, Chandra-Strobos N. Calcium channel blocker overdose mimicking an acute myocardial infarction. Resuscitation 2003; 59: 361–4. 12. Komine N, Takeda Y, Nakamata T. Amlodipineinduced gynecomastia in two patients on long-term hemodialysis therapy. Clin Exp Nephrol 2003; 7: 85–6.

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13. Gaku S, Naoshi K, Teruhiko A. A case of bepridil induced interstitial pneumonitis. Heart 2003; 89: 1415. 14. Cholez C, Trechot P, Schmutz JL, Faure G, Bene MC, Barbaud A. Maculopapular rash induced by diltiazem: allergological investigations in four patients and cross reactions between calcium channel blockers. Allergy 2003; 58: 1207–9. 15. Zanchetti A. Emerging data on calcium-channel blockers: the COHORT study. Clin Cardiol 2003; 26: II-17-20. 16. Lund-Johansen P, Stranden E, Helberg S, Wessel-Aas T, Risberg K, Ronnevik PK, Istad H, Madsbu S. Quantification of leg oedema in postmenopausal hypertensive patients treated with lercanidipine or amlodipine. J Hypertens 2003; 21: 1003–10. 17. Gubinelli E, Cocuroccia B, Girolomoni G. Subacute cutaneous lupus erythematosus induced by nifedipine. J Cutan Med Surg 2003; 7: 243–6. 18. Lang CC, Jamal SK, Mohamed Z, Mustafa MR, Mustafa AM, Lee TC. Evidence of an interaction between nifedipine and nafcillin in humans. J Clin Pharmacol 2003; 55: 588–90. 19. Sánchez-Romero A, García-Delgado R, DuránQuintana JA. ¿Puede el tratamiento asociado con ticlopidina y nifedipina aumentar los niveles séricos de fonobardital? Rev Neurol 2003; 36: 433–4.

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20. Schier JG, Howland MA, Hoffman RS, Nelson LS. Fatality from administration of labetalol and crushed extended-release nifedipine. Ann Pharmacother 2003; 37: 1420–3. 21. White WB, Saunders E, Noveck RJ, Ferdinand K. Comparative efficacy and safety of nisoldipine extended-release (ER) and amlodipine (CESNA-III study) in African American patients with hypertension. Am J Hypertens 2003; 16: 739–45. 22. Marzano AV, Borghi A, Mercogliano M, Facchetti M, Caputo R. Nitrendipine-induced subacute cutaneous lupus erythematosus. Eur J Dermatol 2003; 13: 213–16. 23. Margolin L. Fatal cardiogenic shock and liver failure induced by verapamil in a thyrotoxic patient. Clin Drug Invest 2003; 23: 285–6. 24. Tracqui A, Tournoud C, Kintz P, Villain M, Kummerlen C, Sauder P, Ludes B. HPLC/MS findings in a fatality involving sustained-release verapamil. Hum Exp Toxicol 2003; 22: 515–21. 25. Chiffoleau A, Trochu JN, Veyrac G, Petit T, Abadie P, Bourin M, Jolliet P. Rhabdomyolysis in a cardiac transplant recipient due to verapamil interaction with simvastatin and cyclosporine treatment. Therapie 2003; 58: 168–70.

R. Verhaeghe

19

Drugs acting on the cerebral and peripheral circulations

DRUGS USED IN THE TREATMENT OF ARTERIAL DISORDERS OF THE BRAIN AND LIMBS Calcium dobesilate

(SED-14, 634)

Hematologic During the period 1978–2000, nine cases of agranulocytosis associated with the use of dobesilate were reported in Spain. This is substantially less than expected on the basis of calculations derived from case-control and case-population strategies (1A ). Factors that could explain the disagreement are spontaneous under-reporting, the duration of use, and the age of the patients.

Naftidrofuryl

The authors concluded that the rarity of hepatic injury as an adverse effect of naftidrofuryl reflects a hypersensitivity reaction rather than a toxic effect on the liver in this case.

(SED-14, 632; SEDA-21,

215) Liver Very few cases of reversible liver dysfunction have been reported with naftidrofuryl. Biopsy-proven naftidrofuryl-induced liver injury has been reported (2A ). • A 44-year-old woman developed deteriorating jaundice, despite a recent cholecystectomy for presumed cholecystitis/cholangitis, which was not confirmed at operation. There was no pain, but fatigue and loss of appetite, and she had dark urine. Her liver enzymes were raised. The only drug she admitted to having taken was naftidrofuryl 100 mg bd for intermittent positional dizziness. Autoantibodies and detailed laboratory tests for other causes of liver damage were negative. Liver biopsy showed moderate portal infiltration of lymphocytes and eosinophils with mild extension to adjacent liver parenchyma, compatible with druginduced liver damage. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

DRUGS USED IN THE TREATMENT OF VENOUS DISORDERS Cyclo 3 fort

(SED-14, 635)

Gastrointestinal Cyclo 3 fort is the brand name of a flavonoid derivative marketed in France for complaints of venous insufficiency. It is largely innocuous, but occasionally leads to chronic diarrhea, which is thought to be secondary to altered gastrointestinal motility or rarely to lymphocytic colitis. The difference between the two may be a question of the extent of investigation of the symptoms, as illustrated by a new case (3A ). • A 55-year-old woman took Cyclo 3 fort three tablets a day for 48 hours and started to have loose watery stools at least four times a day. She lost 3 kg in weight over 5 weeks. She remembered that she had a similar problem when taking Cyclo 3 fort a few months before. Clinical examination, laboratory tests for inflammatory disease, stool culture, and extensive endoscopy (stomach, terminal ileum, and colon) were all normal. Several biopsies taken from the colon all showed lymphocytic infiltration of the superficial layers of the epithelium. The diarrhea disappeared shortly after withdrawal of the drug.

Without biopsy proof of lymphocytic colitis, this case would probably have been classified as “functional” diarrhea.

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DRUGS USED IN THE TREATMENT OF MIGRAINE Ergot alkaloids

(SED-14, 431, 635; SEDA-25, 237; SEDA-27, 151) Drug interactions Ergot alkaloids are metabolized by CYP3A4, which is inhibited by the protease inhibitors ritonavir and indinavir. Severe vascular involvement leading to a persistent vegetative state has been reported from an interaction between ergotamine and ritonavir (4A ). • A 34-year-old woman, who had taken ritonavir, lamivudine, and stavudine for 3 years, took three tablets of ergotamine tartrate 1 mg for 4 days and developed dizziness, loss of vision, headache, vomiting, diarrhea, and cold feet. Her condition deteriorated and she became unconscious. Angiography showed diffuse vasospasm in large and medium sized vessels throughout the body. Repeat late brain imaging showed multiple subcortical infarcts, which had not been seen on initial imaging. Despite intensive vasodilatory and antithrombotic treatment, she remained comatose in a persistent vegetative state.

OTHER PERIPHERAL VASODILATORS Inhibitors of phosphodiesterase type V (SED-14, 636; SEDA-25, 238; SEDA-26, 231; SEDA-27, 210) Sildenafil remains a popular theme in the medical and lay press. Each year, new reviews emphasize over and again its efficacy in erectile dysfunction and also its good safety profile, even in men with cardiovascular disease (5R , 6R ). Tadalafil and vardenafil are new phosphodiesterase type V inhibitors, which have been launched to compete with sildenafil in a highly lucrative market. The adverse effects and drug interactions of the new compounds appear to be similar to those of sildenafil.

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R. Verhaeghe

Sensory systems Sporadic cases of ischemic ocular complications (branch artery occlusion, ischemic optic neuropathy) associated with sildenafil feed discussion about a coincidental versus a possibly causative role of the drug (SEDA-25, 238; SEDA-26, 231; SEDA-27, 211). • A 51-year-old man with poorly controlled hypertension had sudden superior hemifield loss in the left eye during sexual activity 4 hours after taking sildenafil 100 mg (7A ). He had used sildenafil repeatedly over the previous few weeks without unwanted effects. Fundoscopy and fluorescein angiography confirmed an embolic occlusion of the inferior hemiretinal artery.

The authors thought that debris from an atherosclerotic plaque at the carotid bifurcation had been dislodged as a result of increased cardiac workload during sexual activity, rather than a direct effect of sildenafil itself. Liver Acute hepatitis has been reported in a patient using sildenafil (8A ). • A 65-year-old man with diabetes and hypertension had taken 50 mg of sildenafil about once every 2 weeks for 1 year, when he suddenly felt generally unwell. He had a tender liver, and blood tests showed mild thrombocytopenia, a lymphocytosis, and markedly raised aminotransferases, which had been normal shortly before and returned to normal over a few weeks after withdrawal of sildenafil, while he continued to take his antidiabetic and antihypertensive drugs. Other causes of hepatitis were ruled out by appropriate tests.

Definite proof of liver toxicity of a drug is difficult to provide. The authors invoke an ischemic rather than an immunoallergic pathogenesis to explain the hepatotoxic effect of sildenafil in this patient. This could also have explained his subsequent occasional use of sildenafil without recurrence of liver toxicity. The concomitant use of antihypertensive drugs may have facilitated the single episode of hepatitis. Drug interactions None of these drugs should be combined with nitrate derivatives because of a risk of abrupt hypotension (9R –11R ).

Drugs acting on the cerebral and peripheral circulations

Chapter 19

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REFERENCES 1. Zapater P, Horga JF, Garcia A. Risk of druginduced agranulocytosis: the case of calcium dobesilate. Eur J Clin Pharmacol 2003; 58: 767–72. 2. Cholongitas E, Papatheodoridis GV, Mavrogiannaki A, Manesis E. Naftidrofuryl-induced liver injury. Am J Gastroenterol 2003; 98: 1448–50. 3. Thiolet C, Bredin C, Rimlinger H, Nizou C, Mennecier D, Farret O. Colite lymphocytaire secondaire à la prise de Cyclo 3 fort. Presse Med 2003; 32: 1323–4. 4. Pardo Rey C, Yebra M, Borallo M, Vega A, Ramos A, Montero MC. Irreversible coma, ergotamine, and ritonavir. Clin Infect Dis 2003; 37: e72–3. 5. Tran D, Howes LG. Cardiovascular safety of sildenafil. Drug Saf 2003; 26: 453–60. 6. Salonia A, Rigatti P, Montorsi F. Sildenafil in erectile dysfunction: a critical review. Curr Med Res Opin 2003; 19: 241–62.

7. Bertolucci A, Latkany RA, Gentile RC, Rosen RB. Hemi-retinal artery occlusion associated with sexual activity and sildenafil citrate (Viagra). Acta Ophthalmol Scand 2003; 81: 198–200. 8. Maroy B. Hépatite aiguë cytolitique probablement due à la prise de sildénafil (Viagra). Gastroenterol Clin Biol 2003; 27: 564–5. 9. Curran M, Keating G. Tadalafil. Drugs 2003; 63: 2203–12. 10. Meuleman EJ. Review of tadalafil in the treatment of erectile dysfunction. Expert Opin Pharmacother 2003; 4: 2049–56. 11. Hellstrom WJ. Vardenafil: a new approach to the treatment of erectile dysfunction. Curr Urol Rep 2003; 4: 479–87.

Pieter Joubert

20

Antihypertensive drugs

Choice of antihypertensive drugs in patients with diabetes and hypertension

Calcium channel blockers combined with ACE inhibitors appear to provide additional renoprotection. The LIFE study Further commentaries on the LIFE study in over 9000 patients (2C ) have appeared in 2003. The key findings alluded to in a commentary (3r ), in terms of hypertension and diabetes, were that atenolol or losartan as monotherapy reduced blood pressure in patients with diabetes and hypertension, but not to the target blood pressure, suggesting that more intensive therapy is required than was used in the LIFE study. The data suggest that the onset of diabetes can be prevented or delayed by losartan, and losartan is also more effective than atenolol in reducing cardiovascular mortality and morbidity in patients with diabetes taking suboptimal treatment. In another commentary (4r ) it was suggested that losartan is clearly better and that elderly patients with hypertension should not be exposed to beta-blockers.

The choice of drugs in patients with diabetes and hypertension is important because antihypertensive drugs affect the development of complications such as albuminuria and the development of nephropathy, and because the metabolic effects of antihypertensive drugs can complicate treatment or enhance the development of diabetes. The authors of a review of the treatment of combined diabetes and hypertension pointed out the importance of tight blood pressure control (aiming for a blood pressure below 130/80 for all diabetics and below 125/75 in the presence of significant proteinuria) for the prevention of cardiovascular mortality and morbidity, and the development and progression of diabetic nephropathy (1M ). Adequate control of blood pressure is more important than the choice of drug, and multiple drugs are often required. The general consensus is that ACE inhibitors should be the first-line choice, angiotensin II receptor blockers being a reasonable alternative. Thiazide diuretics impair glucose tolerance. On the other hand the increase in renin that they cause enhances the effects of ACE inhibitors and angiotensin II receptor blockers. It also appears that the adverse effect on blood glucose can be eliminated by avoiding hypokalemia. Beta-blockers reduce proteinuria and cardiovascular mortality. They can worsen glycemic control, reduce awareness of hypoglycemia, and adversely affect lipid profiles. However, in patients with diabetes and hypertension and a history of myocardial infarction, the benefits may outweigh the risks.

The ALPINE study In a 1-year study, 392 newly diagnosed patients with hypertension were randomized to either candesartan 16 mg/day or hydrochlorothiazide 25 mg/day; if the blood pressure did not fall below 135/85 in patients aged under 65 years or 140/90 in patients aged 65 years or older, extended-release felodipine 2.5–5.0 mg was added to candesartan or atenolol 50–100 mg to hydrochlorothiazide (5C ). The fall in blood pressure was similar in the two groups and most patients required two drugs. Fasting insulin and glucose concentrations increased in the hydrochlorothiazide + atenolol group, but were unaffected in the candesartan + felodipine group. Eight patients in the thiazide group developed diabetes mellitus compared with one in the candesartan group.

© 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

Other studies in diabetes In 463 patients with type II diabetes and hypertension, a combination of atenolol + chlortalidone produced

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worse metabolic control (HbA1c ), whereas metabolic control was minimally affected with verapamil + trandolapril (6C ). Both regimens produced similar suboptimal falls in mean blood pressure. In 457 patients with type II diabetes, hypertension, and albuminuria, the effect of daily perindopril 2 mg + indapamide 0.625 mg was compared with the effect of daily enalapril 10 mg (7C ). Based on blood pressure, doses could be increased to a maximum of 8.0 mg of perindopril + 2.5 mg of indapamide or 40 mg of enalapril. The combination produced a statistically significant greater fall in blood pressure, but it is difficult to see this as clinically relevant (3.0 and 1.5 mm more for systolic and diastolic pressures respectively). There was a significantly greater reduction in albuminuria with the combination (−40%), than with monotherapy (−27%). Combination therapy Several smaller studies have suggesting that monotherapy is usually not optimal for patients with diabetes and hypertension, and that combination therapy would be required in most cases. In 24 patients with diabetes and hypertension, dual renin–angiotensin blockade with lower doses of an ACE inhibitor and an angiotensin II receptor blocker was superior to maximal doses of either alone (8c ). In 38 patients with diabetes and hypertension benazepril + amlodipine produced better reduction in blood pressure and a more favorable effect on fibrinolytic balance than either drug alone (9c ).

ANGIOTENSIN CONVERTING ENZYME INHIBITORS (SED-14, 638; SEDA-25, 240; SEDA-26, 234; SEDA-27, 213)

Benazepril

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(SED-14, 643)

Endocrine Hypoaldosteronism with metabolic acidosis has been reported in a child taking an ACE inhibitor (10A ). • A 4-year-old boy with minimal-change nephrotic syndrome since the age of 11 months had been treated with cyclophosphamide and glucocorticoids. After several relapses and the development

of mild hypertension and proteinuria, he was given benazepril 0.3 mg/kg/day. He was admitted 4 months later with a metabolic acidosis (pH 7.28, base excess −15) and mild hyperchloremia (chloride 110 mmol/l). He had mild proteinuria and a normal creatinine clearance. The diagnosis was metabolic acidosis due to gastroenteritis and he was treated with intravenous saline and bicarbonate and discharged, but was re-admitted with anorexia and nausea and the same findings as before. A 24-hour urine sample showed high sodium and a low potassium and chloride excretion. The serum aldosterone concentration was below the limit of detection. The dose of benazepril was reduced to 0.2 mg/kg/day for 1 week and then withdrawn. Ten days later the aldosterone concentration was normal (29 pg/ml). After 9 months of follow-up, he still had mild proteinuria, but there had been no further episodes of metabolic acidosis.

The authors pointed out that there is evidence of ACE inhibitor-induced hypoaldosteronism in adults. This condition should be considered in children and adults taking ACE inhibitors who present with metabolic acidosis.

Enalapril

(SED-14, 643; SEDA-25, 242;

SEDA-26, 235) Liver Hepatotoxicity is a recognized adverse effect of enalapril. Enalapril-induced ductopenia with cholestatic hepatitis has now been reported (11r ). • A 58-year-old man with no previous history of liver disease, intravenous drug abuse, blood transfusion, or alcohol abuse, developed progressively worsening jaundice. He had been taking enalapril 20 mg/day for 2 years. He was afebrile, and had raised bilirubin, alkaline phosphatase, and transaminases. Serological tests for viral hepatitis, HIV, Epstein–Barr virus, cytomegalovirus, Varicella, Rickettsiae, and Salmonella were negative. Tests for a variety of antibodies and congenital liver disease were negative. A liver biopsy showed ductopenia and cholestasis with centrilobular hepatocyte necrosis. Enalapril was withdrawn, and the biochemical parameters improved over a period of 20 days. Ten days later he was readmitted with severe cholestatic jaundice. A second liver biopsy confirmed the presence of ductopenia (bile duct-to-portal tract ratio 0.5, normal 0.9–1.8). The jaundice progressively improved and resolved within 2 months.

Pancreas There have been many reports of pancreatitis associated with ACE inhibitors, including enalapril, as in a case with recurrence after inadvertent rechallenge (12A ).

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Urinary tract Acute renal insufficiency has been reported in a neonate after treatment with enalapril for congestive heart failure (13A ). Although impaired renal function has been reported in young infants, cases in neonates are sparse.

The author of the second report speculated that in the presence of psoriasis, a T cell mediated disorder, enalapril acted as an exogenous trigger.

• A 2.75 kg male neonate developed signs of congestive heart failure 3 days after birth and a diagnosis of a ventricular septal defect was made. Because of persistence of heart failure after digoxin and diuretic therapy, oral enalapril 0.1 mg/kg was started on day 6. The signs of congestive heart failure improved, but 3 days later oliguria developed. The child was normotensive, urinalysis was normal, and there was no evidence of infection or renal artery stenosis. Enalapril was withdrawn. He became anuric and had a dangerously raised serum potassium concentration (8.1 mmol/l). Peritoneal dialysis was started and digoxin and diuretics withdrawn. By day 20, the renal function tests were normal and dialysis was stopped. By week 3, congestive heart failure recurred and digoxin and diuretics were restarted. At follow-up at 1 year of age, the ventricular septal defect was closing spontaneously and renal function has remained normal.

Lisinopril

The authors conclude that ACE inhibitors should be given with extreme caution to neonates, particularly in the presence of left-to-right shunts and congestive heart failure. Renal function should be carefully monitored. Skin There have been two reports of skin reactions associated with enalapril, a lichenoid eruption and pemphigus in a patient with preexisting psoriasis. • A 45-year-old woman developed a lichenoid eruption shortly after starting to take enalapril (14r ). The condition cleared when enalapril was withdrawn and subcutaneous enoxaparin given. The patient was not rechallenged. • A 70-year-old man with plaque psoriasis for 35 years, treated topically, developed new erythematous scaly plaques on his trunk and scalp 2 months after starting to take enalapril and lacidipine (15r ). He also had a history of hypertension and congestive heart failure treated with digoxin, acenocoumarol, theophylline, amiloride, furosemide, isosorbide mononitrate, and pravastatin. The diagnosis was pemphigus foliaceus, based on the clinical picture and a skin biopsy. He was treated intermittently for the next 2 years with hostacycline and prednisone, with periods of improvement and relapse. When seen again with extensive skin lesions, a firm diagnosis of pemphigus foliaceus co-existing with psoriasis was made, based on a skin biopsy and immunofluoresence testing. Enalapril was withdrawn and he was given topical betamethasone. Four months later the skin condition had cleared completely.

(SEDA-25, 242; SEDA-26, 236; SEDA-27, 213) Teratogenicity An intact renin-angiotensin system is required for the normal intrauterine development of the kidneys. The use of ACE inhibitors during pregnancy can result in multiple organ failure, resulting in oligohydramnios, pulmonary hypoplasia, neonatal renal insufficiency, and bony abnormalities. In one such case lisinopril was successfully cleared from the neonate’s blood by early peritoneal dialysis (16A ).

Perindopril

(SED-14, 643)

Ear, nose, and throat Dysphonia has been associated with perindopril (17r ). • An 84-year-old man, who had been taking nifedipine for hypertension for 10 years, was switched to lisinopril 4 mg/day because of inadequate control. One week later the patient became hoarse. Because of persistent hoarseness, he came to hospital 3 weeks later. The blood pressure was normal and apart from dysphonia there were no abnormalities of the ear, nose, and throat. The presence or absence of cough was not reported. Lisinopril was withdrawn and amlodipine started. Within 72 hours his voice was normal. Two months later he ran out of amlodipine and started taking lisinopril tablets he still had at home. Four days later the dysphonia recurred. Laryngoscopy was normal and 3 days after stopping lisinopril his voice returned to normal.

The author pointed out that although ACE inhibitors can cause dry cough, dysphonia has not been reported before.

Ramipril

(SEDA-24, 239; SEA-27, 214)

Pancreas Fatal fulminant pancreatitis has been reported in a patient taking ramipril (18r ). Pancreatitis, a rare adverse effect of ACE inhibitors, has been reported with benazepril, captopril, enalapril, lisinopril, and quinapril; this is the first case associated with ramipril.

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Skin Recurrent angioedema and urticaria associated with ramipril 2.5 mg/day has been reported (19r ). The patient had recurrent episodes, including three emergency admissions for respiratory distress, over 5 years. After she stopped taking ramipril her signs and symptoms cleared and she had no relapses during 6 months of follow-up. The authors pointed out that the rarity of this adverse effect can result in delayed diagnosis and they advocated greater awareness of ACE inhibitor-induced allergy.

ANGIOTENSIN II RECEPTOR ANTAGONISTS (SED-14, 645; SEDA-25, 245; SEDA-26, 236; SEDA-27, 214) Hematologic A Japanese group has studied the effects of various concentrations of angiotensin II receptor antagonists and ACE inhibitors on in vitro burst-forming erythroid units in seven healthy volunteers (40–47 years) and in 10 men (40–49 years) with chronic renal insufficiency undergoing hemodialysis, seven of whom required erythropoietin 42 185 IU/week to maintain a hematocrit of 30% (20c ). None was taking an angiotensin II receptor antagonist or an ACE inhibitor. The blood from healthy volunteers yielded about four times the number of burst-forming erythroid units than blood from patients. Angiotensin II significantly increased the number of burstforming units. Losartan inhibited this effect dose-dependently in both healthy volunteers and patients, but enalaprilat and trandolaprilate had no effects. The authors conclude that angiotensin II receptor blockade causes direct inhibition of erythropoiesis and they suggested that hematocrit and hemoglobin should be monitored when angiotensin II receptor antagonists are given to patients with chronic renal insufficiency. Drug interactions Drug interactions with angiotensin II receptor blockers have been reviewed (21M ).

been attributed to candesartan (22A ). Hepatotoxicity has been reported with losartan, but this appears to be the first case associated with candesartan. Susceptibility factors Genetic An 89-yearold hypertensive Japanese man with the CYP2C9*1/*3 slow metabolizer genotype had reduced clearance of candesartan, resulting in excessive blood pressure lowering (23A ). The authors pointed out that although losartan metabolism is also reduced in CYP2C9*1/*3 slow metabolizers, the inhibition results in reduced formation of the active metabolite E-3174, with no apparent effect on blood pressure lowering. In contrast, as candesartan has an inactive metabolite, its blood pressure lowering effect is enhanced.

Irbesartan

(SEDA-24, 240;

SEDA-25, 244) Skin Maculopapular allergic skin lesions developed 5 days after introduction of irbesartan for hypertension in a 76-year-old man (24r ). Skin biopsy showed upper dermal lymphocytic infiltration resembling an early phase T cell lymphoma. This cleared rapidly and completely after withdrawal of irbesartan. Similar findings have been described with enalapril (25A ).

Losartan (SED-14, 645; SEDA-25, 245; SEDA-26, 236; SEDA-27, 214) Urinary tract Acute renal insufficiency has been attributed to losartan in a patient with bilateral renal artery stenosis, reinforcing the fact that the same caution is needed with angiotensin II receptor antagonists as with ACE inhibitors in such patients (26A ).

Candesartan

Telmisartan

Liver Jaundice and ductopenic hepatitis, similar to that described above under enalapril, has

Immunologic Severe angioedema has been attributed to telmisartan (27r ).

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Teratogenicity Intra-uterine exposure to angiotensin II receptor antagonists can be associated with neonatal abnormalities. • A neonate exposed to telmisartan during the first trimester of pregnancy developed acute renal insufficiency, presenting with oligohydramnios, and survived (28A ).

In reviewing the literature the authors found reports of five fetal deaths and one neonatal death associated with first-trimester exposure to angiotensin II receptor antagonists. All of these cases presented with severe oligohydramnios. In three fetuses there were abnormalities of the feet and face with hypoplastic skull bones. The kidneys were enlarged with tubular dysgenesis.

DRUGS THAT ACT ON THE SYMPATHETIC NERVOUS SYSTEM (SED-14, 646; SEDA-25, 245; SEDA-27, 216)

PRESYNAPTIC ALPHA-ADRENOCEPTOR AGONISTS Clonidine

(SED-14, 646; SEDA-25, 245;

SEDA-27, 216) Drug abuse A case of clonidine dependence has been reported (29r ). The authors pointed out that abuse of clonidine in combination with other drugs, particularly opioids, is relatively common. The case they reported was unusual, as it involved clonidine as the sole drug of abuse. • A 37-year-old man requested admission for voluntary detoxification from clonidine. He had started using alcohol and marijuana in his teens, became dependent on intravenous heroin at the age of 20, and switched to methadone at 27. He had several unsuccessful attempts at methadone withdrawal using clonidine, benzodiazepines, and other therapies. In a final attempt at the age of 35, he managed to self-detoxify using clonidine 0.8 mg 3–5 times per day. At the time of admission he was using 1.8– 3.2 mg/day, compared with the recommended antihypertensive dose of 0.2–0.6 mg/day. Clonidine relieved his anxiety, controlled his anger, relieved headaches, and allowed him to sleep. When he ran

Pieter Joubert

out of clonidine he had severe headaches, chest pain, blurred vision, and irritability, with slurred speech and some paranoia. His blood pressure was 218/110 and his blood chemistry was normal. He was detoxified over a period of 3 days and his blood pressure was controlled. He was discharged taking benazepril 40 mg/day, gabapentin 900 mg tds, hydrochlorothiazide 25 mg/day, and a 0.3 mg clonidine patch to be removed the next day. On the same evening he took an unknown amount of clonidine and had a seizure. He was unconscious, with a blood pressure of 78/46 mmHg. He was resuscitated and had raised cardiac enzymes with no electrocardiographic evidence of myocardial infarction. He was discharged 4 days later taking diltiazem, benazepril, gabapentin, low-dose aspirin, paroxetine, and a clonidine patch 0.3 mg per day.

The authors commented that hyperactive central alpha2 adrenergic neurons mediate symptoms such as anxiety, irritability, and insomnia, and that alleviation of these symptoms can result in clonidine dependence. They also quoted rodent evidence that alpha2 adrenoceptors mediate GABA release, which could explain a benzodiazepine-like effect of clonidine. Drug overdose Clonidine overdose with marked hypothermia has been reported (30r ). • A 39-year-old woman taking multiple psychiatric medications became apneic and a core body temperature of 28.9◦ C and was thought to have died. Twenty doses of clonidine 0.2 mg and 20 of amitriptyline 25 mg were unaccounted for. After resuscitation she made a full recovery within 3 days.

A literature search revealed three cases of clonidine overdose with hypothermia and an extended recovery period.

DIRECT VASODILATORS Hydralazine

(SED-14, 650; SEDA-25, 247; SEDA-27, 217) Urinary tract Pauci-immune renal vasculitis in association with renal cell carcinoma has been reported in a patient taking hydralazine (31A ). • A 61-year-old man taking hydralazine 50 mg bd for hypertension developed weight loss, proteinuria and hematuria, biochemical features of renal

Antihypertensive drugs

Chapter 20

insufficiency, and a mass in the upper pole of the left kidney. Antinuclear antibodies were strongly positive. Biopsy of the right kidney showed focal proliferative glomerulonephritis. A left radical nephrectomy was performed and a renal clear cell carcinoma with no evidence of local or metastatic spread was found. He required five postoperative hemodialysis sessions and was entered into a permanent hemodialyis program 12 months later, at which time hydralazine was withdrawn. He remained well 1 year later, with no evidence of tumor recurrence, but antinuclear antibodies re-

231 main strongly positive and he did not recover renal function.

The authors cited several reports of an association between antinuclear antibody-positive renal vasculitis and either renal cell carcinoma or hydralazine therapy. The fact that the patient remained positive for antinuclear antibodies could have been due to the failure to withdraw hydralazine early enough or the presence of undetected residual tumor.

REFERENCES 1. Padilla R, Estacio RO. New insights into the combined burden of type 2 diabetes and hypertension. Heart Drug 2003; 3: 25–33. 2. Dahlop B, Devereux RB, Kjeldsen SE. Cardiovascular mortality and morbidity in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359: 995–1003. 3. Nadar I, Lim HS, Lip GYH. Implications of the LIFE trial. Exp Opin Investig Drugs 2003; 12: 871– 7. 4. Messerli FH. The LIFE study: the straw that should break the camel’s back. Eur Heart J 2003; 24: 487–9. 5. Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svenssson A, Samuelsson O. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation (ALPINE study). J Hypertens 2003; 21: 1563–74. 6. Holzgreve H, Nakov R, Beck K, Janka HU. Antihypertensive therapy with verapamil SR plus trandolapril versus atenolol plus chlorthalidone on glycaemic control. Am J Hypertens 203; 16: 381–6. 7. Morgensen CE, Viberti G, Halimi Í, Ritz E, Ruilope L, Jermendy G, Widimsky J, Sarelli, P, Taton J, Rull J, Erdogan G, De Leeuw PW, Ribeiro A, Sanchez R, Mechmeche R, Nolan J, Sirotiokova J, Hamani A, Scheen A, Hess B, Luger A, Thomas SM. Effect of low-dose perindopril/indapamide on albuminuria in diabetes. Hypertension 2003; 41: 1063–71. 8. Jacobsen P, Andersen S, Rossing K, Jensen BR, Parving H. Dual blockade of the renin angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int 2003; 63: 1874–80. 9. Fogari R, Preti P, Lazzari P, Corradi L, Zoppi A, Fogari E, Mugellini A. Effect of benazepril amlodipine combination on fibrinolysis in hypertensive diabetic patients. Eur J Clin Pharmacol 2003, 59: 271–3. 10. Bruno I, Pennesi M, Marchetti F. ACEinhibitors-induced metabolic acidosis in a child

with nephrotic syndrome. Pediatr Nephrol 2003; 18: 1293–4. 11. Macías FMJ, Campos FRR, Salguerro TP, Soria TP, Carrasco FG, Martin JMS. Ductopenic hepatitis related to enalapril. J Hepatol 2003; 39: 1091–2. 12. Carnovale A, Esposito P, Bassano P, Russo L, Uomo G. Enalapril-induced acute recurrent pancreatitis. Dig Liver Dis 2003; 35: 55–7. 13. Dutta I, Narang A. Enalapril-induced acute renal failure in a newborn infant. Pediatr Nephrol 2003; 18: 570–2. 14. Villaverdi RR, Melguizo JB, Solano JL, Ortega SS. Lichen planus-like eruption due to enalapril. J Eur Acad Dermatol Venereol 2003; 17: 612–14. 15. Stavropoulos PG. Coexistence of psoriasis and pemphigus after enalapril intake. Dermatology 2003; 207: 337–8. 16. Filler G, Wong H, Condella AS, Charbonneau C, Sinclair B, Kovesi T, Hutchison J. Early dialysis in a neonate with intrauterine lisinopril exposure. Arch Dis Child Fetal Neonatal Ed 2003; 88: F154– 6. 17. Vázquez JF. Dysphonia secondary to perindopril treatment. Am J Hypertens 2003; 16: 329–30. 18. Anagnostopoulus GK, Kostopoulus P, Tsiakos Í, Margantinis G, Arvantidis A. Fulminant pancreatitis associated with ramipril therapy. Pancreas 2003; 3: 278. 19. Bhalla M, Thami GP. Delayed diagnosis of angiotensin-converting enzyme (ACE) inhibitor induced angioedema and urticaria. Clin Exp Dermatol 2003; 28: 333–4. 20. Naito M, Kawashima A, Akiba T, Takanashi M. Effects of an angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitors on burst-forming units-erythroid in chronic hemodialysis patients. Am J Nephrol 2003; 23: 287–93. 21. Unger T, Kaschina E. Drug interactions with angiotensin blockers: a comparison with other antihypertensives. Drug Saf 2003; 26: 707–20. 22. Basile G, Villari D, Gangemi S, Ferrara T, Accetta MG, Nicita-Mauro V. Candesartan cilexetil-induced severe hepatotoxicity. J Clin Gastroenterol 2003; 36: 273–5.

232 23. Uchida I, Watanabe H, Nishio I, Hashimoto H, Yamasaki K, Hayashi H, Ohasi K. Altered pharmacokinetics and excessive hypotensive effect of candesartan in a patient with the CYP2C9*1/*3 genotype. Clin Pharmacol Ther 2003; 74: 505–8. 24. Gambini D, Sala F, Gianotti R, Cusini M. Exanthematous reaction to irbesartan. Eur Acad Dermatol Venereol 2003; 17: 469–90. 25. Furness PM, Goodfield MJ, MacLennan KA, Stevens A, Millard LG. Severe cutaneous reactions to captopril and analapril; histological study and comparison with early mycosis fungoides. J Clin Pathol 1986; 39: 902–7. 26. Wargo KA, Chong K, Chan CY. Acute renal failure secondary to angiotensin II receptor blockade in a patient with bilateral renal artery stenosis. Pharmacotherapy 2003; 23: 1199–204.

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27. Borazan A, Üstin H, Yilmaz A. Angioedema induced by angiotensin II blocker telmisartan. Eur J Allergy Clin Immunol 2003; 58: 454. 28. Pieterement C, Malot L, Santerne B, Roussel B, Motte J, Morville P. Neonatal acute renal failure secondary to maternal exposure to telmisartan, angiotensin II receptor antagonist. J Perinatol 2003; 23: 254–5. 29. Lanford W, Myrick M, O’Bryan E. A severe case of clonidine dependence and withdrawal. J Psychiatr Pract 2003; 9: 167–9. 30. Quail MT, Shannon M. Severe hypothermia caused by clonidine. Am J Emerg Med 2003; 21: 86. 31. Norris JH, Leeds J, Jeffrey RF. P-ANCA positive renal vasculitis in association with renal cell carcinoma and prolonged hydralazine therapy. Renal Fail 2003; 25: 311–14.

Domenic A. Sica

21 CARBONIC ANHYDRASE INHIBITORS (SED-14, 669; SEDA-25, 249; SEDA-26, 238; SEDA-27, 22)

Acetazolamide Fluid balance Acetazolamide can cause rapid volume changes. • A 47-year-old woman with diabetes who took acetazolamide (250 mg bd for 6-days) for left cystoid macular edema developed profound hyperosmolar non-ketotic hyperglycemia (1A ). This occurred as the result of marked diuresis and an associated fall in glomerular filtration rate.

Diuretics systemic medications included hydrochlorothiazide and verapamil. There was a peripheral choroidal detachment in the left eye, which completely resolved 1 week after withdrawal of dorzolamide together with topical glucocorticoid therapy.

In this case, the systemic hydrochlorothiazide may have sensitized the choroidal epithelium sufficiently to result in aqueous fluid shutdown.

THIAZIDE AND LOOP DIURETICS (SED-14, 656; SEDA-25, 252; SEDA-26, 239; SEDA-27, 220)

Hematologic Acetazolamide can cause rapid hematological changes, including thrombocytopenia. • A 67-year-old man developed isolated thrombocytopenia (platelet count 31 × 109 /l) after taking acetazolamide 250/mg day for 2 days for raised intraocular pressure (2A ). Several months later acetazolamide 375 mg/day was prescribed again and 2 weeks later he developed extensive purpura and a platelet count of 3 × 109 /l. Acetazolamide was withdrawn and the platelet count rose spontaneously to 20, 73, and 246 × 109 /l after 1, 3, and 10 days respectively.

Dorzolamide Sensory systems Eyes that have not undergone surgery have not been reported to undergo choroidal detachment with topical hypotensive agents. • A 76-year-old woman with a 7-year history of open-angle glaucoma presented with distorted visual acuity after applying two doses of dorzolamide eye-drops 2% bd to both eyes (3A ). Other © 2005 Published by Elsevier B.V. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

Thiazides Musculoskeletal In a nested case-control study in patients with type 2 diabetes there were 26 cases of a first leg amputation among 12 140 cases. Subjects who used thiazide diuretics alone or together with other antihypertensive medications had a higher risk of leg amputation (crude odds ratio = 6.11) compared with subjects taking ACE inhibitor monotherapy. Thiazide diuretics were also associated with an increased risk of leg amputation than non-thiazide antihypertensive drugs (adjusted odds ratio = 7.04). These findings suggest that thiazide-type diuretics be used cautiously in patients with type 2 diabetes particularly when there is significant lower limb peripheral vascular disease (4c ).

Furosemide Sensory systems Hearing loss is a significant problem in survivors in neonatal intensive care units and has been attributed to underlying disease processes and/or exposure to ototoxic drugs, including furosemide. A retrospective chart review (July 2000 to January

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234 2002) of all survivors in a neonatal intensive care unit was undertaken to evaluate the effect of furosemide on hearing loss (5M ). Of the 57 neonates who had received furosemide nine had a subsequent abnormal hearing screen, and of the 207 neonates who had not received furosemide 33 also had an abnormal hearing screen. This suggests that hearing loss in these neonates is not directly related to the use of furosemide. Nutrition Furosemide has been associated with thiamine deficiency in patients with heart failure. Erythrocyte transketolase activity suggested severe thiamine deficiency in 24 of 25 patients with heart failure who were taking at least 80 mg/day of furosemide and in four of seven patients who were taking 40 mg/day (OR = 19; CI = 1.1, 601) (6c ). Thiamine status was not associated with any other clinical variables. These findings suggest that thiamine deficiency occurs in a substantial proportion of patients with heart failure who are taking furosemide; however, this is of unclear clinical significance. Salivary glands Diuretics cause altered salivary flow rate and composition and have been associated with both subjective and objective evidence of xerostomia. In a randomized trial in 12 healthy women randomly assignment to placebo, bendroflumethiazide (2.5 mg/day for 7 days) and furosemide (40 mg/day for 7 days), xerostomia increased with furosemide in conjunction with a reduction in submandibularsublingual salivary secretion (7c ). This was particularly so at lunchtime. This suggests that diuretics may potentiate dryness of the mouth and should be used carefully in patients with abnormal salivary flow. Urinary tract A 900-gram girl born before term with bronchopulmonary dysplasia developed ureteral obstruction, urinoma, and acute renal insufficiency as a result of furosemiderelated hypercalciuria (cumulative dose 27.5 mg) and nephrolithiasis (8A ). Percutaneous drainage of the urinoma plus conversion to hydrochlorothiazide resolved the urinoma and hydronephrosis. Acute renal insufficiency carries a high mortality and morbidity. Diuretics may increase mortality in patients with acute renal insufficiency (SEDA-27, 221), but this has not been

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studied prospectively. In a prospective, multicenter, multinational, epidemiological study of 1743 consecutive patients, who were either treated with renal replacement therapy or who fulfilled predefined criteria for acute renal insufficiency, about 70% were taking diuretics at enrolment (9M ). Severe sepsis/septic shock (48%), major surgery (39%), low cardiac output (30%), and hypovolemia (28%) were the most common conditions associated with the development of acute renal insufficiency. Furosemide was the most common diuretic used (98%). In all three multivariate models, diuretic use was not associated with a significantly increased risk of mortality. The use of diuretics in patients with acute renal insufficiency should continue, but only according to a specific need to control volume excess. Immunologic Furosemide rarely causes type 1 allergic reactions. • A 24-year-old woman took one tablet of furosemide 40 mg and 10 minutes later developed oral itching, generalized urticaria, facial angioedema, dyspnea, and hypotension (10A ). She recovered after the administration of parenteral adrenaline, methylprednisolone, and diphenhydramine. A furosemide skin prick test 10 mg/ml was negative. An intradermal skin test was positive for furosemide 1% and sulfamethoxazole 0.03 mg/ml.

IgE-mediated reactions to furosemide are infrequent, but can be life-threatening. The positive intradermal test to sulfamethoxazole in this case raises the question of cross-reactivity between non-aromatic and antimicrobial sulfonamides. There is little clinical or pharmacological evidence that a self-reported sulfa allergy is likely to be associated with a life-threatening crossreaction with acetazolamide or furosemide (11M , 12M ). Most patients who report sulfa allergy have actually had an adverse reaction to a sulfonamide antimicrobial drug. There are significant structural differences between sulfonamide antibiotics and other sulfonamide non-antimicrobial drugs such as furosemide and acetazolamide, and generally cross-reactivity would not be expected. In a retrospective cohort study using the General Practice Research Base in the UK, 969 cases with a so-called allergic reaction to an antimicrobial sulfonamide were reviewed (12M ).

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Only 96 (9.9%) had an allergic reaction after receiving a non-antimicrobial sulfonamide. Of 19 257 who had no allergic reaction after a antimicrobial sulfonamide, 315 (1.6%) had an allergic reaction However, the risk of allergic reactions was even greater after the use of a penicillin among patients with a prior hypersensitivity reaction to a antimicrobial sulfonamide, compared with patients with no such history (adjusted odds ratio = 3.9) after receiving a non-antimicrobial sulfonamide (adjusted odds ratio = 2.8). In addition, among those with a prior hypersensitivity reaction after an antimicrobial sulfonamide, the risk of an allergic reaction after the subsequent receipt of a nonantimicrobial sulfonamide was lower than the risk of an allergic reaction with penicillin (adjusted odds ratio = 0.7). Finally, the risk of an allergic reaction after an antimicrobial sulfonamide was lower among patients with a history of hypersensitivity to an antimicrobial sulfonamide than among patients with a history of hypersensitivity to penicillins (adjusted odds ratio = 0.6). These results suggest that there is an association between hypersensitivity after an antimicrobial sulfonamide and a subsequent allergic reaction after a non-antimicrobial sulfonamide, but this association appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs. Drug interactions Of 10 615 elderly patients continuously taking lithium for over 10 years, 413 (3.9%) were admitted to the hospital at least once with lithium toxicity. After adjustment for potential confounders, there was a 5.5-fold increase in the relative risk of lithium toxicity within 1 month of starting therapy with a loop diuretic (13c ). Thiazide diuretics were not independently associated with an increased risk of hospitalization for lithium toxicity. This population-based nested case-control study stresses the importance of monitoring for lithium toxicity whenever a loop diuretic is started.

ALDOSTERONE RECEPTOR ANTAGONISTS (SED-14, 674; SEDA-25, 254; SEDA-240; SEDA-27, 221)

Eplerenone Electrolyte balance Hyperkalemia is always a consideration with spironolactone and eplerenone, but the relation between a beneficial response to eplerenone and the change in serum potassium concentration has been poorly characterized. In 397 hypertensive patients (responders and non-responders) taking eplerenone 50– 200 mg/day without other susceptibility factors for hyperkalemia, eplerenone caused an increase in serum potassium concentration of 0.2 mmol/l (14C ). The blood pressure lowering effect of eplerenone did not correlate with the change in serum potassium concentration. This suggests that in patients with uncomplicated hypertension, eplerenone can be used without a significant risk of hyperkalemia.

Spironolactone Urinary tract Of 226 patients with heart failure in a retrospective analysis, 25 stopped therapy because of renal dysfunction, 13 primarily because of hyperkalemia and 12 primarily because of a rising creatinine (15c ). The mean baseline creatinine in the latter was 140 µmol/l, rising to a mean of 197 µmol/l at the time of stopping therapy. Eight of 11 patients had a serum creatinine over 200 µmol/l. Spironolactone should be considered as one of the several pharmacological factors that can cause deterioration of renal function in heart failure. Skin Drug rash with eosinophilia and systemic symptoms (DRESS) has been attributed to spironolactone. • A 58-year-old man developed erythroderma, fever, anorexia, peripheral edema, eosinophilia, and multi-organ failure while taking several drugs, including spironolactone (16A ). All the medications were stopped and the condition completely remitted over 4 months. Patch testing was positive for spironolactone.

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OSMOTIC DIURETICS (SED-14, 1162, 1236)

Mannitol Uses of mannitol The number of uses of mannitol continues to increase. Reducing raised intracranial pressure The use of mannitol in the treatment of raised intracranial pressure has been reviewed, in the light of disagreements about the appropriate timing of administration, the optimal fluid management protocol, and the mechanisms of action of osmotic diuretics (17R –19R ). The effects of four methods of infusion of mannitol and glycerol on raised intracranial pressure, as monitored by epidural pressure recordings, have been studied in 65 patients (20c ). A. mannitol 0.5 g/kg was infused over 15, 30, or 60 minutes; B. mannitol 1.0 g/kg was infused over 30, 60, or 90 minutes; C. glycerol 0.5 g/kg in 5% fructose was infused over 30, 60, or 90 minutes; D. glycerol 1.0 g/kg was infused over 60, 120, or 180 minutes. In group A, there were no differences in the reduction in intracranial pressure across the three infusion rates. In group B, the degree of reduction in intracranial pressure increased with shorter times of infusion. In groups C and D the reduction in intracranial pressure was inversely related to the rate of infusion. In each group, the slower the infusion rate of the same dosage, the longer the reduction in intracranial pressure lasted. There was a rebound increase in intracranial pressure in 12% of those given mannitol and 34% of those given glycerol. The dose and the rate of mannitol infusion did not affect the rebound. In 22 patients with meningoencephalitis and hypertensive cranial syndrome from cerebral edema, mannitol was given to 13 and dexamethasone to nine (21c ). There were three therapeutic failures in those given mannitol and none in those given dexamethasone, although the two

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drugs had similar effects on the duration of the hypertensive cranial syndrome (39–44 hours). The patients who were treated with mannitol had hyponatremia after 48 hours. In 43 patients, osmotherapy with mannitol 20% and sorbitol 40% increased the serum concentration of lactate but not pyruvate, causing an increased ratio of lactate to pyruvate (22c ). Sorbitol had the greater effect, with a maximum at 1 hour. Mannitol had its maximum effect at 4 hours. The author concluded that acidosis, shock, diabetes mellitus, and hepatic dysfunctions increase the risk of osmotherapy, especially with sorbitol. Randomized trials of mannitol in patients with acute traumatic brain injury of any severity have been reviewed (23M ). In the preoperative management of patients with acute intracranial hemorrhage high-dose mannitol reduced mortality (RR = 0.55; 95% CI = 0.36, 0.84) and reduced death and severe disability (RR = 0.58; 95% CI = 0.45, 0.74) compared with conventional-dose mannitol. In one trial treatment intended to lower intracranial pressure was compared with “standard care” (RR for death = 0.83; 95% CI = 0.47, 1.46). In one trial mannitol and pentobarbital were compared (RR for death = 0.85; 95% CI = 0.52, 1.38). In one trial pre-hospital mannitol was compared with placebo (RR for death = 1.75; 95% CI = 0.48, 6.38). The reviewers concluded that high-dose mannitol is preferable to conventional-dose mannitol in the pre-operative management of patients with acute intracranial hematomas. However, there is little evidence about the use of mannitol as a continuous infusion in patients with raised intracranial pressure who do not have an operable intracranial hematoma. In 20 patients with head trauma and persistent coma who required infusions of an osmotic agent to treat episodes of intracranial hypertension resistant to standard modes of therapy, isovolumic infusions of either 7.5% hypertonic saline reduced the number of episodes of intracranial hypertension per day (6.9 versus 13.3) and the daily duration of episodes of intracranial hypertension (67 versus 131 minutes) compared with 20% mannitol (24C ). Stroke In 805 patients who were given intravenous mannitol (mean dose, 47 g/day; mean duration, 6 days) or no treatment within 72

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hours of the onset of a stroke, the case fatality was 25% versus 16% at 30 days and 38% versus 25% at 1 year (25c ). The prognostic scores on the Scandinavian Neurological Stroke Scale were similar in treated and untreated patients, both in ischemic and hemorrhagic strokes. However, the patient groups differed in several factors that might have affected survival. Thus, this uncontrolled study was inconclusive. Serum and cerebrospinal fluid osmolarity were measured in 30 patients with severe head injuries or subarachnoid hemorrhage, 10 of whom received mannitol for at least 72 hours, 10 of whom received it for 24–48 hours, and 10 of whom were controls (26c ). Serum osmolarity increased quickly in all those who received mannitol and was unchanged in controls. Average cerebrospinal fluid osmolarity increased slowly in all those who received mannitol and was unchanged in controls. This is a potentially dangerous effect and the authors recommended that cerebrospinal fluid osmolarity should be measured regularly in all patients who receive mannitol for longer than 24 hours. Disrupting the blood–brain barrier Mannitol has been used to disrupt the blood–brain barrier temporarily in order to allow better penetration of chemotherapeutic drugs. In eight patients with gliomas and one with a primary lymphoma of the central nervous system the blood–brain or blood–tumor barrier was reversibly opened by intra-arterial injection of hyperosmolar mannitol 25% (27c ). There was tumor regression or a tumor progression-free interval in five patients. In 10 patients with malignant gliomas intraarterial chemotherapy with 5-fluorouracil, nitrosourea, or interferon beta was given after osmotic blood-brain barrier disruption with intraarterial 20% mannitol (28c ). In nine evaluable cases there were one complete and three partial responses; in five there was no change and no progressive disease on CT. The most untoward effect was myelosuppression: platelet and leukocyte counts fell below 20 × 109 /l and 2 × 109 /l respectively in three patients, of whom two died of severe infections. The other complications were eye pain during mannitol infusion in all cases in which selective catheterization of the internal carotid artery failed to pass the origin of the ophthalmic artery. There was reduced activity in 70%, nausea and vomiting

237 in 50%, swelling of the external decompression area in 33%, and increased neurological deficits in 20%. However, all these adverse effects were transient. Of 21 patients with malignant brain tumors, 16 were treated by operation, irradiation, and two or more courses of intracarotid infusion of nitrosourea 100 mg after 20% mannitol 200 ml, and five were treated similarly but without mannitol (29c ). The 2-year survival rate in those who received mannitol was 79% (11 of 14 cases followed for longer than 2 years) and the 3-year survival rate was 67%. Five of seven patients with grade 4 astrocytomas survived for more than 18 months, whereas four of five patients with grade 4 astrocytomas who did not receive mannitol died within 18 months. Over 4 years, 37 patients with high-grade malignant gliomas underwent 246 treatment procedures with a combination of methotrexate, cyclophosphamide, and procarbazine given together with hyperosmolar mannitol-induced transient breakdown of the blood–brain barrier (30c ). There were complete remissions in 16% and 24 patients (65%) had partial or temporary remissions. Progression-free intervals were 1– 47 (mean 15) months and median survival was 22 months. Neurotoxicity was minimal with one periprocedural death and five instances of worsened neurological deficits after a procedure. The delivery of chemotherapeutic agents in the treatment of malignant brain tumors is improved by osmotic opening of the blood– brain barrier by prior infusion of mannitol into the internal carotid or vertebral artery. Over 4200 blood-brain barrier disruption procedures have been performed in over 400 patients with primary central nervous system lymphomas, gliomas, primitive neuroectodermal tumors, germ cell and metastatic cancers in the National Blood–Brain Barrier Program (31C ). In patients with primary nervous system lymphomas, long-lasting responses have been obtained without loss of cognitive function and without the use of radiotherapy. The results in patients with primitive neuroectodermal tumors and germ cell tumors are also said to be very encouraging. The efficacy of mannitol in augmenting the tumoricidal effect of etoposide has been studied in 99 children aged 1–21 years with recurrent brain tumors (32C ). They were randomly

238 assigned to intravenous etoposide 150 mg/m2 with or without mannitol 15 g/m2 , daily for 5 days every 3 weeks for 1 year or until disease progression or death. CT or MRI scans, obtained after three cycles of therapy, were compared with pre-therapy scans. Of 87 evaluable patients, 12 had an objective response according to the radiologist and of 66 patients reviewed centrally, seven responded (two of 12 low grade astrocytomas, four of 26 medulloblastomas or primitive neuroectodermal tumors, one of 13 high-grade astrocytomas, and one of 15 brain stem gliomas). Survival at 1 year was 53% for low grade astrocytomas, 38% for medulloblastomas or primitive neuroectodermal tumors, 28% for high-grade astrocytomas and 9% for brain stem gliomas. Mannitol had no beneficial effect. Use in bowel cleansing Mannitol has been used for preoperative bowel cleansing before radiological investigations (33c ), diagnostic and operative endoscopy (34c ), and bowel surgery. In whole gut irrigation mannitol is badly tolerated and leaves a bowel full of gas and fluid although it causes only small changes in serum electrolytes (35R ). In a study of the effect of an intravenous infusion of saline on the volume of rectal effluent and quality of bowel preparation produced by a smaller oral dose of mannitol, 19 patients drank 2–3 l of 5% mannitol, supplemented by an intravenous infusion of isotonic saline and 19 patients drank 4–5 l of 5% mannitol (36c ). The volume of rectal effluent and the quality of bowel preparation was the same in both groups. Loss of sodium in the oral group was corrected by the intravenous infusion, but the infusion resulted in greater water retention. There was no difference in the incidence of vomiting between the two groups. Polyethylene glycol electrolyte lavage solution has been compared with 10% mannitol for preoperative colonic cleansing in 80 patients (37c ). Colonic cleansing was better with polyethylene glycol (90% optimal cleansing versus 75%). Mannitol caused subclinical dehydration according to hematological, biochemical, and weight changes before and after bowel preparation and caused more nausea, cramps, and abdominal pain. Two patients given mannitol had combustible amounts of hydrogen gas in the colon.

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Three formulations, two based on magnesium citrate and one an optimized oral mannitol regimen, have been compared for their effectiveness in clearing the large bowel before double-contrast barium enema and for effects on barium mucosal coating (38c ). The formulations based on magnesium citrate were equally good and caused significantly less nausea and vomiting than mannitol. The authors concluded that mannitol should not be used for preparing the bowel for barium enema. Two hypotonic non-hemolysing irrigating solutions, sorbitol + mannitol (2% + 1%) and glycine (1.5%), have been compared in patients undergoing transurethral resection of the prostate (39c ). Ethanol (1%) was added to the irrigating fluid as a marker to allow early detection of fluid absorption by breath analysis. There was very little absorption (less than 1 l). However, in other cases large volumes of fluid have been absorbed. In 39 patients having transurethral resection of the prostate for benign prostatic hyperplasia, large quantities of mannitol, which was used as the irrigating fluid, entered the circulation (40c ). There was a corresponding fall in serum sodium concentration. Patients who had serum mannitol concentrations over 4 mg/ml had hypotension and bradycardia; because they were nearly all hypovolemic, the bradycardia was thought to be inappropriate. Irrigating fluid bags containing mannitol 3% or glycine 1.5%, both with added ethanol 1% as an indicator of fluid absorption, were used to investigate adverse effects in a randomized, double-blind study during 394 transurethral prostatic resections (41C ). The incidence of 13 symptoms was studied in 52 patients (13%) who absorbed more than 500 ml of fluid. The incidence of circulatory symptoms did not differ between the fluids, but the risk of neurological symptoms, such as nausea, was 4.8 times higher with glycine 1.5%. An increase of 1000 ml in the volume of irrigant absorbed increased the overall risk of circulatory symptoms by a factor of 3.4 and the risk of neurological symptoms by a factor of 4.4. The authors concluded that absorption of mannitol 3% during transurethral prostatic resection is associated with fewer neurological symptoms than glycine 1.5%. In 80 patients randomized for precolonoscopic cleansing with either 10% mannitol 750

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ml or sodium phosphate 180 ml there were statistically significant differences in serum sodium, phosphorus, potassium, and calcium between the two groups, but no clinical symptoms and no significant differences in the frequencies of adverse effects (42C ). Six of eight patients who were treated with sodium phosphate and who had mannitol for a previous colonoscopy preferred sodium phosphate. The endoscopists, who were blinded to the treatment, reported excellent or good bowel preparation in 85% of those prepared with sodium phosphate versus 83% for mannitol. The authors concluded that although the quality of preparation and the frequencies of adverse effects were similar with the two solutions, retention of sodium and phosphate ions contraindicates the use of sodium phosphate in patients with renal insufficiency, cirrhosis, ascites, and heart failure. In a retrospective study of patients who underwent elective surgery for colorectal carcinomas, traditional bowel preparation was performed the day before the operation either with oral castor oil 30 ml and three soap enemas (n = 154) or with mannitol 500 ml (n = 36) (43c ). There were infectious wound complications in 26 patients (17%) pretreated with castor oil compared with 13 patients (36%) treated with mannitol. There were no differences in the incidence of anastomotic leaks or mortality rate. Systemic antimicrobial prophylaxis with metronidazole and gentamicin has been compared with metronidazole alone in elective colorectal surgery in a prospective randomized trial, in which all the patients received 10% mannitol solution before surgery (44C ). Although there were no serious infections in either group, the incidence of superficial wound infections was relatively high: 19% in those given metronidazole and gentamicin prophylaxis and 25% in those given metronidazole alone. Escherichia coli was isolated from all these wounds, and no obligate anerobic bacteria were cultured. The high rate of wound infection was probably caused by overgrowth after irrigation, due to residues of mannitol in the colon, which serve as a nutrient for Escherichia coli. Both sets of authors concluded that mannitol should not be used for preoperative mechanical preparation of the large bowel before elective colorectal surgery.

239 Hydrogen gas can accumulate in the colon after the administration of mannitol (37c ). This can cause a risk of explosion. • Colonic explosion during colonoscopic polypectomy occurred after mannitol had been used for bowel preparation and the colon was completely clean (45A ). In spite of emergency surgery, with transfusion of 45 units of blood, uncontrollable hemorrhage persisted from multiple bleeding points and the patient died.

Use as a radiocontrast medium In 56 patients undergoing abdominal CT the gastrointestinal tract was defined by negative contrast with 2.5% mannitol instead of the conventional positive contrast from an iodine-containing contrast medium (46c ). The number of artifacts due to high-contrast boundaries was slightly greater with negative contrast than it would have been with positive contrast, but differentiation of the gastrointestinal tract from other abdominal organs was equally good. Negative contrast was poor for diagnosing cystic tumors but much better than positive contrast for evaluating the wall of the gastrointestinal tract. The effect of oral mannitol in an aqueous solution in enhancing pelvic MRI has been reported in a retrospective study in 72 patients with suspected or proven pelvic abnormalities: In 36 patients bowel marking was not carried out and in 36 patients the bowel was contrast-enhanced by oral mannitol 1000 ml (47c ). Mannitol significantly improved delineation of the intestinal structures and pelvic organs or pathological lesions, but eight patients had diarrhea, nausea, or meteorism. Diagnosis of diarrhea In chronic diarrhea intestinal permeability to sugars, such as raffinose, lactose, lactulose, sucrose and mannitol (48c ), can detect intestinal damage. The absorption of a combined dose of lactulose and mannitol has been studied in 261 consecutive patients with three or more bowel movements daily for at least 3 weeks; 120 (46%) were found to have an organic cause for chronic diarrhea, whereas in 141 (54%) a functional condition was diagnosed (49c ). The lactulose/mannitol test and C-reactive protein were independent predictors for the final diagnosis of an organic cause of chronic diarrhea, with odds ratios of 1.5 (95% CI = 1.29, 1.78) and 5.2 (95% CI = 1.90, 14.12) respectively.

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Cardiopulmonary bypass The effects of mannitol and dopamine, alone and in combination, on beta2 -microglobulin excretion rates in 100 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass have been studied in a double-blind, randomized, placebo-controlled study (50C ). Mannitol 1 g/kg was added to the cardiopulmonary bypass prime and dopamine 2 micrograms/kg/minute was given from the time of induction of anesthesia to 1 hour after bypass. Dopamine significantly increased the excretion rate of beta2 -microglobulin compared with placebo. Thus, rather than being protective during cardiopulmonary bypass, dopamine reduces renal tubular dysfunction. This effect was not ameliorated by the addition of mannitol.

fluids containing ethanol and all of them caused slight hypoglycemia. There was no evidence of ethanol-induced tachycardia.

Treatment of cisplatin nephrotoxicity Saline alone, saline + furosemide, and saline + mannitol have been used to prevent nephrotoxicity in 49 women who received cisplatin 75 mg/m2 every 3 weeks (51C ). Hydration with saline or saline + furosemide was associated with less cisplatin nephrotoxicity than hydration with saline + mannitol.

Sensory systems The effects of intravenous mannitol on aqueous fluid protein concentration have been evaluated in healthy young adults (average age 20 years) and older adults (average age 61 years), and in patients with diabetes mellitus, hypertension, or pseudoexfoliation syndrome who were about to undergo intraocular surgery (average age 66 years) (58c ). Mannitol increased aqueous humor protein concentration in all subjects, with a maximum effects at around 1 hour. The magnitude and the duration of the effect were significantly greater in the healthy older subjects than in the young subjects, but the same in older adults with and without diseases. The effect was reversed within 6 hours.

Equiosmolar loads of mannitol 20% and hypertonic saline 7.5% over 10 minutes have been compared with isotonic saline in 30 ASA I and II patients undergoing non-hemorrhagic surgery under general anesthesia (52c ). The serum sodium concentration was lowest after mannitol (129 mmol/l) at the end of the infusion and highest after hypertonic saline (151 mmol/l), with normalization at 60 minutes. The hemodynamic effects were similar in the three groups. Temperature was lower after isotonic saline, because of the volume infused. Cardiovascular Glycine (1% or 1.5%) 15 ml/kg, or 3% mannitol (all containing 1% ethanol), or sorbitol 2% + mannitol 1% (with no ethanol) were infused intravenously over 20 minutes into 10 healthy men to determine their hemodynamic effects using Doppler ultrasonography (53c ). All reduced cardiac output 30 minutes after infusion, and glycine reduced the heart rate and cardiac output and raised mean arterial pressure, indicating an increase in systemic resistance. Almost identical breathethanol curves were obtained with the three

Respiratory Inhaled mannitol increases airway responsiveness in asthmatic subjects (54c ) and may act through mast cell activation (55c ). It has been used to investigate the effects of therapeutic drugs or to predict responsiveness to their effects and to determine susceptibility to exercise-induced bronchoconstriction (56c ). In 18 asthmatic subjects the inhaled glucocorticoid budesonide caused a reduction in airway sensitivity and reactivity to inhaled mannitol and this was associated with expected improvements in lung function and symptoms (57c ).

Urinary tract Four cases of acute renal insufficiency have been described in a series of men aged 20–42 years who received mannitol 1172 (SD 439) g over 58 (28) hours (59A ). The onset of acute renal insufficiency was detected 48 (22) hours after the start of infusion. All the patients had dilutional hyponatremia (average 120 mmol/l), and serum hyperosmolality (osmolar gap 70 mosm/kg water). In the three patients with anuria, in whom hemodialysis was performed, there was immediate recovery of diuresis. This emphasizes the risk of renal insufficiency with mannitol and stresses the importance of early hemodialysis. Mannitol is dialysable, and functional recovery is prompt once its suppressive effect on renal perfusion is eliminated.

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Musculoskeletal Mannitol can cause a compartment syndrome if it extravasates into soft tissues (60A , 61A ). • A 17-year-old woman was treated for carbosulfan poisoning with atropine, isotonic saline, and intra-

241 venous mannitol (20%) (60A ). Her right forearm became edematous, cyanotic, and tender at the site of the mannitol infusion and compartment pressures were raised. A fasciotomy was required and recovery occurred over several days.

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of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. New Engl J Med 2003; 349: 1628–35. 13. Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc 2004; 52: 794–8. 14. Levy DG, Rocha R, Funder JW. Distinguishing the antihypertensive and electrolyte effects of eplerenone. J Clin Endocrinol Metab 2004; 89: 2736–40. 15. Witham MD, Gillespie ND, Struthers AD. Tolerability of spironolactone in patients with chronic heart failure – a cautionary message. Br J Clin Pharmacol 2004; 58: 554–7. 16. Ghislain PD, Bodarwe AD, Vanderdonckt O, Tennstedt D, Marot L, Lachapelle JM. Druginduced eosinophilia and multisystem failure with positive patch-test reaction to spironolactone: DRESS syndrome. Acta Dermatol Venereol 2004; 84: 65–8. 17. Paczynski R-P, Osmotherapy. Basic concepts and controversies. Crit Care Clin 1997; 13: 105–29. 18. Better O-S, Rubinstein, I, Winaver J-M, Knochel J-P. Mannitol therapy revisited (1940– 1997). Kidney Int 1997; 52: 886–94. 19. Hansen P-H, Rosenorn J, Westergaard L. Mannitolbehandling ved forhojet intrakranielt tryk. Ugeskr Laeger 1983; 145: 1125–7. 20. Node Y, Nakazawa S. Clinical study of mannitol and glycerol on raised intracranial pressure and on their rebound phenomenon. Adv Neurol 1990; 52: 359–63. 21. Sanchez R, Brindis LC, Fierro H, Strecker C, Munoz O. Uso de manitol y dexametasona en el manejo del edema cerebral agudo de origen infeccioso. Bol Med Hosp Infant Mex 1977; 34: 283–90. 22. Spring A. Veranderungen des Laktat-PyruvatSpiegels im Blut auf eine Osmotherapie mit Mannit und Sorbit. Neurochirurgia (Stuttg) 1980; 23: 176– 81. 23. Roberts I, Schierhout G, Wakai A. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 2003; 2: CD001049. 24. Vialet R, Albanese J, Thomachot L, Antonini F, Bourgouin A, Alliez B, Martin C. Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 ml/kg 7.5% saline is more effective than 2 ml/kg 20% mannitol. Crit Care Med 2003; 31: 1683–7.

242 25. Bereczki D, Mihalka L, Szatmari S, Fekete K, Di Cesar D, Fulesdi B, Csiba L, Fekete I. Mannitol use in acute stroke: case fatality at 30 days and 1 year. Stroke 2003; 34: 1730–5. 26. Polderman KH, van de Kraats G, Dixon JM, Vandertop WP, Girbes AR. Increases in spinal fluid osmolarity induced by mannitol. Crit Care Med 2003; 31: 584–90. 27. Heimberger K, Samec P, Binder H, Podreka I, Reisner T, Deecke L, Horaczek A, Dittrich C, Steger G, Zimpfer M, et al. Blood brain barrier modification and chemotherapy. Interventional neuroradiology in the treatment of malignant gliomas. Acta Radiol Suppl 1986; 369: 223–6. 28. Yamada K, Takahama H, Nakai O, Takanashi T, Hosoya T. Intra-arterial chemotherapy of malignant glioma after osmotic blood-brain barrier disruption [in Japanese]. Gan To Kagaku Ryoho 1989; 16: 2692–6. 29. Miyagami M, Tsubokawa T, Tazoe M, Kagawa Y. Intra-arterial ACNU chemotherapy employing 20% mannitol osmotic blood–brain barrier disruption for malignant brain tumors. Neurol Med Chir (Tokyo) 1990; 30: 582–90. 30. Gumerlock MK, Belshe BD, Madsen R, Watts C. Osmotic blood–brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: patient series and literature review. J Neurooncol 1992; 12: 33–46. 31. Doolittle ND, Petrillo A, Bell S, Cummings P, Eriksen S. Blood–brain barrier disruption for the treatment of malignant brain tumors: The National Program. J Neurosci Nurs 1998; 30: 81–90. 32. Kobrinsky NL, Packer RJ, Boyett JM, Stanley P, Shiminski-Maher T, Allen JC, Garvin JH, Stewart DJ, Finlay JL. Etoposide with or without mannitol for the treatment of recurrent or primarily unresponsive brain tumors: a Children’s Cancer Group Study. J Neurooncol. 1999; 45: 47–54. 33. Lou-Moller P, Olsen L, Schierbeck J, Hansen H, Christau B, Bonnevie O. Bisakodyl (Toilax) og peroral mannitol som udrensningsmidler for rontgenundersogelse af colon. Ugeskr Laeger 1983; 145: 3093–6. 34. Noya G, Dettori G, Muscas AG, Delogu L, Antona C, Marongiu G, Frassetto A, Biglioli P. Il mannitolo nella preparazione del colon alla endoscopia diagnostica ed operativa. Minerva Dietol Gastroenterol 1984; 30: 397–9. 35. Kujat R, Pichlmayr R. Nebenwirkungen verschiedener Spullosungen bei der orthograden Darmspulung. Chirurg Z Geb Operat Med 1983; 54: 669–72. 36. Hares MM, Nevah E, Minervini S, Bentley S, Keighley M, Alexander-Williams J. An attempt to reduce the side effects of mannitol bowel preparation by intravenous infusion. Dis Colon Rectum 1982; 25: 289–91. 37. Beck DE, Fazio VW, Jagelman DG. Comparison of oral lavage methods for preoperative colonic cleansing. Dis Colon Rectum 1986; 29: 699–703. 38. Foord KD, Morcos SK, Ward P. A comparison of mannitol and magnesium citrate preparations for double-contrast barium enema. Clin Radiol 1983; 34: 309–12.

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Domenic A. Sica

39. Dimberg M, Norlen H, Allgen LG, Allgen T, Wallin M. A comparison between two hypotonic irrigating solutions used in transurethral resections of the prostate: sorbitol (2%)–mannitol (1%) and 1.5% glycine solutions. Scand J Urol Nephrol 1992; 26: 241–7. 40. Logie JR, Keenan RA, Whiting PH, Steyn JH. Fluid absorption during transurethral prostatectomy. Br J Urol 1980; 52: 526–8. 41. Hahn RG, Sandfeldt L, Nyman CR. Doubleblind randomized study of symptoms associated with absorption of glycine 1.5% or mannitol 3% during transurethral resection of the prostate. J Urol 1998; 160: 397–401. 42. Habr-Gama A, Bringel RW, Nahas SC, Araujo SE, Souza-Junior AH, Calache JE, Alves PA. Bowel preparation for colonoscopy: comparison of mannitol and sodium phosphate. Results of a prospective randomized study. Rev Hosp Clin Fac Med Sao Paulo 1999; 54: 187–92. 43. Todorov AT, Mantchev ID, Atanasov TB. Traditional bowel preparation versus osmotic agent mannitol for preoperative colonic cleansing in elective colorectal surgery. Folia Med (Plovdiv) 2002; 44: 36–9. 44. Weidema WF, Van den Boogaard AE, Wesdorp RI, Van Boven CP, Greep JM. 24-hour systemic antimicrobial prophylaxis with gentamicin and metronidazole, or metronidazole alone, in elective colorectal surgery after mechanical bowel preparation with mannitol and whole gut irrigation. Acta Chir Belg 1985; 85: 349–53. 45. Bigard M-A, Gaucher P, Lassalle C. Fatal colonic explosion during colonoscopic polypectomy. Gastroenterology 1979; 77: 1307–10. 46. Schunk K, Wiessner J, Schadmand S, Kaltenborn H, Duber C, Brunier A. Zur Frage der Darmkontrastierung in der abdominellen Computertomographie. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1992; 156: 443–7. 47. Schunk K, Kersjes W, Schadmand-Fischer S, Grebe P, Kauczor HU, Thelen M. Eine Mannitollosung als orales Kontrastmittel in der pelvinen MRT. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1995; 163: 60–6. 48. Hessels J, Eidhof HH, Steggink J, Roeloffzen WW, Wu K, Tan G, Van de Stadt J, Van Bergeijk L. Assessment of hypolactasia and site-specific intestinal permeability by differential sugar absorption of raffinose, lactose, sucrose and mannitol. Clin Chem Lab Med 2003; 41: 1056–63. 49. Di Leo V, D’Inca R, Diaz-Granado N, Fries W, Venturi C, D’Odorico A, Martines D, Sturniolo GC. Lactulose/mannitol test has high efficacy for excluding organic causes of chronic diarrhea. Am J Gastroenterol 2003; 98: 2245–52. 50. Carcoana OV, Mathew JP, Davis E, Byrne DW, Hayslett JP, Hines RL, Garwood S. Mannitol and dopamine in patients undergoing cardiopulmonary bypass: a randomized clinical trial. Anesth Analg 2003; 97: 1222–9. 51. Santoso JT, Lucci 3rd JA, Coleman RL, Schafer I, Hannigan EV. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a ran-

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domized trial.Cancer Chemother Pharmacol 2003; 52: 13–18. 52. Erard AC, Walder B, Ravussin P. Effêts de charges equiosmolaires de mannitol 20%, de NaCl 7.5% et de NaCl 0.9% sur l’osmolarité, l’hémodynamique et les electrolytes plasmatiques. Ann Fr Anesth Réanim 2003; 22: 18–24. 53. Nilsson A, Randmaa I, Hahn RG. Haemodynamic effects of irrigating fluids studied by Doppler ultrasonography in volunteers. Br J Urol 1996; 77: 541–6. 54. Barben J, Roberts M, Chew N, Carlin JB, Robertson CF. Repeatability of bronchial responsiveness to mannitol dry powder in children with asthma. Pediatr Pulmonol 2003; 36: 490–4. 55. Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M. Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J 2003; 22: 491–6. 56. Holzer K, Anderson SD, Chan HK, Douglass J. Mannitol as a challenge test to identify exerciseinduced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003; 167: 534–7.

243 57. Brannan JD, Koskela H, Anderson SD, Chan HK. Budesonide reduces sensitivity and reactivity to inhaled mannitol in asthmatic subjects. Respirology 2002; 7: 37–44. 58. Miyake Y, Miyake K, Maekubo K, Kayazawa F. Increase in aqueous flare by a therapeutic dose of mannitol in humans [in Japanese]. Nippon Ganka Gakkai Zasshi 1989; 93: 1149–53. 59. Perez-Perez AJ, Pazos B, Sobrado J, Gonzalez L, Gandara A. Acute renal failure following massive mannitol infusion. Am J Nephrol 2002; 22: 573–5. 60. Eroghu A, Uzunlar H. Forearm compartment syndrome after intravenous mannitol extravasation in a carbosulfan poisoning patient. J Toxicol Clin Toxicol 2004; 42: 649–652. 61. Edwards JJ, Samuels D, Fu ES. Forearm compartment syndrome from intravenous mannitol extravasation during general anesthesia. Anesth Analg 2003; 96: 245–6.

Gijsbert B. van der Voet, and Frederik A. de Wolff

22 Aluminium

(SED-14, 683; SEDA-25, 257; SEDA-26, 243; SEDA-27, 224)

Occupational aluminium exposure and aluminium poisoning occurs in aluminium mineral mining, aluminium materials production, and aluminium utilization. Occupational exposure to aluminium is one of the surest ways of ingesting increased amounts of aluminium. Since aluminium is not an essential element for mammals, there is no risk of aluminium deficiency. At the same time, it is important to detect subclinical increases in intake among those who are occupationally exposed and others at risk of high-level exposure. The potential risks of aluminium in overthe-counter drugs (1R ) and phosphate binders (2R ) have been highlighted as has the risk of hepatic accumulation and damage from aluminium loading in premature and ill infants on parenteral nutrition (3R ). Nervous system There were adverse effects on neurobehavioral parameters, especially movement coordination and negative mood, reduced autonomic function, and increased CD4–CD8+ T lymphocyte subsets in 33 men (mean age 35 years) occupationally exposed to aluminium for a mean of 15 years, compared with workers from a flour factory matched for age, sex, family income, and educational level and with comparable drinking and smoking habits (4c ). Those with nervous system diseases, such as epilepsy and brain trauma, heart disease, diabetes, and hypertension were excluded, as were those who drank alcohol at least 500 ml of ethanol per week and/or smoked at least 40 cigarettes per day. Immunologic Aluminium has been associated with macrophagic myofasciitis, which is © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

244

Metals related to adjuvants containing aluminium hydroxide in vaccines and causes diffuse myalgia, chronic fatigue, and signs of immune disease developing from the site of vaccination (5R , 6R ). • A 67-year-old man developed macrophagic myofasciitis with a 6-week history of slowly progressive muscle pain and generalized muscle weakness (7A ). Neurological examination showed symmetrical proximal weakness (MRC grade 4/5). The creatine kinase activity was slightly raised at 124 U/l (reference range below 80). Needle electromyography showed pathological spontaneous activity in proximal muscle groups. A muscle biopsy taken from the left deltoid muscle showed a characteristic infiltrate of PAS-positive and acid phosphatase positive macrophages. Electron microscopy of muscle tissue did not show aluminium hydroxide inclusion. Serological analysis excluded antibodies against hepatitis A and B, but was compatible with previous tetanus vaccination. Treatment with glucocorticoids and azathioprine for 2 years led to complete recovery of muscle strength without subsequent relapse.

Antimony (SED-14, 683; SEDA-25, 258; SEDA-26, 244; SEDA-27, 224) Antimonials, especially pentavalent compounds, form the classic treatment of cutaneous, mucosal and visceral leishmaniasis (8R ). The disadvantages of the antimonials are the need for daily intramuscular or intravenous injection for 20–28 days, toxicity, and the development of resistance (9R ). Cardiovascular Cardiotoxicity of pentavalent antimonials is not new but continues to be reported (10C ). In April and May 2000, an outbreak of fatal cardiotoxicity occurred in Nepal amongst patients with visceral leishmaniasis who were treated with a recently introduced batch of generic sodium stibogluconate. Eight of 23 patients died and in five cases death was attributed to cardiotoxicity. This contrasted with

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the low total death rate (3.2%) and death rate due to cardiotoxicity (0.8%) observed among 252 patients treated between August 1999 and December 2001 with generic sodium stibogluconate from another company. • A 22-year-old man presented with an ulcer in the left leg diagnosed as cutaneous leishmaniasis and was treated with sodium stibogluconate (Shandong Xinhua) equivalent to a dose of antimony of 10 mg/kg/day for 20 days (11A ). After dose 3 he developed arthralgia, myalgia, nausea, and weakness. During continued therapy his symptoms worsened, with abdominal pain and irradiation into the thorax. After dose 7 he developed mild dyspnea and thoracic pain. After dose 9 there was further deterioration, but therapy was continued up to dose 11, when he deteriorated to such an extent that he was hospitalized in the intensive care unit. He died from cardiorespiratory insufficiency.

Pregnancy Premature birth has been associated with antimony (12A ). • A 19-year-old pregnant woman with visceral leishmaniasis was treated from 24 weeks with meglumine antimoniate 850 mg/day for 20 days. Premature birth occurred on day 5 and the neonate died 1 day after birth.

Arsenic (SED-14, 686; SEDA-25, 258; SEDA-26, 244; SEDA-27, 225) Inorganic arsenic (trioxide) continues to be used in the treatment of acute promyelocytic leukemia and its use is being extended to other malignancies, such as multiple myeloma (13R , 14R ). Arsenic is also still used in endodontics, although it can cause severe damage to periodontal tissue (15R ). Arsenic in homeopathic medicines can cause toxicity if improperly used (16R ).

Bismuth (SED-14, 686; SEDA-25, 259; SEDA-26, 244; SEDA-27, 225) Bismuth compounds are still used for a number of gastrointestinal disorders. Bismuth subcitrate is part of the treatment protocol to eradicate Helicobacter pylori. Bismuth subsalicylate is used in the treatment of microscopic colitis (17R ).

Calcium salts

(SED-14, 1706)

The use of nutritional supplements in the general population and in cancer patients has become very popular. These supplements are not perceived as medications and are presumed to be safe by patients with cancer, who may however be at risk of hypercalcemia, which accounts for about 30% of all cases of hypercalcemia (18R ) and which can occur with or without bone metastases. To improve their nutritional status, patients with cancer who are losing weight may supplement their diet with multivitamins and other nutritional supplements. Shark cartilage capsules, which have high calcium content and are sold over the counter in health food stores, are popular in the USA and can be associated with symptomatic hypercalcemia (19c ). • A 64-year-old woman with metastatic colon cancer developed acute mental changes because of hypercalcemia. Serum calcium has been normal 3 weeks before. She had taken a daily multivitamin formulation containing calcium 200 mg and vitamin D 400 IU. She was also taking shark cartilage, which yielded an additional daily dose of calcium of 900 mg. • A 67-year-old man with malignant mesothelioma developed acute onset of shortness of breath. His corrected serum calcium concentration was 2.9 mmol/l. He was taking mineral supplements obtained from a health food store and containing both calcium and vitamin D (dose and frequency unknown). His respiratory status worsened and he died. • A 72-year-old man with stage IV non-Hodgkin’s lymphoma, had three episodes of hypercalcemia. He was taking daily multivitamins containing calcium 162 mg and vitamin D 400 IU. His corrected serum calcium concentration was 2.9 mmol/l. On a fourth occasion his corrected serum calcium was 3.1 mmol/l and he had been taking a different brand of multivitamins containing calcium 450 mg and vitamin D 400 IU. • A 78-year-old woman with metastatic breast cancer and multiple osteolytic bone metastases developed nausea, vomiting, weakness, and constipation. Her corrected serum calcium concentration was 3.4 mmol/l. She was taking a daily generic multivitamin formulation containing vitamin D 400 IU and calcium 600 mg and supplementing her diet by consuming significant amounts of various daily products.

In conclusion, hypercalcemic patients may be taking vitamin and mineral supplements without their physicians’ knowledge. These supplements may contain compounds that influence the natural history, frequency, or severity

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of hypercalcemia. Careful review of each patient’s medication list should include specific questions regarding such formulations. While supplementing a cancer patient’s diet with vitamin D and calcium alone may not cause hypercalcemia, it is prudent to withdrawn such agents in those who have documented hypercalcemia or are deemed to be at high risk.

Chromium

(SED-14, 683; SEDA-25, 259; SEDA-26, 245; SEDA-27, 226) Chromium (picolinate) continues to be used as a nutritional supplement, to treat weight loss, and to aid muscle development (20R ). It can generate oxidative damage, although the significance of this in humans is unclear. Its potential neurological effects require further study. The role of chromium as adjunctive and safe treatment for type 2 diabetes has been reviewed (21R ).

Gijsbert B. van der Voet and Frederik A. de Wolff

Gallium

(SED-14, 690; SEDA-25, 260; SEDA-26, 245; SEDA-27, 227)

The anticancer potential of gallium nitrate has been reviewed (24R ). Gallium-67 continues to be used in diagnostic medical imaging. The quality of gallium-based dental alloys should be improved (25c ). In 14 patients, all of whom had at least two molar teeth that required restoration, 32 gallium and 32 amalgam restorations were placed in molar teeth. In this way both restoratives were used in the same oral cavity. The restorations were examined at baseline, 6 months, 1, 2, and 3 years. At baseline, six teeth restored with gallium alloy showed postoperative sensitivity, whereas none of those restored with amalgam were sensitive. After 3 years, only a few amalgam restorations showed slight surface tarnish and marginal loss of integrity. None needed replacement. Of the 32 gallium restorations, five had to be removed because of sensitivity, corrosion, and tooth fractures. There was dramatic surface roughness and corrosion in 12 gallium restorations. These results suggest that galliumbased restoratives should not be used before their physical properties are improved.

Copper

(SED-14, 688; SEDA-25, 259; SEDA-26, 245; SEDA-27, 226) Copper metabolism and the role of copper in medicine has been reviewed (22R ). Coppercontaining intrauterine devices are still used as contraceptives (IUCDs) and do not guarantee risk-free use. Gastrointestinal Migration of an IUCD can cause bowel perforation. • A 40-year-old woman who had an IUCD (copper T) inserted 1 month after delivery presented 7 months later with secondary amenorrhea and transient pelvic cramps (23A ). She was 8 weeks pregnant and laboratory tests were normal. Transvaginal ultrasonography showed that the IUCD was located outside the uterus, near the sigmoid colon, as if it were attached to the bowel. The pregnancy was terminated and a diagnostic laparoscopy showed bowel perforation owing to the migration of the IUCD, which was partially embedded in the sigmoid colon and was removed via laparoscopy.

Gold (SED-14, 690; SEDA-25, 260; SEDA-26, 245; SEDA-27, 227) Respiratory Fatal interstitial pneumonitis has been attributed to gold (26A ). • A 65-year-old woman with seronegative rheumatoid arthritis was treated for 6 weeks with intramuscular sodium aurothiomalate 50 mg/week and prednisone 5 mg/day. Her joint symptoms improved but later she developed a skin rash, a dry cough, oppressive chest pain, dyspnea on exertion, weakness, and low-grade fever. An X-ray showed reduced lung volumes and a diffuse bilateral interstitial infiltrate, most marked in the lower zones. Infectious causes for the lung disorder were excluded; gold was withdrawn. She required progressively higher concentrations of oxygen to avoid hypoxemia. A chest CT scan showed a small left pleural effusion and multiple alveolar infiltrates and ground-glass opacities, which were most marked in the middle and lower zones of both lungs. Her condition deteriorated and she died of respiratory failure 18 days after admission.

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Hematologic Thrombocytopenia has been attributed to aurothioglucose (27A ). • A 51-year-old woman with rheumatoid arthritis was treated with intramuscular aurothioglucose 100 mg/week to a cumulative dose of 1000 mg then 50 mg aurothioglucose once every 2 weeks. When the cumulative dose was 1350 mg she developed petechiae and hematomas and the platelet count had fallen from 238 × 109 /l to 6 × 109 /l. • A 47-year-old woman with rheumatoid arthritis was given intramuscular aurothioglucose 50 mg weekly to a cumulative dose of 1000 mg and then 25 mg every third week. After a cumulative dose of 2700 mg she mentioned that hematomas had started to develop. Three days after the previous injection she had petechiae and hematomas and the platelet count had fallen from 280 × 109 /l to 18 × 109 /l.

Both patients made an uneventful recovery and the platelet count returned to normal within several weeks without further treatment. As a cause for the thrombocytopenia a rapid autoantibody induction was considered.

Iron

(SED-14, 697; SEDA-25, 260; SEDA-26, 247; SEDA-27, 227) Aspects of iron deficiency and iron overload have been reviewed (28R ). Oral iron is preferred to parenteral iron to treat iron deficiency. However, the major obstacle to successful oral therapy is nausea and epigastric discomfort, which occur 30–60 minutes after taking iron. The main indications for parenteral iron are uncontrolled blood loss, intolerance of oral iron, intestinal malabsorption, and poor adherence to an oral regimen. Immunologic The issue of the comparative safety of iron gluconate and iron dextran is still unresolved. Reactions to a total of 65 intravenous infusions of either iron dextran or iron gluconate in 35 patients over 3 years have been reviewed (29C ). All patients were directly observed for allergic reactions. The reactions were grouped into three categories: severe (anaphylactoid shock, cardiovascular collapse), moderate (dyspnea, urticaria, neck and back spasms), and mild (headache, dizziness, tachycardia, hypertension). Over the 3 years 22% of infusions provoked reactions to intravenous iron. In contrast to previous reports, acute allergic reactions

were as common with iron gluconate as with iron dextran. Of all these reactions only one was severe, four were moderate, and the rest were mild. These results challenge the common notion that iron gluconate, which requires eight infusions in place of the single infusion of iron dextran, is a safer alternative to iron dextran.

Lead

(SED-14, 701; SEDA-25, 261; SEDA-26, 248; SEDA-27, 228) The FDA has issued a warning to the public not to use “Litargirio” for any health-related or personal purposes, as the powder contains dangerous amounts of lead (up to 79%). This warning follows a health alert issued by the Rhode Island Department of Health after it was discovered that several children undergoing treatment for lead poisoning had been using Litargirio as a deodorant, and their blood lead concentrations only began to fall after they stopped using Litargirio (30S ). The FDA says that Litargirio powder is manufactured by Roldan, Ferreira, and possibly by other laboratories in the Dominican Republic and is used particularly by people from the Dominican Republic. The product has been used as a deodorant, foot fungicide, to heal burns and wounds, and for other purposes as a traditional remedy, despite having no proven health benefits. According to the FDA, the high concentration of lead in Litargirio poses health risks when it is used in contact with the skin or ingested, and this risk is particularly serious in children, in whom it can cause permanent neurological damage. The FDA has advised the public to stop using Litargirio immediately, to place any unused product in a sealable container or plastic bag and contact their local sanitation/waste department regarding disposal and to thoroughly wash hands and other body parts or household surfaces that have come into contact with the powder. They also recommend that children or pregnant/nursing women who have used Litargirio should be tested for lead poisoning.

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Magnesium Magnesium deficiency may play a role in the pathogenesis of variant angina or coronary spasm (31c ) and infusion of Mg can produce coronary dilatation and suppress acetylcholineinduced coronary spasm in patients with vasospastic angina (32c ). Neuromuscular Hypomagnesemia induces neuromuscular hyperexcitability while hypermagnesemia causes neuromuscular weakness as well as a reduction or even abolition of deep tendon reflexes (33R ). When experimental magnesium depletion is induced in human volunteers, the effects are anorexia, generalized weakness, positive Trousseau and Chvostek signs, hypokalemia, and hypocalcaemia (34R ). The main clinical effects of hypomagnesemia are general weakness, anorexia, apathy, tremor, tetany, cardiac dysrhythmias, hypertension, sudden death, and metabolic alkalosis (35R ).

Manganese

(SED-14, 702; SEDA-25, 261; SEDA-26, 248; SEDA-27, 229) Nervous system The neurotoxicity of manganese has been reviewed (36R ). Manganese-induced parkinsonism has been reported in a patient with hereditary hemorrhagic telangiectasia (37A ).

• A 44-year-old right-handed woman complained of difficulty in moving. She and her relatives had skin telangiectasia or recurrent epistaxis. She had a mask-like facies and bradykinesia, iron deficiency anemia, and mild liver dysfunction with raised serum manganese. On T1 weighted cranial MRI there were hyperintense areas in the globus pallidus bilaterally, suggesting manganese deposition. Abdominal angiography confirmed multiple portosystemic shunts in the liver, and a needle biopsy of the liver showed diffuse dilatation of the sinusoids with fatty change. Levodopa did not improve the bradykinesia.

This appears to have been a case of hereditary hemorrhagic telangiectasia with manganese-induced parkinsonism, which may be a new type of neurological disorder. The authors argued that chronic iron deficiency might have promoted the uptake of manganese into the brain.

Gijsbert B. van der Voet and Frederik A. de Wolff

Mercury

(SED-14, 702; SEDA-24, 260; SEDA-25, 262; SEDA-26, 248; SEDA-27, 229) Nervous system There is recent epidemiological evidence, based on tens of millions of doses of vaccine administered in the USA, that neurodevelopmental disorders are associated with increasing use of thiomersal in vaccines (38C ). Specifically, an analysis of the Vaccine Adverse Events Reporting System (VAERS) database showed significant increases in the incidence rate of autism (RR = 6.0), mental retardation (RR = 6.1), and speech disorders (RR = 2.2) after the use of thiomersal-containing diphtheria, tetanus, and acellular pertussis (DTaP) vaccines compared with thiomersal-free DTaP vaccines. Autism (male : female ratio = 17) and speech disorders (ratio = 2.3) were reported more in male recipients than female recipients, whereas mental retardation (ratio = 1.2) was more equally reported. Controls showed that there were no biases in the data. Overall, adverse reactions were reported in populations of similar ages after thiomersal-containing DTaP (mean age 2.4 years) and thiomersal-free DTaP (2.1 years). Acute control adverse reactions, such as deaths (RR = 1.0), vasculitis (RR = 1.2), seizures (RR = 1.6), hospital visits (RR = 1.4), total adverse reactions (RR = 1.4), and gastroenteritis (RR = 1.1), were reported similarly after thiomersal-containing and thiomersal-free DTaP. There was an association between neurodevelopmental disorders and thiomersal-containing DTaP, but additional studies should be conducted to confirm and extend this study.

Psychiatric International concern over an association between thiomersal in childhood vaccines and autism has not abated. Epidemiological studies have yet to provide an unequivocal answer. Two recent studies, a population-based cohort study from Denmark (39C ), and a twophase retrospective cohort study from the USA (40C ), have both suggested that there is no causal relation between autism and childhood vaccination with thiomersal-containing vaccines. A third epidemiological study using data from the US Vaccine Adverse Event Reporting System showed an association with increasing thiomersal from vaccines with neurodevelopmental disorders (38C ). Following calls from

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regulatory agencies for thiomersal to be withdrawn from vaccines, new childhood vaccines have been developed and in many countries are replacing those that contain thiomersal. Psychological The safety of mercury in vaccines (thiomersal = thimerosal) has been discussed in relation to the possibility of neurocognitive damage (41R ). • Previously well, developmentally normal 20month-old twin girls presented with weakness, anorexia, a papular rash, and increasingly swollen, red, painful hands and feet of 1 month’s duration (42A ). They had no history of fever, conjunctivitis, lymphadenopathy, or oral changes characteristic of Kawasaki disease. They were irritable and unwell and were sweating but afebrile. Both had a tachycardia, and one had a raised blood pressure of 130/90 mmHg (95th centile for age 108/62 mmHg). Both had reduced muscle power and diminished reflexes. Their palms and soles were erythematous and indurated, with desquamation, judged to be acrodynia. The infants had been given a mercury-containing “teething powder” from India once or twice a week over the 4 preceding months. Their blood mercury concentrations were 176 and 209 (reference range below 18) µmol/l. Chelation therapy with 2,3-dimercaptosuccinic acid was administered by nasogastric tube. Before admission the twins had regressed developmentally and were unable to feed, sit, or walk. Over the next 8 weeks they had some minor neurocognitive improvements, but their long-term prognosis was uncertain.

Immunologic The debate about amalgams that contain mercury continues unresolved. • A 61-year-old woman presented with a 2-year history of an abnormal erythematous swelling on the upper lip and cheek (43A ). There were no other physical findings. Histology showed discreet sarcoid granulomas in the lower dermis. Routine laboratory studies, chest radiography, and pulmonary function tests were all normal. The diagnosis was orofacial granulomatosis. A patch test was positive for mercury after 48 and 72 hours. During the previous decade the patient had received amalgam fillings in several dental cavities, including one adjacent to the swollen cheek. The unilateral localization of the soft tissue swelling adjacent to the amalgam tooth fillings, along with the positive patch test for mercury, raised the possibility that the orofacial granulomatosis was part of a delayed hypersensitivity reaction to the fillings. She therefore underwent total amalgam replacement; the swelling overlying the right cheek completely disappeared within 7 weeks and the swelling of the upper lip subsided completely within 6 months.

The authors proposed that mercury in amalgam tooth fillings is a cause of orofacial granulomatosis and suggested appropriate patch testing in patients who have orofacial granulomatosis without an apparent cause.

Nickel (SED-14, 704; SEDA-25, 262; SEDA-26, 248; SEDA-27, 229) Immunologic The most prominent response to all nickel-containing compounds is usually a form of allergy (44R ), which can be caused by nickel-based orthodontic braces and wires (45A ). • A 12-year-old boy with a 10-month history of angular cheilitis with associated fissuring denied lip licking or using any cosmetics on his face or lips and had not changed his toothpaste recently (45A ). He had metallic orthodontic braces inserted 2 months before the rash started. There was no personal or family history of atopy. Cheilitis is an eczematous eruption of the skin and contiguous labial mucous membrane at the angle of the mouth. There was no eczema around the mouth and no evidence of gingivostomatitis or erosions of the oral mucosa. Bacterial and mycological swabs from the angles of the mouth were negative. The condition did not respond to a variety of emollients, topical glucocorticoids, and antifungal drugs. He was patch tested with the European standard series and his toothpaste. There were strong positive reactions to nickel sulfate on day 2 ++ and day 4 + + +, and no reactions to the other patch tests. Removal of the braces resulted in complete remission and there was no recurrence over the next 18 months.

Potassium salts Neuromuscular Disturbed potassium homeostasis can have significant adverse effects on the neuromuscular system and the myocardium. Symptoms of neuromuscular dysfunction, such as weakness, tingling, flaccid paralysis of the limbs, and weakness of the respiratory muscles become apparent at potassium concentrations over 7.5 mmol/l (46R ). However, the most important manifestations of hyperkalemia relate to alterations in the excitability of cardiac muscle and are evident on electrocardiography.

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Death The potential lethality of intravenous injection of potassium salts is well known and has been used in judicial execution by lethal injection and even in the crude “suicide machine” used by Dr. Jack Kevorkian (47R ). Patients who receive intravenous potassium can progress from minimal signs and symptoms to cardiac arrest within minutes (48R ). For this reason, many hospitals have published rigid guidelines for the correct preparation, labelling, storage, use, and administration of potassium salts. Three cases of fatal intravenous injection of potassium salts have been reported (49A ). • An 81-year-old man with coronary artery disease and chronic renal insufficiency being given intravenous antibiotics suddenly yelled and threw back his head. his face turned pale and his eyes rolled. He had ventricular fibrillation, which progressed to cardiopulmonary arrest. The port had been flushed with 6 ml of potassium phosphate 4.4 mmol/ml instead of heparin. • A 10-month-old girl had a ventricular septal defect repaired and about 12 hours after surgery suddenly developed head twitching, and eyes rolling back. There were electrocardiographic changes consistent with hyperkalemia, with peaked T waves and widening of the QRS complex. Within seconds to minutes, she developed a junctional bradycardia and reduced systolic blood pressure. She became progressively hypotensive with no palpable pulses. The potassium concentration was 10 mmol/l. Despite resuscitative efforts she died. • A 6-month-old girl had surgery for severe subvalvular aortic stenosis and on the third postoperative day had a serum potassium concentration of 2.9 mmol/l. Potassium chloride, 1 mmol/kg intravenous to be given over 2 hours was prescribed and was being infused when she had a cardiac arrest and died, despite attempts at resuscitation. Analysis of the remaining fluid in the infusion showed that the pharmacy had prepared a concentrated form of potassium chloride.

Selenium

(SED-14, 704; SEDA-25, 263; SEDA-26, 249; SEDA-27, 230) The use of selenium compounds in medicine continues to be explored. The role of selenium in thyroid function, its role as antioxidant, and its use in the treatment of cancer has been reviewed (50R –52R ).

Gijsbert B. van der Voet and Frederik A. de Wolff

Silver

(SED-14, 705; SEDA-25, 263; SEDA-26, 249; SEDA-27, 230) The use of silver-containing formulations, such as the topical antibacterial agent sulfadiazine and colloidal silver supplements, incidentally leads to argyria.

• A 65-year-old woman with insulin-dependent diabetes had undergone coronary artery bypass grafting 3 years before, and her postoperative course had been complicated by severe contact dermatitis from betadine (53A ). The surgical wound required 3 months to heal and she was treated with silver sulfadiazine cream, which was also used to treat dermatitis on her chest and upper abdomen. She developed extensive blue-gray discoloration of the chest and a non-healing ulcer. Photographs taken about 4 months after surgery showed a slight bluish tinge in the scar. An ulcer had developed within the wound about 1 year after surgery and had grown to a maximum of 3 cm. She was treated with open wet dressings, hydrogen peroxide, debridement, and 2% mupirocin ointment, and the ulcer healed within 6 months. The blue-gray discoloration did not change appreciably over the next 3 years. Three biopsies from the margins of the stellate scar and the ulcer showed epidermal ulceration and dermal scarring as well as acute and chronic inflammatory infiltrates. There was no evidence of squamous cell carcinoma. There were fine, round, brown-black granules extracellularly and within macrophages in the dermis. Dark-field microscopy showed brilliantly refractile, white particles against a dark background in the dermis, which indicated the presence of silver granules. Scanning electron energy dispersion X-ray analysis (EDXA) confirmed the presence of silver in the biopsy specimen.

Titanium

(SED-14, 706; SEDA-25, 263; SEDA-26, 249; SEDA-27, 230) Titanium is a high quality material for use in orthopedic implants and its use in dental medicine is increasing (54R ). In spite of the mechanical potential of titanium-related materials (in alloys with cobalt, chromium, and nickel), incidentally undesired biological effects have been reported. Musculoskeletal sis.

Titanium can cause osteoly-

• A 57-year-old woman with a subtrochanteric fracture of the left femur was treated by closed reduction and intramedullary fixation with a 420 ×

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11 mm Ace titanium nail locked proximally with a single screw into the femoral head and distally with two transverse screws (55R ). Six months later she developed left thigh and knee pain and radiology showed significant osteolysis around the proximal end of the nail and proximal screw. Bone biopsies contained abundant deposits of black particulate metal debris within fibrosclerotic connective tissue, confirmed spectrophotometrically as titanium. It was believed that wear and fretting corrosion between the proximal screw and the intramedullary nail was the most likely source of the titanium debris. No further treatment could be given because the patient died of atypical pneumonia.

Tumorigenicity There is an increased risk of malignancies associated with implant alloy materials. • A 62-year-old man with severe osteoarthritis underwent a left total hip arthroplasty with a titaniumcontaining prosthesis and 32 months later developed pain, stiffness, and swelling of the left hip (56A ). He had gross swelling of the thigh surrounding the left proximal femur. An X-ray showed an osteoblastic lesion in the left proximal femur. The differential diagnosis included a malignant neoplasm, osteomyelitis, and Paget’s disease but the final diagnosis was osteosarcoma. Detailed spectroscopic trace metal analysis of the tumor showed debris and raised concentrations of vanadium and chromium, but not aluminum, nickel, or titanium. However, the cause of the tumor could not be related to a specific metal.

Zinc (SED-14, 706; SEDA-25, 264; SEDA-26, 250; SEDA-27, 230) Metal metabolism Antagonism between copper and zinc metabolism gives rise to copperrelated effects caused by excess zinc (57A ). • A 46-year-old man developed severe bone marrow suppression and then a progressive myelopathy with a sensory ataxia. Neuroimaging was unremarkable. He had an increased plasma zinc concentration (1840 µg/l; reference range 800– 1200 µg/l), a low plasma copper concentration (under 100 µg/l; reference range 800–1200 µg/l), and a low ceruloplasmin concentration. There was no evidence of an external source of zinc. Daily oral supplementation with 2 mg copper resulted in prompt reversal of the hematological abnormalities, an improved but still subnormal plasma copper concentration, and normalization of the ceruloplasmin concentration. The neurological condition deteriorated further; the myelopathy worsened and a polyneuropathy developed. There was persistent hyperzincemia and subnormal copper concentrations during 4 years of follow-up. Increased copper supplementation to 8 mg/day partly reversed the neurological signs. Investigation of six siblings and one surviving parent did not identify family members with similar abnormalities.

Persistent hyperzincemia without an identifiable external source appears to be a primary metabolic defect, while copper deficiency is a secondary phenomenon, causing hematological and neurological abnormalities.

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6. Gherardi RK, Authier FJ. Aluminum inclusion macrophagic myofasciitis: a recently identified condition. Immunol Allergy Clin North Am 2003; 23: 699–712. 7. Fischer D, Reimann J, Schroder R. Macrophagic myofasciitis: inflammatory, vaccination-associated muscular disease. Dtsch Med Wochenschr 2003; 128: 2305–8. 8. Berman J. Current treatment approaches to leishmaniasis. Curr Opin Infect Dis 2003; 16: 397–401. 9. Leandro C, Campino L. Leishmaniasis: efflux pump and chemoresistance. Int J Antimicrob Agents 2003; 22: 352–7. 10. Rijal S, Chappuis F, Singh R, Boelaert M, Loutan L, Koirala S. Sodium stibogluconate cardiotoxicity and safety of generics. Trans R Soc Trop Med Hyg 2003; 97: 597–8.

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11. Costa JML, Garcia AM, Rebelo JMM, Guimaraes KM, Guimaraes RM, Nunes PMS. Fatal case during treatment of American tegumentary leishmaniasis with sodium stibogluconate bp 88® (Shandong Xinhua). Rev Soc Bras Med Trop 2003; 36: 295–8. 12. Silveira BP, Sobrinho JA, Leite LF, Sales MdaNA, Gouveia MdoS, Mathias RL, Guedes Filho RA, Barbosa SM. Premature birth after the use of pentavalent antimonials: case report. Rev Soc Bras Med Trop 2003: 36; 523–5. 13. Parmar S, Tallman MS. Acute promyelocytic leukaemia: a review. Expert Opin Pharmacother 2003; 4: 1379–92. 14. Hussein MA. Trials of arsenic trioxide in multiple myeloma. Cancer Control 2003; 10: 370–4. 15. Fonzi R, Fonzi M, Cananzi G, Fonzi L. Arsenic still survives 21st century endodontics. Bull Group Int Rech Sci Stomatol Odontol 2003; 45: 79–81. 16. Chakraborti D, Mukherjee SC, Saha KC, Chowdhury UK, Rahman MM, Sengupta MK. Arsenic toxicity from homeopathic treatment. J Toxicol Clin Toxicol 2003: 41; 963–7. 17. Loftus EV. Microscopic colitis: epidemiology and treatment. Am J Gastroenterol 2003: 98 Suppl: S31–6. 18. Mundy GR, Mazzaferri EL. Evaluation and treatment of hypercalcemia. Hosp Pract 1994; 29: 79–86. 19. Lagman R, Walsh D. Dangerous nutrition? Calcium, vitamin D, and shark cartilage nutritional supplements and cancer related hypercalcemia. Support Care Cancer 2003; 11: 232–5. 20. Vincent JB. The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent. Sports Med 2003; 33: 213–30. 21. Ryan GJ, Wanko NS, Redman AR, Cook CB. Chromium as adjunctive treatment for type 2 diabetes. Ann Pharmacother 2003; 37: 876–85. 22. Brewer GJ. Copper in medicine. Curr Opin Chem Biol 2003; 7: 207–12. 23. Nceboz US, Ozcakir HT, Uyar Y, Caglar H. Migration of an intrauterine contraceptive device to the sigmoid colon: a case report. Eur J Contracept Reprod Health Care 2003; 8: 229–32. 24. Chitambar CR. Gallium nitrate revisited. Semin Oncol 2003; 30: 1–4. 25. Kiremitci A, Bolay S. A 3-year clinical evaluation of a gallium restorative alloy. J Oral Rehabil 2003; 30: 664–7. 26. Soler MJ, Barroso E, Aranda FI, Alonso S, Romero S. Fatal, gold-induced pneumonitis. Rheumatol Int 2003; 23: 207–10. 27. Levin M-D, Van ’t Veer MB, De Veld JC, Markusse HM. Two patients with acute thrombocytopenia following gold administration and five-year follow-up. Neth J Med 2003; 61: 223–5. 28. Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology (Am Soc Hematol Educ Program) 2003: 40–61. 29. Eichbaum Q, Foran S, Dzik S. Is iron gluconate really safer than iron dextran? Blood 2003; 101: 3756–7.

Gijsbert B. van der Voet and Frederik A. de Wolff 30. Anonymous. Litargirium. Presence of dangerous levels of lead. WHO Pharm Newslett 2004; 1: 3. 31. Goto K, Yasue H, Okumura K. Magnesium deficiency detected by intravenous loading test in variant angina pectoris. Am J Cardiol 1990; 65: 709–12. 32. Teragawa H, Kato M, Yamagata T, Matsuura H, Kajiyama G. The preventive effect of magnesium on coronary spasm in patients with vasospastic angina. Chest 2000; 118: 1690–5. 33. Saris NEL, Mervaala E, Kerppanen H, Khawaja JA, Levenstam A. Magnesium. An update of physiological, clinical and analytical aspects. Clin Chim Acta 2000; 294: 1–26. 34. Kelepouris E, Agus ZS. Hypomagnesaemia: renal magnesium handling. Semin Nephrol 1998; 18: 58–73. 35. Dube L, Grancry JC. The therapeutic use of magnesium in anaesthesiology, intensive care and emergency medicine: a review. Can J Anesth 2003; 50: 732–46. 36. Levy BS, Nassetta WJ. Neurologic effects of manganese in humans: a review. Int J Occup Environ Health 2003; 9: 153–63. 37. Yoshikawa K, Matsumoto M, Hamanaka M, Nakagawa M. A case of manganese induced parkinsonism in hereditary haemorrhagic telangiectasia. J Neurol Neurosurg Psychiatry 2003; 74: 1312–14. 38. Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med (Maywood) 2003; 228: 660–4. 39. Hviid A, Stellfeld M, Wohfahrts J, Melbye M. Association between thiomersal-containing vaccine and autism. J Am Med Assoc 2003; 13: 1763–6. 40. Verstraetan T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, Shinefield H, Chen RT. Safety of thiomersal containing vaccines: a two phased study of computerised health maintenance organisation data bases. Pediatrics 2003; 112: 1039–48. 41. Hessel L. Mercury in vaccines. Bull Acad Natl Med 2003; 187: 1501–10. 42. Weinstein M, Bernstein S. Pink ladies: mercury poisoning in twin girls. Can Med Assoc J 2003; 168: 201. 43. Guttman-Yassky E, Weltfriend S, Bergman R. Resolution of orofacial granulomatosis with amalgam removal. J Eur Acad Dermatol Venereol 2003; 17: 344–7. 44. Rahilly G, Price N, Nickel allergy and orthodontics. J Orthodont 2003; 30: 171–4. 45. Yesudian PD, Memon A. Nickel-induced angular cheilitis due to orthodontic braces. Contact Dermatitis 2003; 48: 287–8. 46. Tietz NW, Pruden EL, Siggaard-Andersen O. Electrolytes. In: Tietz NW (editor). Textbook of Clinical Chemistry. Philadelphia: WB Saunders, 1986: 1172–91. 47. Humphry D. A doctor’s suicide machine. In: Final Exit: The Practicalities of Self-deliverance and Assisted Suicide for the Dying. New York: Dell, 1999: 131–41.

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48. Lippmann BJ. Fluid and electrolyte management. In: Ewald GA, McKenzie CR (editors). Manual of Medical Therapeutics. 28th edition. Boston: Little, Brown and Company, 1995: 43–64. 49. Wetherton AR, Corey TS, Buchino JJ, Burrows AM. Fatal intravenous injection of potassium in hospitalized patients. Am J Forensic Med Pathol 2003; 24: 128–31. 50. Chanoine JP. Selenium and thyroid function in infants, children and adolescents. Biofactors 2003; 19: 137–43. 51. Tapiero H, Townsend DM, Tew KD. The antioxidant role of selenium and seleno-compounds. Biomed Pharmacother 2003; 57: 134–44. 52. Thompson IM, Basler J, Hensley D, Von Merveldt D, Jenkins CA, Higgins B, Leach R, Troyer D, Pollock B. Prostate cancer prevention: what do we know now and when will we know more? Clin Prostate Cancer 2003; 1: 215–20. 53. Fisher NM, Marsh E, Lazova R. Scar-localized argyria secondary to silver sulfadiazine cream. J Am Acad Dermatol 2003; 49: 730–2.

253 54. Akagawa Y, Abe Y. Titanium: the ultimate solution or an evolutionary step? Int J Prosthodont 2003; 16 Suppl: 28–9; discussion 47–51. 55. Foguet P, Hashmi F, Lawrence T. Case report: metaphyseal osteolysis around a titanium reconstruction nail. Injury Int J Care Injured 2003; 34: 374–7. 56. Adams JE, Jaffe KA, Lemons JE, Siegal GP. Prosthetic implant associated sarcomas: a case report emphasizing surface and spectroscopic trace metal analysis. Ann Diagnost Pathol 2003; 7: 35– 46. 57. Hedera P, Fink JK, Bockenstedt PL, Brewer GJ. Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome. Arch Neurol 2003; 60: 1303– 6.

R.H.B. Meyboom

23 COPPER CHELATORS Ammonium tetrathiomolybdate Hematologic In a study of ammonium tetrathiomolybdate in 55 patients with Wilson’s disease, neurological deterioration was seen in only two (1CR ). The drug was started in a dose of 120–140 mg/day and increased to 200–260 mg/day in most patients. Anemia and leukopenia developed in five patients and was associated with thrombocytopenia in two of them. Three patients had increased aminotransferase activities. In all patients recovery followed temporary withdrawal and a subsequent reduction in dosage. The total trial duration was 8 weeks, but no information was given as regards the time to onset. The hemotoxicity of ammonium tetrathiomolybdate is thought to be due to copper depletion.

IRON CHELATORS Iron compounds, as oxygen radical transporters, play a crucial role in many physiological and pathological biochemical processes. Since the success in improving the expectancy and quality of life in patients with iron overload diseases, thanks to much progress in the understanding of iron metabolism and effective chelation treatments (2R –4R ), iron chelators seem to be on their way up in the management of several other refractory disorders, including Alzheimer’s disease (5R ), Friedreich’s ataxia (6R ), Parkinson’s disease (7R ), and malignant diseases (8R ). In the last 10 years a vast body of work has greatly increased our understanding of the © 2005 Published by Elsevier B.V. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

254

Metal antagonists physiology of iron (9R , 10R ). Iron balance is largely determined through iron absorption since iron is poorly excreted. Iron absorption and excretion are both about 1 mg/day; a little too much can lead to iron overload, and too little can cause deficiency. Iron absorption takes place in the duodenum. Newly formed enterocytes in the crypts of Lieberkühn take up alimentary iron while they differentiate and migrate to the tips of the villi. Iron is absorbed from the lumen at the apical brushborder membrane by the proton-coupled divalent cation transporter DCT1 into the cytosolic iron pool, in part bound to ferritin. There are different pathways for heme-bound and nonheme-bound iron and for Fe2+ or Fe3+ . At the basolateral membrane, iron is transferred out of the enterocyte by the transmembrane protein ferroportin into the portal circulation, where it can be combined with apoferritin to form the transport protein transferrin. Not all iron leaves the enterocytes; as a function of body iron requirements, iron can be sequestered in the enterocytes and excreted after aging and exfoliation of the cells. In the complex metabolism of iron there are a variety of possible sites for chelation: serum iron in the form of transferrin; nontransferrin-bound serum iron (NTBI, when the iron-binding capacity of transferrin is saturated); the storage proteins ferritin (in the cytosol) and hemosiderin (in lysosomes); and the labile iron pool in the cytoplasm of the cells (3R , 4R , 9R ). Deferoxamine is a naturally occurring siderophore produced by Streptomyces pilosus, which was discovered by chance (2R ). It is a large hexadentate molecule that is not absorbed and cannot enter cells. Orally active drugs are much smaller and bidentate or tridentate ligands and, depending on their properties, can enter cells and cellular structures and capture iron in different compartments (11R , 12R ). Drugs such as deferiprone can reach body compartments

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inaccessible to deferoxamine. When deferoxamine and deferiprone are given together they can synergistically increase urine and fecal iron excretion. Deferiprone can chelate iron from inside cells and make it available to deferoxamine in the plasma for further excretion (“sink and shuttle effect”) (13R ; SEDA 26, 253). Several studies have suggested that the combined use of these drugs can increase iron chelation without increased or additional toxicity (13R ). Two recent studies have added to the evidence that combining deferoxamine and deferiprone can achieve a negative iron balance with acceptable toxicity (14C , 15C ). However, long-term studies are required to validate the efficacy and safety of this combination. In transfusion-dependent hemolytic anemia, cardiac injury due to iron storage is a major cause of death. Recent evidence suggests that in patients with established cardiac damage continuous 24-hour infusion of deferoxamine through an indwelling intravenous catheter can reverse cardiac iron toxicity (10CR ). The mechanisms by which iron chelators cause tissue injury include the removal of iron from critical cellular sites, potentiation of ironmediated free radical generation, and the induction of aberrant iron distribution (10R ). Transfusion-dependent thalassemia is a relatively common and serious genetic disorder of hemoglobin, prevalent in the USA, Mediterranean countries, the Middle East, and SouthEast Asia. Over 80% of affected patients live in the last two regions (16R ). Long-term blood transfusion invariably leads to iron storage and ultimately fatal heart injury, unless extensive use is made of iron chelators. However, these drugs are largely restricted to patients in affluent countries, because they are expensive, although probably unnecessarily so (4R ). Deferiprone could be sold at a price 50 times lower than that of deferoxamine. However, in Europe it is sold at the same price, and in India it is only eight times cheaper than deferoxamine. Deferoxamine is no longer patented but is difficult to produce. Deferiprone is easy to make but is still protected by various patents. In this context it is worth mentioning that much of the knowledge of the adverse effects of these drugs and improved treatment strategies have been developed by academic institutions without company support. Because chelating drugs are expensive

255 many patients on transfusion therapy are deprived of iron chelation, with premature death as a result. In 24 patients with thalassemia the efficacy of either deferoxamine or deferiprone was determined by (a) the fall in serum ferritin concentration, (b) the reduction in the iron content in liver specimens, (c) the improvement in cardiac function (left ventricular ejection fraction, LVEF), and (d) the reduction in the gross signal intensity in T2-weighted MRI scans of the liver and heart without contrast medium (17CR ). The findings suggested that MRI and LVEF are useful non-invasive tools for monitoring of iron chelation and cardiac involvement in thalassemia. In patients with chronic severe iron overload, such as in thalassemia major, iron-induced injury to the heart is the most important cause of death and prevention of cardiac injury is the major aim of chelation treatment. However, intensive iron chelation is a heavy burden on patients, and non-adherence is a major cause of heart disease in patients with thalassemia major. Technical improvements, such as implantable devices for 24-hour intravenous administration of deferoxamine and disposable infusors with weekly home-delivery, can substantially improve patient adherence (18R ). With intensive treatment regimens with iron chelators such as deferoxamine and deferiprone, negative iron balance can be achieved and cardiac dysfunction may regress. In eight patients with thalassemia major, symptomatic heart disease, and poor adherence to conventional deferoxamine treatment, intermittent daily intensive deferoxamine (mean dose about 95 mg/kg/day intravenously for 8–10 hours), using indwelling central venous catheters successfully reversed cardiac toxicity (19CR ). Later on, the re-introduction of regular subcutaneous deferoxamine was associated with good adherence in most of the patients. Although there were no serious adverse effects of deferoxamine, complications associated with the use of central venous access lines were common. Five patients had 14 episodes of exitsite infections and/or tunnel infections and 10 episodes of proven bacterial sepsis (most often Klebsiella pneumoniae, Pseudomonas, and Staphylococcus species). The rate of bacterial infections was 1.4 episodes of local infections and 1.1 episodes of bacteremia per 1000 days

256 of catheter use. In addition, there was catheterrelated thrombosis in four of seven patients; the overall rate of thrombosis was 0.4 episodes per 1000 days of catheter use. Excess iron can cause chromosomal injury (clastogenesis), through the production of reactive oxygen species. Chelators can counteract this effect but, on the other hand, they are suspected to have a clastogenic effect themselves (20R ). The occurrence of chromosomal rearrangements in circulating leukocytes has been studied in 10 patients using long-term deferoxamine and 10 using deferiprone and after they had switched treatments (20C ). In contrast to previous studies, the values found were generally within the reference range, but there was a small but consistent increase in deferoxamine users compared with deferiprone users.

Deferiprone

(SED-14, 719; SEDA-25, 268; SEDA-26, 253; SEDA-27, 233) A review of the safety and effectiveness of longterm treatment with deferiprone (21C ) appears to be a republication of material already presented in last year’s Annual (SEDA-27, 233).

Immunologic The Thalassaemia Unit in Thessaloniki has compared the immune status of 44 thalassemic patients receiving deferiprone, with or without simultaneous deferoxamine, with 20 age-matched controls (22CR ). Patients who used deferiprone had increased absolute lymphocyte counts. The CD4+ and CD8+ counts were increased because of lymphocytosis, but the CD4/CD8 ratio did not significantly differ from the comparison group. There were no differences in antibody titers, apart from a change to positivity for anti-liver/kidney mitochondria antibodies in four (but not with concomitant anti-smooth muscle antibodies) and for anti-reticulin antibodies in five; none of these patients had signs of autoimmune disease. In a study of deferiprone in nine patients with thalassemia, not regularly requiring transfusions adverse effects were mild and included gastrointestinal symptoms in six and arthralgia in one (23c ). One patient, with a normal neutrophil count, died at 17 weeks of treatment as a result of an infection that was not thought to be related to the drug; severe diarrhea and fever

Chapter 23

R.H.B. Meyboom

progressed within 2 days to fatal septicemia, but blood cultures and other laboratory tests were not available. This patient had a splenectomy 18 years before and had not been taking prophylactic penicillin. This observation is of interest in the light of a report of another patient who died of unexplained pneumonia during the use of deferiprone for malaria (SEDA-17, 233) and the fact that deferoxamine increases the virulence of Yersinia enterocolitica and other micro-organisms (SED-14, 717).

Deferoxamine

(SED-14, 714; SEDA-25, 267; SEDA-26, 253; SEDA-27, 233) Subcutaneous infusion of deferoxamine often (85%) causes local reactions, with itching, pain, erythema, swelling, and induration (14c ). The complex problem of short stature and impaired bone growth in patients with thalassemia major, and the roles of chronic anemia, gonadal dysfunction, pharmacological induction of puberty, chronic liver disease, cytotoxic drugs (in bone-marrow transplantation), and deferoxamine-induced bone dysplasia have been reviewed (24R ). Sensory systems Retinal damage has been attributed to long-term deferoxamine treatment.

• After 22 years of iron chelation treatment with deferoxamine (dose and diagnosis not specified), a 40-year-old woman developed retinal injury, with pigmentary degeneration and a “bull’s eye” maculopathy in both eyes, progressing to serious persistent visual impairment (OD 20/80; OS 20/60) (25Ar ).

Urinary tract Of 91 well-controlled patients with thalassemia, 55 had signs of early renal tubular dysfunction, as judged by urinary concentrations of albumin, beta2 -microglobulin, and N-acetyl-beta-D-glucosaminidase (26cr ). The tubular dysfunction correlated with iron overload, as measured by liver MRI and serum ferritin concentrations, and not with deferoxamine exposure. Drug overdose Acute renal insufficiency has been described after an inadvertent overdose of deferoxamine; it responded to high-efficiency hemodialysis (27AR ).

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• A 17-year-old African-American boy was receiving continuous deferoxamine infusion, 45 g (700 mg/kg) weekly, using a home intravenous AIM pump. On one occasion the pump was accidentally programmed to deliver the full 96-hour dose of 45 g over 8 hours. The next day he developed generalized itching, a burning sensation of the skin, shortness of breath, chest pain, crampy abdominal pain, and reduced urine output. His blood pressure was 147/82 mmHg, heart rate 108/minute, temperature 36.5◦ C, and pulse oximetry 100% on room air. He had a metabolic acidosis and uremia. The urine pH was 5.0, specific gravity 1.020, and it contained protein 150 mg/l and a trace of blood; the urine was red-orange in color, characteristic of iron chelation. Microscopic examination showed 25–30 hyaline casts and 3–5 white blood cells per high-power field but no red cells. Despite intravenous hydration and forced diuresis with mannitol he remained oliguric and hemodialysis was performed. His urine output increased 10-fold and his serum creatinine fell. Mild hypertension was treated for 12 days with oral isradipine. One month later he was well, with normal blood pressure, urine output, and serum creatinine.

ICL670 ICL670 is an orally active representative of a new class of tridentate iron chelators, developed for the treatment of iron overload, with two- to five-fold greater potency than deferoxamine. In a two-period, randomized, doubleblind, placebo-controlled, sequential, parallelgroup study in 24 patients (three study groups of eight patients each), the most common adverse event was headache (n = 6); there was no dose relation (28c ). Three of the eight patients had nausea and diarrhea, possibly related to the dense oral suspension used. Single occurrences of influenza, joint pains, and vertigo were thought to be drug-related. In a dose-escalation study skin rashes developed after 8–10 days in four of 21 patients who received ICL670 (29cR ). Five patients had biochemical evidence of liver injury, serious in one and there were four episodes of nausea and four of diarrhea, predominantly occurring during use of higher doses (20– 40 mg/day).

PENICILLAMINE AND RELATED DRUGS Penicillamine

(SED-14, 723; SEDA-25, 269; SEDA-26, 255; SEDA-27, 235) For decades NSAIDs have been first-line treatment in rheumatoid arthritis. Disease-modifying antirheumatic drugs (DMARDs), of which penicillamine was one of the first, constituted the second-line strategy, used in refractory patients. However, accumulating evidence in the past few years that the long-term use of NSAIDs is connected with substantial toxicity and lack of efficacy in controlling disease progression has led to a reversal of this approach. Drastic intervention schemes with DMARDs in early disease, aiming at halting progress are now the preferred primary management of rheumatoid arthritis, while glucocorticoids and new biologicals, such as tumor necrosis factor inhibitors are in the second line (30R ).

Nervous system In 18 patients treated with Wilson’s disease penicillamine 600–3000 mg/day was gradually introduced over a period of 2–3 weeks, adjusted to urinary copper excretion, and after clinical improvement a maintenance dose of 600–900 mg/day was given (31cR ). There was initial neurological deterioration, in particular of tremor and dysarthria, in 10 of the patients, but it reversed within 2–4 months. One patient had a hypersensitivity reaction (rash with leukopenia) and another developed cutaneous elastosis of the neck, characteristic of high doses of penicillamine. In one case acute neurological deterioration in a young child after high doses of penicillamine had a fatal outcome (32A ). • A seriously ill 8-year-old girl, weight 22 kg, with progressive jaundice, hepatomegaly, bilious vomiting, abdominal distension, coagulopathy, swelling of the feet, low-grade fever, drowsiness, and Kayser–Fleischer rings, was given fresh frozen plasma. After a challenge test with penicillamine 1 g plus pyridoxine 25 mg she developed jerky movements of the limbs, titubation of the head, and dysarthria. Since these symptoms were suspected to be due to penicillamine, oral zinc sulfate was begun and 3 days later penicillamine was resumed in a dose of 62.5 mg/day, increasing the dose by doubling every 2 days. When a dose of 500 mg/day (22.7 mg/kg/day) was reached there was recurrence of the neurological symptoms and penicillamine was withdrawn. Subsequently there was

258 worsening of liver failure, gastrointestinal bleeding, peritonitis, and hepatic encephalopathy, and the child died.

Urinary tract There has been a report of a patient with a disorder resembling Goodpasture’s syndrome, attributed to penicillamine, accompanied by a review of 13 previous such cases (33AR ; SEDA-22, 258; SEDA-23, 267; SED-14, 729). • A 65-year-old man with systemic sclerosis was given penicillamine, slowly increasing from an initial dose of 250 mg/day to a maintenance dose of 1000 mg/day. Over 2.5 years his skin lesions improved markedly. However, he developed atrial fibrillation and impaired renal function (serum creatinine 186 µmol/l, proteinuria, red cell casts, and an abnormal sediment with 50–100 red cells and 20–50 white cells per high-power field). He was given a beta-blocker, an anticoagulant, and an antianginal drug, and soon after had severe hemoptysis; the anticoagulant was withdrawn. His renal insufficiency and hemoptysis worsened and chest X-rays showed increasing alveolar infiltrates, suggesting continued hemorrhage. A diagnosis of Goodpasture’s syndrome was made, penicillamine was withdrawn and plasmapheresis begun. Serological studies for anti-dsDNA and antiglomerular basement membrane antibodies were negative (ANCA not done). Nine days after hospitalization a ventricular septum defect developed and he died 36 days after admission. At autopsy there was focal segmental sclerosing glomerulopathy with periglomerular inflammatory infiltrates in some sections and mesangial thickening due to an increase in the mesangial matrix. Immunofluorescence showed diffuse global granular deposits in the glomeruli; staining for IgG, IgM, IgA, or C3 was negative. Electron microscopy showed diffuse thickening of the glomerular basement membrane. In the lungs there were interstitial fibrosis and severe hemorrhages. Pulmonary artery plexiform lesions suggested pulmonary hypertension. There was a pattern of cystic transformation of the lung parenchyma in the lower lobes, and metaplasia of the alveolar lining. The alveolar capillary membrane was replaced by interstitial fibrosis. There was profound intra-alveolar hemorrhage, diffusely distributed throughout the lung. In addition to severe coronary artery disease, there was a recent anterior wall infarct, leading to rupture of the ventricular septum.

The authors commented that anti-glomerular basement membrane antibodies had been present in only one of the previously published cases and that in three of these patients no immunoglobulins or C3 deposits were found on immunofluorescence examination. Presumably penicillamine sensitizes against basement

Chapter 23

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membrane epitopes that are somewhat different from those in genuine Goodpasture’s syndrome. They did not comment on the mixed nature of the pulmonary pathology and hemorrhages in this patient and the link with Goodpasture’s syndrome. Skin Penicillamine has been associated with the entire spectrum of pemphigus (pemphigus foliaceus, pemphigus erythematosus, pemphigus vulgaris, bullous pemphigoid) (SED14, 731). There has been a detailed report of histopathology and immunomorphology in three patients with superficial pemphigus, in one possibly related to previous use of penicillamine (34A ). The findings suggested that pemphigus erythematosus and pemphigus foliaceus are respectively localized and generalized variants of superficial pemphigus. The patients had antibodies against desmoglein 1 (but not desmoglein 2) and against a 230 kDa and a 190 kDa protein. Although the co-existence of pemphigus and bullous pemphigoid is considered to be extremely rare, all three patients also had bullous pemphigoid antigen BP230-specific antibodies. A case report of typical penicillamine dermopathy in a woman with Wilson’s disease was of particular interest because of its resemblance to pemphigus (35CR ). • A 49-year-old Chinese woman, who had been taking penicillamine 1.5 g/day for Wilson’s disease for 5 years (cumulative dose about 3 kg), developed skin fragility, easy bruising, and over both elbows recurrent hemorrhagic blisters and multiple tiny white papules with underlying cutaneous atrophy and purpura; there were no intact vesicles or bullae. A skin biopsy showed a milium cyst containing laminated keratin, consistent with milia secondary to a healed hemorrhagic blister. There was paucity of elastic fibers in the dermis; direct and indirect immunofluorescence tests were negative. Other manifestations of penicillamine dermopathy (elastosis perforans serpiginosa, pseudoxanthoma elasticum, and cutis laxa) were absent. Reducing the dose of penicillamine to 500 mg/day was followed by marked improvement.

In this patient the negative immunohistochemical findings excluded pemphigus. Penicillamine presumably interferes with elastin and collagen metabolism, by impairing crosslinking through binding to aldehyde groups and inhibiting the copper-dependent enzyme lysyl

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oxidase. Since it has no effect on mature (insoluble) collagen, penicillamine dermopathy takes a long time to develop. Pseudomycosis fungoides, a subset of the pseudolymphoma syndrome, is a rare skin disease that has been associated with a variety of drugs, notably carbamazepine, but also penicillamine (36r ).

of premature rupture of the membranes and uterine contractions. The baby had respiratory distress syndrome despite antenatal betametasone and was treated with mechanical ventilation, exogenous surfactant (Survanta 100 mg/kg), sultamicillin, and amikacin. During the 24 hours after birth, neutropenia developed (1.47 × 109 /l; leukocytes 387 × 106 /l). Neutropenia resolved spontaneously during the next 4 days.

Teratogenicity Although prenatal exposure to high doses of penicillamine can cause connective tissues disorders and cutis laxa (SED14, 734), the drug is commonly used in pregnant women with Wilson’s disease. In a recent study of 18 patients taking penicillamine (mean dosage 1000 mg/day), three women had five neonates, none of whom had teratogenic effects (31c ).

Although penicillamine was the suspected cause, a possible role of other drugs, notably the surfactant and antibiotics, was difficult to rule out.

Fetotoxicity Neonatal neutropenia has been reported in connection with maternal use of penicillamine (37Ar ). • A 22-year-old woman, who had been taking penicillamine (600 mg/day) and zinc sulfate (600 mg/day) for Wilson’s disease diagnosed at age 9, gave birth after 29–30 weeks gestation to a boy of 1.3 kg after elective cesarean section because

POLYSTYRENE SULFONATES (SEDA-25, 271; SEDA-26, 256; SEDA-27, 236) Gastrointestinal Intestinal perforation occurred in a premature infant after rectal administration of calcium polystyrene sulfonate resin (38Ar ). Bezoars due to sodium polystyrene sulfonate have been treated with serial water-soluble contrast enemas (39A ).

REFERENCES 1. Brewer GJ, Hedera P, Kluin KJ, Carlson M, Askari F, Dick RB, Sitterly J, Fink JK. Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 2003; 60: 379–85. 2. Davis BA, Porter JB. Results of long term iron chelation treatment with deferoxamine. Adv Exp Med Biol 2003; 509: 91–125. 3. Tam TF, Leung-Toung R, Li W, Wang Y, Karimian K, Spino M. Iron chelator research: past, present, and future. Curr Med Chem 2003; 10: 983– 95. 4. Kontoghiorghes GJ, Neocleous K, Kolnagou A. Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions: comparison of epidemiological and therapeutic aspects with deferoxamine. Drug Saf 2003; 26: 553–84. 5. Finefrock AE, Bush AI, Doraiswamy PM. Current status of metals as therapeutic targets in Alzheimer’s disease. J Am Geriatr Soc 2003; 51: 1143–8. 6. Richardson DR. Friedreich’s ataxia: iron chelators that target the mitochondrion as a therapeutic

strategy? Expert Opin Investig Drugs 2003; 12: 235–45. 7. Levenson CW. Iron and Parkinson’s disease: chelators to the rescue? Nutrition Rev 2003; 61: 311–13. 8. Buss JL, Torti FM, Torti SV. The role of iron chelation in cancer therapy. Curr Med Chem 2003; 10: 1021–34. 9. Crichton RR, Ward RJ. An overview of iron metabolism: molecular and cellular criteria for the selection of iron chelators. Curr Med Chem 2003; 10: 997–1004. 10. Chaston TB, Richardson DR. Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity. Am J Hematol 2003; 73: 200–10. 11. Nick H, Acklin P, Lattmann R, Buehlmayer P, Hauffe S, Schupp J, Alberti D. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem 2003; 10: 1065–76. 12. Hider RC, Liu ZD. Emerging understanding of the advantage of small molecules such as hydroxypyridinones in the treatment of iron overload. Curr Med Chem 2003; 10: 1051–64.

260 13. Hoffbrand VA, Wonke B. Long term deferiprone chelation therapy. Adv Exp Med Biol 2003; 509: 127–39. 14. Mourad FH, Hoffbrand AV, Sheikh-Taha M, Koussa S, Khoriaty AI, Taher A. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. Br J Haematol 2003; 121: 187–9. 15. Kattamis A, Kassou C, Berdousi H, Ladis V, Papassotiriou I, Kattamis C. Combined therapy with desferrioxamine and deferiprone in thalassemic patients. Effect on urinary iron excretion. Haematologica 2003; 88: 1423–5. 16. Marx JJM. Pathophysiology and treatment of iron overload in thalassemia patients in tropical countries. Adv Exp Med Biol 2003; 531: 57–68. 17. Peng C-T, Chow K-C, Chen J-H, Chiang Y-P, Lin T-Y, Tsai C-H. Safety monitoring of cardiac and hepatic systems in beta-thalassemia patients with chelating treatment in Taiwan. Eur J Haematol 2003; 70: 392–7. 18. Hershko C, Link G, Konijn AM. Cardioprotective effect of iron chelators. Adv Exp Med Biol 2003: 509: 77–89. 19. Miskin H, Yaniv I, Berant M, Hershko C, Tamary H. Reversal of cardiac complications in thalassemia major by long-term intermittent daily intensive iron chelation. Eur J Haematol 2003; 70: 398–403. 20. Marshall R, Tricta F, Galanello R, Leoni G, Kirkland D, Minto S, Spino M. Chromosomal aberration frequencies in patients with thalassaemia major undergoing therapy with deferiprone and deferoxamine in a comparative crossover study. Mutagenesis 2003; 18: 457–63. 21. Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003: 102: 1583–7. 22. Athanassiou-Metaxa M, Tzimouli V, Economou M, Taparkou A, Tourkantoni N, KanakoudiTsakalidou F. Immune status of thalassemic patients receiving deferiprone or combined deferiprone and desferrioxamine chelation treatment. Acta Haematol 2003; 110: 224–6. 23. Pootrakul P, Sirankapracha P, Sankote J, Kachintorn U, Maungsub W, Sriphen K, Thakernpol K, Atisuk K, Fucharoen S, Chantraluksri U, Shalev O, Hoffbrand AV. Clinical trial of deferiprone iron chelation therapy in betathalassaemia/haemoglobin E patients in Thailand. Br J Haematol 2003; 122: 305–10. 24. Raiola G, Galati MC, De Sanctis V, Nicoletti MC, Pintor C, De Simone M, Arcuri VM, Anastasi S. Growth and puberty in thalassemia major. J Pediatr Endocrinol Metab 2003; 16 Suppl 2: 259–66. 25. Bansal V, Elgarbly I, Ghanchi FD, Atkinson PL. Bull’s eye maculopathy with deferoxamine. Eur J Haematol 2003; 70: 420–1. 26. Koliakos G, Papachristou F, Koussi A, Perifanis V, Tsatra I, Souliou E, Athanasiou M. Urine

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biochemical markers of early renal dysfunction are associated with iron overload in beta-thalassaemia. Clin Lab Haematol 2003; 25: 105–9. 27. Prasannan L, Flynn JT, Levine JE. Acute renal failure following deferoxamine overdose. Pediatr Nephrol 2003; 18: 283–5. 28. Galanello R, Piga A, Alberti D, Rouan MC, Bigler H, Sechaud R. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusiondependent iron overload due to beta-thalassemia. J Clin Pharmacol 2003; 43: 565–72. 29. Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Sechaud R, Krebs-Brown AJ, Anderson JR, Alberti D, Sizer KC, Nathan DG. Effectiveness and safety of ICL670 in ironloaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2003; 361: 1597–602. 30. Smolen JS. Objectives and strategies for rheumatoid arthritis therapy: yesterday vs. today. Drugs Today 2003; 39 Suppl B: 3–8. 31. Pellecchia MT, Criscuolo C, Longo K, Campanella G, Filla A, Barone P. Clinical presentation and treatment of Wilson’s disease: a single-centre experience. Eur Neurol 2003; 50: 48–52. 32. Paul AC, Varkki S, Yohannan NB, Eapen CE, Chandy G, Raghupathy P. Neurologic deterioration in a child with Wilson’s disease on penicillamine therapy. J Gastroenterol 2003; 22: 104–5. 33. Derk CT, Jimenez SA. Goodpasture-like syndrome induced by D-penicillamine in a patient with systemic sclerosis: report and review of the literature. J Rheumatol 2003; 30: 1616–20. 34. Karlhofer FM, Hashimoto T, Slupetzky K, Kiss M, Liu Y, Amagai M, Pieczkowski F, Foedinger D, Kirnbauer R, Stingl G. 230-kDa and 190-kDa proteins in addition to desmoglein 1 as immunological targets in a subset of pemphigus foliaceus with a combined cell-surface and basement membrane zone immune staining pattern. Exp Dermatol 2003; 12: 646–54. 35. Tang MBY, Chin TM, Yap CK, Ng SK. A case of penicillamine-induced dermopathy. Ann Acad Med Singapore 2003; 32: 703–5. 36. Gül Ü, Kiliç A, Dursun A. Carbamazepineinduced pseudo mycosis fungoides. Ann Pharmacother 2003; 37: 1441–3. 37. Yalaz M, Aydogdu S, Ozgenc F, Akisu M, Kultursay N, Yagci RV. Transient fetal myelosuppressive effect of D-penicillamine when used in pregnancy Minerva Pediatr 2003; 55: 625–8. 38. Grammatikopoulos T, Greenough A, Pallidis C, Davenport M. Benefits and risks of calcium resonium therapy in hyperkalaemic preterm infants. Acta Paediatr 2003; 92: 118–20. 39. Koneru P, Kaufman R-A, Talati A-J, Jenkins MB, Korones S-B. Successful treatment of sodium polystyrene sulfonate bezoars with serial watersoluble contrast enemas. J Perinatol 2003; 23: 431– 3.

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BISBIGUANIDES Chlorhexidine

(SED-14, 764; SEDA-25, 276; SEDA-26, 258; SEDA-27, 239) Immunologic Anaphylactic reactions due to chlorhexidine-coated central venous catheters are well known. In 1998 the FDA issued an alert and in 1990 Japan withdrew chlorhexidinecoated catheters after a cluster of reports of anaphylactic reactions. Despite these warnings and references in package inserts to avoid using these catheters in individuals who are thought to be sensitive to chlorhexidine, cases of anaphylaxis continue to be reported (SEDA-27, 239). Increased vigilance is still required, as described in a case of anaphylaxis in a patient known to be allergic to chlorhexidine (1A ). • A 79-year-old man, with a history of acute anaphylaxis to chlorhexidine given in a urethral gel 1 year before, underwent laparotomy for suspected small bowel obstruction. Before general anesthesia, an arterial catheter, a peripheral venous catheter, and an epidural catheter were inserted using povidone iodine as an antiseptic. A four-lumen central line was also inserted using local anesthetic while the patient was awake. Immediately on insertion the patient stated, “I’m not feeling well”. Within 30 seconds his systolic blood pressure fell to about 50 mmHg and his heart rate rose to over 120/minute. There were no electrocardiographic ST segment changes. Anaphylaxis was suspected and the skin antiseptic and catheters were reviewed. On closer inspection of the central line packaging it became clear that it was impregnated with chlorhexidine. The catheter was immediately withdrawn, adrenaline, glucocorticoids, and fluids were administered, and he was successfully resuscitated. After a period of stabilization, surgery proceeded and he made an uneventful recovery. © 2005 Published by Elsevier B.V. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

The presence of chlorhexidine in the central venous catheter was mentioned in small writing on the outside of the package, but this was given much less emphasis than the latex-free statement in larger font on the main label. Four other cases of allergy to chlorhexidine in urethral gel have been reviewed with reference to previous reports (2A ).

CATIONIC SURFACTANTS Benzalkonium compounds (SEDA-10, 225) Respiratory Benzalkonium chloride is widely used as a preservative in pharmaceutical formulations for the eyes, ears, and nose. Its adverse effects as a preservative have been extensively reported. However, its adverse effects when used in disinfectants are less well documented. Bronchiolitis obliterans organizing pneumonia has been reported (3A ). • Bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed in a 46-year-old cleaning lady who had severe dyspnea, cough, and fever 2 weeks after spilling a large amount of cleaning agent and inhaling its vapor. The components of the cleaning agent were benzalkonium compounds.

BOOP is an inflammatory lung disease that simultaneously involves the terminal bronchioles and alveoli. It is regarded as idiopathic in most cases, but it can be secondary to drugs, infections, organ transplantation, radiotherapy, and rarely occupational exposure to hazardous agents.

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DYESTUFFS Triphenylmethane dyes (SED-14, 761; SEDA-26, 259) The use of gentian violet for oral and vaginal candidiasis or preparation of the vagina for gynecological operations has largely been abandoned. Its use is restricted in many countries, owing to concern over its mutagenic and carcinogenic effects (SEDA-26, 259). Urinary tract Chemical cystitis due to intravesical installation of gentian violet is rare. Cases have occurred in adult women when an undiluted solution was used. Cystitis has now been reported in a child after bladder instillation of diluted gentian violet (4A ). • A 16-month-old boy developed painful gross hematuria after a herniorrhaphy. During the operation, gentian violet solution diluted to 0.1% had been instilled into the bladder to rule out bladder injury, and hematuria developed several hours later. There was no pyuria. Ultrasonography showed multiseptate structures resulting from edema and hematoma in the bladder and bilateral hydronephrosis. The hematuria responded to intravenous hydration, and follow-up ultrasonography showed bladder wall thickening with resolution of the strictures and less hydronephrosis.

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concluded that ethylene oxide may be associated with breast cancer, but a causal interpretation was weakened owing to inconsistencies in exposure-reported trends and possible biases from non-responses and incomplete cancer ascertainment.

HALOGENS Hypochlorite

(SED-14, 767;

SEDA-26, 259) In the USA 2.95 billion pounds of disinfectants were used in 1999. Most consisted of chlorine/hypochlorites used in disinfecting portable waste and in recreational water. Unlike work regulations regarding agriculture, no specific US laws regulate the exposure of young people to pesticides or disinfectants in non-agricultural industries. An epidemiological assessment of acute occupational disinfectant-related illnesses amongst young people in 1993–8 showed that hypochlorites were responsible for 45% of the illnesses (6C ). Most of the illnesses were mild (78%); there were no deaths.

IODOPHORS Ethylene oxide

(SED-14, 761;

SEDA-26, 258) Mutagenicity and tumorigenicity Ethylene oxide is a direct alkylating agent that causes increased chromosomal aberrations and sisterchromatid exchange (SEDA-26, 258). It is considered to be a human carcinogen, with an excess of hemopoietic cancers reported in cohorts of occupationally exposed sterilization workers (SEDA-25, 277). Ethylene oxide causes mammary tumors in mice, and the incidence of breast cancer has been estimated in a cohort study in 7576 women employed for at least 1 year in commercial sterilization facilities and exposed for an average of 10.7 years (5C ). Compared with the nonexposed population, those in the upper quintile of cumulative exposure had a 27% increase in breast cancer, with a 15-year lag. The authors

(SED-14, 768; SEDA-25; 277; SEDA-27, 240)

Polyvinylpyrrolidone Polyvinylpyrrolidone (povidone) is widely used in medical products, hair care products and cosmetics. Povidone iodine is a compound of polyvinylpyrrolidone and iodine, which is commonly used as an antibacterial agent and antiseptic. Nervous system Seizures, which can occur with iodinated contrast media, have only rarely been associated with the use of povidone iodine. Partial complex seizures with secondary generalization occurred after intrapleural povidone iodine irrigation (7A ). • A 67-year-old healthy white man developed a parapneumonic effusion, which was treated with chest drainage and systemic antibiotics. One week later

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100 ml of povidone iodine 10%, equivalent to iodine 1%, was instilled and drained after 10 minutes via the chest tube. Ten minutes after drainage, he reported headache, especially on the right side, vertigo, deviation of the head and eyes toward the right side, and uncontrolled rapid movements of the right hand. This episode lasted several seconds. Soon after, he became unconscious for a few minutes; his blood pressure was 120/80 mmHg, heart rate 88/minute, and temperature 37◦ C. On the same night he had a similar seizure and recovered spontaneously after 10 minutes, with complaints of fatigue, headache, somnolence, amnesia, nausea, and vomiting. Thereafter he had no further seizures or neurological disturbances. He was not rechallenged with povidone iodine.

Endocrine Hypothyroidism has been reported in infants whose mothers have received local povidone iodine during pregnancy and at delivery (SEDA-25, 277). In the case of premature twins who had markedly enhanced thyroid stimulating hormone concentrations the mother had used povidone iodine pessaries for 7 weeks during pregnancy to prevent vaginal infection (8A ). Altered metabolism of thyroid hormones occurs in children undergoing open heart surgery. The changes typically last from the onset of cardiopulmonary bypass until 5–7 days after surgery. Studies of the effects of perioperative disinfection of the skin with povidone iodine have suggested that cardiopulmonary bypass has a more profound effect on the hypothalamic–pituitary axis than povidone iodine. In a prospective study of the effect of perioperative topical povidone iodine on thyroid hormone status in 20 infants with delayed sternal closure, there was transient hypothyroidism in four of the infants (9c ). The authors concluded that although changes in thyroid hormone metabolism in critically ill infants are difficult to interpret, hypothyroidism in the late postoperative period can be caused by exposure to iodine from povidone iodine. Urinary tract Both povidone iodine irrigation and topical application can cause iodineinduced renal insufficiency (SEDA-27, 240). In a patient who developed hepatic and renal dysfunction, with toxic iodine concentrations during continuous mediastinal irrigation with povidone iodine, hemodialysis and hemofiltration were used for iodine clearance (10A ). Hepatic function and renal function improved with falling plasma iodine concentrations.

Skin Contact dermatitis from povidone iodine is not rare, and the responsible antigens are iodine (11A ) and polyoxyethylene nonylphenyl ether (12c ). However, immediate-type allergy is uncommon. • A 59-year-old woman who had several episodes of contact urticaria after hair treatment developed anaphylaxis after vaginal application of povidone iodine solution for disinfection (13A ). Prick tests showed wheal-and-flare responses to both povidone iodine (0.1% aqueous) and polyvinylpyrrolidone (0.001% aqueous) but not to iodine or polyoxyethylenenonylphenyl ether, both of which are also contained in povidone iodine solution. Basophils from her peripheral blood released considerable amounts of histamine on stimulation by polyvinylpyrrolidone. She was recommended to avoid products containing polyvinylpyrrolidone and remained free of symptoms.

Both the shampoo and the permanent wave solution contained polyvinylpyrrolidone styrene-copolymer emulsion and polyvinylpyrrolidone N,N-dimethylaminoethylmethacrylic acid copolymer diethyl sulfate solution. Both of these agents provoked immediate skin responses on prick testing.

Phenolic compounds

(SED-14, 472,

773, 1703; SEDA-26, 261) Respiratory A flu-like illness has been attributed to phenol. • A 44-year-old man with hemorrhoids underwent submucosal injection sclerotherapy with 5% phenol in almond oil on two occasions 3 weeks apart (14A ). After the second injection he developed a flu-like illness with cough and dyspnea. He had no history of significance and was not taking any medications. He had a core temperature of 37.2◦ C, with a pulse of 115/minute, sinus rhythm, an initial blood pressure of 160/100 mmHg, a respiratory alkalosis, and mild hypoxia. His erythrocyte sedimentation rate was raised (38 mm/hour). An electrocardiogram was normal. A chest X-ray showed diffuse bilateral parenchymal changes with mottled shadowing. A high-resolution CT scan of the lungs showed peripheral interstitial involvement with limited subpleural parenchymal consolidation. He was given oxygen, intravenous fluids, and antibiotics (cefuroxime and levofloxacin) and recovered within 48 hours.

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REFERENCES 1. Kluger M. Anaphylaxis to chlorhexidine-impregnated central venous catheter. Anaesth Intens Care 2003; 31: 697–8. 2. Jayathallake A, Mason DFC, Broome K. Allergy to chlorhexidine gluconate in urethral gel. Report of four cases and review of the literature. Urology 2003; 61: 837. 3. DiStefano F, Verna N, DiGiampaolo L, Boscolo P, DiGioacchino M. Cavitating BOOP associated with myeloperoxidase deficiency in a floor cleaner with incidental heavy exposure to benzalkonium compounds. J Occup Health 2003; 45: 182–4. 4. Kim SJ, Koh H, Park JS, Ahn HS, Choi JB, Kim YS. Hemorrhagic cystitis due to intravesical instillation of gentian violet completely recovered with conservative management. Yonsei Med J 2003; 44: 163–5. 5. Steenland K, Whelan E, Deddens J, Stayner L, Ward E. Ethylene oxide and breast cancer incidence in a cohort study of 7576 women. Cancer Causes Control 2003; 14: 531–9. 6. Brevard TA, Calvert GM, Blondell JM, Mehler LN. Acute occupational disinfectant related illness among youth 1993-1998. Environ Health Perspect 2003; 111: 1654–9. 7. Azzam ZS, Farhat D, Braun E, Krivoy N. Seizures: an unusual complication of intrapleural povidone-iodine irrigation. J Pharm Technol 2003; 19: 94–6. 8. Muthers S, Krude H, Jager R, Rhode W, Graters A, Rossi R. Hypothyroidism in dizygotic premature

twins due to excessive prepartal vaginal iodine application. Zentralbl Gynakol 2003; 125: 226–8. 9. Kovacikova L, Kunovsky P, Lakomy M, Skrak P, Miskova Z, Siman J, Kostalova L, Tomeckova E. Thyroid hormone status after cardiac surgery in infants with delayed sternal closure and continued use of cutaneous povidone-iodine. Endocrine Regul 2003; 37: 3–9. 10. Kanakiriya S, DeChazal I, Nath KA, Haugen EN, Albright RC, Juncos LA. Iodine toxicity treated with haemodialysis and continuous venovenous hemodiafiltration. Am J Kidney Dis 2003; 41: 702–8. 11. Erdmann S, Hertl M, Merk HF. Allergic contact dermatitis from povidone-iodine. Contact Dermatitis 1999; 40: 331–2. 12. Nishioka K, Seguchi T, Yasuno H, Yamamoto T, Tominaga K. The results of ingredients patch testing in contact dermatitis elicited by povidoneiodine preparations. Contact Dermatitis 2000: 42: 90–4. 13. Adachi A, Fukunaga A, Hayashi K, Kunisada M, Horikawa T, Anaphylaxis to polyvinylpyrrolidone after vaginal application of povidone-iodine. Contact Dermatitis 2003; 48: 133–6. 14. Lattuneddu A, Farneti F, Lucci E, Colinelli C. A pulmonary allergic reaction after injection sclerotherapy for hemorrhoids. Int J Colorectal Dis 2003; 18: 459–460.

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Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Prudent future use of antibiotics Soon after the Second World War, when Fleming, Florey, and Chain had received the Nobel Prize for their discovery, doctors, scientists, health authorities, and pharmaceutical companies started to claim that the development of new antibiotics would create a world free of infections. The number of new antibiotics and derivatives of the older one increased year by year, as did the number and types of conditions in which antibiotics were supposed to be of benefit. They therefore soon became amongst the most widely used classes of drugs: 15 years ago they accounted for over 25% of drug costs in many hospitals, and for a generally unknown (but almost certainly higher) proportion of prescriptions in the community (1R ). This is probably still true today. However, the scenario has changed, and the optimistic view has been replaced by great pessimism. Nearly every common pathogenic microbial species, bacteria, viruses, fungi, have developed varying degrees of resistance to an increasing number of drugs. And they are ubiquitous. The SARS virus can be in China one day and Canada the next. It is mainly the total use of antibiotics that is of the greatest importance for the development of resistance, not so much in which milieu they are prescribed. Any use, overuse, or misuse in any sphere of activity, such as human or veterinary medicine, agriculture, or fish farming, can lead to increased resistance, which can later affect any other sphere. The “eco-shadow” principle (2R ) tells us that environmental longevity and a broad © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

spectrum are two factors that have to be taken more seriously into account when explaining the spread of resistance. The pharmaceutical industry is often blamed for this. They have certainly marketed antimicrobial drugs with great enthusiasm and convincing arguments. But we should emphasize that it was we, ordinary prescribers, who asked for drugs with broad spectra and prolonged half-lives; and when the pharmaceutical companies succeeded in making such drugs, we welcomed them. Until a few years ago, the regulatory agencies did nothing more than to introduce some very simple rules for companies that developed and introduced new antibiotics. With few exceptions, they never gave themselves the chance of being active in creating a prudent antimicrobial drugs policy. However, there are two groups that should be highlighted. The first group consists of the national and international professional societies in this field who organize meetings and symposia on anti-infective therapy. Over the years the numbers of such meetings have increased drastically, and so has the influence of the pharmaceutical industry. At many meetings, several sections are devoted to topics such as “Substance X, a new cephalosporin with an extended spectrum”, “Clinical experience with the new macrolide Y”, and so on. As a rule these sessions are heavily sponsored by the manufacturers of the compound, who are often given the task, or privilege, of choosing the speakers. It goes without saying that these sections are often chaired by one of a few members in an international jet set of so-called experts, other members of which may be keynote speakers. The outcome is close to predictable and objectivity is not always high. After a series of optimistic lectures, the chairman sums up by stating that

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266 the drug in question is very promising. However, the memories of these experts are often remarkably short, and they are likely to have told precisely the same story about another drug some few months before (SEDA-16, 274). But the ordinary participants in these meetings can also be blamed. Why are we not more active in arguing? There are several reasons: before the meeting we have too little knowledge about the new compound, we do not want to stick our necks out, and we have learned that it does not help to argue. It has always been difficult and dangerous for soldiers to complain about bad generals. The second group consists of the microbiologists and infectious disease specialists, who are the first investigators of new compounds. It is always easy to jump on the bandwagon and join a multicenter study sponsored by a company that has marketed a new drug or a new formulation of an old one. While accepting that drugs have to be investigated, it is disappointing to see leading experts in infective diseases year after year coming up with exactly the same types of papers, such as “the impact of substance X on the gut flora”, “the antimicrobial profile of substance Y”, “treatment of urinary tract infections by substance Z for three days versus 5 days”, and so on. It is amazing and disappointing to realize that these experts continue to be interested in every single new drug, instead of using their huge knowledge in order to create new trends in the war against microorganisms. There is a real danger when leaders fail to see the wood for the trees. Over the years, when we have charted increasing antimicrobial drug resistance, we have often been told that it might return to normal, or at least be reduced, if we stopped using that particular drug or group of drugs. This assumption has been based in the principle of “biological cost”, i.e. the microbe has to pay for the extra gene or genes that confer resistance. This may be true, but it is far from the whole truth. Resistant microbes will not be outnumbered by sensitive ones, but they can live side by side for an unknown period (3R ). It generally confers biological benefit on a microbe to become resistant in the presence of antibiotic pressure. Increased efflux, by which the microbe can get rid of several compounds, including antibiotics, is an example of a positive benefit. Once established, antimicrobial drug

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resistance can be coupled to resistance to other compounds present in the surroundings, such as disinfectants (4R ) or heavy metals (5R ). As mentioned before (SEDA-25, 279), there is promising work going on. The World Health Organization, the European Union, and several countries have started to collect data about levels of resistance in important groups of pathogens, and international study groups have been established for rapid interchange and evaluation of these data. Of course, this is of great importance, but the outcome is clear: if we continue to use antimicrobial drugs in the way that we are currently using them, more and more microbial strains in more and more countries will become increasingly resistant to an increasing number of drugs. However, there is light at the end of the tunnel. National and international bodies have been established to provide guidance; these include ISGNAS (the International Study Group for New Antimicrobial Strategies; http://www. isgnas.org and SACAR (the Special Advisory Council for Antimicrobial Resistance in the UK; http://www.advisorybodies.doh.gov.uk/ sacar). The use of lytic bacterial phages, even genetically engineered, may have a renaissance (6R ). The search for naturally occurring plant products has intensified, and there are already promising results; for example, a study of Brazilian traditional medicinal plants has shown that “these natural products can be effective potential candidates for the development of new strategies to treat MRSA infections” (7R ). However, the most promising agents may come from the animal kingdom. It is now well recognized that all types of animals, mammals, birds, amphibians, fish, insects, etc, produce a long series of antimicrobial peptides to protect themselves. These antimicrobial peptides are cornerstones in our so-called innate immunity. The discovery of specific mediators that influence the productions of these peptides or “autobiotics” has created new possibilities for the development of alternative treatment strategies (8R ). However, all these compounds and strategies should be looked on in a broader sense. The mere fact that horizontal gene transfer is a major mechanism for transfer of resistance in microbes makes it unlikely that any new compound will have more than a temporary effect.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

To be honest “modern society knows that it desperately needs to learn how to live in harmony with the biosphere” (9R ) and “a new biology for a new century” should include increased exposure to beneficial microbes, as probiotics.

BETA-LACTAM ANTIBIOTICS (SED-14, 785; SEDA-25, 262; SEDA-26, 279; SEDA-27, 242)

Immunologic reactions to penicillins: cross-reactivity with cephalosporins Penicillins and other beta-lactam antibiotics, such as cephalosporins and carbapenems, are still by far the most widely used antibiotics for common infections. However, they are also by far the most common cause of drug allergy, especially IgE-mediated reactions, such as urticaria and anaphylaxis. Over the years, an important question has been cross-reactivity between the different classes of beta-lactams, and there is still confusion about whether it is safe to give a cephalosporin to a patient who is allergic to penicillin. This can lead to either underestimation or overestimation of the risks. In both cases, there can be negative consequences for the patient. It has recently been reported that six of 12 fatal anaphylactic reactions occurred after the first dose of cephalosporin (10C ). Three of the six patients were known to be allergic to amoxicillin and one was allergic to benzylpenicillin. On the other hand, because of the fear of cross-reactivity, the most common therapeutic approach to patients who are allergic to penicillin is to select antibiotics that do not contain a beta-lactam ring. However, reduced effectiveness, increased antimicrobial resistance, and higher costs are major drawbacks of this policy (11C ). Cross-reactivity to cephalosporins in patients with well documented severe penicillin allergy has been studied in 128 consecutive patients who had an anaphylactic reaction (n = 81) or urticaria (n = 47) and had positive skin tests for at least one of the penicillin reagents tested (penicilloyl-polylysine, minor determinant mixture, benzylpenicillin) (12C ).

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They were skin tested with cefamandole, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and cephalothin. Patients with negative results with four cephalosporins were challenged with cefuroxime axetil and ceftriaxone. Fourteen of the 128 patients (11%) had positive skin tests for one or more of the cephalosporins tested. Challenge with a cephalosporin was refused by 22 patients. All 101 patients with negative results on skin tests tolerated cefuroxime axetil and ceftriaxone. The authors stated that their data confirmed the advisability of avoiding cephalosporins in patients with positive skin tests for penicillins. However, it should be emphasized that crossreactivity can be very specific and not easy to predict, as shown in a recent report (13c ). • A 3-year-old girl developed an anaphylactic reaction within 10 min after intravenous administration of the second dose (750 mg) of ceftriaxone for a urinary tract infection (14c ). After treatment with anti-shock therapy, her symptoms were considerably reduced within 1 hour and completely resolved after 12 hours. She had no previous history of drug allergy or atopy and no family history of allergic disease. Six months later she underwent prick and intradermal skin tests with standard concentrations of penicilloyl-polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, amoxicillin, cefaclor, cefotaxime and ceftabuten, cefalexin. Assays for specific IgE were performed for penicilloyl G and penicilloyl V. The patient had positive responses to prick testing with ceftriaxone and ampicillin. All assays for specific IgE were negative. When both in vivo and in vitro tests were negative, single-blind, placebocontrolled challenges with progressively increasing amounts of the respective drugs were performed. Challenges were positive only to cefalexin.

Taken together, these results suggest the presence of antigenic determinants unrelated to the beta-lactam ring but at the same time not completely side-chain specific. The patient reacted to cefalexin and ampicillin but not to cefaclor, all drugs with identical side-chains. In fact, the difference between cefalexin and cefaclor is in only one functional group (a methyl group instead of a chlorine at the R2 position of the thiazolidine ring). Whatever the mechanisms might be this is the first case of immediate hypersensitivity to ceftriaxone and cross-reactivity with cefalexin and ampicillin in a child. There are few data about the cross-reactivity of the carbapenems (imipenem-cilastatin, meropenem, ertapenem) with other beta-lactams and

268 between the three compounds in the group. In an early report it was stated that about 50% of patients with penicillin allergy also reacted to imipenem-cilastatin (15C ). However, the statement was based on skin testing of only 20 patients. A more recent retrospective review of patients undergoing bone marrow transplantation found about 10% cross-reactivity with imipenem-cilastatin in patients with self-reported or confirmed penicillin allergy (16C ). There has been a large retrospective study of the comparative incidence of cross-reactivity associated with a carbapenem (imipenem-cilastatin or meropenem) in patients with and without penicillin allergy (n = 100 and n = 111 respectively) (17C ). Of those with reported or documented penicillin allergy 11% had an allergic-type reaction to a carbapenem, 5.2 times greater than the risk in patients who were reportedly not allergic to penicillin. There was no difference in the occurrence of allergictype reactions between the two carbapenems. The authors concluded that “clinicians should be cautious whenever imipenem-cilastatin or meropenem is administered to patients who are allergic to penicillins.” Thus, cross-reactivity between carbapenems and penicillins is well established. Crossreactivity between the various carbapenems is still a more open question. In animals, antimeropenin antibodies raised in rabbits and guinea pigs had cross-reacted weakly with imipenem (18r ). In one report of anaphylaxis in a patient treated with imipenem-cilastatin, skin testing 2 weeks after the reaction was positive for imipenem- cilastatin and for imipenem alone, but negative for cilastatin alone and for meropenem (19c ). A similar case was recently published. • A 41-year-old woman was admitted to an intensive care unit with postoperative septicemia and was given imipenem-cilastatin (dosage not stated) for a presumed intra-abdominal infection (20C ). Within 48 hours of starting imipenem-cilastatin, a large erythematous maculopapular rash with areas of urticaria appeared in several places on her body. Imipenem-cilastatin was withdrawn and within some days the skin eruption faded. However, she developed several other complications, and after 10 weeks in the intensive care unit several abdominal abscesses had to be drained subcutaneously. Cultures from these abscesses showed Gram negative rods and Gram positive cocci, resistant to nearly all commercially available antibiotics.

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One of the few antibiotics that had some activity against both groups of bacteria was imipenem. It was believed that the benefit of using meropenem outweighed the possible risks, and she received challenge doses of meropenem, which she tolerated well, followed by a full 14-day course without skin eruptions. About 7 days after the completion of the course of meropenem her clinical status had not improved significantly, her family opted to withdraw care, and she died.

The authors reported that they did not recommend indiscriminate use of meropenem in patients with a history of imipenem allergy, and that it should only be considered if clinical circumstances demand a carbapenem antibiotic and then only after a dose-challenging regimen.

CEPHALOSPORINS

(SED-14, 821; SEDA-25, 283; SEDA-26, 264; SEDA-27, 245)

Nervous system Since penicillin G-induced convulsions were observed in 1945 (21c ), many investigators have studied the convulsive effects of the beta-lactams, the mechanism(s) of action, and structure-activity relations. The convulsive effects of seven different cephalosporins have been studied both in vivo and in vitro, by intracerebroventricular administration in mice, labelled 3 H-muscimol binding in mouse brain synaptosomes, and inhibition assays in Xenopus oocytes (22R ). The rank orders of convulsive effects were cefazolin > cefoselis > cefotiam > cefpirome > cefepime > ceftazidime > cefozopran. The authors suggested that the strong correlation between this effect and affinity for muscimol binding sites implies that most cephalosporins inhibit GABA-mediated transmission by binding to some specific subunits of the GABA receptors. They speculated that cefazolin and cefoselis might recognize a different molecular motif on GABA receptors from that detected by other cephalosporins. However, they also emphasized that while these results are suggestive, they do not completely clarify the convulsive risk of these cephalosporins and that intensive pharmacokinetic and pharmacodynamic studies will be required to predict the potential convulsive risk of these antibiotics. The convulsive effects of the cephalosporins may be caused by suppression of inhibitory neurotransmission via modulation of GABAA

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

receptors (23R ). Furthermore, radioligand binding studies show that cephalosporins inhibit GABA binding (24r ). Consistent with this hypothesis, positive modulators of these receptors, such as benzodiazepines and barbiturates, can prevent or treat cephalosporin-induced convulsions.

Cefepime Nervous system Cefepime can cause neurotoxic and neuropsychiatric symptoms (SEDA26, 264; SEDA-27, 245), and clinical reports (25R , 26c ) and experimental reports (27r ) concerning this and other beta-lactams continue to appear. The following two case reports can be taken as brief reminders. • A 60-year-old man with diabetes mellitus and endstage renal disease on hemodialysis was given cefepime 2 g/day for a supposed pneumonia (28c ). Five days later he became confused and agitated and had visual and auditory hallucinations. His symptoms did not improve with further dialysis over 2 days, and cefepime was withdrawn. Within 1 day he started to improve, and 2 days later had regained his baseline mental status. He had hallucinations and confusion after taking ceftazidime a year before. • A 66-year-old woman with acute myeloid leukemia had a fever on third day of the initial chemotherapy cycle (29c ). She was given empirical antibiotic treatment with cefepime 2 g every 8 hours and 10 days later developed acute renal insufficiency and altered consciousness (Glasgow coma scale 6). An electroencephalogram showed generalized spike and sharp wave activity compatible with nonconvulsive status. Cefepime was withdrawn and the epileptiform activity disappeared with clonazepam. She regained consciousness 48 hours after cefepime withdrawal.

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derivatives of cephalosporins continue to be marketed, as do reports that they can be given to healthy volunteers without concern (30C ). However, taking a closer look at the data, it is evident that healthy volunteers lost around 10% of their body stores of carnitine within 2 weeks of being given antibiotics containing pivalic acid (31C ). The authors emphasized that prolonged used of such drugs might result in profound carnitine depletion and that this depletion might be associated with clinical sequelae. Valproate also causes urinary loss of carnitine (SEDA-12, 209), most probably by a different mechanism than pivalic acid (32r ). However, the combination can rapidly cause serious adverse effects (33c ). • A 72-year-old woman taking valproate as monotherapy for her epilepsy developed a urinary tract infection and was given pivmecillinam 600 mg/day. During the next few days she became stuporose; her serum ammonia concentration was high (113 mmol/l) but liver function was normal. Pivmecillinam and valproate were withdrawn and she recovered rapidly.

Ceftriaxone

The authors recommended caution when treating patients taking valproate with pivmecillinam because of the risk of hyperammonemic encephalopathy. It seems reasonable to assume that this caution should include all beta-lactams that incorporate pivalic acid. However, there may be another mechanism by which cephalosporins can interfere with carnitine metabolism. Cephalosporins with a quaternary nitrogen (cefepime, cefluprenam, cefoselide, and cefaloridine) compete with carnitine for renal reabsorption due to OCNT2, a major member of the family of organic cationic transporters (34R ). Mutations in the OCNT2gene are responsible for the genetic disorder primary systemic carnitine deficiency (35r , 36r ). Since carnitine and the cephalosporins mentioned above compete for the same substrate-binding site on OCTN2, it is likely that such mutations will interfere with the pharmacokinetics of these drugs. Consequently these cephalosporins should not be given to patients with such mutations.

Metabolism Although possible interference with the metabolism of carnitine by pivaloylmethyl-esterified beta-lactams is a matter of concern (SEDA-21, 260), new similar prodrug

Urinary tract Soon after ceftriaxone had been introduced it became clear that it can cause pseudolithiasis or gall-bladder sludge in many patients, especially children (SEDA-15,

The authors emphasized that neurotoxic symptoms are not uncommon in patients receiving cephalosporins and that non-convulsive status epilepticus is often underdiagnosed.

270 258), and reports continue to appear. One patient had both biliary pseudolithiasis and renal stones (37C ). Since then, at least seven other cases have been reported, six in children (38c , 39c ) and one in an adult. All had some form of renal impairment with either anuria, a raised serum creatinine, or a dilated collecting system on imaging. One required extracorporeal shockwave lithotripsy and one required nephrostomy. Now another case has been reported (40c ). • A 14-year-old boy with severe sinusitis complicated by an epidural abscess was given intravenous ceftriaxone 4 g/day and metronidazole. On day 8 he developed colicky abdominal pain and vomiting. His serum creatinine had risen from 70 to 420 µmol/l. His urine output fell and he had anuria for 24 hours. A CT scan of the abdomen showed high-density material in his gallbladder and in the collecting system of both kidneys and throughout both ureters. The ceftriaxone was withdrawn. On day 9 bilateral urethral stents were placed at cystoscopy and proteinaceous toothpaste-like material was found in both ureters. After another 3 weeks a CT scan showed complete resolution of the biliary pseudolithiasis and the material in the ureters, and the serum creatinine had returned to 60 µmol/l.

Taking all reports together, it is easy to accept the authors’ suggestion that nephrolithiasis secondary to ceftriaxone is generally more serious than the biliary complications, since intervention to relieve renal obstruction is often necessary. In patients receiving ceftriaxone, any impairment in renal function should be taken as a warning signal.

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In general, antimicrobial agents that are directly administered to the periodontal pocket to treat periodontitis should cause little or no damage to host cells. This holds true even when they are used after conventional surgical surface scaling and curettage, because epithelial regeneration is of importance for healing of inflammation. This is the background for a recent investigation of the cytocidal effect of eight different antimicrobial agents on a human gingival epithelial cell line (NDUSD-1) (41R ). The order of the agents according to their cytocidal effects (LD-50) was minocycline > tetracycline > enoxacin > clarithromycin > roxithromycin = ofloxacin > azithromycin > erythromycin. The maximum non-cytocidal concentrations were 0.3 µmol/l of minocycline and 100 µmol/l for erythromycin. In a previous study the cytocidal effect of minocycline on normal human gingival cells in secondary culture was greater than that of tetracycline, and the effect depended on both the intracellular concentrations of the compounds and their persistence in the cells (42r ). These findings need to be extrapolated to in vivo conditions, but in the meantime it would be wise not to use minocycline locally for periodontitis.

Doxycycline

(SED-14, 911; SEDA-25, 346; SEDA-27, 247)

TETRACYCLINES

Nervous system The idiopathic form of benign intracranial hypertension typically occurs in obese women in their 30s and 40s. Intracranial hypertension has been described in two patients taking doxycycline (43A ).

Mouth Periodontitis is very common in adults and is thought to be due to microbial imbalance in the tooth pocket, giving rise to chronic inflammation. In the last decade, long-term topical use of various antibiotics, including tetracyclines such as doxycycline and minocycline, has been tried, with some success. The effects of the tetracyclines may partly be due to their antibacterial effect and partly due to their effects on matrix metalloproteases (SEDA-24, 278). Whatever the mechanisms might be, tetracyclines designed for topical application are now being marketed in several countries.

• A slightly overweight 21-year-old woman presented with headaches and blurred vision after taking doxycycline 100 mg/day for malaria prophylaxis during a 3-week vacation. She had severe papilledema with hemorrhages and cotton wool spots. Lumbar puncture showed an increased opening pressure of 52 cm of fluid, and intracranial hypertension was diagnosed. Doxycycline was withdrawn, and her symptoms gradually resolved. • A slightly overweight 19-year-old woman presented with vomiting, headache, and blurred vision after taking doxycycline 100 mg/day for malaria prophylaxis over about 4 months. Her vision was severely reduced and her visual fields constricted. She had papilledema with hemorrhages and cotton

(SED-14, 906; SEDA-25, 284; SEDA-26, 265; SEDA-27, 247)

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines wool spots. Lumbar puncture showed an increased cerebrospinal fluid pressure of over 40 cm of fluid. Intracranial hypertension was diagnosed and doxycycline was withdrawn. Her symptoms stabilized and the disc swelling resolved, but optic atrophy developed. Colour vision and visual fields remained poor, with an estimated 70% loss of vision.

The authors concluded that doxycycline should be prescribed with caution to overweight women of childbearing age or with a history of idiopathic intracranial hypertension and that awareness of this adverse drug reaction in travellers should be increased to allow prompt withdrawal of the causing drug and appropriate medical therapy in affected individuals. Skin Annular and semicircular actinic granulomata have been described in two patients taking doxycycline 100 mg/day for 1–5 months for malaria prophylaxis (44A ). Both had phototoxicity and severe sunburn after starting doxycycline.

Minocycline Nervous system Tetracyclines, including minocycline, can cause benign intracranial hypertension, with increased intracranial pressure without evidence of an intracranial spaceoccupying lesion, hydrocephalus, infection, or hypertensive encephalopathy. • A 15-year-old woman developed worsening bilateral headache and a perception of intracranial noise (45c ). She had begun taking minocycline for acne several days before the onset of the headache. There was papilledema with loss of physiological cupping, indistinct disc margins, and small retinal hemorrhages bilaterally. Visual acuity was reduced in her right eye (29/60) but her visual fields were full. She had also bilateral sixth nerve palsies on extreme lateral gaze. Minocycline was withdrawn and she was given acetazolamide 250 mg bd. One month later fundoscopy showed indistinct disc margins and she had episodes of blurred vision; acetazolamide was continued.

The pathogenesis of drug-induced intracranial hypertension is not well understood, and the symptoms may be more diffuse than in the present case. There is experimental evidence that minocycline may be neuroprotective in Parkinson’s disease (46c ).

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Psychiatric Transient depersonalization symptoms have been attributed to by minocycline (47c ) and may have been caused by increased intracranial pressure. Skin The incidence of skin discoloration from minocycline varies from 2.4% to almost 15% (48R , 49R ). According to a well-accepted classification there are three distinct clinical pictures. Type I is blue-black pigmentation confined to sites of scarring or inflammation on the face. Type II is blue-grey circumscribed pigmentation of normal skin of the lower legs and forearms. Type III is diffuse muddy brown pigmentation of normal skin accentuated in sun-exposed areas. Now a fourth type has been described (50c ). • Two 22-year-old men with acne were given minocycline. The first took minocycline 100 mg/day for 1 month, estimated cumulative dose 3 g, 2 years before presentation. The second took minocycline in two different periods before presentation, estimated dose 13.5 g. Both had blue-grey pigmentation confined to acne scars on the back, whereas scars on the face and chest were unaffected, and there was no hyperpigmentation in other areas. Histology showed pigment within dendritic cells and extracellularly throughout the dermis. Histochemistry identified a calcium-containing melanin-like substance. Electron microscopy showed electron-dense granules, both free and membrane bound, within macrophages and some other cells in the dermis. Energy-dispersive X-ray analysis confirmed the presence of calcium. The patients were followed for 3 years and their pigmentation did not change.

Skin discoloration is not a serious adverse effect, but is cosmetically undesirable. Therefore, although it is rare, it has to be taken into consideration when minocycline is prescribed. Musculoskeletal An acute myopathy has been attributed to minocycline. • A 17-year-old youth, who had taken minocycline 100 mg/day for acne 15 days before admission, abruptly developed diffuse myalgia (51c ). He had increased creatine kinase, aspartate transaminase, alanine transaminase, lactate dehydrogenase, aldolase, alkaline phosphatase, and gammaglutamyltransferase activities. Other baseline laboratory results were normal. Minocycline was withdrawn. After 1 month the enzyme activities returned to normal and his symptoms resolved.

272 • A 20-year-old black professional ballet dancer, with no significant past medical history or other drug use, took minocycline for 3 weeks to treat acne and developed arthralgias and facial swelling (52c ). She stopped taking minocycline and started to take dexamethasone and loratadine for what she

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described as “an allergic reaction”. However, after about 1 month she was admitted to hospital with erythema and edema around her eyes. Her muscle enzyme activities were increased and a tentative diagnosis of rhabdomyolysis was made.

REFERENCES 1. Smith AJ, Aronson JK, Thomas M. Antibiotic policies in the developing world. Eur J Clin Pharmacol 1991; 41: 85–7. 2. Midtvedt T. The ECO-SHADOW concept – a new way of following environmental impacts of antimicrobials. In Kammerer K (editor): Pharmaceuticals in the environment. Source, fate, effects and risks. Berlin-Heidelberg-New York: Springer Verlag, 2001: 230–6. 3. Johnsen PG, Simonsen GS, Olsvik O, Midtvedt T, Sundsfjord A. Stability, persistence, and evolution of plasmid-encoded Van A glycopeptide resistance in enterococci in the absence of antibiotic selection in vitro and in gnotobiotic mice. Microbial Drug Res 2002; 8: 161–70. 4. Heir E, Langsrud S, Sidhu MS, Steinbakk M. Kan desinfeksjonsmidler bidra til bakteriel antibiotikaresistens? Tidsskr Nor Laegeforen 2001; 121: 3201–6. 5. Lazar V, Cernat R, Balotescu C, Cotar A, Coipan E, Cojocaru C. Correlation between multiple antibiotic resistance and heavy-metal tolerance among some E. coli strains isolated from polluted water. Bacteriol Virusol Parazitol Epidemiol 2002; 47: 155–160. 6. Westwater C, Kasman LM, Shofield DA, Werner PA, Dolan JW, Schmidt MG, Norris JS. Use of genetically engineered phage to deliver antimicrobial agents to bacteria: an alternative therapy for treatment of bacterial infections. Antimicrob Agents Chemother 2003; 47: 1301–7. 7. Machado TB, Pinto AV, Pinto MC, Leal IC, Silva MG, Amaral AC, Kuster RM, Netto dos Santos KR. In vitro activity of Brazilian medical plants, naturally occurring naphthoquinones and their analogues, against methicillin-resistant Staphylococcus aureus. Int J Antimicrobial Agents 2003; 21: 279–84. 8. Yeman MR, Yuont NY. Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev 2003; 55: 27–55. 9. Woese CP. A new biology for a new century. Microbiol Molec Biol Rev 2004; 68: 173–86. 10. Pumphrey RS, Davis S. Under-reporting of antibiotic anaphylaxis may put patients at risk. Lancet 1999: 353; 1157–8. 11. Kelkar PS, Li JT. Cephalosporin allergy. New Engl J Medicine 2001; 345: 804–9. 12. Romano A, Gueant-Rodrique RM, Viola M, Gueant JL. Cross-reactivity and tolerability of cephalosporins in patients with immediate hyper-

sensitivity to penicillins. Ann Intern Med 2004; 141: 16–22. 13. Atanaskovic-Markovic M, Gavrovic-Jankulovic M, Cirkovic Velickovic T, Vuckovic O, Todoric D. Type-I hypersensitivity to ceftriaxone and crossreactivity with cefalexin and ampicillin. Allergy 2003; 58: 537–8. 14. Romano A, Quaratino D, Venemalm L, Torres MJ, Venuti A, Blanca M. A case of IgE-mediated hypersensitivity to ceftriaxone. J Allergy Clin Immunol 1999; 104: 1113–14. 15. Saxon A, Adelman DC, Patel A, Hajdu R, Calandra GB. Imipenem cross- reactivity with penicillins in humans. J Allergy Clin Immunol 1988; 88: 213–17. 16. McConnell SA, Penzal SR, Warmack TS, Anaisse EJ, Gibbins PO. Incidence of imipenem hypersensitivity reactions in febrile neutropenic bone marrow transplant patients with a history of penicillin allergy. Clin Infect Dis 2000; 31: 1512– 14. 17. Prescott WA, DePestel DD, Ellis JJ, Regal RE. Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy. Clin Infect Dis 2004; 38: 1101–7. 18. Nakanish T, Kohda A, Kato T, Appleford DJA, Pulsford AH. Antigenicity tests of meropenem. Chemotherapy (Tokyo) 1992; 40: 251–7. 19. Chen Z, Baus X, Kutscha-Lissberg F, Merget R. IgE-mediated anaphylactic reaction to imipenem. Allergy 2000; 55: 92–3. 20. Bauer SL, Wall GC, Skoglund KJ, Peters LK. Lack of cross-reactivity to meropenem in a patient with an allergy to imipenem-cilastatin. J Allergy Clin Immunol 2004; 113: 173–5. 21. Johnson HC, Walker AE. Intraventricular penicillin; a note of warning. J Am Med Assoc 1945; 127: 212–19. 22. Sugimoto M, Uchida I, Mashimo T, Yamazaki S, Hatano K, Ikeda F, Mochizuki Y, Terai T, Matsuoka N. Evidence for the involvement of GABA A receptor induced by cephalosporins. Neuropharmacology 2003; 45: 304–14. 23. Fujimoto M, Munakata M, Akaike N. Dual mechanisms of GABA-A response inhibition by beta-lactam antibiotics in the pyramidal neurones of the rat cerebral cortex. Br J Pharmacol 1995; 116: 3014–20. 24. Hori S, Kurioka M, Matsuda M, Shimada J. Inhibitory effect of cephalosporins on gammaaminobutyric acid receptor binding in rat synaptic

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines membranes. Antimicrob Agents Chemother 1985; 27: 650–1. 25. Chow KM, Szeto CC, Hui AC, Wong TY, Li PK. Retrospective review of neurotoxicity induced by cefepime and ceftazidime. Pharmacotherapy 2003; 23: 369–73. 26. Primavera A, Cocito L, Audenino D. Nonconvulsive status epilepticus during cephalosporin therapy. Neuropsychobiology 2004; 49: 218–22. 27. Zivanovic D, Stanojlovic O, Stojanovic J, Susic V. Induction of audiogenic seizures in imipenem/cilastatin-treated rats. Epilepsy Behav 2004; 5: 151–8. 28. Dakdouki GK, Al-Alwar GN. Cefepimeinduced encephalopathy. Int J Inf Dis 2004; 8: 59–61. 29. Abanades S, Nolla J. Reversible coma secondary to cefepime neurotoxicity. Ann Pharmacother 2004; 38: 606–8. 30. Brass EP, Mayer MD, Mulford DJ, Stickler TK, Hoppel CHL. Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil. Clin Pharmacol Ther 2003; 73: 338–47. 31. Abrahamsson K, Melander M, Eriksson BO, Holme E, Jodal U, Jonasson A. Transient reduction of human left ventricular mass in carnitine depletion induced by antibiotics containing pivalic acid. Br Heart J 1995; 74: 656–9. 32. Melegh B, Kerner J, Jaszai V, Bieber L. Differential excretion of xenobiotic acylesters of carnitine due to administration of pivampicillin and valproate. Biochem Med Metabol Biol 1990; 43: 30–8. 33. Lokrantz CM. Eriksson B, Rosen I, Asztely F. Hyperammonemic encephalopathy induced by a combination of valproate and pivmecillinam. Acta Neurol Scand 2004; 109: 297–301. 34. Ganapapathy ME, Huang W, Rajan DP, Carter AL, Sugawara M, Isek K, Leiback FH, Ganapathy V. Beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. J Biol Chem 2000; 275: 1699–707. 35. Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, Say Y, Koizumi A, Shoji Y, Takada G, Matsuishi T, Yoshino M, Kato A, Ohura T, Tsujimoto G, Hayakawa J, Shimane M, Tsuji A. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter, Nature Genet 1999; 21: 91–4. 36. Burwinkel B, Kreuder J, Schweitzer S, Vorgerd M, Gempel K, Gerbitz KD, Kilimann MW. Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation asso-

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ciated with an unconventional splicing abnormality. Biochem Biophys Res Commun 1999; 261: 484–7. 37. Shaad UB, Tschaeppler H, Lentze MJ. Transient formation of precipitations in the gallbladder associated with ceftriaxone therapy. Pediatric Infect Dis 1986; 5: 708–10. 38. De More RA, Egberts ACG, Schroder CH. Ceftriaxone-associated nephrolithiasis and biliary pseudolithiasis. Eur J Pediatr 1999; 158: 975–7. 39. Grasberger H, Otto B, Loeschke K. Ceftriaxone-associated nephrolithiasis. Ann Pharmacother 2000; 34: 1076–7. 40. Prince JS, Senac MO. Ceftriaxone-associated nephrolithiasis and biliary pseudolithiasis in a child. Pediatr Radiol 2003; 33: 648–51. 41. Inoue K, Kumakura S, Uchida M, Tsutsui T. Effects of eight antibacterial agents on cell survival and expression of epithelial cell- or cell-adhesionrelated genes in human gingival epithelial cells. J Periodontal Res 2004; 39: 50–8. 42. Sato H, Tsutsui T. Effect of tetracyclines on cell survival of cultured human gingival keratinocytes and intracellular concentrations of incorporated tetracyclines. J Jap Soc Periodont 1998; 40: 1–8. 43. Lochhead J, Elston JS. Doxycycline induced intracranial hypertension. Br Med J 2003; 326: 641–2. 44. Lim DS, Triscott J. O’Brien’s actinic granuloma in association with prolonged doxycycline phototoxicity. Australas J Dermatol 2003; 44: 67–70. 45. Cellucci T, Lee L, Juurlink DN. The headache of teenage acne. Can Med Assoc J 2004; 170–1. 46. Thomas M, Le WD. Minocycline: neuroprotective mechanisms in Parkinson’s disease. Curr Pharm Des 2004; 10: 679–86. 47. Cohen PR. Medication-associated depersonalizing symptoms: report of transient depersonalization symptoms induced by minocycline. South Med J 2004; 97: 70–3. 48. Goulden V, Glass D, Cunliffe WJ. Safety of long-term high dose minocycline in the treatment of acne. Br J Dermatol 1996; 134: 693–5. 49. Dwyer CM, Cuddihy AM, Kerr REI. Skin pigmentation due to minocycline treatment of facial dermatosis. Br J Dermatol 1993; 129: 158–62. 50. Mouton RW, Joordan HF, Schneider JW. A new type of minocycline-induced cutaneous hyperpigmentation. Clin Exp Dermatol 2004; 29: 8–14. 51. Narvaez J, Vilaseca-Momplet J. Severe acute myopathy induced by minocycline, Am J Med 2004; 116: 282–3. 52. Rahman Z, Weinberg J, Scheinfeld N. Minocycline hypersensitivity syndrome manifesting with rhabdomyolysis. Int J Dermatol 2002; 41: 430.

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Miscellaneous antibacterial drugs

AMINOGLYCOSIDES

(SED-14, 837; SEDA-25, 287; SEDA-26, 271; SEDA-27, 251)

Sensory systems In an animal model of ototoxicity, the most severe degeneration in the cristae ampullaris, utricle, and saccule was observed after administration of streptomycin. The severity of the vestibular damage in terms of magnitude was in the order streptomycin > gentamicin > amikacin > netilmicin (1E ). Urinary tract Non-oliguric renal insufficiency is a well-known nephrotoxic consequence of aminoglycosides, although reversible tubular damage in the absence of any change in renal function has occasionally been found. Two representative cases of reversible tubular damage due to prolonged aminoglycoside administration have been reported: a patient with a Fanconi-like syndrome of proximal tubular dysfunction and a patient with a syndrome of hypokalemic metabolic alkalosis associated with hypomagnesemia (2A ).

disturbance in his ability to smell, which led to complete anosmia within a few days. Psychometric examination was compatible with complete anosmia. Some 18 months later, he reported that his sense of smell had largely returned during the previous 6 months.

Arbekacin In a retrospective study of the efficacy and safety of arbekacin in 29 children the overall clinical effectiveness rate was 79% with no differences associated in different types of infection (4c ). There were no abnormal auditory brainstem responses or significant changes in serum creatinine associated with arbekacin. Urinary tract Animal experiments have suggested that pazufloxacin has a protective effect on arbekacin-induced nephrotoxicity, and that this is attributable to inhibition of uptake of arbekacin by cortical renal tubules (5E ).

Amikacin Gentamicin Sensory systems Olfactory disorders are among the rare adverse effects of antibiotic therapy. Reversible anosmia has been described. • A 50-year-old man with lymphangitis of the forearm was given intravenous amikacin sulfate 500 mg bd and intravenous co-amoxiclav 1.2 g tds for 5 days (3A ). Before treatment began, there was no investigation of his nose or sense of smell. However, after a septoplasty some 5 years earlier he thought that his olfaction was completely normal. At the end of the treatment period, he noticed a © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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Sensory systems Intratympanic injections of gentamicin 27 mg/ml were performed at weekly intervals in 71 patients with Menière’s disease (6C ). Vertigo was controlled by gentamicin instillation in 83%. Two years after treatment, there was hearing loss as a result of the gentamicin injections in only 11 patients. Mineral balance In a prospective study in 659 neonates who received gentamicin for more than 4 days, the incidence of hypocalcemia was five times higher after the dosage was changed from 2.5 mg/kg bd to 4 mg/kg/day (7C ).

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Urinary tract In a retrospective review of 744 patients who were dose-individualized with gentamicin once daily, in those patients in whom nephrotoxicity was predicted from a change in gentamicin clearance, this change occurred on average 3 days before the change in creatinine clearance (8C ). Agents that can augment aminoglycosideinduced nephrotoxicity (for example calcium channel blockers and nephrotoxic agents such as ciclosporin) should not be combined with these antibiotics. However, antioxidant drugs, especially the natural antioxidants, seem to have the most potential for clinical use. Of these natural antioxidants, melatonin seems to be the most promising in abating nephrotoxicity (9R , 10E , 11E ). Musculoskeletal In human osteoblast-like cells in vitro, gentamicin, at high concentrations (100 µg/ml and above), as achieved after topical application, inhibited cell proliferation; It may therefore be detrimental to repair in vivo (12E ). Immunologic Systemic allergy to gentamicin, including drug-induced cytopenias and rashes, is very rare. • Systemic anaphylaxis after intravenous gentamicin has been reported in a 70-year-old woman (13A ). During the first injection of gentamicin she developed anaphylaxis and was treated in intensive care for 5 days. A few weeks after full recovery, open patch testing showed type IV sensitization to gentamicin sulfate.

Kanamycin Sensory systems Antioxidant therapy protects against aminoglycoside-induced ototoxicity in animals. In adult mice receiving concurrent treatment with kanamycin (700 mg/kg bd for 15 days), extracts of Salviae miltiorrhizae significantly attenuated auditory threshold shifts induced by kanamycin (approximately 50 dB) but did not reduce the serum concentrations or antibacterial efficacy of kanamycin (14E ).

Neomycin Immunologic Contact dermatitis has again been attributed to neomycin (15A ). • Contact dermatitis occurred in an 86-year-old woman with pemphigus foliaceus using a topical triple antibiotic containing polymyxin B sulfate, neomycin, and bacitracin. This was accompanied by an acute flare in her pemphigus over the chest, back, and arms, the most severe flare that she had experienced since her initial presentation.

Tobramycin Respiratory Bronchospasm is an expected acute response in some patients after inhalation, and can be associated with factors that are specific to the formulation (for example osmolality, pH, and the use of preservatives). Bronchospasm within 30 minutes of administration of tobramycin solution for inhalation was transient and similar to that observed after inhalation of placebo (16R , 17R ). Sensory systems Hearing loss, as measured by audiological testing, did not occur in patients using tobramycin by inhalation, and neither did patients complain of hearing loss when they had tinnitus (16R ). However, some patients receiving tobramycin by inhalation have reported hearing loss in postmarketing experience. These patients also frequently reported tinnitus. Some had previous or concurrent systemic aminoglycoside treatment. Parenteral aminoglycosides are toxic to both auditory and vestibular neurosensory cells. There were no significant audiometric abnormalities in 10 patients with cystic fibrosis who received single-dose nebulized tobramycin 400 mg. Drug administration route There was no difference between recipients of tobramycin by inhalation or placebo in serum creatinine concentrations at week 0 or week 20 in clinical trials (16R ). In two studies in which nebulized tobramycin 300 mg twice/day was administered, systemic peak concentrations were below 0.2 and 3.62 µg/ml, and trough concentrations were undetectable, making toxicity from this route of administration negligible. However, high concentrations can occur.

276 • A 19-year-old woman who received a heart transplant was given tobramycin by inhalation for Acinetobacter baumanii pneumonia; her serum trough concentrations were toxic (>2.0 µg/ml) (18A ). Her risk factors for these toxic concentrations were renal Insufficiency and administration of the drug by positive pressure ventilation.

Susceptibility factors Renal impairment Renal excretion of tobramycin accounts for 90% of the administered dose, and its elimination is prolonged in patients with impaired renal function. The amount of tobramycin eliminated during plasma exchange represented less than 10% of total body stores (19R ).

CHLORAMPHENICOL AND RELATED DRUGS (SED-14, 848; SEDA-25, 292; SEDA-26, 273; SEDA-27, 254)

Chloramphenicol Hematologic Chloramphenicol can cause two types of hemotoxicity. First, reversible bone marrow depression, which is common. Secondly, idiosyncratic irreversible aplastic anemia, which has a 50% mortality rate, and is not related to dose or duration (20R ). Drug interactions There is a rapid and severe interaction between chloramphenicol and tacrolimus, with greatly increased tacrolimus concentrations during co-administration, and a rapid fall after chloramphenicol withdrawal. This significant interaction was reported in a 56-year-old man with a cadaveric kidney– pancreas transplant (21A ).

FLUOROQUINOLONES (SED-14, 852; SEDA-25, 293; SEDA-26, 274; SEDA-27, 254) After the introduction of the first quinolone (nalidixic acid), structural modifications to the basic quinolone and naphthyridone nucleus and to the side chains allowed improvements in the coverage of bacterial pathogens with high activity against Gram-negative species and a number

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of atypical pathogens and good-to-moderate activity against Gram-positive species. Despite the broad spectrum and clinical success, defects became evident, and compounds developed in recent years have targeted improvements in pharmacokinetic properties (improved systemic availability, once-daily dosing), greater activity against Gram-positive cocci and anaerobes, activity against fluoroquinolone-resistant strains, and better coverage of non-fermenting Gram-negative species. However, owing to adverse effects (including severe anaphylaxis, QT interval prolongation, and potential cardiotoxicity), several fluoroquinolones have had to be withdrawn (for example temafloxacin and grepafloxacin) or strictly limited in their use (for example trovafloxacin) after marketing. A serious idiosyncratic reaction profile is possibly related to the immunologically reactive 1-difluorophenyl substituent that characterizes temafloxacin, trovafloxacin, and tosufloxacin (22R ). Skin Experience reported to date suggests that for gatifloxacin, gemifloxacin, and moxifloxacin phototoxicity occurs at a lower rate than with widely used fluoroquinolones such as ciprofloxacin and levofloxacin (23R ).

Alatrofloxacin and trovafloxacin Alatrofloxacin is a fluoronaphthyridone that is hydrolysed to the active moiety, trovafloxacin, after intravenous administration. This fourthgeneration broad-spectrum fluoroquinolone has activity against Gram-positive, Gram-negative, anaerobic, and atypical respiratory pathogens. Owing to significant hepatotoxicity of trovafloxacin, the list of appropriate indications has been restricted (USA) or suspended (Europe) (22R ). Sensory systems Intravitreal trovafloxacin in doses of 50 mg and higher in the pigmented rabbit eye caused retinal and nerve fiber injury; intravitreal doses of 25 mg and lower appear to be safe, with no evidence of ocular toxicity (24E ). Musculoskeletal In rats experimental fractures systemically exposed to trovafloxacin had impaired healing during the early stages of fracture repair (25E ).

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Ciprofloxacin Nervous system Ciprofloxacin can exacerbate the risk of seizures in epilepsy. • A 65-year-old woman on peritoneal dialysis had recurrent generalized tonic-clonic seizures while taking Ciproxin ear drops (ciprofloxacin 2 mg, hydrocortisone 10 mg) for otitis media. She had a seizure-free period of 9 months after she stopped using the eardrops, despite tapering of the dose of sodium valproate (26A ).

Psychiatric Psychosis occurred in a 32-yearold woman who was taking ciprofloxacin for multidrug resistant tuberculosis; the symptoms resolved within 48 hours after the ciprofloxacin was withdrawn (27A ). Urinary tract Ciprofloxacin can cause acute interstitial nephritis, as in the case of an 81year-old man with diabetic nephropathy (28A ). Hematologic Treatment with ciprofloxacin and piperacillin/tazobactam was associated with thrombocytosis in a 50-year-old man (29A ). Liver Severe liver injury was associated with ciprofloxacin 500 mg bd in a 79-year-old woman with a Gram-negative infection; she developed a metabolic acidosis 48 hours after the first dose and her symptoms resolved after withdrawal (30A ). Skin Two cases of Stevens–Johnson syndrome and one of toxic epidermal necrolysis associated with ciprofloxacin have been reported (31A , 32A ). Musculoskeletal In children being treated with ciprofloxacin the rates of arthralgia and quinolone-induced cartilage toxicity were low (33R ). Episodes of arthralgia were mostly reversible, based on published surveillance data. Recent data from Bayer’s ciprofloxacin clinical trials database showed that the incidence of arthralgia in children did not differ between ciprofloxacin and non-quinolone antimicrobial drugs. Ciprofloxacin can cause partial or complete tendon rupture, as corroborated by two new case reports (34A , 35A ).

Immunologic An anaphylactoid reaction occurred in a 79-year-old following a first-time exposure to intravenous ciprofloxacin (400 mg) (36A ). Drug interactions Reports of possible drugdrug interactions between ciprofloxacin and glibenclamide have suggested that this may be a class effect that should be monitored (23r ). Drug administration route In a prospective multicenter trial in 624 patients with presumed bacterial keratitis who were treated with topical ciprofloxacin 0.3% solution 95 (15%) developed a white corneal precipitate during ciprofloxacin therapy, and 473 (76%) began within the first 3 days of treatment (37C ). Older patients treated with topical ciprofloxacin for bacterial keratitis have a higher risk of corneal deposition.

Enoxacin Skin Enoxacin 200 mg tds caused significant phototoxicity in healthy volunteers (38c ).

Garenoxacin Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that is effective in vitro against a wide range of clinically important pathogens, including Gram-positive and Gram-negative aerobes and anaerobes. In a randomized, double-blind, placebocontrolled, dose escalation trial in 40 healthy subjects receiving garenoxacin 100–1200 mg/day, the most common adverse events in the subjects who received garenoxacin were headache (23%), pharyngitis (17%), dizziness (13%), and a white exudate (13%). There was no relation between the dose of garenoxacin and either the type or the frequency of adverse events (39R ). Nervous system In rodents the effects of garenoxacin on the central nervous system were weaker than those of norfloxacin, ciprofloxacin, sitafloxacin, and trovafloxacin (40E ). Garenoxacin may therefore have a low potential for central nervous system adverse reactions.

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Gatifloxacin

Gemifloxacin

Gatifloxacin is an advanced-generation 8-methoxyfluoroquinolone with enhanced activity against Gram-positive and atypical agents and broad-spectrum activity against Gram-negative bacteria (23R ). It is bactericidal and has a post-antibiotic effect against Gram-positive and Gram-negative bacteria. The standard dose is 400 mg/day and both oral and intravenous formulations are available.

Skin The risk of skin rash with gemifloxacin is quite high (3%), especially in women under 40 years of age who take it for more than 7 days (23R ). More serious skin reactions, such as Stevens–Johnson syndrome, toxic epidermal necrolysis, or eosinophilic dermatosis, have not been reported (43r ).

Psychiatric Psychiatric adverse effects occur at a rate of 2–4%, causing headache (2– 4% of patients), dizziness (2–3%), and other symptoms (under 1%), including confusion, agitation, insomnia, depression, somnolence, vertigo, light-headedness, and tremors. Seizures are rare. Some quinolones displace GABA or compete with GABA binding at receptor sites in the nervous system. Substitution of compounds containing 7-piperazinyl or 7pyrrolidinyl, such as gatifloxacin, gemifloxacin, and moxifloxacin, is associated with reduced seizure-causing potential. Administration of non-steroidal anti-inflammatory drugs concurrently with certain quinolones has been linked to an increase in the possibility of seizures (23R ). • Delirium occurred in a 69-year-old white man with a history of depression, non-insulin-dependent diabetes mellitus, hypertension, and atherosclerotic disease who was treated with intravenous gatifloxacin 400 mg/day (41A ). After the first dose of gatifloxacin he had numerous hallucinations and the symptoms got worse after each dose. After withdrawal no further hallucinations occurred.

Susceptibility factors Renal impairment Gatifloxacin is excreted in the urine unchanged, via glomerular filtration alone, resulting in 80–95% recovery of an administered dose by this route (23R ). Doses should therefore be reduced in renal insufficiency. Drug interactions During the post-marketing period, reports to the manufacturers of gatifloxacin of hypoglycemia and hyperglycemia caused a revision of the package insert to include warnings of serious disturbances in glucose metabolism. Hyperglycemia was reported in two patients taking gatifloxacin 200 mg/day and glipizide. Hypoglycemia occurred in a 68year-old woman who was also taking glibenclamide and gatifloxacin (42A ).

Drug interactions Simultaneous co-administration of calcium carbonate 1000 mg in 16 healthy volunteers reduced the systemic availability of gemifloxacin 320 mg (44r ). Cmax fell by 21% and AUC by 17%. Administration of calcium either 2 hours before or 2 hours after gemifloxacin had no effect.

Levofloxacin The most frequently reported adverse events of levofloxacin are nausea and diarrhea; compared with some other quinolones it has a low photosensitizing potential, and clinically significant cardiac and hepatic adverse events are rare (45R ). Cardiovascular In healthy volunteers who took levofloxacin 1000 mg the QTc interval was significantly prolonged compared with placebo (46r ). Liver Levofloxacin can cause liver injury. Two patients with renal insufficiency developed acute hepatitis, which resolved on withdrawal (47A , 48A ). Another case of hepatitis after treatment with levofloxacin was reported in a 22year-old woman who took amoxicillin 2 g/day for 12 days before levofloxacin 500 mg/day) (49A ). Hematologic Autoimmune hemolytic anemia due to levofloxacin is extremely rare, but potentially fatal. However, hemolytic anemia was reported in an 82-year-old white man 3 days after the end of a course of levofloxacin 500 mg/day for cellulitis (50A ). Urinary tract Granulomatous interstitial nephritis with associated granulomatous vasculitis was reported in a 47-year-old woman who took levofloxacin 250 mg/day for a urinary tract infection (51A ).

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Musculoskeletal The risk of tendinopathy with fluoroquinolones increases with age and renal dysfunction (52C ). Several cases of tendinopathy and tendon rupture were reported during treatment with levofloxacin (53A –59A ). In rats systemically exposed to levofloxacin, experimental fractures healed less well during the early stages of fracture repair (25E ). Drug interactions Co-administration of warfarin with levofloxacin did not affect the INR compared with warfarin alone (60r ).

Lomefloxacin Skin In a retrospective study the data on fluoroquinolones and other antibacterial drugs were obtained from a spontaneous reporting system database. Lomefloxacin was associated with the reporting rate from 196 reports/daily defined dose/1000 inhabitants/day, and the most frequent were phototoxic reactions (52C ). Mutagenicity Lomefloxacin was a weak clastogen in mouse bone marrow cells and nonmutagenic in germ cells (61E ). Drug interactions There have been reports that fluconazole can prolong the QT interval, and co-administration of fluconazole with levofloxacin may further increase this risk (62r ).

Gastrointestinal A 22-year-old woman developed Clostridium difficile-associated diarrhea after taking moxifloxacin 400 mg/day) for 5 days; metronidazole was begun, and the diarrhea resolved with continued moxifloxacin administration (64A ). Skin Moxifloxacin has a low propensity for causing phototoxic reactions relative to other fluoroquinolones (23R ). Drug interactions Combination therapy of moxifloxacin 400 mg/day with warfarin can prolong the INR, as reported in three elderly patients; healthy volunteers did not experience this interaction (65A ).

Norfloxacin Musculoskeletal The incidence of tendinopathy in patients treated with norfloxacin is 10/ 10 000 (66r ).

Ofloxacin Psychiatric Ofloxacin can cause serious psychiatric adverse effects, particularly in those with a past psychiatric history (67r ).

Pefloxacin Moxifloxacin In a prospective, multicenter trial in 216 patients with acute maxillary sinusitis, oral moxifloxacin 400 mg/day for 7 days resulted in a bacteriological response of 93%. Drug-related adverse events were reported in 13% of moxifloxacin-treated patients and included abdominal pain (2.4%), nausea (2.4%), and diarrhea (1.2%) (63R ). Cardiovascular Moxifloxacin can prolong the QT interval (46c ). However, torsade de pointes has only been reported in one case associated with moxifloxacin (23R ).

In a retrospective study the data on fluoroquinolones and other antibacterial drugs were obtained from a spontaneous reporting system database, pefloxacin was associated with the highest reporting rate (982 reports/daily defined dose/1000 inhabitants/day), and the most frequent were musculoskeletal disorders (52r ).

Prulifloxacin Cardiovascular In vitro and in dogs prulifloxacin did not prolong the QTc interval (68E ).

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Psychiatric In a retrospective study the data on fluoroquinolones and other antibacterial drugs, rufloxacin was associated with a reporting rate of 221 reports/daily defined dose/1000 inhabitants/day, and the most frequent were psychiatric disorders (52C ).

Drug interactions Acute rhabdomyolysis has been reported in a 71-year-old man taking simvastatin (40 mg/day) plus fusidic acid 250 mg tds for an infection due to methicillin resistant Staphylococcus aureus (73A ). In a model of staphylococcal meningitis in rabbits, there was antagonism between methicillin and fusidic acid (74E ).

Sitafloxacin

GLYCOPEPTIDES

Skin In a randomized study in 40 Caucasian volunteers 100 mg bd sitafloxacin was associated with a mild degree of phototoxicity (38C ).

Teicoplanin

Sparfloxacin Cardiovascular Sparfloxacin can prolong the QTc interval. In rabbits intravenous mexiletine 3 mg/kg reduced the electrical vulnerability of the heart during sparfloxacin overdose and may be a pharmacological strategy against the druginduced long QT syndrome (69E ).

Tosufloxacin Immunologic An anaphylactic reaction was reported in patient who took tosufloxacin tosilate (70A ).

FUSIDIC ACID (SED-14, 912; SEDA-25, 303; SEDA-26, 281; SEDA-27, 259) Hematologic The hematological adverse effects of fusidic acid, such as granulocytopenia and thrombocytopenia, have been rarely reported. Two cases of fusidic acid-induced leukopenia and thrombocytopenia after 2 weeks of fusidic acid treatment have been reported; in both cases, the abnormality resolved in 3–6 days after withdrawal of fusidic acid (71R ). Gastrointestinal The major adverse effects of fusidic acid are mild gastrointestinal discomfort and diarrhea (72A ).

(SED-14, 858; SEDA-25, 303; SEDA-26, 281; SEDA-27, 259)

Susceptibility factors Renal impairment Teicoplanin is more effectively administered once daily than vancomycin and may be given intramuscularly or intravenously, but it is not absorbed after oral administration. Teicoplanin is 90% bound to plasma proteins, and it is primarily eliminated by renal excretion; since clearance is predictably reduced in renal insufficiency, dosage adjustments can be made on the basis of the ratio of impaired clearance to normal clearance. Steady state concentrations are reached more slowly with increasing renal impairment. In patients undergoing continuous ambulatory peritoneal dialysis teicoplanin serum concentrations above 10 µg/ml were detected 24 hours after a single dose of teicoplanin 10 mg/kg; all dialysate concentrations were very low (75R ). In patients receiving continuous hemodiafiltration teicoplanin is not very effectively eliminated, but continuous hemodiafiltration can remove a relevant dose of the drug from the circulation by ultrafiltration using a high-flux membrane (76c ). Age The recommended dosage regimen (for example 12 mg/kg on day 1 followed by 6 mg/kg/day; premature neonates and children require higher dosing regimens) most often results in efficacious serum concentrations.

Vancomycin Sensory systems Vancomycin can cause irreversible bilateral sensorineural hearing loss.

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• A 63-year-old white man was treated with vancomycin 1 g/day for 4 days because of Corynebacterium jeikeium meningitis associated with an Ommaya reservoir, and with intrathecal vancomycin 5 mg. He developed difficulty in hearing after the first intrathecal dose and complete hearing loss after the second intrathecal dose. An audiogram showed eighth nerve bilateral sensorineural hearing loss (77A ).

Hematologic Treatment with vancomycin rarely causes reversible thrombocytopenia, as described in a 50-year-old man with culturenegative infective endocarditis who was given vancomycin after mitral valve replacement (78r , 79A ). Skin Linear immunoglobulin A bullous disease is a subepidermal blistering disorder that can be caused by vancomycin (80Ar , 81A ). Immunologic Red man syndrome due to vancomycin has been reviewed (82r , 83r ). It typically consists of pruritus and an erythematous rash that involves the face, neck, and upper torso. Less often, hypotension and angioedema can occur. Patients commonly complain of diffuse burning and itching and of generalized discomfort. They can rapidly become dizzy and agitated, and can develop headache, chills, fever, and paresthesia around the mouth. In severe cases, they complain of chest pain and dyspnea. In many patients, the syndrome is a mild, evanescent pruritus at the end of the infusion and can go unreported. Signs of red man syndrome can appear about 4–10 minutes after the start of an infusion or can begin soon after its completion. It is often associated with rapid infusion of the first dose of vancomycin (over less than 1 hour).

KETOLIDES

(SEDA-25, 305; SEDA-26, 283; SEDA-27, 260) Telithromycin (HMR 3647) is the first member of a new family of the macrolide-lincosamidestreptogramin-B (MLS(B)) class of antimicrobials, the ketolides. It has a good spectrum of activity against respiratory pathogens, including penicillin- and erythromycin-resistant pneumococci, intracellular bacteria, and atypical bacteria. It rapidly penetrates bronchopulmonary, tonsillar, and female genital tissues,

sinuses, and middle ear tissues/fluids, achieves high concentrations at sites of infection, and concentrates within polymorphonuclear neutrophil leukocytes. Telithromycin is well tolerated across all patient populations, and adverse events, most commonly diarrhea, nausea, dizziness, and vomiting, were generally mild to moderate in intensity and seldom led to treatment withdrawal (84R –86R ). Cardiovascular Telithromycin did not prolong the QTc interval in healthy men and women (87r ). Musculoskeletal Telithromycin can exacerbate myasthenia gravis in patients with preexisting myasthenia gravis (88r ). Susceptibility factors Hepatic impairment The pharmacokinetic profiles of single and repeated oral doses of telithromycin 800 mg/day were comparable in patients with hepatic impairment and healthy subjects with normal renal function (89c ).

LINCOSAMIDES (SED-14, 871; SEDA-25, 306; SEDA-26, 283; SEDA-27, 260) Clindamycin In a controlled trial in 123 patients with uncomplicated falciparum malaria, intravenous clindamycin 5 mg/kg every 8 hours and quinine 8 mg/kg every 8 hours for 3 days, 12 patients had minor adverse effects, including transient hypoacusis (4%), nausea (3.2%), transient hypoglycemia (1%), anxiety (0.8%), diarrhea (0.8%), and transient rash (0.8%). Treatment was withdrawn in two cases on day 2 because one patient had severe diarrhea and the other had intense abdominal pain. In both of these, the clindamycin was withdrawn and the patients completed therapy with a 7-day course of quinine and remained well (90C ). Gastrointestinal Clindamycin can cause esophageal disorders, including inflammation, strictures, ulcers, and bleeding (91r ). Skin Acute generalized exanthematous pustulosis occurred in two elderly patients taking clindamycin 300 mg qds (92R ).

282 Pregnancy In a randomized study in pregnant women with abnormal vaginal flora and bacterial vaginosis, clindamycin 300 mg bd for 5 days reduced the rate of late miscarriage and spontaneous preterm birth. Adverse effects included any gastrointestinal upset (n = 5), nausea, vomiting, diarrhea, abdominal pains, or a combination of these), rashes (n = 1); vulvovaginal candidiasis (n = 1), and headache (n = 4) (93R ).

MACROLIDES

(SED-14, 873; SEDA-25, 306; SEDA-26, 284; SEDA-27, 261)

Azithromycin In a randomized, double-blind comparison, single doses of azithromycin 1000 mg and levofloxacin 500 mg were used for travelers’ diarrhea (94C ). The most common adverse events in those given azithromycin were mild abdominal pain (20%) and fecal urgency (13%). There were also one case each of anxiety and transient skin rash. Cardiovascular Azithromycin can prolong the QTc interval (95r ). Psychiatric Azithromycin caused delirium in two elderly patients who took 500 mg initially followed by 250 mg/day (96A ). Skin In a double-blind, placebo-controlled trial of azithromycin (750 mg loading dose followed by 250 mg/day) in malaria prophylaxis in 300 patients, the most important adverse event was a maculopapular rash (97C ). Drug interactions The concomitant use of azithromycin (500 mg/day for 3 days) with ciclosporin in eight stable renal transplant patients produced only a 7% increase in the AUC of ciclosporin and a 19% increase in peak plasma concentration, effects that are not likely to be clinically significant (98c ). Anecdotal evidence suggests that azithromycin is effective for ciclosporin-induced gingival hyperplasia in recipients of solid organ transplants. Two heart transplant recipients insidiously developed gingival hyperplasia, probably because of immunosuppression with ciclosporin, which was successfully treated with azithromycin 250 mg/day for 10 days (99A ).

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Immunologic Leukocytoclastic vasculitis occurred in an 8-month-old boy who was treated with azithromycin (100A ). Fever and erythematous lesions on the legs, feet, arms, buttocks, and face were seen on the third day of treatment. After withdrawal of azithromycin, body temperature returned to normal within 3 days; the skin lesions began to fade on the next day and disappeared within 3 days.

Clarithromycin Respiratory Pulmonary infiltration with eosinophilia occurred in a 17-year-old youth who took clarithromycin 500 mg bd for 7 days; clarithromycin was immediately withdrawn, and he quickly recovered (101A ). Sensory systems Tinnitus has been attributed to clarithromycin. • A 50-year-old man developed tinnitus 9 days after he started to take clarithromycin 500 mg bd for a peptic ulcer (102A ). The clarithromycin was withdrawn, but the patient continued to take his other medications (amoxicillin, and lansoprazole). The tinnitus resolved after 2 days and he did not have any other symptoms.

Liver Fulminant liver failure was reported in a 58-year-old white woman while she was taking clarithromycin for pneumonia. She recovered spontaneously within a few days after drug withdrawal (103A ). Pancreas Acute pancreatitis was reported in a 63-year-old woman and in an 84-year-old woman taking clarithromycin (104A , 105A ). Immunologic Henoch–Schönlein purpura occurred 4 days after a 48-year-old white man started to take clarithromycin 500 mg/day; after a few days clarithromycin was withdrawn and his symptoms quickly resolved (106A ). Drug formulations In a multicenter, double blind, randomized comparison of a 5-day course of clarithromycin extended-release 500 mg/day or clarithromycin immediate-release 250 mg bd in 706 subjects with acute bacterial exacerbations, the incidence of drug-related adverse events was 7% in the extended-release

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group and 5% in the immediate-release group. The only drug-related adverse events that occurred with an incidence of over 1% in either treatment group were abdominal pain (1% in each treatment group), diarrhea (2% for the extended-release formulation and 1% for the immediate-release formulation), and taste disturbances (1% for both formulations) (107R , 108R ).

The co-administration of mosapride 15 mg/day with erythromycin 1200 mg/day did not affect the electrocardiogram in healthy men, indicating a reduced likelihood of severe clinical adverse events, such as QT interval prolongation and torsade de pointes (114c ).

Josamycin Drug interactions A clinically important interaction between digoxin and clarithromycin has been suggested. Digoxin concentrations increased during concomitant administration of clarithromycin in eight patients, and this effect was related to the dose of clarithromycin. The percentage increase in digoxin concentrations after the usual oral dose of clarithromycin (400 mg/day) is about 70%. The cause of this interaction could be increased oral systemic availability and reduced non-glomerular renal clearance of digoxin, probably by inhibition of intestinal and renal P glycoproteins (109c , 110E ).

Skin Delayed-type hypersensitivity to josamycin has been reported in a 32-year-old woman, 4 hours after a full dose of josamycin (one tablet of 500 mg) with a generalized maculopapular rash, which increased in intensity during 24 hour and regressed over 1 week (115A ). She had previously had generalized erythema on the second day of treatment with josamycin 2 years before.

Roxithromycin Cardiovascular The dysrhythmogenic effect of macrolide antibiotics is well known.

Dirithromycin In a randomized, investigator-blinded, parallelgroup trial in acute exacerbations of chronic obstructive pulmonary disease, dirithromycin 500 mg/day was well tolerated; the most frequent adverse events were chest pain and paresthesia (111C ).

• A 6-year-old girl with complex cyanotic heart disease developed torsade de pointes after taking roxithromycin 10 mg/kg/day (116A ).

Pancreas Acute pancreatitis occurred in a 58-year-old man 2 days after he took roxithromycin 300 mg/day and betamethasone (4 mg/day) (117A ).

Erythromycin

Spiramycin

Gastrointestinal The prokinetic effect of erythromycin has been investigated in healthy volunteers, In whom a dose of 3 mg/kg seemed to have the largest prokinetic effect (112c ).

Skin In a review of 207 cases of serious acute generalized exanthematous pustulosis, spiramycin was the causal drug in five cases (118C ).

Drug interactions No interaction of voriconazole with erythromycin was reported in an open, randomized, parallel-group study in 30 healthy men who took oral voriconazole 200 mg bd for 14 days plus either erythromycin 1 g bd on days 8–14 or azithromycin 500 mg/day on days 12– 14 (113C ).

Troleandomycin Drug interactions CYP3A4 plays a major part in the formation of omeprazole sulfone, and also contributes to the 5-hydroxylation of

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omeprazole; both CYP2C19 and CYP3A contribute to the further elimination of 5-hydroxyomeprazole and omeprazole sulfone. In 18 healthy men who took oral omeprazole 20 mg alone or with troleandomycin 500 mg/day for 2 days, the effect of troleandomycin on the metabolism of omeprazole and its two principal metabolites differed between the different phenotypes of CYP2C19 (119C ). Mean Cmax and clearance of omeprazole in poor metabolizers were reduced by troleandomycin. The Cmax and AUC of 5-hydroxyomeprazole in poor metabolizers were significantly reduced by troleandomycin. There were similar effects in heterozygous extensive metabolizers, but in homozygous extensive metabolizers troleandomycin had no effect.

NITROFURANTOIN

(SED-14, 884; SEDA-25, 310; SEDA-26, 288; SEDA-27, 264) Respiratory Acute respiratory reactions to nitrofurantoin include dyspnea, cough, interstitial pneumonitis, and pleural effusion; interstitial pneumonitis and fibrosis are common chronic reactions (120R ). Liver Nitrofurantoin has been associated with fatal liver necrosis and chronic hepatitis (121R ). Pancreas Pancreatitis can be caused by nitrofurantoin (122r ).

OXAZOLIDINONES

(SEDA-26, 288;

SEDA-27, 264) In a prospective, multicenter, open, non-comparative, non-randomized trial in patients with serious Gram-positive infections, who received linezolid 600 mg bd, the overall adverse event rate was 18%. The most common adverse effects were increased liver function tests, rash, and gastrointestinal disturbances. Three patients required withdrawal of therapy for rash, one for raised liver function tests, and one for thrombocytopenia (123R ).

Alexander Imhof

Hematologic Linezolid has been associated with myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia. It is recommended that complete blood counts be monitored weekly in patients who take linezolid, especially those who take it for more than 2 weeks (124R ). The mechanism of the anemia has been described and is thought to be inhibition of mitochondrial respiration. It can be managed relatively easily with transfusions. The thrombocytopenia is progressive and may require drug withdrawal; a mechanism for this effect has not been described. A bone marrow biopsy in a patient who developed thrombocytopenia 7 days after starting to take linezolid showed adequate numbers of normal-looking megakaryocytes. This finding alone argues against marrow suppression and supports an immune-mediated mechanism of platelet destruction (125A ). Susceptibility factors Age In children the common adverse effects of linezolid have been similar to those seen in adults (diarrhea, vomiting, loose stools, and nausea); however, thrombocytopenia has not been as common (126r ). Renal and hepatic impairment Linezolid is cleared by renal and hepatic routes, and dosage adjustments are not needed in moderate renal or hepatic insufficiency (124R , 127R ). Drug interactions Because the original oxazolidinones are monoamine oxidase inhibitors, particular attention has been paid to the question of whether there is evidence of adverse interactions with drugs known to be metabolized by monoamine oxidase in patients taking linezolid (124R ). An enhanced pressor response has been seen in patients taking certain adrenergic agents, including phenylpropanolamine and pseudoephedrine, and the doses of these drugs should be reduced in patients taking linezolid. Recent studies have shown no evidence of interactions of linezolid with oral or inhaled salbutamol. There is no evidence of interactions of linezolid with dextromethorphan, pethidine, and the selective serotonin reuptake inhibitor paroxetine hydrochloride. In an open study in 28 healthy volunteers the pharmacokinetics of linezolid 600 mg/day

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were not affected by concomitant administration of vitamin C 1000 mg/day) or vitamin E 800 IU/day (128c ).

Skin Of 207 cases of serious acute generalized exanthematous pustulosis, pristinamycin was the causal drug in 18 (118C ).

POLYMYXINS (SED-14, 887; SEDA-25, 311; SEDA-26, 289; SEDA-27, 265)

Quinupristin/dalfopristin

Urinary tract Nephrotoxicity is the most important adverse effect of colistin and polymyxin B. In a retrospective study in 60 patients taking polymyxin B 1.5–2.5 mg/kg/day for treatment of multiresistant bacteria, the development of renal insufficiency was independent of the daily and cumulative doses of polymyxin B and the length of treatment, but was significantly associated with age. Overall mortality was 20%, but it increased to 57% in those who developed renal insufficiency (129R ). Musculoskeletal Of 23 critically ill patients treated with colistin, one developed diffuse muscular weakness on day 10 of treatment; the symptom resolved within 1 week of withdrawal of colistin (130A ).

The adverse effects of quinupristin/dalfopristin include arthralgia, myalgia, and pain at the infusion site (134R ). Skin Sweet’s syndrome has been reported after treatment with quinupristin/dalfopristin in a 63-year-old woman; the symptoms and cutaneous lesions rapidly resolved after withdrawal (135A ). Susceptibility factors Hepatic impairment In a retrospective study in 50 patients who took quinupristin/dalfopristin, significant risk factors for arthralgia or myalgia were chronic liver disease, liver transplantation, raised bilirubin concentration at baseline, major surgery, and the concomitant use of either mycophenolate or ciclosporin; female sex was a less strong factor (136R ).

Mupirocin Drug administration route In a systematic review of antibiotics for eradication of methicillin-resistant Staphylococcus aureus, there was minimal nasal discomfort associated with topical mupirocin (131R ). However, toxic epidermal necrolysis occurred after intranasal administration of mupirocin in a 76-year-old woman (132A ).

STREPTOGRAMINS

(SEDA-25, 311; SEDA-26, 289; SEDA-27, 265)

Pristinamycin In a prospective study in 53 patients with methicillin-resistant Staphylococcus aureus treated with pristinamycin 0.5–1.5 g tds, adverse effects included diarrhea or loose stools (n = 8) and one possible rash. Another patient had an infection with Clostridium difficile more than 1 month after therapy (133C ).

SULFONAMIDES, TRIMETHOPRIM, AND CO-TRIMOXAZOLE (SED-14, 896; SEDA-25, 312; SEDA-26, 290; SEDA-27, 266)

Trimethoprim Urinary tract Trimethoprim inhibits the tubular secretion of creatinine and can interfere with certain serum creatinine assays, leading to mild increases in serum creatinine concentration without a true reduction in glomerular filtration rate (137R ). These increases tend to be mild (about 10%), and reverse after drug withdrawal. Hematologic Although trimethoprim inhibits dihydrofolate reductase in bacteria, it is estimated that an approximately 50 000 times increased concentration of the drug is required to inhibit the human form of this enzyme. Consequently, trimethoprim does not seem to cause

286 megaloblastic changes when used in the treatment of routine infections, although patients with low folate stores undergoing long-term treatment should be followed up for such an effect (137R ).

Co-trimoxazole Electrolyte balance High-dose of co-trimoxazole can cause hyperkalemia by blocking amiloride-sensitive sodium channels in distal nephrons (137R ). In prospective study in 53 patients there were electrolyte disorders in 9.1% and 22% of patients given co-trimoxazole containing a low dose of trimethoprim (less than 80 mg/day) or a standard dose (80–120 mg/day). There were electrolyte disorders in 86% of patients with renal dysfunction, compared with 18% of those with normal renal function. The dose of trimethoprim and the presence of renal dysfunction increased the incidence of electrolyte disorders, with odds ratios of 2.4 and 80 respectively (138C ). Sensory systems Co-trimoxazole can cause myopia without accommodative spasm (139r ). Psychiatric Delirium and psychosis have been rarely reported with co-trimoxazole, but are more likely in elderly people (137R ). Gastrointestinal Gastrointestinal intolerance occurs in about 3–8% of patients (137R ). The symptoms commonly include nausea, vomiting, and anorexia. Diarrhea, glossitis, and stomatitis are much less frequent. Liver Hepatotoxicity related to co-trimoxazole is rare and is usually characterized by cholestasis or mixed hepatocellular-cholestatic reactions. • A previously healthy 23-year-old man developed acute fulminant liver failure after taking co-trimoxazole for 7 days; after 15 days he received a successful orthotopic liver transplant (140A ).

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Skin Skin reactions occur in 3–4% of all patients who take co-trimoxazole (137R ). Multiple skin reactions have been described, including a maculopapular rash, urticaria, diffuse erythema, morbilliform lesions, erythema multiforme, purpura, and photosensitivity. Severe reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis, have been rarely reported. In 105 patients with established fixed drug eruptions co-trimoxazole was the leading causative agent (64%) and the most common lesions were in the genital mucosa (141C ). Hematologic Co-trimoxazole has been associated with various other hematological disorders, including multiple forms of anemia, granulocytopenia, agranulocytosis, and thrombocytopenia (137R , 142r ). There were nine cases of co-trimoxazoleinduced agranulocytosis in a prospective cohort study of 91patients. The mean dose was 1400 mg/day (range 800–2400 mg/day) and the mean duration of treatment was 37 days (range 3–17 days). The median age of the patients was 69 years (range 22–92 years) and the male-female ratio was 2 (143c ). Hemolytic anemia secondary to co-trimoxazole is rare. • A 10-year-girl with hemolytic anemia due to cotrimoxazole improved with prednisone therapy and erythrocyte transfusion (144A ).

Gastrointestinal In 163 women with uncomplicated acute lower urinary tract infections included in a multicenter randomized comparison of cefpodoxime proxetil (100 mg bd) or cotrimoxazole (160 + 800 mg bd) for 3 days both antimicrobials were well tolerated, with the exception of one patient in the co-trimoxazole arm who withdrew because of abdominal pain (145C ). Immunologic Co-trimoxazole can cause a drug hypersensitivity syndrome. • A 24-year-old woman with severe liver failure developed erythema multiforme and thrombocytopenia after the acute onset of hepatotoxicity and after all medications had been withdrawn. All these features resolved over weeks, but laboratory abnormalities persisted for up to 8 months (146A ).

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Susceptibility factors In immunocompetent patients, adverse reactions to co-trimoxazole are most often related to the skin or gastrointestinal tract and occur in about 8% of cases. In contrast, in patients who are HIV positive there is a much higher incidence of adverse reactions, with frequencies as high as 83% in one study. • A 37-year-old woman with AIDS developed tremor, acute pancreatitis, and raised serum creatinine concentrations while taking co-trimoxazole (15 mg/kg/day) (147A ).

Pregnancy There is an association between co-trimoxazole combinations in early pregnancy and several major malformations, such as neural tube defects and cardiovascular defects (148r ). Drug interactions Both trimethoprim and sulfamethoxazole can significantly affect the metabolism of several other drugs (137R ). For example, the anticoagulant effect of warfarin can be potentiated, the half-lives of phenytoin and digoxin can be prolonged, and cotrimoxazole can induce the metabolism of oral contraceptives.

OTHER ANTIMICROBIAL DRUGS Daptomycin (SEDA-25, 317; SEDA-26, 292; SEDA-27, 267) Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important Gram-positive bacteria, including resistant strains, and was the first inhibitor of lipoteichoic acid synthesis. In September 2003 the FDA approved daptomycin by injection to treat complicated skin infections. Most of the reported adverse effects of daptomycin have been mild to moderate in intensity; the most common included gastrointestinal disorders, injection site reactions, fever, headache, insomnia, dizziness, and rash (149R ). Musculoskeletal Daptomycin can have adverse effects on skeletal muscle as indicated by raised creatine kinase activity (149R ). People taking it should be monitored for muscle pain or weakness, and creatine kinase activity should be monitored weekly.

Susceptibility factors Sex In a double-blind pharmacokinetic study in 24 healthy subjects given three doses of daptomycin (4, 6, and 8 mg/kg/day for 7–14 days there was no difference between the sexes (150C ).

Fosfomycin

(SED-14, 911; SEDA-25, 317; SEDA-26, 292; SEDA-27, 267) Liver Increased transaminase activities occurred in 0.3% of patients treated with fosfomycin (151R ). Gastrointestinal The most frequent adverse effects of oral fosfomycin are nausea (1%) and dyspepsia (151R , 152R ). Skin Urticaria occurred in 0.3% of patients treated with fosfomycin (151R ).

Fosmidomycin

(SEDA-27, 268)

Fosmidomycin acts by inhibiting 1-deoxy-Dxylulose 5-phospahte reductoisomerase, a key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. It inhibits the synthesis of isoprenoids by Plasmodium falciparum and suppresses the growth of multidrug-resistant strains in vitro (153E ). In an open, uncontrolled trial in 26 patients, fosmidomycin 1200 mg every 8 hours for 7 days caused at least one adverse reaction in 20 subjects. None was serious and all were mild or moderate in intensity. Ten adverse events were categorized as being possibly related to the drug, and of these gastrointestinal events were the most frequent: loose stools (n = 3), diarrhea (n = 2), and flatulence (n = 2). There were increases in alanine transaminase activity in two subjects and dizziness in one (154C ).

Novobiocin Drug interactions Novobiocin potentiated the anti-angiogenic effect of vincristine in vitro (155E ).

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Ramoplanin Ramoplanin is the first in a new class of antimicrobial drugs. It is a glycolipodepsipeptide produced by fermentation of Actinoplanes species. Ramoplanin blocks bacterial cell wall biosynthesis by interfering with peptidoglycan production. It inhibits the N-acetylglucosaminyl transferase-catalysed conversion of lipid intermediate I to lipid intermediate II, a step that occurs before transglycosylation and transpeptidation reactions. Unlike glycopeptides, ramoplanin does not complex with the D-Ala–D-Ala sequence of cell wall precursors. It is highly active against Gram-positive aerobic and anaerobic bacteria (156Cr ). In a phase I multiple-dose study in 24 healthy male volunteers, ramoplanin was well

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tolerated and was not absorbed after oral doses of 200, 400, or 800 mg bd for 10 days (156Cr ).

Virginiamycin

(SEDA-24, 302; SEDA-26, 293; SEDA-27, 268) Drug tolerance (antibacterial resistance) The use of virginiamycin has been linked with selection of quinupristin/dalfopristin-resistant Enterococcus faecium. Because virginiamycin has been used in animals, but streptogramins have been used infrequently in humans, an animal origin of resistance has been suggested, and spread of resistance via the food chain to humans is probable (157E , 158E ).

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11. Maldonado PD, Barrera D, Medina-Campos ON, Hernandez-Pando R, Ibarra-Rubio ME, Pedraza-Chaverri J. Aged garlic extract attenuates gentamicin induced renal damage and oxidative stress in rats. Life Sci 2003; 73: 2543–56. 12. Isefuku S, Joyner CJ, Simpson AH. Gentamicin may have an adverse effect on osteogenesis. J Orthop Trauma 2003; 17: 212–16. 13. Schulze S, Wollina U. Gentamicin-induced anaphylaxis. Allergy 2003; 58: 88–9. 14. Wang AM, Sha SH, Lesniak W, Schacht J. Tanshinone (Salviae miltiorrhizae extract) preparations attenuate aminoglycoside-induced free radical formation in vitro and ototoxicity in vivo. Antimicrob Agents Chemother 2003; 47: 1836–41. 15. Guin JD. Recurrence of pemphigus foliaceus after allergic contact dermatitis from triple antibiotic ointment. Contact Dermatitis 2003; 49: 115. 16. Cheer SM, Waugh J, Noble S. Inhaled tobramycin (TOBI): a review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis. Drugs 2003; 63: 2501– 20. 17. Ryan G, Mukhopadhyay S, Singh M. Nebulised anti-pseudomonal antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2003; (3): CD001021. 18. Kahler DA, Schowengerdt KO, Fricker FJ, Mansfield M, Visner GA, Faro A. Toxic serum trough concentrations after administration of nebulized tobramycin. Pharmacotherapy 2003; 23: 543– 5. 19. Kintzel PE, Eastlund T, Calis KA. Extracorporeal removal of antimicrobials during plasmapheresis. J Clin Apheresis 2003; 18: 194–205. 20. Isenberg SJ. The fall and rise of chloramphenicol. J AAPOS 2003; 7: 307–8.

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21. Bakri R, Breen C, Maclean D, Taylor J, Goldsmith D. Serious interaction between tacrolimus FK506 and chloramphenicol in a kidney-pancreas transplant recipient. Transpl Int 2003; 16: 441–3. 22. Ball P. Adverse drug reactions: implications for the development of fluoroquinolones. J Antimicrob Chemother 2003; 51 Suppl 1: 21–7. 23. Saravolatz LD, Leggett J. Gatifloxacin, gemifloxacin, and moxifloxacin: the role of 3 newer fluoroquinolones. Clin Infect Dis 2003; 37: 1210– 15. 24. Ng EW, Joo MJ, Eong KG, Green WR, O’Brien TP. Ocular toxicity of intravitreal trovafloxacin in the pigmented rabbit. Curr Eye Res 2003; 27: 387– 93. 25. Perry AC, Prpa B, Rouse MS, Piper KE, Hanssen AD, Steckelberg JM, Patel R. Levofloxacin and trovafloxacin inhibition of experimental fracture-healing. Clin Orthop Relat Res 2003; (414): 95–100. 26. Orr CF, Rowe DB. Eardrop attacks: seizures triggered by ciprofloxacin eardrops. Med J Aust 2003; 178: 343. 27. Norra C, Skobel E, Breuer C, Haase G, Hanrath P, Hoff P. Ciprofloxacin-induced acute psychosis in a patient with multidrug-resistant tuberculosis. Eur Psychiatry 2003; 18: 262–3. 28. Fogo AB. Quiz page. Diabetic nephropathy with superimposed acute interstitial nephritis. Am J Kidney Dis 2003; 41: A47, E1–3. 29. Finsterer J, Kotzailias N. Thrombocytosis under ciprofloxacin and tazobactam/piperacillin. Platelets 2003; 14: 329–31. 30. Goetz M, Galle PR, Schwarting A. Non-fatal acute liver injury possibly related to high-dose ciprofloxacin. Eur J Clin Microbiol Infect Dis 2003; 22: 294–6. 31. Jongen-Lavrencic M, Schneeberger PM, Van der Hoeven JG. Ciprofloxacin-induced toxic epidermal necrolysis in a patient with systemic lupus erythematosus. Infection 2003; 31: 428–9. 32. Hallgren J, Tengvall-Linder M, Persson M, Wahlgren CF. Stevens–Johnson syndrome associated with ciprofloxacin: a review of adverse cutaneous events reported in Sweden as associated with this drug. J Am Acad Dermatol 2003; 49 Suppl 5: S267–9. 33. Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J 2003; 22: 1128–32. 34. Ozaras R, Mert A, Tahan V, Uraz S, Ozaydin I, Yilmaz MH, Ozaras N. Ciprofloxacin and Achilles’ tendon rupture: a causal relationship. Clin Rheumatol 2003; 22: 500–1. 35. Khaliq Y, Zhanel GG. Fluoroquinoloneassociated tendinopathy: a critical review of the literature. Clin Infect Dis 2003; 36: 1404–10. 36. Ho DY, Song JC, Wang CC. Anaphylactoid reaction to ciprofloxacin. Ann Pharmacother 2003; 37: 1018–23. 37. Wilhelmus KR, Abshire RL. Corneal ciprofloxacin precipitation during bacterial keratitis. Am J Ophthalmol 2003; 136: 1032–7. 38. Dawe RS, Ibbotson SH, Sanderson JB, Thomson EM, Ferguson J. A randomized controlled trial

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290 ture and tendinopathy. Scand J Infect Dis 2003; 35: 768–70. 56. De La Red G, Mejia JC, Cervera R, Llado A, Mensa J, Font J. Bilateral Achilles tendinitis with spontaneous rupture induced by levofloxacin in a patient with systemic sclerosis. Clin Rheumatol 2003; 22: 367–8. 57. Mathis AS, Chan V, Gryszkiewicz M, Adamson RT, Friedman GS. Levofloxacin-associated Achilles tendon rupture. Ann Pharmacother 2003; 37: 1014–17. 58. Cebrian P, Manjon P, Caba P. Ultrasonography of non-traumatic rupture of the Achilles tendon secondary to levofloxacin. Foot Ankle Int 2003; 24: 122–4. 59. Bernacer L, Artigues A, Serrano A. Levofloxacino y rotura espontanea bilateral del tendon de Aquiles. Med Clin (Barc) 2003; 120: 78–9. 60. Yamreudeewong W, Lower DL, Kilpatrick DM, Enlow AM, Burrows MM, Greenwood MC. Effect of levofloxacin coadministration on the international normalized ratios during warfarin therapy. Pharmacotherapy 2003; 23: 333–8. 61. Singh AC, Kumar M, Jha AM. Genotoxicity of lomefloxacin—an antibacterial drug in somatic and germ cells of Swiss albino mice in vivo. Mutat Res 2003; 535: 35–42. 62. Gandhi PJ, Menezes PA, Vu HT, Rivera AL, Ramaswamy K. Fluconazole- and levofloxacininduced torsades de pointes in an intensive care unit patient. Am J Health-Syst Pharm 2003; 60: 2479– 83. 63. Gehanno P, Berche P, Perrin A. Moxifloxacin in the treatment of acute maxillary sinusitis after firstline treatment failure and acute sinusitis with high risk of complications. J Int Med Res 2003; 31: 434– 47. 64. Carroll DN. Moxifloxacin-induced Clostridium difficile-associated diarrhea. Pharmacotherapy 2003; 23: 1517–19. 65. O’Connor KA, O’Mahony D. The interaction of moxifloxacin and warfarin in three elderly patients. Eur J Intern Med 2003; 14: 255–7. 66. Shah P. Treten Sehnenschaden bei ChinolonGabe auf? Dtsch Med Wochenschr 2003; 128: 2214. 67. Hall CE, Keegan H, Rogstad KE. Psychiatric side effects of ofloxacin used in the treatment of pelvic inflammatory disease. Int J STD AIDS 2003; 14: 636–7. 68. Lacroix P, Crumb WJ, Durando L, Ciottoli GB. Prulifloxacin: in vitro (HERG current) and in vivo (conscious dog) assessment of cardiac risk. Eur J Pharmacol 2003; 477: 69–72. 69. Takahara A, Sugiyama A, Satoh Y, Hashimoto K. Effects of mexiletine on the canine model of sparfloxacin-induced long QT syndrome. Eur J Pharmacol 2003; 476: 115–22. 70. Umebayashi Y, Furuta J. Anaphylaxis due to tosufloxacin tosilate. J Dermatol 2003; 30: 701–2. 71. Liao YM, Chiu CF, Ho MW, Hsueh CT. Fusidic acid-induced leukopenia and thrombocytopenia. J Chin Med Assoc 2003; 66: 429–32.

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72. Garcia-Rodriguez JA, Gutierrez Zufiaurre N, Munoz Bellido JL. Acido fusidico. Rev Esp Quimioter 2003; 16: 161–71. 73. Yuen SL, McGarity B. Rhabdomyolysis secondary to interaction of fusidic acid and simvastatin. Med J Aust 2003; 179: 172. 74. Ostergaard C, Yieng-Kow RV, Knudsen JD, Frimodt-Moller N, Espersen F. Evaluation of fusidic acid in therapy of experimental Staphylococcus aureus meningitis. J Antimicrob Chemother 2003; 51: 1301–5. 75. Stamatiadis D, Papaioannou MG, GiamarellosBourboulis EJ, Marinaki S, Giamarellou H, Stathakis CP. Pharmacokinetics of teicoplanin in patients undergoing continuous ambulatory peritoneal dialysis. Perit Dial Int 2003; 23: 127–31. 76. Yagasaki K, Gando S, Matsuda N, Kameue T, Ishitani T, Hirano T, Iseki K. Pharmacokinetics of teicoplanin in critically ill patients undergoing continuous hemodiafiltration. Intensive Care Med 2003; 29: 2094–5. 77. Klibanov OM, Filicko JE, DeSimone Jr JA, Tice DS. Sensorineural hearing loss associated with intrathecal vancomycin. Ann Pharmacother 2003; 37: 61–5. 78. Peel RK, Sykes A, Ashmore S, Turney JH, Woodrow G. A case of immune thrombocytopenic purpura from intraperitoneal vancomycin use. Perit Dial Int 2003; 23: 506–8. 79. Marraffa J, Guharoy R, Duggan D, Rose F, Nazeer S. Vancomycin-induced thrombocytopenia: a case proven with rechallenge. Pharmacotherapy 2003; 23: 1195–8. 80. Lesueur A, Lefort C, Gauthier JM, Andrivet P. Dermatose a IgA lineaire associée a la prise de vancomycine. Presse Med 2003; 32: 1078. 81. Dellavalle RP, Burch JM, Tayal S, Golitz LE, Fitzpatrick JE, Walsh P. Vancomycin-associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. J Am Acad Dermatol 2003; 48 Suppl 5: S56–7. 82. Sivagnanam S, Deleu D. Red man syndrome. Crit Care 2003; 7: 119–20. 83. Tilles SA, Slatore CG. Hypersensitivity reactions to non-beta-lactam antibiotics. Clin Rev Allergy Immunol 2003; 24: 221–8. 84. Mikamo H, Ninomiya M, Tamaya T. Penetration of oral telithromycin into female genital tissues. J Infect Chemother 2003; 9: 358–60. 85. Carbon C. A pooled analysis of telithromycin in the treatment of community-acquired respiratory tract infections in adults. Infection 2003; 31: 308– 17. 86. Gehanno P, Sultan E, Passot V, Nabet P, Danon J, Romanet P, Attal P. Telithromycin (HMR 3647) achieves high and sustained concentrations in tonsils of patients undergoing tonsillectomy. Int J Antimicrob Agents 2003; 21: 441–5. 87. Demolis JL, Vacheron F, Cardus S, FunckBrentano C. Effect of single and repeated oral doses of telithromycin on cardiac QT interval in healthy subjects. Clin Pharmacol Ther 2003; 73: 242–52. 88. Nieman RB, Sharma K, Edelberg H, Caffe SE. Telithromycin and myasthenia gravis. Clin Infect Dis 2003; 37: 1579.

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89. Cantalloube C, Bhargava V, Sultan E, Vacheron F, Batista I, Montay G. Pharmacokinetics of the ketolide telithromycin after single and repeated doses in patients with hepatic impairment. Int J Antimicrob Agents 2003; 22: 112–21. 90. Adehossi E, Parola P, Foucault C, Delmont J, Brouqui P, Badiaga S, Ranque S. Three-day quinine-clindamycin treatment of uncomplicated falciparum malaria imported from the tropics. Antimicrob Agents Chemother 2003; 47: 1173. 91. Petersen KU, Jaspersen D. Medication-induced oesophageal disorders. Expert Opin Drug Saf 2003; 2: 495–507. 92. Valois M, Phillips EJ, Shear NH, Knowles SR. Clindamycin-associated acute generalized exanthematous pustulosis. Contact Dermatitis 2003; 48: 169. 93. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet 2003; 361: 983–8. 94. Adachi JA, Ericsson CD, Jiang ZD, DuPont MW, Martinez-Sandoval F, Knirsch C, DuPont HL. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis 2003; 37: 1165–71. 95. Matsunaga N, Oki Y, Prigollini A. A case of QT-interval prolongation precipitated by azithromycin. N Z Med J 2003; 116: U666. 96. Cone LA, Padilla L, Potts BE. Delirium in the elderly resulting from azithromycin therapy. Surg Neurol 2003; 59: 509–11. 97. Taylor WR, Richie TL, Fryauff DJ, Ohrt C, Picarima H, Tang D, Murphy GS, Widjaja H, Braitman D, Tjitra E, Ganjar A, Jones TR, Basri H, Berman J. Tolerability of azithromycin as malaria prophylaxis in adults in Northeast Papua, Indonesia. Antimicrob Agents Chemother 2003; 47: 2199– 203. 98. Bachmann K, Jauregui L, Chandra R, Thakker K. Influence of a 3-day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients. Pharmacol Res 2003; 47: 549–54. 99. Strachan D, Burton I, Pearson GJ. Is oral azithromycin effective for the treatment of cyclosporine-induced gingival hyperplasia in cardiac transplant recipients? J Clin Pharm Ther 2003; 28: 329–38. 100. Odemis E, Kalyoncu M, Okten A, Yildiz K. Azithromycin-induced leukocytoclastic vasculitis. J Rheumatol 2003; 30: 2292. 101. Terzano C, Petroianni A. Clarithromycin and pulmonary infiltration with eosinophilia. Br Med J 2003; 326: 1377–8. 102. Uzun C. Tinnitus due to clarithromycin. J Laryngol Otol 2003; 117: 1006–7. 103. Tietz A, Heim MH, Eriksson U, Marsch S, Terracciano L, Krahenbuhl S. Fulminant liver failure associated with clarithromycin. Ann Pharmacother 2003; 37: 57–60.

291 104. Schouwenberg BJ, Deinum J. Acute pancreatitis after a course of clarithromycin. Neth J Med 2003; 61: 266–7. 105. Rassiat E, Michiels C, Jouve JL, Sgro C, Faivre J, Hillon P. Pancreatite aigue après prise de clarithromycine et de beta-methasone. Gastroenterol Clin Biol 2003; 27: 123. 106. Borras-Blasco J, Enriquez R, Amoros F, Cabezuelo JB, Navarro-Ruiz A, Perez M, Fernandez J. Henoch–Schönlein purpura associated with clarithromycin. Case report and review of literature. Int J Clin Pharmacol Ther 2003; 41: 213–16. 107. Darkes MJ, Perry CM. Clarithromycin extended-release tablet: a review of its use in the management of respiratory tract infections. Am J Respir Med 2003; 2: 175–201. 108. Nalepa P, Dobryniewska M, Busman T, Notario G. Short-course therapy of acute bacterial exacerbation of chronic bronchitis: a double-blind, randomized, multicenter comparison of extendedrelease versus immediate-release clarithromycin. Curr Med Res Opin 2003; 19: 411–20. 109. Rengelshausen J, Goggelmann C, Burhenne J, Riedel KD, Ludwig J, Weiss J, Mikus G, WalterSack I, Haefeli WE. Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin–clarithromycin interaction. Br J Clin Pharmacol 2003; 56: 32–8. 110. Tanaka H, Matsumoto K, Ueno K, Kodama M, Yoneda K, Katayama Y, Miyatake K. Effect of clarithromycin on steady-state digoxin concentrations. Ann Pharmacother 2003; 37: 178–81. 111. Castaldo RS, Celli BR, Gomez F, LaVallee N, Souhrada J, Hanrahan JP. A comparison of 5day courses of dirithromycin and azithromycin in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Clin Ther 2003; 25: 542–57. 112. Boivin MA, Carey MC, Levy H. Erythromycin accelerates gastric emptying in a dose-response manner in healthy subjects. Pharmacotherapy 2003; 23: 5–8. 113. Purkins L, Wood N, Ghahramani P, Kleinermans D, Layton G, Nichols D. No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers. Br J Clin Pharmacol 2003; 56 Suppl 1: 30–6. 114. Katoh T, Saitoh H, Ohno N, Tateno M, Nakamura T, Dendo I, Kobayashi S, Nagasawa K. Drug interaction between mosapride and erythromycin without electrocardiographic changes. Jpn Heart J 2003; 44: 225–34. 115. Freymond N, Catelain A, Cousin F, Nicolas JF. Skin delayed-type hypersensitivity to josamycin. Allergy 2003; 58: 1319–20. 116. Promphan W, Khongphatthanayothin A, Horchaiprasit K, Benjacholamas V. Roxithromycin induced torsade de pointes in a patient with complex congenital heart disease and complete atrioventricular block. Pacing Clin Electrophysiol 2003; 26: 1424–6. 117. Renkes P, Petitpain N, Cosserat F, Bangratz S, Trechot P. Can roxithromycin and betamethasone

292 induce acute pancreatitis? A case report. JOP 2003; 4: 184–6. 118. Saissi EH, Beau-Salinas F, Jonville-Bera AP, Lorette G, Autret-Leca E. Medicaments associés a la survenue d’une pustulose exanthematique aigue generalisée. Ann Dermatol Venéreol 2003; 130: 612–18. 119. He N, Huang SL, Zhu RH, Tan ZR, Liu J, Zhu B, Zhou HH. Inhibitory effect of troleandomycin on the metabolism of omeprazole is CYP2C19 genotype-dependent. Xenobiotica. 2003; 33: 211– 21. 120. Anonymous. Pulmonary adverse effects of nitrofurantoin. Prescrire Int 2003; 12: 23. 121. Thiim M, Friedman LS. Hepatotoxicity of antibiotics and antifungals. Clin Liver Dis 2003; 7: 381–99, vi-vii. 122. Mouallem M, Sirotin T, Farfel Z. Nitrofurantoin-induced pancreatitis. Isr Med Assoc J 2003; 5: 754–5. 123. Smith PF, Birmingham MC, Noskin GA, Meagher AK, Forrest A, Rayner CR, Schentag JJ. Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia. Ann Oncol 2003; 14: 795–801. 124. Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Ann Intern Med 2003; 138: 135–42. 125. Bernstein WB, Trotta RF, Rector JT, Tjaden JA, Barile AJ. Mechanisms for linezolid-induced anemia and thrombocytopenia. Ann Pharmacother 2003; 37: 517–20. 126. Kaplan SL, Deville JG, Yogev R, Morfin MR, Wu E, Adler S, Edge-Padbury B, NaberhuisStehouwer S, Bruss JB. Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children. Pediatr Infect Dis J 2003; 22: 677–86. 127. Pigrau C. Oxazolidinonas y glucopeptidos. Enferm Infecc Microbiol Clin 2003; 21: 157–64. 128. Gordi T, Tan LH, Hong C, Hopkins NJ, Francom SF, Slatter JG, Antal EJ. The pharmacokinetics of linezolid are not affected by concomitant intake of the antioxidant vitamins C and E. J Clin Pharmacol 2003; 43: 1161–7. 129. Ouderkirk JP, Nord JA, Turett GS, Kislak JW. Polymyxin B nephrotoxicity and efficacy against nosocomial infections caused by multiresistant Gram-negative bacteria. Antimicrob Agents Chemother 2003; 47: 2659–62. 130. Linden PK, Kusne S, Coley K, Fontes P, Kramer DJ, Paterson D. Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa. Clin Infect Dis 2003; 37: e154–60. 131. Loeb M, Main C, Walker-Dilks C, Eady A. Antimicrobial drugs for treating methicillinresistant Staphylococcus aureus colonization. Cochrane Database Syst Rev 2003; 4: CD003340. 132. Praz SM, de Torrente A, Zender H, Schmied E, Schleppy CA, Genne D. Toxic epidermal necrolysis after topical intranasal application of mupirocin. Infect Control Hosp Epidemiol 2003; 24: 459–60.

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133. Dancer SJ, Robb A, Crawford A, Morrison D. Oral streptogramins in the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. J Antimicrob Chemother 2003; 51: 731–5. 134. Eliopoulos GM. Quinupristin–dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003; 36: 473–81. 135. Choi HS, Kim HJ, Lee TH, Lee SH, Lee TW, Ihm CG, Kim MJ. Quinupristin/dalfopristininduced Sweet’s syndrome. Korean J Intern Med 2003; 18: 187–90. 136. Carver PL, Whang E, VandenBussche HL, Kauffman CA, Malani PN. Risk factors for arthralgias or myalgias associated with quinupristin– dalfopristin therapy. Pharmacotherapy 2003; 23: 159–64. 137. Masters PA, O’Bryan TA, Zurlo J, Miller DQ, Joshi N. Trimethoprim–sulfamethoxazole revisited. Arch Intern Med 2003; 163: 402–10. 138. Mori H, Kuroda Y, Imamura S, Toyoda A, Yoshida I, Kawakami M, Tabei K. Hyponatremia and/or hyperkalemia in patients treated with the standard dose of trimethoprim–sulfamethoxazole. Intern Med 2003; 42: 665–9. 139. Anonymous. Drug-induced myopia. Prescrire Int 2003; 12: 22–3. 140. Zaman F, Ye G, Abreo KD, Latif S, Zibari GB. Successful orthotopic liver transplantation after trimethoprim–sulfamethoxazole associated fulminant liver failure. Clin Transplant 2003; 17: 461– 4. 141. Ozkaya-Bayazit E. Specific site involvement in fixed drug eruption. J Am Acad Dermatol 2003; 49: 1003–7. 142. Ermis B, Caner I, Karacan M, Olgun H. Haemolytic anaemia secondary to trimethoprim/ sulfamethoxazole use. Thromb Haemost 2003; 90: 158–9. 143. Andres E, Noel E, Maloisel F. Trimethoprim– sulfamethoxazole-induced life-threatening agranulocytosis. Arch Intern Med 2003; 163: 1975–6. 144. Papaioannides D, Bouropoulos C, Korantzopoulos P. Co-trimoxazole induced acute thrombocytopenic purpura. Emerg Med J 2003; 20: E3. 145. Kavatha D, Giamarellou H, Alexiou Z, Vlachogiannis N, Pentea S, Gozadinos T, Poulakou G, Hatzipapas A, Koratzanis G. Cefpodoxime-proxetil versus trimethoprim–sulfamethoxazole for shortterm therapy of uncomplicated acute cystitis in women. Antimicrob Agents Chemother 2003; 47: 897–900. 146. Mainra RR, Card SE. Trimethoprim–sulfamethoxazole-associated hepatotoxicity—part of a hypersensitivity syndrome. Can J Clin Pharmacol 2003; 10: 175–8. 147. Floris-Moore MA, Amodio-Groton MI, Catalano MT. Adverse reactions to trimethoprim/sulfamethoxazole in AIDS. Ann Pharmacother 2003; 37: 1810–13. 148. Sivojelezova A, Einarson A, Shuhaiber S, Koren G. Trimethoprim–sulfonamide combination therapy in early pregnancy. Can Fam Phys 2003; 49: 1085–6.

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149. Anonymous. First in a new class of antibiotics. FDA Consum 2003; 37: 4. 150. Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother 2003; 47: 1318–23. 151. Gobernado M. Fosfomicina. Rev Esp Quimioter 2003; 16: 15–40. 152. Lobel B. Short term therapy for uncomplicated urinary tract infection today. Clinical outcome upholds the theories. Int J Antimicrob Agents 2003; 22 Suppl 2: 85–7. 153. Wiesner J, Borrmann S, Jomaa H. Fosmidomycin for the treatment of malaria. Parasitol Res 2003; 90 Suppl 2: S71–6. 154. Lell B, Ruangweerayut R, Wiesner J, Missinou MA, Schindler A, Baranek T, Hintz M, Hutchinson D, Jomaa H, Kremsner PG. Fosmidomycin, a novel chemotherapeutic agent for

293 malaria. Antimicrob Agents Chemother 2003; 47: 735–8. 155. Yang J, Jiang M, Zhen YS. Novobiocin inhibits angiogenesis and shows synergistic effect with vincristine. Yao Xue Xue Bao 2003; 38: 731– 4. 156. Montecalvo MA. Ramoplanin: a novel antimicrobial agent with the potential to prevent vancomycin-resistant enterococcal infection in high-risk patients. J Antimicrob Chemother 2003; 51 Suppl 3: iii31–5. 157. Hayes JR, English LL, Carter PJ, Proescholdt T, Lee KY, Wagner DD, White DG. Prevalence and antimicrobial resistance of Enterococcus species isolated from retail meats. Appl Environ Microbiol 2003; 69: 7153–60. 158. Klare I, Konstabel C, Badstubner D, Werner G, Witte W. Occurrence and spread of antibiotic resistances in Enterococcus faecium. Int J Food Microbiol 2003; 88: 269–90.

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

27 ALLYLAMINES

(SED-14, 937; SEDA-24, 314; SEDA-25, 331; SEDA-26, 309; SEDA-27, 284)

Terbinafine Liver Minor abnormalities in liver function tests have been reported in up to 4% of patients taking oral terbinafine; however, several cases of more severe symptomatic reactions have been reported in association with terbinafine, including at least two cases of fatal liver failure (SEDA-26, 309). Two cases of severe cholestatic hepatitis with prominent eosinophilia associated with terbinafine have been reported. • In the first case, symptoms developed within 4 weeks of starting terbinafine; the patient was treated successfully with glucocorticoids after partial responses to ursodeoxycholic acid and colestyramine and made a full recovery within 6 weeks (1A ). • In the second case, liver dysfunction developed after a 7-day course of terbinafine. Terbinafine was withdrawn and ursodeoxycholic acid and ademethionine were given. Liver tests normalized 6 months later (2A ).

The authors of the first report speculated that terbinafine hepatotoxicity could be more than just an idiosyncratic reaction and that 7,7dimethylhept-2-ene-4-ynal (TBF-A), the allylic aldehyde metabolite of terbinafine, may play a role in its pathogenesis (1A ). Histological changes resembling acute cellular rejection have been attributed to terbinafine in a liver transplant patient (3A ). • A 51-year-old Hispanic man developed raised liver enzymes about 5 years after orthotopic liver transplantation. A biopsy sample was interpreted as © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

294

Antifungal drugs acute cellular rejection, and he was treated with increased immunosuppression. He had started to take terbinafine about 4 weeks before for onychomycosis, and it was withdrawn. However, he developed progressive jaundice, malaise, and nausea, and a second liver biopsy sample showed marked centrilobular cholestasis and severe bile duct damage, consistent with terbinafine hepatotoxicity. He was managed with supportive therapy and discharged 1 month after admission, but continued to have slightly raised transaminases and moderately raised bilirubin concentrations. He died about 3 months after terbinafine was withdrawn after suddenly collapsing in his home. No autopsy was performed.

Fatal hepatic veno-occlusive disease associated with terbinafine was reported in another liver transplant recipient (4A ). • A 35-year-old man with familial amyloid polyneuropathy and orthotopic liver transplantation took terbinafine 250 mg/day for onychomycosis in addition to a stable regimen of ciclosporin. Six weeks later, he developed jaundice, nausea, and vomiting without liver enlargement or ascites. He had a markedly raised serum bilirubin and moderately raised hepatic transaminases; viral causes were excluded. Terbinafine was withdrawn and a liver biopsy showed subacute venous effluent obstruction and occlusion of central veins with intraluminal deposition of fibrous tissue, consistent with veno-occlusive disease. He died 9 weeks later with progressive hepatic and secondary multiorgan failure. Repeat biopsies showed progressive central vein sclerosis.

The temporal relation between the start of terbinafine and the onset of symptoms suggested a drug-induced adverse effect. However, a drug interaction with ciclosporin or transplantation-induced veno-occlusive disease could not be entirely excluded. Skin Cutaneous adverse effects reportedly occur in 1–3% of patients taking terbinafine. Most of these reactions consist of mild to moderate macular rashes. More serious skin disorders, such as erythema multiforme, toxic

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epidermal necrolysis, Stevens–Johnson syndrome, toxic erythema, cutaneous lupus erythematosus, and generalized pustular eruptions are rare (SEDA-23, 299; SEDA-24, 314). Acute generalized exanthematous pustulosis attributed to terbinafine has been described in two cases (5A , 6A ). • Drug-induced bullous pemphigoid occurred in an otherwise healthy 78-year-old patient who took terbinafine 250 mg/day for 20 days for onychomycosis of the toenails. He had a widespread pruritic blistering eruption, more severe on the limbs. He had not taken terbinafine before and was not taking any other drugs. The diagnosis of bullous pemphigoid was confirmed by histopathology. He was treated successfully with oral glucocorticoids.

Use of the Naranjo probability scale indicated a probable relation between bullous pemphigoid and terbinafine in this patient (7A ). Immunologic Subacute lupus erythematosuslike eruptions due to terbinafine have been reported in three women with onychomycosis. Two patients had serological evidence of autoimmune disease predisposing to photosensitivity; the third had neutropenia. Histology in two cases was consistent with subacute lupus erythematosus. All three patients had strikingly similar eruptions that took several weeks to resolve with topical and systemic glucocorticoids (8A ). Susceptibility factors Children Limited data suggest that the safety profile of terbinafine in children is not different from that observed in adults and that terbinafine is well tolerated in this population over short periods of time (SEDA-23, 299; SEDA-24, 314; SEDA-25, 331; SEDA-26, 310; SEDA-27, 285). Terbinafine has been approved for the treatment of tinea capitis in many countries worldwide, and provides good efficacy rates for Trichophyton infection using shorter regimens than griseofulvin. The standard dosing regimens in children with tinea capitis are 62.5 mg/day (10–20 kg), 125 mg/day (20–40 kg), and 250 mg/day (over 40 kg) given for 2–4 weeks; while there is no approved therapy for onychomycosis in children, similar dosages have been used for 6–12 weeks. The safety of terbinafine in children has been reviewed, including 989 children reported in 20 studies. In all, 106 patients had adverse

events (11%). Only eight patients (0.8%) discontinued terbinafine. Adverse events included the gastrointestinal system (2.8%), skin (1.2%), and nervous system (0.9%). There were hematological and hepatic enzyme abnormalities in 1.3 and 1.8% of children respectively. The adverse events in children were similar to those in adults, and most of the events were mild and transient (9R ).

AMPHOTERICIN B

(SED-14, 922; SEDA-25, 331; SEDA-26, 302; SEDA-27, 276) Amphotericin remains an important antifungal drug for the management of invasive mycoses. Compared with conventional amphotericin B deoxycholate, lipid-based formulations (amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B) are less nephrotoxic (10R ). Safety and tolerance of the four marketed amphotericin B formulations and their usefulness for specific indications continues to be investigated.

Amphotericin B deoxycholate (DAMB) Cardiovascular Amphotericin B deoxycholate (DAMB) has been associated with a number of cardiac events, including hypertension, hypotension, bradycardia, and ventricular dysrhythmias. Only a single case of reversible dilated cardiomyopathy secondary to DAMB has been reported so far. • A 20-year-old man with fluconazole-refractory disseminated coccidioidomycosis without evidence of cardiac involvement developed dilated cardiomyopathy and clinical congestive heart failure after 2 months of therapy with amphotericin B (0.7 mg/kg/day of amphotericin B deoxycholate, switched after 1 month of treatment, because of rising serum creatinine concentrations, to amphotericin B lipid complex 5 mg/kg/day. His echocardiographic abnormalities and heart failure resolved within 6 weeks, posaconazole having been substituted for amphotericin B after about 90 days (11A ).

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Autacoids The effects of amphotericin B on the release of histamine from human peripheral blood cells, mononuclear cells, and mast cells has been investigated in cell cultures in vitro. Cultured human mononuclear (THP-1) and mast (HMC-1) cells from five healthy volunteers were incubated with increasing concentrations of amphotericin B deoxycholate, diphenhydramine, amphotericin B deoxycholate plus diphenhydramine, and the calcium ionophore A23187 for up to 24 hours. Histamine concentrations and histamine Nmethyltransferase activity were determined at various times. Cell viability was assessed by exclusion of erythrocin B. A23187 increased histamine concentrations from baseline in peripheral blood and HMC-1 cells. There was no change in histamine concentrations in response to amphotericin B deoxycholate. There was no change in histamine concentrations in THP-1 cells in response to any agent tested. Similarly, histamine N-methyltransferase activity in peripheral blood was not affected by amphotericin B deoxycholate. These results support the view that amphotericin B-induced infusionrelated reaction is not a histamine-mediated event (12E ). Drug formulations The cellular toxicity of different amphotericin B deoxycholate formulations has been investigated in vitro (13E ). Human mononuclear THP-1 cells were exposed for 2 hours to the following deoxycholate formulations of amphotericin B in concentrations of 2.5 and 5 µg/ml: Apothecon, Pharmacia, Sigma, Gensia, Pharma-Tek, and VHA. Toxicity was assessed by measuring interleukin (IL)-1 beta expression, amphotericin B content was measured by enzyme-linked immunosorbent assay (ELISA), and amphotericin A and B contents were assessed by spectrophotometry. Endotoxin contamination was evaluated in all reagents. Expression of IL-1 beta from Sigma, Pharmacia, and Pharma-Tek formulations was increased by about 250%, 50%, and 25% respectively compared with amphotericin A. The amphotericin B content of Sigma, Pharmacia, Pharma-Tek, and Gensia formulations, as measured by ELISA, was increased by about 450%, 200%, 200%, and 100% respectively compared with Apothecon. This variation could not be explained by differences in amphotericin A or

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

B contents. As in previous clinical observations, the current in vitro evaluation showed significant differences among different formulations of amphotericin B deoxycholate. Probably other polyenes or pyrogenic toxins in differing amounts are present in these formulations and may explain the variability in toxicity. Drug administration route In a randomized, controlled study continuous infusion of amphotericin reduced nephrotoxicity and infusionassociated reactions compared with the standard infusion over 2–4 hours in neutropenic patients with refractory fever and suspected or proven invasive fungal infections (14c ). The same group of investigators has now evaluated dose-escalation using continuous administration of DAMB In 33 patients (31 of whom were neutropenic), who received an initial dosage of DAMB of 1 mg/kg/day that was gradually increased to 2.0 mg/kg/day, provided that renal function remained stable and the drug was tolerated (15c ). Dose escalation was possible without delay in 28 patients. The median duration of therapy was 16 days (range 7–72 days). Infusion-related reactions accompanied under 18% of DAMB infusions. Twenty-seven patients had a fall in creatinine clearance. There was a greater than two-fold reduction in creatinine clearance in five patients, but the reduction was dose-limiting in only one; dialysis was not required. The authors concluded that continuous infusion of DAMB up to 2.0 mg/kg/day seems not to cause additional impairment of vital organ functions and is well tolerated by most patients. However, the concentrationdependent pharmacodynamics of antifungal polyenes (SEDA-27, 276) raise concerns about the effectiveness of this mode of administration, as its therapeutic efficacy has not been studied adequately in animals or in patients with documented infections.

Amphotericin B Colloidal Dispersion (ABCD) Susceptibility factors Children The effectiveness and tolerability of three antifungal formulations, amphotericin B deoxycholate (DAMB), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD), in

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the treatment of neonatal Candida bloodstream infections have been investigated in a prospective study of all patients hospitalized in the neonatal intensive care unit from 1996 to 2000 with Candida bloodstream infections (16c ). Patients with a serum creatinine concentration under 106 µmol/l received DAMB (1 mg/kg), and those with a serum creatinine concentration of 1.2 mg/dl and over received L-AmB (5 mg/kg) or ABCD (3 mg/kg on day 1, followed by 5 mg/kg thereafter). Complete blood counts, and renal and hepatic function tests were obtained before, during, and after treatment; blood cultures were performed daily until three consecutive cultures were negative. If cultures were positive for more than 10 days with clinical signs of fungal infection and/or persistent thrombocytopenia, a second antifungal drug was added. Of 56 infants (four term and 52 preterm, including 36 extremely low birth weight infants) DAMB was the initial treatment in 34, L-AmB in six, and ABCD in 16. There were no differences in mortality between the three groups. Sterilization of the blood was achieved with amphotericin B in 68% of patients, L-AmB in 83%, and ABCD in 57%, when used as monotherapy; with the addition of a second antifungal agent, success rates were 100%, 83% and 93% respectively. There were no differences between the groups in the time to resolution of fungemia or in the total duration of therapy. No patients had immediate local or systemic adverse events and in none was renal function altered. Potassium supplementation during treatment was required by 16 infants (47%) in the DAMB cohort and in none of the infants in the other groups. There were no differences in liver function tests, white blood cell counts, and platelet counts in the three groups.

Amphotericin B Lipid Complex (ABLC) In a retrospective comparison of outcomes in liver transplant recipients with invasive aspergillosis who received amphotericin B lipid complex (ABLC) or conventional amphotericin B, the 60-day mortality rate was lower in the ABLC cohort: four of 12 patients versus 24 of 29 patients. Only one of four ABLC recipients with definite invasive aspergillosis died,

297 compared with all 11 in the amphotericin B group. The 60-day survival probability curves was significantly lower in the amphotericin B group. ABLC therapy was the only independent mortality-protective variable (OR = 0.31; 95% CI = 0.07, 0.44) (17c ).

Liposomal Amphotericin (L-AmB) Liposomal amphotericin B (L-AmB) has been studied in an open study with a combination of fluconazole + itraconazole as prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia and myelodysplastic syndrome (18c ). Patients were randomized to receive either fluconazole 200 mg orally every 12 hours + itraconazole 200 mg orally every 12 hours (n = 67) or L-AmB 3 mg/kg intravenously 3 times a week (n = 72). Altogether, 47% of the patients completed antifungal prophylaxis without a change in therapy for proven or suspected fungal infection. Three patients in each arm developed a proven fungal infection. Because of persistent fever 23% of those treated with L-AmB and 24% of those treated with fluconazole + itraconazole were changed to alternative antifungal therapy. Increases in serum creatinine concentrations to over 177 µmol/l (2 mg/dl) (20% versus 6%) and increases in serum bilirubin concentrations to over 2 mg/dl (43% versus 22%) were more common with L-AmB. There were infusionrelated reactions in five patients who received L-AmB. Responses to chemotherapy and induction mortality rates were similar in the two arms. Thus, while L-AmB and fluconazole + itraconazole appeared to have similar efficacy, L-AmB was associated with higher rates of increased serum bilirubin and creatinine concentrations. Mineral balance Children with acute lymphoblastic leukemia are at risk of serious electrolyte abnormalities. • A child with acute lymphoblastic leukemia and cerebral and paranasal sinus mould infections developed severe hyperphosphatemia (maximum 6.1 mmol/l) as a consequence of a large exogenous load of phosphorus from high-dose liposomal amphotericin B (25 mg/kg/day; approved dosage up to 5 mg/kg/day; maximum tolerated dosage

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administered in a dose-ranging study without doselimiting adverse events 15 mg/kg/day) (19A ). Three days after withdrawal of liposomal amphotericin B, the serum phosphorus concentration had fallen to 2.6 mmol/l and was within the reference range 3 weeks later. There were no symptoms associated with the event.

It is unclear whether the phosphorus measured in the child’s plasma was free phosphorus available for precipitation with calcium or stably bound to the phospholipid moiety of the infused liposomes. However, even considering the desperate clinical problem, the dosage of liposomal amphotericin B administered to this patient was difficult to justify. Urinary tract Amphotericin alters cell membrane permeability and tubular cell function, leading to various tubular transport defects. In two cases of nephrogenic diabetes insipidus there was a possible association with liposomal amphotericin B. • A highly febrile patient with cancer, granulocytopenia, and watery diarrhea receiving empirical amphotericin (1 mg/kg) developed complex metabolic disorders, including mild acute renal insufficiency, nephrogenic diabetes insipidus documented by a high serum antidiuretic hormone concentration (18 pg/ml), polyuria, a negative desmopressin test, and type I renal tubular acidosis (20A ). Amphotericin was withdrawn and replaced by liposomal amphotericin B (3 mg/kg), despite which the diabetes insipidus and distal tubulopathy persisted. Liposomal amphotericin B was therefore withdrawn after 1 week and within 5 days the renal symptoms began to resolve. • A 38-year-old man with acute myelogenous leukemia, who had received a matched unrelated donor allogeneic bone marrow transplant and had glucocorticoid-responsive graft-versus-host disease, developed a fungal pneumonia with Torulopsis glabrata and was given liposomal amphotericin B (2.5 mg/kg/day; baseline serum creatinine 121– 132 µmol/l) (21A ). The dose was increased to 7.5 mg/kg/day and subsequently to 10 mg/kg/day because of immunosuppression and poor response. He required mechanical ventilation for biopsyproven bronchiolitis obliterans organizing pneumonia. He also developed diffuse alveolar hemorrhage and received intravenous desmopressin, with a reduction in bloody secretions. He then developed hypernatremia (serum sodium 155 mmol/l) and had an inappropriately increased urine output consistent with nephrogenic diabetes insipidus, associated with an increasing cumulative dose of liposomal amphotericin B, despite concurrent use of intravenous desmopressin. Aggressive water replacement was effective.

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

Although the second patient received several other nephrotoxic drugs, the Naranjo probability scale classified this as a possible adverse reaction because of the temporal sequence of nephrogenic diabetes insipidus after high-dose liposomal amphotericin B and previously reported cases associated with amphotericin B desoxycholate. Immunologic The clinical characteristics and treatment of patients with a distinctive triad of acute infusion-related reactions to L-AmB have been analysed in patients who participated in trials of L-AmB (22c ). Acute infusion-related reactions occurred alone or in combination in one of three symptom complexes: (1) chest pain, dyspnea, and hypoxia; (2) severe abdominal, flank, or leg pain; and (3) flushing and urticaria. Of 84 patients in a single center, 29 had symptoms of acute infusion-related reactions during the first infusion of L-AmB. Most of the reactions (86%) occurred within the first 5 minutes of infusion. All patients had rapid resolution of symptoms after withdrawal of L-AmB infusion and the administration of intravenous diphenhydramine. The overwhelming majority of patients (93%) were rechallenged and tolerated the remainder of the infusion well; they also tolerated subsequent infusions when given diphenhydramine premedication. In a multicenter analysis there was a mean overall frequency of 20% (range 0–100%) of reactions in 64 centers. There was no effect of medication lot, type of infusion bag and tubing, or infusion rate. The authors concluded that since these reactions are distinctively different from those observed with conventional amphotericin B, the liposomal carrier is probably the key factor in the etiology of acute infusion-related reactions and that complement activation may play a pathogenic role. Drug administration route Mucormycosis is a highly lethal invasive mycotic infection that is characterized by angioinvasion, infarction, and tissue necrosis. A patient with soft tissue mucormycosis of the left thigh developed progressive disease, despite surgical debridement and appropriate systemic amphotericin therapy (23A ). In this difficult case, liposomal amphotericin B was infused directly into the left common iliac artery. The patient responded and was ultimately cured. Although intra-arterial infusion is far from being a standard approach in

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the treatment of mucormycosis, this and other case reports support the notion that intra-arterial infusion of liposomal amphotericin B can be used as adjunctive therapy in selected patients. Susceptibility factors Children High-dose (5–7 mg/kg/day) liposomal amphotericin B has been evaluated prospectively in 41 episodes of systemic candidiasis in 37 neonates (median birth weight: 860 g, range 495–3785; median gestational age: 27 weeks, range 25–40; median age at onset of systemic candidiasis: 17 days, range 25–40). Candida species were isolated from the blood in all the patients and from urine (n = 6), skin abscesses (n = 5), and peritoneal fluid (n = 1). Candidiasis was due to Candida parapsilosis (n = 17), Candida albicans (n = 15), Candida tropicalis (n = 5), Candida guilliermondii (n = 2), Candida glabrata (n = 2), and an unidentified Candida (n = 1). The initial dosage was 1 mg/kg/day, and the final dosage was determined by the clinical course. Highdose liposomal amphotericin B was effective and safe in the treatment of neonatal candidiasis. Infusion-related adverse events were not recorded. Only one patient developed transient liver function disturbances that did not require drug withdrawal. None of the patients developed hypokalemia (potassium below 3 mmol/l). There were no changes in renal function during therapy (24c ). In contrast to the dosing scheme used in this study, treatment of invasive fungal infections in clinical practice should generally start at the target dosage, with careful observation during the first dose in order to provide maximum effective treatment immediately (10R ).

AZOLE DERIVATIVES (SED-14, 928; SEDA-25, 333; SEDA-26, 304; SEDA-27, 278)

Drug interactions with antifungal azoles All-trans-retinoic acid All-trans-retinoic acid toxicity thought to be secondary to an interaction with fluconazole has been reported.

299 • A 4-year-old boy with acute promyelocytic leukemia underwent induction chemotherapy including all-trans-retinoic acid 45 mg/m2 /day divided into two doses. After an episode of fever and granulocytopenia on day 20 he was given fluconazole 100 mg/day for antifungal prophylaxis and 7 days later developed headache, vomiting, and papilledema. A CT scan of the brain was normal as was a lumbar puncture, except for a raised opening pressure of over 200 mm of fluid, and a diagnosis of pseudotumor cerebri was made. All-trans-retinoic acid was withdrawn and all his symptoms resolved within 24 hours. A few days later, he was rechallenged with all-trans-retinoic acid but only tolerated a dosage of 30% of the original dose until withdrawal of fluconazole, when he was able to tolerate the full target dosage of all-trans-retinoic acid of 45 mg/m2 /day.

All-trans-retinoic acid is hepatically metabolized by CYP2C8, CYP2C9, and CYP3A4. In this case, fluconazole, which inhibits CYP 2C9 and CYP 3A4, may increase exposure to alltrans-retinoic acid, resulting in cerebral adverse events (25A ). Antiretroviral drugs Indinavir is metabolized mainly by CYP3A4. There have been two randomized placebo-controlled studies in healthy men of the pharmacokinetic interactions, safety, and tolerance of voriconazole and indinavir (26c ). The first was an open parallel-group study of the effect of indinavir on the steadystate pharmacokinetics of voriconazole in 18 volunteers. The subjects took voriconazole 200 mg bd (days 1–7), then voriconazole 200 mg bd plus either indinavir 800 mg or placebo tds (days 8–17). The second was a double-blind, randomized, crossover study of the effect of voriconazole on the steady-state pharmacokinetics of indinavir in 14 volunteers, who took indinavir 800 mg tds + voriconazole 200 mg or placebo bd for two 7-day treatment periods separated by a washout period of at least 7 days. There was no important changes in the pharmacokinetics of either compound. Voriconazole co-administered with indinavir was well tolerated without serious adverse events. However, voriconazole has reportedly interacted with other antiretroviral drugs. • A 10-year-old girl (weight 21 kg: height 130 cm) with vertically acquired AIDS received antiretroviral combination therapy and died of liver failure after starting to take voriconazole (27A ). While taking amprenavir (22.5 mg/kg bd), didanosine (120 mg/m2 bd), nevirapine (4 mg/kg bd),

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lopinavir (10 mg/kg bd), and ritonavir (2.5 mg/kg bd), she was given voriconazole 200 mg bd for refractory esophageal candidiasis. The next day her liver function tests rose slightly and rapidly deteriorated within 7 days, when voriconazole was withdrawn. Infectious causes were excluded. After 2 days the plasma concentrations of the antiretroviral drugs were increased (lopinavir, 10 µg/ml; nevirapine, 7.7 µg/ml; amprenavir, 10.9 µg/ml) compared with concentrations during the 6 months before admission (lopinavir, 3.9– 6.0 µg/ml; nevirapine, 3.5–8.4 µg/ml; amprenavir, 3.5–7.7 µg/ml). There was no fever. She was alert and afebrile and neither had any neurological symptoms nor complained of pain. In the presence of progressive liver dysfunction, voriconazole and HAART were withdrawn. However, irreversible liver failure ensued, followed by hepatic coma. She dies 28 days after the start of voriconazole therapy. A postmortem was not performed.

The authors concluded that an interaction with HAART was the most likely explanation for the ultimately fatal liver failure. Benzodiazepines Bromazepam has been reported to be metabolized by cytochrome P450, although the isozyme responsible has yet to be determined. The effects of itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics and pharmacodynamics of bromazepam have been investigated in a double-blind, randomized, crossover study in eight healthy men who took itraconazole 200 mg/day for 6 days or placebo (28c ). On day 4 each subject took a single oral dose of bromazepam 3 mg and blood samples were taken for 70 hours. The time course of the pharmacodynamic effects of bromazepam on the central nervous system was assessed using a subjective rating of sedation, continuous number addition test, and electroencephalography up to 22 hours after bromazepam. Itraconazole caused no significant changes in the pharmacokinetics or pharmacodynamics of bromazepam, suggesting that CYP3A4 is not involved in the metabolism of bromazepam to a major extent and that bromazepam can be used in the usual doses in patients taking itraconazole. Celiprolol The effects of itraconazole on the pharmacokinetics of celiprolol has been investigated in a randomized crossover study in 12 healthy volunteers who took itraconazole 200 mg orally or placebo bd or grapefruit juice 200 ml tds for 2 days (29c ). On the morning of

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

day 3, 1 hour after drug ingestion, each subject took celiprolol 100 mg with 200 ml of water (placebo and itraconazole phases) or grapefruit juice. During the itraconazole phase, the mean AUC from 0 to 33 hours of celiprolol was 80% greater than in the placebo phase. Cumulative urinary excretion of celiprolol was increased by itraconazole by 59%. Hemodynamic variables did not differ between the phases. Itraconazole almost doubles plasma celiprolol concentrations. This interaction probably results from increased availability of celiprolol, possibly as a result of inhibition of P glycoprotein in the intestine. The effects of itraconazole 100 mg/day for 14 days on the pharmacokinetics of a single oral dose of quazepam and its two active metabolites have been studied in 10 healthy men in a double-blind, crossover, randomized, placebo-controlled study (30c ). Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 hours after quazepam. Itraconazole did not change the kinetics of quazepam but significantly reduced the Cmax and AUC of 2oxoquazepam and N-desalkyl-2-oxoquazepam. Itraconazole did not affect psychomotor function. Ciclosporin The extent of the pharmacokinetic interaction between ciclosporin and itraconazole oral solution in eight renal transplant recipients and the effect on daily drug costs has been determined in a single-center, open, nonrandomized study (31c ). After transplantation, renal transplant recipients received itraconazole solution 200 mg bd and ciclosporin to achieve target blood concentrations. At steady state blood samples were collected over 12 hours for pharmacokinetic evaluation of ciclosporin, itraconazole, and hydroxyitraconazole. Itraconazole was withdrawn after about 3 months. Ciclosporin doses were again titrated to achieve target blood concentrations and ciclosporin concentrations were once again determined at steady state. Mean peak and trough itraconazole concentrations were 1.64 and 1.23 µg/ml respectively. Mean peak and trough hydroxyitraconazole concentrations were 2.37 and 2.20 µg/ml respectively. Itraconazole caused a 48% reduction in the mean total daily dose of ciclosporin necessary to maintain target concentrations, 171 versus 329 mg). This

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reduction in ciclosporin dose resulted in a discounted itraconazole daily drug cost of about 30% while providing antifungal coverage with adequate itraconazole trough concentrations. Cyclophosphamide Cyclophosphamide is a prodrug that is metabolized by CYP450 enzymes to cytotoxic alkylating species, and the extent of metabolism correlates with both efficacy and toxicity. In a randomized study of the safety and efficacy of itraconazole or fluconazole in preventing fungal infections in patients undergoing allogeneic stem cell transplantation, itraconazole (200 mg/day intravenously or 2.5 mg/kg orally tds) or fluconazole (400 mg/day intravenously or orally) were given with from start of conditioning therapy until at least 120 days after transplantation (32c ). After enrolment of the first 197 patients, a data and safety monitoring board reviewed the potentially drug-related adverse effects. Patients who had taken itraconazole had higher serum bilirubin and creatinine concentrations in the first 20 days after transplantation; the highest values were in patients who had taken itraconazole concurrently with cyclophosphamide conditioning. Analysis of cyclophosphamide metabolism in a subset of patients showed greater exposure to toxic metabolites (in particular 4-hydroxycyclophosphamide and 4-ketocyclophosphamide) among recipients of itraconazole compared with fluconazole. In contrast, those who took fluconazole had greater exposure to the unmetabolized drug. Adverse effects occurred preferentially in patients who had greater exposure to cyclophosphamide metabolites. These data suggest that azole antifungals, through differential inhibition of hepatic cytochrome P450 isozymes, affect cyclophosphamide metabolism and conditioning-related adverse effects after allogeneic stem cell transplantation. Digoxin The effect of multiple-dose voriconazole on the steady-state pharmacokinetics of digoxin in healthy men has been studied in a double-blind, randomized, placebo-controlled study (33c ). All the subjects took oral digoxin for 22 days (0.5 mg bd on day 1, 0.25 mg bd on day 2 and 0.25 mg/day on days 3–22). On days 11–22 they were randomized to either voriconazole 200 mg bd or placebo. Voriconazole did not significantly alter the Cmax , Cmin , AUC, tmax , or

301 clearance of digoxin at steady state. There were no significant differences in adverse events, all of which were classified as mild and transient. Glucocorticoids In allergic bronchopulmonary aspergillosis itraconazole and topical or systemic glucocorticoids are commonly co-administered. Itraconazole inhibits the metabolic clearance of glucocorticoids by inhibiting CYP3A4 and it also directly inhibits steroidogenesis, thereby causing serious adverse effects. • A 4-year-old boy with cystic fibrosis developed Cushing’s syndrome after taking itraconazole 100 mg bd and inhaled budenoside 200 micrograms bd for 2 weeks (34A ). Adrenal suppression was documented and persisted for 3 months after stopping this combined regimen.

This report is in line with a previous systematic assessment of the pituitary-adrenal axis in patients taking itraconazole and budenoside (35c ). In this study, an adrenocorticotrophic hormone (ACTH) test with tetracosactide 250 micrograms was performed in 25 patients with cystic fibrosis taking both itraconazole and budesonide, and in 12 patients taking itraconazole alone. ACTH tests performed as part of a pretransplantation program in another 30 patients with cystic fibrosis were used as controls. Of the 25 patients taking both itraconazole and budesonide, 11 had adrenal insufficiency. None of the patients taking itraconazole alone nor the control patients had an abnormal ACTH test. Furthermore, in a randomized, doubleblind, crossover study in 10 healthy subjects (36c ), itraconazole increased the mean AUC of inhaled budesonide 4.2 (range 1.7–9.8) times and the Cmax 1.6 times compared with placebo. The mean half-life of budesonide was prolonged from 1.6 to 6.2 hours by itraconazole. Suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole compared with placebo, with a 43% reduction in the plasma cortisol AUC from 0.5 to 10 hours and a 12% reduction in the cortisol concentration 23 hours after administration of budesonide. Thus, itraconazole markedly increases systemic exposure to inhaled budesonide. This interaction can result in enhanced systemic effects of budesonide, including Cushing syndrome.

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Histamine H2 receptor antagonists The effects of the histamine H2 receptor antagonists cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole have been determined in an open, randomized, placebocontrolled, crossover study in 12 healthy men, who took oral voriconazole 200 mg + cimetidine 400 mg, voriconazole 200 mg + ranitidine 150 mg, and voriconazole 200 mg + placebo, all twice a day (37c ). Treatment periods were separated by at least 7 days. Co-administration of cimetidine increased the Cmax and AUC of voriconazole by 18% (90% CI = 6, 32) and 23% (90% CI = 13, 33) respectively; ranitidine had no significant effect. Most of the adverse events were mild and transitory; two subjects withdrew because of adverse events (burning and pruritus of the scrotum during the placebo period and raised hepatic transaminases during the cimetidine period). Thus, co-administration of cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in an important manner. Interleukin-6 Interleukin-6 can down-regulate the hepatic cytochrome P450 system and consequently alter drug disposition. The potential interaction of interleukin-6 (IL-6) with itraconazole has been studied using human hepatocytes in primary cultures from five adult men (mean age 42 years) who had not taken any medicines known to interact with CYP3A4 (38E ). The cultures were exposed to itraconazole 500 ng/ml, and the effects of cimetidine 120 µg/ml, human IL-650 ng/ml, or IL-6 plus IL-6 receptor antagonist were analysed for 2, 4, 8, and 12 hours. IL-6 did not inhibit hydroxyitraconazole formation. Loratadine Loratadine and its metabolite desloratadine are metabolized not only by CYP3A4 but also by CYP2D6. Therefore, administration of loratadine with inhibitors of CYP3A4 does not cause such severe adverse effects as with terfenadine and astemizole. Nevertheless, severe hepatotoxicity after coadministration of desloratadine and fluconazole has been reported. • A 38-year-old woman with cancer was given intravenous fluconazole 400 mg while taking desloratadine 10 mg/day, clemastine, allopurinol, ranitidine, lorazepam, levofloxacin, spironolactone, and filgrastim, and developed a sudden rise in hepatic

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh transaminases (39A ). Her drugs were withdrawn and her hepatic transaminases normalized within 1 week. She had received both fluconazole and desloratadine on separate occasions and had tolerated both drugs well.

Macrolide antibiotics The effects of multipledose erythromycin or azithromycin on the steady-state pharmacokinetics of voriconazole have been investigated in an open, randomized study in 30 healthy men aged 20–41 years, who took oral voriconazole 200 mg bd for 14 days plus erythromycin (1 g bd on days 8–14), or azithromycin (500 mg/day on days 12–14), or placebo (twice daily on days 8–14) (40c ). There were no significant interactions. The most common study drug-related adverse events were visual disturbances (17/30 patients), reported in all groups, and abdominal pain in the voriconazole + erythromycin group (5/10 patients). Meglitinides The effects of fluconazole 200 mg/day for 4 days on the pharmacokinetics and pharmacodynamics of a single dose of nateglinide 30 mg have been investigated in a double-blind, randomized, crossover study in 10 healthy volunteers (41c ). Fluconazole increased the AUC of nateglinide by 48% (range 20–73%) and prolonged its half-life from 1.6 to 1.9 hours, but did not alter Cmax . The Cmax of the M7 metabolite of nateglinide was reduced by 34% by fluconazole and its half-life was prolonged from 2.2 to 3.5 hours. However, fluconazole did not alter the blood glucose responses to nateglinide. Possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide have been investigated in a randomized crossover study in 12 healthy volunteers (42c ). They took gemfibrozil 600 mg bd, itraconazole 100 mg bd (first dose 200 mg), both gemfibrozil and itraconazole, or placebo for 3 days and then took repaglinide 0.25 mg. Plasma drug and blood glucose concentrations were followed for 7 hours and serum insulin and C peptide concentrations for 3 hours. Gemfibrozil increased the AUC of repaglinide 8.1 (range 5.5–15) times and prolonged its half-life from 1.3 to 3.7 hours. Although itraconazole alone increased repaglinide AUC only 1.4 (1.1–1.9) times, the combination of gemfibrozil + itraconazole increased it 19 (13–25) times and prolonged the half-life of repaglinide to 6.1 hours. The plasma

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repaglinide concentration at 7 hours was increased 29 times by gemfibrozil and 70 times by the combination of gemfibrozil + itraconazole. Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide. Concomitant use of gemfibrozil and repaglinide is therefore best avoided. Omeprazole Itraconazole oral solution has improved systemic availability and reduced pH dependency compared with the capsule formulation. The effects of pharmacologically induced gastric hypoacidity with omeprazole on the pharmacokinetics of the oral solution have been investigated in a randomized, open, prospective, crossover study in 15 healthy, nonpregnant adults, who took a single dose of itraconazole oral solution 400 mg on two occasions, at least 7 days apart, with omeprazole 40 mg nightly for 7 days before one of the doses of itraconazole (43c ). Omeprazole did not significantly affect the Cmax , tmax , or AUC0-8 of itraconazole or hydroxyitraconazole following the administration of the cyclodextrin solution of itraconazole. A more than 50% reduction in the AUC0-24 of itraconazole has been observed when omeprazole was given concomitantly with the capsule formulation (44C ) Thus, when both drugs have to be given concomitantly, itraconazole has to be administered In from of the cyclodextrin solution. Omeprazole is predominantly metabolized by CYP2C19 and CYP3A4. The effects of omeprazole on the steady-state pharmacokinetics of voriconazole have been investigated in an open, randomized, placebo-controlled, crossover study in 18 healthy men, who took oral voriconazole 400 mg bd on day 1 followed by 200 mg bd on days 2–9 and a single dose of 200 mg on day 10, with either omeprazole 40 mg/day or placebo for 10 days (45c ). Co-administration of omeprazole increased the mean Cmax and AUC of voriconazole by 15% (90% CI = 5, 25) and 41% (90% CI = 29, 55) respectively, with no effect on tmax . One subject withdrew from the study during the voriconazole + omeprazole treatment period because of treatment-related abnormal liver function tests. All other treatment-related adverse events resolved without intervention. There were visual adverse events in 20 of 35 treatment episodes; the median times to onset for these events

303 were 18 and 35 minutes, and the median durations were 28 and 15 minutes with and without omeprazole respectively. Omeprazole had no important effect on voriconazole exposure, suggesting that no voriconazole dosage adjustment is necessary for patients in whom omeprazole therapy is initiated. Phenytoin Phenytoin induces CYP3A4 activity and is a substrate and inducer of CYP2C9 and CYP2C19. There have been two placebocontrolled studies in healthy men of the pharmacokinetic interaction of voriconazole with phenytoin (46c ). The first was an open study of the effect of phenytoin 300 mg/day on the steady-state pharmacokinetics of voriconazole 200 mg bd and 400 mg bd. The second was a double-blind randomized study of the effects of voriconazole 400 mg bd on the steady-state pharmacokinetics of phenytoin 300 mg/day. Phenytoin reduced the mean steady-state Cmax and AUC of voriconazole by about 50% and 70% respectively; increasing the dose of voriconazole from 200 mg to 400 mg bd compensated for this effect. Voriconazole 400 mg bd increased the mean steady-state Cmax and AUC of phenytoin by about 70% and 80% respectively. Plasma phenytoin concentrations should therefore be monitored and the dose adjusted as appropriate when phenytoin is co-administered with voriconazole. Quinolone antibiotics Torsade de pointes has been associated with the use of fluconazole plus levofloxacin (47A ). While there have been reports that fluconazole and levofloxacin can cause QT interval prolongation when given alone, co-administration may further increase the risk. Statins Antifungal azoles can increase the systemic exposure to certain inhibitors of hydroxymethylglutaryl coenzyme A reductase (statins) by inhibiting CYP3A4 in the liver and perhaps the intestine, potentially leading to hepatotoxicity and rhabdomyolysis (SEDA-27, 281). The effect of itraconazole on the pharmacokinetics of rosuvastatin has been studied in two double-blind, crossover, randomized, placebo-controlled studies in healthy men, who took itraconazole 200 mg/day for 5 days and on day 4 rosuvastatin 10 mg (n = 12) or 80 mg

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(n = 14) (48c ). After co-administration of itraconazole, the rosuvastatin AUC was increased by 28–39% and the Cmax by 15–36%. These effects are unlikely to be of clinical relevance and support previous in vitro findings that CYP3A4 plays a minor role in the metabolism of rosuvastatin. • An 83-year-old white man with a history of congestive heart failure and hyperlipidemia who was taking simvastatin 40 mg/day was given fluconazole. He developed severe muscle weakness and a markedly raised serum creatine kinase activity, which resolved after withdrawal of simvastatin and fluconazole (49A ).

Rhabdomyolysis in this case was probably caused by an interaction of simvastatin with fluconazole; alternative statins should be used if an antifungal triazoles is needed (SEDA-27, 281). Tacrolimus Tacrolimus concentrations and dosage requirements have been compared before and during azole therapy (fluconazole or itraconazole) in 31 pediatric thoracic transplant patients (50c ). The dose of tacrolimus was empirically reduced by about one-third when azole therapy was begun. Mean tacrolimus dosage requirements fell by 68% within the first month of therapy (before azole therapy 0.27 mg/kg/day; 30 days after azole therapy 0.087 mg/kg/day). Despite mean reductions in tacrolimus dosage from baseline of 33%, 42%, and 55% on days 1, 2, and 4 of azole therapy respectively, there was still an unintended 38% increase in tacrolimus concentrations during the first month of azole therapy. There was no difference in tacrolimus dosage reduction between fluconazole and itraconazole. Azole antifungals markedly reduce tacrolimus requirements within the first few days of therapy. An initial reduction in tacrolimus dose by one-third may be insufficient, and a dosage reduction of at least 50% appears to be warranted. Once azole antifungal therapy is begun, frequent monitoring is required. • A 40-year-old Asian woman received a cadaveric renal transplant for end-stage renal disease due to IgA nephropathy and was given tacrolimus, thymoglobulin, mycophenolate mofetil, and prednisone, along with diltiazem for hypertension (51A ). On postoperative day 5, donor bronchoalveolar lavage revealed active tuberculosis. She was

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh given rifampicin 600 mg/day, and the dose of diltiazem was increased. Over the next 12 days, the dose of tacrolimus was increased to 32 mg/day to achieve a target trough concentration of 10–15 ng/ml. She then received a course of fluconazole 100 mg/day and clarithromycin 1000 mg/day. Despite this, there was no increase in tacrolimus concentrations. Rifampicin was withdrawn, after which therapeutic tacrolimus concentrations were finally reached with usual doses.

Rifampicin is a potent inducer of tacrolimus metabolism, sufficient to overcome the inhibitory effects of diltiazem, fluconazole, and clarithromycin. The manufacturers of voriconazole recommend reducing the daily dosage of tacrolimus by one-third when it is co-administered with voriconazole. • A 44-year-old liver transplant recipient taking a stable maintenance dosage of tacrolimus was given voriconazole for coccidioidomycosis. The dosage of tacrolimus was reduced by one-third, but over the next 10 days, the dosage was reduced to one-tenth of the starting dosage in order to maintain tacrolimus blood concentrations within the target range of 5–15 ng/ml.

This case emphasizes that blood tacrolimus concentrations should be carefully monitored when voriconazole is coadministered with tacrolimus or when voriconazole is discontinued in a patient receiving both drugs together (52A ). Tricyclic antidepressants Interactions between tricyclic antidepressants and fluconazole are rare; only five published reports can be found. • A 44-year-old woman became progressively drowsy and unresponsive and then delirious (53A ). Her medications included metoprolol 50 mg bd, extended-release isosorbide mononitrate 60 mg/day, and amitriptyline 200 mg/day for fibromyalgia. Four days before admission, she was given fluconazole 100 mg/day for oral candidiasis. The combined serum concentration of amitriptyline + nortriptyline was 956 ng/ml (usual target range 150–250 ng/ml), and an electrocardiogram showed QTc interval prolongation to 493 ms. A CT scan of the head was normal. Amitriptyline was withdrawn and her delirium resolved within 24 hours. Her serum amitriptyline concentration fell to 190 ng/ml, and her electrocardiogram became normal. She and her husband denied accidental or intentional overdose of amitriptyline.

Amitriptyline is oxidatively metabolized In the liver by CYP3A4, CYP2C9, CYP2C19, and

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CYP2D6; it is likely that fluconazole inhibited the demethylation of amitriptyline by CYP3A4 and CYP2C19, leading to central anticholinergic toxicity.

Fluconazole

Vinca alkaloids Concomitant use of itraconazole can cause unusually severe neurotoxicity of vincristine.

• A 32-year-old Hispanic man with type I diabetes mellitus and coccidioidal meningitis developed increased hepatic transaminases when given fluconazole but subsequently tolerated voriconazole (56A ). Rechallenge with fluconazole again led to increased transaminases, which normalized when voriconazole was reinstated.

• An 8-year-old boy with acute lymphoblastic leukemia developed status epilepticus and inappropriate antidiuretic hormone secretion while taking both itraconazole and vincristine (54A ). • A 2-year-old boy with acute lymphoblastic leukemia developed paraparesis associated with symmetrical bilateral demyelinating changes on an MRI scan of the brain after only three weekly doses of vincristine while taking itraconazole (54A ).

The interaction between these two drugs is dose-related. The mechanisms of this interaction have not been formally elucidated, but probably include either competitive inhibition of the oxidative metabolism of vincristine, leading to increased systemic exposure, or alternatively inhibition of the transmembrane P glycoprotein efflux pump, leading to an increased intracellular concentration of vincristine. The concomitant use of itraconazole and all vinca alkaloids should be contraindicated (SEDA-26, 308). Warfarin The effect of voriconazole 300 mg bd on the pharmacodynamics of a single oral dose of warfarin 30 mg has been investigated in a double-blind, crossover, placebocontrolled study, in healthy men (55c ). Both the mean maximum change from baseline prothrombin time and the mean area under the effect curve for prothrombin time during coadministration with voriconazole (17 seconds and 3211 second.hours respectively) were statistically significantly greater than the mean values observed during the placebo period (8 seconds and 2282 second.hours). Prothrombin times were still prolonged by a mean value of 5.4 seconds 144 hours after warfarin dose following co-administration with voriconazole compared with a mean value of 0.6 seconds in the placebo treatment period. Coadministration of voriconazole potentiates warfarin-induced prothrombin time prolongation. Regular monitoring of the prothrombin time and appropriate adjustment of the dose of warfarin are recommended if these drugs are co-administered.

Liver Hepatotoxicity with azoles is not necessarily a class effect.

This report suggests that voriconazole may be cautiously substituted for fluconazole in patients with fluconazole-induced hepatatotoxicity who require azole therapy. Urinary tract In a randomized, blind, multicenter comparison of fluconazole 800 mg/day plus placebo and fluconazole plus amphotericin B deoxycholate 0.7 mg/kg/day, with the placebo/amphotericin component given only for the first 5–6 days, as therapy for candidemia due to species other than Candida krusei in 219 adults without granulocytopenia, success rates on day 30 were 57% for fluconazole plus placebo and 69% for fluconazole plus amphotericin (57C ). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients) respectively; the bloodstream infection failed to clear in 17% and 6% of subjects respectively. Renal dysfunction led to a reduction in drug dosage in 3% and 23% but was the primary cause of study failure in only 5% and 3% of subjects respectively. There were no differences in mortality within 90 days of starting therapy. Thus, in non-neutropenic subjects, the combination of fluconazole plus amphotericin was not antagonistic compared with fluconazole alone, and the combination tended to produce improved success and more rapid clearance from the bloodstream. Nevertheless, the combination also was associated with a higher rate of nephrotoxicity. Immunologic Fluconazole hypersensitivity has been reported in a healthy man. • A previously healthy 39-year-old man took two single doses of fluconazole 150 mg 7 days apart and 4 days later developed malaise, generalized weakness, low grade fever, jaundice, and a mildly pruritic, erythematous, generalized rash (58A ). He had a mild eosinophilia, a marked increase in hepatic transaminases to over 2000 U/l, and a serum

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Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

after the end of therapy for graft-versus-host disease (60C ). Fluconazole was given for a median of 120 (range 1–183) days after transplantation, and itraconazole for a median of 89 (range 1–189) days after transplantation. More of those who were given itraconazole discontinued therapy because of adverse effects (36% versus 16%); most of the cases of itraTeratogenicity Fluconazole can cause abnor- conazole withdrawal were for gastrointestinal malities of the branchial apparatus (hypoplasia, complaints (24% versus 4%). More of those agenesis, and fusion) in post-implantation ro- who were given itraconazole had at least three dent embryos cultured in vitro. The branchial times the baseline total bilirubin concentration apparatus is essential for the development of the (95% versus 86%). Intention-to-treat analysis facial skeleton. The branchial arch mesenchyme showed no difference in the incidence of inis formed by two different cellular populations: vasive fungal infections (fluconazole 16% verparaxial mesenchyme and ectomesenchyme, sus itraconazole 13%); however, of those given which originate from rhombencephalic neural itraconazole fewer developed invasive fungal crest cell migration. The possible pathogenic infections (fluconazole 15% versus itraconapathways involved in fluconazole-related bran- zole 7%). Itraconazole provided better protecchial arch abnormalities have been investigated tion against invasive mould infections (fluconain rat embryos 9.5 days old exposed in vitro zole 12% versus itraconazole 5%), but similar to fluconazole 0 or 500 µmol/l (59E ). After protection against candidiasis (3% versus 2%). 24, 36, or 48 hours of culture, the embryos There was no difference in overall survival. were examined for apoptosis and cell pro- Itraconazole appears to prevent invasive mould liferation. Rhombencephalic neural crest cell infections in patients who tolerate it; however, migration and the extracellular matrix were adverse effects and poor tolerability may limit analysed using immunostaining. The differenti- its success as prophylactic therapy. The second trial included 140 patients unating capability of the branchial mesenchymes dergoing allogeneic hemopoietic stem cell transwas investigated using anti-endothelin and antiplantation at five selected transplantation cenendothelin receptor antibodies. During the whole ters in the USA (61C ). The patients received culture period, there were no changes in physitraconazole (200 mg intravenously every 12 iological apoptosis, cell proliferation, or meshours for 2 days followed by 200 mg intraenchymal cell induction in fluconazole-exposed venously every 24 hours or a 200 mg oral embryos, but in contrast there were major solution every 12 hours) or fluconazole (400 changes in neural crest cell migration pathways. mg intravenously or orally every 24 hours) These findings suggest that fluconazole profrom day 1 until day 100 after transplantaduces teratogenic effects by interfering with the tion. Proven invasive fungal infections occurred cellular and molecular mechanisms that control in six of 71 itraconazole recipients and in 17 neural crest cell migration. of 67 fluconazole recipients during the first 180 days after transplantation. Prophylaxis with itraconazole was associated with fewer invasive infections caused by either yeasts or molds. ExItraconazole cept for more frequent gastrointestinal adverse effects (nausea, vomiting, diarrhea, or abdomThere have been two randomized studies of inal pain) in patients given itraconazole (24% whether itraconazole prevents invasive fungal versus 9%), both itraconazole and fluconazole infections after allogeneic stem cell transplan- were well tolerated. The overall mortality rate tation. was similar in the two groups (32 of 71 patients In the first (single center) trial, 304 patients given itraconazole versus 28 of 67 patients were randomized to receive fluconazole (400 given fluconazole). mg/day) or itraconazole (orally 2.5 mg/kg tds In a double-blind, randomized trial in 71 or intravenously 200 mg/day) for 180 days af- adults undergoing orthotopic liver transplantater stem cell transplantation, or until 4 weeks tion to investigate the role of itraconazole for bilirubin of over 513 µmol/l. There was no evidence of viral or autoimmune hepatitis, and a liver biopsy showed portal and lobular inflammation with cholestasis and apoptosis; a skin biopsy showed numerous necrotic keratinocytes. He was treated with methylprednisolone and two doses of immunoglobulin and made a full recovery within 3 months.

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prevention of invasive fungal infections, the patients were randomly assigned to either oral itraconazole (5.0 mg/kg preoperatively and 2.5 mg/kg bd postoperatively) or placebo (62c ). Therapy continued for a maximum of 56 days or until the patient was discharged from hospital or met a predefined end-point. Nine patients in the placebo group and one patient in the itraconazole group developed fungal end-points requiring therapy with amphotericin. Adverse events were reported by 97% and 100% of the patients given itraconazole and placebo respectively, and there were one and six deaths respectively. The efficacy of itraconazole as prophylaxis against serious fungal infections has been investigated in a randomized, double-blind, placebo-controlled study in 39 patients (mean age 15 years) with chronic granulomatous disease, a rare disorder in which the phagocytes fail to produce hydrogen peroxide (63c ). After the initial treatment, each patient alternated between itraconazole and placebo annually. Patients aged 13 years or older and all patients weighing at least 50 kg took itraconazole 200 mg/day; those under 13 years or weighing less than 50 kg took 100 mg/day. One patient (who had not adhered properly to treatment) had a serious fungal infection while taking itraconazole, compared with seven who had a serious fungal infection while taking placebo. There were no serious adverse effects, although one patient had a rash and another had abnormal liver function tests, both of which resolved after withdrawal of itraconazole. Itraconazole prophylaxis appears to be effective and welltolerated in chronic granulomatous disease, but monitoring for long-term adverse effects is warranted. Nervous system Symptoms of neurotoxicity of itraconazole are very rare. • A 74-year-old man without a previous psychiatric history developed delirium 1 day after starting to take itraconazole 200 mg bd for disseminated histoplasmosis (64A ). Extensive diagnostic work-up for potential causes was negative, and he continued to take itraconazole because of clinical improvement. Four days later, his delirium worsened and the dose of itraconazole was reduced to 200 mg/day. Despite the lower dosage, his delirium continued to worsen, and itraconazole was withdrawn, after which his mental status improved rapidly. However, the fungal infection recurred, and itraconazole 200 mg/day was restarted. One day later, the delirium recurred.

307 The mechanism of this adverse effect is unclear; hypothetically, release of prostaglandins and cytokines after successful therapy could have resulted in delirium, although it could simply have been due to the patient’s inherent risk of delirium secondary to age, anemia, and disseminated histoplasmosis. Electrolyte balance Hypokalemia occurs in about 6% of patients taking long-term itraconazole (65c ); the exact mechanism is unknown. • Severe hypokalemia followed by rhabdomyolysis occurred in a 19-year-old man with chronic granulomatous disease 20 days after he started to take oral itraconazole (200 mg bd) for a cutaneous abscess caused by Aspergillus fumigatus; hypokalemia may have been aggravated by concomitant treatment with intravenous amphotericin B during the first seven days of antifungal therapy (66A ).

Hematologic Leukopenia has been attributed to itraconazole. • A 14-year-old patient received itraconazole 1 mg/kg/day for dermatophytosis and had a fall in white blood cell count from 5 × 109 /l at baseline (53% neutrophils) to 2.1 × 109 /l (41% neutrophils) after 16 weeks of therapy with itraconazole. The white blood cell count returned to normal 9 weeks after drug withdrawal (67A ).

Hematologic adverse events have been reported with fluconazole and voriconazole, and are listed in the package inserts. However, the package insert for itraconazole is devoid of such a reference. The joint database of the German Arzneimittelkomission der Deutschen Ärzteschaft (AkDÄ) and the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), based on voluntary reports, lists 683 reports of untoward drug effects of itraconazole, of which 4% are reduced erythrocyte counts, 3.2% reduced leukocyte counts, and 9.2% reduced platelet counts. Although compared with fluconazole and voriconazole, hematological adverse events associated with itraconazole were less frequent in absolute and relative terms, monitoring of blood counts is recommended when itraconazole is prescribed for prolonged periods of time (68R ). Immunologic Immediate hypersensitivity to itraconazole is extremely rare.

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• Angioedema of the face and generalized urticaria occurred in a 65-year-old man on day 3 of oral treatment with itraconazole 100 mg bd for prophylaxis of candidiasis (69A ). The symptoms responded promptly to parenteral glucocorticoids. Oral rechallenge with itraconazole resulted in a maculopapular rash and angioedema within 2 hours after ingestion. The patient had no personal or family history of allergy.

Voriconazole

(SEDA-27, 281)

Voriconazole is a synthetic antifungal triazole, used intravenously and orally, with activity against a wide spectrum of clinically important yeasts and molds, including Candida species, Cryptococcus neoformans, Aspergillus and other hyaline molds, dematiaceous moulds, and dimorphic molds (SEDA-27, 281; 10R ). It undergoes complex hepatic metabolism and has the potential for drug-drug interactions mediated by CYP 3A4, CYP2C9, and CYP2C19. Voriconazole had excellent efficacy in phase 2 studies in patients with oropharyngeal and esophageal candidiasis, acute and chronic invasive aspergillosis, and infections by rare fungal pathogens. In phase 3 trials, voriconazole was superior to conventional amphotericin for first-line therapy of invasive aspergillosis and yielded comparable success rates but less proven and probable breakthrough infections compared with liposomal amphotericin as empirical antifungal therapy in patients with persistent neutropenia. Apart from a higher incidence of liver function test abnormalities compared with fluconazole, transient visual adverse effects, in particular enhanced brightness of light and color, are common with voriconazole. The safety, tolerance, and pharmacokinetics of oral voriconazole after single and multiple dosing have been investigated in 64 healthy subjects (70c ). Groups of eight subjects each took voriconazole doses of 2 mg/kg bd, 4 mg/kg/day, 2 mg/kg tds, or 3 mg/kg bd, 11 took 1.5 mg/kg tds, and 21 took placebo. The pharmacokinetics of voriconazole were non-linear (dose- and time-related), and there was intersubject variability in Cmax and AUC. Visual inspection of Cmin values together with statistical analyses of Cmax and AUC suggested that steady-state concentrations were achieved by 5–6 days of multiple dosing. There were

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

treatment-related adverse events in 67% of those who took voriconazole compared with 81% of those who took placebo. Visual disorders, including abnormal vision, conjunctivitis, eye pain, lacrimation disturbance, and photophobia, were reported by 16 subjects taking active treatment, 14 of whom reported a change in brightness of vision. All visual adverse effects cleared without intervention or after withdrawal. Blood pressure, pulse rate, electrocardiograms, and Holter data did not show any effects of voriconazole. Five of those who took voriconazole withdrew from the study because of visual disturbances (n = 3), ventricular tachycardia (n = 1), or ST segment depression (n = 1); in the placebo group, two subjects withdrew. The oral dosage regimen selected for subsequent phase 2/3 clinical trials was 200 mg bd, equivalent to 3 mg/kg bd. The pharmacokinetics and safety of intravenous voriconazole have been investigated in healthy men in two single-blind, placebocontrolled studies (71c ). In the first study 12 subjects were randomized to voriconazole (3 mg/kg) or placebo, administered once daily on days 1 and 12, and every 12 hours on days 3–11. In the second study, 18 subjects were randomized to voriconazole or placebo; voriconazole was given as a loading dose of 6 mg/kg twice on day 1, then 3 mg/kg bd on days 2–9, and 3 mg/kg once on day 10. The use of a loading dose in the second study resulted in a shorter time to steady-state Cmin than in the first study. The final day pharmacokinetics in the two studies were similar. On multiple dosing, voriconazole accumulated to an extent that was not predictable from the single-dose data. Multiple doses of voriconazole were well tolerated and no subject withdrew in either study. There were seven cases of possibly drug-related visual disturbances in three subjects. There were no clinically significant electrocardiographic changes and no abnormalities on Holter recording in those who took voriconazole. The efficacy, tolerability, and safety of voriconazole have been studied in 301 patients (72C ). Intravenous voriconazole was given in a loading dose of 6 mg/kg bd for the first 24 hours, followed by 4 mg/kg bd for at least 3 days, after which patients could switch to oral voriconazole 200 mg bd. Oral voriconazole was given in a dose of 400 mg bd on the first day, followed by 200 mg bd. Voriconazole was given intravenously for a median of 18

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(range 1–138) days and orally for a median of 69 (range, 1–326) days. The efficacy rates for voriconazole were 44% for aspergillosis, 58% for candidiasis, 39% for cryptococcosis, 46% for fusariosis, and 30% for scedosporiosis. The most common treatment-related adverse effects were visual abnormalities (26%), rash (7.5%), nausea (6.5%), vomiting (4.8%), and headache (4.6%). There were abnormal increases in liver function tests in up to 11% of patients with normal baseline values and in up to 29% of patients with abnormal baseline values. Treatment had to be withdrawn in 8.5% of patients. In 52 patients with invasive candidiasis intolerant of other antifungal agents or with infection refractory to other antifungal agents the median duration of voriconazole therapy was 60 (range 1–314) days, and the median dosage was 400 mg/day (7.48 mg/kg/day). The overall rate of response was 56% (95% CI = 41– 70; Candida albicans 44%; Candida glabrata 38%; Candida krusei 70%; Candida tropicalis 67%; and other Candida species 100%) (73c ). The response rate in patients who had failed previous azole therapy was 58%. Common adverse effects included nausea and vomiting (25%), abnormal liver enzymes (23%), visual disturbances (21%), rash (15%), dysrhythmias (13%), and abdominal pain (12%). There were serious adverse effects in four patients. The antifungal efficacy and safety of voriconazole in patients with invasive fungal infections intolerant to or progressive despite standard therapy have been analysed in 45 patients, 38 of whom had invasive Aspergillus, three had Fusarium, and two had Scedosporium, affecting the lungs (n = 26), the central nervous system (n = 5), the sinuses (n = 3), or more than one body site (n = 9) (74c ). The most common underlying illnesses were solid organ transplantation (n = 13), bone marrow transplantation (n = 11), and hematological malignancies (n = 7). The median duration of voriconazole therapy was 79 days and nine patients took it for over 1 year. Four patients withdrew because of adverse effects: abnormal liver function tests (n = 4), rash (n = 1), and atrial fibrillation (n = 1). There were no significant visual abnormalities. Liver There have been concerns about voriconazole-related liver toxicity, and individual voriconazole dosage modification based

on plasma concentrations has been suggested (75A ). In a reply, the manufacturers cited data from three large randomized trials of voriconazole (76M ). These data showed no differences in the frequency of liver function test abnormalities between voriconazole and amphotericin formulations in patients with invasive aspergillosis, fever, and granulocytopenia; only in patients with esophageal candidiasis was the frequency of abnormal liver function tests greater among patients taking voriconazole than among those taking fluconazole. According to the authors, these data suggest that among patients with multiple co-morbidities and multiple co-medications, the frequency of abnormal liver function tests may depend on factors other than the type of antifungal agent. Furthermore, they presented a summary of unpublished logistic regression analyses that they had performed to identify any possible relation between plasma concentrations and abnormal liver function tests (76M ). These analyses, performed on about 3000 samples from 1000 patients enrolled into 10 trials showed only a weak and inconsistent association of plasma concentrations of voriconazole with abnormal liver function tests.

ECHINOCANDINS

(SEDA-25, 338;

SEDA-26, 311) The echinocandins anidulafungin, caspofungin, and micafungin have been reviewed (10R ). All three compounds have dose-independent pharmacokinetics with half-lives of 10–15 hours. They are highly protein bound (over 95%) and distribute into all major tissues, including the brain; concentrations in non-inflammatory CSF are low. They are metabolized by the liver and are slowly excreted as inactive metabolites into the urine and feces; only small fractions are excreted into the urine unchanged. They lack significant potential for drug interactions mediated by CYP450 isozymes. The efficacy of anidulafungin, caspofungin, and micafungin against Candida species has been documented in phase 2 and phase 3 studies in immunocompromised patients with superficial and invasive fungal infections, in empirical antifungal therapy in granulocytopenic

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patients with persistent fever despite broadspectrum antibacterial therapy, and in prophylaxis in high-risk granulocytopenic patients after hemopoietic stem cell transplantation. Currently, caspofungin is the only echinocandin licensed in the European Union and the USA. Caspofungin is approved in patients over 18 years of age for second-line therapy of definite or probable invasive aspergillosis, for primary therapy in non-neutropenic patients with invasive Candida infections, and for empirical antifungal therapy in granulocytopenic patients with persistent fever.

single loading dose of 70 mg on day 1. The median duration of combination therapy was 24 (range 3–74) days. In 18 patients there was a favorable antifungal response, defined as improvement in both clinical and radiographic signs of fungal pneumonia. There was mild to moderate nephrotoxicity in 15 patients, necessitating the substitution of liposomal amphotericin. There were mild rises in alkaline phosphatase activity in nine patients. Caspofungin was temporarily withheld from one patient who developed moderate but reversible biochemical hepatotoxicity. These analyses suggest that caspofungin and L-AmB can be used safely together.

Caspofungin

Susceptibility factors Children In a retrospective analysis of the safety of off-label caspofungin in 25 immunocompromised children (median age 9.8 years; range 0.3–26) who had received at least one dose of caspofungin, 21 received it in combination with L-AmB, and four received caspofungin alone (79c ). The median duration of caspofungin therapy was 32 (range 1–116) days; patients weighing over 50 kg received 50–75 mg/day, and those weighing under 50 kg received 0.8–1.6 mg/kg/day. Three patients had at least one adverse event that was judged possibly related to caspofungin: hypokalemia (n = 3), raised serum bilirubin (n = 2), reduced hemoglobin (n = 1), and increased alanine transaminase (n = 1). No patient had an adverse event that was probably or definitely related to caspofungin, and there were no serious drug-related adverse events. Antifungal efficacy was not analysed.

The use of caspofungin with other agents against certain types of invasive fungal infections is appealing, given the poor response rates to standard agents and its unique mechanism of action. Two retrospective analyses have explored the safety and potential benefits of a combination of caspofungin with liposomal amphotericin B (L-AmB). In the first analysis the efficacy and safety of caspofungin in combination with L-AmB in 48 patients with hematological malignancies with definite or probable or possible invasive aspergillosis were evaluated (77c ). Caspofungin was given intravenously as a 70 mg loading dose on day 1, followed by a daily dose of 50 mg; L-AmB was started at an intravenous dose of 5 mg/day. The median duration of therapy with the combination was 20 (range 7–180) days. The combination of caspofungin and LAmB was well tolerated: seven patients developed mild-to-moderate renal insufficiency that was attributed to the use of L-AmB and four required withdrawal. There was hypokalemia in three of the patients. One patient had a fever associated with caspofungin and another had hepatic dysfunction of multifactorial origin. In no patient was the combination withheld due to unanticipated adverse effects. The second analysis included 30 patients with hematological malignancies and proven (n = 6), probable (n = 4), or possible (n = 20) invasive fungal lung infections refractory to LAmB monotherapy 3–5 mg/kg/day (78c ). The dosage of caspofungin was 50 mg/day with a

Autacoids The effects of caspofungin and amphotericin B on the release of histamine from human peripheral blood cells, mononuclear cells, and mast cells have been investigated in in vitro cell culture experiments (12E ). Cultured human mononuclear (THP-1) and mast (HMC-1) cells from five healthy volunteers were incubated with increasing concentrations of amphotericin B deoxycholate, diphenhydramine, amphotericin B deoxycholate plus diphenhydramine, caspofungin, caspofungin plus diphenhydramine, and the calcium ionophore A23187 for up to 24 hours. Histamine concentrations and histamine N-methyltransferase activity were determined at various

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times. Cell viability was assessed by exclusion of erythrocin B. A23187 increased histamine concentrations from baseline in peripheral blood and HMC-1 cells. There were no change in histamine concentrations in response to amphotericin B deoxycholate, whereas caspofungin caused a significant increase in histamine release in peripheral blood cells and HMC-1 cells. There were no changes in histamine concentrations in THP-1 cells in response to any agent. Similarly, histamine Nmethyltransferase activity in peripheral blood was not affected by amphotericin B deoxycholate, but was significantly reduced by caspofungin. These results suggest that the amphotericin B-induced infusion-related reaction is not a histamine-mediated event. Conversely, caspofungin increased histamine concentrations in whole blood and HMC-1 cells and inhibited histamine N-methyltransferase activity. Thus, infusion-related reactions associated with caspofungin may be mediated by histamine release secondary to caspofungin.

PYRIMIDINE ANALOGUES

311 effects of flucytosine; conversion of flucytosine to fluorouracil is thought to be responsible in most cases (80R ). The conversion of flucytosine to fluorouracil by micro-organisms in the human intestinal microflora has been studied in vitro using viable and non-viable Escherichia coli at different concentrations of flucytosine (81E ). Flucytosine conversion was also studied in fecal specimens from three neutropenic patients at the start of antimicrobial/antifungal prophylaxis (C/A regimen) and 1 week later. Flucytosine concentrations fell by an average of 72, 71, and 72% after incubation for 48 hours with viable Escherichia coli organisms 1010 /ml in suspension in broth containing flucytosine 13, 130, and 1300 µg/ml respectively. There was a 44% reduction in flucytosine concentrations when non-viable Escherichia coli were used, showing that bacterial viability is not necessary for this conversion. When fecal specimens from two patients were investigated before the C/A regimen, there was significant flucytosine conversion, whereas there was no conversion in the corresponding fecal specimens after 1 week of the C/A regimen.

Flucytosine

(SED-14, 926; SEDA-24, 295; SEDA-27, 278)

Increases in hepatic transaminases and depression of hemopoiesis are the principal adverse REFERENCES 1. Ajit C, Suvannasankha A, Zaeri N, Munoz SJ. Terbinafine-associated hepatotoxicity. Am J Med Sci 2003; 325: 292–5. 2. Zapata Garrido AJ, Romo AC, Padilla FB. Terbinafine hepatotoxicity. A case report and review of literature. Ann Hepatol 2003; 2: 47–51. 3. Lovell MO, Speeg KV, Havranek RD, Sharkey FE. Histologic changes resembling acute rejection in a liver transplant patient treated with terbinafine. Hum Pathol 2003; 34: 187–9. 4. Walter RB, Lukaschek J, Renner EL, Mullhaupt B, Bachli EB. Fatal hepatic veno-occlusive disease associated with terbinafine in a liver transplant recipient. J Hepatol 2003; 38: 373–4. 5. Lombardo M, Cerati M, Pazzaglia A. Acute generalized exanthematous pustulosis induced by terbinafine. J Am Acad Dermatol 2003; 49: 158–9. 6. Taberner R, Puig L, Gilaberte M, Alomar A. Acute generalized exanthematous pustulosis induced by terbinafine. Eur J Dermatol 2003; 13: 313–14.

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Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh 25. Vanier KL, Mattiussi AJ, Johnston DL. Interaction of all-trans-retinoic acid with fluconazole in acute promyelocytic leukemia. J Pediatr Hematol Oncol 2003; 25: 403–4. 26. Purkins L, Wood N, Kleinermans D, Love ER. No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers. Br J Clin Pharmacol 2003; 56 Suppl 1: 62–8. 27. Scherpbier HJ, Hilhorst MI, Kuijpers TW. Liver failure in a child receiving highly active antiretroviral therapy and voriconazole. Clin Infect Dis 2003; 37: 828–30. 28. Oda M, Kotegawa T, Tsutsumi K, Ohtani Y, Kuwatani K, Nakano S. The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers. Eur J Clin Pharmacol 2003; 59: 615–19. 29. Lilja JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ. Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol. Clin Pharmacol Ther 2003; 73: 192–8. 30. Kato K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Kanno M, Otani K. Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug. Ther Drug Monit 2003; 25: 473–7. 31. Florea NR, Capitano B, Nightingale CH, Hull D, Leitz GJ, Nicolau DP. Beneficial pharmacokinetic interaction between cyclosporine and itraconazole in renal transplant recipients. Transplant Proc 2003; 35: 2873–7. 32. Marr KA, Leisenring W, Crippa F, Slattery JT, Corey L, Boeckh M, McDonald GB. Cyclophosphamide metabolism is affected by azole antifungals. Blood 2004; 103: 1557–9. 33. Purkins L, Wood N, Kleinermans D, Nichols D. Voriconazole does not affect the steady-state pharmacokinetics of digoxin. Br J Clin Pharmacol 2003; 56 Suppl 1: 45–50. 34. De Wachter E, Vanbesien J, De Schutter I, Malfroot A, De Schepper J. Rapidly developing Cushing syndrome in a 4-year-old patient during combined treatment with itraconazole and inhaled budesonide. Eur J Pediatr 2003; 162: 488–9. 35. Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J 2002; 20: 127–33. 36. Raaska K, Niemi M, Neuvonen M, Neuvonen PJ, Kivisto KT. Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole. Clin Pharmacol Ther 2002; 72: 362– 9. 37. Purkins L, Wood N, Kleinermans D, Nichols D. Histamine H2 -receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole. Br J Clin Pharmacol 2003; 56 Suppl 1: 51–5. 38. Gubbins PO, Melchert RB, McConnell SA, Franks AM, Penzak SR, Gurley BJ. Effect of interleukin 6 on the hepatic metabolism of itraconazole and its metabolite hydroxyitraconazole using pri-

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mary human hepatocytes. Pharmacology 2003; 67: 195–201. 39. Schottker B, Dosch A, Kraemer DM. Severe hepatotoxicity after application of desloratadine and fluconazole. Acta Haematol 2003; 110: 43–4. 40. Purkins L, Wood N, Ghahramani P, Kleinermans D, Layton G, Nichols D. No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers. Br J Clin Pharmacol 2003; 56 Suppl 1: 30–6. 41. Niemi M, Neuvonen M, Juntti-Patinen L, Backman JT, Neuvonen PJ. Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide. Clin Pharmacol Ther 2003; 74: 25–31. 42. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46: 347–51. 43. Johnson MD, Hamilton CD, Drew RH, Sanders LL, Pennick GJ, Perfect JR. A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution. J Antimicrob Chemother 2003; 51: 453– 7. 44. Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol 1998; 54: 159–61. 45. Wood N, Tan K, Purkins L, Layton G, Hamlin J, Kleinermans D, Nichols D. Effect of omeprazole on the steady-state pharmacokinetics of voriconazole. Br J Clin Pharmacol 2003; 56 Suppl 1: 56–61. 46. Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A. Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol 2003; 56 Suppl 1: 37–44. 47. Gandhi PJ, Menezes PA, Vu HT, Rivera AL, Ramaswamy K. Fluconazole- and levofloxacininduced torsades de pointes in an intensive care unit patient. Am J Health-Syst Pharm 2003; 60: 2479– 83. 48. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 2003; 73: 322–9. 49. Shaukat A, Benekli M, Vladutiu GD, Slack JL, Wetzler M, Baer MR. Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother 2003; 37: 1032–5. 50. Mahnke CB, Sutton RM, Venkataramanan R, Michaels M, Kurland G, Boyle GJ, Law YM, Miller SA, Pigula FA, Gandhi S, Webber SA. Tacrolimus dosage requirements after initiation of azole antifungal therapy in pediatric thoracic organ transplantation. Pediatr Transplant 2003; 7: 474–8. 51. Bhaloo S, Prasad GV. Severe reduction in tacrolimus levels with rifampin despite multiple cytochrome P450 inhibitors: a case report. Transplant Proc 2003; 35: 2449–51. 52. Pai MP, Allen S. Voriconazole inhibition of tacrolimus metabolism. Clin Infect Dis 2003; 36: 1089–91.

313 53. Duggal HS. Delirium associated with amitriptyline/fluconazole drug. Gen Hosp Psychiatry 2003; 25: 297–8. 54. Ariffin H, Omar KZ, Ang EL, Shekhar K. Severe vincristine neurotoxicity with concomitant use of itraconazole. J Paediatr Child Health 2003; 39: 638–9. 55. Purkins L, Wood N, Kleinermans D, Nichols D. Voriconazole potentiates warfarin-induced prothrombin time prolongation. Br J Clin Pharmacol 2003; 56 Suppl 1: 24–9. 56. Spellberg B, Rieg G, Bayer A, Edwards Jr JE. Lack of cross-hepatotoxicity between fluconazole and voriconazole. Clin Infect Dis 2003; 36: 1091– 3. 57. Rex JH, Pappas PG, Karchmer AW, Sobel J, Edwards JE, Hadley S, Brass C, Vazquez JA, Chapman SW, Horowitz HW, Zervos M, McKinsey D, Lee J, Babinchak T, Bradsher RW, Cleary JD, Cohen DM, Danziger L, Goldman M, Goodman J, Hilton E, Hyslop NE, Kett DH, Lutz J, Rubin RH, Scheld WM, Schuster M, Simmons B, Stein DK, Washburn RG, Mautner L, Chu TC, Panzer H, Rosenstein RB, Booth J; National Institute of Allergy and Infectious Diseases Mycoses Study Group. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003; 36: 1221–8. 58. Su FW, Perumalswami P, Grammer LC. Acute hepatitis and rash to fluconazole. Allergy 2003; 58: 1215–16. 59. Menegola E, Broccia ML, Di Renzo F, Giavini E. Pathogenic pathways in fluconazole-induced branchial arch malformations. Birth Defects Res Part A Clin Mol Teratol 2003; 67: 116–24. 60. Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA, Nichols WG, Musher B, Corey L. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103: 1527–33. 61. Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, Blumer JL, Leitz GJ, Territo MC. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 2003; 138: 705–13. 62. Sharpe MD, Ghent C, Grant D, Horbay GL, McDougal J, David Colby W. Efficacy and safety of itraconazole prophylaxis for fungal infections after orthotopic liver transplantation: a prospective, randomized, double-blind study. Transplantation 2003; 76: 977–83. 63. Gallin JI, Alling DW, Malech HL, Wesley R, Koziol D, Marciano B, Eisenstein EM, Turner ML, DeCarlo ES, Starling JM, Holland SM. Itraconazole to prevent fungal infections in chronic granulomatous disease. New Engl J Med 2003; 348: 2416–22. 64. Mittal D, Wikaitis J. Itraconazole-induced delirium. Psychosomatics 2003; 44: 260–1.

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65. Tucker RM, Haq Y, Denning DW, Stevens DA. Adverse events associated with itraconazole in 189 patients on chronic therapy. J Antimicrob Chemotherapy 1990; 26: 561–6. 66. Ruiz-Contreras J, Rodriguez R, Gomez de Quero P, Gonzalez Tome MI, Sanchez Diaz JI. Severe hypokalemia and rhabdomyolysis associated with itraconazole therapy. Pediatr Infect Dis J 2003; 22: 1024–5. 67. Nagaoka Y, Okochi H, Tamaki K. Leukocytopenia after administration of itraconazole. Mycoses 2003; 46: 240–1. 68. Arzneimittelkommission der Deutschen Ärzteschaft. Blutbildstoerungen unter einer antimykotischen Therapie mit Itraconazol. Deutsches Ärzteblatt 2004; 101: B2033–4. 69. Martinez-Alonso JC, Dominguez-Ortega FJ, Fuentes-Gonzalo MJ. Urticaria and angioedema due to itraconazole. Allergy 2003; 58: 1317–18. 70. Purkins L, Wood N, Greenhalgh K, Allen MJ, Oliver SD. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol 2003; 56 Suppl 1: 10–16. 71. Purkins L, Wood N, Greenhalgh K, Eve MD, Oliver SD, Nichols D. The pharmacokinetics and safety of intravenous voriconazole—a novel widespectrum antifungal agent. Br J Clin Pharmacol 2003; 56 Suppl 1: 2–9. 72. Perfect JR, Marr KA, Walsh TJ, Greenberg RN, DuPont B, De la Torre-Cisneros J, Just-Nubling G, Schlamm HT, Lutsar I, Espinel-Ingroff A, Johnson E. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 2003; 36: 1122–31. 73. Ostrosky-Zeichner L, Oude Lashof AM, Kullberg BJ, Rex JH. Voriconazole salvage treatment of invasive candidiasis. Eur J Clin Microbiol Infect Dis 2003; 22: 651–5.

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh 74. Baden LR, Katz JT, Fishman JA, Koziol C, DelVecchio A, Doran M, Rubin RH. Salvage therapy with voriconazole for invasive fungal infections in patients failing or intolerant to standard antifungal therapy. Transplantation 2003; 76: 1632–7. 75. Potoski BA,Brown JR. The safety of voriconazole. Clin Infect Dis 2002; 35: 1273–5. 76. Lutsar I, Hodges MR, Tomaszewski K, Troke PF, Wood ND. Safety of voriconazole and dose individualization. Clin Infect Dis 2003; 36: 1087–8. 77. Kontoyiannis DP, Hachem R, Lewis RE, Rivero GA, Torres HA, Thornby J, Champlin R, Kantarjian H, Bodey GP, Raad II. Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer 2003; 98: 292–9. 78. Aliff TB, Maslak PG, Jurcic JG, Heaney ML, Cathcart KN, Sepkowitz KA, Weiss MA. Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin. Cancer 2003; 97: 1025–32. 79. Franklin JA, McCormick J, Flynn PM. Retrospective study of the safety of caspofungin in immunocompromised pediatric patients. Pediatr Infect Dis J 2003; 22: 747–9. 80. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998; 44: 343–500. 81. Vermes A, Kuijper EJ, Guchelaar HJ, Dankert J. An in vitro study on the active conversion of flucytosine to fluorouracil by microorganisms in the human intestinal microflora. Chemotherapy 2003; 49: 17–23.

Jacqueline Buser and Karin Fattinger

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ANTIMALARIAL DRUGS Clinical research on malaria prophylaxis and malaria treatment currently focuses mainly on the evaluation and comparison of drug combinations, especially the combination of atovaquone + proguanil, recently approved in several countries as Malarone™, and combinations of Artemisia derivatives (artemisinin, artemether, or artesunate), with previously established antimalarial drugs.

4-AMINOQUINOLINES (CHLOROQUINE AND CONGENERS) (SED-14, 950; SEDA-25, 343; SEDA-26, 315; SEDA-27, 289)

Amodiaquine Hematologic The protective effect of intermittent amodiaquine during the high-risk seasons on anemia and malarial fever has been investigated in a double-blind, randomized, placebo-controlled study in 291 infants aged 12–16 weeks, of whom 146 received amodiaquine for 3 days (10, 10, and 5 mg/kg) every 2 months for 6 months, either alone or combined with an iron supplement (1c ). The protective efficacy of intermittent amodiaquine for malarial fever and anemia compared with placebo was 65% (95% CI = 42, 77%) and 67% (34, 84) respectively. Except for one infant with a neutrophil count of 1.5 × 109 /l, there were no adverse effects on neutrophils or the liver, and in particular no cases of agranulocytosis or liver failure. Furthermore, no patient died or stopped taking the drugs because of severe adverse effects. Thus, at least for this dosage regimen in © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

infants, the incidence of severe hematological and hepatic adverse events is under 3%.

Chloroquine A study in children has suggested that the antihistamine chlorphenamine might reverse chloroquine resistance (SEDA-24, 331). Furthermore, ketotifen, another antihistamine, reversed chloroquine resistance in Plasmodium falciparum in vitro. Chloroquine (10 mg chloroquine base/kg for 3 days) alone and in combination with ketotifen (0.25 mg/kg followed by 0.125 mg/kg tds for 4 days) have therefore been compared in an open, randomized study in 150 children aged 1–10 years (2c ). Although the fever lasted slightly shorter in patients who took the combination of chloroquine and ketotifen compared with those treated with chloroquine only, parasite clearance times and cure rates were comparable, suggesting no effect of ketotifen on chloroquine resistance. Metabolism Hypoglycemia has often been reported in chloroquine-treated patients with malaria, but it is not clear whether the chloroquine or the malaria itself caused the hypoglycemia (SED-14, 952). • A 16-year-old girl was treated empirically with chloroquine (total 450 mg of chloroquine base) for fever, had no malarial parasites in the peripheral blood smear, but had severe hypoglycemia of 1.5 mmol/l (27 mg/dl) (3A ).

This suggests that therapeutic doses of chloroquine can cause hypoglycemia even in the absence of malaria. Hematologic Chloroquine can cause methemoglobinemia, especially in enzyme-deficient subjects. An exceptionally severe case of methemoglobinema has been reported.

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• A 16-year-old girl treated empirically for fever with chloroquine (total 450 mg of chloroquine base) developed cyanosis, jaundice, and altered consciousness (3A ). She had a moderate hemolytic anemia (hemoglobin 13.3 g/dl), severe methemoglobinema (70%), and hypoglycemia (1.5 mmol/l; 27 mg/dl). No malarial parasites were found, a Coomb’s test was negative, and erythrocyte glucose-6-phosphate dehydrogenase (G6PD) activity was normal. NADPH methemoglobin reductase was not evaluated. Other causes, such as exposure to nitro-compounds, solvents, or drugs other than chloroquine were excluded. She was treated with methylthioninium (methylene blue) and the methemoglobinemia resolved over the next few days.

Skin Different types of skin lesions, including hypopigmentation and vascular purpura, have been attributed to chloroquine. Case reports now suggest that chloroquine can cause vitiligo-like depigmentation and cutaneous necrotizing vasculitis.

Musculoskeletal Chloroquine and hydroxychloroquine occasionally cause a myopathy associated with muscle weakness, reduced or absent tendon reflexes, and raised creatine kinase activity; it usually develops gradually after 5–7 months of treatment. The muscle biopsy findings have been described in detail: atrophic muscle fibers, muscle fiber necrosis with vacuolar degradation, vacuoles staining positive with acid phosphatase with a granular pattern, autophagic vacuoles, and cytosomes with electron-dense curvilinear profiles on electron microscopy (4A ). Urinary tract Chloroquine-induced kidney damage has occasionally been reported. A remarkably well-documented case report further elucidates this adverse drug reaction. • A 46-year-old woman with impaired renal function (glomerular filtration rate of 23–26 ml/minute/1.7 m2 , serum creatinine 186 µmol/l (2.1 mg/dl) took chloroquine 155 mg/day for Sjögren’s syndrome (5A ). After 5 months, her serum creatinine had increased to 339 µmol/l (2.7 mg/dl) and after 11 months to 442 µmol/l (5 mg/dl) with a glomerular filtration rate of 8 ml/minute/1.7 m2 . Light microscopy of a kidney biopsy showed vascular parenchymal atrophy with accumulation of colloid material in atrophic tubules. Electron microscopy showed osmiophilic lamellated bodies mainly in podocytes and to a lesser degree in glomerular and vascular endothelial and vascular smooth muscle cells. Fabry’s disease was ruled out based on normal activity of alpha-galactosidase A. Because the histopathological findings resembled those seen in chloroquine-induced myopathy/cardiomyopathy, chloroquine was withdrawn and 9 months later, her glomerular filtration rate was 19 ml/minute/1.7 m2 and serum creatinine 221 µmol/l (2.5 mg/dl), close to baseline values.

Jacqueline Buser and Karin Fattinger

• A 44-year-old Hispanic woman developed depigmented patches on her chest, shoulders, forearms, back, and shins 1 month after switching from hydroxychloroquine to chloroquine 500 mg/day for cutaneous discoid lupus erythematosus (6A ). Chloroquine was immediately withdrawn, and within 2 months spontaneous re-pigmentation occurred in most of the depigmented patches. • A 49-year-old man developed severe cutaneous necrotizing vasculitis after 13 days of treatment with a combination of chloroquine 100 mg and proguanil 200 mg/day (7A ). He had taken no other drugs. The lesions consisted of diffuse painful purpuric and extensive necrotizing plaques on the upper and lower limbs, mainly on the hands and feet, maculopapular erythema on the trunk, and petechial maculae on the hard palate. His temperature was normal and he had no organomegaly. Laboratory findings were normal, except for a eosinophilia of 0.72 × 109 /l and a C-reactive protein of 133 mg/l. Chloroquine and proguanil were withdrawn and his condition normalized within 3 weeks. Skin tests 3 month later were positive for chloroquine, but negative for quinine and the biguanide derivatives proguanil and metformin.

Teratogenicity In 133 consecutive pregnancies in 90 women who took 200 mg hydroxychloroquine twice a day (n = 122) or once a day (n = 11) the same number of pregnancies resulted in live births as in 70 consecutive pregnancies in 53 women with similar disorders who did not take hydroxychloroquine (8c ). Pregnancy outcomes and the results of followup examination of the children were comparable.

Mefloquine Psychiatric Mefloquine can cause severe mental changes such as psychosis. • After 4 weeks of malaria prophylaxis with mefloquine 250 mg/week, a 25-year-old woman developed bizarre paranoid delusions with auditory and visual hallucinations (9A ). MRI and MRA scans of the brain were unremarkable, but electroencephalography showed diffuse cerebral dysfunction. A malaria smear was negative. Mefloquine

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was withdrawn and the psychotic symptoms resolved over 6 days with temporary risperidone treatment. The symptoms did not re-occur during a 2-year follow-up period.

8-AMINOQUINOLINES (PRIMAQUINE AND CONGENERS) (SED-14, 958; SEDA-25, 345; SEDA-26, 318; SEDA-27, 291)

Atovaquone + proguanil (Malarone™ ) Atovaquone is a naphthoquinone that is effective in the treatment and prophylaxis of malaria. Since atovaquone monotherapy was associated with malaria recrudescence and can lead to plasmodial atovaquone resistance, atovaquone is generally used in combination with a second antimalarial drug. In most studies it is combined with proguanil, and a fixed combination of atovaquone 250 mg and proguanil 100 mg has been approved by several drug agencies as Malarone™ . Atovaquone structurally resembles the protein ubiquinone expressed in protozoal mitochondria and it therefore inhibits mitochondrial electron transport, resulting in collapse of the mitochondrial membrane potential, which impairs the function of the enzyme dihydro-orotate dehydrogenase and thus impairs pyrimidine synthesis and protozoal DNA synthesis. Proguanil is metabolized to an active metabolite, cycloguanil, which inhibits the plasmodial enzyme dihydrofolate reductase and thus interferes with the synthesis of folate required for plasmodial DNA synthesis. Since, atovaquone and proguanil interfere with different pathways required for DNA synthesis, they act synergistically. Resistance has not yet been a problem during clinical trials. However, at least one case of acquired Plasmodium falciparum resistance to atovaquone/proguanil has been reported in a non-immune female traveller to Kenya who had been treated for Plasmodium falciparum malaria (10A ). Observational studies So far, eight randomized, open trials have shown that atovaquone + proguanil (1000 mg/day + 400 mg/day for 3

317 days) is effective in acute uncomplicated Plasmodium falciparum malaria (11R ). In these trials, atovaquone + proguanil produced higher or equal cure rates compared with previously approved antimalarial regimens. In an open study in Gabon atovaquone + proguanil (20 + 8 mg/kg/day for 3 days) and amodiaquine (10 mg/kg/day for 3 days) were compared in 200 children weighing 5–11 kg (12C ). On day 27, atovaquone + proguanil produced a cure rate of 95%, whereas the cure rate was only 53% for amodiaquine. However, atovaquone + proguanil has so far not been directly compared with regimens containing an artemisinin derivative. The efficacy of atovaquone + proguanil in the prophylaxis of malaria has so far been investigated in six trials in semi-immune and immune populations (11R ). Success rates were 98–100%. Because atovaquone + proguanil is active against exoerythrocytic and erythrocytic forms of Plasmodium species, it provides causal and suppressive prophylaxis. Atovaquone + proguanil therefore needs to be taken for malaria prophylaxis in adults at a dosage of 250 + 100 mg mg/day starting 1– 2 days before exposure until only 1 week after departure from the malarious area. Atovaquone + proguanil is generally well tolerated. Adverse effects occur more often with the four-times higher doses required for malaria treatment than with the rather low doses used in prophylaxis. Common adverse effects include abdominal pain (17%), nausea (12%), vomiting (12%), headache (10%), diarrhea (8%), dizziness (5%), anorexia (5%), weakness (5%), pruritus (up to 6%), tinnitus (3–13%), dyspepsia, gastritis, insomnia, rash, urticaria, and rises in transaminases. However, most of these are relatively common in acute malaria and frequencies were similar in patients receiving placebo (11R ). Two studies have confirmed that the above listed complaints are the most common adverse effects of atovaquone + proguanil. The safety of malaria prophylaxis with atovaquone + proguanil has been evaluated in an open study for 6 months in 300 Danish soldiers in Eritrea using a questionnaire (13c ). The most common complaints were diarrhea, abdominal pain, headache, cough, and loss of appetite. There were no serious adverse events and no cases of Plasmodium falciparum malaria. Furthermore, a post-marketing surveillance study

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recorded the following adverse event frequencies in 150 patients with mefloquine intolerance taking atovaquone + proguanil as malaria prophylaxis for 4.5–34 weeks: diarrhea (18%), abdominal pain (11%), headache (9%), dizziness (5%), and insomnia (6%) (14c ).

PYRIMETHAMINE AND COMBINATIONS (SED-14, 959;

Psychological The effects of primaquine and atovaquone + proguanil on psychomotor performance have been explored in a double-blind crossover study in 28 healthy volunteers (18–52 years old), who took atovaquone + proguanil 250 + 100 mg/day, or primaquine 30 mg/day, or placebo for 7 days separated by wash-out periods of 3 weeks (15c ). Neither primaquine nor atovaquone + proguanil caused any effects on psychomotor performance, mood, sleepiness, or fatigue. Pregnancy The pharmacokinetic properties of atovaquone + proguanil have been studied in 24 women with recrudescent multidrug resistant falciparum malaria during the second and third trimester of pregnancy (16c ). The clearance and volume of distribution were about twice those reported previously in non-pregnant women. Correspondingly, plasma concentrations in the pregnant women were only half of previously reported values, suggesting that pregnant women might need higher doses of atovaquone + proguanil. The pregnant women tolerated atovaquone + proguanil well and the 21 women with follow-up information gave birth to healthy infants. Drug interactions Proguanil is metabolized by CYP2C19 to its active metabolite cycloguanil, which interferes with folate synthesis in Plasmodium species. In 43 pregnant women, plasma proguanil and cycloguanil concentrations 6 hours after a single dose of proguanil (4 mg/kg) and urinary excretion were determined in the 3rd trimester and 2 months after delivery; the same was done in 40 women before and 3 weeks after starting an oral contraceptive, since estrogens inhibit CYP2C19 (17C ). Both in the third trimester and after administration of an oral contraceptive there was reduced formation of the active metabolite cycloguanil. The authors therefore recommended increasing proguanil doses by 50% in such patients.

Jacqueline Buser and Karin Fattinger

SEDA-26, 320; SEDA-27, 293)

Pyrimethamine + sulfadoxine Comparative studies Pyrimethamine + sulfadoxine 25 + 500 mg (Fansidar™ ) is being increasingly used for the treatment of Plasmodium falciparum malaria in Africa (SED-14, 960). However, the efficacy of pyrimethamine + sulfadoxine seems to be unsatisfactory, at least in Laos, where 100 patients with uncomplicated falciparum malaria were randomized to either pyrimethamine + sulfadoxine (a single dose of pyrimethamine 1.25 mg/kg and sulfadoxine 25 mg/kg) or chloroquine (10 mg base/kg immediately, followed by 10 mg/kg 24 hours and 5 mg/kg 48 hours after the start of therapy) (18c ). There were treatment failures in 18% of those treated with pyrimethamine + sulfadoxine and in 36% of those treated with chloroquine. Thus, both regimens were considered inadequate.

QUININE AND CONGENERS (SED-14, 962; SEDA-26, 318; SEDA-27, 290)

Quinine Hematologic Reports of quinine-induced thrombocytopenia, acute intravascular hemolysis, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, and disseminated intravascular coagulation have repeatedly been published (SED-14, 963; SEDA-24, 333; SEDA26, 318). A well documented report has now shown that re-exposure to a single dose of quinine for leg cramps about 40 years after a previous exposure can be sufficient to cause a severe episode of hemolytic-uremic syndrome + thrombotic thrombocytopenic purpura. • A 67-year-old woman with hypertension, chronic kidney disease (serum creatinine 177 µmol/l (2 mg/dl) and a history of a short period of hemodialysis for acute renal insufficiency 10 years before developed nausea, vomiting, diffuse abdominal cramp, and blurred vision 1 hour after taking one tablet of quinine for leg cramps (19A ). She had a fever of 39.7◦ C, a raised blood pressure,

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and confusion, an anemia of 10.4 g/dl with schistocytes and burr cells, thrombocytopenia of 14 × 109 /l, acute renal insufficiency with a serum creatinine of 504 µmol/l (5.7 mg/dl), raised total and direct bilirubin, raised liver enzymes, and raised lactate dehydrogenase activity. She was given antibiotics for presumed sepsis, and her symptoms resolved within 24 hours. However, her urine output continued to fall and hemolytic-uremic syndrome with thrombotic thrombocytopenic purpura was diagnosed. After 7 sessions of plasmapheresis, the hematological parameters normalized. After 3 weeks of hemodialysis, kidney function returned to baseline. At a follow-up visit 9 months later, quinine-associated antiplatelet antibodies were detected. She then recalled that about 40 years before she had taken quinine for malaria prophylaxis.

There have been 16 cases of quinine-induced disseminated intravascular coagulation, most of them in women (20A ). The symptoms usually started within hours of taking quinine. Single small doses of quinine may be sufficient to provoke disseminated intravascular coagulation. Most (80%) of the cases presented with gastrointestinal complaints, such as abdominal pain, nausea, vomiting, diarrhea, and hematemesis and/or melena. Other common symptoms were petechial or ecchymotic rashes, back pain, myalgia, headache, fever, chills, and malaise. Typical laboratory results included thrombocytopenia, raised fibrin degradation products, raised D dimers, and coagulopathy. In addition, there can be uremia, raised plasma creatinine, lactate dehydrogenase, and bilirubin, lactic acidosis, reduced haptoglobin, and a urinary sediment. Quinine induces antiplatelet antibodies of the IgG or IgM classes and possibly also antibodies against erythrocytes, neutrophils, T lymphocytes, B lymphocytes, and endothelial cells. In some cases, antibodies were not detected during the initial days of the disease, but were detected after the patient had recovered. Patients with quinine-induced disseminated intravascular coagulation are treated with supportive care and plasmapheresis. Renal function recovered in most cases, but 31% developed chronic renal insufficiency and 19% required permanent hemodialysis. Patients with a history of quinine-induced disseminated intravascular coagulation must avoid quinine and all quinine-containing products. Drug interactions Since the use of antimalarial drugs in combination increases cure rates

and can prevent drug resistance, and since rifampicin has antimalarial activity in experimental studies, the combination of quinine with rifampicin has been compared with standard quinine treatment in 59 adults with uncomplicated falciparum malaria (21c ). However, quinine + rifampicin failed, since its recrudescence rates were five times higher than with standard quinine. A pharmacokinetic evaluation showed that rifampicin co-therapy increases quinine clearance and thus lowers plasma concentrations of quinine and its partly active metabolite 3-hydroxyquinine. This effect is probably due to induction of intestinal and hepatic CYP3A4. Quinine and rifampicin should therefore not be combined in the treatment of malaria, and the dose of quinine should be increased in patients who are already taking rifampicin. Grapefruit juice inhibits CYP3A4, which is involved in the metabolism of quinine. Thus, concomitant use of grapefruit juice with quinine might increase plasma quinine concentrations and increase the risk of adverse effects of quinine. • A 31-year-old woman taking atenolol for asymptomatic long QT syndrome developed diabetes mellitus and took excessive amounts of tonic water containing quinine and grapefruit juice (22A ). Shortly after admission, she developed torsade de pointes with a QTc interval of 0.58 seconds. Serum electrolytes, blood glucose, and thyroid function were normal. Two days later, after withdrawal of the drinks, her QTc interval had shortened to 0.45 seconds and there were no dysrhythmias, even after programmed electrical stimulation.

The authors suggested that QT interval prolongation might have been caused by a pharmacokinetic interaction of quinine with grapefruit juice.

MEPACRINE (QUINACRINE) (SED-14, 965) The efficacy of quinacrine in the treatment of Creutzfeldt–Jakob disease is being investigated (23A , 24A ).

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Liver Three patients with probable Creutzfeldt–Jakob disease were given quinacrine 1000 mg on the first day followed by 300 mg/day and liver enzymes were monitored (23A ). At 7–42 days after the start of therapy there were increases in liver enzymes: aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, and alkaline phosphatase activities increased 3–30 times, 2–11 times, 2– 4 times, and 2–8 times respectively. Since the neurological symptoms did not improve, quinacrine was withdrawn. In two patients, the liver enzymes normalized on days 21 and 30 after withdrawal of quinacrine. Although all three patients died shortly thereafter, no death was related to hepatic insufficiency. Autopsy confirmed Creutzfeldt–Jakob disease in all three, and histological examination of the liver showed cytolytic hepatitis and cholangitis. Since liver enzymes and liver histology were normal in five other patients who died from Creutzfeldt–Jakob disease, the hepatitis and cholangitis in the former three patients was probably unrelated to Creutzfeldt–Jakob disease, but caused by the experimental use of quinacrine.

vestigated in a double-blind, placebo-controlled study in 322 schoolchildren randomized to receive either artemether 6 mg/kg once every 4 weeks to a total of 6 doses (n = 156) or placebo (n = 150) (26C ). Based on urinary egg counts 3 weeks after the last dose, artemether was efficacious in preventing Schistosoma hematobium infection. However, its protective efficacy against Schistosoma hematobium was considerably less than its protective efficacy against Schistosoma japonicum and Schistosoma mansoni in previous studies. The adverse events reported within 72 hours of oral administration of artemether were headache, dizziness, abdominal pain, diarrhea, nausea, vomiting, fever, chills, cough, itching, and constipation. None of these symptoms was reported more often with artemether than placebo.

ENDOPEROXIDES Artemisia derivatives (SED-14, 966; SEDA-25, 346; SEDA-26, 319; SEDA-27, 292) Observational studies The efficacy and safety of a 3-day course of oral artesunate (4 mg/kg/ day) for uncomplicated Plasmodium falciparum malaria have been evaluated in 50 Gabonese children (25c ). On day 14, cure rates were high (92%), but fell to 72% by day 28. Optimal dosage regimens for several of the artemisinin derivatives still need to be established. If artemisinin derivatives are used in monotherapy, treatment for 5–7 days is probably acceptable. However, the combination of artemisinin derivatives with longer acting antimalarial drugs is generally recommended.

Artemether Placebo-controlled studies The antischistosomal properties of artemether have been in-

Jacqueline Buser and Karin Fattinger

Nervous system In animals, high doses of intramuscular artemether were associated with damage to certain brainstem nuclei, especially those implicated in hearing and balance (SEDA27, 293). The brains of 21 adults who died despite treatment with high doses of artemether (4 mg/kg followed by 2 mg/kg every 8 hours, total dose 4–44 mg/kg; n = 6) or quinine (n = 15) for severe falciparum malaria have been examined (27c ). There was no histological evidence of neurotoxicity and in particular no evidence of either irreversible neuronal injury or selective distribution of neuropathological abnormalities confined to certain brain stem nuclei. The widespread neuronal stress responses and axonal injuries that were found were comparable in recipients of artemether and quinine. The authors therefore concluded that these injuries had resulted from the severe malaria itself and not from artemether. These data suggest that artemether does not acutely damage the nervous system in humans. However, the duration of artemether exposure was rather short (time to death only 8–331 hours) and so neurotoxic effects of artemether cannot be definitively ruled out. Immunologic A hypersensitivity reaction to artemether + lumefantrine has been reported (28A ). • A 9-year-old boy with suspected malaria was given oral artemether + lumefantrine (three weightadjusted doses of 80 + 480 mg over 24 hours).

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After the second dose, he developed severe coughing and vomiting and his eyelids became swollen. The coughing and vomiting worsened after the third dose and the swelling extended to his cheeks. An allergic reaction was suspected, artemether + lumefantrine was withdrawn, and the coughing and swelling resolved within 1–2 days. Plasmodium falciparum malaria was confirmed on the fourth day. However, parasitemia always remained low (160 asexual parasites/µl), and recovery was uneventful.

The coughing and swelling was thought to have resulted from a hypersensitivity reaction to artemether/lumefantrine. Since the boy had previously been exposed to artesunate but not to lumefantrine, hypersensitivity to dihydroartemisinin, the active metabolite of both artesunate and artemether, was suspected.

Artemisinin Drug interactions Artemisinin is metabolized in vitro by CYP2B6, CYP3A4, and CYP2A6. Since artemisinin induces CYP2C19, the question arises whether artemisinin also induces some of the cytochromes involved in its own metabolism and thus increases its own elimination (autoinduction) (29c ). During treatment with oral artemisinin for 10 days (250 mg/day for 9 days and 500 mg on the tenth day), artemisinin oral clearance increased 5.3 times in six poor CYP2C19 metabolizers and eight extensive metabolizers. The underlying mechanism was probably induction of CYP2B6. Induction of CYP2B6 by artemisinin could affect the metabolism of drugs given concomitantly and lead to suboptimal artemisinin concentrations towards the end of artemisinin treatment.

Artesunate The efficacy of the addition of artesunate to standard regimens of Plasmodium falciparum malaria has been evaluated based on data from 5948 patients in 16 randomized trials (30M ). The addition of artesunate (4 mg/kg/day) resulted in lower therapy failure rates compared with standard regimens. The addition of artesunate resulted in significantly shorter parasite clearance times and significantly reduced gametocyte counts.

321 Metabolism According to a randomized, open comparison in 113 adults with severe falciparum malaria in Thailand, hypoglycemia seems to occur less often in patients with malaria treated with artesunate (2.4 mg/kg intravenously followed by 1.2 mg/kg 12 hours later and then by 1.2 mg/kg/day intravenously or 12 mg/kg orally for 7 days) compared with those treated with quinine (20 mg/kg intravenously over 4 hours followed by 10 mg intravenously over 2 hours or orally tds for 7 days) (31c ). Artesunate and quinine had comparable efficacy, but hypoglycemia was only observed in 10% of the patients treated with artesunate whereas it occurred in 28% of those treated with quinine. Body temperature Because vomiting, prostration, and impaired consciousness often preclude oral administration and since parenteral therapy is generally not feasible in remote areas, rectal artesunate (10–15 mg/kg at 0 and 12 hours) was evaluated in 47 children in Papua New Guinea with uncomplicated Plasmodium falciparum (n = 42) or Plasmodium vivax (n = 5) malaria (32c ). The children were monitored during the first 24 hours and then chloroquine and sufadoxine + pyrimethamine were given and the children were discharged. Artesunate suppositories were well tolerated in all cases. After 24 hours, only one child had not defervesced and one other had persistent parasitemia. However, three children had a high body temperature, tachycardia, and vomiting 24 hours after having received their first dose of artesunate. None of those three children had a history of significant fever or chills and all had rapid and sustained parasite clearance. The late fever therefore seemed unlikely to have resulted from active parasite replication or the parasiticidal effect of artesunate. The authors concluded that the late fever might have resulted from a mild intercurrent viral infection or a druginduced or metabolic effect.

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DRUGS USED IN THE TREATMENT OF PNEUMOCYSTIS JIROVECI INFECTIONS

Liver Co-trimoxazole can cause hepatocellular and mixed liver injury and chronic active hepatitis (SED-14, 899). Now fulminant liver failure has been associated with co-trimoxazole.

(SED-14, 970; SEDA-25, 347; SEDA-26, 320; SEDA-27, 295)

Co-trimoxazole (sulfamethoxazole + trimethoprim) (SED-14, 971; SEDA-24, 334; SEDA-25, 347; SEDA-26, 32; SEDA-27, 296; see also Chapter 26) Nervous system Both sulfamethoxazole and trimethoprim have been suggested to cause aseptic meningitis (SED-14, 897). Now a patient with positive re-exposure to co-trimoxazole, and thus confirmed aseptic meningitis, has been reported. • An 80-year-old woman developed severe headache, nausea, vomiting, and rigors 6 hours after the first dose of co-trimoxazole for dysuria (33A ). Cerebrospinal fluid examination showed an increased leukocyte count of 717/µl with predominance of polymorphonuclear leukocytes. No infectious cause was identified and autoimmune disease was ruled out.

The patient’s history revealed a similar episode 6 months earlier after treatment with co-trimoxazole, and therefore the diagnosis of aseptic meningoencephalitis due to co-trimoxazole was made. Metabolism Trimethoprim 15 mg/kg/day increased urinary uric acid excretion and reduced the plasma uric acid concentration in five healthy volunteers from 333 µmol/l (5.6 mg/dl) to 226 µmol/l (3.8 mg/dl) (34c ). In 90 inpatients with hypouricemia co-trimoxazole was identified as the likely cause in four patients (35c ). However, since the study was limited to patients with hypouricemia and since exposure rates for co-trimoxazole were not reported for hypouricemic or non-hypouricemic patients, no conclusions about the incidence and the relevance of trimethoprim-associated hypouricemia can be made. Hematologic Co-trimoxazole can have adverse effects on all bone marrow cells and can also cause hemolytic anemia (SED-14, 898). Now severe hemolytic anemia has been associated with co-trimoxazole in a 10-year old girl without glucose-6-phosphate-dehydrogenase (G6PD) deficiency (36A ).

Jacqueline Buser and Karin Fattinger

• A 23-year-old previously healthy man presented with myalgia and fever after taking co-trimoxazole for 7 days for otitis externa (37A ). On the next day, he developed a rash on his neck and chest and jaundice, rapidly followed by fulminant liver failure. His liver enzymes peaked on day 3. Total bilirubin was 176 µmol/l (10.3 mg/dl), direct bilirubin 142 µmol/l (8.3 mg/dl), prothrombin time 61 seconds, and INR 7.5. Screening for paracetamol was negative. Blood cultures and laboratory tests for hepatitis A, B, and C, CMV, HIV, and toxoplasmosis were negative. A liver biopsy showed acute hepatitis with focal hepatocellular necrosis; immunohistochemical studies were negative for HSV, hepatitis B, CMV, and acid-fast bacilli; PAS and Giemsa stains for micro-organisms, and Wharton– Starry and Dieterel stains for spirochetes were negative. On day 8 after admission (15 days after taking co-trimoxazole) he underwent successful liver transplantation.

Immunologic Cross-reactions between sulfonamides and other drugs with a sulfa group have been discussed controversially. Possible cross-sensitivity between sulfamethoxazole and celecoxib has been described in the context of an anaphylactic reaction. • A 47-year-old woman developed an anaphylactic reaction, with vomiting, flushing, shivering, hypotension, and finally loss of consciousness, 30 minutes after taking celecoxib 200 mg (38A ). She had a previous episode of vomiting and vertigo after taking co-trimoxazole. Scratch and patch tests were negative for all substances, but lymphocyte proliferation tests were clearly positive for sulfamethoxazole and celecoxib.

The authors concluded that the patient had either coincidental sensitization to both drugs or real cross-sensitivity between sulfamethoxazole and celecoxib. Susceptibility factors Genetic There is conflicting evidence about a possible association between slow acetylator phenotype or genotype and sulfamethoxazole hypersensitivity in HIVinfected patients. Therefore, 40 HIV-infected patients (32 of them with sulfamethoxazole hypersensitivity) and 26 healthy controls were genotyped and phenotyped for acetylator status (39c ). Furthermore, these data were pooled

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with the data of 56 patients reported in previously published studies addressing the acetylator status in HIV-infected sulfamethoxazole hypersensitive patients. The frequencies of slow acetylator genotype and phenotype did not differ significantly between HIV-infected patients with and without sulfamethoxazole hypersensitivity and healthy controls. However, since the pooled odds ratio of 2.25 had a wide 95% confidence interval (0.45 to 11), an effect of slow acetylator genotype and phenotype can even now not be definitively ruled out.

DRUGS USED IN THE TREATMENT OF OTHER PROTOZOAL INFECTIONS Metronidazole (SED-14, 977; SEDA-25, 350; SEDA-26, 323; SEDA-27, 298) Nervous system Metronidazole can cause headache, dizziness, neuropathy, visual loss, tinnitus, encephalopathy, cerebellar toxicity, aseptic meningitis, convulsions, and psychosis. Central nervous system symptoms have generally been associated with high doses and long-term therapy. However, symptoms have now also been reported in some cases after short-course metronidazole treatment. • A middle-aged woman took metronidazole 400 mg tds for 9 days for suspected irritable bowel syndrome (40A ). On the ninth day, she developed profound weakness of the left arm and leg and an ascending sensory loss on the left side. Her reflexes were unaffected. The sensory hemisyndrome resolved after 6 days, but weakness of the left arm and lower leg, and sensory loss of the left distal leg partly persisted after 18 months. Except for metronidazole, no other cause for this sensorimotor neuropathy could be identified despite extensive further testing and examinations. • A 74-year-old man took metronidazole 500 mg tds, levofloxacin, and amoxicillin for a purulent abdominal abscess (41A ). After a total dose of 75 g of metronidazole, he developed bilateral leg weakness, a mild peripheral neuropathy, dysarthria, dysmetria, ataxia, and mild left gaze nystagmus. MRI scanning showed a symmetrical, non-enhancing increased signal intensity In the dentate nuclei on T2 weighted and FLAIR images, and subtle non-enhancing areas of increased T2 intensity in the subcortical and periventricular white matter. Metronidazole toxicity was suspected, and metronidazole was withdrawn. Thereafter, his condition

improved dramatically, and an MRI scan 8 weeks later showed complete resolution. • Similar findings of high signal intensity in the diffuse subcortical white matter, anterior commissure, splenium, midbrain, cerebellar white matter, and basal ganglia were seen in the T2 weighted and FLAIR MRI images of a 74-old woman who presented with dysarthria, dysphagia, and gait disturbances after taking metronidazole 1000 mg/day for 6 months (42A ).

Psychiatric ium.

Metronidazole can cause delir-

• A 75-year-old man took oral metronidazole 500 mg tds for Clostridium difficile colitis and 48 hours after the start of therapy he became withdrawn and less responsive; during the next 24 hours he developed hallucinations and confusion (43A ). Metronidazole was switched to oral vancomycin, and his symptoms resolved within 24 hours. One month later, he was re-challenged with metronidazole for recurrent Clostridium difficile diarrhea without knowledge of his prior adverse drug reaction. Soon after taking the first dose of metronidazole, he again developed hallucinations, which resolved after switching to vancomycin, confirming that metronidazole was the cause of his mental confusion.

Metabolism Since anecdotal observations suggested a hypolipidemic effect of metronidazole, the effect of metronidazole 250 mg tds on serum lipids has been evaluated in 30 volunteers who twice took metronidazole for 14 days (44c ). On both occasions total serum cholesterol fell by 16% and LDL cholesterol by 21%. Skin Patients with Stevens–Johnson syndrome or toxic epidermal necrolysis (n = 46) and controls (n = 92) have been compared in a case-control study. There was an increased risk among individuals exposed to metronidazole + mebendazole during the previous 6 weeks (OR = 9.5; 95% CI = 3.9, 24) (45c ). However, exposure to metronidazole or mebendazole alone was not associated with an increased risk. Drug interactions Metronidazole and busulfan are often co-administered in patients undergoing hemopoietic stem cell transplantation. The effect of metronidazole on busulfan pharmacokinetics was therefore studied in patients taking busulfan with and without metronidazole (46c ). Metronidazole co-administration significantly increased busulfan trough concentrations

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by about 80%. Patients who took metronidazole and busulfan concomitantly also had more frequent severe adverse effects. The authors concluded that patients taking high dose busul-

fan should use other drugs than metronidazole as prophylaxis for graft-versus-host disease.

Jacqueline Buser and Karin Fattinger

REFERENCES 1. Massaga JJ, Kitua AY, Lemnge MM, Akida JA, Malle LN, Ronn AM, Theander TG, Bygbjerg IC. Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial. Lancet 2003; 361: 1853–60. 2. Sowunmi A. A randomized comparison of chloroquine and chloroquine plus ketotifen in the treatment of acute, uncomplicated, Plasmodium falciparum malaria in children. Ann Trop Med Parasitol 2003; 97: 103–17. 3. Sharma N, Varma S. Unusual life-threatening adverse drug effects with chloroquine in a young girl. J Postgrad Med 2003; 49: 187. 4. Richter JG, Becker A, Ostendorf B, Specker C, Stoll G, Neuen-Jacob E, Schneider M. Differential diagnosis of high serum creatine kinase levels in systemic lupus erythematosus. Rheumatol Int 2003; 23: 319–23. 5. Muller Hocker J, Schmid H, Weiss M, Dendorfer U, Braun GS. Chloroquine-induced phospholipidosis of the kidney mimicking Fabry’s disease: case report and review of the literature. Hum Pathol 2003; 34: 285–9. 6. Martin Garcia RF, del R Camacho N, Sanchez JL. Chloroquine-induced, vitiligo-like depigmentation. J Am Acad Dermatol 2003; 48: 981–3. 7. Luong MS, Bessis D, Raison Peyron N, Pinzani V, Guilhou JJ, Guillot B. Severe mucocutaneous necrotizing vasculitis associated with the combination of chloroquine and proguanil. Acta Dermatol Venereol 2003; 83: 141. 8. Costedoat-Chalumeau N, Amoura Z, Duhaut P, Huong du LT, Sebbough D, Wechsler B, Vauthier D, Denjoy I, Lupoglazoff JM, Piette JC. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 2003; 48: 3207–11. 9. Kukoyi O, Carney CP. Curses, madness, and mefloquine. Psychosomatics 2003; 44: 339–41. 10. Schwartz E, Bujanover S, Kain KC. Genetic confirmation of atovaquone–proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin Infect Dis 2003; 37: 450–1. 11. Marra F, Salzman JR, Ensom MH. Atovaquone–proguanil for prophylaxis and treatment of malaria. Ann Pharmacother 2003; 37: 1266–75. 12. Borrmann S, Faucher JF, Bagaphou T, Missinou MA, Binder RK, Pabisch S, Rezbach P, Matsiegui PB, Lell B, Miller G, Kremsner PG. Atovaquone and proguanil versus amodiaquine for the treatment

of Plasmodium falciparum malaria in African infants and young children. Clin Infect Dis 2003; 37: 1441–7. 13. Petersen E. The safety of atovaquone/proguanil in long-term malaria prophylaxis of nonimmune adults. J Travel Med 2003; 10 Suppl 1: S13–15; discussion S21. 14. Overbosch D. Post-marketing surveillance: adverse events during long-term use of atovaquone/proguanil for travelers to malaria-endemic countries. J Travel Med 2003; 10 Suppl 1: S16–20; discussion S21–3. 15. Paul MA, McCarthy AE, Gibson N, Kenny G, Cook T, Gray G. The impact of Malarone and primaquine on psychomotor performance. Aviat Space Environ Med 2003; 74: 738–45. 16. McGready R, Stepniewska K, Edstein MD, Cho T, Gilveray G, Looareesuwan S, White NJ, Nosten F. The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria. Eur J Clin Pharmacol 2003; 59: 545–52. 17. McGready R, Stepniewska K, Seaton E, Cho T, Cho D, Ginsberg A, Edstein MD, Ashley E, Looareesuwan S, White NJ, Nosten F. Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil. Eur J Clin Pharmacol 2003; 59: 553–7. 18. Mayxay M, Newton PN, Khanthavong M, Tiengkham P, Phetsouvanh R, Phompida S, Brockman A, White NJ. Chloroquine versus sulfadoxinepyrimethamine for treatment of Plasmodium falciparum malaria in Savannakhet Province, Lao People’s Democratic Republic: an assessment of national antimalarial drug recommendations. Clin Infect Dis 2003; 3: 1021–8. 19. Baliga RS, Wingo CS. Quinine induced HUSTTP: an unusual presentation. Am J Med Sci 2003; 326: 378–80. 20. Knower MT, Bowton DL, Owen J, Dunagan DP. Quinine-induced disseminated intravascular coagulation: case report and review of the literature. Intensive Care Med 2003; 29: 1007–11. 21. Pukrittayakamee S, Prakongpan S, Wanwimolruk S, Clemens R, Looareesuwan S, White NJ. Adverse effect of rifampin on quinine efficacy in uncomplicated falciparum malaria. Antimicrob Agents Chemother 2003; 47: 1509–13. 22. Hermans K, Stockman D, Van den Branden F. Grapefruit and tonic: a deadly combination in a patient with the long QT syndrome. Am J Med 2003; 114: 511–12. 23. Scoazec JY, Krolak-Salmon P, Casez O, Besson G, Thobois S, Kopp N, Perret-Liaudet A, Streichenberger N. Quinacrine-induced cytolytic hepatitis

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in sporadic Creutzfeldt-Jakob disease. Ann Neurol 2003; 53: 546–7. 24. Kobayashi Y, Hirata K, Tanaka H, Yamada T. [Quinacrine administration to a patient with Creutzfeldt–Jakob disease who received a cadaveric dura mater graft—an EEG evaluation.] Rinsho Shinkeigaku 2003; 43: 403–8. 25. Borrmann S, Adegnika AA, Missinou MA, Binder RK, Issifou S, Schindler A, Matsiegui PB, Kun JF, Krishna S, Lell B, Kremsner PG. Shortcourse artesunate treatment of uncomplicated Plasmodium falciparum malaria in Gabon. Antimicrob Agents Chemother 2003; 47: 901–4. 26. N’Goran EK, Utzinger J, Gnaka HN, Yapi A, N’Guessan NA, Kigbafori SD, Lengeler C, Chollet J, Shuhua X, Tanner M. Randomized, double-blind, placebo-controlled trial of oral artemether for the prevention of patent Schistosoma haematobium infections. Am J Trop Med Hyg 2003; 68: 24–32. 27. Hien TT, Turner GD, Mai NT, Phu NH, Bethell D, Blakemore WF, Cavanagh JB, Dayan A, Medana I, Weller RO, Day NP, White NJ. Neuropathological assessment of artemether-treated severe malaria. Lancet 2003; 362: 295–6. 28. Krippner R, Staples J. Suspected allergy to artemether–lumefantrine treatment of malaria. J Travel Med 2003; 10: 303–5. 29. Simonsson US, Jansson B, Hai TN, Huong DX, Tybring G, Ashton M. Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9. Clin Pharmacol Ther 2003; 74: 32–43. 30. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004; 363: 9–17. 31. Newton PN, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis 2003; 37: 7–16. 32. Karunajeewa HA, Kemiki A, Alpers MP, Lorry K, Batty KT, Ilett KF, Davis TM. Safety and therapeutic efficacy of artesunate suppositories for treatment of malaria in children in Papua New Guinea. Pediatr Infect Dis J 2003; 22: 251–6. 33. Sharan L. Trimethoprim-sulfamethoxazoleinduced aseptic meningoencephalitis. Infect Med 2003; 20: 19–20. 34. Don BR. The effect of trimethoprim on potassium and uric acid metabolism in normal human subjects. Clin Nephrol 2001; 55: 45–52.

325 35. Bairaktari ET, Kakafika AI, Pritsivelis N, Hatzidimou KG, Tsianos EV, Seferiadis KI, Elisaf MS. Hypouricemia in individuals admitted to an inpatient hospital-based facility. Am J Kidney Dis 2003; 41: 1225–32. 36. Ermis B, Caner I, Karacan M, Olgun H. Haemolytic anaemia secondary to trimethoprim/sulfamethoxazole use. Thromb Haemost 2003; 90: 158–9. 37. Zaman F, Ye G, Abreo KD, Latif S, Zibari GB. Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure. Clin Transplant 2003; 17: 461– 4. 38. Schuster C, Wuthrich B. Anaphylactic drug reaction to celecoxib and sulfamethoxazole: cross reactivity or coincidence? Allergy 2003; 58: 1072. 39. Alfirevic A, Stalford AC, Vilar FJ, Wilkins EG, Park BK, Pirmohamed M. Slow acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole hypersensitivity. Br J Clin Pharmacol 2003; 55: 158–65. 40. Rustscheff S, Hulten S. An unexpected and severe neurological disorder with permanent disability acquired during short-course treatment with metronidazole. Scand J Infect Dis 2003; 35: 279– 80. 41. Heaney CJ, Campeau NG, Lindell EP. MR imaging and diffusion-weighted imaging changes in metronidazole (Flagyl)-induced cerebellar toxicity. Am J Neuroradiol 2003; 24: 1615–17. 42. Seok JI, Yi H, Song YM, Lee WY. Metronidazole-induced encephalopathy and inferior olivary hypertrophy: lesion analysis with diffusionweighted imaging and apparent diffusion coefficient maps. Arch Neurol 2003; 60: 1796–800. 43. Mahl TC, Ummadi S. Metronidazole and mental confusion. J Clin Gastroenterol 2003; 36: 373–4. 44. Shamkhani K, Azarpira M, Akbar MH. An open label crossover trial of effects of metronidazol on hyperlipidaemia. Int J Cardiol 2003; 90: 141–5. 45. Chen KT, Twu SJ, Chang HJ, Lin RS. Outbreak of Stevens–Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan. Am J Public Health 2003; 93: 489–92. 46. Nilsson C, Aschan J, Hentschke P, Ringden O, Ljungman P, Hassan M. The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2003; 31: 429–35.

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DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS

Ganciclovir

Cidofovir

Pre-emptive oral ganciclovir 1 g every 8 hours (n = 42) or conventional deferred ganciclovir (n = 38) have been compared in 80 renal transplant patients who developed cytomegalovirus antigenemia (pp65) within 8 weeks after transplantation (3c ). The incidence of cytomegalovirus disease during the first 12 weeks after transplantation was significantly reduced in the pre-emptive group (0% versus 24%). Two patients in each group developed late cytomegalovirus diseases in the 4–12 month period after transplantation and there was no difference in acute rejection rates. There were no differences in serum creatinine until 1 year after transplantation.

(SED-14, 989; SEDA-25, 353; SEDA-26, 328; SEDA-27, 303)

Urinary tract Nephrotoxicity is the major dose-limiting adverse effect of cidofovir. It is dose- and schedule-related and is reduced by concomitant treatment with oral probenecid and intravenous hydration. Unfortunately, adverse effects of probenecid (nausea, vomiting, fever, headache, and rash) are frequent (in about 50% of patients) and lead to withdrawal in 4– 7%. Based on preliminary studies in monkeys, the effect of an alternative probenecid regimen on renal function during cidofovir administration (5 mg/kg in 100 ml isotonic saline over 1 hour) has been examined in 24 HIV-infected individuals with cytomegalovirus retinitis who were randomly assigned to receive one of two probenecid regimens: 2 g 3 hours before cidofovir infusion and 1 g at 2 and 8 hours after (total 4 g) or 2 g 1 hour before the start of the infusion (1c ). In both regimens, one liter of isotonic saline was infused 1–2 hours before cidofovir and again after completion of the cidofovir infusion. Renal function was similar in the two groups and the serum concentration time curves of cidofovir were virtually superimposable. The authors suggest that the modified regimen of 2 g 1 hour before cidofovir infusion protects patients from renal toxicity as effectively as the standard dose. A previous study with a low dose of probenecid (1 g 3 hours before the cidofovir infusion followed by 0.5 g at 2 and 8 hours after the infusion failed to protect patients from cidofovirinduced nephrotoxicity (2c ). © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

326

(SED-14, 990; SEDA-25, 354; SEDA-26, 329; SEDA-27, 303)

Hematologic Neutropenia is the dose-limiting adverse effect of ganciclovir. Of 75 of 165 patients undergoing allogeneic peripheral blood stem cell transplantation who developed cytomegalovirus viremia, 58 received low-dose intravenous ganciclovir 5 mg/kg/day for 21 days (4c ). Only two of 58 patients had a fall in neutrophil count to below 100×106 /l, one of whom was switched to foscarnet. In no other patient did the neutrophil count fall below 500 × 106 /l. Cytomegalovirus disease developed in only five of the 58 patients and six of the 90 patients who did not develop cytomegalovirus viremia. Four of the five patients with cytomegalovirus disease after low-dose ganciclovir died. Oral ganciclovir has been evaluated in the prevention of cytomegalovirus disease in 219 liver transplant patients (5C ). After a 2-week induction period with intravenous ganciclovir 6 mg/kg the patients were randomized to receive either oral ganciclovir 1 g every 8 hours (n = 110) or aciclovir 800 mg every 6 hours (n = 109) until 100 days after transplantation. Cytomegalovirus diseases occurred during the first year after transplantation in only one patient given ganciclovir compared with eight

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of those given aciclovir. Reversible leukopenia (under 3.0 × 109 /l) was more common with oral ganciclovir (35%) than with aciclovir (18%). Congenital cytomegalovirus infection is the most frequently identified viral cause of hearing loss and treatment is not well established. The effect of ganciclovir on subsequent hearing loss has been evaluated in a multicenter study in 100 neonates with symptomatic cytomegalovirus infection (6c ). The patients were randomized to no treatment or intravenous ganciclovir 6 mg/kg 12-hourly for 6 weeks. Only 42 of the patients had available baseline and 6-month data; 21 of 25 ganciclovir recipients and 10 of 17 control patients had normal hearing. None of 25 patients who were given ganciclovir compared with 41% of controls had worse hearing between baseline and 6 months. In the total study population, 63% of those given ganciclovir and 21% of the controls developed grade 3 or 4 neutropenia during the study.

DRUGS ACTIVE AGAINST HEPATITIS C VIRUS Ribavirin (tribavirin)

(SED-14, 992; SEDA-25, 355; SEDA-26, 329; SEDA-27, 304)

The combination of interferon + ribavirin has the same adverse effects in patients who are coinfected with hepatitis C and HIV as in those who have hepatitis C only. However, in one series of 68 patients some unexpected adverse effects were recorded (7c ). One subject developed pancreatitis and four others developed asymptomatic hyperamylasemia, which disappeared after withdrawal. All of them were taking concomitant didanosine. Secondly, lactate concentrations increased slightly in two individuals, both of whom were taking stavudine. Significant weight loss (4.5 kg on average within 6 months) may be another adverse effect resulting from the interaction of ribavirin and HIV nucleoside analogues. Nervous system Headache is a frequent adverse effect of combination therapy with ribavirin + interferon. However, headaches have not been reported in early controlled trials of ribavirin monotherapy for chronic hepatitis C,

327 and the frequency of this adverse effect is comparable in patients treated with interferon and ribavirin and in interferon monotherapy. Of 452 patients treated with combination therapy for chronic hepatitis C, seven developed new severe migraine headaches and two had worsening of pre-existing migraine (8r ). The symptoms mostly started with a delay of several weeks to months. In seven patients, the migraine improved considerably or resolved when ribavirin was withheld or the dose was reduced. All of them had a recurrence when they were rechallenged with full-dose ribavirin. A causal link between ribavirin and migraine appears plausible, but has not been proven. Skin Pruritus, xerosis, and mild skin eruptions, such as eczema and lichen planus, are common (23%) during ribavirin plus interferon therapy (9r ). Control of these symptoms mostly requires sustained therapy with moderately potent to potent topical glucocorticoids, combined with baseline emollients throughout the combination treatment period. However, there are occasional reports of marked erythematous maculopapular eruptions starting 3–4 days after the start of combination therapy (10r ). Although this form of skin reaction (which is probably T cell mediated) is rare, it should be emphasized that it can occur early during treatment and can evolve into Stevens–Johnson syndrome. Urinary tract Ribavirin can cause hemoglobinuria, resulting in black urine (11A ). Susceptibility factors Renal impairment The clearance of ribavirin is impaired in patients with renal dysfunction, and it is not removed by hemodialysis. It is therefore not recommended for patients with a creatinine clearance under 50 ml/minute. However hepatitis C infection is associated with renal complications, such as membranoproliferative glomerulonephritis with or without cryoglobulinemia, membranous glomerulonephritis, and focal segmental glomerulosclerosis. Of seven patients treated with interferon six became HCV-RNA PCR negative, four maintained both virological and renal remission, and one maintained virological and partial renal remission (12c ). Ribavirininduced anemia was managed in five patients with low-dose iron and erythropoietin. The authors concluded that ribavirin can be used, with

328 reasonable safety, in HCV-related vasculitis and glomerulonephritis irrespective of renal function.

DRUGS ACTIVE AGAINST HERPESVIRUSES (SED-14, 990; SEDA-25, 353; SEDA-26, 329)

Aciclovir

(SED-14, 990; SEDA-25, 353; SEDA-26, 329; SEDA-27, 305) Psychiatric High-dose aciclovir can cause disturbed cognition, changes in the level of consciousness, tremor, asterixis, hallucinations, and psychiatric syndromes. Often, symptoms of aciclovir toxicity are difficult to differentiate from neurological deterioration caused by Herpes encephalitis. • A 67-year old man developed severe neurotoxicity after a 7-day course of high-dose aciclovir (800 mg/day) for Herpes zoster (13A ). He had severe disturbance of consciousness, stupor, and loss of spontaneous movement but regained consciousness after only two sessions of hemodialysis.

The authors concluded that hemodialysis is highly effective in eliminating aciclovir and that it can help to differentiate aciclovir-induced neurotoxicity from neurological deterioration due to the underlying encephalitis. In a retrospective analysis of samples sent for analysis of aciclovir concentrations, neuropsychiatric syndromes correlated with concentrations of 9-carboxymethoxymethylguanine (CM MG), the main metabolite of aciclovir (14C ). Based on a retrospective chart analysis, one psychiatrist unaware of the drug concentrations divided patients in one group with neuropsychological symptoms (n = 49) and one group without (n = 44). By ROC analysis, CM MG was the strongest predictor of neuropsychiatric symptoms. Symptoms included agitation, confusion, pronounced tiredness, lethargy, coma, dysarthria, myoclonus, and hallucinations and started within 1–2 days of aciclovir administration. Using a cut-off value of 11 µmol/l of CM MG, sensitivity and specificity were 91 and 93% respectively. CM MG was by far the best predictor of neuropsychiatric disorders, compared with aciclovir drug concentrations or exposure, serum creatinine or creatinine

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clearance. Thus, CM MG concentrations might be a useful alternative tool to differentiate conditions associated with Herpes infection from adverse effects of aciclovir. This group also reported the effect of hemodialysis. Among 39 patients who recovered from their condition, 12 received hemodialysis and recovered shortly thereafter. Thus, this study supports the preliminary findings reported in the case report above. Skin Recall phenomenon, classically chemotherapy-induced reactivation of skin damage caused by radiotherapy months or years later, has been attributed to aciclovir (15A ). • A 48-year-old woman took aciclovir 800 mg five times a day for thoracic Herpes zoster. After most of the skin lesions had healed at day 7, she developed a generalized cutaneous erythematous maculopapular eruption. On the previously affected dermatome, confluent linear erythema appeared, designated by the authors as a recall phenomenon, classically a chemotherapy-induced reactivation of skin damage caused by radiotherapy months or years later.

Brivudine Brivudine [(E)-5-(2-bromovinyl)-2 -deoxyuridine] is a nucleoside analogue with high and selective antiviral activity against Varicella zoster virus and Herpes simplex virus. Brivudine (125 mg/day) has been compared with aciclovir (800 mg five times a day) for 7 days in immunocompetent patients with Herpes zoster in a double-blind, randomized study (16c ). The two regimens had similar incidences of potentially treatment-associated adverse events (7.7% for brivudine versus 10% for aciclovir).

Valaciclovir

(SEDA-26, 330;

SEDA-27, 305) After oral administration valaciclovir, a prodrug of aciclovir, has 3–5 times higher systemic availability than aciclovir. In two placebocontrolled studies in the short-term treatment of herpes labialis, one-day treatment (two doses of 2 g) was compared with two-day treatment (two doses of 2 g on day 1 and two doses of

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Chapter 29

1 g on day 2) (17C ). Both regimens significantly reduced the duration of the episode and the time to healing. Despite the high doses of valaciclovir, adverse events (headache, nausea, diarrhea, dyspepsia) occurred at similar frequencies in the three groups. In a randomized, placebo-controlled study of valaciclovir 500 mg bd for suppression of recurrent genital herpes in HIV-infected subjects (18C ) recurrence was significantly less common in patients who took valaciclovir (35% versus 74%) and the time to first herpes occurrence was significantly shorter in placebo recipients (median 59 days versus over 180 days). Adverse events were equally frequent in the two groups with daily rates of 2.2% (placebo) versus 2.0% (valaciclovir). The most common adverse events with valciclovir versus placebo were headache (13% versus 8%), diarrhea (12% versus 12%), upper respiratory tract infections (9% versus 7%), vomiting (3% versus 9%), fatigue (8% versus 5%), influenza (8% versus 3%), nasopharyngitis (8% versus 2%), nausea (8% versus 8%), and rash (8% versus 1%). Urinary tract Herpes simplex mucositis occurs in more than two-thirds of patients receiving bone marrow transplants and can be prevented by aciclovir. In 60 patients who took valaciclovir 500 mg bd for prevention of Herpes simplex mucositis after bone marrow transplantation (19c ) treatment with valaciclovir was given from the start of transplant conditioning until resolution of neutropenia (over 1.0 × 109 /l). The patients were compared with a historical control group of 60 patients who had taken aciclovir 600 mg 6-hourly. There were no serious adverse reactions, but 10% required dosage adjustment because of an increase in serum creatinine compared with 35% in the historical controls.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS Metabolic complications and antiretroviral therapy Presentation Dyslipidemia is a common accompaniment of the lipodystrophy syndrome

observed in HIV-infected patients. This syndrome presents as a combination of peripheral lipoatrophy and the metabolic syndrome (central adiposity, insulin resistance, and dyslipidemia). The term lipodystrophy syndrome was first used in two case reports to describe a clinical picture of subcutaneous fat wasting in the face and limbs of HIV infected patients treated with indinavir, reminiscent of the rare congenital lipodystrophy syndromes (20A , 21A ). In addition, benign symmetric lipomatoses on the trunk and neck were described. A systematic study of this syndrome in the Australian HIV cohort showed co-existence of peripheral lipoatrophy with abdominal visceral obesity, dyslipidemia, and insulin resistance in HIVinfected patients with or without treatment with protease inhibitors (22c ). In general, most of the morphological and metabolic changes appear to aggregate in the same population and resemble the so-called “metabolic syndrome”, also called “syndrome X”. The WHO describes this syndrome as an accumulation of three or more of the following clinical features: • • • • •

abdominal obesity; raised triglycerides; low HDL cholesterol; raised blood pressure; raised fasting glucose.

More specifically, the ATP III guidelines, from the third report of the National Cholesterol Education Program’s expert Adult Treatment Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (23S ), define the metabolic syndrome as involving three or more of the following: • central/abdominal obesity as measured by waist circumference [men: greater than 102 cm (40 inches); women: greater than 88 cm (35 inches)]; • fasting triglycerides greater than or equal to 1.7 mmol/l (150 mg/dl); • HDL cholesterol [men: less than 1 mmol/l (40 mg/dl); women: less than 1.3 mmol/l (50 mg/ dl)]; • blood pressure greater than or equal to 130/85 mmHg; • fasting glucose greater than or equal to 6.1 mmol/l (110 mg/dl).

330 In the HIV infected population, further evidence suggested that visceral fat accumulation, dyslipidemia, and insulin resistance are closely linked and associated with antiretroviral treatment, most pronounced with the use of protease inhibitors. In contrast, subcutaneous fat wasting is primarily determined by the choice of nucleoside reverse transcriptase inhibitor (NRTI). Switching studies have supported this notion, since substitution of stavudine has been associated with improvement in fat wasting, while switching a protease inhibitor had no beneficial effect in more than 30 clinical trials (24R ). Mechanisms Several pathophysiological mechanisms have been proposed, including adverse effects of protease inhibitors on hepatocyte and fat cell function (25c ), mitochondrial toxicity from nucleoside analogues (26r ), excess of reactive oxygen species (27c ), and cytokinemediated events (28r ). In vitro data and studies in healthy volunteers suggest a role for protease inhibitors in insulin resistance (29E ) and dyslipidemia (30E ).

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DNA content per cell. Compared with HIVinfected controls, mitochondrial DNA depletion was 45% or 87% in those taking zidovudine and stavudine respectively. These results support in vitro findings that stavudine causes more pronounced mitochondrial toxicity than zidovudine (33E ). There was significant improvement in signs of mitochondrial toxicity in 49 patients who switched from stavudine to abacavir compared with 63 patients who continued to take stavudine in a non-randomized study for 12 months (34c ). Only patients who remained on their assigned treatment were included in the analysis. Lactate concentrations were assessed at baseline, week 24, and week 48, and electrical bioimpedance was performed in 22 cases and 12 controls at baseline and week 48. There were significant falls in serum lactate concentrations at weeks 24 and 48 in cases compared with controls. Patients who switched had a trend towards fat gain, while controls had significant reductions in total body fat and percentage of body fat.

• A patient taking HAART including didanosine and zidovudine developed a syndrome that evolved over 4 months, starting with weight loss (25%), vomiting, polyuria, bone fracture due to osteoporosis, profound proximal weakness, and a stocking sensory neuropathy. He had a Fanconi-type proximal renal tubular dysfunction, lactic acidosis, myopathy, and pancreatic dysfunction. All signs and symptoms improved markedly after withdrawal of the antiretroviral drugs.

Lactic acidosis Lactic acidosis is a consequence of long-term mitochondrial toxicity of NRTIs. In a systematic review of published cases of lactic acidosis, NRTI use and female sex were identified as significant risk factors (35R ). Among patients taking a triple drug regimen, all were taking stavudine as one of their NRTIs (52% in combination with didanosine). The most frequent clinical manifestations were gastrointestinal (nausea, vomiting, abdominal pain) in 50%, and 41% had dyspnea and tachypnea. The median lactate concentration in symptomatic patients was 11 mmol/l and liver enzymes were abnormal in 65%. Almost half of the patients died within a median period of 7 days.

This case demonstrates almost the full clinical spectrum of mitochondrial toxicity. Depletion of mitochondrial DNA and morphological changes in adipocytes have been assessed in a small study of fat biopsies from HIV-negative patients (n = 6), HIV-positive but drug naïve patients (n = 11), and patients taking NRTIs (zidovudine (n = 9) or stavudine (n = 12)) (32c ). Drug-naïve HIV-infected patients had similar contents of mitochondrial DNA in adipocytes, while patients taking NRTIs had significantly reduced mean mitochondrial

Lipids and lipodystrophy The effects of the protease inhibitor indinavir and the NNRTI efavirenz on lipid concentrations have been compared in a large comparative randomized study (36C ). Each of the two comparison drugs were used in one arm (with a zidovudine + lamivudine backbone) and the combination of the two drugs in a third arm. Zidovudine and lamivudine did not play a role in the lipid changes. However, both of the comparison drugs significantly increased cholesterol concentrations.

Mitochondria Nucleoside-reverse transcriptase inhibitors (NRTI) have a number of adverse effects on mitochondria. Mitochondrial dysfunction can result in several adverse effects, depending on the affected organ system, as demonstrated by an illustrative case (31A ).

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In a prospective, non-randomized analysis of 212 patients treated with a regimen containing a protease inhibitor, the overall incidences of hypertriglyceridemia and hypercholesterolemia at 12 months of treatment were 38% and 25% respectively (37c ). Increased concentrations of triglycerides and LDL cholesterol were more pronounced in patients taking ritonavir or lopinavir/ritonavir compared with other protease inhibitors. In a small randomized, open, comparative study patients who switched to abacavir from either stavudine or stavudine plus a protease inhibitor or NNRTI, or a protease inhibitor + NNRTI had improved total and LDL cholesterol (38c ). Total arm and leg fat mass, measured by DEXA scan, rose significantly in those who switched from stavudine to abacavir, suggesting an important role of stavudine in the pathogenesis of lipodystrophy. Support for the hypothesis of a casual relation between stavudine and lipodystrophy comes from another randomized study in which stavudine-containing HAART regimens were switched to a combination of zidovudine, lamivudine, and abacavir (39c ). Eight patients were randomized to continue stavudine and 14 patients switched to the triple combination. Imbalance in the treatment arms resulted from exclusion of patients who maintained treatment for a minimum of 6 months of follow up. Over 48 weeks after randomization, the average leg and arm fat mass fell in the continuation arm but increased in the switch arm. One patient in the switch arm, who had previously taken zidovudine and lamivudine, had a therapeutic failure. In a retrospective analysis of 36 patients who switched from stavudine to tenofovir while HIV RNA was below 20 copies/ml for more than 6 months, two switched because of peripheral neuropathy and 34 because of lipoatrophy; the median duration of observation was 36 weeks (40A ). There was a significant fall in cholesterol concentrations from 5.5 mmol/l to 5.0 mmol/l at week 4, and 4.7 mmol/l at week 36. There was also a non-significant trend toward a fall in triglyceride concentrations. In patients who had taken their first antiretroviral regimen for more than 6 months, using either stavudine (n = 75) or zidovudine (n = 75) plus lamivudine and indinavir total fat was significantly lower in patients taking

331 stavudine, but the lean body mass was similar in the two groups (41c ). Fat redistribution was common: 20 patients were classified as having lipoatrophy, 33 lipodystrophy, and 41 a mixed syndrome. However, there were no statistically significant differences between the two groups. Lack of physical activity was the only independent predictor of isolated or mixed lipoatrophy. Whether physical activity in fact improves lipodystrophy is not known. Lipid abnormalities are a major adverse effect of HIV protease inhibitors (22c ). In a 48-week comparison with nelfinavir, atazanavir did not significantly increase total cholesterol, fasting LDL cholesterol, or triglyceride concentrations (+6.8%, −7.1%, +1.5% respectively), while the respective concentrations rose by 28%, 31%, and 42% in those who took nelfinavir. The incidence of grade 1–4 lipodystrophy was infrequent in both groups, but this endpoint was poorly defined in this study. The effect of the combination of lopinavir + ritonavir on the atherogenic lipid profile has been evaluated in 24 HIV infected patients (42c ). At baseline, there was an abnormally small LDL density. After 1 month lopinavir + ritonavir increased triglyceride and apolipoprotein CIII concentrations, and LDL size fell further. Insulin resistance The independent effect of protease inhibitors on insulin resistance has been investigated. A single dose of indinavir was sufficient to produce a significant reduction in insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp testing, in both HIVinfected and HIV-negative individuals (43c ). Diabetes mellitus A retrospective analysis of the development of diabetes in 1011 patients has been summarized (44c ). All were non-diabetic when antiretroviral treatment was started. Over 10 months, diabetes was diagnosed in 16 patients (2.06 per 100 personyears). Older age (HR = 1.1, 1.06–1.16) was associated with a higher risk. In multivariate analysis adjusted for age and sex, the onset of diabetes was not related to CD4 cell count, viral load, or type of antiviral therapy (with or without protease inhibitors). However, patients taking stavudine or indinavir were at significantly higher risks (stavudine HR = 16, 95% CI = 3, 84; indinavir HR = 4.0, 95% CI = 1.3,

332 13). The strong association of stavudine with diabetes is surprising and needs further confirmation. In a cohort study (45C ) in 1785 women, 69 incident cases of diabetes mellitus were diagnosed, with an average incidence of 1.5 cases per 100 patient-years. In patients taking protease inhibitors, incidence rates were about twice as high (2.8 cases per 100 patient-years) as among users of NNRTIs or untreated patients (1.2%) and uninfected controls (1.4%). In a multivariate model use of protease inhibitors (HR = 2.9; 1.5, 5.6), age and BMI were independent risk factors for diabetes. Conclusions Metabolic disturbances are frequent in patients with HIV infection and represent a multifactorial condition related both to the underlying disease and to the antiviral treatment. HIV infection itself appears to cause hyperlipidemia and insulin resistance in some patients. Protease inhibitor therapy is a major contributor to fat accumulation, hyperlipidemia, and insulin resistance. NNRTIs contribute mainly through augmentation of lipid concentrations and NRTIs to the development of lipid-associated toxicity. NRTIs can cause mitochondrial dysfunction.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) (SED-14, 993; SEDA-25, 356;

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drugs (efavirenz, nevirapine) could not be ruled out in one-third of the cases of hypersensitivity reaction. Intercurrent influenza infection can be difficult to distinguish from hypersensitivity reactions to abacavir. In a comparison of the clinical presentation of 15 patients with abacavir hypersensitivity with culture confirmed influenza A infection in 30 controls, gastrointestinal symptoms were clearly associated with abacavir hypersensitivity in febrile patients, while the presence of cough with gastrointestinal symptoms and fever was more suggestive of influenza A (47c ).

Lamivudine

(SED-14, 995; SEDA-24, 343; SEDA-27, 308)

Long-term lamivudine 100 mg/day (n = 14) was as effective as lamivudine plus hepatitis B immune globulin (n = 15) in the prevention of recurrence of hepatitis B after liver transplantation (48c ). No major adverse effects were reported. Of 20 children and adolescents with chronic hepatitis B infection after failure of interferon given lamivudine 3 mg/kg (maximum 100 mg/day) for 1 year, 44% had sustained undetectable hepatitis B virus DNA and there were no adverse effects (49c ). Lamivudine 100 mg/day was also used in a 6-year-old patient with nephrotic syndrome associated with hepatitis B and resulted in complete resolution after 12 months without adverse effects (50A ).

SEDA-26, 330; SEDA-27, 306)

Stavudine (D4T) Abacavir

(SEDA-20, 273; SEDA-23, 319; SEDA-26, 331)

Immunologic Abacavir can cause hypersensitivity reactions, which usually occur within the first 28 days of treatment. Fatal outcomes have been described after rechallenge. In an analysis of the HIV cohort at Montpellier, early withdrawal of abacavir was studied in 331 patients (46c ). The rate of hypersensitivity reaction in this retrospective study was higher than in other studies (8.5%) and the role of other

Nervous system Distal sensory polyneuropathy is a complication of HIV infection and is often difficult to distinguish from stavudineassociated polyneuropathy, the mechanism of which is most likely mitochondrial toxicity. In a small prospective study serum lactate concentration discriminated between distal sensory polyneuropathy and stavudine-associated neuropathy (51c ). A lactate concentration above the upper end of the reference range (2.2 mmol/l)

(SED-14, 995; SEDA-24, 342; SEDA-26, 330; SEDA-27, 307)

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had a sensitivity and a specificity of 90% for stavudine-associated neuropathy. In a systematic review of NRTI-associated neuropathies current knowledge in the field has been summarized (52M ). At the usual dose of stavudine the 1-year rate of sensory neuropathy is 12–15% and synergistic neurotoxicity with didanosine is marked.

Zidovudine (SED-14, 994; SEDA-24, 343; SEDA-27, 308) Hematologic Hypoproliferative anemia is a typical, severe adverse effect of zidovudine; it usually resolves promptly after withdrawal of the drug. However, three patients developed zidovudine-induced anemia that could have been mistaken for hemolytic disease, especially in the first 2 weeks after withdrawal of the drug (53A ).

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOTIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS Tenofovir

(SEDA-26, 331)

Tenofovir is the first licensed nucleotide inhibitor for the treatment of HIV infection. Nucleotide inhibitors appear to have only little if no activity against the mitochondrial gammapolymerase. However, two other nucleotide drugs, adefovir and cidofovir are strongly associated with proximal renal tubular damage and acute renal insufficiency. Tenofovir is delivered as a prodrug (tenofovir disoproxil fumarate) and has a favourable safety profile and good antiviral activity even against drug-resistant strains of HIV (54C ). It has a long intracellular half-life, which permits once-daily dosing. Metabolism In vitro studies have shown that tenofovir has a favorable mitochondrial toxicity profile (33E ). Fatal lactic acidosis was reported in a patient who had recently switched to tenofovir (55A ). However, this patient was

333 also taking didanosine and stavudine, a combination that is typically associated with lactic acidosis. Given the excellent in vitro characteristics of tenofovir in all known mitochondrial test systems and the notorious association of didanosine/stavudine combination with lactic acidosis, a causal relation of lactic acidosis with tenofovir use seems highly unlikely. Urinary tract The potential of tenofovir for nephrotoxicity has been reviewed (56R ). The similarity of tenofovir to other highly nephrotoxic drugs (cidofovir, adefovir) is a concern, but no conclusive study has yet defined its nephrotoxic potential. Of 160 patients who received tenofovir in the Hôpital Saint-Louis in Paris three developed a nephropathy (57A ). All three had a very long history of HIV infection and had taken several antiretroviral drugs before tenofovir. None had renal insufficiency nor was taking another nephrotoxic agent. All three had a CD4 count below 50 × 106 /l and a slight initial rise in serum creatinine within a few weeks after tenofovir was started. After several months of uneventful treatment with tenofovir, two patients had a rapid decline in renal function, for no other discernible reason. There was hypokalemia with increased potassium excretion, metabolic acidosis, and hypophosphatemia. Kidney biopsies showed severe acute tubular necrosis associated with marked interstitial fibroedema. The proximal and distal tubules were equally affected by severe epithelial lesions, and there was profound karyomegaly and large vacuoles (indicative of hypokalemia) in the proximal tubular cells. Withdrawal of all antiviral drugs was associated with rapid recovery of renal function and normalization of electrolyte changes, but the serum creatinine remained raised in both cases, suggesting irreversible damage. The third patient developed severe nephrogenic diabetes insipidus with proteinuria and normoglycemic glycosuria 6 months after starting to take tenofovir. All signs of tubular damage disappeared within 3 months after tenofovir was withdrawn. The authors presented four arguments for a causal relation between tubular damage and tenofovir: 1. The laboratory values normalized after withdrawal.

334 2. Known nephrotoxicity from animal studies. 3. Similar nephrotoxicity from other compounds of the same class (cidofovir, adefovir). 4. A similar previous case report. Drug interactions If tenofovir is combined with didanosine, the standard dose of the latter needs to be reduced to 250 mg/day (56R ). Tenofovir reduces the Cmax but not the AUC of lamivudine and indinavir (56R ). Tenofovir slightly reduces the AUC of lopinavir (by 15%) but no dosage adjustment is needed (56R ). Tenofovir concentrations increases with concomitant use of lopinavir/ritonavir (AUC + 30%) and indinavir (Cmax + 14%) but no dosage adjustments are needed (56R ). Probenecid inhibits the elimination of tenofovir and significantly increases drug concentrations (56R ).

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) (SED-14, 996; SEDA-24, 344; SEDA-25, 357; SEDA-27, 308)

Efavirenz

(SED-14, 996; SEDA-25, 357; SEDA-26, 331; SEDA-27, 309) In recent years, efavirenz has become a standard first-line antiretroviral drug. Its main adverse effects, which usually occur during the first few weeks of drug administration and disappear over time, are rash and neuropsychiatric effects. The most commonly reported problems are dizziness, insomnia, difficulty in concentrating, somnolence, and abnormal dreams. However, severe depression, hallucinations, aggressive behavior, and paranoia or suicidal ideation have been observed. • A 40-year-old man had a classic manic episode after taking efavirenz for 2 weeks (58A ). He had no previously personal or family psychiatric history. The symptoms completely disappeared 1 month after withdrawal of efavirenz.

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• A 40-year-old patient with pre-existing depressive symptoms developed suicidal thoughts and schizophrenia-like first-rank symptoms within the first month of efavirenz administration and attempted suicide (59A ).

Nevirapine (SED-14, 997; SEDA-25, 357; SEDA-26, 332; SEDA-27, 310) Liver Hepatotoxicity was studied in 1731 nevirapine-treated patients enrolled in trials and compared with 1912 control patients (60c ). In this analysis, risk factors for asymptomatic rises in liver transaminases were increased baseline concentrations (over 2.5 times the upper limit of the reference ranges, RR = 4.3) and co-infection with hepatitis B (RR = 2.3) or hepatitis C (RR = 5.2). In men, but not in women, a CD4 cell-count above 400 × 106 /l was also marginally associated with an increased risk of asymptomatic rises in liver enzymes. The authors also summarized the results of large observational cohorts and found no significant differences in the rate of serious hepatic events among patients treated with nevirapine and other antiretroviral regimens. Skin Rash is a well-known adverse effect of nevirapine. • A pregnant woman had a febrile episode with a pruritic rash and eosinophilia at 32 weeks of gestation, 6 weeks after starting to take antiretroviral therapy including nevirapine (61A ). The symptoms resolved after nevirapine withdrawal and glucocorticoid treatment. Most other differential diagnoses were ruled out.

Of a retrospective case series of 74 children treated with nevirapine in the UK between 1997 and 1999, 20% developed a rash (62c ). Rash developed independent of drug dose after a median duration of treatment of 9 (1–44) days and lasted for a median of 10 (1–60) days. In 5%, the rash led to withdrawal of nevirapine. There were no cases of Stevens–Johnson syndrome. Of 216 patients 18% developed a rash of some grade, leading to drug withdrawal in seven (63c ). In contrast, none of 33 healthy subjects developed a rash when nevirapine was given in a pre-exposure prophylaxis trial once or twice a week or every other day for 12 weeks (64c ).

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Similarly, there were no adverse effects in three comparative trials of single or short administration of nevirapine for the prevention of mother-to-child transmission in 2080 subjects (65C –67C ). Susceptibility factors Liver impairment Viral hepatitis is a frequent co-morbidity in HIV infection. The effect of chronic hepatitis C on nevirapine drug concentrations has been examined in 70 patients taking a nevirapinecontaining triple drug regimen (68c ). Nevirapine concentrations were similar in those with positive (n = 32) and negative (n = 38) titers of hepatitis C virus antibody.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: PROTEASE INHIBITORS (SED-14, 997; SEDA-24, 345; SEDA-25, 358; SEDA-26, 332)

Atazanavir Liver In the first phase 2 licensing study the protease inhibitor atazanavir 200 mg, 400 mg, and 500 mg was evaluated against nelfinavir 750 mg tds in combination with a didanosine and stavudine backbone (69C ). The 400 mg dose of atazanavir was chosen for further development. Most of the adverse events in this study were grade 1–2 and the rates of grade 3–4 were comparable across the regimens. Jaundice was the most prominent adverse effect of atazanavir and was clearly dose related (6%, 6%, 12% for the three dosing arms) and was not observed in the nelfinavir arm. Rises in bilirubin were predominantly due to the unconjugated form. There was no correlation with raised transaminases. Preclinical data support the hypothesis that atazanavir-associated hyperbilirubinemia is attributable to inhibition of uridine diphosphate glucuronosyltransferase (UDP-GT) 1A1 (70c ). This is also the apparent mechanism for the reversible rise in bilirubin that occurs with indinavir (71E ). Grade 3–4 rises in transaminases were significantly more frequent in patients infected with hepatitis B or C (20–40%) than in patients with negative hepatitis B and C serology (2–12%).

335

Indinavir (SED-14, 998; SEDA-25, 359; SEDA-26, 332; SEDA-27, 313) The recommended dose of indinavir is 800 mg tds, given without food. However, as for most other protease inhibitors, the use of indinavir has been markedly simplified by co-administration of low-dose ritonavir, which allows indinavir to be given twice daily with or without food. However, increased exposure to indinavir also results in increased adverse effects. In a randomized comparison of ritonavir-boosted indinavir versus indinavir alone the two regimens resulted in similar efficacy (72c ). However, because of an increase in adverse effects, drug withdrawals were more frequent in the boosted indinavir arm (47/161 versus 20/162). The following adverse effects were significantly more common in the boosted arm: nausea/vomiting, diarrhea, nephrolithiasis and hematuria, dry skin, in-grown toenails, rash, and oral paresthesia. Similarly, in a randomized, open comparison of ritonavir-boosted saquinavir versus indinavir, adverse events were reported significantly more often in the indinavir/ritonavir arm (73c ). While there were no differences in hematological, renal, or hepatic toxicity (except increased bilirubin concentrations with indinavir), there were significantly higher lipid concentrations (total cholesterol, LDL cholesterol, and total triglycerides) in the indinavir arm. Adverse effects (renal, dermatological, and gastrointestinal) were more frequent in the indinavir/ritonavir arm. Hematologic Thrombocytopenia has been attributed to indinavir. • A man suddenly developed severe thrombocytopenia while taking stavudine + lamivudine + indinavir (74A ). After withdrawal and treatment with glucocorticoids and immunoglobulin, the platelet count recovered and he was treated with stavudine + didanosine + nevirapine. Six months later, after re-exposure to the initial combination, thrombocytopenia immediately occurred and spontaneously recovered after replacing indinavir with efavirenz.

Biliary tract Cholelithiasis has been attributed to indinavir. Of three patients who developed cholelithiasis while taking a protease inhibitor, one was taking indinavir (75A ).

336 Urinary tract Urolithiasis is a frequent adverse effect of indinavir, and is more frequent when indinavir is given with ritonavir. The cause of this urolithiasis has been evaluated in 24 patients taking protease inhibitors, of whom 14 were taking indinavir, three ritonavir, two nelfinavir, and five other drugs (76c ). Of the 14 patients taking indinavir, only four had kidney stones that contained indinavir, the others being calcium oxalate and urate stones. Ten patients underwent 24-hour urine collection and 80% had metabolic abnormalities: five had hypocitraturia, four hyperoxaluria, four hypomagnesuria, three hypercalciuria, three supersaturation of calcium oxalate, and two hyperuricosuria. The authors concluded that the development of kidney stones is probably attributable to underlying metabolic abnormalities rather than to the use of specific protease inhibitors. In a prospective study of 184 patients taking indinavir, there was persistent leukocyturia in 35% of them at least once during a median follow-up of 48 weeks with 3-monthly visits (77c ). Leukocyturia coincided with slight increases in serum albumin, erythrocyturia, and crystalluria. Leukocyturia was persistent in 24% of patients with repeated follow-up. Persistent leukocyturia was associated with loss of renal function. The risk of renal toxicity was increased in patients with high indinavir plasma concentrations (over 9000 ng/ml) and a urine pH over 5.7. In summary, these studies suggest that indinavir toxicity is dose-related and they support the use of plasma concentration monitoring in patients taking indinavir. In fact, a pilot study of low-dose indinavir (400 mg plus ritonavir 100 mg bd) has shown markedly increased tolerability of the drug (78A ). There was dry skin in only one of 20 patients and it disappeared after dosage reduction to indinavir 200 mg + ritonavir 100 mg bd. In all 20 patients, HIV-RNA remained fully suppressed below 200 cpm/ml. Susceptibility factors Liver impairment In a pharmacokinetic study of low-dose indinavir, all of six patients with chronic viral hepatitis had an indinavir concentration above the target range defined by the study protocol (150– 675 ng/ml) despite low-dose indinavir/ritonavir (400/100 mg bd) (79A ). Altering the dose to 200/100 mg resulted in drug concentrations in

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the target range while HIV-RNA concentrations remained suppressed below 200 cpm/ml in all patients.

Lopinavir + ritonavir (SEDA-26, 333; SEDA-27, 314) Drug interactions Rhabdomyolysis occurred in a 34-year-old man with AIDS and severe liver disease, because of a drug interaction involving clarithromycin 500 mg/day, atorvastatin 40 mg/day, and lopinavir/ritonavir (80A ).

Nelfinavir

(SED-14, 998; SEDA-25, 359; SEDA-26, 333; SEDA-27, 315)

Gastrointestinal Stool abnormalities were the most common adverse effects in a 48-week, phase 2, open comparison of nelfinavir versus atazanavir + didanosine + stavudine; diarrhea was 2.5 times more frequent in those who took nelfinavir (61% versus 25%) (69C ).

Ritonavir

(SED-14, 998; SEDA-25, 360; SEDA-26, 333; SEDA-27, 315) Drug interactions Ritonavir is mainly restricted to its use as a potent inhibitor of cytochrome P450 metabolism. When it is given in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, or saquinavir, ritonavir prolongs their half-lives and increases their trough concentrations and AUCs, allowing twice or even once-daily and administration. For this indication, ritonavir is given in very low doses (100 mg od or bd), which significantly reduces ritonavir-associated adverse effects (81R ).

Saquinavir (SED-14, 998; SEDA-24, 348; SEDA-26, 334; SEDA-27, 316) Drug formulations Saquinavir has a very low systemic availability (4%), and is used in

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combination with ritonavir. In an attempt to improve its systemic availability, saquinavir softgel capsules have been manufactured. However, when they were co-administered with ritonavir, the soft-gel and the hard-gel formulations resulted in similar drug exposures in healthy volunteers (82c ). Drug exposure was even slightly better for the hard-gel capsules, but diarrhea was far less frequent.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: INHIBITORS OF HIV FUSION Enfuvirtide Enfuvirtide is the first available fusion inhibitor for the treatment of HIV infection. It has poor oral systemic availability and is given subcutaneously. Adverse effects were reported in a phase 2 trial of enfuvirtide 45 mg, 67.5 mg, and 90 mg bd combined with other antiretroviral drugs (83c ). Among 52 patients who received enfuvirtide, all but one reported at least one adverse event. However, the frequency of adverse events was similar in the 19 patients in the control arm, with the exception of injection site reactions, which were reported at least once in 36 patients. However, injection site reactions occasioned drug withdrawal in only three patients receiving enfuvirtide.

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: NEURAMINIDASE INHIBITORS (SED-14, 999; SEDA-25, 360; SEDA-26, 334; SEDA-27, 317)

Oseltamivir The safety and pharmacology of oseltamivir have been reviewed (84R ). Transient gastrointestinal disturbances are the major adverse effects and are reduced when the drug is taken with a light snack. In the clinical trials program, severe adverse events were reported at the same frequency as with placebo (1.3% with 75 mg bd, 0.7% with 150 mg bd, 1.2% with placebo). In a large placebo-controlled efficacy study in adolescents, oseltamivir was well tolerated and mild gastrointestinal symptoms were the major adverse effects, in 14% (oseltamivir) versus 8% (placebo); vomiting was reported in 8% versus 3% (85C ).

Zanamivir The safety and efficacy of zanamivir have been evaluated in hospitalized patients with serious influenza (86C ). Zanamivir + rimantadine was compared to rimantadine + placebo in a randomized blinded design in seven centers. The study was terminated prematurely after approval of zanamivir made enrolment untenable (41 patients, calculated sample size 100). There were no differences in the proportions of patients shedding virus by treatment day 3, or duration of hospitalization, or use of oxygen. More patients taking zanamivir had a slight cough on day 3.

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30. Liang JS, Distler O, Cooper DA, Jamil H, Deckelbaum RJ, Ginsberg HN, Sturley SL. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nature Med 2001; 7: 1327–31. 31. Miller RF, Shahmonesh M, Hanna MG, Unwin RJ, Schapira AH, Weller IV. Polyphenotypic expression of mitochondrial toxicity caused by nucleoside reverse transcriptase inhibitors. Antivir Ther 2003; 8: 253–7. 32. Nolan D, Hammond E, Martin A, Taylor L, Herrmann S, McKinnon E, Metcalf C, Latham B, Mallal S. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 2003; 17: 1329–38. 33. Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002; 46: 716–23. 34. Garcia-Benayas T, Blanco F, de la Cruz JJ, Soriano V, Gonzalez-Lahoz J. Replacing stavudine by abacavir reduces lactate levels and may improve lipoatrophy. AIDS 2003; 17: 921–4. 35. Arenas-Pinto A, Grant AD, Edwards S, Weller IV. Lactic acidosis in HIV infected patients: a systematic review of published cases. Sex Transm Infect 2003; 79: 340–3. 36. Tashima KT. Lipid changes in patients initiating efavirenz- and indinavir-based antiretroviral regimens. HIV Clin Trials 2003; 4: 29–36. 37. Calza L, Manfredi R, Farneti B, Chiodo F. Incidence of hyperlipidaemia in a cohort of 212 HIVinfected patients receiving a protease inhibitorbased antiretroviral therapy. Int J Antimicrob Agents 2003; 22: 54–9. 38. Moyle GJ, Baldwin C, Langroudi B, Mandalia S, Gazzard BG. A 48-week, randomized, openlabel comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J Acquir Immune Defic Syndr 2003; 33: 22–8. 39. John M, McKinnon EJ, James IR, Nolan DA, Herrmann SE, Moore CB, White AJ, Mallal SA. Randomized, controlled, 48-week study of switching stavudine and/or protease inhibitors to combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients. J Acquir Immune Defic Syndr 2003; 33: 29–33. 40. Lafeuillade A, Jolly P, Chadapaud S, Hittinger G, Lambry V, Philip G. Evolution of lipid abnormalities in patients switched from stavudine- to tenofovir-containing regimens. J Acquir Immune Defic Syndr 2003; 33: 544–6. 41. Domingo P, Sambeat MA, Perez A, Ordonez J, Rodriguez J, Vazquez G. Fat distribution and metabolic abnormalities in HIV-infected patients on first combination antiretroviral therapy including stavudine or zidovudine: role of physical activity as a protective factor. Antivir Ther 2003; 8: 223–31. 42. Badiou S, De Boever CM, Dupuy AM, Baillat V, Cristol JP, Reynes J. Small dense LDL and

339 atherogenic lipid profile in HIV-positive adults: influence of lopinavir/ritonavir-containing regimen. AIDS 2003; 17: 772–4. 43. Noor MA, Lo JC, Mulligan K, Schwarz JM, Halvorsen RA, Schambelan M, Grunfeld C. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001; 15: F11–18. 44. Brambilla AM, Novati R, Calori G, Meneghini E, Vacchini D, Luzi L, Castagna A, Lazzarin A. Stavudine or indinavir-containing regimens are associated with an increased risk of diabetes mellitus in HIV-infected individuals. AIDS 2003; 17: 1993– 5. 45. Justman JE, Benning L, Danoff A, Minkoff H, Levine A, Greenblatt RM, Weber K, Piessens E, Robison E, Anastos K. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women. J Acquir Immune Defic Syndr 2003; 32: 298–302. 46. Peyriere H, Guillemin V, Lotthe A, Baillat V, Fabre J, Favier C, Atoui N, Hansel S, Hillaire-Buys D, Reynes J. Reasons for early abacavir discontinuation in HIV-infected patients. Ann Pharmacother 2003; 37: 1392–7. 47. Keiser P, Nassar N, Skiest D, Andrews C, Yazdani B, White A, Hetherington S. Comparison of symptoms of influenza A with abacavir-associated hypersensitivity reaction. Int J STD AIDS 2003; 14: 478–81. 48. Buti M, Mas A, Prieto M, Casafont F, Gonzalez A, Miras M, Herrero JI, Jardi R, Cruz de Castro E, Garcia-Rey C. A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation. J Hepatol 2003; 38: 811–17. 49. Hartman C, Berkowitz D, Shouval D, EshachAdiv O, Hino B, Rimon N, Satinger I, Kra-Oz T, Daudi N, Shamir R. Lamivudine treatment for chronic hepatitis B infection in children unresponsive to interferon. Pediatr Infect Dis J 2003; 22: 224–9. 50. Connor FL, Rosenberg AR, Kennedy SE, Bohane TD. HBV associated nephrotic syndrome: resolution with oral lamivudine. Arch Dis Child 2003; 88: 446–9. 51. Brew BJ, Tisch S, Law M. Lactate concentrations distinguish between nucleoside neuropathy and HIV neuropathy. AIDS 2003; 17: 1094–6. 52. Cherry CL, McArthur JC, Hoy JF, Wesselingh SL. Nucleoside analogues and neuropathy in the era of HAART. J Clin Virol 2003; 26: 195–207. 53. Koduri PR, Parekh S. Zidovudine-related anemia with reticulocytosis. Ann Hematol 2003; 82: 184–5. 54. Schooley RT, Ruane P, Myers RA, Beall G, Lampiris H, Berger D, Chen SS, Miller MD, Isaacson E, Cheng AK; Study 902 Team. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002; 16: 1257–63. 55. Rivas P, Polo J, De Gorgolas M, FernandezGuerrero ML. Fatal lactic acidosis associated with tenofovir. Br Med J 2003; 327: 711.

340 56. Grim SA, Romanelli F. Tenofovir disoproxil fumarate. Ann Pharmacother 2003; 37: 849–59. 57. Karras A, Lafaurie M, Furco A, Bourgarit A, Droz D, Sereni D, Legendre C, Martinez F, Molina JM. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003; 36: 1070–3. 58. Shah MD, Balderson K. A manic episode associated with efavirenz therapy for HIV infection. AIDS 2003; 17: 1713–14. 59. Poulsen HD, Lublin HK. Efavirenz-induced psychosis leading to involuntary detention. AIDS 2003; 17: 451–3. 60. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003; 34 Suppl 1: S21–33. 61. Knudtson E, Para M, Boswell H, Fan-Havard P. Drug rash with eosinophilia and systemic symptoms syndrome and renal toxicity with a nevirapinecontaining regimen in a pregnant patient with human immunodeficiency virus. Obstet Gynecol 2003;101: 1094–7. 62. Verweel G, Sharland M, Lyall H, Novelli V, Gibb DM, Dumont G, Ball C, Wilkins E, Walters S, Tudor-Williams G. Nevirapine use in HIV-1infected children. AIDS 2003; 17: 1639–47. 63. De Maat MM, Ter Heine R, Mulder JW, Meenhorst PL, Mairuhu AT, Van Gorp EC, Huitema AD, Beijnen JH. Incidence and risk factors for nevirapine-associated rash. Eur J Clin Pharmacol 2003; 59: 457–62. 64. Jackson JB, Barnett S, Piwowar-Manning E, Apuzzo L, Raines C, Hendrix C, Hamzeh F, Gallant J. A phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1 transmission in uninfected subjects at high risk. AIDS 2003; 17: 547–53. 65. Moodley D, Moodley J, Coovadia H, Gray G, McIntyre J, Hofmyer J, Nikodem C, Hall D, Gigliotti M, Robinson P, Boshoff L, Sullivan JL; South African Intrapartum Nevirapine Trial (SAINT) Investigators. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis 2003; 187: 725–35. 66. Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 2003; 362: 859–68. 67. Taha TE, Kumwenda NI, Gibbons A, Broadhead RL, Fiscus S, Lema V, Liomba G, Nkhoma C, Miotti PG, Hoover DR. Short postexposure prophylaxis in newborn babies to reduce mother-to-child

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Pietro L. Vernazza and Patrick Schmid

transmission of HIV-1: NVAZ randomised clinical trial. Lancet 2003; 362: 1171–7. 68. Nunez M, Gonzalez-Requena D, GonzalezLahoz J, Soriano V. Short communication: interactions between nevirapine plasma levels, chronic hepatitis C, and the development of liver toxicity in HIV-infected patients. AIDS Res Hum Retroviruses 2003; 19: 187–8. 69. Sanne I, Piliero P, Squires K, Thiry A, Schnittman S; AI424-007 Clinical Trial Group. Results of a phase 2 clinical trial at 48 weeks (AI424007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviralnaive subjects. J Acquir Immune Defic Syndr 2003; 32: 18–29. 70. O’Mara EM, Mummaneni V, Randall D, et al. Assessment of the effect of uridine diphosphate glucuronosyltransferase (UDP-GT) 1A1 genotype on indirect bilirubin elevations in healthy subjects dosed with BMS-232632. Presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, September 2000. http://www.asmusa.org/memonly/abstracts/ abstractsearch.asp 71. Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, Feinberg J, Sherman KE. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci USA 2001; 98: 12671–6. 72. Arnaiz JA, Mallolas J, Podzamczer D, Gerstoft J, Lundgren JD, Cahn P, Fatkenheuer G, D’Arminio-Monforte A, Casiro A, Reiss P, Burger DM, Stek M, Gatell JM; BEST Study Team. Continued indinavir versus switching to indinavir/ritonavir in HIV-infected patients with suppressed viral load. AIDS 2003; 17: 831–40. 73. Dragsted UB, Gerstoft J, Pedersen C, Peters B, Duran A, Obel N, Castagna A, Cahn P, Clumeck N, Bruun JN, Benetucci J, Hill A, Cassetti I, Vernazza P, Youle M, Fox Z, Lundgren JD; MaxCmin1 Trial Group. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. J Infect Dis 2003; 188: 635– 42. 74. Camino N, Nunez M, Blanco F, GonzalezRequena D, Gonzalez-Lahoz J, Soriano V. Indinavir-induced thrombocytopenia. AIDS Patient Care STDS 2003; 17: 103–4. 75. Siveke JT, Bogner JR. Cholelithiasis possibly induced by protease inhibitors in 3 patients. Clin Infect Dis 2003; 36: 1498–500. 76. Nadler RB, Rubenstein JN, Eggener SE, Loor MM, Smith ND. The etiology of urolithiasis in HIV infected patients. J Urol 2003; 169: 475–7. 77. Dieleman JP, van Rossum AM, Stricker BC, Sturkenboom MC, de Groot R, Telgt D, Blok WL, Burger DM, Blijenberg BG, Zietse R, Gyssens IC. Persistent leukocyturia and loss of renal function in a prospectively monitored cohort of HIV-infected patients treated with indinavir. J Acquir Immune Defic Syndr 2003; 32: 135–42. 78. Ghosn J, Lamotte C, Ait-Mohand H, Wirden M, Agher R, Schneider L, Bricaire F, Duvivier C, Calvez V, Peytavin G, Katlama C. Efficacy of a

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twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients. AIDS 2003; 17: 209–14. 79. Bossi P, Peytavin G, Lamotte C, Calvez V, Bricaire F, Costagliola D, Katlama C. High indinavir plasma concentrations in HIV-positive patients co-infected with hepatitis B or C virus treated with low doses of indinavir and ritonavir (400/100 mg twice a day) plus two nucleoside reverse transcriptase inhibitors. AIDS 2003; 17: 1108–10. 80. Mah Ming JB, Gill MJ. Drug-induced rhabdomyolysis after concomitant use of clarithromycin, atorvastatin, and lopinavir/ritonavir in a patient with HIV. AIDS Patient Care STDS 2003; 17: 207– 10. 81. Cooper CL, Van Heeswijk RP, Gallicano K, Cameron DW. A review of low-dose ritonavir in protease inhibitor combination therapy. Clin Infect Dis 2003; 36: 1585–92. 82. Kurowski M, Sternfeld T, Sawyer A, Hill A, Mocklinghoff C. Pharmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers. HIV Med 2003; 4: 94–100.

341 83. Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine F, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J. A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in non-nucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 2003; 8: 279–87. 84. Dutkowski R, Thakrar B, Froehlich E, Suter P, Oo C, Ward P. Safety and pharmacology of oseltamivir in clinical use. Drug Saf 2003; 26: 787– 801. 85. Singh S, Barghoorn J, Bagdonas A, Adler J, Treanor J, Kinnersley N, Ward P. Clinical benefits with oseltamivir in treating influenza in adult populations: Results of a pooled and subgroup analysis. Clin Drug Invest 2003; 23: 561–9. 86. Ison MG, Gnann JW Jr, Nagy-Agren S, Treannor J, Paya C, Steigbigel R, Elliott M, Weiss HL, Hayden FG; NIAID Collaborative Antiviral Study Group. Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antivir Ther 2003; 8: 183–90.

Soumya Swaminathan

30

Drugs used in tuberculosis and leprosy

Pharmacogenetics: genetic susceptibility, drug metabolism, and adverse effects Differences in drug response between individuals can be due to the occurrence of genetic polymorphisms in drug metabolizing enzymes (1R ). Because of genetic variation in drug metabolizing capacity, a predisposed individual may experience: 1. lack of efficacy at a normal drug dose, requiring a higher dose to achieve the expected therapeutic response; 2. a much larger effect at the usual dose, leading to adverse effects. Acetylation Drug metabolizing enzymes are responsible for degradation of drugs and environmental pollutants and are important determinants of drug action. An example is the polymorphism in acetylation that is mediated by N-acetyltransferase isoenzymes NAT1 and NAT2 in the liver (2R ). More than 25 NAT2 genotypes and about 20 NAT1 genotypes have been reported. Based on NAT2 phenotype, individuals are characterized as rapid, intermediate, or slow acetylators. Isoniazid and some sulfonamides, such as sulfadimidine, are typical substrates for NAT2, while NAT1 metabolizes para-aminosalicylic acid and paraaminobenzoic acid. Caffeine is metabolized by both enzymes. There is significant variation in the distributions of various phenotypes in different parts of the world. The Inuit and Japanese have the lowest rates for slow acetylators (about 10%), while in India it is high at around 60%. This has implications for the metabolism © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

342

and detoxification of isoniazid. Slow acetylators have an increased risk of peripheral neuropathy during therapy with isoniazid while rapid acetylators are more likely to have treatment failure and relapse if they take isoniazid twice weekly. Hepatotoxic reactions may be more common in slow acetylators, who also have an increased susceptibility to phenytoin toxicity. There is an increased risk of lupus-like syndrome among slow acetylators who take isoniazid, hydralazine, or procainamide. Oxidation The cytochrome P450 (CYP) monooxygenase system of enzymes is responsible for the major portion of drug metabolism in humans. Among the numerous P450 subtypes, CYP2D6, CYP3A4/5, CYP1A2, CYP2E1, CYP2C9, and CYP2C19 play important roles in genetically determined responses to a broad spectrum of drugs. If the in vitro clearance of a drug is largely mediated by a single polymorphically expressed or allelic variant, poor metabolizers will be characterized by disparate pharmacokinetics (for example high plasma AUCs and/or prolonged half-lives). About 40% of human CYP-dependent drug metabolism is carried out by enzymes that are polymorphically distributed. Combined polymorphisms There has been a recent evaluation of whether polymorphism of the CYP2E1 gene is associated with the development of antituberculosis drug-induced hepatitis (3c ). The CYP2E1 and NAT2 genotypes were determined using PCR. Patients with the homozygous wild genotype CYP2E1 c1/c1 had a very significantly higher risk of hepatotoxicity (20%, OR = 2.52) than those with the mutant allele c2 (9%). When the CYP2E1 genotype was combined with acetylator status, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 plus rapid acetylator status to 7.43 for

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CYP2E1 c1/c1 plus slow acetylator status. The authors concluded that CYP2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis, even after adjustment for age. Such genetic variations may account for the variability in reported adverse effects due to antituberculosis drugs in different populations. Thus, drug metabolism is affected by genetic factors impacting enzyme activity as well as external and internal factors, such as age, sex, environment, diet, and drug–drug interactions. Future prospects The study of pharmacogenetic differences holds the potential to improve therapeutic effectiveness and limit the adverse effects of available drugs, in other words to individualize medicine. Pharmacogenetics can also provide substantial efficiency in clinical research by facilitating the conduct of smaller clinical trials by targeting groups of patients with similar genetic backgrounds. Pharmacogenomics will also play a role in the development of new clinical entities in order to reduce adverse drug reactions.

Dapsone

(SED-14, 1021; SEDA-25, 365; SEDA-26, 340) Hematologic Agranulocytosis is a rare complication of dapsone treatment (SED-14, 1022) and a fatal case has been reported:

• A 60-year-old man took 100 mg dapsone daily for leprosy and after 3 weeks developed pneumonia and agranulocytosis (4A ). He died a few hours after diagnosis despite parenteral antibiotics.

Dapsone was the suspected cause of agranulocytosis. However, the patient had also received concomitant rifampicin, clofazimine, and prednisolone.

Immunological Hypersensitivity to dapsone, called the “sulfone syndrome”, manifests as fever, malaise, rash, liver involvement, lymphadenopathy, methemoglobinemia, and hemolytic anemia. • A 42-year-old HIV-infected African-American man taking dapsone prophylaxis for Pneumocystis jiroveci pneumonia developed fever, lymphadenopathy, exfoliative dermatitis, hepatitis, and methemoglobinemia 4 weeks after starting to take dapsone. His symptoms and laboratory abnormalities completely resolved on withdrawal of dapsone (6A ). • A similar syndrome occurred in a 55-year-old Caucasian woman with urticarial vasculitis, who developed near-fatal sulfone syndrome with hepatic and renal failure (7A ).

Isoniazid

(SED-14, 1009; SEDA-25, 364; SEDA-26, 341)

Liver Drug users have multiple risk factors for hepatotoxicity, including chronic infection with hepatitis C. In a prospective study among drug users the only two factors that were independently associated with isoniazid hepatotoxicity were excessive alcohol consumption (OR = 4.2, 95% CI = 1.6, 10.8) and a high baseline alanine transaminase activity (OR = 4.3, 95% CI = 1.6, 11.4) (8c ). The presence of hepatitis C antibodies by itself did not confer an additional risk of toxicity, which was observed in 20 of 415 patients (4.8%). In another study, among 3788 patients taking isoniazid in a US county tuberculosis clinic, 673 (18%) had one or more adverse effects, including 10 (0.3%) with isoniazid-associated liver damage (9C ). There were higher rates with increasing age, but the overall rates were not alarming, even in individuals with risk factors. However, the greatest obstacle to the successful use of isoniazid preventive therapy is not toxicity but low completion rates.

Pancreas A case of pancreatitis associated with sulfone syndrome has been documented; a second case has now been reported (5A ).

Immunologic Anaphylaxis secondary to prophylactic isoniazid has been reported (10A ).

• An 87-year-old white man developed acute abdominal pain 4 weeks after starting to take dapsone 100 mg/day. He had raised serum amylase and lipase activities. His symptoms resolved when dapsone was withdrawn and recurred when it was re-introduced 4 months later.

• A 40-year-old Hispanic man with a 20-mm positive PPD reaction was given isoniazid 900 mg and pyridoxine 50 mg twice weekly. One month later, he developed chest pain and nausea 1 hour after taking isoniazid. This was repeated 1 week later after another dose, when he also had a tachycardia,

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a low blood pressure, and oxygen desaturation. He recovered after treatment for an anaphylactic reaction.

The hydrazine metabolite of isoniazid may be the cause of allergy in susceptible patients. Drug overdose Acute isoniazid overdose or poisoning presents with a triad of coma, seizures, and metabolic acidosis. Two reports highlight the fact that isoniazid poisoning should be considered in the differential diagnosis of adults or children who present with intractable seizures or an encephalopathy-like syndrome (11A , 12A ). Slow acetylators of the drug are at greater risk because of higher peak concentrations. Isoniazid produces a deficiency of endogenous pyridoxine, by both increasing the renal excretion of pyridoxine and inhibiting its action. This causes a rapid fall in nervous system GABA (γ -aminobutyric acid) because of non-availability of pyridoxal phosphate, thereby lowering the intrinsic seizure threshold. The symptoms of isoniazid intoxication are nausea, vomiting, fever, skin rashes, ataxia, speech disorders, and altered consciousness, followed by seizures and coma. The specific antidote is pyridoxine (vitamin B6 ) which should be given intravenously.

Pyrazinamide

(SED-14, 1013;

SEDA-27, 323) Susceptibility factors In a retrospective analysis of 430 patients with tuberculosis at a chest center between 1990 and 1999, the incidence of all major adverse effects was 1.48 per 100 person-months of exposure (95% CI = 1.31, 1.61) for pyrazinamide compared with 0.49 (0.42, 0.55) for isoniazid, 0.43 (0.37, 0.49) for rifampicin, and 0.07 (0.04, 0.1) for ethambutol

Soumya Swaminathan

(13c ). The occurrence of any major adverse effect was associated with female sex, age over 60 years, birthplace in Asia, and HIV-positive status. The incidence of pyrazinamide-induced hepatotoxicity and rash during treatment for active tuberculosis was substantially higher than with other first line antituberculosis drugs.

Rifampicin (SED-14, 1014; SEDA-25, 364; SEDA-26, 341; SEDA-27, 324) Drug interactions Because it induces the cytochrome P450 enzyme system in the liver and intestine, rifampicin can produce many clinically important drug interactions. Antidiabetic drugs The effects of rifampicin on the pharmacokinetics of gliclazide (14E ) and nateglinide (15E ) have been investigated in two different studies in healthy subjects. Rifampicin reduced the plasma concentration of both drugs; the mean AUC for gliclazide was reduced by 70% and for nateglinide by 24%. Rifampicin may reduce the blood glucose-lowering effect of these drugs. Quinine The effect of adding rifampicin to quinine has been assessed in adults with uncomplicated falciparum malaria in Thailand (16c ). Although parasite clearance times were shorted in patients who took quinine + rifampicin (mean 70 versus 82 hours), recrudescence rates were five times higher than those obtained with quinine alone (15/23, 65% versus 3/25, 12%). Rifampicin increases the metabolic clearance of quinine and reduces cure rates. Rifampicin should not be combined with quinine and doses of quinine should probably be increased in patients who are already taking rifampicin.

REFERENCES 1. Srivastava P. Drug metabolism and individualized medicine. Curr Drug Metab 2003; 4: 33–44. 2. Pande JN, Pande A, Singh SPN. Acetylator status, drug metabolism and disease. Natl Med J India 2003; 16: 24–6.

3. Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY and Lee SD. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 2003; 37: 924–30.

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4. Bhat RM, Radhakrishnan K. A case report of fatal dapsone-induced agranulocytosis in an Indian mid-borderline leprosy patient. Lepr Rev 2003; 74: 167–70. 5. Jha SH, Reddy JA, Dave JK. Dapsone-induced acute pancreatitis. Ann Pharmacother 2003; 37: 1438–40. 6. Lee KB, Nashed TB. Dapsone-induced sulfone syndrome. Ann Pharmacother 2003; 37: 1044–6. 7. Leslie KS, Gaffney K, Ross CN, Ridley S, Barker TH, Garoich JJ. A near fatal case of the dapsone hypersensitivity syndrome in a patient with utricarial vasculitis. Clin Exp Dermatol 2003; 28: 496–8. 8. Fernandez-Villar A, Sopena B, Vasquez R, Ulloa F, Fluiters E, Mosteiro M, Martinez-Vasquez C, Pineiro L. Isoniazid hepatotoxicity among drug users: the role of hepatitis C. Clin Infect Dis 2003; 36: 293–8. 9. Lobue PA, Moser KS. Use of isoniazid for latent tuberculosis infection in a public health clinic. Am J Resp Crit Care Med 2003; 168: 443–7. 10. Crook MJ. Isoniazid induced anaphylaxis. J Clin Pharmacol 2003; 43: 545–6. 11. Caksen H, Odabas D, Erol M, Anlar O, Tuncer O, Atas B. Do not overlook acute isoniazid poi-

345 soning in children with status epilepticus. J Child Neurol 2003; 18: 142–3. 12. Maw G, Aitken P. Isoniazid overdose: a case series, literature review and survey of antidote availability. Clin Drug Invest 2003; 23: 479–85. 13. Yee D, Valiquette C, Pelletier M, Parisiea I, Rocher I, Menzies D. Incidence of serious side effects from first line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003; 167: 1472–7. 14. Park JY, Kim KA, Park PW, Part CW, Shin JG. Effect of rifampin on pharmacokinetics and pharmacodynamics of gliclazide. Clin Pharmcol Ther 2003; 74: 334–40. 15. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects. J Clin Pharmacol 2003; 56: 427–32. 16. Pukrittayakamee S, Prakongpan S, Wancoimotruk S, Clemens R, Looareesuwan S, White NK. Adverse effect of rifampicin on quinine efficacy in uncomplicated falciparum malaria. Antimicrob Agents Chemother 2003: 47: 1509–13.

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Antihelminthic drugs

BENZIMIDAZOLES

(SED-14, 1030; SEDA-25, 367; SEDA-26, 344; SEDA-27, 326)

Albendazole, mebendazole, and thiabendazole Observational studies Benzimidazoles and paragonimiasis Five patients, aged 7–38 years, with Paragonimus skrjabini infections, were treated with oral triclabendazole (10 mg/kg bd for 3 consecutive days), an antihelminthic benzimidazole derivative used in the treatment of fascioliasis in sheep (1c ). One patient had cerebral involvement and received two courses. All five were cured. Blood eosinophilia completely disappeared. There were no adverse effects. Hepatic and renal function tests were unaffected. These data suggest that Paragonimus skrjabini infections can be safely treated with triclabendazole. Benzimidazoles and Trichuris trichiura In a randomized trial in 168 patients the duration of albendazole therapy (400 mg/day) for 3, 5, or 7 days was studied in relation to its effectiveness in the treatment of Trichuris trichiura infection (2C ). Treatment with albendazole for 7 days resulted in a significantly higher cure rate, in particular in patients who had heavy infections (at least 1000 Trichuris eggs/g of feces). The authors therefore suggested that albendazole should be given for at least 3 days to those with light infections and for 5–7 days to patients with heavy infections. All reported adverse effects were mild. One patient (treated for 3 days) reported headache. Two patients (one treated for 3 days the other for 7 days) reported dizziness. Insomnia was reported in two patients treated for 7 days. Jaundice was not detected at any time. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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Comparative studies Benzimidazoles and echinococcosis In a meta-analysis the clinical outcomes in 769 patients with hepatic cystic echinococcosis treated with percutaneous aspiration-injection-reaspiration (PAIR) plus albendazole or mebendazole (group 1) was compared with 952 era-matched historical control subjects undergoing surgical intervention (group 2) (3M ). The rates of clinical and parasitological cure were higher in patients receiving PAIR plus chemotherapy with albendazole or mebendazole. Disease recurrence, minor non-life-threatening complications, major complications such as anaphylaxis, biliary fistula, cyst infection, sepsis, liver/intra-abdominal abscess, and death occurred more often among surgical control subjects. Patients in this metaanalysis took antiparasitic drug therapy for 1 week before and 4 weeks after PAIR. Hepatic and hematological adverse effects were the most common, but detailed information was not given. Benzimidazoles and giardiasis In a comparison of mebendazole and secnidazole for giardiasis, 146 children aged 5–15 years were randomly assigned to mebendazole 200 mg tds for 3 days or secnidazole 30 mg/kg in a single dose (4C ). There was no difference in cure rates (78% versus 79%). Both treatment regimens were well tolerated. Transient abdominal discomfort was significantly more common with mebendazole than secnidazole (27% versus 8.2%). A bitter taste was reported in six patients who took secnidazole (8.2%) but not in patients who took mebendazole. The other reported adverse effects were nausea (in about 9.5% in each group) and vomiting (in 4–5% in each group). Benzimidazoles and neurocysticercosis In an open, randomized, controlled trial, children with neurocysticercosis and seizures, aged 1–14 years, the efficacy of albendazole plus dexamethasone was studied (5C ). Of 123 children, 61

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were given dexamethasone 0.15 mg/kg/day for 5 days plus albendazole 15 mg/kg/day for 28 days. The controls (n = 62) were given neither dexamethasone nor albendazole. Antiepileptic therapy was given to both groups. The cysticercal brain lesions resolved completely or partially in significantly more children in the treatment than the control group (79 versus 57%). The proportion of children who had seizures was significantly lower in the albendazole plus dexamethasone treatment group compared with the control group at 3 months (10% versus 32%) and at 6 months (13% versus 33%). In the 15 days follow-up after enrolment, there were no significant differences in the proportions of children with headache, vomiting, or visual problems. Thus, albendazole plus dexamethasone increased complete or partial resolution of cysticercal brain lesions and reduced the risk of subsequent recurrence of seizures among children with neurocysticercosis and seizures. In another study, the appropriate duration of albendazole therapy in neurocysticercosis was established in a double-blind, randomized, placebo-controlled trial in 122 children with neurocysticercosis and seizures, who were randomized to albendazole (15 mg/kg/day) for 7 days followed by either albendazole (n = 60) or placebo (n = 62) for the following 21 days (6C ). It appeared that 1 week of therapy with albendazole was as effective as 4 weeks in children with neurocysticercosis. A minority reported nausea or mild epigastric discomfort (seven children taking albenzazole, four taking placebo). Two developed headache not associated with raised intracranial pressure. One developed a transient skin rash. All adverse effects were mild and resolved spontaneously. Benzimidazoles and pediculosis capitis To test the potential effectiveness of thiabendazole in pediculosis capitis, girls aged 7–12 years took oral thiabendazole 20 mg/kg bd for 1 day, with repeat treatment after 10 days (7C ). Of 23 patients, 21 responded to treatment, 14 showing complete resolution of infestation. The only adverse reactions were nausea and mild dizziness, which occurred in four patients, three of whom took the drug on an empty stomach. Skin Many laborers take antihelminthic drugs, such as mebendazole or metronidazole,

347 to avoid a positive stool test that may exclude them from work overseas. In a casecontrol study 46 Filipino laborers with Stevens– Johnson syndrome or toxic epidermal necrolysis were matched with 92 controls according to age, sex, and month of arrival in Taiwan (8C ). The odds ratio for the skin rashes was 9.5 (95% CI = 3.9, 24) among workers who had used both metronidazole and mebendazole at some time in the preceding 6 weeks. There was an increasing risk with increasing level of exposure to metronidazole (in particular with doses over 2000 mg). There was a reverse dose–response relation between the risk of the rashes and the level of exposure to mebendazole (in particular with doses under 1000 mg). Combination therapy involving metronidazole and mebendazole should therefore be avoided because of the increased risk of developing Stevens–Johnson syndrome or toxic epidermal necrolysis. Teratogenicity The use of mebendazole in pregnancy gives reason for concern, because of the relative scarcity of data on its safety in pregnancy. The Israeli Teratogen Information Service followed 192 women exposed to mebendazole in pregnancy (9C ). Most of them were exposed to mebendazole during the first trimester (71.5%), 21.5% during the second trimester, and 7.0% during the third trimester. Similar proportions of women reported using mebendazole in a single dose of 100 mg (29%), a single dose of 100 mg repeated after an interval (36%) and 100 mg/day for 3 consecutive days (35%). There was no increase in the rate of major anomalies after exposure to mebendazole compared with controls. In addition, the incidence of major anomalies was not increased in the subgroup of patients who received mebendazole in the first trimester of pregnancy compared with controls. These data suggest that mebendazole does not represent a major teratogenic risk in humans when it is used in the doses commonly prescribed for pinworm infestation. In another study inadvertent exposure of pregnant women to albendazole and ivermectin during a mass drug administration program for lymphatic filariasis was investigated (10C ). Of 2985 women of childbearing age who were interviewed, 343 were pregnant, of whom 293 were excluded from the programme. However, 50 pregnant women were inadvertently treated. Of the six children with some congenital malformations identified in these communities, one

348 had been exposed to the drugs in utero. The relative risk for congenital malformations after exposure was 1.05. Two of nine women with spontaneous abortions had been exposed to the drugs (RR = 1.67). Thus, there seems to be no evidence of a higher risk of congenital malformations or abortions in pregnant women inadvertently exposed to albendazole and ivermectin. Susceptibility factors Genetic Although certain individuals have an increased susceptibility to adverse reactions to multiple pharmaceutical agents, familial or genetic predisposition has not been elucidated. • A 4-year-old Mexican girl with ascariasis, who was treated with thiabendazole syrup 375 mg tds for 3 days, developed a severe skin rash compatible with Stevens–Johnson syndrome after 21 days (11A ). The pediatrician prescribed the same treatment for her four siblings (aged 2–7 years). Two of them developed a similar skin rash after 7 and 10 days.

These observations suggest that these severe skin rashes may be subject to genetic predisposition. Children Experience with albendazole and mebendazole in children under 24 months has been reviewed (12R ). In 17 studies, over 2189 children under 24 months received treatment with a benzimidazole derivative. In an epidemiological survey of 1209 courses of treatment no adverse effects were documented. In another 979 courses of treatment adverse effects were actively sought but were not found. There was only one episode of convulsion reported in a 7week-old infant treated with mebendazole, but the symptoms were thought not to have been related to mebendazole. In a double-blind, randomized, placebocontrolled trial in 212 children aged under 24 months there was no statistically significant difference in the incidence rate of adverse effects with mebendazole compared with placebo (13C ). Thus, the evidence suggests that albendazole and mebendazole can be used to treat soil-transmitted helminthiasis in children aged 12 months and older, provided that the case for their use is established. Under 12 months of age, drug absorption may be increased, resulting in an increased risk of benzimidazole toxicity.

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Diethylcarbamazine

(SED-14, 1034; SEDA-25, 368; SEDA-26, 345; SEDA-27, 328)

Diethylcarbamazine is a microfilaricidal drug that is widely used, in particular for Loa Loa infections and lymphatic filariasis caused by Wuchereria bancrofti and Brugia malayi. It can be associated with significant systemic adverse effects, which can compromise adherence to therapy. It is commonly believed that adverse reactions to diethylcarbamazine result from proinflammatory responses to antigens released from killed microfilariae rather than by direct drug or metabolite toxicity. The frequency, severity, and costs of adverse reactions after mass treatment for lymphatic filariasis in 71 187 people in Leogane (Haiti) using diethylcarbamazine and albendazole have recently been reported in detail (14C ). They received diethylcarbamazine plus albendazole 400 mg (n = 38 655 men and boys and 16 482 women and girls) or diethylcarbamazine alone (n = 15 335 women and girls). Of those treated, 17 421 (24%) reported one or more adverse reactions. The reactions were considered minor in 15 916 (91%) and moderate in 1502 (9%). The most commonly reported minor adverse reactions were systemic: 9766 (61%) reported some combination of headache, fever, or body aches. Local problems attributed to worm death were reported in 2170 (14%). Moderate adverse reactions were reported primarily by adults. Men outnumbered women in reporting moderate adverse reactions. Among children under 15 years (n = 27 115), boys were less likely to report moderate adverse reactions than girls. Adverse reactions were systemic in 131. In 355 there were localized scrotal reactions only; 83 reported itching, 70 reported gastrointestinal problems, six reported dizziness, and 56 reported miscellaneous problems. A total of 801 persons reported multiple adverse reactions: these were combinations of systemic, localized scrotal, and other problems. Three patients were hospitalized with severe adverse reactions (0.02% of all reactions). All three reported multiple problems: • an acute scrotal reaction, fever, headache, vomiting, and abdominal pain in a 25-year-old man; • itching, body aches, abdominal pain, and heartburn in a 14-year-old girl; • dizziness, body aches, and abdominal pain in an 18-year-old woman.

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Of the patients who reported moderate adverse reactions, 1136 (76%) reported their problems during the 4 days of mass drug distribution. By the third day after the end of mass drug distribution, 98% of all moderate adverse reactions had been reported.

Ivermectin

(SED-14, 1035; SEDA-25, 370; SEDA-26, 346; SEDA-27, 329)

Observational studies Ivermectin and filariasis The incidence of serious adverse events after mass treatment with ivermectin in areas co-endemic for loiasis and onchocerciasis has been determined in a retrospective analysis (15C ). In addition, potential risk factors associated with these serious adverse events, including encephalopathy, were identified. In the period December 1998 to November 1999, a total of 784 653 people were given ivermectin in onchocerciasis mass treatment programmes in Cameroon; 47 serious adverse events were reported, resulting in an overall incidence of about six serious adverse events per 100 000 people treated. The five most frequent initial symptoms and signs were as follows: • fatigue and/or weakness and/or difficulty or inability to stand (43%); • confusion, obtundation, stupor, or unconsciousness (26%); • nausea and/or vomiting and/or diarrhea and/ or dehydration (17%); • fever and/or chills (17%); • dysarthria and/or aphasia (15%). The median age of the cases was 35 (range 6–72) years. Male patients represented 75% of the caseload and 87% of the patients experienced ivermectin for the first time. Symptoms began within the first 24–48 hours of administration, but there was a delay of about 48–84 hours in seeking help after the onset of symptoms. There was a presumptive neurological diagnosis in 35 cases; 29 were considered to be so-called PLERM (Probable Loa loa Encephalopathy temporally Related to Mectizan treatment). Six of the 47 reported patients with a serious adverse event died; five fitted the diagnosis of PLERM. First-time exposure to ivermectin was primarily associated with PLERM.

349 In another study, 890 subjects were interviewed to monitor adverse reactions after repeated ivermectin treatment of onchocerciasis in Nigeria (16C ). After the first treatment round with ivermectin, 202 subjects reported pains in joints, 108 reported fever, 30 reported headache, 18 reported itching, and four reported dizziness. There were no adverse reactions in 528 (59%). After the sixth treatment round, no reactions were reported in 756 subjects (85%). Pains in joints were reported by 76, itching by 26, fever by 24, and dizziness by eight subjects. The relatively mild adverse reactions observed during the first treatment round did not affect future participation in community treatment with ivermectin. In a study in Uganda, 737 of 1246 patients (59%) with onchocerciasis developed adverse reactions after first treatment with a single oral dose of ivermectin 150 micrograms/kg (17C ). Pain, swelling, and cutaneous reactions were the three most dominant symptoms of adverse effects (in 57%, 50%, and 38% of the 737 symptomatic patients respectively). Ten patients had severe adverse reactions, including severe postural hypotension and high fever. In spite of the fact that many patients had adverse reactions to ivermectin, the drug was well accepted and appreciated by the population. Ivermectin and scabies Two cases of scabies treated with oral ivermectin (200 µg/kg) have been reported (18A ). • A 72-year-old man developed crusted scabies, having used an oral glucocorticoid, owing to a presumed misdiagnosis by an earlier physician. He was successfully treated with two oral doses of ivermectin 7 days apart with topical crotamiton 10% and a keratolytic ointment (5% salicylic acid in petrolatum). However, the nail scabies failed to respond. Live mites were detected from all his toenails 2 weeks after the second dose of ivermectin. Complete cure was achieved by occlusive dressings with lindane for 1 month. Follow-up observations did not reveal any adverse effects of ivermectin or signs of relapse. • A 52-year-old woman, who had taken oral glucocorticoids for mesangial nephritis, developed common scabies, but a topical scabicide, crotamiton, was not effective, and 2 weeks after treatment with a single dose of oral ivermectin eggs were still detected from a burrow on her trunk. Her treatment was completed after a further two doses of oral ivermectin at 7 day intervals.

In both cases, oral ivermectin did not cause any clinical or laboratory adverse effects. Oral

350 ivermectin is effective for crusted scabies, but not effective for nail scabies. A repeat treatment with ivermectin appears to result in the highest rate of cure. Placebo-controlled studies Ivermectin and filariasis In a randomized, double-blind, placebo-controlled trial the efficacy and pharmacokinetic interaction of co-administration of ivermectin with albendazole in onchocerciasis was studied and compared with ivermectin alone in male patients, who were randomized to receive ivermectin 200 µg/kg (n = 14), albendazole 400 mg (n = 14), or both (n = 14) (19C ). The adverse effects were mild to moderate in intensity and there were no serious adverse effects. Comparison of the two ivermectin-treated groups showed no significant differences in the intensity or frequency of any type of adverse effect, or on the perceived need for additional medications, such as paracetamol. Although the combination, but not ivermectin alone, produced a significantly higher total Mazzotti reaction score than albendazole, the clinical significance of this difference was minor. Thus, the safety profile of ivermectin was not altered by co-administration of albendazole. In addition, albendazole did not alter systemic exposure to ivermectin or vice versa. However, the coadministration of ivermectin with albendazole offered no advantage over ivermectin alone in terms of efficacy against Onchocerca volvulus.

Levamisole

(SED-14, 1037; SEDA-25, 372; SEDA-26, 347; SEDA-27, 330) Levamisole was originally developed as an antihelminthic drug, but is nowadays mainly used as an immunomodulating drug in adjuvant therapy for colon cancer, usually in combination with 5-fluorouracil. It is also used in other conditions, including nephrotic syndrome, and in some infections, such as pediculosis recurrent aphthous ulcerations. Comparative studies Levamisole and colon cancer Adjuvant 5-fluorouracil and levamisole have been considered standard treatment for stage III colon cancer. However, the uncertain contribution of levamisole has led many oncologists to prefer of combination fluorouracil +

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leucovorin. In a multicenter, phase 3, randomized comparison of fluorouracil + levamisole (n = 92) versus fluorouracil alone (n = 93) in 185 patients with stage III colon cancer the relative contribution of levamisole (50 mg tds for 3 consecutive days, repeated every 2 weeks for 1 year) was established (20C ). After a median follow-up time of 48 months, 80 patients had recurrent disease (40 in each arm) and there were no advantages in terms of disease-free survival and overall survival for fluorouracil + levamisole. However, leukopenia (18% versus 4.3%) and hepatic toxicity (16% versus 4.4%) were more frequent in patients receiving fluorouracil + levamisole compared with fluorouracil alone, whereas other adverse effects were equally distributed among both treatment arms. Some patients had neurological symptoms, consisting of mood-altering effects and disabling cerebellar ataxia, attributed to treatment with levamisole. They abated when therapy was withdrawn. In a randomized trial in 218 patients with stage II–III resectable rectal cancer, adjuvant postoperative radiotherapy has been compared with sequential radiotherapy and chemotherapy with fluorouracil + levamisole (21C ). Adherence to chemotherapy in patients undergoing sequential radiotherapy and chemotherapy was poor; 32% of the patients had to stop chemotherapy owing to severe toxicity, mostly gastrointestinal. The authors concluded that fluorouracil + levamisole is not effective in patients with resected rectal cancer. Levamisole and nephrotic syndrome In a systematic review of randomized controlled trials levamisole significantly reduced the risk of relapse in nephrotic syndrome (22R ). Few adverse effects were reported in trials in children; however, important adverse effects include neutropenia, gastrointestinal effects, and rarely disseminated vasculitis.

Moxidectin Moxidectin, a macrocyclic lactone like ivermectin, is approved and marketed worldwide as a treatment for internal and external parasites in wide variety of companion and farm animals. It is currently under investigation in human

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onchocerciasis. In a single ascending-dose, double-blind, randomized, placebo-controlled study, 30 subjects (23C ) were randomized to moxidectin 3, 9, 18, 36, or 54 mg, with or without food. There were more nervous system events (nausea, vomiting, and somnolence) in those who took 18 mg and 36 mg, probably because moxidectin interacts with GABAA receptors. Eight subjects had dizziness or somnolence/lethargy (one in the placebo group, two who took 9 mg, one who took 18 mg, and four who took 36 mg). Based on these observations it was decided not to proceed to the dose of 54 mg. All adverse events were grade 1 (mild) or 2 (moderate), with the exception of one grade 3 (severe) enteritis at 57 days after administration, which was thought to be due to food poisoning, unrelated to moxidectin. There was no statistical difference across dose groups in the total incidence of adverse events. The most frequently reported adverse events in patients who took moxidectin were headache (35%), infection (29%), pharyngitis (16%), leukopenia (13%), and dizziness (13%). Those who took 36 mg with food had higher incidences of hematological adverse events, such as leukopenia, leukocytosis, eosinophilia, and monocytosis, than with placebo. All hematological adverse events were of grade 1. A high-fat breakfast delayed and increased overall absorption but did not alter Cmax .

Praziquantel

(SED-14, 1041; SEDA-25, 372; SEDA-26, 349; SEDA-27, 331)

Observational studies Praziquantel and schistosomiasis The efficacy and adverse effects of two courses of praziquantel (40 mg/kg 4 weeks apart) for Schistosoma haematobium infection have been evaluated in 354 school children aged 5–15 years (24C ). The two doses of praziquantel were highly effective. Of the 354 children, 165 complained of one (33%), two (11%), or even three symptoms (2.5%). These adverse effects occurred within 1 hour of treatment, were mild, and gradually resolved without specific interventions; abdominal pain (18%), nausea (12%), headache (9.6%), and dizziness (9.6%) were the most common. None of the symptoms appeared to be related to the intensity of the infection. Significantly more

351 girls than boys complained of vomiting, dizziness, and abdominal pain and they were more frequent among older children. There were fewer adverse effects after the second dose. Only 43 (13%) of the children reported adverse effects after the second treatment dose, and headache was the most prevalent. The children who reported adverse effects after the first dose were no more likely to report adverse effects after the second dose than children who were asymptomatic after the first dose. Praziquantel and tapeworm infections The efficacy and safety of praziquantel in Diphyllobothrium nihonkaiense infections has been studied in 14 Japanese men who took a single dose of praziquantel 5–10 mg/kg (25C ). All were cured and had not expelled proglottides after 1 year of follow-up. There were no adverse effects. Comparative studies Praziquantel and schistosomiasis Oxamniquine and praziquantel have been compared in a triple-masked, randomized, controlled trial in 106 patients with Schistosoma mansoni infections (26C ). They were randomized to treatment with praziquantel 60 mg/kg/day on 3 consecutive days, oxamniquine 10 mg/kg twice on 1 day followed by placebo on days 2 and 3; starch for 3 consecutive days. When cure was evaluated by stool examination, oxamniquine and praziquantel had cure rates of 90% and 100% respectively. However, when the oogram was used as an indicator of sensitivity, the oxamniquine cure rate fell to 42% whereas the rate for praziquantel remained high, at 96%. The adverse effects of the two drugs were similar and mild; the most common adverse effects were headache, dizziness, drowsiness, and abdominal pain. Patients who took the placebo also had drowsiness and abdominal pain. Teratogenicity With the introduction of praziquantel in the early 1980s, a safe, single-dose antihelminthic drug became available for the treatment of schistosomiasis. In addition, several other parasitic diseases, such as clonorchiasis, paragonimiasis, and cysticercosis, could be cured. Unfortunately, praziquantel was not tested in pregnant and lactating women before marketing, despite its lack of known toxicity. It was therefore released as a pregnancy category B drug (presumed to be safe based on

352 animal studies). In consequence, a large number of pregnant and lactating women living in endemic countries are currently not treated in targeted antihelminthic mass treatment programs or are treated after a significant delay. The available evidence on the toxicology of praziquantel, combined with over two decades of clinical experience has been reviewed with special emphasis on pregnancy and lactation (27R ). In contrast to most other antihelminthic drugs, praziquantel, given either acutely or chronically and in doses well above those routinely used in humans had no detrimental effect on experimental animals or in reproductive studies in rats, rabbits, and hamsters. Since its release, no cases have been reported that suggest adverse birth outcomes. In addition, several pregnant women have intentionally taken praziquantel for cysticercosis with no apparent adverse outcomes. In some mass treatment studies, several hundred pregnant women were inadvertently treated without adverse birth outcomes. Lactation Praziquantel is excreted in small quantities in breast milk, but the dose would be considerably lower than that to which unborn children of mothers treated with praziquantel would be exposed. To avoid unwanted problems, lactating women can take curative therapy with praziquantel and refrain from breastfeeding for 48 hours. As long as a short-term alternative (bottle feeding) exists, this seems a reasonable alternative, especially since schistosomiasis is rather uncommon in children under 2 years of age. Since a double-blind placebocontrolled trial that would resolve the issue of praziquantel in pregnant and lactating women is thought to be unethical, pregnant and lactating women should be treated with praziquantel. Drug tolerance (parasite resistance) Although praziquantel is currently the drug of choice for schistosomiasis, there is concern that schistosomes might become resistant. • A previously healthy 26-year-old British man travelled to Kenya for 10 weeks and acquired Schistosoma mansoni (28A ). He received standard treatment with praziquantel 40 mg/kg, with no adverse effects. Evidence of active infection persisted after three courses of praziquantel in 4 years. Since oxamniquine as an alternative treatment agent was not available in the UK, he received a prolonged

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course of praziquantel 40 mg/kg/day for 3 consecutive days, with suggestion of a response to treatment. There was some response to treatment, suggesting tolerance to praziquantel or in part dosedependent resistance.

Unfortunately, although this patient was followed for several years, the authors did not provide details about the follow-up nor did they mention polymerase chain reaction-based studies on this potential praziquantel-resistant Schistosoma mansoni strain. In general, resistance to praziquantel has occasionally been suggested but rarely or not at all observed in travellers. From studies in regions in which Schistosoma mansoni is endemic, it usually appeared that although parasite resistance or tolerance to praziquantel could not be definitively excluded, poor cure rates after praziquantel were more likely to be due to high pre-treatment parasite burdens, high rates of re-infections, or schistosome immaturity.

Suramin (SED-14, 1042; SEDA-25, 373; SEDA-26, 350; SEDA-27, 331) Observational studies Suramin and human African trypanosomiasis Human African trypanosomiasis is a fatal disease that has reemerged in recent years; it is caused by Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. However, little progress has been made in the development of new drugs; most of the drugs still in use were developed one or more decades ago and are generally toxic and of limited effectiveness. Suramin, a symmetrical polysulfonated naphthylamine polyanionic compound was introduced in the 1920s and to this day remains the drug of choice for the early phase of Trypanosoma brucei rhodesiense infections (29R , 30R ). The trypanocidal action of suramin is slow. It is given by slow intravenous injection. Subcutaneous or intramuscular injections are not recommended, because they cause local inflammation and necrosis. Because of its poor central nervous system penetration, suramin is not effective in late-stage trypanosomiasis, although it has been used in pre-treatment to reduce the toxicity of melarsoprol or to sterilize patients until they reach hospital, where melarsoprol will be given. Immediate life-threatening adverse effects include

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collapse, with nausea, vomiting and shock. Severe delayed reactions include renal damage, particularly in malnourished patients, exfoliative dermatitis, agranulocytosis, hemolytic anemia, jaundice, and severe diarrhea, all of which can be fatal. Polyneuropathy and stomatitis have also been described. A test dose of 200 mg is sometimes recommended to prevent idiosyncratic reactions. Trypanosomal resistance to suramin has not been a serious problem, even after 80 years of treating trypanosomiasis with this drug. Suramin and bladder cancer Intravesical suramin once weekly for 6 weeks has been studied in nine patients with histologically proven transitional cell carcinoma (31C ). The dose was slowly increased from 18 to 36 800 mg in 60 ml of fluid. Plasma suramin concentrations after treatment were 2–38 µg/ml and were not related to dose. Complications included self-limiting bladder irritation in four of 54 treatments, bladder spasm in four, and new or worsening vesicoureteral reflux in three. Another patient had bladder spasm, skin flushing, and fever. These symptoms resolved within 48 hours and did not recur after five subsequent treatments. An intravesical dose of 9180 mg/in 60 ml was defined as safe, with acceptable plasma concentrations and minimal adverse effects. Suramin and lung cancer The properties of low-dose suramin every 3 weeks as a chemosensitizer have been evaluated in a phase 1 study in 15 patients with advanced non-small cell lung cancer (32C ). The patients received 85 courses of suramin followed by paclitaxel (175–200 mg/m2 ) and carboplatin (AUC of 6 minutes.mg/ ml). The initial dose of suramin was 240 mg/m2 , and the doses for subsequent cycles were calculated based on the 72-hour pretreatment plasma

353 concentrations. The most common adverse effects were neutropenia (31 courses resulted in grade 3 neutropenia and 30 courses resulted in grade 4 neutropenia lasting for less than 5 days and never associated with neutropenic fever), nausea/vomiting grade 3 (after one course), malaise/fatigue grade 3 (after 13 courses), grade 3 peripheral neuropathy (after one course), grade 3 hypersensitivity/rash (after one course), and grade 3 diarrhea (after one course). There were no cases of adrenal dysfunction or episodes of sepsis. Dividing the suramin dose to be administered into two doses 24 hours apart yielded the target concentrations and avoided undesirable peak concentrations. There was discernible antitumor activity in seven of 10 patients with measurable disease, including two with prior chemotherapy. The median time to tumor progression was 8.5 months. The authors concluded that low-dose suramin does not increase the toxicity of the combination of paclitaxel + carboplatin. Nervous system Guillain–Barré syndrome has been attributed to suramin. • A 37-year-old woman with a poorly differentiated metastatic pulmonary adenocarcinoma developed Guillain–Barré syndrome after receiving suramin + interferon alfa (33A ). She received 2 cycles of intravenous immunoglobulin and her flaccid tetraparesis remitted over a few weeks.

Although treatment with suramin may be associated with a Guillain–Barré type of sensorimotor neuropathy, interferon was considered the most likely cause in this case, given the simultaneous existence of autoimmune liver disease, hematological changes, and autoantibodies.

REFERENCES 1. Gao J, Liu Y, Wang X, Hu P. Triclabendazole in the treatment of Paragonimiasis skrjabini. Chin Med J 2003; 116: 168–6. 2. Sirivichayakul C, Pojjaroen-Anant C, Wisetsing P, Praevanit R, Chanthavanich P, Limkittikul K. The effectiveness of 3, 5 or 7 days of albendazole for the treatment of Trichuris trichiura infection. Ann Trop Med Parasitol 2003; 97: 847–53.

3. Smego RA, Bhatti S, Khaliq AA, Beg MA. Percutaneous aspiration–injection–reaspiration drainage plus albendazole or mebendazole for hepatic cystic echinococcosis: a meta-analysis. Clin Infect Dis 2003; 37: 1073–83. 4. Escobedo AA, Canete R, Gonzalez ME, Pareja A, Cimerman S, Almirall P. A randomized trial comparing mebendazole and secnidazole for the

354 treatment of giardiasis. Ann Trop Med Parasitol 2003; 97: 499–504. 5. Kalra V, Dua T, Kumar V. Efficacy of albendazole and short-course dexamethasone treatment in children with 1 or 2 ring-enhancing lesions of neurocysticercosis: a randomized controlled trial. J Pediatr 2003; 143: 111–14. 6. Singhi P, Dayal D, Khanderwal N. One week versus four weeks of albendazole therapy for neurocysticercosis in children: a randomized, placebocontrolled double blind trial. Pediatr Infect Dis J 2003; 22: 268–72. 7. Namazi MR. Treatment of pediculosis capitis with thiabendazole: a pilot study. Int J Dermatol 2003; 42: 973–6. 8. Chen KT, Twu SJ, Chang HJ, Lin RS. Outbreak of Stevens–Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan. Am J Public Health 2003; 93: 489–92. 9. Diav-Citrin O, Shechtman S, Arnon J, Lubart I, Ornoy A. Pregnancy outcome after gestational exposure to mebendazole: a prospective controlled cohort study. Am J Obstet Gynecol 2003; 188: 282– 5. 10. Gyapong JO, Chinbuah MA, Gyapong M. Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic filariasis. Trop Med Int Health 2003; 8: 1093–101. 11. Johnson-Reagan L, Bahna SL. Severe drug rashes in three siblings simultaneously. Allergy 2003; 58: 445–7. 12. Montresor A, Awasthi S, Crompton DWT. Use of benzimidazoles in children younger than 24 months for the treatment of soil-transmitted helminthiasis. Acta Trop 2003; 86: 223–32. 13. Montresor A, Stolzfus RJ, Albonico M, Tielsch JM, Rice A, Chwaya HM, Savioli L. Is the exclusion of children under 24 months from anthelminthic treatment justifiable? Trans R Soc Trop Med Hyg 2002; 96: 197–9. 14. McLaughlin SI, Radday J, Michel MC, Addiss DG, Beach MJ, Lammie PJ, Lammie L, Rheingans R, Lafontant J. Frequency, severity and costs of adverse reactions following mass treatment for lymphatic filariasis using diethylcarbamazine and albendazole in Leogane, Haiti, 2000. Am J Trop Med Hyg 2003; 68: 568–73. 15. Twum-Danso NA, Meredith SEO. Variation in incidence of serious adverse events after onchocerciasis treatment with ivermectin in areas of Cameroon co-endemic for loiasis. Trop Med Int Health 2003; 8: 820–31. 16. Oyibo WA, Fagbento-Beyioku AF. Adverse reactions following annual ivermectin treatment of onchocerciasis in Nigeria. Int J Infect Dis 2003; 7: 156–9. 17. Kipp W, Bamhuhiiga J, Rubaale T, Buttner DW. Adverse reactions to ivermectin treatment in Simulium neavei-transmitted onchocerciasis. Am J Trop Med Hyg 2003; 69: 621–3. 18. Ohtaki N, Taniguchi H, Ohtomo H. Oral ivermectin treatment in two cases of scabies: effective

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in crusted scabies induced by corticosteroid but ineffective in nail scabies. J Dermatol 2003; 30: 411–16. 19. Awadzi K, Edwards G, Duke BOL, Opoku NO, Attah SK, Addy ET, Ardrey AE, Quartey BT. The co-administration of ivermectin and albendazole— safety, pharmacokinetics and efficacy against Onchocerca volvulus. Ann Trop Med Parasitol 2003; 97: 165–78. 20. Cascinu S, Catalano V, Piga A, Mattioli R, Marcellini M, Pancotti A, Bascioni R, Torresi U, Silva RR, Pieroni V, Giorgi, Catalano G, Cellerino R. The role of levamisole in the adjuvant treatment of stage III colon cancer patients: a randomized trial of 5-fluorouracil and levamisole versus 5-fluorouracil alone. Cancer Invest 2003; 21: 701–7. 21. Cafiero F, Gipponi M, Lionetto R and the PAR Cooperative Study Group. Randomised clinical trial of adjuvant postoperative RT vs. sequential postoperative RT plus 5-FU and levamisole in patients with stage II–III resectable rectal cancer: a final report. J Surg Oncol 2003; 83: 140–6. 22. Hodson EM. The management of idiopathic nephrotic syndrome in children. Pediatr Drugs 2003; 5: 335–49. 23. Cotreau MM, Warren S, Ryan JL, Fleckenstein L, Vanapalli SR, Brown KR, Rock D, Chen CY, Schwertschlag US. The antiparasitic moxidectin: safety, tolerability and pharmacokinetics in humans. J Clin Pharmacol 2003; 43: 1108–15. 24. N’Goran EK, Gnaka HN, Tanner M, Utzinger J. Efficacy and side-effects of two praziquantel treatments against Schistosoma haematobium infection, among schoolchildren from Côte d’Ivoire. Ann Trop Med Parasitol 2003; 97: 37–51. 25. Ohnishi K, Kato Y. Single low-dose treatment with praziquantel for Diphyllobothrium nihonkaiense infections. Intern Med 2003; 42: 41–3. 26. Ferrari MLA, Coelho PMZ, Antunes CMF, Tavares CAP, Da Cunha AS. Efficacy of oxamniquine and praziquantel in the treatment of Schistosoma mansoni infection: a controlled trial. Bull WHO 2003; 81: 190–6. 27. Olds GR. Administration of praziquantel to pregnant and lactating women. Acta Trop 2003; 86: 185–95. 28. Lawn SD, Lucas SB, Chiodini PL. Case report: Schistosoma mansoni infection: failure of standard treatment with praziquantel in a returned traveller. Trans R Soc Trop Med Hyg 2003; 97: 100–1. 29. Fairlamb AH. Chemotherapy of human African trypanosomiasis: current and future prospects. Trends Parasitol 2003; 19: 488–94. 30. Docampo R, Moreno SNJ. Current chemotherapy of human African trypanosomiasis. Parasitol Res 2003; 90: S10–13. 31. Uchio EM, Linehan WM, Figg WD, Walther MM. A phase I study of intravesical suramin for the treatment of superficial transitional cell carcinoma of the bladder. J Urol 2003; 169: 357–60. 32. Villalona-Calero MA, Wientjes MG, Otterson GA, Kanter S, Young D, Murgo AJ, Fischer B, DeHoff C, Chen D. Yeh TK, Song SH, Grever M, Au JLS. Phase I study of low-dose suramin as

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a chemosensitizer in patients with advanced nonsmall cell lung cancer. Clin Cancer Res 2003; 9: 3303–11. 33. Bachmann T, Koetter KP, Muhler J, Fuhrmeister U, Seidel G. Guillain-Barré syndrome after

355 simultaneous therapy with suramin and interferonalpha. Eur J Neurol 2003; 10: 599.

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32 Editor’s note: Abbreviations used in this chapter include: • BCG: Bacillus Calmette–Guérin • DTaP: Diphtheria + tetanus toxoids + acellular pertussis • DTaP-Hib-IPV: Diphtheria + tetanus toxoids + acellular pertussis + IPV + Hib • DTwP: Diphtheria + tetanus toxoids + whole cell pertussis • HB vaccine: Hepatitis B vaccine • HbOC (also called PRP-CRM): conjugated Hib vaccine (Hib capsular antigen polyribosylphosphate covalently linked to the nontoxic diphtheria toxin variant CRM197) • Hib: Hemophilus influenzae type b • JE vaccine: Japanese encephalitis vaccine • MMR: measles + mumps + rubella • PRP-D-Hib: conjugated Hib vaccine (Hib capsular antigen polyribosylphosphate covalently linked to a mutant polypeptide of diphtheria toxin) • SV40: Simian virus 40 • Td: Diphtheria + tetanus toxoids (adult formulation)

Surveillance of adverse events following immunization Standardized case definitions The Brighton collaboration (1S ) was launched in 2000 as a voluntary international organization to facilitate the development, evaluation, and dissemination of high-quality information about the safety of vaccines. As its first task, the Collaboration focused on harmonization and standardization of case definitions of adverse events following immunization (AEFI). The case definitions could © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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Vaccines be useful worldwide for clinical trials, epidemiological studies and post-marketing surveillance (2r , 3r ). The first six standardized case definitions have been developed: fever (4S ), generalized convulsive seizure (5S ), hypotonichyporesponsive episodes (HHE) (6S ), intussusception (7S ), nodule at injection site (8S ), and persistent crying (9S ). New working groups have already been formed or will soon be formed on: allergic reactions, chronic fatigue syndrome, idiopathic thrombocytopenia, myalgia, paresthesia, rash, and smallpox vaccineassociated AEFI (2r , 3r ). Large linked databases Combining administrative databases for pharmacovigilance purposes became possible in the 1980s with increased automation of pharmacy prescriptions and medical outcome records. These combined databases were referred to as “large linked databases” (LLDBs) because of their relatively large size (storing details about millions of patients) and the need for linkage of different data sets that were created separately from each other. Such databases became popular in vaccine safety surveillance. Their most obvious advantage is the ability to study rare events. The rarity of an event that can be studied depends on the size of population and the level of immunization coverage. Owing to the rarity of intussusception (25 per 100 000 infants per year) and the relatively low prevalence of rotavirus immunization (less than 20%), a cohort study of rotavirus vaccine and intussusception required the participation of 10 Health Maintenance Organizations, with a combined population of over 460 000 infants 1–11 months of age. The use of large linked databases is most advanced in the UK and the USA and the opportunities and hazards that they afford have been reviewed (10R ).

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The safety of thiomersal-containing vaccines A WHO consultation on thiomersal (thimerosal) in vaccines from the regulatory perspective was held in 2002 (11S ). The main conclusions were as follows: • recommendations for the removal of thiomersal developed by health authorities are mainly driven by public perceptions of risk and not by any scientific evidence of toxicity; • limits for chronic exposure to methyl mercury derivatives from food should not be used to set limits for acute exposure to ethyl mercury derivatives (for example thiomersal) that can occur through immunization; • making changes to the thiomersal content of vaccines already licensed to include thiomersal is a complex issue that requires careful consideration; any change in a formulation could have a serious impact on the quality, safety, and efficacy of vaccines and should be considered on a case-by-case basis; generally, products whose formulation changes are considered as new products and may require clinical trials. In 2003, the Global Advisory Committee on Vaccine Safety (GACVS) noted that there is insufficient evidence to reach definite conclusions regarding the safety of thiomersal-containing vaccines in groups that may be at special risk, notably malnourished infants and preterm or low-birth-weight neonates. The GACVS reported to WHO that there is no scientific basis for changing current WHO recommendations for thiomersal-containing vaccines, including administration of a birth dose of hepatitis B vaccine and immunization of low-birth-weight infants when indicated (12S ). In a review of the safety of thiomersal in vaccines Clements stated that generally thiomersal has been convincingly shown to be safe (13R ). However, the scientific evidence is not sufficiently strong to provide the same level of assurance for thiomersal-containing vaccines for use in pregnant women or premature or lowbirth-weight infants. The fetal brain is more sensitive to mercury, whether ethyl mercury or methyl mercury, and it is at least possible that premature infants of very low birth weights may be at increased risk from thiomersal-containing

vaccines. Until scientific evidence is available, thiomersal-free products of hepatitis B vaccine are to be preferred for the dose that is given at birth. Reactogenicity of aluminium-containing vaccines A meta-analysis has compared the reactogenicity of vaccines containing aluminium hydroxide versus vaccines without adjuvants in children aged up to 18 months, and vaccines containing different types of aluminium versus vaccines without adjuvants in children aged 10–16 years (14M ). In young children, vaccines containing adjuvants caused significantly more erythema and induration than plain vaccines (OR = 1.87; 95% CI = 1.57, 2.24) and significantly fewer reactions of all types (OR = 0.21; 0.15, 0.28). In older children, there was no association between exposure to aluminiumcontaining vaccines and the onset of local reactions or a raised temperature, but there was an association with local pain lasting up to 14 days (OR = 2.05; CI = 1.25, 3.38). The authors found no evidence that aluminium salts in vaccines cause any serious or long-lasting adverse effects.

BACTERIAL VACCINES Anthrax vaccine

(SEDA-25, 378;

SEDA-26, 354) The authors of an extremely controversial review of anthrax vaccine concluded that the vaccine has not been shown to be safe or effective and accused the US Department of Defense of having withheld reports on vaccine-related adverse events and criticized the Food and Drug Administration (FDA) for not properly performing many of its oversight duties (15R ). Sensory systems Optic neuritis has been attributed to anthrax vaccine. • Two patients, aged 23 and 39 years, developed acute optic neuritis 2 weeks and 1 month after anthrax booster immunizations. The first had excellent visual recovery, but the second required chronic immunosuppression to maintain his vision (16A ).

358 Pregnancy A recent study was designed to determine whether military’s women’s pregnancy rates were affected by having been immunized with anthrax vaccine (17c ). The pregnancy rate ratio, birth odds ratio, and adverse birth outcomes ratio of 385 women was comparable with non-immunized women.

Bacille Calmette-Guérin (BCG) vaccine (SED-14, 1056; SEDA-25, 380; SEDA-26, 355; SEDA-27, 337) Drug administration route The intravesical instillation of BCG is the treatment of choice for recurrent superficial transitional cell carcinoma of the bladder, and BCG instillation is said to be effective for carcinoma in situ. Overviews, case reports, and case series have confirmed the efficacy of BCG and have described the resulting adverse effects (SED-14, 1064; SEDA-25, 380; SEDA-26, 355; SEDA27, 337). • In a 77-year-old patient BCG ileitis followed BCG instillation to treat recurrent bladder carcinoma (18A ). The abnormal part of the terminal ileum was resected, and two years after surgery the patient was well and with no evidence of neoplastic disease.

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All participating children received three doses of Hib vaccine at 4, 6, and 14–18 months of age, either PRP-D-Hib vaccine (children with an odd day of birth) or HbOC vaccine (children with an even day of birth). All cases of childhood leukemia diagnosed in Finland were taken from the Finnish Cancer Registry. A total of 80 cases of leukemia were diagnosed from birth to age 12 years among children born during the trial period. There were 35 cases among children born on an odd date and 45 among those born on an even date. This corresponds to a relative risk of 1.14 (95% CI = 0.63, 2.08) for subjects in the HbOC vaccine group. There were 69 cases of acute lymphoblastic leukemias, of which 30 were in the cohort of children born on an odd date, and 39 in the cohort born on an even date. There was no suggestion of different risks of childhood leukemia among Finnish children who received either PRP-DHib or HbOC vaccine. The authors concluded that the results of their study could be taken to suggest that the studies mentioned above did not show a causal relation, i.e. lack of protective effect of Hib immunization against childhood leukemia (22C ).

Lyme disease vaccine

(SEDA-24, 366;

SEDA-25, 380; SEDA-26, 357)

Hemophilus influenzae type b (Hib) vaccine (SED-14, 1065; SEDA-23, 337; SEDA-24, 365; SEDA-25, 381) Tumorigenicity The results of a large casecontrol study in the USA in 1999 raised the possibility that conjugate vaccine against Hemophilus influenzae type b was inversely associated with the risk of childhood leukemia (19C ). In 2000, re-analysis of data from an earlier trial in Finland suggested a non-significant protective effect of early versus late administration of a Hib conjugate vaccine (20C ). A further re-analysis of data from a nationwide immunization trial in Finland in the 1980s (21C ) was recently used to study the incidence of childhood leukemia in Hib-immunized children. In the 1980s, all 125 129 children born in Finland between 1 September 1987 and 31 August 1989 were enrolled, with a participation rate of 94%.

In December 1998, the first Lyme disease vaccine (LYMErix, manufactured by SmithKline Beecham) was licensed by the Food and Drug Administration (FDA). In the 1990s, suspicions were expressed that LYMErix could cause an incurable form of autoimmune arthritis. Poor sales resulted from the promotion of concerns and public misconceptions, and in early 2002 the vaccine was withdrawn from the market by the manufacturer. Reports collected through the Vaccine Adverse Events Reporting System (VAERS) from December 1998 to October 2000 have been analysed to examine adverse reactions (arthritis, neuropathy, convulsions, thrombocytopenia, lymphadenopathy, flu-like syndrome, alopecia, gastrointestinal disease, and paralysis) after Lyme immunization in the adult population of the USA. Statistical methods were used to determine whether the increased incidence rates of serious adverse reactions achieved statistical significance over

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Chapter 32 Table 1. Adverse reactions after Lyme vaccine compared with Td vaccine

Type of reaction

Incidence per million Lyme vaccine doses

Incidence per million Td doses

Relative risk

Attributable risk

Percent association

Statistical significance (P value)

Chronic arthritis Arthritis Gastrointestinal disease Chronic gastrointestinal disease Flu-like syndrome Alopecia Thrombocytopenia Chronic paralysis Paralysis Chronic neuropathy Neuropathy Chronic lymphadenopathy Lymphadenopathy Convulsions

16 27 3.6 2.1

0.054 0.22 0.039 0.023

296 123 92 91

295 122 91 90

99 99 99 99

<0.0001 <0.0001 <0.0001 <0.0001

64 1.4 2.1 1.4 2.9 2.1 5 2.1 7.1 2.9

1.0 0.39 0.070 0.054 0.12 0.12 0.36 0.18 2.2 1.2

98 97 97 97 96 95 93 92 76 70

<0.0001 NS <0.0001 NS <0.0001 <0.0001 <0.0001 <0.0001 <0.00005 NS

those reactions that were reported after Td and rubella immunizations in adults. Table 1 shows the increases in both acute and chronic adverse reactions after Lyme vaccine compared with Td vaccine (23C ). The authors also compared the incidence of arthritic reactions reported after Lyme immunization with those reported after adult rubella immunization, and found a statistical increase in the incidence of arthritic reactions after Lyme vaccine (RR = 3.4, attributable risk = 2.4, percent association = 77). There was also a statistical increase in the incidence of chronic arthritis after Lyme immunization compared with adult rubella immunization (RR = 4.8, attributable risk = 3.8, percent association = 83). Based on these results, the authors concluded that the withdrawal of Lyme vaccine from the market seems to have been justified (23C ).

Meningococcal vaccine (SED-14, 1080; SEDA-25, 389; SEDA-27, 337) Drug formulations Meningococcal diseases that occur worldwide are mainly caused by serogroups A, B, C, W135 , and Y. Bivalent and tetravalent polysaccharide vaccines against meningococcal diseases caused by Neisseria meningitidis serogroups A, C, W135 , and Y have been commercially available for several years, and have been considered to be safe

64 36 30 30 24 18 14 12 3.2 2.4

63 35 29 29 23 17 13 11 2.2 1.4

and effective. However, the vaccines suffer from drawbacks common to polysaccharide vaccines. These drawbacks have been overcome by conjugation of the polysaccharide immunogen to a protein. In addition to conjugated Hib and pneumococcal vaccines, conjugated meningococcal vaccines of serogroup C have been developed, licensed, and very effectively introduced in some national immunization programs. Other conjugated meningococcal vaccines, such as bivalent A/C vaccines and tetravalent A/C/W135 /Y vaccines, are currently being developed or are undergoing clinical trials. The development of a meningococcal serogroup B vaccine (either as polysaccharide or conjugated vaccine) is difficult and will take several more years. The safety and immunogenicity of a tetravalent (A/C/W135 /Y) diphtheria toxoid conjugate meningococcal vaccine in 89 healthy adults, 18–55 years old have been evaluated (24C ). A single dose containing 1, 4, or 10 micrograms of each serogroup was acceptably tolerated and immunogenic. One volunteer reported a severe local and systemic reaction after receiving 4 micrograms. The proportion of vaccinees with local reactions (mainly swelling, erythema) and/or systemic reactions (mainly headache and malaise) increased with increasing dose. The symptoms were most often rated as mild and resolved by the third day after immunization.

360 Simultaneous administration of meningococcal C conjugate vaccine and other routine childhood vaccines In a randomized, double-blind, controlled clinical trial 351 healthy 2-monthold infants were randomized to either meningococcal C conjugate vaccine or (as a control) hepatitis B vaccine (25C ). Simultaneously all infants received a pentavalent combination DTaPHib-IPV vaccine. DTaP-Hib-IPV vaccine was given at 2, 4, 6, and 15–18 months; meningitis C and hepatitis B vaccines were given at 2, 4, and 6 months or at 2, 4, and 15–18 months. The administration of meningitis C vaccine at the same time as the first four doses of DTaPHib-IPV vaccine did not adversely affect the antibody response to the antigens contained in either vaccine. All the vaccines were well tolerated. Local reactions at the injection site were significantly more commonly reported by recipients of meningitis C than recipients of hepatitis B. Injection site reactions in the limb injected with the pentavalent combination vaccine occurred at similar rates in those who were given meningitis C and hepatitis B, and generally at higher rates than in the limbs that had been injected with meningitis C and hepatitis B. Systemic reactions were also reported at similar rates; persistent crying was reported more often with the booster dose of meningitis C (in 3% of infants). Based on these results the Canadian National Advisory Committee on Immunization recommended that all Canadian infants be immunized simultaneously with meningitis C vaccine at 2, 4, and 6 months of age, at the same time that they receive DTaP-Hib-IPV. Cardiorespiratory complications (apnea, bradycardia) after DTwP immunization of preterm infants are well recognized. Similar events have been sought in 76 preterm infants after simultaneous administration of conjugated meningitis C and DTaP-Hib vaccines (26c , 27c ). The infants (mean gestational age 27 weeks mean birth weight 990 g) were immunized at a median age of 65 days and monitored for cardiorespiratory events for 24 hours before and after immunization. There was no significant increase in the number of events and serious events were not seen.

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Pertussis vaccine, acellular (including diphtheria–tetanus–acellular pertussis vaccine [DTaP]) (SED-14, 1083; SEDA-23, 340; SEDA-24, 369; SEDA-25, 381) A retrospective assessment among the population of the Group Health Cooperative from 1997 to 2000 confirmed the safety of DTaP vaccine (27C ). Administrative databases were used to identify medical visits linked with diagnostic codes indicative of injection site reactions, seizures, allergic responses, and febrile episodes after DTaP immunization. During the study 76 133 doses of DTaP were administered, mainly as the fourth or fifth immunization doses. There were 26 injection site reactions; four involved the entire upper arm but were self-limiting. Febrile seizures occurred in 1 per 19 496 immunizations. There was no evidence of allergic responses. The immune system is partly immature at birth, and therefore immunization schedules for the majority of childhood vaccines including pertussis vaccine do not recommend immunization before 2 months of age. However, the pertussis case fatality rate is highest in infants below 6 months of age. For this reason 45 infants were immunized at birth and at 3, 5, and 11 months of age (group 1) and compared with 46 infants who were immunized at 3, 5, and 11 months of age (group 2) with a trivalent acellular pertussis vaccine (genetically detoxified pertussis toxin, filamentous hemagglutinin, pertactine) (28C ). There were no adverse effects in children in the two groups. After the second dose of vaccine (administered at 3 months) the antibody titers of infants in group 1 were already similar to the titers achieved after the second dose (administered at 5 months) in infants in group 2. The authors concluded that immunization at birth may lead to earlier prevention of pertussis in infants under 6 months of age.

Pneumococcal vaccine (SED-14, 1086; SEDA-23, 343; SEDA-24, 371; SEDA-25, 384) The first heptavalent conjugate pneumococcal vaccine, Prevnar (containing polysaccharides of

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pneumococcal serotypes 4, 6B, 9V, 14, 19F, and 23F, and oligosaccharide of serotype 18C, conjugated to the protein carrier CRM197 , a non-toxic variant of diphtheria toxin), was licensed in the USA in 2000, and in all EU member states as well as in selected other countries in 2001. The efficacy, immunogenicity, and safety of conjugated pneumococcal vaccine have been evaluated in 1756 low birth weight infants (under 2500 g) and 4340 preterm infants (before 38 weeks) compared with infants of normal birth weight and infants born at full term (29C ). Vaccine efficacy was 100% in both groups. Fever and local events were similar when adjusted for clustering among multiple doses per child. After dose 3, there was more redness and swelling in infants of low birth weights and more swelling in preterm infants.

VIRAL VACCINES Herpes simplex virus vaccine Genital herpes infection is caused by Herpes simplex virus type 2 (HSV-2). The infection can be asymptomatic or severe, with painful skin lesions and complications. There have been two double-blind, randomized trials in volunteers whose sexual partners had genital herpes (study 1: 847 volunteers seronegative for Herpes simplex virus type 1 and type 2; study 2: 1867 volunteers of any Herpes simplex virus status) (30C ). The volunteers were randomized to receive a Herpes simplex virus type 2 glycoprotein-D subunit vaccine or placebo at 0, 1, and 6 months. There were follow-up visits, including serological analyses, over 19 months. The vaccine did not prevent infection with Herpes simplex virus type 2 in group 1, but was 74% effective in women who were seronegative for both Herpes simplex virus types 1 and 2. Adverse events were mainly limited to pain at the injection site. The use of condoms and antiviral agents to prevent Herpes simplex virus type 2 infection in sexual partners should still be emphasized.

Human papilloma virus vaccine (SEDA-26, 358; SEDA-27, 338) Cancer of the uterine cervix is the third most common cancer among women worldwide. Hu-

man papilloma virus types 16 (which can be detected in about 57% of tumor specimens) and type 18 (which can be detected in about 15% of tumor specimens) are thought to be responsible for all cases. Other types of human papilloma virus, such as types 31, 33, and 45, are also tumorigenic and, in addition to cervical cancer, are involved in the development of less common cancers (oropharyngeal, esophageal, penile, and anal cancers). Human papilloma virus types 6 and 11 are associated with benign anogenital warts. A vaccine that reduces the incidence of infection caused by human papilloma virus may therefore provide important health benefits. Various vaccines are currently under development or are undergoing trials. The results of a controlled trial with human papilloma virus type 16 vaccine developed by Merck Research Laboratories have been submitted (SEDA-27, 338; 31C ). A bivalent human papilloma virus vaccine including types 16 and 18, developed by MedImmune in collaboration with GlaxoSmithKline, has been studied in phase 1 and phase 2 trials. The phase 1 data demonstrated the safety of the vaccine and showed that it could induce the desired immune response and produce neutralizing antibodies. Results from phase 2 trials are awaited (32c ).

Influenza vaccine

(SED-14, 1072; SEDA-24, 375; SEDA-25, 386; SEDA-26, 358)

Oculorespiratory syndrome In 2000, oculorespiratory syndrome was identified as a new influenza vaccine-associated adverse effect in Canada. The case definition requires the presence of red eyes or respiratory symptoms or facial edema at 2–24 hours after immunization and lasting 48 hours (33c , 34c ). About 20% of vaccinees with oculorespiratory syndrome described the symptoms as mild and 42% described them as severe. The cause of oculorespiratory syndrome is debated, but the main hypothesis is that it is due to large viral aggregates in the vaccine. The reduction In the number of oculorespiratory syndrome reports in 2001–2 with the use of reformulated vaccines with lower aggregate content supports this hypothesis. The authors recommended that manufacturers should consider oculorespiratory

362 syndrome in order to improve the acceptance of influenza vaccines through limitation of the aggregate and unsplit virion content. Respiratory Pulmonary edema is a rare complication of influenza immunization. • Interstitial lung edema occurred 3 days after influenza immunization in a 67-year-old patient (35A ). An infectious cause was excluded and an allergic reaction was suspected. After antibiotic treatment and high-dosage glucocorticoids the patient recovered.

Nervous system The Vaccine Safety Committee of the Institute of Medicine (IOM), Academies of Science, reviewed the data on influenza vaccine and neurological conditions (36M ) and reached the following conclusions: • Studies that examined the association between the swine influenza vaccine campaign in 1976 and Guillain–Barré syndrome, including analysis and reanalysis of nationwide data and state-based studies, consistently showed an increased risk of Guillain–Barré syndrome in the immunized population. The evidence therefore favors acceptance of a causal relation between the 1976 swine influenza vaccine and Guillain–Barré syndrome in adults. • The Committee reviewed several population-based studies and a study of military personnel concerning the occurrence of Guillain–Barré syndrome after the use of influenza vaccines introduced after 1976. These studies differed in terms of their design, the case definitions for Guillain–Barré syndrome, the methods of ascertainment, the sizes of study populations, and the influenza seasons covered. The findings were mixed. The Committee concluded that the evidence that influenza vaccines other than the 1976 swine flu vaccine caused Guillain-Barré syndrome is inadequate to accept or reject a causal relation. • The Committee examined reports on epidemiological studies of relapses among patients with multiple sclerosis after influenza immunization; it separately examined a smaller set of reports concerning the risk of onset of multiple sclerosis. All the studies concerned influenza vaccines in various years, including the swine flu vaccines of 1976. The Committee concluded that the evidence favors rejection of a causal relation between influenza vaccines and relapse of Guillain–Barré syndrome in adults. Only one of the small set of studies on influenza immunization and the onset of multiple sclerosis provided a thorough description of the study methods and outcomes. This study found no increased risk for the onset of multiple sclerosis associated with influenza immunization, but in the absence of confirmation from other sources the Committee concluded that the evidence is inadequate to accept or reject a causal relation between influenza vaccines and multiple sclerosis in adults.

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• However, the biological mechanisms involved in the onset of multiple sclerosis are presumed to be related to those involved in relapse. With the data favoring the rejection of a causal relation between influenza vaccines and relapse of multiple sclerosis, the committee saw no reason to suspect that there might be a causal relation between influenza vaccines and the onset of multiple sclerosis. • With a single epidemiological study available (on optic neuritis) and several case reports mentioning the occurrence of other demyelinating neurological disorders (acute disseminated encephalomyelitis, transverse myelitis) after influenza immunization, the Committee concluded that the evidence is inadequate to accept or reject a causal relation between influenza vaccines and other demyelinating neurological disorders. • Based on the lack of published evidence on influenza vaccines and demyelinating neurological disorders in children, especially those aged 6–23 months, the Committee concluded that there is no evidence to support a causal relation between influenza vaccines and demyelinating neurological disorders in children aged 6–23 months.

Among 382 patients with Guillain–Barré syndrome after influenza vaccine to the Vaccine Adverse Events Reporting System (VAERS) database from 1991 through 1999 (37c ) there was a statistically significant increase in the incidence of Guillain–Barré syndrome after influenza immunization, compared with a Td vaccine control group. The overall mean incidence of Guillain–Barré syndrome was 0.95 per million influenza immunizations compared with 0.22 per million Td immunizations. However, in the report of the Vaccine Safety Committee on neurological complications after influenza vaccine mentioned above (36M ) it was concluded that the information from VAERS added little to the Committee’s ability to assess causality. Drug interactions Influenza immunization is often used in patients taking anticoagulants. In a case-control study 90 patients (88 taking warfarin and two taking acenocoumarol) were immunized with influenza vaccine; 45 non-immunized patients were used as controls (38C ). Influenza immunization caused significant prolongation of the prothrombin time within 7–10 days in 49 patients, and two had bleeding episodes. The authors concluded that the data supported the hypothesis of a potentially serious interaction between warfarin and influenza vaccine and recommended monitoring the International Normalized Ratio (INR) in patients taking anticoagulants during the immediate period after immunization.

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Table 2. GMT ratios healthy elderly vaccinees and in elderly vaccinees with chronic diseases

exception of China, where a live attenuated vaccine is used, all countries practising immunizaAntigen Healthy elderly Elderly vaccinees tion against Japanese encephalitis use formalininactivated mouse brain vaccines. The vaccine vaccinees with chronic diseases is generally well tolerated. Injection site reactions were reported in about 20%, and sysA/H3N2 antigen 1.18 1.43 temic adverse effects (fever, headache, malaise, B antigen 1.17 1.37 A/H1N1 antigen 1.10 1.17 rashes, chills, myalgia, gastrointestinal symptoms) in 5–10% of vaccinees. More serious adverse events fall into two categories: allergic and neurological. Hypersensitivity reactions Susceptibility factors Data on immunogenic(urticaria, angioedema, and bronchospasm) ity and safety from about 3500 individuals are reported at an incidence of 0.2–0.6 per (healthy elderly and elderly with underlying 1000 vaccinees. Most patients respond well to chronic diseases) immunized in 13 clinical anti-allergic treatment. Anaphylaxis can be lifetrials with either MF59-adjuvanted influenza threatening, and at least three deaths have been vaccine (n = 1890) or non-adjuvanted influenza attributed to the vaccine. vaccine (n = 1374) were analysed (39M ). On In children passive surveillance in Japan beday 28 the GMT ratios (adjuvanted versus tween 1965 and 1978 showed an incidence of non-adjuvanted vaccine) were as given in Ta- neurological complications (encephalitis, enble 2. Local and systemic reactions were more cephalopathy, convulsions, peripheral neuropacommon in those who received the adjuvanted thy, transverse myelitis) of 1.0–2.3 per million vaccine: pain at the injection site: 33% ver- vaccinees. Between 1992 and 1996, 16 cases sus 13%, erythema 18% versus 13%, induration of acute disseminated encephalomyelitis were 15% versus 9%; malaise 6% versus 4%, myal- recognized in Japan, South Korea, and Dengia 8% versus 3%, headache 6% versus 4%. mark. The incidence in Japan was estimated to The reactions were mainly mild and transient, be below 11 per million vaccinees, but much and there were no serious reaction. higher in Denmark at 1 per 50 000–75 000 vaccinees. Some researchers suspect that the illness Drug administration route A cold-adapted, originates from mouse brain tissue. live, attenuated, trivalent influenza vaccine to New inactivated JE vaccines manufactured be administered by intranasal spray has been in Vero cells are in advanced preclinical or early licensed by the Food and drug Administra- clinical development. A new live attenuated tion (FDA) for children, adolescents, and adults vaccine that uses a reliable flavivirus (yellow aged 5–49 years. and its immunogenicity, ef- fever 17D) as a live vector is in early trials ficacy, and safety have been reviewed (40R ). and a single dose appears to be immunogenic Nasal congestion occurred in 7–11% of im- and well tolerated. Other approaches such as munized children and fever in 4%. Vomiting, vaccinia and avipox vectored vaccines, recomabdominal pain, and myalgia were rare. The re- binant subunit vaccines, have been taken into actions were usually self-limiting. In most pub- consideration (42R ). lished studies, there was no statistically significant difference between vaccine and placebo. The safety profile in adults is similar, except that in half of the studies a sore throat was re- Measles-mumps-rubella (MMR) ported in significantly more vaccine recipients vaccine (SED-14, 1078; SEDA-25, 387; (10–15%) than in controls. SEDA-26, 359; SEDA-27, 338)

Japanese encephalitis vaccine (SED-14, 1075; SEDA-23, 347; SEDA-26, 359) Current and future Japanese encephalitis (JE) vaccines have been reviewed (41R ). With the

MMR vaccine and autism The hypothesis that MMR vaccine can cause autism and Crohn’s disease, mainly suggested by Wakefield, has been discussed at length (SED-14, 1079; SEDA-25, 387; SEDA-26, 359;

364 SEDA-27, 338). Subsequently, it became known that Dr Wakefield was paid for a second study into whether children allegedly damaged by the MMR could sue. The MMR research was therefore compromised by a financial conflict of interests. The Editor of the Lancet concluded, “If we knew then what we know now, we certainly would not have published the part of the paper (43c ) that related to MMR” (44S ). In March 2004, 10 of the 12 authors of the article in question issued a “Retraction of an interpretation”. The authors made it clear that in this paper no causal link was established between MMR vaccine and autism, as the data were insufficient to prove the hypothesis (45S ). In 2004, the Vaccine Safety Committee of the Institute of Medicine of the US National Academies of Sciences published the Immunization Safety Review on Vaccines and Autism. The Committee examined the hypothesis that vaccines, specifically the MMR vaccine and thiomersal-containing vaccines, are causally associated with autism. The Committee concluded that the body of epidemiological evidence favors rejection of a causal relation between the MMR vaccine and autism as well as a causal relation between thiomersal-containing vaccines and autism. The Committee further found that potential biological mechanisms for vaccine-induced autism that have been generated to date are theoretical only. In addition, the Committee recommended that available funding for autism research be channelled to the most promising areas (46M ). The results of a retrospective study including 535 544 children aged 1–7 years who were immunized between November 1982 and June 1986 in Finland, based on linkage of individual MMR immunization data to a hospital discharge register, have been published (47C ). The numbers of cases of encephalitis and aseptic meningitis within a 3-month risk interval after immunization were compared with the estimated numbers of naturally occurring cases of encephalitis and aseptic meningitis during the subsequent 3-month interval. Changes in the overall number of hospitalizations because of autism and Crohn’s disease were also checked throughout the study period. Of the 535 544 immunized children, 199 were hospitalized with encephalitis, 161 with aseptic meningitis, and 352 with autistic disorders. In nine children with encephalitis and 10 with meningitis, the

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disease developed within 3 months of immunization, revealing no increased occurrence within this designated risk period. Furthermore, in eight of nine cases of encephalitis, a very short interval of 2 days or an interval exceeding 1 month between immunization and hospitalization makes an association with immunization unlikely. As with encephalitis, an association between immunization and meningitis occurring on day 2 or over 1 month after immunization is unlikely. No clustering of hospitalization for autism has been detected after immunization; none of the autistic children went into hospital because of Crohn’s disease. A study on MMR immunization and autism has been carried out in Denmark in all 537 303 children born in Denmark from 1991 to 1998. Using national registry data on autistic disorders, the investigators found no association between MMR immunization and a subsequent diagnosis of autism (RR = 0.92; 95% CI = 0.68, 1.24) or a related disorder (RR = 0.83; 95% CI = 0.65, 1.07). This national cohort study obviated the problems of selection bias and misclassification bias (48C ). In a case-control study of age at first MMR immunization in children with autism (n = 624) and children without (n = 1824), including children with regression in development, the overall distribution of ages at MMR immunization among children with autism was similar to that of matched control children (49C ). Most of the cases (71%) and control children (68%) were immunized at 12–17 months of age. Similar proportions of case and control children had been immunized before 18 or before 24 months of age. There were no significant associations for either of these age cutoffs in specific case subgroups, including those with evidence of developmental regression. One of the major reasons that measles occurred among bone marrow transplant recipients during an outbreak of measles in Brazil was that they had not been immunized. In Brazil, a 2-year interval between bone marrow transplantation and measles immunization was recommended. Following a study in 79 patients the investigators concluded that MMR immunization between 12 and 24 months after bone marrow transplantation is safe and will therefore be recommended at 15 months after transplantation. However, because the seroconversion rate to measles is only 46% (rubella

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91%), serology should be performed after immunization to confirm protection (50c ).

Parvovirus vaccine Parvovirus B19 usually causes a mild and selflimiting illness. However, it can cause a variety of more serious conditions in immune-deficient individuals and hydrops fetalis or abortion in pregnant women. A recombinant human parvovirus B19 vaccine has been developed and evaluated in a randomized, double-blind phase 1 trial In 24 parvovirus B19-seronegative adults, who received 2.5 or 25 micrograms at 0, 1, and 6 months. All developed neutralizing antibodies. Mild or moderate injection site pain was reported by 75–92%. Systemic reactions such as fever, headache, gastrointestinal symptoms, and fatigue occurred in 25–50% of volunteers. One volunteer reported severe fatigue for 6 days after the first immunization. The rate and intensity of adverse effects did not increase with vaccine dose or number of immunizations (51c ).

Poliomyelitis vaccine

(SED-14, 1087; SEDA-23, 352; SEDA-24, 378; SEDA-25, 389) Tumorigenicity Simian virus 40 (SV40) occurs naturally in some species of monkeys. Poliovaccine made in the 1950s could be contaminated, because rhesus monkey kidney cells were used in preparing the vaccine. After the discovery of SV40 in 1960 and the finding in 1961 that the virus can cause tumors in rodents, SV40 was completely removed from the seed strains of the vaccine virus in the early 1960s. However, possibly contaminated polio vaccines were used until at least 1963. Interest in SV40 has increased in recent years, because the virus was found in certain forms of cancer in humans, for instance mesotheliomas, brain and bone tumors, and more recently some types of non-Hodgkin’s lymphoma. It has not been determined that SV40 causes these cancers (52S ). In 2002, the Vaccine Safety Committee of the Institute of Medicine of the US Academies of Sciences, reviewed the epidemiological evidence of an association between exposure to

polio vaccines containing SV40 and the subsequent development of cancer (53M ). The available studies on cancer incidence, cancer mortality, and cancers after prenatal exposure to SV40-containing vaccines were reviewed. The committee concluded that • there is strong biological evidence that SV 40 is a transforming virus; • there is moderate biological evidence that SV40 exposure could lead to cancer in humans under natural conditions; • there is moderate biological evidence that SV40 exposure from the polio vaccine is related to SV40 in humans; • the evidence is inadequate to accept or reject a causal relation between SV40-containing polio vaccines and cancer.

Rotavirus vaccine (SED-14, 1091; SEDA-25, 390; SEDA-26, 360; SEDA-27, 338) Gastrointestinal RotaShield was a tetravalent rhesus-based rotavirus vaccine, which was linked to a rare bowel obstruction called intussusception in some children and was therefore withdrawn from the US immunization schedule in 1999 (SED-14, 1091; SEDA-23, 354; SEDA25, 390; SEDA-26, 360). The two frontrunners in the race to replace it are GlaxoSmithKline and Merck & Co. Both are currently testing their oral vaccine candidates (GSK human strains, Merck a mixture of cow and human strains) for safety and efficacy. GSK is conducting clinical trials in 60 000 children in Latin America. Both companies say their vaccines do not appear to cause intussusception (54r ). Meanwhile, the US National Institutes of Health (NIH) has licensed the rights of RotaShield to Minneapolis-based BIOVIRx, which hopes to eliminate the risk of intussusception and re-introduce the vaccine into the US market (55r ).

Smallpox vaccination (SEDA-25, 378; SEDA-26, 354; SEDA-27, 339) Taking into account the risk of conventional smallpox vaccines, various research institutions and producers have started to develop

366 new smallpox vaccines. In a phase 1 trial in 350 volunteers an investigational cell-cultured smallpox vaccine developed in a joint venture between Computer Science Corporation and Porton International has been evaluated. The vaccine induces fewer adverse effects than the historic Dryvax vaccine, and fever, lymphangitis, rash, fatigue, headache, and nausea were at least 8% less common (42c ).

Yellow fever vaccine (SED-14, 1097; SEDA-22, 354; SEDA-25, 391) In addition to seven cases of viscerotropic disease associated with yellow fever vaccine (previously called multiple organ system failure) reported in 2001 (SEDA-25, 391), two

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new suspected cases have been reported to the Vaccine Adverse Event Reporting System (VAERS) between 20 June 2001 and 31 August 2002. Both patients recovered. Since 1996, 12 cases have been reported worldwide, among them five occurred in people under 50 years of age. During the same period four new cases of suspected yellow fever vaccine-associated neurotropic disease (previously called postvaccinal encephalitis) have been reported to the VAERS. All four patients recovered. Encephalitis after yellow fever immunization has long been recognized as a vaccine-associated adverse event, but the incidence fell substantially with implementation of the seed-lot standardization process in 1945. Since then, 27 cases of yellow fever vaccine-associated neurotropic disease have been reported worldwide (56A ).

REFERENCES 1. The Brighton Collaboration. secretariat@ brightoncollaboration.org. 2. Bonhoeffer J, Heininger U. Standardized cases definitions of adverse events following immunization. Vaccine 2004; 22: 547–50. 3. Kohl KS, Bonhoeffer J, Chen R, Duclos P, Heijbel H, Heininger U, Loupi E. The Brighton Collaboration: enhancing comparability of vaccine safety data. Pharmacoepidemiol Drug Saf 2003; 12: 335– 40. 4. Marcy SM, Kohl KS, Dagan R, Nalin D, Blum M, Jones MC; Hansen J, Labadie J, Lee L, Martin BL, O’Brien K, Rothstein E, Vermeer P; The Brighton Collaboration Fever Working Group. Fever as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004; 22: 551– 6. Available online at www.sciencedirect.com. 5. Bonhoeffer J, Menkes J, Gold SM, de SouzaBrito G, Fisher MC, Halsey N, Vermeer P; The Brighton Collaboration Seizure Working Group. Generalized seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004; 22: 557–62. 6. Bonhoeffer J, Gold SM, Heijbel H, Vermeer P, Blumberg D, Braun M, De Souza-Brito G, Davis RL, Halperin S, Heininger U, Khuri-Bulos N, Menkes J, Nokleby H; The Brighton Collaboration HHE Working Group. Hypotonic-hyporesponsive episode (HHE) as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004; 22: 563–568.

7. Bines JE, Kohl KS, Gorster J, Zanardi LR, Davis RL, Hansen J, Murphy TM, Music S, Niu M, Varicchio F, Vermeer P, Wong EJC; The Brighton Collaboration Intussusception Working Group. Acute intussusception in infants and children as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004; 22: 569–74. 8. Rothstein E, Kohl KS, Ball L, Halperin SA, Halsey N, Hammer SJ, Heath PT, Hennig R, Kleppinger C, Labadie J, Varicchio F, Vermeer P, Walop W; The Brighton Collaboration Local Reaction Working Group. Nodule at injection site as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004; 22: 575–85. 9. Bonhoffer J, Vermeer P, Halperin S, Kempe A, Music S, Shindman J, Walop W; The Brighton Collaboration Persistent Crying Working Group. Persistent crying in infants and children as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004; 22: 586–91. 10. Verstraeten T, DeStefano F, Chen RT, Miller E. Vaccine safety surveillance using large linked databases: opportunities, hazards, and proposed guidelines. Expert Rev Vaccines 2003; 2: 21–9. 11. Knezevic I, Griffiths E, Reigel F, Dobbelaer R. Thiomersal in vaccines: a regulatory perspective. Meeting report on a WHO consultation, Geneva, April 15–16, 2002. Vaccine 2004; 22: 1836–41. 12. Global Advisory Committee on Vaccine Safety, 11–12 June, 2003. Weekly Epidemiol Rec 2003; 78: 284.

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13. Clements CJ. The evidence for the safety of thiomersal in newborns and infant vaccines. Vaccine 2004; 22: 1854–61. 14. Jefferson T, Rudin M, Di Pietrantonj C. Adverse events after immunization with aluminiumcontaining DTP vaccines: systematic review of evidence. Lancet Infect Dis 2004; 4: 84. 15. Nass M, Nicolson GL. The anthrax vaccine: historical review and current controversies. J Nutr Environ Med 2002; 12: 277–86. 16. Kerrison JB, Lounsbury D, Thirkill CE, Lane RG, Schatz MP, Engler RM. Optic neuritis after anthrax vaccination. Ophthalmology 2002; 109: 99–104. 17. Wiesen AR, Littell CT. Relationship between pre-pregnancy anthrax vaccination and pregnancy and birth outcomes among US army women. J Am Med Assoc 2002; 287: 1556–60. 18. Satgé D, Pommepuy I, Goburdhun J, Flejou J-F. Ulcerative terminal ileitis after BCG therapy for bladder. Histopathology 2002; 41: 266–8. 19. Groves FD, Gridley G, Wacholder S, Shu X-O, Robison LL, Linet MS. Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the United States. Br J Cancer 1999; 81: 175–8. 20. Auvinen A, Hakulinen T, Groves FD. Haemophilus influenzae type b vaccination and risk of childhood leukaemia in a vaccine trial in Finland. Br J Cancer 2000; 83: 956–8. 21. Peltola H, EskolaJ, Kayhty H, Takala AK, Makela PH. Clinical comparison of the Haemophilus influenzae type b polysaccharidediphtheria toxoid and the oligosaccharide-CRM197 protein vaccines in infancy. Arch Pediatr Adolesc Med 1994; 148: 620–5. 22. Groves F, Sinha D, Auvinen A. Haemophilus influenzae type b vaccine formulation and risk of childhood leukaemia. Br J Cancer 2002; 87: 511– 12. 23. Geier DA, Geier MR. Lyme vaccination safety. J Spirochetal Tick-borne Dis 2002; 9: 16–22. 24. Campbell JD, Edelman R, King Jr. JC, Papa T, Ryall R, Rennels MB. Safety, reactogenicity, and immunogenicity of a tetravalent meningococcal polysaccharide-diphtheria toxoid conjugate vaccine given to healthy adults. J Infect Dis 2002; 186: 1848–51. 25. Halperin SA, Mcdonald J, Samson L, Danzig L, Santos G, Izu A, Smith B, MacDonald N. Simultaneous administration of meningococcal C conjugate vaccine and diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophlus influenzae type b conjugate vaccine in children: a randomized double-blind study. Clin Invest Med 2002; 25: 243–51. 26. Slack MH, Schapira C, Thwaites RJ, Andrews N, Schapira D. Acellular pertussis and meningococcal C vaccines: cardiorespiratory events in pre-term infants. Eur J Pediatr 2003; 162: 436–7. 27. Jackson LA, Carste BA, Malais D, Froeschle J. Retrospective population-based assessment of medically-attended injection site reactions, seizures, allergic responses and febrile episodes after acellular pertussis vaccine combined with

367 diphtheria and tetanus toxoids. Pediatr Infect Dis J 2002; 21: 781–6. 28. Belloni C, De Silvestri A, Tinelli C, Avanzini MA, Marconi M, Strano F, Rondini G, Chirico G. Immunogenicity of a three-component acellular pertussis vaccine administered at birth. Pediatrics 2003; 111: 1042–5. 29. Shinefield H, Black S, Ray P, Fireman B, Schwalbe J, Lewis E. Efficacy, immunogenicity and safety of heptavalent pneumococcal conjugate vaccine in low birth weight and preterm infants. Pediatr Infect Dis J 2002; 21: 182–6. 30. Cole C. Vaccine prevents genital herpes in subgroup of women. J Fam Pract 2003; 52: 94–6. 31. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, Chiacchierini LM, Jansen KU. A controlled trial of a human papillomavirus type 16 vaccine. New Engl J Med 2002; 347: 1645– 51. 32. Billich A. HPV vaccine MedImmune/ GlaxoSmithKline. Curr Opin Invest Drugs 2003; 4: 210–13. 33. De Serres G, Grenier JL, Toth E, Menard S, Roussel R, Tremblay M, Douville Fradet M, Landry M, Robert Y, Skowronski DM. The clinical spectrum of the oculo-respiratory syndrome after influenza vaccination. Vaccine 2003; 21: 2354–61. 34. Skowronska DM, Strauss B, De Serres G, MacDonald D, Marion SA, Naus M, Patrick DM, Kendall P. Oculo-respiratory syndrome: a new influenza vaccine-associated adverse event? Clin Infect Dis 2003; 36: 705–13. 35. Franzen D, Schneider M, Karsten R, Von Eiff M. Interstitielles Lungenoedem nach Grippeschutzimpfung. Atemwegs Lungenkrankheiten 2003; 29: 86–8. 36. Immunization Safety Review Committee, Institute of Medicine, National Academies. Immunization Safety Review. Influenza Vaccines and Neurological Complications. Washington, DC: The National Academies Press, 2004. 37. Geier MR, Geier DA, Zahalsky AC. Influenza vaccination and Guillain–Barré syndrome. Clin Immunol 2003; 107: 116–21. 38. Paliani U, Gresele P. Significant potentiation of anticoagulation by flu vaccine during the season 2001–2002. J Haematol 2003; 88: 539–40. 39. Banzhoff A, Nacci P, Podda A. A new MF59adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases. Results from an immunogenicity meta-analysis. Gerontology 2003; 49: 177–84. 40. Zangwill KM. Cold-adapted, live attenuated intranasal influenza virus vaccine. Pediatr Infect Dis 2003; 22: 273–4. 41. Monath TP. Japanese encephalitis vaccines: current vaccines and further prospects. Curr Top Microbiol Immunol 2002; 267: 105–38. 42. Dynport smallpox vaccine shows fewer side effects than Dryvax in phase I study. Clin Infect Dis 2003; 36: News. 43. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies

368 SE, Walker-Smith JA. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998; 351: 637–41. 44. Horton R. The lessons of MMR. Lancet 2004; 363: 747–9. 45. Murch SH, Anthony A, Casson DH, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Valentine A, Davies SE, Walker-Smith JA. Retraction of an interpretation. Lancet 2004; 363: 750. 46. Immunization Safety Review Committee. Institute of Medicine, National Academies of Sciences. Vaccines and autism. Washington, DC: National Academies Press, 2004. http://NationalAcademies.org (accessed 20 July, 2004). 47. Mäkelä A, Nuorti JP, Peltola H. Neurologic disorders after measles–mumps–rubella vaccination. Pediatrics 2002; 110: 957–63. 48. Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfart J, Thorsen P, Olsen J, Melbye M. A population-based study of MMR and autism. New Engl J Med 2002; 347: 1477–82. 49. DeStefano F, Karapurkar Bhasin T, Thompson WW, Yeargin-Allsopp M, Boyle C. Age at first MMR vaccination in children with autism and school-matched control subjects: a populationbased study in Metropolitan Atlanta. Pediatrics 2004; 113: 259–66.

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50. Shaw PJ, Bleakley M Burges M. Safety of early immunization against measles/mumps/rubella after bone marrow transplantation. Blood 2002; 99: 3486. 51. Ballou WR, Reed JL, Young NS, Koenig S. Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59. J Infect Dis 2003; 187: 675–8. 52. Centers for Disease Control and Prevention (CDC), National Immunization Program. Simian virus 40 (SV40), poliovaccine, and cancer. Questions and Answers. htpp://www.cdc.gov/nip/ vacsafe/concerns/cancer/default.htm (accessed July 24, 2004). 53. Immunization Safety Review Committee of the Institute of Medicine, National Academies. Immunization Safety Review: SV40 contamination of poliovaccine and cancer. Washington, DC: The National Academies Press, 2002. 54. http://internationalrotavirus.com (accessed July 20, 2004). 55. Zimmerman R. Drug companies race to develop virus vaccine. Wall Street J 2004; June 30. 56. Adverse events associated with 17D-derived yellow fever vaccination—United States, 2001– 2002. Morbid Mortal Weekly Rep 2002; 51: 989– 93.

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Blood, blood components, plasma, and plasma products

ALBUMIN In reaction to the continuous debate about the safety of albumin (SEDA-27, 342), a metaanalysis of 79 randomized trials with a total of 4755 patients was performed and showed clinical benefit and reduced morbidity of albumin in a variety of clinical settings (1M ). In another retrospective analysis of discharge data relating to 19 578 US patients who underwent coronary artery bypass surgery and received different types of colloids in 1997 and 1998 albumin was associated with a lower mortality than nonprotein colloids (2C ). Furthermore, the Australian and New Zealand Intensive Care Society, the Institute for International Health of the University of Sydney and the Australian Red Cross Blood Service have initiated a prospective double blind randomized controlled trial of albumin versus saline for fluid resuscitation of critically ill patients in intensive care (3r ). Cardiovascular In a randomized comparison of albumin solution and saline used as plasma expanders following large-volume paracentesis, albumin was less likely to cause paracentesisinduced circulatory dysfunction (4c ).

ANTICOAGULANT PROTEINS Recombinant activated protein C, which has anti-inflammatory, anticoagulant and profibrinolytic properties, has been approved for the treatment of severe sepsis (5r , 6r ). The most common adverse effect, as expected, is bleeding (7R , 8M ). Activated protein C is therefore contraindicated in severe, life-threatening bleeding. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

When invasive surgery is required it should be performed 12 hours before starting activated protein C or at least 2 hours after withdrawal of activated protein C (7R ).

BLOOD TRANSFUSION Cardiovascular The administration of Solvent-Detergent (SD)-plasma during plasma exchange in the management of thrombotic thrombocytopenic purpura, is associated with risks of venous thromboembolism (9c ). Respiratory Transfusion-related acute lung injury (TRALI) is a mild to severe immunemediated reaction that occurs within 6 hours of transfusion of a blood component that contains anti-granulocyte antibodies, anti-HLA antibodies, or biologically active lipids of donor origin (10R ). Donors of blood products implicated in TRALI reactions are usually multiparous women (10R ). The symptoms are acute respiratory distress, acute pulmonary edema, hypotension, and fever. It is fatal in 6–10%. After transfusion reactions due to ABO mismatched erythrocyte transfusion, TRALI is the second most common cause of transfusion-related death (10R ). The incidence has been reported to range from 1/5000 to 1/1323, but several reports suggest that this is an underestimate (11R , 12C ). There are no known susceptibility factors, only a possible association with a poor clinical condition (10R ). Storage time of blood units also seems to play a role. A higher incidence of TRALI has been associated with relatively old platelet concentrates (12C ). In some countries preventive actions have been taken, such as exclusion of multiparous women from donation or exclusion of female blood from the manufacture of fresh frozen plasma.

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Immunologic Only a minor part of anaphylactic transfusion reactions is related to anti-IgA antibodies or anti-haptoglobin antibodies in the recipient. However, the cause of most of these reactions is still unknown (13R ). The highest incidence of anaphylactic reactions is observed during transfusion of platelet concentrates, followed by fresh frozen plasma (13R ). IgA-related anaphylactic reactions during transfusion are rare in patients with IgA deficiency and the presence of anti-IgA antibodies. Transfusion of washed erythrocytes, washed platelets, blood components collected from IgA-deficient donors, or IgA-depleted intravenous immunoglobulin may avoid these reactions. In urgent cases, slow controlled transfusion of conventional blood components can be considered (14R ). A hemolytic transfusion reaction after transfusion of erythrocytes was reported in a 37year-old multiparous woman, perhaps related to HLA antibodies, which are often found in multitransfused patients or in multiparous women, but seldom cause reactions (15A ). Infection risk In the UK, variant Creutzfeldt– Jakob disease (vCJD) has been reported in a patient who had received a blood transfusion from a donor who later died because of vCJD. The TSE Task Force of the World Federation of Hemophilia released a statement that it is reasonable to accept this as a possible case of blood transmission of vCJD. The risk of such transmission appears to be predominantly a risk in recipients of blood components collected in the UK (16S ). As a precautionary measure, depletion of leukocytes in all blood products has been introduced in several European countries, because the prion protein that is responsible for vCJD probably binds to leukocytes. In some countries anyone who has lived for 6 or more months in the UK from 1980 to 1996 is excluded from blood or plasma donation. Other diseases that have been reported to be transmitted via blood include tick-borne diseases, such as babesiosis (17R ) and West Nile Virus (18c ).

P.J.M. Vossebeld, P.F.W. Strengers, and W.G. van Aken

BLOOD SUBSTITUTES Hemoglobin-based oxygen carriers Perfluorocarbons Artificial oxygen carriers can be divided into two groups: modified hemoglobins (such as surface-modified hemoglobin, intramolecular cross-linked hemoglobin, polymerized hemoglobin or liposome-encapsulated hemoglobin) and perfluorocarbon-based products. Polymerized bovine hemoglobin (Hemopure® ) is only approved in South Africa for clinical use in the treatment of acute anemia to avoid the use of allogeneic blood during surgery (19R ). Although diaspirin cross-linked hemoglobin (DCLHb) has been used safely in elective surgery, there was increased mortality when it was used for early treatment of trauma patients; it is likely that increased vasoconstriction contributed. A randomized, double-blinded study with DCLHb versus packed erythrocytes in 181 non-cardiac surgery patients was stopped prematurely because of safety concerns, notably a relatively high incidence of pancreatitis (20C ). Other adverse effects were transient hemoglobinuria, jaundice, slightly increased blood pressure, and enzyme increases, as was also observed in earlier studies (20C , 21R , 22r ). Perfluorocarbon-based products may induce complement activation, reduced platelet counts, and mild flu-like symptoms with increased body temperature (SEDA-27, 342; 19R , 23R –26R ). Cardiovascular Low molecular weight hemoglobin can cause vasoconstriction and hypertension, mainly due to binding of nitric oxide (SEDA-27, 342). However liposomeencapsulated hemoglobin does probably not scavenge nitric oxide, because these relatively large particles are less able to penetrate the endothelium to bind nitric oxide (19R ). Liver Degradation of hemoglobin products to bilirubin may lead to transient jaundice (27r ). Immunologic Free hemoglobin carries risks of antigenicity, as normally hemoglobin is present within erythrocytes; products that contain free bovine hemoglobin carry even higher risks (19R ). Of 42 surgical patients who were treated with polymerized bovine hemoglobin

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(Hemopure® , HBOC-201), 23 developed IgG antibodies against polymerized bovine hemoglobin (25R ). Infection risk Bovine hemoglobin-containing products carry the risk of transmission of diseases, such as variant Creutzfeldt–Jakob disease (vCJD), the human form of bovine spongiform encephalopathy (BSE) (19R ). Hemoglobin-solutions can increase infection risks by providing an abundance of iron, necessary for growth of bacteria (19R ). Interference with diagnostic testing Hemoglobin-based oxygen carriers, especially hemoglobin vesicles, interfere with colorimetric and turbidimetric methods used for clinical laboratory testing, due to the absorption of light by hemoglobin; to avoid this interference, it is necessary to remove hemoglobin vesicles from serum samples by centrifugation (28E ).

PLASMA SUBSTITUTES (SEDA-14, 1145; SEDA-25, 406; SEDA-26, 374; SEDA-27, 353)

Etherified starches Urinary tract The risk of acute renal insufficiency associated with hydroxyethyl starch is well recognized. However, there are few systematic studies of this issue, and the results are conflicting. In an analysis of postoperative changes in renal function in 238 consecutive patients undergoing coronary artery bypass graft surgery, the use of hydroxyethyl starch was independently associated with a reduction in glomerular filtration rate on both postoperative days 3 and 5, with falls of 7.2 ml/minute/1.73 m2 on day 3 per unit of hydroxyethyl starch administered (95% CI = 1.7, 13), and 6.6 ml/minute/1.73 m2 on day 5 (95% CI = 1.2, 12) (29C ). However, the clinical implications of the modest fall in renal function are unclear from this relatively large study. Immunological Etherified starches, such as hydroxyethyl starch and pentastarch, occasionally cause non-IgE-mediated anaphylactic (i.e. anaphylactoid) reactions. One of their wide

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range of uses is prehydration, which reduces the risk of hypotension after spinal block preceding cesarean delivery. However, the possibility of allergic reactions cannot be discounted, as illustrated by the following case (30A ). • A 28-year-old nulliparous woman developed worsening pre-eclampsia at 28 weeks gestation. Her blood pressure was 187/92 mmHg despite oral atenolol 50 mg bd, and she was given felodipine 5 mg bd. However, her condition worsened, and a cesarean delivery was planned. She was given pentastarch 6% by infusion, and within 1 minute, after the administration of less than 20 ml, she developed moderate bronchospasm, erythema, and perfascial edema. Her blood pressure fell gradually to 100/77 mmHg and her oxygen saturation to 90%. Despite initial treatment with oxygen, ephedrine, and ranitidine, her edema increased and her blood pressure fell, with no change in oxygen saturation. She was given tranexamic acid 1500 mg, promethazine 25 mg, methylprednisolone 125 mg, aminophylline 240 mg, and ipratropium by inhalation; ephedrine was continued up to a maximum dose of 40 mg. She improved over the next 4 hours. The edema subsided after 10 hours.

The authors suggested that this is the first report of an allergic reaction to pentastarch during cesarean delivery.

Polygelines Immunologic Anaphylactoid reactions to plasma substitutes are associated with histamine release. The effects of three commonly used plasma substitutes on histamine release have been studied in 21 volunteers in a randomized, controlled study (31C ). A normovolemic hemodilution technique was used with hydroxyethyl starch (n = 6), human albumin (n = 6), and polygeline (n = 9). Histamine release was common in all three groups at 30 minutes (50– 78%) and up to 4 hours (late release reaction 67–83%) after the start of infusion. Histamine release is a well-known adverse effect of polygeline and, to a lesser extent of albumin, but the authors suggested that it was a novel finding for hydroxyethyl starch. Cross-reactivity between Haemaccel® and Gelofusine® , previously reported, has been reported again (32A ). • A 53-year-old man with insulin-dependent diabetes underwent a femoropopliteal bypass, during

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which he received Gelofusine uneventfully. A year later he had a below-knee amputation, after which he received Gelofusine for blood pressure support. Within 15 minutes he complained of throat tightness and a burning pain radiating to his chest. His blood pressure was 71/55 mmHg with a regular pulse of 105/minute and SpO2 of 92% with oxygen at 3 l/min via nasal spectacles. He responded well to adrenaline. Six weeks later he was tested for reactivity to Gelofusine by intradermal injection, with a positive response. He was also tested for reactivity to Haemaccel, with a similar result, suggesting cross-reactivity.

INTRAVENOUS IMMUNOGLOBULINS Intravenous immunoglobulins are licensed for a number of indications, such as replacement therapy in primary and secondary immune deficiencies, in children with AIDS and recurrent infections, in patients with idiopathic thrombocytopenic purpura, Guillain–Barré syndrome, and Kawasaki disease, and for allogeneic bone marrow transplantation. Intravenous immunoglobulins have been used with success in several other conditions, mainly autoimmune diseases, such as myasthenia gravis, dermatomyositis, multiple sclerosis, and multifocal motor neuropathy. Common adverse reactions are headache, chills, dizziness, fever, nausea, backache, rash, arthralgia, myalgia, pruritus, hypotension, diarrhea, dyspnea, and chest pain (33R , 34R , 35C , 36C ). These reactions are sometimes related to the rate of infusion (33R , 37C , 38C ) and can then be reduced or prevented by lowering the infusion rate. In the case of an underlying infection, administration of immunoglobulins can lead to febrile reactions, probably due to the formation of immune complexes (33R , 35C ). Immunoglobulin products for subcutaneous administration can be used in patients with poor venous access or in patients with severe adverse reactions after intravenous immunoglobulin (39r ). Subcutaneous immunoglobulin can cause local reactions at the infusion site. Cardiovascular Thromboembolic events can complicate the administration of intravenous immunoglobulins (33R , 40C , 41A –43A , 44c , 45r –47r ), such as myocardial infarction, stroke,

P.J.M. Vossebeld, P.F.W. Strengers, and W.G. van Aken

pulmonary embolism, and deep vein thrombosis. Risk factors are obesity, advanced age, immobilization, hypertension, diabetes mellitus, and a history of vascular disease or thrombosis (33R ). Stroke has been described in 16 patients, 15 of whom had recognized risk factors (40C ). These events appear to be related to hyperviscosity of the blood after intravenous immunoglobulin (33R , 44c ). This has been confirmed by analysis of blood viscosity after intravenous immunoglobulin infusion (44c , 48c ). Patients with high plasma concentrations of albumin and fibrinogen are considered to be more susceptible to thrombotic complications after intravenous immunoglobulin infusion (49c ). • A 54-year-old woman developed an acute severe headache, nausea, and difficulty in speech 1 day after receiving intravenous immunoglobulin (21 g) for isolated IgG1 deficiency (50A ). She had a transverse sinus thrombosis, at first considered to be a complication of intravenous immunoglobulin. However, she also had primary thrombocythemia, which is also known to cause headache and is associated with a risk of lateral sinus thrombosis.

Hypotension after treatment with intravenous immunoglobulin is rare and is due to the presence of IgG dimers in some immunoglobulin formulations (51R ). Nervous system Aseptic meningitis has been reported after intravenous immunoglobulin (33R , 34R , 52c ). The risk of aseptic meningitis is higher in patients with a history of migraine (33R ). Among 150 patients who received intravenous immunoglobulin 50, 250, or 500 mg/kg for allogeneic stem cell transplantation, two developed reversible aseptic meningitis (38C ). Sensory systems Annular crystalline keratopathy has been reported in a 6-year-old boy 1 year after treatment with intravenous immunoglobulin 400 mg/kg/day for pyoderma gangrenosum (53A ). Although pyoderma gangrenosum is associated with ocular complications, such as peripheral ulcerative keratitis, annular crystalline keratopathy has never been reported. Annular crystalline keratopathy has been associated with paraglobulinemia in monoclonal gammopathies, also occurring several months after immunoglobulin treatment. The authors suggested that the keratopathy could

Blood, blood components, plasma, and plasma products

have been related to exogenous hypergammaglobulinemia by intravenous immunoglobulin or is a previously unknown complication of pyoderma gangrenosum. Hematologic Transient neutropenia without infectious complications occurred after 20 of 22 infusions of high-dose intravenous immunoglobulin (0.4 g/kg/day for 1–5 days) (54c ). High-dose intravenous immunoglobulin has been used effectively in neonates with proven hemolytic disease of the newborn to reduce the need for exchange transfusion and thereby provide more safety (55M ). However, hemolytic anemia occurred in a 4-month-old girl with Kawasaki disease after intravenous immunoglobulin, reportedly because of anti-Rhesus (D) antibodies present in a specific batch (56r ), indicating the importance of recording batch numbers. The FDA has set limits for the amount of anti-D antibody in intravenous immunoglobulin products; in Europe this has not yet been done (57E ). Patients whose blood group is AB rhesus positive have a relatively higher risk of hemolytic anemia after intravenous immunoglobulin, even though current intravenous immunoglobulin products contain relatively small amounts of anti-A and anti-B antibodies (58r ). Urinary tract Some cases of acute renal insufficiency have been reported, mostly associated with intravenous immunoglobulin products containing sucrose as a stabilizer (33R , 34R , 59C ). Susceptible patients are those with renal insufficiency, diabetes mellitus, obesity, or dehydration, or who are of an advanced age and use nephrotoxic medications (60A ). • Acute renal insufficiency was attributed to intravenous immunoglobulin (35 g) in an overweight 74-year-old woman with diabetes mellitus who had taken nabumetone and furosemide for 2 weeks.

The authors suggested that it was unlikely that the 2.5% glucose stabilizer in this specific intravenous immunoglobulin product had been responsible. They observed an acute increase in colloid osmotic pressure and suggested that this increase was possibly caused by the macromolecular immunoglobulin itself (60A ). In all patients receiving immunoglobulin, good hydration is advised (33R ).

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• Myocarditis and acute renal insufficiency occurred in a 59-year-old woman with hypertension and idiopathic thrombocytopenic purpura, which was treated with intravenous immunoglobulin 110 g on the first day and 50 g on the second day (61A ). The immunoglobulin contained 2% glucose and glycine as stabilizers. • Acute renal insufficiency, probably related to intravascular hemolysis, occurred in a 50-year-old Rh(D)-positive woman with idiopathic thrombocytopenic purpura, treated with intravenous antiRhesus (D) immunoglobulin 50 micrograms/kg (62A ).

Immunologic Allergic reactions can occur in patients with IgA deficiency and antibodies against IgA. The content of IgA in intravenous immunoglobulin products varies. Even small quantities of IgA can cause an allergic reaction, especially in patients with IgE antibodies against IgA (33R ). Anaphylactic reactions occur rarely. In 13 508 infusions in patients who had previously received intravenous immunoglobulin without problems, there were no severe reactions and the authors questioned the need to have adrenaline at home for patients on home treatment (35C ).

Antithymocyte globulin Antithymocyte globulin is a polyclonal antibody directed against T lymphocyte surface antigens. It is used as an induction immunosuppressant and for treatment of acute rejection after transplantation. Major adverse effects include sensitization, fever, nausea, anaphylactic reactions, and higher incidences of cytomegalovirus and Epstein–Barr virus infections. Observational studies Antithymocyte globulin has recently been used to treat myelodysplastic syndrome. In a phase II trial eight anemic patients with myelodysplastic syndrome were treated with antithymocyte globulin 40 mg/kg/day over 4 days plus prednisone (63c ). The study was stopped early, according to a preset termination rule, because of lack of efficacy. Adverse effects included serum sickness (in all patients), transient neutropenia and thrombocytopenia, diarrhea, vomiting, and syncope with a generalized seizure.

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Respiratory Acute respiratory distress syndrome, a rare complication after kidney transplantation, was analysed in a retrospective analysis of the National Registry for EndStage Renal Disease in the USA (64c ). Acute respiratory distress syndrome was diagnosed in 86/42190 (0.2%) kidney recipients, a significantly higher rate than in the US population overall. Demographic factors, indications for transplantation, co-morbidities, antigen mismatch, cytomegalovirus status, and rejection did not correlate with the development of acute respiratory distress syndrome. Of immunosuppressive agents (for example antithymocyte globulin, azathioprine, ciclosporin, muromonab, mycophenolate mofetil, tacrolimus), only antithymocyte globulin was linked with an increased risk of acute respiratory distress syndrome (OR = 3.85; 95% CI = 1.36, 11). Subjects with graft failure were 2.70 (95% CI = 1.33, 5.52) times more likely to develop acute respiratory distress syndrome, and the 28-day mortality was 52%. The 3-year survival after kidney transplantation was 89% in those without acute respiratory distress syndrome compared with 58% in those with. Hematologic Antithymocyte globulin (n = 35) was compared with daclizumab (n = 10) as induction therapy after kidney transplantation. Adverse effects were comparable in the two groups, except for more thrombocytopenia in those who were given antithymocyte globulin. In 244 patients with kidney transplants, seven developed thrombocytopenia and six neutropenia; both recovered spontaneously (65c ). The effect of antithymocyte globulin on hemostasis was studied in 12 patients with hemopoietic stem cell transplants and compared with 10 controls (66c ). At 24 and 48 hours there were transient rises in the concentrations of D dimers, tissue factor, soluble thrombomodulin, and thrombin–antithrombin III complex, and a significant reduction in platelet count. There were no differences between the groups with regard to global coagulation tests or the incidence of bleeding manifestations, thromboembolic complications, or vascular-occlusive-disease of the liver. The phenomenon was named nonovert disseminated intravascular coagulation. Immunologic In a series of 244 recipients of cadaveric renal transplants, induction with

P.J.M. Vossebeld, P.F.W. Strengers, and W.G. van Aken

antithymocyte globulin 8.8 (2–23) mg/kg over 10 (2–21) infusions was tolerated without anaphylaxis (65c ). Additional immunosuppression consisted of glucocorticoids and azathioprine or mycophenolate mofetil, and in 231 patients a calcineurin inhibitor. The commonest adverse event was fever (55%). Serum sickness occurred in 18 patients on median day 11 (10–14). Infection risk In 244 patients with kidney transplants who received antithymocyte globulin 8.8 (2–23) mg/kg over 10 (2–21) infusions, there were 62 non-cytomegalovirus infections (two fatal) and 81 episodes of cytomegalovirus infection (65c ). Induction with antithymocyte globulin given as a single intraoperative bolus after kidney transplantation resulted in a higher infection rate than daclizumab (43% versus 10%) (67c ). Also, bacterial and viral infections were more common in patients who received antithymocyte globulin (69 and 23% versus 10 and 0% respectively). Despite identical 6 months actuarial patient and graft survival (both 100%), there were fewer bacterial and viral infections with daclizumab compared with antithymocyte globulin. Tumorigenicity The incidence of post-transplant lymphoproliferative disorders after monoclonal antilymphocyte antibody, polyclonal antilymphocyte antibody, interleukin-2 receptor antibody, or no induction therapy in primary kidney transplant recipients was investigated in a multivariate Cox analysis of 38 519 primary kidney transplants from 1997 to 2000. IL-2 receptor antibody induction was associated with the smallest risk of post-transplant lymphoproliferative disorders (Table 1) (68M ). In 257 patients after non-T cell depleted allogeneic stem cell transplantation, 19 (7.4%) developed post-transplant lymphoproliferative disorders (69c ). All 19 were Epstein–Barr viruspositive and had been given antithymocyte globulin either for the treatment of steroidresistant acute graft-versus-host disease, or as part of the conditioning. The German Aplastic Anemia Study Group reported 11-year results of the use of antithymocyte globulin, methylprednisolone, and ciclosporin for aplastic anemia (70C ). Of 84 patients, five developed paroxysmal nocturnal hematuria, four developed myelodysplastic syndrome or leukemia, and four developed solid

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Table 1. Incidence and increased risk of post-transplant lymphoproliferative disorders after kidney transplantation in relation to different induction regimens (68M ) Antibody

Number of patients

Incidence of post-transplant lymphoproliferative disorders

Increased risk

Monoclonal Polyclonal Anti-IL2 receptor No induction

2713 4343 7800 23663

0.85% 0.81% 0.50% 0.51%

72% (P = 0.03) 29% (P = 0.27) 14% (P = 0.52)

tumors. The actuarial probability of clonal or malignant diseases was 25%. Rare tumors can also occur during immunosuppressive therapy. Merkel cell carcinoma is a rare highly malignant tumor, thought to be of neuroendocrine origin. A patient developed Merkel cell carcinoma after treatment with antithymocyte globulin and ciclosporin for aplastic anemia (71A ). • A 79-year-old woman with aplastic anemia was treated with intravenous antithymocyte globulin 10 mg/kg/day over 5 days. Concurrent therapy consisted of methylprednisolone 2 mg/kg/day for 5 days, followed by a prednisolone taper schedule. After withdrawal of glucocorticoids, ciclosporin 150 mg/day was given. Three months later a subcutaneous Merkel cell carcinoma developed on the forehead. The tumor stained positive for chromogranin and negative for thyroid transcription factor-1 (TTF-1) and common lymphocyte antigen. Electron microscopy showed dense core neurosecretory granules. Ciclosporin was withdrawn. The excision margins were re-excised followed by radiation therapy. The disease progressed, with metastasis to the left cervical lymph nodes. She underwent a second course of radiation, and chemotherapy could not be performed because of hematological dysfunction. She died of multiorgan dissemination of Merkel cell carcinoma.

Drug dosage regimens After kidney transplantation, antithymocyte globulin is usually given on an in-patient basis. However, 18 patients received a total of 57 out-patient antithymocyte globulin infusions administered over 4–6 hours, with heparin 1000 U and hydrocortisone 20 mg to reduce the incidence of thrombosis and local tissue reactions (72c ). Of the 57 infusions, 52 were without complications and five were complicated by infiltrates. There were no serious reactions. Previous retrospective or non-randomized studies have suggested that intraoperative administration of polyclonal antithymocyte formulations can reduce the incidence of delayed

graft function after kidney transplantation, possibly by reducing ischemia-reperfusion injury. In 58 adult cadaveric renal transplant recipients randomized to intraoperative or postoperative thymoglobulin induction therapy 1 mg/kg intravenously, 3–6 doses were administered during the first week after transplantation (73c ). Additional immunosuppression consisted of tacrolimus (n = 54) or ciclosporin (n = 4), glucocorticoids, and mycophenolate mofetil. Intraoperative thymoglobulin was associated with significantly less delayed graft function and a lower mean serum creatinine on postoperative days 10 and 14, as well as a shorter length of stay after transplantation. The acute rejection rate was also lower in the intraoperative treatment group. There was no difference in the incidence of cytomegalovirus disease.

COAGULATION FACTORS Complications of treatment with coagulation factors include development of inhibitors (antibodies) against the factor, allergic reactions, thrombosis, and transmission of viral infections. Recombinant factor VIIa has been used effectively and safely in hemophilia patients with inhibitors. A number of reports have shown it to have excellent efficacy, but publication bias makes it difficult to judge its real value in controlling major bleeding in non-hemophilia patients. A retrospective study of 40 nonhemophilia patients treated with recombinant factor VIIa for uncontrollable bleeding showed an overall mortality of 58%; seven patients died of continued bleeding and most of the others died from the underlying disease, multiorgan failure, or sepsis. The authors suggested that it is possible that mortality was related to the use of recombinant factor VIIa and emphasized the need for controlled studies (74C ).

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Cardiovascular Problems such as thrombosis may be related to the use of a Port-A-Cath system, but it has been suggested that high dosages of coagulation factors may increase the risk (75R ). To arrest bleeding in hemophilia A with inhibitors or in acquired hemophilia due to antifactor VIII autoantibodies, the options are treatment with high-dose factor VIII, porcine factor VIII, activated prothrombin complex concentrate, or recombinant factor VIIa, all of which carry a risk of thrombosis (76R , 77R ). Recombinant factor VIIa is considered to be relatively safe, because it acts locally at the bleeding site. Since the approval of recombinant factor VIIa in 1996, more than 500 000 doses have been used and 24 cases of thrombosis have been reported (78R ). In most of these cases there were other risk factors, such as advanced age. Three of 40 patients treated with recombinant factor VIIa for uncontrollable bleeding developed thrombosis unrelated to dose; all three had susceptibility factors (74C , 79C ). Whereas low-purity factor IX products have been associated with thromboembolic events, high-purity factor IX is said to be rarely associated with such events (80S ). Hematologic Porcine factor VIII, used in the case of anti-factor VIII antibodies, can cause thrombocytopenia in 3–7% of cases, due to contamination with porcine Von Willebrand factor. The incidence of these reactions seems to be reduced when porcine factor VIII is given by continuous infusion (77R ). Liver Hemophilia patients infected with hepatitis B or C virus after treatment with nonvirus-inactivated coagulation factor may develop chronic hepatitis and more frequently hepatocellular carcinoma (81C ). Urinary tract Hemophilia B patients with factor IX inhibitors may develop nephrotic syndrome after immune tolerance therapy with factor IX (SEDA-25, 396). Skin In a prospective, multicenter, open study of 28 hemophilia B patients receiving continuous infusions of plasma-derived factor IX concentrate, irritation at the infusion site was the most common adverse event (82C ).

P.J.M. Vossebeld, P.F.W. Strengers, and W.G. van Aken

Immunologic Inhibitor development is due to the presence of antibodies against the coagulation factor. This complication is rare, but is more often seen in hemophilia A than in hemophilia B. The risk is not increased by the use of recombinant products or during prophylactic treatment. Genetic predisposition is probably the most important susceptibility factor (75R , 83R , 84R ). However, early prophylaxis, before the age of 6 months, is associated with an increased risk of inhibitor formation (75R ). Recombinant B-domain-deleted factor VIII (BDD-rFVIII) was developed because the Bdomain of factor VIII is not required for coagulant activity and is removed during naturally occurring activation of factor VIII. Different studies with BDD-rFVIII have shown that 1 out of 113 previously treated patients and 32 out of 101 previously untreated patients developed inhibitors (85C ). The authors suggested that these incidences are not different from those reported with other recombinant or plasma-derived factor VIII products. However, there was a higher prevalence of 6.1% in 49 previously treated patients with severe hemophilia in two centers in France (86r ). A retrospective analysis of 54 boys with mild hemophilia suggested that intensive exposure to factor VIII, for instance in the case of continuous infusion during surgery, is a susceptibility factor for inhibitor formation. Of 29 boys exposed to factor VIII, 16 received factor VIII for at least 6 consecutive days, seven by continuous infusion and nine by bolus injection; four boys, all receiving a continuous infusion, developed inhibitors (87c ). Prospective studies are required to investigate the association of continuous infusion with inhibitor development. Seven of 118 patients with congenital factor XI deficiency, treated with plasma infusion, developed inhibitors against factor XI (88C ). Anaphylactic reactions after administration of coagulation factors are rare. When they occur they may be associated with inhibitor development, especially in the case of factor IX inhibitors (75R , 89A ). In such cases, both prothrombin complex concentrate and activated prothrombin complex concentrate are usually contraindicated, but recombinant factor VIIa is an option for treatment. Immunological abnormalities have been suggested to be related to treatment with coagulation factor concentrates, probably also due to

Blood, blood components, plasma, and plasma products

viral infections, such as hepatitis B, hepatitis C, or cytomegalovirus (75R ). Infection risk Although the safety of plasmaderived coagulation concentrates has improved during the last 20 years, there is still a risk of parvovirus B19 transmission. Parvovirus B19 infections are mostly without clinical significance, but some clinically significant events have been reported (90R ). Although currently available coagulation products are safe regarding transmission of HIV, hepatitis B, and hepatitis C, new pathogens, such as transfusion-transmitted virus (TTV), variant Creutzfeld–Jacob disease (vCJD), and West Nile Virus, are being described risks (75R , 90R ). Current virus inactivation procedures used to manufacture plasma-derived blood products, such as pasteurization, vapor heating, solvent/detergent treatment, and low pH incubation, have been validated and shown to be effective in removing West Nile Virus (91E ). These procedures also contribute to reduction of prion proteins, the infectious agent of vCJD, if present in plasma (92E ). Recombinant products can also carry some risks of viral transmission, since first-generation products contain human albumin. Furthermore, contamination of cell cultures required to produce recombinant products, with different viruses is known (75R ). The risk of parvovirus B19 transmission was less when albumin-stabilized recombinant products were used instead of solvent-detergent treated high-purity factor VIII or factor IX concentrates (93C ). Patients with hemophilia have an increased prevalence of hepatitis G, which current virus inactivation procedures remove effectively. Of 37 vials of clotting factor concentrate, only vials treated by pasteurization, solvent detergent, or dry heat for 144 hours were negative for hepatitis G virus. Vapor heat treatment and dry heat treatment for less than 144 hours was not effective in removing hepatitis G virus (94E ). Although hepatitis G virus infections are mostly mild, a few cases of fulminant hepatitis probably associated with hepatitis G virus infection have been reported in the past. Body temperature Two episodes of fever occurred in one of three hemophilia patients with inhibitors who received a total of 114 large doses of recombinant factor VIIa (300 micrograms/kg) (95A ).

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Coagulation factor gene therapy Gene therapy is a promising treatment for hemophilia A, because even low amounts of factor VIII expression would reduce bleeding. One of the risks is carcinogenicity, due to insertional mutagenesis. Concern is increased by a report of two cases of leukemia in children who received gene therapy for severe immunodeficiency disease (92R ).

ERYTHROPOIETIN AND DERIVATIVES Recombinant erythropoietin (epoetin) is an effective treatment for both anemia induced by chronic renal failure and anemia in cancer patients. The most common adverse effect is a flulike illness. Hypertension occurs in about 30% of patients who start with intravenous treatment and less often after subcutaneous administration (96C , 97C , 98R ); it sometimes occurs in patients treated with higher doses of erythropoietin for chronic renal insufficiency, but is uncommon in anemic cancer patients. Extreme hypertension occurs only rarely (99A ). Thrombosis after erythropoietin has been described. Adverse effects as allergic reactions, seizures, hypertensive encephalopathy, hyperkalemia, and thrombocytosis are rare (100R ). Pain or erythema at the site of injection, mostly in case of subcutaneous administration, can occur (96C , 97C ). Fever is rare. Arthralgia has been observed (101R ). Drug-related adverse events of darbepoetin alfa, a derivative of erythropoietin with a prolonged half-life, are similar to those of epoetin (97C , 102R ). Erythropoietin derivatives are well established for use in anemia associated with cancer and various anticancer drugs. However, the finding of erythropoietin receptors on several malignant cells has suggested the need for caution when erythropoietin is used for anemia in cancer patients, because erythropoietin might enhance tumor proliferation (103R , 104R ). In a prospective study 240 patients undergoing primary or revision hip or knee arthroplasty were given erythropoietin, preoperative autologous transfusion, or both. Erythropoietin was well tolerated. There were only minor adverse effects, such as local skin irritation (in 64 of

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160 patients), constipation (in 43), pyrexia (in 15), and nausea (in 42) (105C ). Cardiovascular Erythropoietin can increase blood pressure. Several mechanisms have been postulated, such as increased blood viscosity, attenuation of hypoxic vasodilatation, direct vasoconstriction, activation of neurohumoral systems, including catecholamines, activation of the renin–angiotensin–aldosterone system, or altered concentrations of vasoactive substances, such as endothelin and nitric oxide. Involvement of the kidneys was excluded in a reported case of erythropoietin-induced hypertension in a nephrectomized patient (106A ). However in other cases of hypertension the kidneys may play a role. In 341 dialysis patients treated with darbepoetin alfa for anemia, there was one death due to a stroke in an 87-year-old man with a history of cardiac disease (96C ). This event was judged as being possibly related to darbepoetin alfa, as the hemoglobin concentration was increased at the time of death. Sensory systems An 82-year-old patient who had had implanted intraocular lenses in 1988 and bilateral laser capsulotomies in 1991, developed recurrent capsule opacities in 2001 (107A ). The authors suggested a relation to the use of a high dose of erythropoietin for myelodysplastic syndrome for 6 years. They proposed that erythropoietin increases cortical proliferation, because cells other than bone marrow cells also express erythropoietin receptors. Skin

Epoetin can cause skin reactions.

• A 65-year-old man with myelodysplastic syndrome was treated with recombinant epoetin (10 000 IU 3 times a week) for refractory anemia

P.J.M. Vossebeld, P.F.W. Strengers, and W.G. van Aken (108A ). After 3 months, he developed a papular neutrophilic dermatosis and erythema elevatum diutinum. Rapid resolution followed withdrawal.

Immunologic Since 1998, there has been an increase in the incidence of pure red cell aplasia in dialysis patients receiving subcutaneous epoetin, associated with anti-erythropoietin antibodies; in almost all patients who receive Eprex (109R , 110R , 111A , 112r –115r ). This has been suggested to be related to a change in the production process of Eprex – the removal of human albumin as a stabilizer. It has been suggested that a less stable formulation contains more erythropoietin aggregates, thereby increasing the probability of antibody formation (109R ). Intravenous Eprex was not associated with red cell aplasia, and intravenous administration of Eprex has now been recommended for dialysis patients. There have been no reports of antibodymediated pure red cell aplasia caused by darbepoetin alfa (98R ). Tumorigenicity Three cases of hemangioma in low-birth neonates treated with erythropoietin for anemia have been reported (116A ). The authors suggested that erythropoietin might be a potent angiogenic factor. Drug interactions A phase 2 trial in which patients with myelodysplastic syndrome were treated with thalidomide and darbepoetin alfa (2.25 micrograms/kg/day subcutaneously) was discontinued early because three of seven patients developed a thromboembolic event. The authors suggested that thalidomide in combination with erythropoietin or erythropoietin derivatives may cause an unexpectedly high risk of thrombosis in myelodysplastic syndrome (117c ).

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P.J.M. Vossebeld, P.F.W. Strengers, and W.G. van Aken 52. Yata J, Nihei K, Ohya T, Hirano Y, Momoi M, Maekawa K, Sakakihara Y; Study Group for Pediatric Guillain–Barré Syndrome. High-dose immunoglobulin therapy for Guillain–Barré syndrome in Japanese children. Pediatr Int 2003; 45: 543–9. 53. Budde M, Gusek-Schneider GC, Mayer U, Seitz B. Annular crystalline keratopathy in association with immunoglobulin therapy for pyoderma gangrenosum. Cornea 2003; 22: 82–5. 54. Matsuda M, Hosoda W, Sekijima Y, Hoshi K, Hashimoto T, Itoh S, Ikeda S. Neutropenia as a complication of high-dose intravenous immunoglobulin therapy in adult patients with neuroimmunologic disorders. Clin Neuropharmacol 2003; 26: 306–11. 55. Gottstein R, Cooke RW. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003; 88: F6–10. 56. Cleary AG, Brown B, Minards J, Sills J, BoltonMaggs P. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003; 88: F444. 57. Thorpe SJ, Fox BJ, Dolman CD, Lawrence J, Thorpe R. Batches of intravenous immunoglobulin associated with adverse reactions in recipients contain atypically high anti-Rh D activity. Vox Sanguinis 2003; 85: 80–4. 58. Trifa M, Simon L, Hamza J, Bavoux F, Des Roziers NB. Haemolytic anaemia associated with high dose intravenous immunoglobulin therapy in a child with Guillain–Barré syndrome. Arch Dis Child 2003; 88: 836–7. 59. Wolf HH, Davies SV, Borte M, Caulier MT, Williams PE, Bernuth HV, Egner W, Sklenar I, Adams C, Spath P, Morell A, Andresen I. Efficacy, tolerability, safety and pharmacokinetics of a nanofiltered intravenous immunoglobulin: studies in patients with immune thrombocytopenic purpura and primary immunodeficiencies. Vox Sang 2003; 84: 45–53. 60. Van Zanten AR, Beekhuyzen M, Van der Meer YG, De Gooijer A, Feith GW. Acuut nierfalen na behandeling met intraveneus toegediende immunoglobulinen. Ned Tijdschr Geneeskd 2003; 147: 307–10. 61. Akhtar I, Bastani B. Acute renal failure and myocarditis associated with intravenous immunoglobulin therapy. Ann Intern Med 2003; 139: W65. 62. Chun NS, Savani B, Seder RH, Taplin ME. Acute renal failure after intravenous anti-D immune globulin in an adult with immune thrombocytopenic purpura. Am J Hematol 2003; 74: 276–9. 63. Steensma DP, Dispenzieri A, Moore SB, Schroeder G, Tefferi A. Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome. Blood 2003; 101: 2156–8. 64. Shorr AF, Abbott KC, Agadoa LY. Acute respiratory distress syndrome after kidney transplantation: epidemiology, risk factors, and outcomes. Crit Care Med 2003; 31: 1325–30. 65. Buchler M, Hurault de Ligny B, Madec C, Lebranchu Y; French Thymoglobuline Pharmacovig-

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77. Delgado J, Jimenez-Yuste V, HernandezNavarro F, Villar A. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121: 21–35. 78. Dejgaard A. Update on Novo Nordisk’s clinical trial programme on NovoSeven. Blood Coagul Fibrinolysis 2003; 14 Suppl 1: S39–41. 79. Laffan M, O’Connell NM, Perry DJ, Hodgson AJ, O’Shaughnessy D, Smith OP. Analysis and results of the recombinant factor VIIa extended-use registry. Blood Coagul Fibrinolysis 2003; 14 Suppl 1: S35–8. 80. European Medicines Agency (EMEA). Core Summary of Product Characteristics (SPC) for human plasma-derived and recombinant coagulation factor IX products. CPMP/BPWG/1625/99. 81. Santagostino E, Colombo M, Rivi M, Rumi MG, Rocino A, Linari S, Mannucci PM; Study Group of the Association of Italian Hemophilia Centers. A 6-month versus a 12-month surveillance for hepatocellular carcinoma in 559 hemophiliacs infected with the hepatitis C virus. Blood 2003; 102: 78–82. 82. Hoots WK, Leissinger C, Stabler S, Schwartz BA, White G, Dasani H et al. Continuous intravenous infusion of a plasma-derived factor IX concentrate (Mononine) in haemophilia B. Haemophilia 2003; 9: 164–72. 83. Berntorp E, Astermark J, Bjorkman S, Blanchette VS, Fischer K, Giangrande PL, Gringeri A, Ljung RC, Manco-Johnson MJ, Morfini M, Kilcoyne RF, Petrini P, Rodriguez-Merchan EC, Schramm W, Shapiro A, Van den Berg HM, Hart C. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia 2003; 9 Suppl 1: 1–4. 84. Goodeve A. The incidence of inhibitor development according to specific mutations–and treatment? Blood Coagul Fibrinolysis 2003; 14 Suppl 1: S17–21. 85. Lusher JM, Lee CA, Kessler CM, Bedrosian CL. The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 2003; 9: 38– 49. 86. Roussel-Robert V, Torchet MF, Legrand F, Rothschild C, Stieltjes N. Factor VIII inhibitors development following introduction of B-domaindeleted recombinant factor VIII in four hemophilia A previously treated patients. J Thromb Haemost 2003; 1: 2445–6. 87. Sharathkumar A, Lillicrap D, Blanchette VS, Kern M, Leggo J, Stain AM, Brooker L, Carcao MD. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A. J Thromb Haemost 2003; 1: 1228–36. 88. Salomon O, Zivelin A, Livnat T, Dardik R, Loewenthal R, Avishai O, Steinberg DM, Rosove MH, O’Connell N, Lee CA, Seligsohn U. Prevalence, causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency. Blood 2003; 101: 4783–8. 89. Suzuki N, Watanabe J, Kudoh T, Hori T, Hatakeyama N, Mizue N et al. Successful induction

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P.J.M. Vossebeld, P.F.W. Strengers, and W.G. van Aken 103. Feldman L, Sytkowski AJ. Pleiotropic actions of erythropoietin. Environ Health Prevent Med 2003; 7: 239–45. 104. Samol J, Littlewood TJ. The efficacy of rHuEPO in cancer-related anaemia. Br J Haematol 2003; 121: 3–11. 105. Bezwada HP, Nazarian DG, Henry DH, Booth Jr RE. Preoperative use of recombinant human erythropoietin before total joint arthroplasty. J Bone Joint Surg Am 2003; 85-A: 1795–800. 106. Sasaki N, Ando Y, Kusano E, Asano Y. A case of erythropoietin induced hypertension in a bilaterally nephrectomized patient. ASAIO J 2003; 49: 131–5. 107. Kelly JS. Recurrent capsule opacity and erythropoietin. J Cataract Refract Surg 2003; 29: 415– 17. 108. Gubinelli E, Cocuroccia B, Fazio M, Annessi G, Girolomoni G. Papular neutrophilic dermatosis and erythema elevatum diutinum following erythropoietin therapy in a patient with myelodysplastic syndrome. Acta Dermatol Venereol 2003; 83: 358– 61. 109. Casadevall N. Pure red cell aplasia and antierythropoietin antibodies in patients treated with epoetin. Nephrol Dial Transplant 2003; 18 Suppl 8: viii37–viii41. 110. Locatelli F, Del Vecchio L. Pure red cell aplasia secondary to treatment with erythropoietin. J Nephrol 2003; 16: 461–6. 111. Panchapakesan U, Austin SK, Shafransky A, Lawrence JA, Savdie E. Recovery of pure red-cell aplasia secondary to antierythropoietin antibodies after cessation of recombinant human erythropoietin. Intern Med J 2003; 33: 468–71. 112. Locatelli F, Del Vecchio L. Pure red cell aplasia secondary to treatment with erythropoietin. Artif Organs 2003; 27: 755–8. 113. Garcia RR, Miguel CA, Tormo DM, Torregrosa MI, Perez-Contreras J. Red-cell aplasia due to antibodies against human recombinant erythropoietin (rHuEPO) in a peritoneal dialysis patient treated with rHuEPO. Perit Dial Int 2003; 23: 403– 5. 114. Anand S, Nissenson AR. Pure red-cell aplasia: an emerging epidemic in dialysis patients? Perit Dial Int 2003; 23: 317–19. 115. Guest SS, Levitt L. Pure red-cell aplasia secondary to antierythropoietin antibodies. New Engl J Med 2003; 349: 2572–3. 116. Zaffanello M, Franchini M, Rugolotto S. Recombinant human erythropoietin might induce strawberry haemangiomas in very-low-birthweight preterm infants. Acta Paediatr 2003; 92: 1353–4. 117. Steurer M, Sudmeier I, Stauder R, Gastl G. Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoietin-alpha. Br J Haematol 2003; 121: 101–3.

M.C. Allwood and G. Hardy

34

Formulations used in nutrition

Editor’s note: This chapter is new to SEDA-28. It has been constructed by combining the sections on enteral and parenteral nutrition from what was previously Chapter 34 (Intravenous infusions) and the sections on vitamins from what was previously Chapter 38 (Vitamins). Other substances used in nutrition have been added. The material on plasma substitutes has been transferred to Chapter 33 (Blood, blood components, plasma, and plasma products).

MINERALS Phosphate In 30 patients with re-feeding syndrome, intravenous phosphate infusion 50 mmol as Phosphates Polyfusor, to treat severe hypophosphatemia (<0.5 mmol/l) was effective and safe (1C ). There were three episodes of mild hyperphosphatemia and four patients developed mild hypocalcemia.

PARENTERAL NUTRITION (SED-14, 1150; SEDA-25, 407; SEDA-26, 377; SEDA-27, 355) Metabolism Hypouricemia commonly occurs after several days of parenteral nutrition, although occasional reports of gout have been reported. In one case polyarticular gout developed on two occasions after a sudden fall in serum uric acid after the start of purine-free parenteral nutrition (2A ). • A 61-year-old man with a Stage I adenocarcinoma and a history of polymyalgia rheumatica, hypertension, atrial fibrillation, and cardiomyopathy, who was taking quinapril, warfarin, atorvastatin, digoxin, and atenolol, had a radical esophagogastrectomy. Three days after successful surgery and starting parenteral nutrition he developed generalized stiffness and joint swelling. He had flexion © 2005 Published by Elsevier B.V. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

contractures of both knees and effusions in both ankles and the left wrist. There were no tophi or other joint deformities. Hazy yellow fluid was aspirated from one knee. Culture was negative but the fluid contained a moderate number of white blood cells and numerous intracellular negatively birefringent crystals. He was treated with intravenous methylprednisolone 40 mg 12 hourly, with marked functional improvement and resolution of joint effusions after 24–48 hours. The serum uric acid concentration was 270 µmol/l (4.6 mg/dl). He was readmitted 2.5 months later with vomiting, dehydration, and failure to gain weight. Parenteral nutrition was begun again, and after 4 days he developed a painful left shoulder and swelling of the right knee. He was again successfully treated with glucocorticoids. The serum uric acid was 460 µmol/l (7.7 mg/dl) before admission and fell to 200 µmol/l (3.5 mg/dl) by the fifth day of parenteral nutrition.

The causes of parenteral nutrition-related hypouricemia are not known, although it is postulated that the high glycine content of some parenteral nutrition regimens may be one relevant factor. This case illustrates that gout can be precipitated in susceptible patients; parenteral nutrition in such patients requires careful management. The authors suggested that routine daily monitoring of uric acid concentrations may be helpful in alerting clinicians to falling serum concentrations and potential subsequent exacerbation in patients with a history of gout. Nutrition The severe consequences of thiamine deficiency in patients receiving parenteral nutrition are well recognized. Patients undergoing hemodialysis may be at risk of thiamine deficiency, and one such case has recently been reported (3A ), with the additional observation that the acute encephalopathy that

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384 developed was associated with thiamine deficiency with hyperammonemia. • An 82-year-old woman was given parenteral nutrition between dialyses, including 10% glucose 500 ml, in order to correct malnutrition. She suddenly became confused, with speech disturbance and ophthalmoplegia. Her plasma glucose concentration was 10.3 mmol/l her serum ammonium 110 µmol/l. She had a severe metabolic acidosis and a respiratory acidosis (pH 7.14). Her malnutrition, unexplained metabolic acidosis, and neurological presentation raised the suspicion of an acute encephalopathy due to thiamine deficiency. She was given fursultiamine 100 mg intravenously, and after 2 hours the metabolic acidosis resolved, her serum ammonium fell to 10 µmol/l, and she regained consciousness. Serum lactate and thiamine concentrations were later found to be 64 mmol/l and 270 nmol/l respectively.

The glucose load in this case may have caused worsening of the neurological disorder under the stress of thiamine deficiency. Furthermore, it is possible that there is a relation between thiamine deficiency and hyperammonemia. Metal metabolism Manganese The potential for toxic reactions to manganese included as an essential trace element in long-term parenteral nutrition is well recognized. In particular, accumulation of manganese in the brain has been noted in association with various symptoms associated with changes in brain function, such as gait disturbance, tremor, akinesia, and rigidity. In a recent report, a link appears to have been established between Parkinsonism and raised manganese serum concentrations (4A ). • A 53-year-old women developed dysarthria, gait disturbance, and dysgraphia. She had Crohn’s disease since the age of 26, with almost total bowel resection over this period, and had used home parenteral nutrition since she was 42 years old. She had raised transaminases when she was 47 years old, followed 1 year later by symptoms such as fatigue, dysarthria, gait disturbance, and dysgraphia. She was admitted 18 months later for further assessment. She had a mask-like face and her nose and buttocks were flushed. Sensory and motor neuron functions were intact and her reflexes were normal. There were no extrapyramidal or pyramidal tract symptoms. However, hand pronation and supination and shin tap were poor bilaterally. Her script was small and her writing slightly poor. She had a short-step gait and could not squat. In addition, there was retropulsion, which is characteristic in parkinsonism. Her manganese concentrations were raised in the serum (39 ng/ml; reference

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range 0.8-2.5) and urine (282 ng/l; reference range 2.0 or below). A T1-weighted brain MRI scan showed high-intensity areas in the globus pallidus. As manganese intoxication was suspected, supplementation of her parenteral nutrition regimen with trace elements was reduced from 2 ampoules/day (manganese 40 µmol) to 1 ampoule/day, and withdrawn about 5 months later. Three months later her serum manganese concentration and liver function tests were normal, although high intensity areas on T1-weighted MRI persisted, as did her symptoms, even after a further 3 years without manganese supplementation.

This is another case of manganese toxicity with symptoms closely associated with parkinsonism, although the direct link in this case was not established. However, the persistence of symptoms is further evidence of the dangers of excessive administration of manganese. It may be important that this patient received double the normally recommended daily dose of manganese over a long period, even though her height and weight were substantially below normal. Selenium Selenium deficiency in a patient received long-term parenteral nutrition has been reported again, when the regimen contained no selenium (5A ). • A 22-year-old women with Crohn’s disease underwent a number of bowel resections until her intestine measured only 80 cm. Her oral intake was subsequently restricted to soft drinks and she was given parenteral nutrition. After 4 years, she developed white nail beds and tiredness in the legs. She had macrocytosis with a normal hemoglobin concentration. The concentrations of biotin, vitamin B12 , folic acid, and most trace elements were normal, but her plasma selenium concentration was below the detection limit (under 25 ng/ml). She was given intravenous selenium as sodium selenite 200 µg/day for 2 weeks and then 100 µg/day. After several weeks, she had marked improvement of symptoms, although the plasma selenium concentration remained undetectable.

This case again emphasizes the importance of ensuring that patients who are almost or completely dependent on parenteral nutrition for nutritional needs receive regular selenium. Biliary tract Cholestatic liver disease is a common risk in pre-term and low birth weight children. The incidence of parental nutritionassociated cholestasis has been studied retrospectively in 685 infants who received parenteral nutrition containing either of two commercial amino acids designed for use in neo-

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nates and young children, Aminosyn PF® or Trophamine® (6C ). The first Group (I) received parenteral nutrition containing Trophamine from August 1997 to August 1998 (n = 335), the second group (II) received parenteral nutrition containing Aminosyn PF from August 1998 to January 1999 (n = 157), and the third group (III) received Trophamine from January 1999 to August 1999 (n = 169). There were no cases of cholestasis in any infant who received parenteral nutrition for less than 3 weeks. Of 141 patients given parenteral nutrition for 21 days or more, 24 developed cholestasis: Group I 10/78 (13%); Group II 9/27 (33%); Group III 5/36 (14%). Using logistic regression, birth weight, duration of parenteral nutrition, and the use of Aminosyn PF were significant susceptibility factors for the development of cholestasis. Those who received Aminosyn PF developed cholestasis sooner, had higher peak direct bilirubin concentrations, and remained jaundiced for longer. The authors concluded that Aminosyn PF was temporally associated with a greater than two-fold increase in the incidence of cholestasis compared with Trophamine. In the absence of significant differences in parenteral nutrient or energy intake in the neonates who developed cholestasis, they speculated that possible differences between the amino acid compositions of at least these two commercial sources may have been responsible for the observed differences in the incidence of cholestasis. They also pointed out that the differences could have been associated with differences in age. Pancreas Computed tomography is widely used to diagnose acute pancreatitis. However, it is recognized that iodinated contrast media prolong the duration of pancreatitis and can increase the incidence of local or systemic complications. Parenteral nutrition including intravenous lipid emulsion plays an important role in the management of patients with pancreatitis. Induction of pancreatitis by intravenous lipid emulsion is exceedingly rare. A patient with AIDS developed pancreatitis, which was exacerbated by oral and intravenous contrast medium and by intravenous lipid emulsion in the absence of hypertriglyceridemia (7A ). • A 30-year-old woman with AIDS taking antiretroviral therapy developed abdominal pain, fever, vomiting, and diarrhea over 2 years. She had mild

385 acute pancreatitis according to the Atlanta Classification system and was managed with bowel rest, intravenous hydration, electrolyte replacement, and analgesics. Antiretroviral therapy was withheld. Lipase activity increased from 405 to 1489 U/l on day 3 and this was attributed to the use of an iodinated contrast medium (Omnique® , Nicomed Inc.) and an oral contrast medium (Gastroview® , Millinckrodt Inc.) for an abdominal CT scan. On day 6 she was given All-in-One parenteral nutrition. The lipase activity continued to rise to 2265 U/l, but fell after withdrawal of the lipid emulsion. Lipid emulsion was re-introduced on day 13, with a concomitant increase in lipase activity. The lipid emulsion was again withdrawn and the lipase activity subsequently fell. When she was accidentally given an oral iodinated contrast media for repeat CT the lipase activity again rose to 1475 U/l in association with abdominal pain. Further administration of fat emulsion also then resulted in an increase in lipase activity.

It is well recognized that contrast media can exacerbate pancreatitis, but the possibility that fat emulsion can do the same is controversial. The authors suggested that this was the first case implicating intravenous lipid emulsion in exacerbation of pancreatitis in a patient with AIDS and with normal baseline triglyceride concentrations. They recommended that caution is necessary when using contrast media in recipients of parenteral nutrition lipids in acute pancreatitis. Drug formulations Precipitation of ingredients after compounding of parenteral nutrition mixtures is a recognized and avoidable complication. The risks associated with infusing parenteral nutrition mixtures that contain precipitates, which is usually fatal, have been well documented. A non-fatal case has recently been reported (8A ). • A 26-year-old woman with Crohn’s disease received home parenteral nutrition for 14 days and developed a fever, shortness of breath, and exercise intolerance, which resolved on withdrawal of parenteral nutrition. Three weeks later she was admitted to hospital with dehydration secondary to reduced oral intake, worsening abdominal pain, and fistulae. A chest X-ray showed left lower lobe atelectasis and scarring, but otherwise clear lung fields. Parenteral nutrition was restarted on day 2, but on day 8 she developed a fever, became mildly short of breath, and developed a dry cough and diffuse crackles in the lungs. A chest CT scan showed diffuse ground-glass opacities with miliary nodules, and enlarged lymph nodes scattered throughout the mediastinum and at both hila. She did not respond to intravenous antibiotics.

386 Bronchoscopy showed no endobronchial lesions, and bronchoalveolar lavage yielded no bacteria, viruses, or fungi. An open lung biopsy showed widespread recent organized thrombi in multiple pulmonary artery branches. The thrombi contained broad irregularly shaped refractory crystals, almost filling the blood vessels. The walls of several vessel were also disrupted by foreign body giant-cell granulomata containing similar refractile crystals. The crystals contained calcium, potassium, aluminium, and silica. She improved after withdrawal of parenteral nutrition.

Precipitates during or after the compounding of parenteral nutrition mixtures are most commonly caused by high concentrations of calcium combining with inorganic phosphate to form insoluble calcium phosphate. This can occur during the addition process or after storage of the complete regimen. However, in this case no phosphate was present in the regimen, nor was it possible to inspect the solution for evidence of precipitation as it contained fat emulsion. Another potential source is calcium gluconate, which can interact with glass containers to release aluminium silicate, which was found in this case. This case points to two important issues associated with the management of patients receiving parenteral nutrition. First, an end-line filter should be considered, especially for recipients of long-term parenteral nutrition. Secondly, while the formation of precipitates is normally fatal, early recognition and good management can result in a favorable outcome.

VITAMIN A (CAROTENOIDS) (SED-14, 1340; SEDA-25, 454; SEDA-26, 416; SEDA-27, 405) Vitamin A supplementation to children over 6 months old reduces mortality in low income countries. The WHO policy recommends the administration of vitamin A (100 000 IU) to immunization contacts as soon as possible after 6 months, possibly supplemented by additional doses of 50 000 IU with each diphtheriatetanus-pertussis/polio immunization, usually given at 6, 10 and 14 weeks of age. In a recent review (9R ), it was hypothesized that the mortality effect of vitamin A supplementation may depend not only on prevention of vitamin A deficiency but also on vitamin A amplifying

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non-specific immune modulation induced by routine immunization. However, detailed analysis of the sparse literature undertaken in this careful review failed to confirm this. The authors concluded that, should their hypothesis be true, the WHO recommendation that additional vitamin A be administered at 6, 10, and 14 weeks along with DTP/polio immunization may not contribute to improving child health in developing countries. Musculoskeletal Hypervitaminosis A is associated with bone resorption, hypercalcemia, and bone abnormalities. Recent epidemiological studies have linked high habitual intake of vitamin A to low bone mineral content and a risk of fractures. However, much of the evidence is of variable quality. A review of the published evidence that might show a link between vitamin A consumption and osteoporotic fractures has shown that cross-sectional studies have generally provided no evidence of an association between vitamin A status or intake and skeletal risk (10M ). The authors also warned that all studies can be confounded by co-linearity of nutrient intake and difficulties in assessing vitamin A exposure. Dosage regimens Extremely low birth weight infants often have low plasma and tissue concentrations of vitamin A, which may increase the risk of bronchopulmonary dysplasia (neonatal chronic lung disease). Vitamin A supplementation reduces the risk of bronchopulmonary dysplasia and death. However, the optimum dose remains poorly defined. In one large multicenter trial a standard dose of 5000 IU intramuscularly 3 times a week was used, but only about 50% of the infants achieved optimum vitamin A status (11C ). Another study of 120 infants was designed to compare three different dosing regimens, using a randomized design (12c ). The first group received the “standard” dose (as used in the multicenter trial), the second group received a higher dose (10 000 IU dose 3 times a week), and the third group received one 15 000 IU dose per week. Compared with the standard dosing regimen, once per week dosing was associated with worse vitamin A deficiency and higher doses did not reduce it, at least as determined by serum retinol concentrations at day 28. From these results, and clinical evidence accumulated during the study, the authors conclude that the “standard” dosing regimen should be recommended.

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Beta carotene Tumorigenicity In two large randomized prevention trials beta carotene supplementation increased the risk of lung cancer in male smokers (13C , 14C ). Now a post-intervention follow-up assessment of cancer incidence and mortality in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention study (ATBC study) has been published (15C ). In this study 29 133 male smokers aged 50–69 years took α-tocopherol 50 mg/day, beta carotene 20 mg/day, or placebo for 5–8 years. The overall post-trial relative risk (RR) of lung cancer incidence (n = 1037) was 1.06 (95% CI = 0.94, 1.20) in the beta carotene group compared with placebo. The RR of mortality, 7261 individuals having died during the post-trial follow-up period, was 1.07 (95% CI = 1.02, 1.12) for beta carotene recipients compared with placebo. These data suggest that the excess risk from beta carotene in smokers is no longer evident 4–6 years after the intervention. This was mainly due to cardiovascular diseases. A beneficial effect of α-tocopherol on the risk of prostate cancer that was seen in the original ATBC study also disappeared in the followup period. However the recommendation that smokers should avoid beta carotene supplementation remains valid. In another randomized, double-blind, multicenter trial the effects of beta carotene supplementation on the recurrence of colorectal adenoma were evaluated in 864 patients who had surgery for colorectal adenoma and were at the time polyp-free (16C ). They were assigned to: placebo; beta carotene 25 mg/day; a combination of vitamin C 1000 mg + vitamin E 400 mg; or beta carotene + vitamin C + vitamin E. In those who neither smoked nor drank alcohol beta carotene was associated with a markedly reduced risk of recurrence (RR = 0.56; 95% CI = 0.35, 0.89). In smokers the RR was 1.36 (95% CI = 0.70, 2.62) and in subjects who consumed alcohol it was 1.13 (95% CI = 0.89, 1.43). By far the greatest risk of recurrence was seen in subjects who both smoked and consumed more than one alcoholic drink per day: RR = 2.07 (95% CI = 1.39, 3.08). This was highly significant compared with the risk in those who neither smoked nor drank. The mechanism whereby beta carotene has antineoplastic effects in some circumstances and acts as a neoplastic agent in others is unclear.

The authors suggested that it could be related to the fact that it has antioxidant properties at low oxygen pressures, but can also act as a prooxidant at ambient or high oxygen pressures. High oxygen pressures are not normally found in the bowel (17c ), but smoking appears to increase the formation of oxidized beta carotene metabolites (18E ). If this occurs in the colorectal mucosa, it could explain the interaction between smoking and beta carotene. We must conclude from these data that a careful evaluation of life-style factors on an individual basis is necessary before recommending beta carotene supplementation.

VITAMINS OF THE B GROUP (SED-14, 1344; SEDA-25, 462; SEDA-26, 419; SEDA-27, 407)

Folinic acid Immunologic Allergic reactions to folinic acid (leucovorin), a metabolite of folic acid used in oncology have only very rarely been reported. Two further cases have been reported (19A ). • A 57-year-old man with rectal cancer treated with fluorouracil developed diffuse urticaria and breathing difficulties shortly after the start of intravenous leucovorin. Three months later skin tests were positive for leucovorin and negative for folic acid. • A 59-year-old man with metastatic cancer of the colon was treated with leucovorin, fluorouracil, and oxaliplatin. During the initial infusion of leucovorin he developed diffuse urticaria, and a similar reaction occurred during the second infusion. Three weeks later skin tests were positive for leucovorin. A programme of oral desensitization with gradually increasing doses of up to 375 mg was successful and chemotherapy including leucovorin was resumed without any further adverse reactions.

The authors proposed an IgE-mediated mechanism for these allergic reactions because of the clinical presentation, positive skin tests, and the effectiveness of desensitization. However, an anaphylactoid reaction caused by non-specific release of histamine could not be excluded, since in both cases the reaction occurred at the first introduction of leucovorin. Desensitization could be a useful measure to enable allergic

388 patients to continue palliative treatment with leucovorin. However, this is currently based on very limited evidence.

Vitamin B6 (pyridoxine) Nervous system The neurotoxic effects of vitamin B6 overdosage, amongst them sensory neuropathy, are well known. Paresthesia has recently been reported after chronic use of vitamin B6 in combination with nitrofurantoin (20A ). • A 73-year-old woman with a 10-year history of chronic urinary tract infections developed a tingling and burning sensation in the distal legs and alternate sensations of hot and cold in both feet. She also had some discomfort in the lower abdomen 2 weeks before. She had been taking nitrofurantoin 100 mg/day for 3–10 days at a time and vitamin B6 100 mg/day for 5 years. She had a serum vitamin B6 concentration of 89 ng/ml (reference range 2–26). Physical examination and neurodiagnostic studies showed no abnormalities. One year later she still had paresthesia.

Nitrofurantoin can cause neuropathy particularly in elderly women. The combination of frequent self-medication with nitrofurantoin and a relatively high dose of chronic vitamin B6 in this elderly woman seems to have caused this relatively severe adverse effect of long duration. However, the report included no information about whether the vitamin B6 was withdrawn. This case highlights the potential dangers of chronic self-medication and uncontrolled vitamin supplementation, especially in elderly people.

VITAMIN D (CALCIFEROL) AND ANALOGUES Cardiovascular Hypercalcemia due to vitamin D intoxication with chest pain and electrocardiographic changes mimicking acute myocardial infarction has been reported (21A ). • A 78-year-old man who had taken alfacalcidol 1.0 µg/day for osteoporosis and also made an effort to maximize his dietary calcium intake by

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drinking milk and mineral water developed general fatigue, anorexia and chest pain. An electrocardiogram showed tachycardia, ST elevation in leads V1 –V3 , and diffuse T wave flattening. Emergency coronary angiography showed no significant stenoses. His laboratory results then showed hypercalcemia (4.1 mmol/l). He was given intravenous saline and furosemide and alfacalcidol was withdrawn. His symptoms gradually improved and the electrocardiogram returned to normal as the serum calcium fell to normal. On re-evaluation of the electrocardiogram extreme shortening of the QTc interval was noted.

Chest pain is not a common symptom of hypercalcemia, but in patients with suspected acute myocardial infarction, when emergency calcium assays are not available, a shortened QTc interval is a valuable tool to diagnose hypercalcemia. Most of the adverse effects of alfacalcidol previously reported have not been serious and usually disappear shortly after withdrawal. However, potentially life-threatening congestive heart failure and axonal polyneuropathy has been reported in a patient with systemic lupus erythematosus (22A ). • A 29-year-old women with systemic lupus erythematosus, who had taken alfacalcidol 0.5 µg/day for 9 months to prevent glucocorticoid-induced osteoporosis, presented with painful swellings in the legs, followed by numbness and muscle weakness in both arms and legs. She then developed shortness of breath and bilateral leg edema. Blood tests showed no abnormalities to suggest exacerbation of systemic lupus erythematosus. A chest X-ray showed a right pleural effusion and cardiac enlargement. Alfacalcidol was withdrawn. She recovered from the congestive heart failure within 2 months and the symptoms of axonal polyneuropathy had almost completely disappeared after 4 months.

The mechanisms of toxicity leading to congestive heart failure and axonal polyneuropathy are unknown. However, there is a vitamin D receptor in human heart (23E ) and murine peripheral nerves (24E ), and toxicity could be related to polymorphism of vitamin D receptor genes. Endocrine A patient with psoriasis developed hypercalcemia and hypercalciuria after 28 days of treatment with tacalcitol (25A ). He had been taking long-term thiazide therapy for his hypertension. When he used topical tacalcitol ointment his serum calcium concentration and

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urinary calcium excretion gradually increased to 3.55 mmol/l and 0.475 g/day respectively. Within 7 days of withdrawal of tacalcitol, the serum calcium concentration had normalized. Skin Vitamin D3 derivatives used in the treatment of psoriasis have an irritant effect on sensitive skin areas. In a multicenter, randomized, controlled, investigator-blinded, left-right comparison in 75 patients with mild to moderate chronic plaque psoriasis affecting the face, hairline, and the retroauricular and flexural areas calcitriol ointment 3 µg/g was compared with calcipotriol ointment 50 µg/g (26c ). In all there were 10 treatment-related adverse events in eight subjects, including one who had skin irritation on both the calcitriol and the calcipotriol treated sides. All other adverse events occurred only on the calcipotriol side (irritant dermatitis in six patients, contact dermatitis in one). The global efficacy assessment by the investigators was significantly better for the calcitriol treated lesions and the patients’ global preference strongly favored calcitriol. It would therefore appear that calcitriol is more effective and better tolerated than calcipotriol in patients with psoriasis affecting sensitive areas. Susceptibility factors Patients with cancers often take calcium and vitamin supplements, including vitamin D, trying to improve their general nutritional status, unaware that they have an increased risk of hypercalcemia. This problem has been highlighted by a series of eight cases of cancer-related hypercalcemia associated with the intake of multivitamin supple-

389 ments containing vitamin D 400 IU, alone or in combination with calcium and calcium-rich shark cartilage supplements (27A ). Dosage regimens While vitamin D deficiency rickets remains a major problem in the developing world, the optimal dosage regimen has not yet been finally confirmed. In a randomized study 56 infants with nutritional vitamin D deficiency rickets aged 3–36 months and 20 age-matched healthy controls were given oral vitamin D 150 000, 300 000, or 600 000 IU in an attempt to establish the most effective dose with the fewest adverse effects (28c ). In addition to vitamin D, patients who had hypocalcemic tetany or convulsions were initially treated with intravenous calcium gluconate 50–75 mg/kg/day for 24–48 hours and then with the same dose orally for a further 5 days. Patients without tetany or convulsions received oral calcium gluconate for 7 days. There were no differences in improvement in rickets across the three dosages. Eight infants developed hypercalcemia (two who took 300 000 IU and six who took 600 000 IU). However, all were asymptomatic. The authors concluded that 150 000 and 300 000 IU are adequate to treat nutritional vitamin D deficiency rickets, but that a high oral dose of 600 000 IU can be associated with an increased risk of hypercalcemia. Since there was no difference in improvement of vitamin D deficiency rickets between the two lower dose groups and two cases of hypercalcemia in those who took 300 000 IU, it would seem that 150 000 IU should be the preferred dose.

REFERENCES 1. Terlevich A, Hearing SD, Woltersdort WW, Smyth C, Reid D, Mccullagh E, Day A, Probert CSJ. Refeeding syndrome: effective and safe treatment with Phosphates Polyfusor. Aliment Pharmacol Ther 2003; 17: 1325–9. 2. Moyer RA, St John D. Acute gout precipitated by total parenteral nutrition. J Rheumatol 2003; 30: 849–50. 3. Ookawara S, Suzuki M, Saitou M. Acute encephalopathy due to thiamine deficiency with hyperammonemia in a chronic hemodialysis patient: a case report [In Japanese]. Nippon Jinzo Gakkai Shi 2003: 45: 393–397.

4. Kamata N, Oshitani N, Oiso R, Kawachiya T, Inagawa M, Kawashima D, Iimuro M, Sogawa M, Jinno Y, Higuchi K, Matsumoto T, Arakawa T. Crohn’s disease with Parkinsonism due to longterm total parenteral nutrition. Dig Dis Sci 2003; 48: 992–4. 5. Ishida T, Himeno K, Torigoe Y, Inoue M, Wakisaka O, Tabuki T, Ono H, Honda K, Mori T, Seike M, Yashimatsu H, Sakata T. Selenium deficiency in a patient with Crohn’s disease receiving longterm total parenteral nutrition. Intern Med 2003; 42: 154–7. 6. Wright K, Ernst KD, Gaylord MS, Dawson JP, Burnette TM. Increased incidence of parenteral

390 nutrition-associated cholestasis with Aminosyn PF compared to Trophamine. J Perinatol 2003; 23: 444–50. 7. Kasi VS, Estrada CA, Wiese W. Association of pancreatitis with administration of contrast medium and intravenous lipid emulsion in a patient with the acquired immunodeficiency syndrome. South Med J 2003; 96: 66–9. 8. McNearney T, Bajaj C, Boyars M, Cottingham J, Haque A. Total parenteral nutrition associated crystalline precipitate resulting in pulmonary artery occlusions and alveolar granulomas. Dig Dis Sci 2003; 48: 1352–4. 9. Benn CS, Bale C, Sommerfelt H, Friis H, Aaby P. Hypothesis: Vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines? Int J Epidemiol 2003; 32: 822– 8. 10. Barker ME, Blumsohn A. Is vitamin A consumption a risk factor for osteoporotic fracture? Proc Nutr Soc 2003; 62: 845–50. 11. Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer CR, Korones SB, Fanaroff AA. Vitamin A supplementation for extremelylow-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. New Engl J Med 1999; 340: 1962– 8. 12. Ambalavanan N, Wu T-J. Tyson JE, Kennedy KA, Roane C, Carlo WA. A comparison of three vitamin A dosing regimens in extremely-low-weight infants. J Pediatr 2003; 142: 656–61. 13. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New Engl J Med 1994; 330: 1029–35. 14. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New Engl J Med 1996; 334: 1150–5. 15. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. Incidence of cancer and mortality following α-tocopherol and beta-carotene supplementation. J Am Med Assoc 2003; 290: 476– 85. 16. Baron JA, Cole BF, Mott L, Haile R, Grau M, Church TR, Beck GJ, Greenberg ER. Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma recurrence: results of a randomised trial. J Natl Cancer Inst 2003; 95: 717–22. 17. Sheridan WG, Lowndes RH, Young HL. Tissue oxygen tension as a predictor of colonic anasto-

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motic healing. Dis Colon Rectum 1987; 30: 867– 71. 18. Liu C, Wang XD, Bronson RT, Smith DE, Krinsky NI, Russell RM. Effects of physiological versus pharmacological beta-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets. Carcinogenesis 2000; 21: 2245–53. 19. Vermeulen C, Mathelier-Fusade P, Gaouar H, Leynadier F. Two cases of allergy to leucovorin. Revue Fr Allergol Immunol Clin 2003; 43: 342–3. 20. Lacerna RA, Chien C. Paresthesias developing in an elderly patient after chronic usage of nitrofurantoin and vitamin B6 . J Am Geriatr Soc 2003; 51: 1822–3. 21. Ashizawa N, Arakawa S, Koide Y, Toda G, Seto S, Yano K. Hypercalcemia due to vitamin D intoxication with clinical features mimicking acute myocardial infarction. Intern Med 2003; 42: 340– 4. 22. Kikuchi H, Aramaki K, Hirohata S. Congestive heart failure and axonal polyneuropathy induced by alfacacidol in a patient with systemic lupus erythematosus. Mod Rheumatol 2003; 13: 277–80. 23. O’Connell TD, Simpson RU. Immunochemical identification of the 1,25-dihydroxyvitamin D3 receptor protein in human heart. Cell Biol Int 1996; 20: 621–4. 24. Coret A, Baudet C, Neveu I, Baron-Van Evercooren A, Brachet P, Naveihan P. 1,25dihydroxyvitamin D3 regulates the expression of VDR and NGF genes in Schwann cells in vitro. J Neurosci Res 1998; 15: 742–6. 25. Kawaguchi M, Mitsuhashi Y, Kondo S. Iatrogenic hypercalcemia due to vitamin D3 ointment (1,24 OH2D3) combined with thiazide diuretics in a case of psoriasis. J Dermatol 2003; 30: 801–4. 26. Ortonne JP, Humbert P, Nicolas JF, Tsankov N, Tonev SD, Janin A, Czernielewski J, Lahfa M, Dubertret L. Intra-individual comparison of the cutaneous safety and efficacy of calcitriol 3 µg.g−1 ointment and calcipotriol 50 µg.g−1 ointment on chronic plaque psoriasis localized in facial, hairline, retroauricular or flexural areas. Br J Dermatol 2003; 148: 326–33. 27. Lagman R, Walsh D. Dangerous nutrition? Calcium, vitamin D and shark cartilage nutritional supplements and cancer-related hypercalcemia. Support Cancer Care 2003; 11: 232–5. 28. Cesur Y, Caksen H, Gündem A, Kirimi E, Odabas D. Comparison of low and high dose vitamin D treatment in nutritional vitamin D deficiency rickets. J Pediatr Endocrinol Metab 2003; 16: 1105–9.

David M. Keeling and Jeffrey K. Aronson

35

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

Editor’s note: The clotting factors, such as factor VIII, and anticoagulant proteins, such as activated factor C, are included in Chapter 33.

COUMARIN CONGENERS (SED-14, 1184; SEDA-25, 411; SEDA-26, 379; SEDA-27, 358) Drug interactions Non-steroidal anti-inflammatory drugs Over 1 year all patients in an anticoagulant clinic who reported bleeding were sent a questionnaire about NSAID use (1c ). The local pharmacists detected patients with concomitant coumarin and NSAID prescriptions (but no bleeding). In 681 coumarin users there were 738 hemorrhages, in 12% of which an NSAID had been involved. In contrast, in the whole population of coumarin users, 2.5% were taking an NSAID. Therefore, the relative risk of NSAID use with regard to bleeding complications was 5.8 (95% CI = 2.3, 13.6). Only 7% of bleeding was gastrointestinal; 35% were hematomas and 29% epistaxis. The concomitant use of NSAIDs and coumarin derivatives should be avoided if possible. Choice of long-term analgesia in patients taking warfarin is restricted, and theoretically COX2-selective NSAIDs might be preferred if a NSAID is required.

© 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

HEPARINS (SED-14, 1177; SEDA-26, 379; SEDA-27, 358) Skin Although immediate-type reactions to heparins are rare, delayed-type reactions are being reported increasingly often. The lesions usually develop 2–4 days after injection and are erythematous, infiltrated, and sometimes eczematous; they can become generalized if therapy is continued (2Ar ). In four patients with such reactions, patch, intradermal, and subcutaneous tests were performed with a panel of unfractionated heparins, low-molecular-weight heparins, heparinoids, recombinant hirudins, and fondaparinux sodium (3c ). Three were sensitized to all the unfractionated heparins and low-molecularweight heparins. Tinzaparin sodium was a possible substitute in one patient and the heparinoid pentosan polysulfate in another. The recombinant hirudins and fondaparinux sodium were tolerated without any adverse effects. • A 68-year-old woman had repeated localized skin reactions at injection sites after administration of nadroparin, certoparin, and heparin sodium (2Ar ). The lesions were itchy and eczematous, developed soon after starting the anticoagulants, and persisted for several days. Patch testing with multiple heparin preparations (heparin sodium, heparin calcium, certoparin, dalteparin, nadroparin, the xylanopolyhydrogen sulfate pentosanpolysulfate, and the synthetic heparin pentasaccharide fondaparinux) showed type IV sensitization to certoparin. Prick testing was negative, but intracutaneous tests were positive to nadroparin, dalteparin, heparin calcium, and heparin sodium. Subcutaneous pentosanpolysulfate and fondaparinux had no effects.

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• A 62-year-old woman presented had localized skin reactions at injection sites after nadroparin (2Ar ). Patch tests showed type IV reactions to nadroparin and dalteparin. Intracutaneous tests caused delayed reactions after 6 days to heparin sodium and heparin calcium. Subcutaneous challenge with pentosanpolysulfate was positive but negative with fondaparinux. • A 57-year-old immobile obese Caucasian woman with a history of delayed hypersensitivity reactions to several heparins was given danaparoid for prophylactic anticoagulation while being treated for venous ulcers (4A ). Two days later she developed erythematous plaques and disseminating papulovesicles at the injection sites. She was then given fondaparinux instead, which was well tolerated over 2 weeks. Skin allergy tests 6 weeks later were positive to heparin at days 4–8, with erythematous plaques at the injection sites. Pentosan polysulfate was also injected subcutaneously, and produced a similar lesion. In contrast, all skin tests with fondaparinux were negative, and re-exposure was uneventful. • A 67-year-old man with unstable angina pectoris developed an urticarial rash 10 hours after the second exposure to heparin during coronary artery bypass (5A ). Lymphocyte stimulation tests were positive with porcine heparin, coumadin, and nicorandil. Off-pump coronary bypass surgery was successfully performed with argatroban as an alternative to heparin.

Musculoskeletal Long-term treatment with heparin can cause osteoporosis. In osteoblast cultures unfractionated heparin, dalteparin, and enoxaparin significantly reduced matrix collagen type II content and calcification in concentrations equal to or higher than those that are generally associated with a therapeutic effect; in contrast, fondaparinux had no inhibitory in vitro effects on human osteoblasts at concentrations of 0.01–100 µg/ml (6E ). Mitochondrial activity and protein synthesis in osteoblasts treated with fondaparinux were significantly higher than in cells treated with heparins.

THROMBOLYTIC AGENTS (SED-14, 1187)

Alteplase and streptokinase Nervous system When alteplase and streptokinase are used in the treatment of myocardial infarction the most feared adverse effect is intracranial hemorrhage. A systematic review

David M. Keeling and Jeffrey K. Aronson

identified three studies (GISSI-2/ISG, GUSTO1, and ISIS-3) in which patients had been randomized between the two treatments and recorded the risk of hemorrhagic stroke (7M ). Hemorrhagic stroke was more common with alteplase (0.57%) than streptokinase (0.36%) (OR = 1.8; CI = 1.1, 2.9). If GUSTO-1, in which alteplase was given in an accelerated fashion, was excluded, the hemorrhagic stroke rates were 0.50% and 0.23% (OR = 2.1, CI = 1.0, 4.4). There was no difference in 35-day mortality between the drugs.

SHORT POLYSACCHARIDE INHIBITORS OF COAGULATING FACTORS (SEDA-27, 359) Fondaparinux A review of clinical trials has shown that fondaparinux has a similar safety profile to that of enoxaparin with respect to clinically relevant major bleeding, including fatal bleeding, non-fatal bleeding, and bleeding requiring repeat surgery (8M ). Hematologic Of 1103 patients randomly assigned to receive fondaparinux 42 (3.8%) had recurrent thromboembolic events, compared with 56 of 1110 patients randomly assigned to receive unfractionated heparin (5.0%), an absolute difference of −1.2% in favor of fondaparinux (95% CI = −3.0, 0.5) (9C ). There was major bleeding in 1.3% of those treated with fondaparinux and 1.1% of those treated with unfractionated heparin. Mortality rates at 3 months were similar in the two groups. In four phase III multicenter, randomized, parallel-group, double-blind trials in 375 centers in Argentina, Australia and New Zealand, Europe, North America, and South Africa, 7344 patients (mean age 68 years, 60% women) undergoing elective total hip arthroplasty (two studies), elective knee arthroplasty (one study), or hip fracture surgery (one study) were given either subcutaneous fondaparinux (n = 3668) 2.5 mg once daily, beginning six hours after surgery or subcutaneous enoxaparin (n = 3676) 30 mg bd beginning 12 hours before surgery; 7237 received at least one dose of the study drug and 5385 completed the study (10M ). The

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

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Fig. 1. The structures of fondaparinux (top) and idraparinux.

incidence of venous thromboembolism was significantly lower with fondaparinux (182/2682) than enoxaparin (371/2703). However, major bleeding events were significantly more frequent with fondaparinux (96/3616) than enoxaparin (63/3621). The incidences of death, minor bleeding, and other adverse events did not differ between the two groups. In a double-blind multicenter trial, 656 patients undergoing hip fracture surgery were randomly assigned to receive prophylaxis with once-daily subcutaneous fondaparinux sodium 2.5 mg of placebo for 19–23 days (11C ). Before randomization, all had received fondaparinux for 6–8 days. Fondaparinux reduced the incidence of venous thromboembolism from 35% (77/220) to 1.4% (3/208), with a relative risk reduction of 96% (95% CI = 87, 100%). Although there was a trend towards more major bleeding with fondaparinux than with placebo, there were no differences between the two groups in the incidence of clinically relevant bleeding (leading to death, re-operation, or critical organ bleeding).

Idraparinux Fondaparinux is a synthetic pentasaccharide that contains five of the saccharides found in heparin; idraparinux has a similar structure but is modified, mostly by multiple methylation, to give it a higher affinity for antithrombin III and therefore a longer duration of action (Figure 1).

Liver The effects of idraparinux on plasma liver enzyme activities (gamma-glutamyltransferase, aspartate transaminase, and alanine transaminase) have been studied in 37 patients with deep vein thrombosis in the PERSIST trial (12C ). Patients were first treated with weight-adjusted enoxaparin for 4–7 days and then randomized to either idraparinux (2.5, 5, 7.5 or 10 mg) or warfarin. Gamma-glutamyltransferase was significantly increased after enoxaparin at the baseline visit and at week 2, but returned to screening values at week 3 for the remainder of the study. Transaminases were significantly increased at the baseline visit and returned to screening values at week 2 for the remainder of the study. There was no significant difference between the mean values of plasma liver enzymes in the four idraparinux groups and the warfarin group. The authors concluded that idraparinux, in contrast to enoxaparin, does not alter plasma liver enzyme activities significantly.

DIRECT THROMBIN INHIBITORS (SEDA-27, 359) Argatroban Argatroban is a thrombin inhibitor that has been used to treat thrombosis in patients with heparin-induced thrombocytopenia (13A –16A )

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or heparin allergy (5A ). However, in some patients overanticoagulation has occurred and care with dosage is clearly required (17A ).

David M. Keeling and Jeffrey K. Aronson

35 000 patients have received lepirudin, and so the authors estimated the risk of anaphylaxis as being about 0.015% on first exposure and 0.16% on re-exposure.

Susceptibility factors Little is known about the factors that increase the risk of adverse effects of argatroban. • A 54-year-old white woman with an artificial mitral valve developed anasarca secondary to acute renal insufficiency and was given prophylactic argatroban (18A ). Despite normal hepatic function, she had a raised activated partial thromboplastin time for a prolonged period of time and required a significant dosage reduction. This prolonged effect persisted despite hemodialysis.

These observations suggest that in patients who are fluid-overloaded the anticoagulant effects of argatroban may be prolonged and that argatroban may not be removed by hemodialysis.

Lepirudin Lepirudin is a direct thrombin inhibitor obtained by recombinant technology from the medicinal leech and used for treatment of heparin-induced thrombocytopenia. Hematologic In 25 patients with a history of heparin-induced thrombocytopenia, who underwent a total of 36 percutaneous interventions and were given lepirudin, there was one procedure-related death from a retroperitoneal bleed and three patients had minor bleeding (19c ). • A 50-year-old patient with heart failure and a dilated left ventricle had biventricular floating thrombi, for which lepirudin was given; the thrombi dissolved within 17 days, but the patient developed petechial bleeding, hemoptysis, and gross hematuria, and died of a subarachnoid hemorrhage (20A ).

Immunologic Using databases of lepirudin studies, 26 possible cases of anaphylaxis/severe allergy were found from 1994 to 2002 (21c ). Nine patients were judged to have had severe anaphylaxis within minutes of intravenous lepirudin, and four died. In these four cases, there had been a previous uneventful treatment course with lepirudin 1–12 weeks earlier. About

Ximelagatran Ximelagatran is an orally available direct thrombin inhibitor. It is a prodrug that is converted to the active compound melagatran. With a fixed dose (which nevertheless needs to be altered in renal insufficiency) and no monitoring it will be easier to use than warfarin and may replace warfarin as the anticoagulant of choice for the prevention of stroke in high-risk patients with atrial fibrillation (22R , 23R ). However, this will depend on its efficacy and adverse effects, particularly the risk of major bleeding. Comparative studies Ximelagatran versus dalteparin In a randomized, controlled comparison of ximelagatran 24, 36, 48, or 60 mg bd and dalteparin followed by warfarin in 350 patients with deep vein thrombosis of the leg, there was no difference in the rate of regression of the thrombus; there was progression in 8% and 3% of patients respectively (24C ). Treatment was withdrawn because of bleeding in two patients taking ximelagatran (24 mg and 36 mg) and in two patients taking dalteparin and warfarin. Ximelagatran versus enoxaparin In a randomized, multicenter, double-blind study in patients undergoing total hip replacement ximelagatran 24 mg bd or subcutaneous enoxaparin 30 mg bd were compared with placebo for 7– 12 days (25C ). Overall rates of total venous thromboembolism were 7.9% (62/782) with ximelagatran and 4.6% (36/775) with enoxaparin (absolute difference = 3.3%; 95% CI = 0.9, 5.7%). There were major bleeding events in 0.8% (7/906) patients who used ximelagatran and in 0.9% (8/910) of those who used enoxaparin. In a double-blind study in 2788 patients undergoing total hip or knee replacement subcutaneous melagatran 3 mg followed by oral ximelagatran 24 mg bd was compared with subcutaneous enoxaparin 40 mg/day (26C ). Venous thromboembolism occurred in 355/1146 (31%)

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

and 306/1122 (27%) patients in the ximelagatran and enoxaparin groups respectively, a difference in risk of 3.7% in favor of enoxaparin. Bleeding was comparable in the two groups. Ximelagatran versus warfarin In a randomized, double-blind comparison of oral ximelagatran 24 or 36 mg bd for 7–12 days or warfarin in 1851 patients after total knee replacement, ximelagatran 36 mg bd was better than warfarin in preventing venous thromboembolism and death from all causes (20% versus 28%) (27C ). There were no significant differences in major bleeding (0.8% and 0.7% respectively), perioperative indicators of bleeding, wound characteristics, or the composite secondary end point of proximal deep-vein thrombosis, pulmonary embolism, and death (2.7% and 4.1%). Placebo-controlled studies Ximelagatran plus aspirin versus aspirin alone In a placebocontrolled, double-blind, multicenter study, 1883 patients who had a recent myocardial infarction were randomized to oral ximelagatran 24 mg, 36 mg, 48 mg, or 60 mg bd, or placebo for 6 months; all took aspirin 160 mg/day (28C ). Ximelagatran significantly reduced the risks of all-cause death, non-fatal myocardial infarction, and severe recurrent ischemia compared with placebo from 16% (102/638) to 13% (154/1245) (hazard ratio = 0.76; 95% CI = 0.59, 0.98). Major bleeding events were rare: 1.8% (23/1245) and 0.9% (6/638) (hazard ratio = 1.97; 95% CI = 0.80, 4.84) in the combined ximelagatran and placebo groups respectively. Hematologic In the SPORTIF III trial 1704 patients were treated with ximelagatran and 1703 with warfarin (29C ). The rates of major bleeding in the two groups were 1.3 and 1.8 per 100 patient years respectively (difference −0.5, 95% CI = −1.2, 0.2). This suggests that ximelagatran is at least as safe as warfarin in this regard. In 6% of patients taking ximelagatran serum alanine transaminase activity was over three times the upper limit of normal, consistent with the results of previous studies. In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ ximelagatran or enoxaparin for 8–11 days (30C ).

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The rates of major and total venous thromboembolism were significantly lower with melagatran/ximelagatran and fatal bleeding, critical site bleeding, and bleeding requiring reoperation did not differ between the two groups. However, “excessive bleeding as judged by the investigator”, which was based on an observational assessment of bleeding from the wound, either during the procedure or during drainage, was more frequent with melagatran/ximelagatran than with enoxaparin. Liver In a double-blind, placebo-controlled study, 1233 patients with venous thromboembolism who had taken an anticoagulant for 6 months were randomized to extended secondary prevention with ximelagatran 24 mg bd or placebo for 18 months without monitoring (31C ). Death from any cause occurred in six patients who took ximelagatran group and 7 who took placebo; bleeding occurred in 134 and 111 patients respectively (hazard ratio = 1.19; 95% CI = 0.93, 1.53). The cumulative risk of a transient rise in the alanine transaminase activity to more than three times the upper limit of the reference range was 6.4% with ximelagatran compared with 1.2% with placebo. In a double-blind, randomized study in 254 patients with non-valvular atrial fibrillation ximelagatran (n = 187) 20, 40, or 60 mg bd was compared with warfarin (n = 67) (32C ). Alanine transaminase increased in eight patients taking ximelagatran, but normalized with continuous treatment or withdrawal. Susceptibility factors Genetics In 36 young healthy men of African, Asian, or Caucasian origin, ethnicity had no effect on the pharmacokinetics and pharmacodynamics of melagatran after oral ximelagatran 50 mg (33C ). Age The pharmacokinetics of oral ximelagatran and intravenous melagatran in elderly patients with non-valvular atrial fibrillation were similar to with those in matched healthy controls and dosage adjustment is therefore not necessary in these patients (34C ). In six young and six older subjects there were no agedependent differences in the absorption and biotransformation of ximelagatran and differences in exposure to melagatran were explicable by differences in renal function (35C ).

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Obesity There were no differences in the pharmacokinetics or pharmacodynamics of melagatran between 12 obese and 12 non-obese subjects after oral administration of ximelagatran 24 mg, suggesting that dose adjustment of ximelagatran in obesity (BMI up to 39 kg/m2 ) is not necessary (36C ). Hepatic impairment The pharmacokinetics of ximelagatran were similar in 12 subjects with mild-to-moderate hepatic impairment (classified as Child-Pugh A or B) and 12 age-, weight-, and sex-matched controls with normal hepatic function, although the renal clearance of melagatran was 13% higher in hepatic impairment (37C ). Baseline prothrombin time was slightly longer in hepatic impairment, but when concentrations of melagatran were at their peak, the increase in prothrombin time from baseline values was the same in the two groups. Thus, dosage adjustment is not necessary in patients with mild-to-moderate impairment of hepatic function. Renal impairment After administration of subcutaneous melagatran and oral ximelagatran, 12 subjects with severe renal impairment had significantly higher melagatran exposure and longer half-lives than 12 controls with normal renal function, because of lower renal clearance of melagatran (38C ). These results suggest that in patients with severe renal impairment the dosage of ximelagatran should be reduced. Drug interactions Acetylsalicylic acid In a double-blind, randomized, two-way, crossover study in 12 healthy subjects aspirin, 450 mg on the day 1 and 150 mg just before intravenous administration of melagatran 4.12 mg on day 2, had no effect on the pharmacokinetics or pharmacodynamics of melagatran (39C ). However, the authors’ conclusion that the two can be safely coadministered needs to be tempered by caution until evidence is available in patients who use these drugs. Inhibitors of CYP isozymes In vitro studies have shown no evidence of involvement of CYP isozymes in either the production of melagatran from ximelagatran or its elimination. Diclofenac (an inhibitor of CYP2C9) 50 mg orally, diazepam (an inhibitor of CYP2C19)

David M. Keeling and Jeffrey K. Aronson

0.1 mg/kg intravenously, and nifedipine (an inhibitor of CYP3A4) 60 mg orally were coadministered with oral ximelagatran 24 mg in healthy volunteers; none of these drugs altered the pharmacokinetics of ximelagatran and ximelagatran did not alter their pharmacokinetics (40C ).

DRUGS THAT ALTER PLATELET FUNCTION (SED-14, 1193; SEDA-25, 412; SEDA-26, 380; SEDA-27, 360)

Abciximab

(SED-14, 1194; SEDA-23, 377; SEDA-27, 360) Abciximab is a chimeric anti-glycoprotein IIb/ IIIa monoclonal antibody that inhibits platelet aggregation. It has been studied in percutaneous coronary intervention, ST-elevation myocardial infarction, and non-ST-elevation acute coronary syndromes (41R ).

Comparative studies In the RAPPORT trial, the addition of abciximab was evaluated in 483 patients undergoing angioplasty. Abciximab was associated with an increase in major bleeding complications compared with heparin alone, 17% versus 9.5%. The safety profile of abciximab can be improved by weight-adjusted heparin dosing and reduced thrombolytic therapy (41R ). Abciximab (an intravenous bolus dose of 0.25 mg/kg or a 12-hour infusion of 0.125 micrograms/kg/minute) was evaluated in combination with intravenous reteplase (0.25–1.0 U/hour) and intravenous heparin (100–400 U/hour) in 50 adults with arterial occlusive disease (42c ). Eight developed a major hematoma that necessitated blood transfusion (1–11 U). Two had hematuria and one had hemoptysis. There was thrombocytopenia in two patients, including one with zero platelets. Four developed distal embolization after thrombolysis. Hematologic In consecutive patients undergoing percutaneous coronary interventions who were given either eptifibatide (n = 342) or abciximab (n = 300) during the procedure, thrombocytopenia was more frequent in those given abciximab (6%, versus 0%), including five patients who developed severe thrombocytopenia (under 20 × 109 /l) (43C ).

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

Clopidogrel (SED-14, 1194; SEDA-23, 378; SEDA-24, 399; SEDA-26, 380) Hematologic There have been four previous reports of clopidogrel-associated leukopenia, and another case has been described (44A ). Drug interactions Clopidogrel is a pro-drug that is converted to its active form by CYP3A4. The active drug irreversibly blocks one specific platelet adenosine 5 -diphosphate (ADP) receptor (P2Y12). As certain lipophilic statins (atorvastatin, lovastatin, simvastatin) are substrates of CYP3A4, drug interactions are possible, as suggested in two studies. Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation taking clopidogrel, clopidogrel plus pravastatin, or clopidogrel plus atorvastatin (45c ). Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel; in the presence of clopidogrel plus atorvastatin 0, 10, 20, and 40 mg, platelet aggregation was respectively 34%, 58%, 74%, and 89% of normal. In 47 patients with coronary artery disease blood samples were taken before and 5 and 48 hours after oral clopidogrel (loading dose 300 mg followed by 75 mg/day) (46c ). ADPstimulated expression of P-selectin (CD62P) on platelets was measured by flow cytometry and used as a marker for the antiplatelet effect of clopidogrel. Pre-treatment with statins (atorvastatin, simvastatin) reduced the inhibitory effects of clopidogrel during the loading phase (relative reduction after 5 hours 29%) and to a lesser extent during the maintenance phase (relative reduction after 48 hours 17%). Both sets of authors suggested that if clopidogrel and a statin are given together one should either use a statin that is not metabolized by CYP3A4 or monitor platelet function. This interaction was also studied in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial (47C ). This was a double-blind, placebo-controlled, randomized comparison of two regimens after percutaneous coronary interventions: pretreatment with clopidogrel 300 mg followed by 75 mg/day for 1 year, or clopidogrel 75 mg/day for 1 month without pretreatment. All the patients took aspirin. The 1-year primary endpoint was a composite of death, myocardial infarction, and stroke. Of the 2116 patients

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enrolled, 1001 took a statin that was metabolized by CYP3A4 and 158 took one that was not. In the overall study population, the primary end-point was significantly reduced by clopidogrel (8.5% versus 11.5%, RRR = 27%). This benefit was similar in those who also took a statin, irrespective of whether the statin inhibited CYP3A4 (7.6% versus 11.8%; RRR = 36%; 95% CI = 3.9, 58) or not (5.4% versus 14%; RRR = 61%, 95% CI = 24, 87). The authors concluded that although ex vivo testing has suggested a potential negative interaction when a CYP3A4-metabolized statin is co-administered with clopidogrel, this was not observed clinically in a post-hoc analysis of a placebo-controlled study. Thus, there is currently insufficient evidence to recommend avoiding a CYP3A4-metabolized statin or to recommend platelet function testing in patients taking clopidogrel.

Dipyridamole (SED-14, 1698; SEDA-24, 398; SEDA-25, 412; SEDA-26, 380) Drug overdose An unusual adverse effect has been attributed to dipyridamole overdose, yellow skin discoloration (48A ). • A 66-year-old man who took an overdose dipyridamole (Persantin Depot) of about 34 g developed intense neon-yellow coloring of the skin and urine. He also had an acute myocardial infarction and renal insufficiency. He gradually recovered but hemodialysis was needed for 2 weeks because of acute tubular necrosis after a prolonged period of hypotension.

Drug interactions Dipyridamole, in combination with [99m Tc]-sestamibi, is used to image myocardial perfusion, but the presence and severity of coronary artery disease may be underestimated in patients who are also taking beta-blockers (49C ) or enhanced by glibenclamide (50C ). In a placebo-controlled study in 12 healthy volunteers, dipyridamole 300 mg/day for 3 days altered on the pharmacokinetics of a single oral dose of digoxin 0.5 mg, increasing its AUC by about 13% (51C ). This may have been due to reduced clearance of digoxin, since dipyridamole inhibits the P glycoprotein that secretes digoxin into the gut lumen after its primary absorption and into the urine via the renal tubules.

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However, the effects were very small and probably clinically unimportant. There was no difference in the effect of dipyridamole between subjects with the different MDR1 genotypes, TT and CC.

Eptifibatide Eptifibatide is an inhibitor of platelet glycoprotein IIb/IIIa. Hematologic Eptifibatide can cause thrombocytopenia (52A –54A ) in an estimated 0.2% of patients (55A ). In 305 patients taking eptifibatide there were four cases of acute thrombocytopenia (platelet count less than 100 × 109 /l) (56c ). One had been previously exposed to eptifibatide. The platelet counts fell within 6 hours of the first dose and recovered within 6–30 hours after withdrawal. There were no adverse outcomes from thrombocytopenia. Proposed mechanisms include sequestration of platelets in the liver and an interaction of eptifibatide with naturally-occurring antibodies to ligandinduced binding sites on glycoprotein IIb/IIIa (55A ).

David M. Keeling and Jeffrey K. Aronson

• A 61-year-old woman with acute coronary syndrome was given heparin and eptifibatide and developed thrombocytopenia (platelet count 2.0 × 109 /l) and severe refractory hypotension (57A ). There were no heparin-induced antibodies, but eptifibatide-dependent antibodies specific for platelets were detected.

The authors attributed the thrombocytopenia and the hypotension to the eptifibatide antibodies. Susceptibility factors Renal impairment Eptifibatide is cleared by both renal and non-renal mechanisms, and renal clearance accounts for about 40% of total body clearance (58C ). Severe renal dysfunction prolongs the duration of action of eptifibatide, as has been shown in three patients (59A ). One patient with acute renal insufficiency prolonged inhibition of platelet aggregation; one with acute on chronic renal insufficiency had an intracerebral hemorrhage and normal platelet aggregation was restored by hemodialysis; in a third, with end-stage renal disease, platelet function returned to normal after hemodialysis.

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infarction: a systematic review. Q J Med 2003; 96: 103–13. 8. Tran AH, Lee G. Fondaparinux for prevention of venous thromboembolism in major orthopedic surgery. Ann Pharmacother 2003; 37: 1632–43. 9. Buller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, Prins MH, Raskob G, Van den Berg-Segers AE, Cariou R, Leeuwenkamp O, Lensing AW; Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. New Engl J Med 2003; 349: 1695–702; erratum 2004; 350: 423. 10. Hardy JF. Best evidence in anesthetic practice: prevention: fondaparinux is better than enoxaparin for prevention of major venous thromboembolism after orthopedic surgery. Can J Anaesth 2003; 50: 764–6. 11. Eriksson BI, Lassen MR; PENTasaccharide in HIp-FRActure Surgery Plus Investigators. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, doubleblind study. Arch Intern Med 2003; 163: 1337–42.

Drugs affecting blood coagulation, fibrinolysis, and hemostasis 12. Reiter M, Bucek RA, Koca N, Heger J, Minar E; PERSIST. Idraparinux and liver enzymes: observations from the PERSIST trial. Blood Coagul Fibrinolysis 2003; 14: 61–5. 13. Verme-Gibboney CN, Hursting MJ. Argatroban dosing in patients with heparin-induced thrombocytopenia. Ann Pharmacother 2003; 37: 970–5. 14. Sakai K, Oda H, Honsako A, Takahashi K, Miida T, Higuma N. Obstinate thrombosis during percutaneous coronary intervention in a case with heparin-induced thrombocytopenia with thrombosis syndrome successfully treated by argatroban anticoagulant therapy. Catheter Cardiovasc Interv 2003; 59: 351–4. 15. Edwards JT, Hamby JK, Worrall NK. Successful use of Argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg 2003; 75: 1622–4. 16. Kieta DR, McCammon AT, Holman WL, Nielsen VG. Hemostatic analysis of a patient undergoing off-pump coronary artery bypass surgery with argatroban anticoagulation. Anesth Analg 2003; 96: 956–8. 17. Reichert MG, MacGregor DA, Kincaid EH, Dolinski SY. Excessive argatroban anticoagulation for heparin-induced thrombocytopenia. Ann Pharmacother 2003; 37: 652–4. 18. De Denus S, Spinler SA. Decreased argatroban clearance unaffected by hemodialysis in anasarca. Ann Pharmacother 2003; 37: 1237–40. 19. Cochran K, DeMartini TJ, Lewis BE, O Brien J, Steen LH, Grassman ED, Leya F. Use of lepirudin during percutaneous vascular interventions in patients with heparin-induced thrombocytopenia. J Invasive Cardiol 2003; 15: 617–21. 20. Skowasch D, Potzsch B, Kuntz-Hehner S, Gampert T, Rox J, Omran H, Bauriedel G, Luderitz B. Biventrikulare Thrombenauflosung und Antikorper-Bildung unter Lepirudin-Therapie. Dtsch Med Wochenschr 2003; 128: 1531–4. 21. Greinacher A, Lubenow N, P Eichler. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003; 108: 2062–5. 22. Bergsrud EA, Gandhi PJ. A review of the clinical uses of ximelagatran in thrombosis syndromes. J Thromb Thrombolysis 2003; 16: 175–88. 23. Hrebickova L, Nawarskas JJ, Anderson JR. Ximelagatran: a new oral anticoagulant. Heart Dis 2003; 5: 397–408. 24. Eriksson H, Wahlander K, Gustafsson D, Welin LT, Frison L, Schulman S; Thrive Investigators. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003; 1: 41–7. 25. Colwell Jr CW, Berkowitz SD, Davidson BL, Lotke PA, Ginsberg JS, Lieberman JR, Neubauer J, McElhattan JL, Peters GR, Francis CW. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip re-

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placement. A randomized, double-blind study. J Thromb Haemost 2003; 1: 2119–30. 26. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Mouret P, Rosencher N, Eskilson C, Nylander I, Frison L, Ogren M; METHRO III Study Group. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thromb Haemost 2003; 89: 288–96. 27. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell Jr CW; EXULT A Study Group. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. New Engl J Med 2003; 349: 1703–12. 28. Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrom P, Bylock A; ESTEEM Investigators. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003; 362: 789–97. 29. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362: 1691–8. 30. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P, Rosencher N, Kalebo P, Panfilov S, Eskilson C, Andersson M, Freij A; EXPRESS Study Group. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. J Thromb Haemost 2003; 1: 2490–6. 31. Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H; THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. New Engl J Med 2003; 349: 1713–21. 32. Petersen P, Grind M, Adler J; SPORTIF II Investigators. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study. J Am Coll Cardiol 2003; 41: 1445–51. 33. Johansson LC, Andersson M, Fager G, Gustafsson D, Eriksson UG. No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers. Clin Pharmacokinet 2003; 42: 475–84. 34. Wolzt M, Wollbratt M, Svensson M, Wahlander K, Grind M, Eriksson UG. Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects. Eur J Clin Pharmacol 2003; 59: 537–43. 35. Johansson LC, Frison L, Logren U, Fager G, Gustafsson D, Eriksson UG. Influence of age on the pharmacokinetics and pharmacodynamics of xime-

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lagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42: 381–92. 36. Sarich TC, Teng R, Peters GR, Wollbratt M, Homolka R, Svensson M, Eriksson UG. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2003; 42: 485–92. 37. Wahlander K, Eriksson-Lepkowska M, Frison L, Fager G, Eriksson UG. No influence of mild-tomoderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42: 755–64. 38. Eriksson UG, Johansson S, Attman PO, Mulec H, Frison L, Fager G, Samuelsson O. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet 2003; 42: 743–53. 39. Fager G, Cullberg M, Eriksson-Lepkowska M, Frison L, Eriksson UG. Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, are not influenced by acetylsalicylic acid. Eur J Clin Pharmacol 2003; 59: 283–9. 40. Bredberg E, Andersson TB, Frison L, Thuresson A, Johansson S, Eriksson-Lepkowska M, Larsson M, Eriksson UG. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003; 42: 765–77. 41. Barbaro G, Grisorio B, Fruttaldo L, Bacca D, Babudieri S, Torre D, Francavilla R, Rizzo G, Belloni G, Lucchini A, Annese M, Matarazzo F, Hazra C, Barbarini G. Good safety profile and efficacy of leucocyte interferon-alfa in combination with oral ribavirin in treatment-naive patients with chronic hepatitis C: a multicentre, randomised, controlled study. BioDrugs 2003; 17: 433–9. 42. Tripi S, Soresi M, Di Gaetano G, Carroccio A, Giannitrapani L, Vuturo O, Di Giovanni G, Montalto G. Leucocyte interferon-alfa for patients with chronic hepatitis C intolerant to other alfainterferons. BioDrugs 2003; 17: 201–5. 43. Suleiman M, Gruberg L, Hammerman H, Aronson D, Halabi M, Goldberg A, Grenadier E, Boulus M, Markiewicz W, Beyar R. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, eptifibatide and abciximab: outcomes, complications and thrombocytopenia during percutaneous coronary intervention. J Invasive Cardiol 2003; 15: 319–23. 44. McCarthy MW, Kockler DR. Clopidogrelassociated leukopenia. Ann Pharmacother 2003; 37: 216–19. 45. Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, KE Guyer, Bates ER. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003; 107: 32–7. 46. Neubauer H, Gunesdogan B, Hanefeld C, Spiecker M, Mugge A. Lipophilic statins interfere

David M. Keeling and Jeffrey K. Aronson

with the inhibitory effects of clopidogrel on platelet function – a flow cytometry study. Eur Heart J 2003; 24: 1744–9. 47. Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, Topol EJ. Lack of adverse clopidogrel–atorvastatin clinical interaction from secondary analysis of a randomized, placebocontrolled clopidogrel trial. Circulation 2003; 108: 921–4. 48. Personne M, Mansten A, Svensson JO. Medvetslös patient med neongul hudvar intoxikerad med dipyridamol. Lakartidningen 2003; 100: 4194–5. 49. Taillefer R, Ahlberg AW, Masood Y, White CM, Lamargese I, Mather JF, McGill CC, Heller GV. Acute beta-blockade reduces the extent and severity of myocardial perfusion defects with dipyridamole Tc-99m sestamibi SPECT imaging. J Am Coll Cardiol 2003; 42: 1475–83. 50. Mortensen UM, Nielsen-Kudsk JE, Jakobsen P, Nielsen TT. Glibenclamide blunts coronary flow reserve induced by adenosine and dipyridamole. Scand Cardiovasc J 2003; 37: 247–52. 51. Verstuyft C, Strabach S, El-Morabet H, Kerb R, Brinkmann U, Dubert L, Jaillon P, Funck-Brentano C, Trugnan G, Becquemont L. Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition. Clin Pharmacol Ther 2003; 73: 51–60. 52. Tanaka KA, Vega JD, Kelly AB, Hanson SR, Levy JH. Eptifibatide-induced thrombocytopenia and coronary bypass operation. J Thromb Haemost 2003; 1: 392–4. 53. Nagge J, Jackevicius C, Dzavik V, Ross JR, Seidelin P. Acute profound thrombocytopenia associated with eptifibatide therapy. Pharmacotherapy 2003; 23: 374–9. 54. Salengro E, Mulvihill NT, Farah B. Acute profound thrombocytopenia after use of eptifibatide for coronary stenting. Catheter Cardiovasc Interv 2003; 58: 73–5. 55. Morel O, Jesel L, Chauvin M, Freyssinet JM, Toti F. Eptifibatide-induced thrombocytopenia and circulating procoagulant platelet-derived microparticles in a patient with acute coronary syndrome. J Thromb Haemost 2003; 1: 2685–7. 56. Khaykin Y, Paradiso-Hardy FL, Madan M. Acute thrombocytopenia associated with eptifibatide therapy. Can J Cardiol 2003; 19: 797–801. 57. Rezkalla SH, Hayes JJ, Curtis BR, Aster RH. Eptifibatide-induced acute profound thrombocytopenia presenting as refractory hypotension. Catheter Cardiovasc Interv 2003; 58: 76–9. 58. Alton KB, Kosoglou T, Baker S, Affrime MB, Cayen MN, Patrick JE. Disposition of 14 Ceptifibatide after intravenous administration to healthy men. Clin Ther 1998; 20: 307–23. 59. Sperling RT, Pinto DS, Ho KK, Carrozza Jr JP. Platelet glycoprotein IIb/IIIa inhibition with eptifibatide: prolongation of inhibition of aggregation in acute renal failure and reversal with hemodialysis. Catheter Cardiovasc Interv 2003; 59: 459–62.

S. Dar and H.R. Dalton

36 ANTACIDS

Gastrointestinal drugs (SED-14, 1220)

Pregnancy In an open, multicenter, phase IV study in 148 pregnant women aged 18–40 years with acid reflux symptoms, Gaviscon Advance (sodium alginate + potassium bicarbonate) had no safety concerns for mother or child (1C ). The treatment was efficacious and at least 81% of women expressed a wish to continue taking it. They took the medication for at least 4 weeks in doses of 5–10 ml, up to a maximum of 40 ml/day. Most of the subjects were in the second or third trimesters. The mothers were followed up for 4 weeks after treatment. There were no significant changes in mean sodium and potassium concentrations; however, in one patient there was clinically significant hyperkalemia. There were 240 adverse events, of which nine were thought to be related to the medication. No adverse event experienced by fetus or infant was thought to be related to the treatment.

ANTIEMETICS AND DRUGS THAT AFFECT GASTROINTESTINAL MOTILITY Cisapride

(SED-14, 1223; SEDA-25, 416; SEDA-26, 382; SEDA-27, 362) Susceptibility factors Age A meta-analysis of 10 randomized controlled trials, involving 450 children, has shown that cisapride has no clinically important benefits or harmful effects in children with gastroesophageal reflux (2M ).

© 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

Metoclopramide

(SED-13, 1069; SEDA-25, 417; SEDA-27, 362)

Cardiovascular In a double-blind, randomized, placebo-controlled study of metoclopramide as a single intravenous dose of 10 mg in 10 healthy men, metoclopramide caused an increase in QT slope and QT variance 30 minutes after the dose (3c ). Caution is recommended with other drugs that affect the QT interval. Nervous system An acute dystonic reaction occurred in a 44-year-old woman 45 minutes after an intramuscular injection of metoclopramide 10 mg, as a result of which she had a dislocation of the midfoot (4A ). Four patients aged 69–87 years who took metoclopramide 5–10 mg qds developed Parkinsonian signs, dependence on carers, and reduced functional ability (5A ). The authors described this as metoclopramide-induced “failure to thrive”. One patient had pre-existing Parkinson’s disease and another had type 2 diabetes mellitus. All improved on stopping metoclopramide, but one was unable to walk again owing to contractures. The authors of a review of the safety and efficacy of long-term metoclopramide for diabetic gastroparesis concluded that there is insufficient evidence to recommend long-term use of metoclopramide (6R ). The risk of tardive dyskinesia is significant. They suggested that physicians should make patients aware of the risk of movement disorders. For most patients, prescription for 2–8 weeks should be sufficient, restarting therapy if symptoms recur. Patients should be monitored for movement disorders, perhaps by performing an abnormal involuntary movement scale examination (7R ) every 6 months and after withdrawal of metoclopramide.

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5-HT3 RECEPTOR ANTAGONISTS (SED-14, 1225; SEDA-25, 417; SEDA-26, 382; SEDA-27, 363) Comparative studies Tropisetron, ondansetron, and dolasetron have been compared in a randomized, double-blind, parallel-group study in 118 patients who had undergone major gynecological surgery (8C ). The incidence of nausea and vomiting was similar in all groups in the first 24 hours, but after 24 hours it was 57% in those given tropisetron, 75% in those given ondansetron, and 73% in those given dolasetron. However, as overall and interval nausea scores were similar, and recovery times, satisfaction, and cost per patient did not differ between groups, the authors concluded that the choice between agents should be based on costs.

Alosetron Gastrointestinal When alosetron is used for severe irritable bowel syndrome with predominant diarrhea, constipation is the most frequent adverse effect; it occurs in 20–30% of patients in clinical trials (9R ). The effect was not dose related at 1, 2, and 4 mg/day, but at a dose of 8 mg 35% of patients reported constipation (10C ). Four cases of suspected ischemic colitis have been reported in trials, an incidence of 1 in 750. By November 2000 (when alosetron was withdrawn), 275 000 patients were taking it. A postmarketing safety review reported 84 cases of ischemic colitis; 54 patients required hospitalization, 11 required surgery, and two died; there were also three deaths from small bowel ischemia. There were 113 reports of complications due to constipation: 83 patients required hospitalization, 24 required surgery, and two died. In a meta-analysis of the efficacy of alosetron in irritable bowel syndrome, including six multicenter randomized controlled trials, in 1762 patients given alosetron and 1356 given placebo, constipation was reported by 25% of the patients (NNTH = 3.9), and those who took alosetron were on average 5.64 times more likely to report constipation than those who took placebo (11M ). The proportion of those with constipation who had to withdraw as a result was 10–43%. There were two cases of

Chapter 36

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ischemic colitis, giving a prevalence of 0.1%. Follow-up of these patients suggested an infectious cause in one and a thrombotic tendency in the other. In a retrospective review of the medical notes of 3631 alosetron users and 2480 patients with irritable bowel syndrome not given alosetron, there were no cases of colonic ischemia, an equal incidence of bowel surgery, and an equal rate of hospitalization for constipation (12C ).

Dolasetron When granisetron was replaced by dolasetron in 20 patients receiving chemotherapy, there were no adverse outcomes but a significant cost saving (13c ). Adverse effects were minimal and similar with the two treatments. Drug dosage regimens Dolasetron reduces postoperative vomiting in children aged 2–12 years undergoing strabismus surgery (14C ). In a randomized double-blind controlled study 118 children were given a single dose of 0.35 mg/kg or 12.5 mg or placebo. Patients with no emetic episodes within 24 hours were 62%, 64%, and 33% respectively. Adverse effects were not mentioned.

Granisetron In two double-blind, randomized studies of 120 and 100 patients, the combination of granisetron (40 micrograms/kg intravenously) and dexamethasone (8 mg intravenously) was more effective in relieving nausea and vomiting after laparoscopic cholecystectomy than granisetron alone; adverse events were similar (15C , 16C ). Patients preferred granisetron to ramosetron in a double-blind, crossover, randomized, controlled trial of 30 patients receiving chemotherapy (17c ).

Mosapride Mosapride is a 5HT4 receptor agonist and a 5HT3 receptor antagonist. In chronic gastroesophageal reflux disease in 41 patients in a

Gastrointestinal drugs

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double-blind, randomized, three-way, crossover study it had a small effect on acid reflux and esophageal motor function, comparable to that of cisapride (18c ).

Ranitidine Respiratory In 30 patients with chronic obstructive pulmonary disease and 25 healthy controls there were small falls in FEV1 and FVC 60 and 120 minutes after a single 50 mg dose of intravenous ranitidine (21c ). However, the results did not reach statistical significance.

HISTAMINE H2 RECEPTOR ANTAGONISTS (SED-14, 1225; SEDA-25, 419; SEDA-26, 384; SEDA-27, 363)

PROTON PUMP INHIBITORS

Famotidine

(SED-14, 1230; SEDA-25, 420; SEDA-26, 384; SEDA-27, 364)

Nervous system In a randomized controlled trial in 35 infants aged 1.3–10.5 months, given famotidine 0.5 and 1.0 mg/kg for gastroesophageal reflux, famotidine caused agitation and headache and other minor adverse effects (19c ). Famotidine improved regurgitation frequency, regurgitation volume and crying time. There were 16 minor adverse events in 11 patients; agitation or irritability (n = 6), somnolence (n = 3), anorexia (n = 2), headache (n = 2), vomiting (n = 1), hiccups (n = 1), and candidiasis (n = 1).

Nizatidine Gastrointestinal The gastrointestinal safety of a reduced dose of nizatidine for elderly patients has been addressed in a study in 336 patients aged over 65 years with a reduced creatinine clearance (mean 34 ml/minute) in a nursing home (20C ). The elimination of H2 receptor antagonists is reduced in renal insufficiency. This can contribute to acute central nervous system toxicity, and a reduced dose of the H2 receptor antagonist may therefore be safer. Nizatidine in a mean dose of 100 mg/day given to 198 patients was compared with 184 mg/day given to 138 patients. Follow-up was for up to 12 months. Major and minor gastrointestinal bleeding events were equal in the two groups. The mortality rate was higher in those who took the higher dose of nizatidine (22% versus 12%). The authors suggested that this was because the patients in this group were more ill.

Comparative studies Empirical treatment with a proton pump inhibitor is a less effective strategy than first establishing Helicobacter pylori status and eradicating appropriately before starting proton pump inhibitor therapy only in those who are Helicobacter pylori negative. In a controlled trial 219 patients under 45 years of age, without alarm symptoms, were randomized to omeprazole 20 mg/day or eradication therapy if Helicobacter pylori positive, or to omeprazole 20 mg/day if Helicobacter pylori negative (22C ). Endoscopy was done if symptoms recurred or there was no improvement. In the first group 96/109 patients required endoscopy compared with 61/110 of the second group. There were nine duodenal scars in the first group. Thus, eradication therapy reduces the need for endoscopy in patients aged under 45 years without alarm symptoms. Empirical treatment is likely to result in recurrence and can mask peptic ulcers and esophagitis.

Esomeprazole Comparative studies In a five-way crossover study esomeprazole 40 mg/day produced more acid suppression than lansoprazole 30 mg/day, omeprazole 20 mg/day, pantoprazole 40 mg/day, or rabeprazole 20 mg/day (23C ). The study was conducted in 34 Helicobacter pylori negative patients aged 18–60 years, with symptoms of gastroesophageal reflux. Intragastric pH was maintained above 4 for a mean of 14 hours with esomeprazole, 12 hours with rabeprazole, 12 hours with omeprazole, 12 hours with lansoprazole, and 10 hours with pantoprazole. Adverse events were similar with all treatments.

404

Lansoprazole Comparative studies In an observational comparison of lansoprazole, cimetidine, and famotidine in the prevention of stress ulcers, lansoprazole was the most cost effective agent (24c ).

Omeprazole

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Pantoprazole Drug dosage regimens Pantoprazole 10, 20, or 40 mg/day and ranitidine 150 mg bd have been compared as maintenance treatment for grade 0 or 1 erosive esophagitis in 371 patients (31C ). Pantoprazole 40 mg/day was the most successful therapy in terms of symptom relief and endoscopic remission. It was well tolerated.

Respiratory Chronic persistent cough has been attributed to omeprazole in one patient (25A ). • A 42-year-old non-smoking woman developed a dry, non-productive cough 1 day after starting to take omeprazole 20 mg/day. The cough persisted for 4 months while she continued to take it. When omeprazole was withdrawn before upper gastrointestinal investigation, the cough resolved within 1 day. The patient declined rechallenge. There was no cough during 2 years of follow up, during which time omeprazole was not used.

The manufacturer’s product literature states that cough can occur in 1.1% of patients. Gastrointestinal In nine patients with Helicobacter pylori, given omeprazole 20 mg bd for 6.5 days there was marked extension of corpus inflammation into the gastric pit and an increase in corpus mucosal concentrations of interleukin-1 beta and interleukin-8 (26c ). The authors suggested that Helicobacter pylori eradication therapy should be considered for all patients taking long-term proton pump inhibitor therapy. Electrolyte balance Hyperkalemia has been associated with intravenous omeprazole 20 mg bd (27A ). The peak potassium concentration was 6.6 mmol/l. Immunological Anaphylactic shock has been reported with intravenous omeprazole (28A ). Susceptibility factors Age Omeprazole reduced esophageal acid exposure but not irritability in 30 infants aged 3–12 months (29c ). Drug formulations Pantoprazole 40 mg/day and omeprazole MUPS 40 mg/day were equally efficacious in patients with moderate to severe reflux esophagitis in a randomized, doubleblind, parallel-group, international, multicenter study (30C ). Both drugs were well tolerated.

Rabeprazole Respiratory Rabeprazole 20 mg/day for 8 weeks improved peak expiratory flow rate in 53 patients with asthma and gastroesophageal reflux (32c ). There was a 20% improvement in peak expiratory flow rate in eight of 21 patients with reflux, but no improvement in those who did not have reflux. Drug dosage regimens Rabeprazole 10 and 20 mg have been compared in 212 patients with peptic ulcer disease in a multicenter Japanese randomized study (33C ). Rabeprazole was efficacious. The 20 mg dose provided earlier relief of the primary endpoint, epigastric pain. However, endoscopic cure rates were not significantly different: 96% with 10 mg/day and 99% with 20 mg/day. Adverse events occurred in 13% of those who took 10 mg/day and 20% of those who took 20 mg/day. Two doses of rabeprazole, 10 and 20 mg/day, were equally effective in combination with clarithromycin and tinidazole in Helicobacter pylori eradication therapy in 94 patients (34c ). Eradication rates were 89% and 91% respectively. Adverse effects were similar in the two groups. A randomized, double-blind comparison of rabeprazole 10 and 20 mg/day and omeprazole 20 mg/day has shown all three to be equally efficacious in maintenance therapy of gastroesophageal reflux disease over 5 years in 123 patients (35C ). The relapse rates were 8/82 (9.8%), 9/78 (11.5%), and 11/83 (13%) respectively. All three treatments were well tolerated.

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DRUGS THAT AFFECT HELICOBACTER PYLORI Ecabet Comparative studies Ecabet is an anti-ulcer agent that inhibits adhesion of Helicobacter pylori to the gastric mucosa and is bactericidal (36c ). It works by inhibiting urease and ATPase in Helicobacter pylori. In a randomized study in 63 Helicobacter pylori-positive patients who had been cured of peptic ulcers, a combination of ranitidine and ecabet prevented ulcer recurrence compared with ranitidine alone. The cumulative relapse rates were 66% and 13% respectively after 2 years.

HELICOBACTER PYLORI ERADICATION REGIMENS (SEDA-25, 422; SEDA-26, 386; SEDA-27, 366)

Bismuth biskalcitrate + metronidazole + tetracycline + omeprazole In an international multicenter trial this 10-day regimen, which overcomes metronidazole resistance, was effective and well tolerated (37C ). Eradication rates were 95% (38/40) for strains resistant to metronidazole and 99% (75/76) for strains sensitive to metronidazole.

Esomeprazole + clarithromycin + metronidazole Esomeprazole 20 mg bd + clarithromycin 500 mg bd + metronidazole 400 mg bd was well tolerated and of similar efficacy to a regimen of omeprazole 20 mg bd + clarithromycin + metronidazole in 72 patients (38C ). Adverse effects were diarrhea, taste disturbance, and headache; all were mild and self limiting.

Omeprazole + azithromycin + amoxicillin or tinidazole In randomized comparison of omeprazole + azithromycin + either amoxicillin or tinidazole, both regimens were only partially successful at eradicating Helicobacter pylori (eradication rates 63% and 71% respectively) (39C ). The adverse effects with both regimens were negligible.

Omeprazole + clarithromycin + tinidazole Omeprazole + clarithromycin + tinidazole for 7 days has been compared with the same regimen followed by omeprazole or placebo for 21 days, in a double-blind, placebo-controlled study in 103 patients with Helicobacter pylori positive peptic ulcer disease (40C ). There was no difference in ulcer healing (95% versus 96%) or rate of eradication of Helicobacter pylori (84% versus 83%) at 16 weeks. At 1 year all the patients were free from both peptic ulcer disease and Helicobacter pylori infection.

Rabeprazole + amoxicillin + clarithromycin Rabeprazole 10 mg bd + amoxicillin 1 g bd + clarithromycin 500 mg bd, given for 1 week to 180 patients, was successful in 166 (92%) (41C ). Ulcer healing occurred by 4 weeks (with no continuation of proton pump inhibitor beyond the 1 week triple therapy), in 42/44 patients (96%) in whom eradication therapy was successful. Ulcer healing did not occur in the three patients in whom the bacteria were not eradicated. The authors commented that this underlines the significant role of Helicobacter pylori in ulcer pathogenesis. Adverse effects were bitter taste (39%), giddiness (8%), abdominal pain (5%), lethargy (5%), loose bowel motions (8%), and rash (1%). Triple therapy was not completed in 2% of the patients because of adverse effects.

406

Rabeprazole + amoxicillin + metronidazole As second-line therapy in Japanese patients who remained Helicobacter pylori positive after a proton pump inhibitor + amoxicillin + clarithromycin), a regimen of rabeprazole 20 mg bd + amoxicillin 750 mg bd + metronidazole 250 mg bd for 1 week produced an eradication rate of 97% (61/63) for metronidazolesensitive strains and 82% (18/22) for metronidazole-resistant strains (42C ).

Rabeprazole + levofloxacin + rifabutin Rabeprazole 20 mg bd + levofloxacin 500 mg/day + rifabutin 300 mg/day for 7 days has been compared with rabeprazole 20 mg bd, metronidazole 400 mg tds, bismuth subcitrate 120 mg qds, and tetracycline 500 mg qds for 7 days (43C ). All 109 patients had previously failed Helicobacter pylori eradication therapy. There was significant resistance to metronidazole and clarithromycin in patients who had previously received these drugs. The two regimens were as efficacious as second-line eradication treatments, with eradication rates of 91% in the triple-therapy group and 92% in the quadruple-therapy group.

ANTIDIARRHEAL AGENTS (SED-14, 1233; SEDA-25, 423; SEDA-27, 367)

Loperamide Gastrointestinal A 2-year-old girl developed paralytic ileus after taking loperamide for acute gastroenteritis (44A ).

Racecadotril Racecadotril, an enkephalinase inhibitor, has yet to be shown to be a useful treatment for diarrhea, according to a review article (45R ).

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Oral rehydration therapy Drug formulations In a randomized trial in 4000 children in Burkino Fasu a regimen of a high osmolarity solution (90 mmol/l sodium), followed by a low osmolarity solution (30 mmol/l sodium) and early re-feeding was more effective than a low osmolarity solution given alone or a high osmolarity solution given alone (46C ). Body weight was regained more quickly, stool output fell more, and fewer patients were hospitalized. Patients given only the low osmolarity solution were more lethargic. Patients given the high osmolarity solution developed hypernatremia (over 140 mmol/l). The recommended regimen was well tolerated.

LAXATIVES

(SED-14, 1235; SEDA-25, 423; SEDA-26, 387; SEDA-27, 367)

Oral bowel preparation Patients who had taken both oral bowel preparation (two 45 ml bottles of Fleet Phospho-soda or two sachets of Picolax) and self-administered a single phosphate enema on separate occasions indicated a preference for oral formulations in a postal questionnaire (47C ). They reported that oral formulations were easier to use and caused less incontinence and pain. More said that they would choose the oral formulation in future rather than the enema (61% versus 39%). In a prospective randomized trial in 953 patients seven bowel preparation regimens were compared (48R ): • • • •

sennoside calcium; polyethylene glycol; oral sodium phosphate in one 90 ml dose; oral sodium phosphate in two doses (90 ml and 45 ml); • oral sodium phosphate in two doses (45 ml and 90 ml); • sodium phosphate 45 ml with cisapride 10 mg then 90 ml sodium phosphate (without cisapride); • sodium phosphate 45 ml with domperidone 10 mg then sodium phosphate 90 ml without domperidone.

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Chapter 36

The regimen that contained cisapride was abandoned during the study when reports of its adverse cardiovascular effects were published. The most effective colon cleansing regimens were sodium phosphate + cisapride and sodium phosphate + domperidone, which achieved effective cleansing in all patients. The regimens least well tolerated (in terms of nausea, vomiting, abdominal pain, and weariness) were sennoside calcium and polyethylene glycol; 79% and 89% of patients said they would be unwilling to undergo bowel preparation with these regimens again, compared with 73% who would be willing to take sodium phosphate + domperidone again. Castor oil, polyethylene glycol-electrolyte lavage solution, and sodium phosphate have been compared for tolerability: 122 patients undergoing barium enema were given castor oil 45 ml, 76 patients undergoing sigmoidoscopy were given sodium phosphate 50 ml, and 105 patients undergoing colonoscopy were given PEG-ELS 4 liters (49C ). The most frequent gastrointestinal complaint was abdominal pain, in 52% of patients. This occurred most often in those who took castor oil (68%). Headache and vertigo occurred more often in those who took sodium phosphate and polyethylene glycol-electrolyte lavage solution than in those who took castor oil. The heart rate was reduced more often after polyethylene glycol-electrolyte lavage solution than after castor oil. There were no statistical differences in the prevalences of general weakness and fainting, nausea and vomiting, blood pressure changes, or increased heart rate. Electrolyte and mineral balance Potentially serious electrolyte imbalances occurred in 36 hospitalized patients aged over 65 years who underwent bowel preparation with sodium phosphate (50c ). Dementia was associated with hypokalemia after sodium phosphate administration. Reduced creatinine clearance correlated with an increase in serum phosphate concentration. Mannitol, polyethylene glycol, and oral sodium phosphate have been compared in a prospective randomized trial in 90 patients (51C ). All produced similar tolerance and bowel cleansing. Electrolyte changes occurred in every group, but were least common in those who took polyethylene glycol, and were within the

407 reference ranges in most patients. No complications occurred. Asymptomatic hyperphosphatemia occurred in 93% of patients given sodium phosphate. • Tetany developed in a 74 year old woman after bowel preparation with Fleet Phospho-Soda. She developed hyperphosphatemia (7.29 mmol/l) and hypocalcemia (1.82 mmol/l) (52A ).

Gastrointestinal In a comparison of polyethylene glycol (Klean-PreP), a sulfate-free polyethylene glycol solution (Endofalk), and sodium phosphate (Fleet Phospho-Soda) in 173 patients, adverse effects (mainly nausea, vomiting, and abdominal pain) occurred more often in those given sodium phosphate (53C ). Klean-Prep was significantly better than either Endofalk and Fleet Phospho-Soda in bowel cleansing. Liquid Fleet Phospho-Soda was better tolerated and more effective than Visicol (sodium phosphate in tablet form) in 101 patients (54C ). In 10 healthy subjects various laxatives were assessed in a randomized, blind study: no treatment; oral mannitol; isotonic saline enema; Fleet’s Phospho-Soda enema; and bisacodyl (Dulcolax) 10 mg by enema or suppository (55C ). The rectal mucosa after mannitol-induced diarrhea or saline enema could not be distinguished from untreated rectum by proctoscopy, light microscopy, or scanning electron microscopy. Fleet’s enema and bisacodyl invariably changed proctoscopic appearances, and often altered the appearances on light and scanning microscopy. Both Fleet’s enema and bisacodyl caused sloughing of the surface epithelium. In addition, bisacodyl reduced the uptake of hematoxylin and eosin by crypt epithelial cells, so that the affected cells had a partially erased appearance. The lamina propria in three of 25 biopsies contained polymorphonuclear cells. Transmission electron microscopy showed that the abnormal crypt epithelial cells contained fewer cytoplasmic organelles and less nuclear chromatin. All the lesions resolved within 7 days. Fleet’s enema and bisacodyl by rectum can alter normal rectal mucosa and mislead the proctologist and the pathologist.

408

AMINOSALICYLATES (SED-14, 1237; SEDA-25, 423; SEDA-26, 387; SEDA-27, 367) It has been suggested that aminosalicylates are chemoprotective against colorectal cancer (56R ). The authors suggested that patients with inflammatory bowel disease at high risk of colorectal cancer, for example those with a positive family history, should continue to take aminosalicylates, even with quiescent disease. Comparative studies Mesalazine was less effective and improved quality of life less than budesonide in patients with glucocorticoiddependent Crohn’s disease (57c ). In 29 patients given budesonide 6 mg/day and 28 given mesalazine 1g tds, the 1-year relapse rates were 55% and 82% respectively.

Mesalazine (5-aminosalicylic acid, mesalamine) Respiratory There have been three cases of interstitial lung disease related to the use of mesalazine in patients with inflammatory bowel disease (58A ). They all underwent lung biopsy. There was resolution of the clinical and radiographic signs within 6 weeks of withdrawal of mesalazine. All three were also given glucocorticoids. The authors suggested that this adverse effect was not related to dose or duration of therapy. There have been 11 reports of lung involvement with Crohn’s disease, usually self limiting (59c ). Nervous system Benign intracranial hypertension has been reported in a patient who had taken mesalazine 400 mg tds for 3 years (60A ). • A 23-year-old patient, who had symptoms of intermittent headache for 3 years, suffered severe loss of vision. Rechallenge with mesalazine produced a rise in intracranial pressure within 15 days.

A sensorimotor polyneuropathy has been reported in a patient who took sulfasalazine and then mesalazine (61A ).

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• One month after starting to take sulfasalazine 3 g/day a 69-year-old patient developed skin eruptions and mild dysesthesia in the lower limbs. Sulfasalazine was changed to mesalazine 750 mg/day for 8 months. The skin lesions resolved, but the dysesthesia progressed. Motor weakness, muscle atrophy, absent deep tendon reflexes, and high stepping gait developed. He stopped taking the mesalazine for 3 weeks, and the dysesthesia and muscle power improved and the deep tendon reflexes returned; 2 months later he had only mild atrophy of the right arm and mild disturbance of vibration sense in the left leg.

Gastrointestinal Mesalazine enemas cannot be recommended as prophylaxis against radiation-induced proctitis. In a comparison of enemas of sucralfate 3 g in 15 ml suspension enema (n = 63), mesalazine 4 g (n = 8), and hydrocortisone 100 mg (n = 63), mesalazine was prematurely terminated after seven patients developed rectal toxicity (62C ). Sucralfate and hydrocortisone were equally effective: acute rectal toxicity occurred in 62% and 52% respectively. Pancreas Acute pancreatitis has been attributed to mesalazine (63A ). • A 19-year-old patient with ulcerative colitis, who had taken mesalazine 2.4 g/day for 1 month, then 1.2 g/day for 11 months, developed acute pancreatitis. Rechallenge with mesalazine 5 days after the initial diagnosis resulted in a second bout. Subsequent use of azathioprine resulted in hyperamylasemia.

The authors postulated an allergic mechanism. Urinary tract In an open multicenter study of 18 patients with Crohn’s disease and 29 patients with ulcerative colitis, mesalazine 3 g/day or more did not cause renotubular damage (64c ). Pregnancy and teratogenicity In a cohort study of patients with inflammatory bowel disease given 5-aminosalicylates during pregnancy there was an increased risk of stillbirth and premature birth in patients with ulcerative colitis (65C ). The authors noted that it was difficult to assess the impact of disease activity on pregnancy outcome. Administration of systemic courses of glucocorticoids was used as a surrogate marker for disease activity. The use of systemic glucocorticoids and 5-aminosalicylates further increased the risk of

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stillbirth, suggesting that disease activity may be a risk factor for adverse birth outcome. In 88 pregnancies in which 5-aminosalicylates had been taken during the entire pregnancy, compared with 19 418 pregnancies in which no drugs were taken, the odds ratio for stillbirth was 6.4 (95% CI = 1.7, 25); for preterm birth 1.9 (0.9, 3.9); and for low birth weight 1.2 (0.4, 3.3). In order to assess the risk of malformations, 60 pregnancies were studied in which 5-aminosalicylates had been taken 30 days before pregnancy or in the first trimester. The odds ratio was 1.9 (0.9, 3.9). The authors concluded that there is no substantial increased risk of malformations. The safety of mesalazine has been demonstrated in several trials (66R ). In a post-marketing study the rate of fetal malformations was 3/76 pregnancies (in 55 women). This rate is similar to that in the general population. Another study showed a significant increase in preterm deliveries (13% versus 5%) and a reduction in mean birth weight (3.2 kg versus 3.4 kg) in women who took mesalazine. There were no differences between rates of live births, miscarriages, terminations, or fetal distress. A 4-month-old infant developed thrombosis of the superior saggital sinus, secondary to thrombocytosis (1124 × 109 /l). The mother had taken mesalazine throughout the pregnancy and during lactation (67A ).

SECRETORY STIMULANTS Secretin The secretin stimulation test is used mainly in academic centers to diagnose chronic pancreatitis. Production of biologically derived porcine secretin ceased in 1999, and synthetic forms have been developed. In a randomized crossover comparison of synthetic porcine secretin and synthetic human secretin, followed by a comparison of these with natural porcine secretin, synthetic secretin was interchangeable with natural porcine secretin (68c ). No serious adverse effects were reported by 18 healthy subjects and 12 subjects with chronic pancreatitis. One patient reported flushing and another mild nausea; 80% had an asymptomatic, transient increase in heart rate up to 20% above baseline.

The tachycardia was more pronounced after the synthetic secretins.

CHOLELITHOLYTIC AGENTS (SED-14, 1240; SEDA-25, 426; SEDA-26, 389; SEDA-27, 369) In a randomized, double-blind, placebo-controlled 12-month study, ursodeoxycholic acid 800 mg/day did not improve liver function tests or histology in 60 patients with chronic viral hepatitis who had a heart transplant (69c ). Adverse events and mortality were the same in the two groups. However, combined ursodeoxycholic acid and bezafibrate can reduce pruritus and normalize impaired liver function tests compared with ursodeoxycholic acid alone in patients with primary biliary cirrhosis (70c ). In 22 patients randomized to ursodeoxycholic acid 600 mg/day with or without bezafibrate 400 mg/day, alkaline phosphatase normalized in two of those who took ursodeoxycholic acid alone and five of those who took the combination. There was pruritus in seven patients who took bezafibrate and it only resolved in one. The combination of aspirin and ursodeoxycholic acid is not more effective at gall stone dissolution than ursodeoxycholic acid alone (71c ). The conclusion of a review of 11 published trials of ursodeoxycholic acid in patients with primary biliary cirrhosis (72M ) was that the evidence suggests that it is beneficial for both disease symptoms and disease progression. Although the authors added that no serious adverse effects or complications were reported, the presentation of the safety data was unfortunately inadequate. Metabolism In a randomized controlled study in 86 patients with primary biliary cirrhosis given ursodeoxycholic acid 13–15 mg/kg/day there was significant weight gain (average 3.6 kg) in the first 12 months of treatment, maintained for 4 years, and not related to baseline body mass index (73C ). In this study patients were. Of 73 patients who took placebo, 43 had an average weight gain of 0.6 kg. The authors postulated that the weight gain may have been

410 due to a sense of improved well-being in patients taking ursodeoxycholic acid, resulting in increased enjoyment and intake of food. They suggested that ursodeoxycholic acid may affect cytokine concentrations, which may influence body mass; alternatively, ursodeoxycholic acid may improve malabsorption and thus increase body mass. Gastrointestinal When ursodeoxycholic acid was given for gallstone disease, diarrhea occurred with an incidence of 2–9%. In patients with primary biliary cirrhosis, diarrhea was only occasionally reported. In patients with sclerosing cholangitis and inflammatory bowel disease, severe diarrhea occurred in one of six and two of 18 patients in two studies. In a randomized controlled trial of ursodeoxycholic acid in primary sclerosing cholangitis in 102 patients, diarrhea was not reported. Abdominal pain has been reported in two patients with primary biliary cirrhosis. The pain recurred on re-exposure. Abdominal pain, flatulence, diarrhea, and nausea have also been reported in patients with primary biliary cirrhosis taking ursodeoxycholic acid. Liver Decompensation of liver function in primary biliary cirrhosis has been reported once. It is therefore recommended that ursodeoxycholic acid be started at a low dose in these patients if they are jaundiced with stage IV cirrhosis. Bilirubin concentration should be monitored and ursodeoxycholic acid withdrawn if it rises. Hematologic A systematic review of the literature on adverse events related to ursodeoxycholic acid reported between 1991 and 2003 has shown that it is generally well tolerated (74M ). Only one serious adverse effect was identified amongst 990 patients. This patient developed hemolytic anemia, which was thought unlikely to be due to ursodeoxycholic acid. After treatment of the hemolytic anemia the patient again took ursodeoxycholic acid for 12 years. Skin Pruritus can be exacerbated by ursodeoxycholic acid (74M ). Teratogenicity Ursodeoxycholic acid is not approved for use in early pregnancy because there is insufficient data on fetotoxicity (74M ).

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It can be used in the second and third trimesters for symptomatic intrahepatic cholestasis of pregnancy (75C ). Lactation Ursodeoxycholic acid is not recommended during breast feeding as it is not known whether it enters breast milk. Drug interactions Anion exchange resins such as colestyramine bind ursodeoxycholic acid in the gut, thereby preventing absorption (76C ). Aluminium hydroxide and smectite also form inabsorbable complexes (77C ). Ciclosporin bioavailability may increase In patients taking ursodeoxycholic acid (78A ). A possible explanation is induction of CYP3A by ursodeoxycholic acid. Ciprofloxacin absorption may have been reduced because of ursodeoxycholic acid according to one case report (79A ). Dermatitis herpetiformis treated with dapsone flared during co-administration of ursodeoxycholic acid for gallstone disease, improved on withdrawal, and flared again on reintroduction (80A ). The pharmacokinetics of nitrendipine were affected by ursodeoxycholic acid (81C ). Ursodeoxycholic acid improved the absorption of vitamin E in one patient with cystic fibrosis and pancreatic insufficiency (82A ).

OTHER GASTROINTESTINAL AGENTS Sclerosant injections

(SED-13, 1086;

SEDA-25, 387) Immunologic A pulmonary allergic reaction has been reported following a second sclerotherapy procedure in a 44-year-old patient 3 weeks after the first (83A ). The patient developed a flu-like illness in the following days. Chest radiography showed diffuse bilateral parenchymal changes, and a high-resolution CT scan of the lungs showed peripheral interstitial involvement. The symptoms and signs resolved after 48 hours.

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50. Beloosesky Y, Grinblat J, Weiss A, Grosman B, Gafter U, Chagnac A. Electrolyte disorders following oral sodium phosphate administration for bowel cleansing in elderly patients. Arch Intern Med 2003; 163: 803–8. 51. Macedo E, Ferrari A. Comparative study among three methods for oral colonoscopy preparation: mannitol, polyethylene glycol and oral sodium phosphate enema. Dig Endosc 2003; 15: 43–7. 52. Ma KK, Mg CSH, Mui K, Chan C, Ng EKW, Chung SCS. Severe hyperphosphataemia and hypocalcaemia following sodium phosphate bowel preparation: a forgotten menace, Endoscopy 2003; 35: 717. 53. Ell C, Fischbach W, Keller R, Dehe M, Mayer G, Schneider B, Albrecht U. Schuette W. A randomised, blinded, prospective trial to compare the safety and efficacy of three bowel-cleansing solutions for colonoscopy (HSG-01). Endoscopy 2003; 35: 300–4. 54. Balaban DH, Leavell Jr BS, Obiner MJ, Thompson WO, Bolton ND, Pambianco DJ. Low volume bowel preparation for colonoscopy: randomised endoscopist-blinded trial of liquid sodium phosphate versus tablet sodium phosphate. Am J Gastroenterol 2003; 98: 827–32. 55. Meisel JL, Bergman D, Graney D, Saunders DR, Rubin CE. Human rectal mucosa: proctoscopic and morphological changes caused by laxatives. Gastroenterology 1977; 72: 1274–9. 56. Ryan BM, Russel GVM, Langholz E, Stockbrugger RW. Aminosalicylates and colorectal cancer in IBD: a not so bitter pill to swallow. Am J Gastroenterol 2003; 98: 1682–7. 57. Mantzaris GJ, Petraki K, Sfakianakis M, Archaviis E, Christidou A. Budesonide versus mesalamine for maintaining remission in patients refusing other immunomodulators for steroiddependent Crohn’s disease. Clin Gastroenterol Hepatol 2003; 1: 122–128. 58. Foster R, Zander D, Mergo P, Valentine J. Mesalamine related lung disease: clinical, radiographic and pathologic changes. Inflamm Bowel Dis 2003; 9: 308–15. 59. Casey MB, Tazelaar HD, Myers JL, Hunninghake GW, Kaker S, Kalra SX, Ashton R, Colby TV, Non-infectious lung pathology in patients with Crohn’s disease, Am J Surg Pathol 2003: 27: 213– 19. 60. Rosa N, Giamundo A, Jura A, Iaccarino G, Romano A. Mesalazine-associated benign intracranial hypertension in a patient with ulcerative colitis. Am J Ophthalmol 2003; 136: 212–13. 61. Ono K, Iwasa K, Shirasaki H, Takamori M. Sensorimotor polyneuropathy with 5-aminosalicylic acid: a case report. J Clin Neurosci 2003; 10: 386– 9. 62. Sanguineti G, Franzone P, Marcenaro M, Foppiano F, Vitale V. Sucralfate versus mesalazine versus hydrocortisone in the prevention of acute radiation proctitis during conformal radiotherapy for prostate carcinoma: a randomised study. Strahlenther Onkol 2003; 179: 464–70. 63. Toubanakia C, Batziou E, Sipsas N, Galanopoulos G, Tzivras M, Archimandritis A. Acute pancre-

413 atitis after long term therapy with mesalazine, and hyperamylasaemia associated with azathioprine in a patient with ulcerative colitis. J Gastroenterol Hepatol 2003; 15: 933–4. 64. Hagmann HB, Schneider W. No dosedependent tubulotoxicity of 5-aminosalicylic acid: a prospective study in patients with inflammatory bowel diseases. Int J Colorectal Dis 2003; 18: 406–12. 65. Norgard B, Fonager K, Pederson L, Jacobsen BA, Sorensen HT. Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy: a Danish cohort study. Gut 2003; 52: 243–7. 66. Kane S. Inflammatory bowel disease in pregnancy. Gastroenterol Clin N Am 2003; 32: 323–40. 67. Barriuso LM, Yoldi-Petri ME, Olaciregui O, Iceta-Lizarraga A, Goni-Orayen C. Trombosis del seno longitudinal superior en un lactante: secundaria a una exposicion prolongada a mesalazina? Rev Neurol 2003; 1142–4. 68. Somogyi L, Ross SO, Cintron M, Toskes PP. Comparison of biologic porcine secretin, and synthetic human secretin in pancreatic function testing. Pancreas 2003; 27: 230–4. 69. Cadranel JF, Di Martino V, Dorent R, Bernard B, Hoang C, Myara A, Pauwels A, Ghoussoub JJ, Perrin M, Grippon P, Thabut D, Trivin F, Huraux JM, Gandjbakhch I, Opolon P, Lunel F. Effects of ursodeoxycholic acid (Ursodiol) treatment on chronic viral hepatitis in heart transplant patients: results of a prospective, double-blind, placeborandomised study. Transplantation 2003; 75: 977– 82. 70. Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol 2003; 38: 573–8. 71. Tuncer I, Harman M, Mercan R, Ozturk M, Arslan I, Meral C, Turkdogan MK. The effects of ursodeoxycholic acid alone and ursodeoxycholic acid plus low-dose acetylsalicylic acid on radiolucent gallstones. Turk J Gastroenterol 2003; 14: 91–6. 72. Van den Bogaert E, Francque S, Pelckmans P, Michielsen P. The use of ursodeoxycholic acid in patients with primary biliary cirrhosis: sense or nonsense. Acta Gastro-Enterol Belg 2003; 66: 283– 7. 73. Siegal J, Jorgensen R, Angulo P, Lindor K. Treatment with ursodeoxycholic acid is associated with weight gain in patients with primary biliary cirrhosis. J Clinical Gastroenterol 2003; 37: 183–5. 74. Hempfling W, Dilger K, Beuers U. Systematic review: ursodeoxycholic acid—adverse effects and drug interactions. Aliment Pharmacol Ther 2003; 18: 963–72. 75. Palma J, Reyes H, Ribalta J, Hernandez I, Sandoval L, Almuna R, Liepins J, Lira F, Sedano M, Silva O, Toha D, Silva JJ. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomised double blind study controlled with placebo. J Hepatol 1997: 27: 1022–8. 76. Rust C, Sauter GH, Oswald M, Buttner J, Kullak-Ublick GA, Paumgartner G, Beuers U. Effect of cholestyramine on bile acid pattern and

414 synthesis during administration of ursodeoxycholic acid in man. Eur J Clin Invest 2000: 30: 135–9. 77. Bachrach WH, Hoffman AF. Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Part I. Dig Dis Sci 1982: 27: 737–61. 78. Gutzier F, Zimmerman R, Ring GH, Sauer P, Stiehl A. Ursodeoxycholic acid enhances the absorption of cyclosporin in a heart transplant patient with short bowel syndrome. Transplant Proc 1992: 24: 2620–1. 79. Belliveau PP, Nightingale CH, Qunitiliani R, Maderazo EG. Reduction in serum concentrations of ciprofloxacin after administration of urodiol to a patient with hepatobiliary disease. Clin Infect Dis 1994: 19: 354–5.

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80. Stroubou E, Dawn G, Forsyth A. Ursodeoxycholic acid causing exacerbation of dermatitis herpetiformis. J Am Acad Dermatol 2001: 45: 319–20. 81. Sasaki M, Maeda A, Sakamoto K, Fujimura A. Effect of bile acids on absorption of nitrendipine in healthy subjects. Br J Clin Pharmacol 2001: 52: 699–701. 82. Thomas PS, Bellamy M, Geddes D. Malabsorption of vitamin E in cystic fibrosis improved after ursodeoxycholic acid. Lancet 1995: 346: 1230–1. 83. Lattuneddu A, Farneti F, Lucci E, Colinelli C. A pulmonary allergic reaction after injection sclerotherapy for haemorrhoids. Int J Colorectal Dis 2003; 18: 459–60.

Thierry Vial, Jacques Descotes, Felix Braun, and Matthias Behrend

37

Drugs that act on the immune system: cytokines and monoclonal antibodies

Editor’s note: In this chapter Drs Vial and Descotes contributed the sections on cytokines and Drs Ludwig and Behrend the sections on monoclonal antibodies.

COLONY-STIMULATING FACTORS (SED-14, 1270; SEDA-25, 437; SEDA-26, 398; SEDA-27, 391)

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) Cardiovascular Cardiovascular complications have previously been described with GMCSF (SED-14, 1275). In a randomized nonplacebo-controlled study in 93 patients with myelodysplastic syndrome, the addition of GMCSF (molgramostim) to standard induction chemotherapy in 46 patients did not improve the remission rate and was associated with significantly higher rates of non-hematological adverse effects (1C ). In particular, there were fluid retention, pulmonary edema, or weight gain in 14 patients receiving GM-CSF compared with only one in those who were not given GM-CSF. All six patients who had acute myocardial infarctions were receiving GM-CSF. According to experimental evidence that endogenous GM-CSF might contribute to the development of acute coronary syndrome, the © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

authors suggested caution in elderly patients with advanced coronary atherosclerosis. Hematologic Splenomegaly after chronic exposure to G-CSF and reports of spontaneous spleen rupture after short-term administration have previously been described (SED-14, 1272; SEDA-26, 398; SEDA-27, 392). In 13 healthy volunteers and 22 patients with hematological malignancies who received a brief course of lenograstim for peripheral blood stem cell mobilization, there was significant spleen enlargement in almost all patients (2c ). The median increase in spleen volume was 122% in healthy volunteers and 67% in patients, and directly correlated with an increase in white blood cell count. Although no patients reported specific symptoms in this study, severe complications are possible, as illustrated by fatal spontaneous splenic rupture shortly after a 60-year-old man started G-CSF treatment for myelodysplastic syndrome (3A ). Skin G-CSF reportedly triggered disseminated lobular capillary hemangiomas (pyogenic granulomas) in a 25-year-old man (4A ). Musculoskeletal Bone pain is the most frequent adverse effect of G-CSF, encountered in 20–30% of patients. From an analysis of two phase III comparisons of pegfilgrastim and filgrastim there was no significant difference in the incidence, severity, or duration of generalized bone pain between the groups (5M ). In both

415

416 studies, the incidence of bone pain fell from one cycle to another and was about twice lower in the fourth cycle compared with the first cycle, although the analysis did not take into account the use of analgesics. Immunologic The engraftment syndrome, which is characterized by fever, skin rash, capillary leak, and pulmonary infiltrates, is a possible complication of engraftment in patients undergoing autologous bone marrow transplantation. Retrospective analysis of the medical records of 152 patients who received G-CSF (n = 87) or GM-CSF (n = 65) after autologous hemopoietic stem cell transplantation after high-dose chemotherapy suggested a significant increase in the risk of the engraftment syndrome in patients treated with GM-CSF (24%) compared with G-CSF (4%), particularly in patients with breast cancer (6c ). The difference was still present after controlling for potential confounders. The authors therefore suggested avoiding GM-CSF as a post-transplant growth factor, at least in patients with breast cancer. Tumorigenicity There is a continuing debate about whether prolonged use of G-CSF can increase the risk of acute myeloid leukemia in patients with severe chronic neutropenia or aplastic anemia, mostly because the natural history of these underlying disorders was incompletely known before the era of G-CSF. In a nonrandomized study in 112 children with aplastic anemia there was no significant difference in the incidence rate of myelodysplastic syndrome between patients who did or did not receive GCSF, and no case of acute myeloid leukemia after a median follow-up of more than 3 years (7c ). Pregnancy There is limited information on the outcome of pregnancy after treatment with colony-stimulating factors. From the data collected in the Severe Chronic Neutropenia International Registry, G-CSF has been given during 20 pregnancies; 13 resulted in normal neonates, three in spontaneous abortion, and four were electively terminated (8c ). Although the data are still very limited, these results may help to reassure exposed patients.

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INTERFERONS

(SED-14, 1246; SEDA-25, 431; SEDA-26, 393; SEDA-27, 383)

Interferon alfa The safety profile of ribavirin plus human leukocyte interferon alfa was more favourable than ribavirin plus interferon alfa-2b in a randomized, controlled study of 423 therapy-naive patients with chronic hepatitis C infection (9C ). Whereas patients in the two groups achieved similar virological responses to treatment, there were fewer adverse events in those who were given human leukocyte interferon alfa and fewer patients withdrew because of adverse events or laboratory abnormalities compared with interferon alfa-2b (4% versus 11%). In particular, the flu-like syndrome was observed in 52 and 75% of patients respectively, and there were no severe adverse effects in either group. Conversion to human leukocyte interferon alfa may be therefore considered in patients with poor tolerability of recombinant interferon alfa. The safety of retreatment with leukocyte interferon alfa has been confirmed in 43 patients with chronic hepatitis C intolerant of previous recombinant or lymphoblastoid interferon alfa monotherapy (10c ). Only five patients had to discontinue interferon alfa owing to the reappearance of the same adverse effect in four and the occurrence of a new adverse effect in one. In six other patients, dosage reduction was required because of the recurrence of the same adverse effect. Fatigue is a frequent adverse effect that may require dosage reduction during the first months of treatment. The efficacy of L-carnitine on interferon alfa-induced fatigue has been studied in 50 patients with chronic hepatitis C (11c ). The patients who were given L-carnitine (2 g/day) plus interferon alfa had less severe fatigue and an earlier reduction of physical and mental fatigue levels. It was therefore concluded that carnitine supplementation may ameliorate this adverse effect. Cardiovascular Acute myocardial infarction occurred about 12 hours after the administration of pegylated interferon alfa-2b 1 microgram/kg in a healthy 76-year-old woman during a singledose pharmacokinetic study in 24 patients, of whom 18 were over 65 years (12c ). Although

Drugs that act on the immune system: cytokines and monoclonal antibodies

the case was poorly documented, the close temporal relation strongly suggested a causal role of the drug. Pulmonary hypertension has previously been reported in one patient (SEDA-26, 393) and was briefly mentioned as a potential complication of interferon alfa in two other patients who also had multiple ulcers involving the feet or toes (13A ). Other vascular events including Raynaud’s phenomena, digital ulcerations and gangrene, pulmonary vasculitis, and thrombotic thrombocytopenic purpura are occasionally reported (13A ). Pericarditis has been attributed to interferon alfa (14A ). • A 42-year-old woman with a history of atrioventricular septal defect and atrial fibrillation was given interferon alfa-2b for chronic hepatitis C. Pre-treatment echocardiography showed moderate mitral valve disease and left atrial hypertrophy but no pericardial anomalies. Six hours after her first injection of interferon alfa (3 MU) she had an acute episode of thoracic pain, which disappeared spontaneously within 24 hours. Echocardiography showed a moderate non-constrictive pericardial effusion. Similar symptoms recurred 7 hours after a subsequently reduced dose of interferon alfa (1 MU), and echocardiography again showed a reversible pericardial effusion. Autoimmune diseases, cryoglobulinemia, and myocardial infarction were ruled out. Interferon alfa was withdrawn and no recurrence of pericarditis was noted over 5 years of follow-up.

This seems to have been the first case of interferon alfa-induced pericarditis, because lupus-like syndrome and mixed type 2 cryoglobulinemia with vasculitis were deemed to be the direct cause in two previously reported cases. Respiratory Severe pulmonary toxicity from interferon alfa is increasingly reported. Among 558 Japanese patients with chronic hepatitis C treated with or without ribavirin, interstitial pneumonitis was found in six (1.1%) patients aged 54–66 years (15c ). One woman had two reversible episodes of interstitial pneumonitis 9 years apart with two different forms of interferon. Two patients were also taking Sho-saikoto, a herbal medicine previously involved in interstitial pneumonitis. Serum concentrations of KL-6, a lung epithelium-specific protein, were increased at the onset of interstitial pneumonitis in all cases. Serum KL-6 concentrations

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were increased before starting interferon alfa in five of the seven episodes and in only three of 48 age-adjusted patients (6%) who did not develop interstitial pneumonitis during interferon alfa treatment. The authors suggested that measurement of serum KL-6 concentrations may be helpful not only in diagnosing interferon alfa-induced interstitial pneumonia, but also before starting interferon alfa for detecting patients who are more likely to develop interstitial pneumonia during treatment. It is also tempting to speculate that increased concentrations of serum KL-6 before treatment indicate subclinical hepatitis C-related interstitial pneumonitis, which can be triggered by subsequent interferon alfa administration. • A 49-year-old man taking pegylated interferon alfa-2b and ribavirin developed interstitial pneumonitis with subsequent adult respiratory distress syndrome after 2 weeks of treatment (16A ). He died on day 26 from sepsis and multiorgan failure. At necropsy his lungs were five times the normal weight, with diffuse alveolar damage and advanced fibrosis.

Whether the pharmacokinetics of pegylated interferon alfa accounted for the rapid onset or a more severe outcome is speculative, but prompt withdrawal of treatment is advised in cases of unexplained pulmonary symptoms. Nervous system Interferon alfa can cause seizures in patients with no history of epilepsy, and one report of three patients suggested that seizures can occur at any time during treatment (17A ). Seizures were also reported in two of five children after intrathecal interferon alfa for subacute sclerosing panencephalitis, suggesting a much higher incidence in this condition (18A ). Movement disorders have rarely been attributed to interferon alfa. In one report, severe and complex diffuse spinal myoclonus developed after 6 weeks of interferon alfa-2a (27 MU/week) in a 63-year-old man with metastatic renal cancer, but his symptoms were only partially improved after interferon withdrawal and anticonvulsant treatment (19A ). The exact role of interferon was therefore only speculative. Involuntary facial movements have been more convincingly described (20A ). • A 49-year-old woman progressively developed involuntary facial movements after taking interferon alfa-2a (6 MU/day) for 1.5 years for chronic

418 myeloid leukemia. She had bilateral, involuntary, rhythmic, repetitive contractions of her frontalis, nasalis, orbicularis oris, and lower facial muscles. The movements worsened with anxiety and lack of sleep and during talking. Electromyography showed rhythmic synchronous muscle contractions compatible with myorhythmia. Neurological examination was otherwise normal and no other causes were found. The facial movements completely resolved 1 month after interferon withdrawal, and recurred a few weeks after interferon rechallenge.

Features resembling multiple sclerosis have been reported in two women aged 29 and 62 years, treated with recombinant interferon alfa for chronic hepatitis C or chronic myelogenous leukemia (21C ). Both developed bilateral optic neuritis. Other symptoms included increased deep tendon reflexes and reduced sensation of vibration in one patient, and numbness of the legs and bowel and bladder dysfunction in the other. MRI findings and cerebrospinal fluid examination simulated multiple sclerosis. Similar manifestations were again noted in one patient after readministration of natural interferon alfa, and both partially recovered visual acuity after glucocorticoid treatment. Other demyelinating events attributed to interferon alfa have included a report of Guillain– Barré syndrome 2 months after the end of a course of interferon alfa-2b and suramin sodium for metastatic pulmonary cancer in a 37-year-old woman (22A ). Although the concomitant use of suramin made the association of interferon alfa with the Guillain–Barré syndrome unclear, the authors suggested that the simultaneous occurrence of autoimmune liver disease and hematological changes in this patient argued for a causal role of interferon alfa, and they also suggested that this combination may have had a synergistic effect. Bell’s palsy has previously been attributed to interferon alfa (SEDA-25, 432), and there have been further reports in two patients aged 42 and 49 years with chronic hepatitis C (23A ). These patients, who also took ribavirin, developed Bell’s palsy after 2–3 months of treatment. They recovered fully after withdrawal, but prednisone was also required in one. Whether interferon alfa played a direct role is questionable, because the first patient subsequently restarted the same treatment without recurrence, and the second patient had an attack of Herpes simplex stomatitis shortly before the cranial nerve deficit occurred.

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Sensory systems Eyes Interferon alfa often produces ophthalmic complications. Of 42 patients taking interferon alfa-2b and ribavirin for chronic hepatitis C and regularly followed for ocular complications, 27 developed a retinopathy with cotton–wool spots (n = 27), retinal hemorrhages (n = 6), subconjunctival hemorrhage (n = 2), and asymptomatic optic nerve edema (n = 1) (24c ). These lesions were usually transient, but some had recurrent episodes of retinopathy while continuing therapy. Although the retinopathy was considered benign in most cases, two patients complained of ocular symptoms consisting of blurring of vision in one and permanent peripheral monocular scotoma in the other. Three patients had to discontinue treatment because of more severe posterior segment complications. In contrast to several studies, the incidence of retinopathy was not dose related and hypertension was not identified as a significant risk factor. Owing to the possible risk of severe retinopathy, regular ophthalmic monitoring before treatment and at regular intervals during treatment is advocated by most authors. That interferon alfainduced retinopathy is not always self-limiting and benign has been supported by the development of severe proliferative retinopathy in a 69-year-old woman with chronic myeloid leukemia who required extensive laser therapy and unilateral vitrectomy (25A ). Other severe posterior ocular complications recently described in patients with chronic hepatitis C treated with interferon alfa-2b have included: • the development of an epiretinal membrane in a 47-year-old man (26A ); • permanent visual loss attributed to combined retinal artery and central retinal vein obstruction in a 51-year-old woman (27A ); • bilateral simultaneous anterior ischemic optic neuropathy in two patients (28A ).

The first case of Vogt–Koyanagi–Harada disease, an autoimmune syndrome with potentially severe ocular complications, has been reported (29A ). • A 52-year-old woman developed visual blurring, eye pain, tinnitus, and alopecia after taking interferon alfa-2b 9 MU/week and ribavirin 1200 mg/day for 9 months. Further examination showed poliosis of the left eyelashes and reduced bilateral auditory acuity. Ophthalmic examination showed severe bilateral panuveitis with posterior

Drugs that act on the immune system: cytokines and monoclonal antibodies synechiae, vitritis, and choroidal and scleral thickening. The antiviral treatment was withdrawn and she received local and systemic glucocorticoids.

The authors suggested that Vogt–Koyanagi– Harada disease, the pathophysiology of which involves a T cell-mediated autoimmune response to melanocytes, may have been exacerbated by interferon alfa in a genetically predisposed patient. Ears The ototoxic effects of interferon alfa have rarely been investigated, but previous studies have suggested the possibility of mild reversible sensorineural hearing loss (SED-14, 1254). Of 27 patients treated with interferon alfa 30 MU/week for chronic hepatitis B and prospectively assessed for auditory function, hearing loss was found in nine after 7 days of treatment, with an increase in the degree of hearing loss until day 21 (30c ). However, auditory disability did not exceed 20 dB for any frequency despite continued treatment. Complete recovery was observed 1 month after withdrawal. More severe sudden hearing loss and tinnitus have been reported in six patients treated with pegylated interferon alfa and ribavirin (31C ). Symptoms occurred after 1 day or several weeks of treatment, suggesting that hearing loss can occur at any time. Although symptoms did not worsen on continued treatment in two patients, hearing loss persisted or improved minimally after withdrawal in four. Taste In a 40-year-old man taking interferon alfa for chronic hepatitis C ageusia and hyposmia resulted in loss of appetite and weight loss, but reversed on withdrawal (32C ). Psychiatric The incidence, risk factors, and pathophysiological mechanisms of psychiatric disorders associated with interferon alfa are being continuously investigated. Psychiatric symptoms have been prospectively examined in 104 patients with chronic hepatitis C, of whom 84 received interferon alfa-2b 15 MU/week and 20 were not treated (33c ). The incidence of clinically relevant scores for depression, anxiety, or anger/hostility increased from 23% of patients before interferon alfa to 58% of patients during treatment, and returned to 30% and 19% of patients 4 weeks and 6 months after withdrawal respectively. In contrast, there were no significant changes in the reference group. There

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were also significantly higher scores in the 40 patients who took concomitant ribavirin. Six patients successfully received antidepressant therapy, but withdrawal because of untreatable psychiatric symptoms was needed in 8.3% of patients, i.e. about half of the patients who had interferon-induced major depressive disorders. As regular psychiatric assessment is not always possible, the identification of easily detectable predictive factors of severe psychiatric disorders may help select which patients should undergo close psychiatric assessment. In 71 patients treated with interferon alfa alone or combined with ribavirin for chronic hepatitis C, female sex, scores on the MADRS at 4 months of treatment, sleep disorders, and prior antidepressant use were independent risk factors of suicidal behavior or depression (34c ). This study also suggested that prolonged follow-up is required, as 8% of patients still had suicidal behavior 6 months after the end of treatment. The use of interferon alfa in patients with psychiatric disorders is still debated. A prospective study in 81 patients with chronic hepatitis C taking interferon alfa-2a and ribavirin compared adherence to treatment, adverse effects, response rates, and dropout rates in 23 patients without any psychiatric history or drug addiction (control group), 16 patients with psychiatric disorders, 21 patients in a methadone substitution programme, and 21 patients with former intravenous drug addiction (35c ). There were no significant differences between groups as regards the frequency and severity of new depressive episodes during treatment, but significantly more patients in the psychiatric groups had to take antidepressants before and during interferon alfa treatment. The rate of dropouts was significantly higher in the drug addiction group (43%) compared with the other groups (13–18%). The cause was psychiatric or somatic adverse effects in half of these patients. No patients in the psychiatric or methadone groups had to stop treatment because of psychiatric adverse effects. Although the limited number of patients and heterogeneity in psychiatric diagnoses precluded any definitive conclusion, these results suggested that treatment with interferon alfa and special psychiatric care is possible in at-risk psychiatric groups. The pathophysiology of neuropsychiatric adverse effects of interferon alfa has been reviewed. Interactions of interferon alfa with

420 the central opioid, serotonin, dopamine, and glutamate neurotransmitter systems are probably involved (36R ). The possible predominant role of the serotonergic system has again been emphasized in two studies, with evidence of early and significant changes in tryptophan metabolism resulting in persistently low tryptophan concentrations and increased kynurenine concentrations and kynurenine/tryptophan ratio during interferon alfa treatment compared with values obtained before treatment (37c ) and in an untreated control group (38c ). In addition, the fall in tryptophan concentrations correlated with the development and intensity of mood and cognitive symptoms during interferon alfa treatment (37c ). Endocrine Data on interferon alfa-associated thyroid disease have been comprehensively reviewed (39R , 40R ). There was a mean prevalence of 6% for incident thyroid dysfunction, and treatment for malignancies was associated with the highest prevalence (11%). Hypothyroidism occurs more often than hyperthyroidism, and spontaneous resolution is expected in almost 60% of patients with or without interferon alfa withdrawal. Finally, female sex and the presence of baseline thyroid autoimmunity were confirmed to be the most significant risk factors. The mechanisms of interferon alfainduced thyroid dysfunction are not yet fully clarified. Although an autoimmune reaction or immune dysregulation are the most likely mechanisms, a direct inhibitory effect of interferon alfa on thyrocytes should be considered in patients without thyroid antibodies. In patients with chronic hepatic B or C the respective prevalences of pancreatic autoantibodies increased from 2% and 3% at baseline to 5% and 7% after interferon (41R ). In all, 31 published cases of type 1 diabetes mellitus attributed to interferon alfa treatment were detailed, mostly in patients with hepatitis C. Irreversible diabetes required permanent insulin treatment in all but eight cases. At least one marker of pancreatic autoimmunity was positive in nine of 18 patients before treatment, and in 23 of 30 patients at the onset of diabetes. In accordance with these results and the likelihood of a genetic predisposition, the authors recommended screening for islet cell and glutamic acid decarboxylase autoantibodies before and during interferon alfa treatment. However,

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owing to the low number of reported cases and the paucity of studies that have examined the relation between pancreatic autoimmunity and the occurrence of diabetes, further research on the predictive potential of such a systematic investigation is warranted. • The first case of autoimmune polyglandular syndrome with progressive thyroid autoimmunity, type 1 diabetes mellitus, amenorrhea, and adrenal insufficiency has been reported in a 51-year-old woman treated with interferon alfa for chronic hepatitis C (42A ). Pancreas and pituitary gland autoantibodies, which were undetectable before interferon alfa treatment, were present at the time of diagnosis. After withdrawal, she recovered normal thyroid function, but was still insulin dependent with amenorrhea and adrenal insufficiency.

Hypopituitarism is rarely described with interferon alfa but two further cases have recently been reported in patients with chronic hepatitis C. • A 44-year-old woman developed severe weakness after 2 months of interferon alfa 9 MU/week (43A ). Interferon was withdrawn and subsequent treatment with 4.5 MU/week produced similar symptoms within 3 months. Serum cortisol concentrations were dramatically reduced and plasma ACTH was undetectable. Other hormonal concentrations were within the reference ranges and adrenal cortex antibodies were negative. Biological anomalies normalized after interferon alfa withdrawal and 6month substitutive hydrocortisone treatment. • A 39-year-old man received interferon alfa-2b 9 MU/week and ribavirin 400 mg/day for 1 year, and amantadine 200 mg/day for 9 months (44A ). He had major weight gain (23 kg), reduced libido, and neuropsychiatric disturbances during treatment, and there was only partially improvement 1 year after the completion of treatment. There was testosterone, gonadotrophin, and growth hormone deficiency, but antipituitary antibodies were not detected. Although his symptoms markedly improved with recombinant human growth hormone, permanent pituitary impairment was suspected.

The authors suggested that in the second case pituitary dysfunction might have caused persistent symptoms after interferon alfa treatment. Although involvement of the immune system was suggested in both cases, autoantibodies were not detected. Hematologic Bone marrow aplasia has been attributed to interferon alfa. • Severe bone marrow hypoplasia occurred in a 48year-old woman with multiple myeloma also taking thalidomide. She recovered after interferon alfa

Drugs that act on the immune system: cytokines and monoclonal antibodies withdrawal and supportive treatment with G-CSF and erythropoietin (45A ). • A 21-year-old woman developed severe bone marrow aplasia after about 3 years of interferon alfa treatment for chronic myelogenous leukemia (46A ). She recovered after interferon alfa withdrawal, G-CSF supportive treatment, and ciclosporin-based immunosuppressive treatment.

The authors of the second report identified only eight cases with complete recovery from the 18 previously published cases of bone marrow hypoplasia induced by interferon alfa in patients with chronic myelogenous leukemia. They suggested that interferon alfa-induced aplasia is immune mediated and speculated that immunosuppressive therapy may accelerate recovery. Acute thrombocytopenia, presumably of autoimmune origin, is an uncommon adverse effect of interferon alfa. New cases have been reported with both standard and pegylated forms of interferon alfa in five patients with chronic hepatitis C or chronic myeloid leukemia (47A – 50A ). All resolved when interferon alfa was withdrawn and/or with intravenous immunoglobulin and glucocorticoid therapy. Pernicious anemia has been associated with interferon alfa once before [SEDA-26, 395] and a new case has been reported (51A ). • A 61-year-old man with macrocytosis received interferon alfa-2a 9 MU/week for chronic hepatitis C. His hemoglobin concentration progressively fell from 15.6 to 8.1 g/dl after 2 months of treatment and he had worsening of pre-existing paresthesia, tongue pain, ataxia, and mucosal pallor. There was hypergastrinemia, low serum vitamin B12 concentrations, and chronic atrophic gastritis. The anemia resolved after interferon alfa withdrawal and intramuscular administration of vitamin B12 and calcium folate. Anti-intrinsic factor antibodies were later detected.

Urinary tract Two further cases of hemolyticuremic syndrome have been reported (52A ). • A 29-year-old patient and a 57-year-old patient with chronic myeloid leukemia had received interferon alfa and hydroxycarbamide for 5 and 51 months. Thrombocytopenia and microangiopathic hemolytic anemia promptly resolved after interferon alfa withdrawal in both patients, whereas renal dysfunction progressed to dialysis-dependent renal insufficiency in one.

Of 11 other published cases of hemolyticuremic syndrome associated with interferon

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alfa in patients with chronic myelogenous leukemia, five developed end-stage renal disease despite prednisolone and plasmapheresis in some. • Focal segmental glomerulosclerosis has been attributed to interferon alfa in a 40-year-old man with chronic myelogenous leukemia and in a 56year-old woman with chronic hepatitis C (53A ) (54A ). The times to occurrence of the first symptoms were 1 and 2.5 months after starting interferon alfa. The interferon dosages were 9 MU/week and 21 MU/week. Although the first patient improved after interferon alfa withdrawal and prednisone treatment, the second patient progressed to end-stage renal disease and required long-term hemodialysis.

Skin The type and incidence of interferon alfa-induced cutaneous adverse effects has been systematically examined before and after every 3 months of treatment in 33 patients treated with interferon alfa-2a 9 MU/week for malignant melanoma (55c ). There were cutaneous adverse effects in 29, but they were usually mild and never required withdrawal. The most common symptoms were hair loss (n = 16), eczematous reactions at the injection site or at a distance (n = 13), hair discoloration (n = 6), xerostomia (n = 6), Raynaud’s phenomenon (n = 4), and livedo reticularis (n = 4). Other effects included widespread and isolated pruritus, livedo reticularis, seborrheic dermatitis, recurrent herpes labialis, urticaria or angioedema, pytiriasis versicolor, aphthous ulcers, and vitiligo, but it was unclear whether they were fortuitous and how the causal relation with treatment was assessed in each case. In another briefly reported study in 52 patients treated with a combination of pegylated interferon alfa and ribavirin for chronic hepatitis C there were de novo skin lesions, mostly eczematous, in 12 patients (56r ). The lesions did not require withdrawal and regressed on completion of treatment. Hyperpigmentation of the skin and tongue has been reported after several weeks of interferon alfa and ribavirin in two patients with chronic hepatitis C (57A ). The hyperpigmented regions disappeared slowly after withdrawal or diminished in intensity after dosage reduction of interferon alfa. Immunohistochemical analysis of a tongue biopsy in one patient showed melanin deposits, and the authors speculated that interferon alfa may have facilitated increased production of melatonin.

422 Musculoskeletal There has been a further report of severe but reversible acute rhabdomyolysis, a very rare adverse effect of interferon alfa, in a 70-year-old man who had taken interferon alfa-2b 9MU/week alone for only 2 weeks for chronic hepatitis C (58A ). Infection risk Abscess formation has been attributed to interferon alfa in three patients with chronic hepatitis B or C (59A ). All three required surgical drainage. None had other underlying diseases, local ports of entry, or concomitant immunosuppressive treatment. Their neutrophil counts were normal. The infection recurred once on interferon alfa readministration in one patient, but all the patients later restarted their treatment uneventfully. Although the role of interferon alfa was debatable in these cases, the authors found three cases of abscesses among 68 patients treated with interferon alfa for chronic hepatitis, but no such cases among 132 chronic healthy carriers or 39 patients with chronic hepatitis B treated with lamivudine. Susceptibility factors Interferon alfa can cause an acute exacerbation of autoimmune hepatitis (SED-14, 1252), but whether interferon can be used safely for patients with chronic hepatitis C who also have autoimmune hepatitis is still not established. Of 2342 patients treated with interferon alfa or beta for chronic hepatitis C, three developed jaundice and increased transaminases during or after interferon treatment, but HCV-RNA concentrations fell dramatically in all (60A ). Retrospective investigations suggested concomitant probable autoimmune hepatitis before treatment in these patients. Based on these findings, the authors suggested that interferon alfa should remain the frontline regimen in patients with autoimmune hepatitis-like manifestations if autoantibody titers are low, chronic hepatitis C is strongly suspected, and interferon alfa is expected to be effective. The efficacy and safety of interferon alfa monotherapy in dialysis patients with chronic hepatitis C have been systematically reviewed (61M ). There were 14 published prospective studies (269 patients), but only two were controlled trials. Flu-like symptoms, neuropsychiatric disorders, and gastrointestinal abnormalities were the most frequent causes of

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withdrawal, and the overall rate of withdrawal because of adverse effects was 17%. Altered pharmacokinetics of interferon, older age, and frequent co-morbid conditions in hemodialysis patients may have accounted for poorer tolerance.

Interferon beta In a meta-analysis of seven trials in 1215 patients with relapsing remitting multiple sclerosis, there was a modest effect of recombinant interferon beta on the rate of clinical exacerbation at 1 year of treatment, but no clear clinical benefit beyond 1 year (62M ). Compared with placebo, the most common adverse effects were flu-like symptoms (48% versus 28%), injectionsite reactions (62% versus 14%), nausea and vomiting (32% versus 20%), hair loss (36% versus 2.5%), leukopenia (6% versus 0.6%), thrombocytopenia (3.5% versus 0.5%) and increased alanine transaminase activity (9% versus 3%). Psychiatric Although isolated reports of psychotic delusional symptoms and depression continue to be published (63A ), recent controlled trials or longitudinal studies have not provided evidence of an increase in depression scores or in the rate of depression in patients treated with interferon beta (SEDA-27, 389). In a meta-analysis of seven trials in 1215 patients with relapsing remitting multiple sclerosis, the incidence of depression was 16% and did not differ between interferon-beta and controls, but the scales used to assess depression were specified in only three trials (62M ). Using a public reimbursement database for multiple sclerosis, the prevalence and incidence of depression and depression scores were not different in 163 patients treated with interferon beta or glatiramer, but the study was poorly controlled for potential biases (64c ). Overall, the current data suggest that interferon-beta is not substantially associated with depression. Endocrine Interferon-beta can cause thyroid disorders (SEDA-25, 435). Among 700 patients with multiple sclerosis treated with interferon beta-1a (n = 467) or beta-1b (n = 233), overt hyperthyroidism occurred in five

Drugs that act on the immune system: cytokines and monoclonal antibodies

patients treated with interferon-beta-1b, three of whom required withdrawal and long-term carbimazole, while there were two cases of hypothyroidism and one of goiter without thyroid dysfunction in patients treated with interferon beta-1a (65c ). Clinical abnormalities occurred after a mean of 14 months and there were thyroid antibodies in four of the eight patients. The frequency of clinical thyroid dysfunction was higher, but not statistically different for interferon-beta-1b compared with interferon beta-1a (2.15% versus 0.64%). A severe form of hypothyroidism with signs of Hashimoto’s encephalopathy has also been attributed to interferon beta-1a treatment in a 54-year-old woman (66A ). Hematologic Acquired hemophilia A has been attributed to interferon beta-1a (67A ). • A 41-year-old man with a history of autologous stem-cell transplantation received interferon beta1a for multiple sclerosis. After 18 months of treatment, he developed persistent hematuria and 1 month later developed large ecchymoses, and bleeding from puncture sites. Prothrombin and activated partial thromboplastin times were prolonged. Factor VIII activity was only 2% and increased after administration of immunosuppressive drugs, gammaglobulins, and factor VIIa, but again fell to 4%. The patient died from severe hemorrhage.

This first report of an acquired factor VIII inhibitor after administration of interferon beta is reminiscent of previous cases associated with interferon-alfa (SED-14, 1252; SEDA-25, 433). Liver Increased transaminase activities are common in patients taking interferon-beta, and regular assessment of liver tests is usually recommended during the first 6–12 months. In a retrospective review of the charts of 844 patients with multiple sclerosis treated with one of the three commercially available forms of interferon-beta, there were de novo rises in alanine transaminase in 37% of patients (68c ). There were marked increases (5–20 times the upper limit of the reference range) in only 1.4% of the patients, and only two developed jaundice. There was a relation between increasing dose, the frequency of injections, and transaminase increases. Transaminase activity peaked within the first 6 months of treatment with subcutaneous administration, and at 6–12 months

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with intramuscular administration. The manufacturer of the subcutaneous form of interferon beta-1a (Rebif® ) also specifically analysed the data from six controlled trials and concluded that raised alanine transaminase activity was mostly asymptomatic, dose-related, and resolved either spontaneously or after dosage adjustment (69R ). Only 0.4% of patients discontinued treatment because of liver damage. From post-marketing surveillance data, the estimated rate of serious symptomatic liver injury was 1/2300 patients, but it is not known how many cases were clearly related to interferon beta-1a. The authors also mentioned that the only reported case of fulminant hepatitis attributed to interferon beta-1a (SEDA-25, 436) was confounded by concomitant exposure to nefazodone, which is hepatotoxic. Urinary tract There has been a further report of nephrotic syndrome with minimal glomerular lesions on histological examination in a 39-year-old man given interferon beta-1a for relapsing-remitting multiple sclerosis (70A ). Immunologic Interferon beta-1b induces neutralizing antibodies earlier and more often than interferon beta-1a, but whether the development of neutralizing antibodies is associated with reduced clinical efficacy in multiple sclerosis is a matter of continuing debate (71r ). In a large longitudinal study in which neutralizing antibodies were regularly assessed in 541 patients with relapsing remitting multiple sclerosis who were treated with various formulations of interferon beta, the presence of neutralizing antibodies was associated with a significantly higher rate of relapse and a shortened time to first relapse, but did not affect disease progression (72C ). No predictors of antibody formation were identified. However, these results were strongly disputed because of possible methodological flaws and the use of a non-standard assay (73r ). In another study the development of neutralizing antibodies was investigated in 718 patients with secondary progressive multiple sclerosis in a placebo-controlled trial, of whom 360 received interferon beta-1b (74C ). The incidence of neutralizing antibody, defined by at least two consecutive positive titers, was 28%. Again, there was no significant effect of the presence of neutralizing antibodies on the progression of disability. The impact of neutralizing antibodies on the relapse rate was inconsistent,

424 but suggested an increased relapse rate during periods of high neutralizing antibody titers. The study also showed that 37% of patients with neutralizing antibodies durably reverted to antibody-negative status. Accordingly, most authors agreed that treatment decisions in patients with positive neutralizing antibodies should still be based on the clinical outcome.

INTERLEUKINS

(SED-14, 1260; SEDA-25, 436; SEDA-26, 397; SEDA-27, 390)

Interleukin-1 receptor antagonist (anakinra) In 1414 patients with rheumatoid arthritis of varying severity and various co-morbid conditions randomized to receive anakinra 100 mg/day (n = 1116) or placebo (n = 283) the rate of serious adverse events and malignancies after 6 months of treatment was similar in the two groups (75C ). Serious infectious episodes occurred more often in the treated group (2.1%) than in the placebo group (0.4%), but the difference was not statistically significant. Unusual or opportunistic infections were not identified. Mild-to-moderate injection-site reactions were the most commonly reported adverse effects attributed to anakinra (73%). Gastrointestinal Acute exacerbation of Crohn’s disease has been attributed to anakinra (76A ). • A 40-year-old with a previous history of chronic intermittent diarrhea had worsening arthralgia and fever, increased diarrhea, and abdominal pain within 3–4 days of anakinra 100 mg/day for rheumatoid arthritis. Most of the symptoms abated after withdrawal, but promptly reappeared on rechallenge. Further investigations were consistent with a diagnosis of Crohn’s disease.

Infection risk Anakinra was suspected to favor the development of an abscess in the forearm in a 38-year-old diabetic man who underwent local surgery (77A ).

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received IL-2 alone and 239 a combination of IL-2 plus histamine hydrochloride, the incidence of toxicity requiring drug withdrawal, dosage reduction, or study discontinuation was similar in the two groups (78M ). As expected, adverse effects attributable to the physiological effects of histamine (vasodilatation, headache, hypotension, injection site reaction, rhinitis, and dizziness) were more frequent in the combination group. Psychiatric According to a study in 32 patients with cancers, the presence of emotional symptoms and sleep disturbance before treatment can predict the early development of severe depressive symptoms after subsequent therapy with IL-2 and/or interferon alfa (79c ). Although the number of patients was small, the authors suggested that this potentially high-risk population might benefit from prophylactic antidepressant treatment. Skin In a 50-year-old man high-dose IL-2 therapy was suspected to favor the occurrence of multifocal fixed drug eruption in response to other drugs (granisetron, ondansetron, indometacin, and paracetamol) (80A ). Immunologic IL-2 induces antigen-independent T cell activation and can increase the risk of drug-induced hypersensitivity reactions (SED-14, 1266; SEDA-25, 437).

Interleukin-11 (IL-11, oprelvekin) Musculoskeletal There was radiological evidence of periosteitis in five of 24 children with malignant or non-malignant diseases who received oprelvekin 75 micrograms/kg/day for a median of 17 days (81c ). These changes were predominantly found in the clavicle and long bones, and disappeared after oprelvekin was withdrawn. Similar periosteal changes were also described in non-human primates.

Interleukin-2 (IL-2)

Interleukin-12

In a safety analysis of two trials involving metastatic melanoma patients, of whom 152

A randomized placebo-controlled trial of IL12 (500 nanograms/kg) in 225 patients with

Drugs that act on the immune system: cytokines and monoclonal antibodies

chronic hepatitis C unresponsive to previous antiviral treatment was halted, because the treatment was not efficacious and poorly tolerated (82C ). There were serious adverse effects possibly related to IL-12 in seven patients, including immune thrombocytopenic purpura, profound neutropenia, anemia, ascites, melena, and abdominal pain.

TUMOR NECROSIS FACTOR ANTAGONISTS (SEDA-25, 440; SEDA-26, 399; SEDA-27, 393) The differences and similarities in safety between the available TNF alfa antagonists has been reviewed (83R ). Cardiovascular There is a risk of using infliximab in patients with congestive heart failure (SEDA-26, 400). The final results of the ATTACH (Anti-TNF Therapy Against Congestive Heart Failure) trial, which showed no benefit of short-term infliximab in 150 patients with moderate-to-severe heart failure, and a risk of worsening heart failure with high doses of infliximab, have now been published (84C ). In addition, a recent analysis of reports to the FDA Adverse Event Reporting System identified 38 cases of new-onset heart failure and nine cases of worsening heart failure in patients with Crohn’s disease, rheumatoid arthritis, or related disorders (85A ). Of these, 29 cases were attributed to etanercept and 18 to infliximab. There were identifiable susceptibility factors in 19 of the 38 patients who developed new-onset heart failure. All 10 patients aged under 50 years had new-onset heart failure and only three had an underlying susceptibility factor. Withdrawal of the TNF alfa antagonist and heart failure therapy in these 10 patients resulted in complete recovery in three, improvement in six, and death in one. Liver Non-obstructive, sterile cholecystitis was reported in association with etanercept and infliximab for juvenile polyarticular rheumatoid arthritis (86A ).

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Immunologic Patients treated with TNF alfa antagonists have an increased incidence of positive antinuclear antibodies and anti-doublestranded DNA antibodies, but that did not predict the risk of lupus-like syndrome. Indeed, few cases of overt autoimmune diseases have been reported (SEDA-26, 400; SEDA-27, 395). An accumulating number of cases of lupuslike syndrome with positive serological markers have been recently described after treatment with infliximab (n = 5) or etanercept (n = 6) in patients with rheumatoid arthritis or mixed connective tissue disease (87A –94A ). Whereas all tested patients except one had positive antinuclear antibodies before treatment, none was previously positive for anti-DNA antibodies, and in most patients these autoantibodies were detected only during treatment. Symptoms were commonly limited to the skin, joints, or pericardium. All recovered with normalization of autoimmune serological markers after the TNF alfa antagonist was withdrawn. In one patient, the causal relation to treatment was highly likely, as the lupus-like symptoms reappeared on infliximab rechallenge (88A ). Another patient with infliximab-associated lupus-like syndrome later took etanercept without relapse, suggesting that there is no cross-reactivity (89A ). Infection risk Bacterial infections TNF alfa antagonists increase the risk of bacterial infections, and the incidence in practice may be higher than in trials. Among 60 patients treated with etanercept or infliximab for rheumatoid arthritis, there were serious bacterial infections requiring hospitalization and/or intravenous antibiotics in 11 (95c ). The calculated incidence was 0.181 per treatment year compared with 0.008 in the two years preceding treatment with TNF alfa antagonists. There was a broad variety of infectious agents and clinical presentations, but no relation with the treatment duration. The authors noted that clinical and laboratory signs of infection can be blunted by TNF alfa antagonists or concomitant immunosuppressive treatment. An increase in C reactive protein may be an indicator of infection in these cases. Tuberculosis is the major infectious complication associated with TNF alfa antagonists. The mechanisms, prevention, and management of TNF alfa antagonist-associated tuberculosis have been comprehensively reviewed (96R ).

426 The authors also discussed whether the higher rate of tuberculosis reported with infliximab compared with etanercept reflects a true difference between these two drugs or results from reporting biases, but suggested that recommendations proposed for infliximab should also apply to etanercept. The Spanish Working Group on Crohn’s Disease and Ulcerative Colitis has published a consensus guideline on tuberculosis and the treatment of inflammatory bowel disease with infliximab (97S ). As of September 2002, the FDA Adverse Event Reporting System had received 24 reports of Listeria infections in patients taking infliximab and two in patients taking etanercept (98A ). The median age of 15 of these patients was 70 years and the median number of doses before diagnosis of Listeria infection was 2.5. The estimated incidence in infliximabtreated patients in the USA was 43 per million compared with 3 per million in the general population, but this estimate did not take into account under-reporting and the incidence of listeriosis in patients with rheumatoid arthritis or Crohn’s disease. Patient education to avoid alimentary risk factors of Listeria infection is therefore advisable during treatment with TNF alfa antagonists. Fungal infections Fungal infections can also occur during treatment with TNF alfa antagonists. Disseminated histoplasmosis has been reported in three patients taking infliximab or etanercept (99A ), disseminated sporotrichosis in a patient who successively took etanercept and infliximab (100A ), and pulmonary aspergillosis in patients taking infliximab or etanercept (101AS , 102A , 103A ). Although fungal infections are reported less frequently than tuberculosis, careful vigilance should be exercised in patients who live in or visit high-risk areas. • A 61-year-old man with a 6-year history of rheumatoid arthritis developed shortness of breath and anemia (101AS ). Immunosuppressive therapy consisted of prednisone 10 mg/day, methotrexate 25 mg/week, leflunomide 20 mg/day, and infliximab 3 mg/kg. The last of three infliximab doses was given 3 months before presentation. Chest radiography showed a round opacity with adjacent airspace disease in the lung. Fungal cultures from a CT-guided fine-needle aspiration grew Cyryptococcus neoformans. Infliximab was withdrawn and he recovered after being given amphotericin followed by fluconazole.

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• A 73-year-old woman with chronic rheumatoid arthritis developed Aspergillus fumigatus pneumonia 4 months after infliximab therapy. Prior therapy consisted of methotrexate, leflunomide, and prednisone. She had also been exposed to building construction (102A ).

Tumorigenicity Whether the use of TNF alfa antagonists is associated with an increased risk of lymphoma has previously been discussed and remains controversial (SEDA-27, 393). Based on recent isolated case reports, it has been also speculated that etanercept or infliximab may have contributed to acute leukemia in two patients (104A , 105A ).

Adalimumab Adalimumab, a fully human monoclonal antibody, is the third commercially available TNF alfa antagonist for patients with rheumatoid arthritis for whom previous treatment with disease-modifying antirheumatic drugs has failed. Double-blind, placebo-controlled comparisons of adalimumab alone or combined with disease-modifying antirheumatic drugs showed no significant differences in the incidence of serious adverse effects and infections, but more frequent injection-site reactions with adalimumab (106C –108C ). Respiratory Pulmonary granulomas with caseating necrosis, but no evidence of mycobacteria or other infectious agents, were attributed to adalimumab in a 73-year-old man (109A ). That pulmonary lesions persisted for more than 1 year after withdrawal made interpretation difficult. Urinary tract A 64-year-old man developed nephrotic syndrome with membranous glomerulopathy on renal biopsy 1 year after starting to take adalimumab (110A ). Although proteinuria resolved spontaneously after adalimumab withdrawal and recurred on rechallenge, the case was complicated by simultaneous reduction of the prednisone dosage before each episode of proteinuria. Skin A 63-year-old woman developed an erythema multiforme-like eruption after the sixth injection of adalimumab; the lesions disappeared after withdrawal (111A ).

Drugs that act on the immune system: cytokines and monoclonal antibodies

Immunologic According to the package insert of adalimumab, the rate of positive antinuclear antibodies was 12% compared with 7% in placebo groups. There was only one case of lupus-like syndrome, reversible on adalimumab withdrawal, among 2334 treated patients. Infection risk In a double-blind, placebo controlled study of the addition of adalimumab (20 mg every week or 40 mg every other week) to methotrexate in 619 patients there was a significantly higher incidence of serious infections requiring hospitalization or intravenous antibiotics in patients taking adalimumab (3.8%) than in those taking placebo (0.5%) (112C ). The highest incidence (5.3%) was in those who took adalimumab 40 mg every other week, and tuberculosis, histoplasmosis, and herpes encephalitis (one case each) were observed only in this group. Overall, there were 13 cases of tuberculosis, mostly within the first 8 months of treatment, during 4870 patient-years of trials with adalimumab, but eight occurred in phase I and II trials with doses higher than those currently used. Recommendations regarding the risk of tuberculosis are therefore similar to those for infliximab.

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opportunistic infections. Laboratory abnormalities were of mild to moderate intensity and did not necessitate withdrawal. Eight patients who received etanercept had serum samples positive for anti-etanercept antibodies. There were no differences in efficacy or adverse event profiles between these patients and those without antibodies. In a double-blind, placebo-controlled study, 112 patients were randomized to placebo or etanercept 25 mg subcutaneously twice a week for 24 weeks (115C ). Etanercept resulted in significant improvements in psoriasis area-andseverity indices. Similar numbers of patients had adverse events in the two groups. Injection site reactions occurred more often with etanercept than placebo (9% versus 0% respectively). One patient who received etanercept developed guttate psoriasis, which was considered to be possibly related to the drug and another had worsening psoriasis after 4 days. Both withdrew from the study.

Etanercept

Sensory systems There have been two reports of anterior uveitis associated with etanercept in a 44-year-old woman with ankylosing spondylitis and a 31-year-old woman with juvenile rheumatic disease, both of whom had responded well to etanercept (116A , 117A ). Both had a long-standing rheumatic disease with no previous episodes of uveitis before etanercept and one patient had severe relapse of uveitis on etanercept rechallenge. By contrast, two other patients who responded to etanercept, but also developed scleritis or uveitis, fully recovered with local and systemic treatment despite etanercept continuation (118A ). Although it was difficult to establish whether this condition was related to the underlying disease or to etanercept, these reports at least suggest that etanercept may fail to prevent ocular involvement in rheumatic disease.

Placebo-controlled studies In a double-blind study in 672 patients randomized to either placebo or etanercept subcutaneously at a low dose (25 mg once weekly), a medium dose (25 mg twice weekly), or a high dose (50 mg twice weekly) significantly more patients had improved psoriasis area-and-severity indices with etanercept compared with placebo at weeks 12 and 24 (114C ). Adverse events and infections occurred in similar proportions in each group. There were no cases of tuberculosis or

Hematologic Previous post-marketing warnings have highlighted the risk of pancytopenia or aplastic anemia with etanercept (SEDA-24, 420). Since then, only one case of reversible aplastic anemia has been detailed in a 78-yearold man who had taken etanercept during the previous 16 weeks (119A ). Although he had taken methotrexate uneventfully for 3 years, the potential role of methotrexate or a synergistic effect of the drug combination could not be ruled out.

Tumorigenicity Non-Hodgkin’s lymphoma in a 70-year-old man was attributed to adalimumab, but he had also taken long-term glucocorticoids and methotrexate (113A ). During clinical trials, 10 of 2468 patients taking adalimumab developed lymphoma (1.8 were expected), but it is not yet known whether adalimumab per se increases the risk of lymphoma in patients with active rheumatoid arthritis.

428 Abrupt exacerbation of the macrophage activation syndrome has been previously reported (SEDA-26, 399). Etanercept has again been reported to be a likely triggering factor of the macrophage activation syndrome in a 4year-old girl with juvenile rheumatoid arthritis (120A ). Her symptoms abated after etanercept withdrawal and glucocorticoid treatment. Skin Exacerbation of atopic dermatitis has been attributed to etanercept (121A ). • Atopic dermatitis worsened soon after etanercept was started in a 10-year-old girl. Although initial concomitant withdrawal of ciclosporin made interpretation difficult, the dermatitis persisted during the whole 6 months of etanercept treatment and resolved only after withdrawal. Etanercept-induced abnormalities of Th2 cytokines were suggested as the most likely mechanism.

Musculoskeletal Direct injection of etanercept into arthritic joints has been used in some patients with mono- or oligoarticular arthritis. This was presumably the cause of an acute intra-articular injection site reaction with painful local effusion in a 35-year-old man (122A ). Infection risk There were no major change in global immune functions, assessed by cell surface antigen expression of peripheral leucocytes, delayed-type hypersensitivity, T cell proliferation, serum immunoglobulin concentrations, and neutrophil function, in 33 patients taking etanercept compared with 16 patients taking placebo (123c ). The incidence of infections was also similar in the two groups. Although these results may account for a lower number of reports of infection with etanercept than with infliximab, etanercept also contributed to the occurrence of severe infectious complications. In a retrospective study of 180 patients taking etanercept for various systemic rheumatic diseases, there was no difference in the frequency of serious infections between the periods that preceded or followed etanercept use, but two of the five patients who developed serious infections while taking etanercept died as a result of complicated sepsis (124C ). The possible role of etanercept in the development of multifocal septic arthritis (125A , 126A ), tonsil or peritoneal tuberculosis (127A , 128A ), and cerebral toxoplasmosis (129A ) has also been discussed in recent isolated case reports.

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Infliximab Infliximab is a chimeric, human-murine antiTNF monoclonal antibody that is used to treat active refractory Crohn’s disease, rheumatoid arthritis, and ankylosing spondylitis (130R ). Recent reports have highlighted several potential serious adverse effects associated with infliximab, including infusion reactions, congestive heart failure, drug-induced lupus-like syndrome, and demyelination. In addition, reactivation of mycobacterial and fungal infections can occur in patients taking infliximab, mandating appropriate tuberculosis screening before drug therapy (131R ). Observational studies A total of 33 patients with plaque psoriasis were treated with infliximab 5 or 10 mg/kg by intravenous infusion (132c ). One patient treated with 10 mg/kg infliximab complained of severe itching of the feet, which resolved on withdrawal. Three of 33 patients had infusion reactions, which were generally mild and transient. There were infections (for example cellulitis, tooth abscess, ear infection, infected wisdom tooth, bronchitis, pneumonia) in seven patients. Seven patients with various inflammatory disorders were treated with infliximab 5 mg/kg by intravenous infusion; three had pityriasis rubra pilaris, one had panniculitis, one had eosinophilic fasciitis, one had discoid lupus erythematosus, and one had necrobiosis lipoidica diabeticorum (133c ). One patient with discoid lupus erythematosus did not respond to treatment and reported insomnia and mild confusion, which resolved after 1 month. Five patients with hidradenitis suppurativa were treated with infliximab 5 mg/kg by intravenous infusion (134c ). All improved. One developed a tender submandibular swelling; a fine needle aspirate of the enlarged lymph node showed acid-fast bacteria, but culture was negative. This patient was treated for presumed Mycobacterium tuberculosis, with reduction of the size of the node. The number of patients in this series was small, but the authors commented that tuberculosis in infliximab-treated patients has previously been reported to be more common than expected. Infliximab-related adverse drug reactions have been studied in 32 patients with rheumatoid arthritis (135c ). In all, there were 43

Drugs that act on the immune system: cytokines and monoclonal antibodies

reactions in 21 patients, four patients had serious reactions, and in five patients infliximab was withdrawn. Adverse reactions consisted of infections (n = 21), allergies (n = 3) and cardiovascular complications (n = 3). The incidence of reactions was as follows: respiratory 28%; urinary 22%; cutaneous 16%; allergic 9.4%; cardiovascular 9.4%. TNF-α has been suggested to be an important mediator of circulatory disturbances in alcoholic hepatitis. The effects of infliximab on portal and systemic hemodynamics have been studied in 10 patients with severe biopsy proven alcoholic hepatitis (136c ). After treatment, serum bilirubin, C-reactive protein, white cell count, and plasma concentrations of interleukin-6 and interleukin-8 were significantly reduced. Nine of 10 patients were alive at 28 days. Mean hepatic venous pressure gradient fell significantly at 24 hours. Mean arterial pressure and systemic vascular resistance increased significantly, mirrored by a reduction in cardiac index. Hepatic and renal blood flow also increased significantly. There was also a reduction in hepatic inflammation and improved organ blood flow, suggesting an important role for TNF-alpha in mediating circulatory disturbances in alcoholic hepatitis. The authors concluded that infliximab produces a highly significant, early, and sustained reduction in hepatic venous pressure gradient in patients with alcoholic hepatitis, possibly by a combination of reduced cardiac output and intrahepatic resistance. Comparative studies In a retrospective study, 122 patients with Crohn’s disease who received infliximab infusions were also given azathioprine (n = 47), mercaptopurine (n = 11), methotrexate (n = 23), prednisone (n = 64), mesalazine (n = 51), and antibiotics (n = 16) (137c ). Mean follow-up was 52 weeks (14–864 days). The overall response rate to infliximab was similar between patients who received immunomodulators and patients who received infliximab alone. There were more frequent adverse drug reactions in those who took infliximab alone (22%) than in those who took methotrexate (13%) and azathioprine/mercaptopurine (14%), but this was not statistically significant. Concomitant use of immunomodulators with infliximab in patients with Crohn’s disease did not improve clinical

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response rates, dosage reduction of prednisone, fistula response, and mean intervals between infliximab infusions. Cardiovascular Venous thrombosis has been associated with infliximab in two patients. • A 55-year-old woman with psoriatic arthritis and possible systemic lupus erythematosus developed inspiratory pain, slight dyspnea, and left leg pain 1 week after receiving a second infusion of infliximab 3 mg/kg (138A ). A respiratory infection was suspected and she recovered. Similar pulmonary symptoms with right leg pain recurred 6 days after her third infusion of infliximab, and a pulmonary embolism was suggested on spiral CT. She also had raised anti-DNA antibodies and slightly raised cardiolipin antibodies. • A 45-year-old woman with no history of hypertension, hypercholesterolemia, or diabetes received infliximab for Crohn’s disease (139A ). She had visual changes after her third dose of infliximab and ophthalmoscopy showed retinal vein thrombosis. There was no underlying coagulation disorder.

Although vascular complications have been associated with Crohn’s disease or rheumatoid arthritis, there was a close temporal relation with infliximab treatment in both cases. In addition, the second patient had no evidence of susceptibility factors. Respiratory Four patients developed severe features of methotrexate pneumonitis shortly after they received their third infusion of infliximab, raising the possibility that infliximab could potentiate the pulmonary toxicity of methotrexate (140A , 141A ). Allergic bronchiocentric granulomatosis of the lung was reported in one of a series of patients who received infliximab 5 mg/kg for ankylosing spondylitis; the patient received glucocorticoids for 2 weeks and recovered (142A ). Nervous system A debatable case of rapidly progressive Parkinson’s disease has been attributed to infliximab in a 72-year-old woman (143A ). Until more data are available, this report should be considered as anecdotal. Sensory systems Three cases of bilateral toxic optic neuropathy have been reported in patients with rheumatoid arthritis after infliximab treatment (144A ). • A 54-year-old man had blurred vision 34 days after a third dose of infliximab. Co-medication consisted

430 of leflunomide, prednisone, naproxen, diazepam, fluoxetine, famotidine, metoprolol, and paracetamol or codeine. Fluorescein angiography showed capillary dilatation and vascular leakage in both optic nerve heads. He did not recover vision with glucocorticoid therapy. • A 62-year-old woman had blurred vision 40 days after a third dose of infliximab. Co-medication consisted of atenolol, enalapril or hydrochlorothiazide, salicylic acid, terfenadine, and rofecoxib. Fluorescein angiography showed profuse vascular leakage. The left eye had a central scotoma and the optic nerve head was pale. A fourth dose of infliximab was given 7 weeks after the third dose, after which symptoms started in the right eye with a central scotoma. Methylprednisolone did not improve vision. • A 54-year-old man developed loss of vision field 2 weeks after a third dose of infliximab. Comedication consisted of prednisone, diclofenac, and omeprazole. Fluorescein angiography showed capillary dilatation and vascular leakage in the optic nerve heads.

All three patients had the toxic form of anterior optic neuropathy. Glucocorticoids, given to exclude external temporal arteritis, did not improve vision in any of the patients. Accumulation was speculated to be a factor in this adverse effect, because all three patients developed anterior optic neuropathy after the third dose of infliximab. Hematologic Pancytopenia has been reported on several occasions in patients taking infliximab. • A 45-year-old woman with underlying renal insufficiency developed pancytopenia 2 weeks after a single infusion of infliximab for scleroderma (145A ). There were no other suspected drug exposures and she later died from infectious complications. • Neutropenia and thrombocytopenia occurred in a 60-year-old woman (146A ). • Pancytopenia with bone marrow hypoplasia on biopsy occurred in a 66-year-old man (147A ).

The second and third cases were complicated by the use of concomitant drugs (methotrexate, leflunomide) known to be associated with hematological disorders. Additional data are therefore required before adding hematological toxicity to the adverse effects of infliximab. A hemophagocytic syndrome was reported a patient with rheumatoid arthritis treated with infliximab (148A ).

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• A 46-year-old woman with seropositive rheumatoid arthritis had active disease despite treatment with glucocorticoids, methotrexate, and sulfasalazine. Six weeks after the seventh infusion of infliximab 3 mg/kg she developed fever, dehydration, weight loss, profound lethargy, hepatomegaly, and pain in the right flank. She had thrombocytopenia (platelets 16 × 109 /l), anemia, leukocytosis (15 × 109 /l) lymphopenia (760 × 106 /l), a low CD4 lymphocyte count (72 × 106 /l), renal insufficiency, hyponatremia, hypoalbuminemia, and hypogammaglobulinemia. Liver enzymes were 20 times the upper end of the reference range, bilirubin 1.5 times, and lactate dehydrogenase five time. Urine and blood cultures grew Escherichia coli. Hemophagocytic syndrome was confirmed by bone marrow aspiration. Screening ruled out others possible causes than Escherichia coli and infliximab. Infliximab was withdrawn and the patient recovered with intravenous immunoglobulin and antibiotics.

Skin Various skin reactions have recently been described in patients treated with infliximab, including lichenoid dermatitis, a perniosis-like eruption, and superficial granuloma annulare (Table 1), but coincidental eruptions could not be ruled out and the authors provided no convincing evidence of causal relations (149c ). Other cases with recurrence or flare of the skin lesions on rechallenge gave more definitive evidence of the role of infliximab and included eczematous purpura of Doucas and Kapetenakis (150A ), eczema-like toxiderma (151A ) and an atopic dermatitis-like eruption (152A ). Infliximab-related vasculitis has rarely been described. Eight cases of vasculitis or vasculitic rash associated with infliximab (n = 7) or etanercept (n = 1) have been detailed in patients with rheumatoid arthritis, but only two were biopsy proven (153A ). Two patients had a concomitant rise in autoantibodies and the resolution of skin lesions was noted after withdrawal of the TNF alfa antagonist and/or treatment with prednisolone or cyclophosphamide. Although rheumatoid vasculitis could not be ruled out in several of these cases, the two patients who later received etanercept after developing lesions with infliximab had recurrent vasculitis or rash. Another case of biopsy-proven leukocytoclastic vasculitis has been reported after a single infusion of infliximab in a 24-year-old woman (154A ). This was probably a hypersensitivity reaction, as TNF alfa antagonists have sometimes been used to treat severe vasculitis.

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Table 1. Infliximab-related adverse skin reactions (149c ) Age Sex

Disease

Medication

Adverse skin reaction

Outcome

30 F

Crohn’s disease

Mesalazine 4 g/day Infliximab 1 × 5 mg/kg

Leukocytoclastic vasculitis

Infliximab withdrawn; improved with glucocorticoids

64 F

Rheumatoid arthritis

Methotrexate 10 mg/week Prednisolone 2 mg/day Infliximab 3 × 3 mg/kg

Lichenoid eruption

Improved with glucocorticoids; infliximab re-administered

68 F

Rheumatoid arthritis

Methotrexate 10 mg/week Infliximab 6 × 3 mg/kg

Perniosis

Infliximab withdrawn

46 M

Psoriasis

Infliximab 1 × 3 mg/kg

Superficial granuloma annulare

Infliximab continued; treated with glucocorticoids

38 F

Rheumatoid arthritis

Methotrexate 10 mg/week Infliximab 3 mg/kg

Perniosis

Infliximab withdrawn

36 F

Psoriasis

Prednisolone 8 mg/day Infliximab 3 mg/kg

Acute folliculitis and dyshidrotic dermatitis

Topical erythromycin, glucocorticoids; infliximab continued

Musculoskeletal Of three patients who received intravenous infliximab 5 mg/kg for peristomal pyoderma gangrenosum, one developed reactive arthritis and infliximab was withdrawn (155A ). Immunologic The incidence of autoimmune disorders after long-term use of infliximab has been poorly studied. In a prospective study of autoimmunity in 125 patients treated with infliximab for Crohn’s disease, the cumulative incidence of antinuclear antibodies during 24 months was 57%, and positivity was found after less than three infusions in almost 80% of patients (156C ). Among the antinuclear antibody-positive patients, about 30% were positive for double-stranded DNA and 21% for antihistone autoantibodies. Antinuclear antibodies were still present up to 1 year after the last infusion of infliximab. Two patients with high antinuclear antibody titers, both of whom were antihistone and double-stranded DNA autoantibody-positive, developed a lupus-like syndrome without any major organ involvement. One additional antinuclear antibodypositive patient had autoimmune hemolytic anemia 6 months after the first infusion of infliximab. There was a similar incidence of new autoantibodies after prolonged treatment in another study in 42 patients with rheumatic diseases, albeit that none developed clinical

symptoms of autoimmunity (157c ). This study also suggested an increased risk of biological autoimmunity with the number of infusions or the total dose of infliximab. Changes in antinuclear antibody (ANA) have been evaluated in 36 patients (mean age 30 years, range 12–59) with Crohn’s disease treated with intravenous infliximab 5 mg/kg (158c ). Concomitant immunosuppressive drugs were given in 28 cases. At baseline, eight patients were ANA positive. At 6 weeks, no anti-double-stranded DNA antibodies were detectable. After retreatment, three of these eight patients had increasing ANA titers and two developed antibodies to dsDNA. Six of 28 ANA-negative patients changed their ANA status from baseline to 6 weeks. One re-treated patient had further increase in ANA titer and developed antibodies to dsDNA. None of the 36 patients developed a lupus-like syndrome. In 62 adults with rheumatoid arthritis and 35 with spondylarthropathy, 32 and six respectively were ANA-positive (159c ). After infliximab, the numbers shifted to 51 and 31. At baseline, none of the patients had antibodies to dsDNA. After infliximab, seven and six patients respectively became anti-dsDNA positive, with IgM and IgA in seven and three. In some patients, there were antinucleosome antibodies, antihistone antibodies, or antibodies to extractable nuclear antigen after infliximab. Lupus-like syndrome was not observed.

432 Two cases of polymyositis associated with infliximab have been reported (160A , 161A ). • A 52-year-old woman with a 20-year history of inadequately controlled seropositive rheumatoid arthritis treated with non-steroidal anti-inflammatory drugs, prednisone 15 mg/day, and methotrexate 15 mg/week received intravenous infliximab 3 mg/kg after 0, 2, and 6 week and then every eighth week. After 14 months she had diffuse pain in the lower and upper limbs and progressive symmetrical proximal muscle weakness, accompanied by fever, dysphagia, dyspnea, and weight loss. Rheumatoid factor was 155 IU/ml, creatine kinase over 12 000 U/l, (MB fraction 529 U/l), aspartate transaminase 542 U/l, and lactate dehydrogenase 4533 U/l. Autoantibody tests were positive for antinuclear antibody 1 : 320, antidsDNA 1 : 20, pANCA 1 : 20, and double immunodiffusion for anti-Jo-1 antibody. Muscle biopsy showed diffuse fibre necrosis and inflammatory infiltrates. Infliximab-induced polymyositis was diagnosed and improved after intravenous methylprednisolone 1 g tds. • An 18-year-old man had Behçet’s syndrome inadequately controlled by various immunosuppressive drugs. Mycophenolate mofetil was combined with infliximab 3 mg/kg at 0, 2, and 6 weeks. After the third infusion of infliximab, atraumatic pain and swelling of the right upper arm persisted for 3 days. An anechoic collection near the biceps muscle was detected by ultrasound and 2 ml of pus was aspirated, from which Staphylococcus aureus was isolated. The diagnosis was pyomyositis and infliximab was withdrawn. He recovered with flucloxacillin and gentamicin.

Of 82 children with Crohn’s disease who received 432 infusions, 12 (5.3% of 432 infusions and 15% of 82 patients) had infusion reactions (162c ). Eight received a total of 47 infusions after an infusion reaction; in 11 instances (23%), infusion reactions recurred. Thus, reexposure to infliximab after an infusion reaction increases the risk of a further infusion reaction, but does not require withdrawal of infliximab. Infusion reactions and the relation between antibodies to infliximab and the loss of response after infliximab have been studied in 53 patients with Crohn’s disease who received 199 infusions of infliximab (5 mg/kg) (163c ). There were antibodies to infliximab in 19 of 53 patients (36%), including all seven patients with serious infusion reactions, and in 11 of 15 patients (73%) who lost their initial response compared with none of 21 continuous responders. Giving a second infusion within 8 weeks of the first or concurrent immunosuppressants significantly reduced the formation of antibodies to

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infliximab. In a subsequent randomized trial, 80 patients with Crohn’s disease were randomized to intravenous hydrocortisone 200 mg or placebo immediately before their first and subsequent infliximab infusions. Titers of antibodies to infliximab were lower at week 16 among those who received hydrocortisone (1.6 versus 3.4 µg/ml), 26% of whom developed antibodies compared with 42% of placebo-treated patients. The authors concluded that loss of initial response and infusion reactions after infliximab is strongly related to the formation and titer of antibodies to infliximab. Giving a second infusion within 8 weeks of immunosuppressant therapy significantly reduces antibody formation. Intravenous hydrocortisone premedication significantly reduces the titers of antibodies to infliximab but does not eliminate their formation or infusion reactions. • A macrophage activation syndrome was reported in a 15 year old boy with a 9-year history of systemic polyarthritis (164A ). Less than 24 hours after a second infusion of infliximab he developed a high fever, chills, a rash, general malaise, and raised ESR, C-reactive protein, and transaminases, and pancytopenia. He recovered after 3 pulses of methylprednisolone 30 mg/kg.

Infection risk Infectious complications associated with infliximab include tuberculosis, listeriosis, invasive aspergillosis, cutaneous nocardiosis, fatal Streptococcus pneumoniae sepsis with necrotizing fasciitis, fatal group A β-hemolytic streptococcus sepsis with necrotizing fasciitis, Pneumocystis jiroveci pneumonia, histoplasmosis, coccidioidomycosis, and systemic candidiasis (98A , 165c ). The reported rates of opportunistic infections implicate a higher risk among patients treated with infliximab than with etanercept. This difference might be explained by the more common concurrent use of methotrexate with infliximab in patients with rheumatoid arthritis. Tuberculosis The increased risk of tuberculosis with infliximab is of great concern, and more accurate epidemiological data have now been published. However, the incidence rate of tuberculosis varies considerably according to several factors, such as race and country. In a recent US survey, the estimated incidence of tuberculosis among 6460 patients treated with infliximab was 62 cases per 100 000 patients compared with 6.2 in patients with rheumatoid arthritis

Drugs that act on the immune system: cytokines and monoclonal antibodies

before the widespread use of infliximab (166C ). The four cases reported in this survey occurred in patients without complete screening or prophylaxis for tuberculosis. In 107 patients (191 patient-years) treated with infliximab for spondylarthropathy, severe infections occurred in eight (167c ). In particular, two patients developed disseminated tuberculosis and three had severe retropharyngeal abscesses. The development of tuberculosis has also been studied in 1540 patients, 86% of whom received infliximab and 14% etanercept, in a Spanish national database established for the long-term surveillance of patients with rheumatic diseases and treated with biological response modifiers (168C ). Tuberculosis was reported in 17 patients treated with infliximab (no case with etanercept), including four who had negative tuberculin tests and normal chest X-rays before treatment. Most cases involved extrapulmonary sites of infection and were diagnosed within 3 months of treatment. Two patients died from their infections. The estimated incidence of tuberculosis associated with infliximab ranged from 1113 to 1893 cases per 100 000 patients in the first 2 years of surveillance. Accordingly, the risk ratio for tuberculosis in infliximab-treated patients was 53–90 compared with the background rate, and 12–20 compared with a cohort of rheumatoid arthritis patients not treated with infliximab. The authors mentioned only one additional case of tuberculosis during the 10 months after the establishment of guidelines and recommendations by health authorities, but such reassuring data should be confirmed by further studies. Indeed, there have been reports of reactivation of latent tuberculosis in two patients after isoniazid prophylaxis for 6 months, suggesting that more prolonged prophylactic treatment should be completed before starting infliximab (169A , 170A ). Viral infections Although TNF alfa has potent antiviral activity, few cases of viral infections with TNF alfa antagonists have been reported. Recent detailed cases have associated infliximab with Varicella infection in a 45-year-old man (171A ) and disseminated Herpes simplex infection associated with the macrophage activation syndrome in an 8-year-old girl (172A ). The risk of infliximab treatment in carriers of hepatitis B surface antigen is also of concern, and there have been reports of hepatitis

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B reactivation in a chronic carrier (173A ), and fulminant hepatitis in a patient with a positive hepatitis B virus surface antigen before infliximab treatment (174A ). By contrast, infliximab or etanercept did not produce deleterious effects on liver function or viremia in 24 patients with hepatitis C virus infection (175c ). Death On the basis of so-called spontaneous capture, the Paul Ehrlich Institute was notified of 44 adverse drug reactions leading to the death of the patient after the use of infliximab in Germany (130S ). Sepsis or serious infections was reported in 24. According to the manufacturer, 20 000 patients have been treated in Germany with infliximab. Tumorigenicity Lymphoproliferative malignancies can develop during immunosuppressive therapy. These lymphomas are mainly B cell non-Hodgkin’s lymphomas associated with Epstein–Barr virus. A relation between the new anti-TNF-α agents and lymphoproliferative malignancies has been debated. • A 47-year-old man with erythrodermic psoriasis was treated with phototherapy, which was ineffective, and methotrexate 10 mg/week, which was withdrawn because of severe cytolytic hepatitis after the third dose (176A ). Ciclosporin 5 mg/kg, which he had taken for 5 years, was withdrawn because of renal impairment. Mycophenolate mofetil 2 mg/day over 6 weeks was ineffective. He was given infliximab 6 mg/kg at 0, 2, 6, 7 and 10 weeks and ciclosporin was reintroduced 3 months later. After 3 weeks, he developed a CD30+ T cell lymphoma. Epstein–Barr virus was negative. Ciclosporin was withdrawn and within 4 weeks the tumor regressed.

The authors cited a total of nine cases of lymphoid proliferation associated with TNF-α therapies. Because of the short delay between ciclosporin reintroduction and the development of the tumor, infliximab was directly implicated as a co-factor that might have accelerated the development of the lymphoma. Teratogenicity The outcome of pregnancy after maternal exposure to infliximab immediately before conception or early in pregnancy has been detailed in two patients. One had a healthy baby (177A ) and the other, who had active disease and other drug exposure, delivered an extremely premature infant, who died

434 3 days later from intracerebral and intrapulmonary bleeding (178A ). In a brief report, the manufacturer mentioned 35 pregnancies with exposure to infliximab before and during pregnancy (179r ). There were miscarriages in five pregnancies, termination of pregnancy in four, and live births in 26; one infant had tetralogy of Fallot and one neonate died. However, the exact time of exposure was known in only 20 patients, and it occurred during the first trimester in 14. The data are therefore still insufficient to estimate the risk of inadvertent infliximab exposure during pregnancy. Drug interactions Data from a study in 32 patients treated with azathioprine for Crohn’s disease showed a significant increase in thioguanine nucleotide concentrations within 1–3 weeks after the first infusion of infliximab, suggesting an interaction between the two drugs (180c ). There were also a significant reduction in leukocyte count and a significant association between the increase in thioguanine nucleotide concentrations and the clinical response to infliximab. Whether these findings will also translate into an increased risk of azathioprine adverse effects has not been specifically investigated.

MONOCLONAL ANTIBODIES (SED-14, 1308; SEDA-25, 438; SEDA-26, 402; SEDA-27, 378)

Abciximab See Chapter 35.

Adalimumab See Tumor necrosis factor antagonists.

Alemtuzumab (Campath-1H
) Alemtuzumab is an unconjugated, humanized, monoclonal antibody directed against the cell surface antigen CD52 on lymphocytes and monocytes.

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Hematologic Cytopenias associated with alemtuzumab are often transient, although erythrocyte and platelet transfusions may be required (181R ). Grade 3–4 cytopenias have been observed in patients with mycosis fungoides receiving intravenous alemtuzumab 30 mg three times per week over 12 weeks (182c ). In a phase II trial in patients with advanced or refractory chronic leukemia, hematological toxicity included long-lasting lymphocytopenia and transient neutropenia and thrombocytopenia (183c ). Immunologic First-dose symptoms are common after intravenous infusion of alemtuzumab (181R ). It produces profound T cell depletion in humans and might reduce the need for maintenance immunosuppression after renal transplantation. Thus, pretransplant T cell depletion with alemtuzumab has been evaluated for induction of tolerance in seven nonsensitized recipients of living-donor kidneys who were treated perioperatively with alemtuzumab (184c ). Postoperatively they were not given maintenance immunosuppression. All developed reversible episodes of rejection within the first month, characterized by predominantly monocytic infiltrates and only rare T cells in the peripheral blood or allograft. These episodes responded to glucocorticoids or sirolimus or both. After therapy, the patients remained rejectionfree on reduced immunosuppression. T cell depletion alone does not induce tolerance in humans. Infection risk In two phase II studies, severe infections were reported with the use of alemtuzumab in patients with mycosis fungoides (182c , 185c ). There was reactivation of cytomegalovirus in four of 22 patients. Six others had suspect or manifest infection: three had a fever of unknown origin, one generalized Herpes simplex, one fatal aspergillosis, and one fatal Mycobacterium pneumonia. All serious infectious (except cytomegalovirus) occurred in patients who had received three or more prior regimens. Alemtuzumab had promising clinical activity in patients with advanced mycosis fungoides, if they were not heavily pretreated. In patients with heavily pretreated, refractory, advanced mycosis fungoides, alemtuzumab is associated with significant toxicity and only modest clinical utility (182c ). Anti-infective prophylaxis is mandatory (181R ).

Drugs that act on the immune system: cytokines and monoclonal antibodies

Alemtuzumab has been evaluated in a phase II trial in advanced or refractory chronic lymphocytic leukemia (n = 42) or T cell prolymphocytic leukemia (n = 18) (183C ). Alemtuzumab was given intravenously in doses of 3, 10, and 30 mg on 3 consecutive days, after which 30 mg was given 3 times a week over 4–12 weeks, depending on disease response. All the patients received prophylactic co-trimoxazole and valaciclovir. The overall response rate was 35%. The most common infusion-related adverse events were fever, rigors, skin rash, nausea, and dyspnea. These were most common during the first week of therapy. There was at least one episode of fever or infection in 36 patients. Drug administration route Alemtuzumab can be administered intravenously or subcutaneously. First-dose flu-like symptoms, which are common after intravenous infusion, can be managed by premedication and minimized by dose escalation or subcutaneous injection (181R ).

Anti-CD3 antibody (T3/4.A) Various new engineered anti-CD3 monoclonal antibodies (T3/4.A, YTH 12.5, HuOKT3gamma1, HuM291) have been developed to avoid mitogenic and Fc receptor-binding adverse effects related to muromonab (186R ). T3/4.A is a non-mitogenic murine IgA monoclonal antibody to human CD3 that was investigated in a phase II trial in 18 patients after kidney transplantation, 15 of whom had a first rejection episode and received a full course of intravenous T3/4.A 5 mg/day over 10 days. Four patients were switched to glucocorticoids because of deteriorating kidney function and lost their grafts. Fourteen rejection episodes responded to T3/4.A therapy, four patients had a second episode of rejection within 2 weeks, and one had chronic rejection after 2.5 years. Two patients died, one with a functioning graft and one after returning to dialysis. In the 3 hours after the first infusion of T3/4.A, 15 of 18 patients had a fever or chills. Headache and vomiting were infrequent, and one patient had dyspnea. After a second administration, 15 of 18 patients developed vomiting and/or diarrhea, accompanied by fever or chills in five of 15 patients, and

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hypovolemia, hypotension, and anuria in two of five patients (187c ).

Anti-CD40 antibody (BG9588) BG9588 is an anti-CD40L antibody. The CD40CD40L interaction plays a significant role in the production of autoantibodies and tissue injury in lupus nephritis (188c ). Cardiovascular In an open, multiple-dose study, 28 patients with active proliferative lupus nephritis received intravenous BG9588 20 mg/kg at biweekly intervals for the first three doses and at a monthly interval for four additional doses (188c ). The study was prematurely terminated because of thrombembolic events in this and other BG9588 protocols. One or more adverse event was reported in 27/28 patients including headache (32%), fatigue (25%), chest pain (21%), and pharyngeal pain (18%). Severe or moderately severe adverse events occurred in 17/28 (61%), including myocardial infarction (n = 2), death (n = 1), progression to end-stage renal failure (n = 1), tracheobronchitis (n = 1), and fever/chills (n = 1). Serum C3 concentrations rose significantly at 1 month after the last dose. The authors discussed recent data suggesting that CD40L stabilizes arterial thrombi by a β3 integrin-dependent mechanism. Inhibition by anti-CD40L antibody may render platelet plugs unstable and thus ready to embolize.

Basiliximab Basiliximab is a genetically engineered chimeric mouse/human anti-IL-2R (CD25) monoclonal antibody that blocks IL-2R (CD25) without lysis of activated T cells. It is used for induction immunoprophylaxis in solid organ transplantation. In kidney recipients, basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, when combined with standard dualor triple-immunotherapy (189R ).

436 Respiratory Three patients developed severe non-cardiogenic pulmonary embolism within 2 days after kidney transplantation (190A ). Pretransplant cardiorespiratory evaluation was normal in all three. Immunosuppression consisted of basiliximab induction, glucocorticoids, and tacrolimus. Standard fluid management was used during and after transplant surgery. • A 17-year-old girl and a 21-year-old woman had immediate postoperative diuresis after kidney transplantation. Both developed non-cardiogenic pulmonary embolism 2 days later. In both cases, pulmonary embolism resolved within 1 week. • A 19-year-old man with a pretransplant hematocrit of 43% developed non-cardiogenic pulmonary embolism 2 days after kidney transplantation and required assisted ventilation. He died from sudden cardiopulmonary arrest the next day.

Cytokine release from basiliximab, with increased capillary permeability, volume overload, and ischemic-reperfusion injury, was implicated as the mechanism of pulmonary embolism. The authors recommended improved awareness of this potential complication, prudent fluid management, and efforts to minimize graft ischemia in order to prevent further cases. Immunologic Repeated administration of chimeric or humanized monoclonal antibodies is generally well tolerated and anti-idiotypic sensitization is rare. However, cases of anaphylactic shock have been reported after basiliximab retreatment (191A , 192A ). • A child had anaphylactic shock after a second course of basiliximab having received a second renal transplant (191A ). Anti-basiliximab IgE antibodies appeared after the second course of basiliximab. There was no IgE reactivity towards a control murine IgG2a monoclonal antibody, suggesting that the IgE response was directed exclusively against basiliximab idiotypes. Furthermore, there was no IgE reactivity against the humanized anti-interleukin-2 receptor monoclonal antibody daclizumab, which was derived from a distinct parental murine monoclonal antibody. The patient’s basophils harvested months after the anaphylactic shock produced leukotrienes in vitro on exposure to basiliximab.

Patients exposed to chimeric antibodies can develop an anti-idiotypic IgE response that can trigger anaphylactic shock on further exposure. Specific anti-idiotypic IgE may be bound to basophils even in the absence of circulating IgE (191A ).

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Bevacizumab Bevacizumab (rhuMab VEGF) is monoclonal antibody developed against vascular endothelial growth factor. In a phase II trial, bevacizumab 5 mg/kg (n = 33) or 10 mg/kg (n = 33) was given in combination with fluorouracil + leucovorin to patients with metastatic colorectal cancer (193c ). Fluorouracil + leucovorin (n = 36) without bevacizumab served as the control arm. The most common adverse effects were diarrhea, leukopenia, and stomatitis attributable to fluorouracil + leucovorin. Bevacizumab was associated with a higher incidence of headache, rash, chills, epistaxis, and hypertension. Two patients had gastrointestinal bleeding with bevacizumab 5 mg/kg and five with 10 mg/kg. Thrombotic complications occurred in 9% in the control arm, 26% with bevacizumab 5 mg/kg, and 13% with bevacizumab 10 mg/kg.

Daclizumab Daclizumab is a humanized anti-IL2 (CD25) monoclonal antibody that is used to prevent rejection after organ transplantation. It has been used to treat inflammatory bowel disease. Gastrointestinal In 10 patients with refractory ulcerative colitis in an open pilot trial, intravenous daclizumab 1 mg/kg was given twice with a 4-week interval (194c ). There was clinical and histological improvement. Nausea was the most common adverse event, but always in patients who were also taking azathioprine.

Efalizumab Efalizumab is a humanized monoclonal antibody that inhibits T cell activation by binding to LFA-1 (the alpha subunit of CD11a). Placebo-controlled studies Efalizumab 1 or 2 mg/kg/week was given subcutaneously to 597 patients with psoriasis in a phase III multicenter, double-blind, randomized, placebocontrolled study (195C ). Adverse events included non-specific infections in 13%, pruritus

Drugs that act on the immune system: cytokines and monoclonal antibodies

(6%), and arthritis (5%). Efalizumab antibodies developed in 5%. There were serious adverse events in 13 patients (3%), including five nonfatal infections. None of the adverse events resulted in study withdrawal. In a randomized, double-blind study subcutaneous efalizumab (1 or 2 mg/kg/week) was compared with placebo in 597 subjects with psoriasis (196C ). Efalizumab resulted in significant improvement in the extent and severity of the psoriasis. Acute adverse events (most commonly headache, chills, fever, nausea, and myalgia, occurring on the day of administration or within 2 days after) were most frequent after the first dose, were generally mild to moderate, and fell in frequency over time. The rate of infection was not increased by efalizumab. There was no evidence of end-organ toxicity. The efficacy and safety of efalizumab has been studied in a randomized, double-blind, parallel-group, placebo-controlled trial in 556 adults with stable moderate to severe plaque psoriasis (197C ). Efalizumab significantly improved both physician-assessed and patientreported outcomes. There were five types of adverse events with efalizumab (headache, chills, fever, myalgia, and pain) in at least 5% more patients than with placebo. Serious adverse events (not further specified in the publication) were infrequent, occurring in 2% of patients who were given efalizumab and 1% of those who were given placebo. The rate of diagnosed infections was 27% with efalizumab and 23% with placebo. Infections that occurred at least in 1% more of the efalizumab-treated patients included mild to moderate upper respiratory tract infections, bacterial infections (for example impetigo, streptococcal pharyngitis, cellulitis), and fungal (yeast) infections. There were no clinically important laboratory abnormalities.

Gemtuzumab The monoclonal antibody gemtuzumab ozogamicin was developed to treat CD33 positive acute myeloid leukemia (198c ). Cardiovascular Gemtuzumab ozogamicin has been associated with veno-occlusive disease. Of 62 patients with previously treated

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acute myelogenous leukemia or myelodysplastic syndrome who underwent allogeneic stem cell transplantation and who were studied retrospectively, 14 received gemtuzumab before stem cell transplantation (198c ). Veno-occlusive disease developed in 13 patients, including nine of 14 who had prior exposure to gemtuzumab, compared with four of 48 without prior exposure. Nine of 10 patients who underwent stem cell transplantation up to 3.5 months after gemtuzumab developed veno-occlusive disease compared with none of four patients who underwent stem cell transplantation more than 3.5 months after gemtuzumab administration. Three of 14 patients who received gemtuzumab before stem cell transplantation died of venoocclusive disease. In another study, children with acute myelogenous leukemia were treated with intravenous gemtuzumab monotherapy 4–9 mg/m2 for up to three courses (199c ). One of 15 children developed veno-occlusive disease and one grade 3 hypotension. Liver Gemtuzumab monotherapy in 15 children with acute myelogenous leukemia resulted in transient grade 3 hyperbilirubinemia (n = 1) and grade 3 transiently increased transaminases (n = 1) (199c ).

Infliximab See Tumor necrosis factor antagonists.

Muromonab-CD3 (OKT3) Muromonab specifically recognizes the ε chain of the CD3 complex and blocks the function of the CD3 molecule in the membranes of human T cells. Pretreatment with glucocorticoids, paracetamol, and antihistamines reduces the first-dose effect that is caused by binding to Fc receptors, which causes cytokine release and flu-like symptoms. Human-antimouse antibody-screening is recommended before a second course. Muromonab can cause sensitization, fever, pulmonary edema, anaphylactic reactions, and neurotoxicity, and increases the risk of infections and neoplasia. Patients receiving muromonab should be monitored on an intermediate care unit.

438 Comparative studies In a retrospective singlecenter study in recipients of cadaveric kidney transplants, induction with muromonab (n = 26) and basiliximab (n = 100) were compared (200c ). The basiliximab-treated patients had reduced ciclosporin and glucocorticoid dosage requirements, and both groups received mycophenolate mofetil. Length of stay, number of readmissions, total hospitalization days, and cytomegalovirus infections were lower in the basiliximab group. The rate of biopsy-proven acute rejection episodes was 14% with basiliximab and 35% with muromonab. Nervous system Neurotoxicity from muromonab usually manifests as a transient aseptic meningitis and is uncommon. After orthotopic heart transplantation, a patient developed muromonab-associated akinetic mutism (201A ). • A patient receiving muromonab developed a neurological syndrome characterized by akinetic mutism, blepharospasm, anomic aphasia, and delirium. An MRI scan showed meningeal enhancement and a SPECT scan showed markedly reduced tracer uptake. Withdrawal of muromonab resulted in resolution of the syndrome and reversal of the abnormalities on neuroimaging that coincided with normalization of CD3+ lymphocyte count.

The use of SPECT is recommended in patients with supposed muromonab-associated encephalopathy. Biliary tract The rate of recurrence of primary sclerosing cholangitis is 15–30% after liver transplantation. In a retrospective study, 15 of 71 patients had recurrence of primary sclerosing cholangitis (202c ). Muromonab was associated with a higher risk of recurrence (29% versus 10%). Recurrence was not influenced by immunosuppression with either ciclosporin or tacrolimus. The authors concluded that immunosuppression seems to be detrimental to the outcome of patients with primary sclerosing cholangitis. Tumorigenicity Intense immunosuppression and Epstein–Barr virus positivity are often implicated in the development of post-transplant lymphoproliferative disorders, and muromonab is often speculated to increase the risk. In a retrospective, non-randomized, single-center study, all lymphoma-like lesions in kidney recipients grafted during 1969 to 2002 were

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reviewed (203c ). There was no significant difference in the incidence of post-transplant lymphoproliferative disorders comparing prednisolone/azathioprine, and ciclosporin or the periods before and after muromonab, or those before or after antilymphocyte globulin. In another retrospective analysis of 2030 renal transplantations performed between 1969 and 2001, 29 patients (1.4%) developed posttransplant lymphoproliferative disorders after a median period of 0.5 (range 0.1–23) years (204c ). Patients with post-transplant lymphoproliferative disorders were more likely to have taken ciclosporin (76% versus 62%), tacrolimus (10% versus 2%), or muromonab (28% versus 10%). The risks of early-onset, extensive-stage, polymorphic, Epstein–Barr virus-associated, and fatal post-transplant lymphoproliferative disorders progressively increased from dual to triple immunosuppression to muromonab. Most of the patients presented with an extra-nodal mass (45%), were afebrile (76%), and had stage IV disease (60%). Post-transplant lymphoproliferative disorders have been studied in patients who received heart or heart-lung transplants between 1968 and 1997 (205c ). Post-transplant lymphoproliferative disorders occurred in 57 of 874 heart recipients and eight of 152 heart-lung recipients. During this time, four different immunosuppressive regimens (azathioprine, prednisone, ciclosporin, muromonab induction, tacrolimus, and mycophenolate mofetil) were used sequentially, and there was no correlation with the development of post-transplant lymphoproliferative disorders. Recipient age, rejection frequency, and high-dose ciclosporin immunosuppression were significantly associated with post-transplant lymphoproliferative disorders. Drug dosage regimens Antithymocyte globulin and muromonab are usually administered in fixed doses over 5–10 days. Individualized T cell monitoring has been proposed as a tool for dose finding. In a randomized study, antithymocyte globulin (n = 27) and muromonab (n = 28) were compared in the treatment of biopsyverified acute glucocorticoid-resistant rejection when both drugs were administered on the basis of daily individualized T cell measurements (206C ). A fall in CD2+ T cell count to under 50 × 106 /l was considered adequate and was used to guide doses. There were 26 biopsyverified re-rejections (12 with antithymocyte

Drugs that act on the immune system: cytokines and monoclonal antibodies

globulin and 14 with muromonab) within 3 months. To keep the T cell count below 50 × 106 /l, the average dose of antithymocyte globulin was 354 mg (2.3 administrations, range 1–4) and the average dose of muromonab was 33 mg in 10 doses.

Natalizumab Natalizumab is a humanized monoclonal antibody to alpha-4 beta-1 integrin (VLA-4) currently under development for the treatment of Crohn’s disease and multiple sclerosis. Phase II trials in both indications have been completed, and by December 2002 phase III trials in Crohn’s disease and multiple sclerosis had been initiated (207R ).

Rituximab Rituximab is a chimeric anti-CD20 monoclonal antibody which has become part of standard therapy for patients with non-Hodgkin’s lymphoma. Worldwide, over 300 000 patients have been treated with rituximab, including patients with indolent and aggressive non-Hodgkin’s lymphoma, Hodgkin’s disease, and other B cell malignancies. Rituximab is generally well tolerated, and most adverse events are associated with infusions, including chills, fever, and rigors, which are related to the release of cytokines (208R ). Nervous system A fatal central nervous system lesion was reported during therapy with rituximab for an Epstein–Barr virus-linked lymphoma after transplantation (209A ).

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The pathophysiological mechanisms of rituximab related hemolysis are unknown. Severe delayed neutropenia after rituximab was evaluated in 53 consecutively treated patients with non-Hodgkin’s lymphoma (211c ). There were eight episodes of grade 4 neutropenia at 1–5 months after rituximab, including three occasions in combination with chemotherapy. Sepsis occurred in three cases. All the episodes developed after a period of either normal or mildly depressed neutrophil counts after treatment with rituximab. Episodes of neutropenia were associated with disordered immune status, manifested by lymphopenia and hypogammaglobulinemia, raising the possibility that either a disturbance of the balance of lymphocyte subsets or an immune dyscrasia induced by rituximab resulted in the development of this type of neutropenia. Agranulocytosis unresponsive to growth factors was reported after rituximab therapy (212A ). • A 46-year-old man with lymphocyte-predominant Hodgkin disease stage IV achieved a partial response after standard chemotherapy. When the diagnosis was modified to diffuse large B cell lymphoma, standard CHOP chemotherapy resulted in another brief partial response. After disease progression, he responded to two cycles of ifosphamide, mesna, carboplatin, and etoposide. After CD34 cell transplantation he was given rituximab on days 30 and 37. From day 77 to day 122, his white blood cell count fell from 5 × 109 /l to 1 × 109 /l and his neutrophils from 86% to 0%. The bone marrow was hypocellular with little maturation of the myeloid series and no evidence of relapse. Screening for infection and autoantibodies was negative. Despite drug withdrawal and administration of GCSF/GM-CSF, the neutropenia persisted for 2 months. Ciclosporin was started and the neutrophil count recovered within 5 days.

Neutropenia in rituximab-treated patients with lymphomas can be considered as one Hematologic Autoimmune hemolytic anemia end of a spectrum of immunohematological sequelae due to autoimmune myelopathy, ofhas been attributed to rituximab (210A ). ten associated with rituximab-induced T cell • A 64-year-old man with a low-grade non-Hodgkin’s large granular lymphocytes. Patients treated lymphoma of lymphoplasmacytoid type received chlorambucil and prednisolone, second-line che- with rituximab were divided into four groups motherapy with cyclophosphamide, doxorubicin, by peripheral blood morphology and flow cyvincristine, and prednisolone, and thereafter ritux- tometry: imab 375 mg/m2 /wk for 4 weeks. After the fourth dose of rituximab, a pre-existing, asymptomatic, mild hemolytic anemia deteriorated into severe hemolysis with a hemoglobin of 4.6 g/dl. Autoimmune hemolysis was suggested by positive direct Coombs’ test. He recovered after prednisone and immunoglobulin therapy over 5 days.

1. those with peripheral blood T-LGL lymphocytosis (n = 11), including profound neutropenia (n = 10) of 1–5 months duration or thrombocytopenia (n = 1); eight patients developed neutropenia after transplantation;

440 2. those with neutropenia without T-LGL lymphocytosis (n = 4); 3. those with T-LGL lymphocytosis without cytopenias (n = 2); 4. those with neither cytopenias nor T-LGL lymphocytosis (n = 17). After a median follow-up of 13 months the patients with neutropenia did not have an increased risk of infection (213r ). Immunologic Delayed hypersensitivity or serum sickness has been reported after rituximab (214c ). In a phase II trial of the German Hodgkin Lymphoma Study Group, 14 patients were treated with rituximab 375 mg/m2 once a week for 4 weeks (215c ). Paracetamol and antihistamines were given 1 hour before rituximab infusion that was started at 50 mg/hour during the first hour and gradually increased to a maximum of 400 mg/hour. There were infusion-related adverse effects in 11 patients. The most common adverse effects were chills in 71%, fever (50%), rhinitis (21%), nausea (21%), pruritus (21%), leukopenia (14%), and dizziness (14%). The adverse effects occurred mainly during the first infusion and resolved within 1 hour after the end of the infusion. In addition, one patient died 5 months after treatment from a pneumonia related to a tracheoesophageal fistula and one patient developed a lung adenocarcinoma 11 months after treatment. Infection risk There have been isolated reports of viral infections and hepatitis B virus reactivation in carriers of hepatitis B surface antigen (HbsAg) (216A , 217A ). Hepatitis B virus escape mutants can be essential for reactivation after rituximab. • A 73-year-old man with a history of hepatitis B was treated with five courses of CHOP and then with rituximab for a diffuse large-cell lymphoma (216A ). After complete resolution, he had anti-HBs antibodies over 1000 IU/l and HbsAg was negative. He subsequently had acute hepatitis (anti-HBs 868 IU/l, HbsAg positive, HBV-DNA 8.6 × 108 copies/ml). Lamivudine reduced the viral load (HBV-DNA 2.4 × 105 copies/ml) within 2 weeks, but he did not recover hepatic function and died after 19 days. Hepatitis B virus sequence analysis showed five mutations in the major antigenic region (L110R, R122K, Y/F134S, P142L, and D144A), compatible with escape of an endogenous strain from the patient’s own anti-HBs, which was non-pathogenic until rituximab therapy.

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Treatment with the chimeric anti-CD20 monoclonal antibody rituximab induces rapid and long-lasting depletion of circulating B cells. Enteroviral meningoencephalitis after rituximab occurred in a child with immune thrombocytopenia and in an adult with relapsed B cell lymphoma. • A boy with severe autoimmune thrombocytopenia was treated from 4 to 10 years of age with intensive immunosuppression and hemopoietic stem cell transplantation when he was 8 (218A ). Twenty months after transplantation, he was given four courses of rituximab 375 mg/m2 /week in combination with prednisone 0.4 mg/kg/day and dapsone 3 mg/kg/day. After 6 months, the prednisone was tapered to 0.15 mg/kg/day and he relapsed. A second course of four infusions of rituximab were given, resulting in resolution of thrombocytopenia. Eleven months later, he developed progressive alteration in cognitive function, aphasia, sensorimotor deafness, a mild fever, and an extrapyramidal syndrome. A brain MRI scan showed diffuse white matter abnormalities, and enteroviral protein was detected by PCR in plasma and cerebrospinal fluid. The leukocyte count in the cerebrospinal fluid was 27–33 × 106 /l. He was given intravenous immunoglobulin and pleconaril, and dapsone was withdrawn. Seven months later he recovered from the enteroviral meningoencephalitis, with negative PCR but unchanged brain MRI abnormalities. • A 53-year-old man with a follicular lymphoma Ann Arbor stage IIIA responded to low-dose chemotherapy but relapsed 28 months later (218A ). Rituximab 375 mg/m2 /week over 4 weeks induced a second complete remission. He developed a fever, headache, diffuse paresthesia, difficulty in concentrating, sensorimotor deafness, diplopia, ataxia, and a pyramidal syndrome 6 months after the last infusion of rituximab. A brain MRI scan showed evidence of myelitis and asymmetric signal enhancement in the right parietal meninges. In the cerebrospinal fluid the lymphocyte count was 300 × 106 /l and echovirus 13 was isolated. The duodenal wall was thickened on a CT scan and duodenal biopsy showed a second lymphoma. After high-dose glucocorticoids, and polychemotherapy the neurological symptoms partially improved and hemopoietic stem cell transplantation was performed. Two months after transplantation the neurological symptoms and mild fever returned. Enterovirus was detected by PCR in the cerebrospinal fluid. He recovered with residual effects after high-dose intravenous immunoglobulin and pleconaril.

Mixed cryoglobulinemia is a chronic immune-complex mediated disease, often associated with vascular, renal, and neurological lesions and hepatitis C. Almost 10% of patients

Drugs that act on the immune system: cytokines and monoclonal antibodies

progress to frank B-cell non-Hodgkin’s lymphoma. Rituximab 375 mg/m2 /week was given intravenously for 4 consecutive weeks to 20 patients with mixed cryoglobulinemia and hepatitis C virus-positive chronic active liver disease

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resistant to interferon alfa (219c ). There was a complete response in 16. Rituximab caused an increase in HCV-RNA to about twice baseline without significant variation in serum transaminases or deterioration of liver disease.

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448 anti-interleukin-2 receptor monoclonal antibody basiliximab. Transplantation 2003; 76: 459–63. 192. Barros VR, Rocha V, Garcia VD, Garcia CD. Anaphylactic shock after retreatment with basiliximab. Transplant Proc 2003; 35: 579. 193. Fernando NH, Hurwitz HI. Inhibition of vascular endothelial growth in the treatment of colorectal cancer. Sem Oncol 2003; 30: 39–50. 194. Van Assche G, Dalle I, Noman M, Aerden I, Swijsen C, Asnong K, Maes B, Ceuppens J, Geboes K, Rutgeerts P. A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis. Am J Gastroenterol 2003; 98: 369–76. 195. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, Walicke P, Dummer W, Wang X, Garovoy MR, Pariser D; Efalizumab Study Group. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349: 2004–13. 196. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, Walicke P, Dummer W, Wang X, Garovoy MR, Pariser D; Efalizumab Study Group. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. New Engl J Med 2003; 349: 2004–13. 197. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnahan BW, Menter A; Efalizumab Study Group. Efalizumab for patients with moderate to severe plaque psoriasis. J Am Med Assoc 2003; 290: 3073–80. 198. Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, Alyea EP, Antin JH, Stone RM, Soiffer RJ, DeAngelo DJ. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003; 102: 1578–82. 199. Zwaan CM, Reinhardt D, Corbacioglu S, et al. Gemtuzumab ozogamicin: first clinical experiences in children with relapsed/refractory acute myeloid leukemia treated on compassionate-use basis. Blood 2003; 101: 3868–71. 200. Kode R, Fa K, Chowdhury S, Ranganna K, Fyfe B, Stabler S, Damask A, Laftavi MR, Kumar AM, Pankewycz O. Basiliximab plus low-dose cyclosporin vs. OKT3 for induction immunosuppression following renal transplantation. Clin Transplant 2003; 17: 369–76. 201. Pittock SJ, Rabinstein AA, Edwards BS, Wijdicks EF. OKT3 neurotoxicity presenting as akinetic mutism. Transplantation 2003; 75: 1058–60. 202. Kugelmas M, Spiegelman P, Osgood MJ, Young DA, Trotter JF, Steinberg T, Wachs ME, Bak T, Kam I, Everson GT. Different immunosuppressive regimens and recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl 2003; 9: 727–32. 203. Birkeland SA, Hamilton-Dutoit S. Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific imunosuppressive drug or by the transplantation per se? Transplantation 2003; 76: 984–8. 204. Herzig KA, Juffs HG, Norris D, Brown AM, Gill D, Hawley CM, Cobcroft R, Petrie JB, Marlton

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P, Thomson D, Campbell SB, Nicol DL, Johnson DW. A single-centre experience of post-renal transplant lymphoproliferative disorder. Transpl Int 2003; 16: 529–36. 205. Gao SZ, Chaparro SV, Perlroth M, Montoya JG, Miller JL, DiMiceli S, Hastie T, Oyer PE, Schroeder J. Post-transplantation lymphoproliferative disease in heart and heart-lung transplant recipients: 30-year experience at Stanford University. J Heart Lung Transplant 2003; 22: 505–14. 206. Midtvedt K, Fauchald P, Lien B, Hartmann A, Albrechtsen D, Bjerkely BL, Leivestad T, Brekke IB. Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection. Clin Transplant 2003; 17: 69–74. 207. Elices MJ. Natalizumab. Elan/Biogen. Curr Opin Investig Drugs 2003; 4: 1354–62. 208. Boye J, Elter T, Engert A. An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 2003; 14: 520–35. 209. Sirvent-Von Bueltzingsloewen A, Sirvent N, Morand P, Cassuto JP. Fatal central nervous system lesions emerging during anti-CD20 monoclonal antibody therapy (Rituximab) for a post transplantation Epstein Barr virus-linked lymphoma. Med Pediatr Oncol 2003; 40: 408–9. 210. Jourdan E, Topart D, Richard B, Jourdan J, Sotto A. Severe autoimmune hemolytic anemia following rituximab therapy in a patient with a lymphoproliferative disorder. Leuk Lymphoma 2003; 44: 889–90. 211. Chaiwatanatorn K, Lee N, Grigg A, Filshie R, Firkin F. Delayed-onset neutropenia associated with rituximab therapy. Br J Haematol 2003; 121: 913–8. 212. Rose AL, Forsythe AM, Maloney DG. Agranulocytosis unresponsive to growth factors following rituximab in vivo purging. Blood 2003; 101: 4225– 6. 213. Papadaki T, Stamatopoulos K, Anagnostopoulos A, Fassas A. Rituximab-associated immune myelopathy. Blood 2003; 102: 1557–8. 214. Hellerstedt B, Ahmed A. Delayed-type hypersensitivity reaction or serum sickness after rituximab treatment. Ann Oncol 2003; 14: 1792. 215. Rehwald U, Schulz H, Reiser M, et al. Treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lyphoma Study Group. Blood 2003; 101: 420–4. 216. Westhoff TH, Jochimsen F, Schmittel A, Stoffler-Meilicke M, Schafer JH, Zidek W, Gerlich WH, Thiel E. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood 2003; 102: 1930. 217. Hernandez JA, Diloy R, Salat D, del Rio N, Martinez X, Castellvi JM. Fulminant hepatitis subsequent to reactivation of precore mutant hepatitis B virus in a patient with lymphoma treated with chemotherapy and rituximab. Haematologica 2003; 88: ECR22. 218. Quartier P, Tournilhac O, Archimbaud C, Lazaro L, Chaleteix C, Millet P, Peigue-Lafeuille

Drugs that act on the immune system: cytokines and monoclonal antibodies H, Blanche S, Fischer A, Casanova JL, Travade P, Tardieu M. Enteroviral meningoencephalitis after anti-CD20 (rituximab) treatment. Clin Infect Dis 2003; 36: e47-9. 219. Sansonno D, De Re Valli, Lauletta G, Tucci FA, Boiocchi M, Dammacco F. Monoclonal anti-

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body treatment of mixed cryoglobulinemia resistant to interferon a with an anti-CD20. Blood 2003; 101: 3818–26.

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Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs

IMMUNOSUPPRESSIVE DRUGS Azathioprine and mercaptopurine (SED-14, 1280; SEDA-25, 440; SEDA-26, 404; SEDA-27, 373) Endocrine Hyperprolactinemia has been attributed to azathioprine (1A ). • A 24-year-old woman, with a 3-year history of psoriasis, in the last trimester of her first pregnancy developed autoimmune thrombocytic purpura, which resolved after delivery. After 1 year, her liver function tests rose to 10 times normal values, associated with fatigue, weakness, and splenomegaly. Fine-needle liver aspiration showed autoimmune hepatitis. Her transaminases normalized with a glucocorticoid. She was then given azathioprine 50 mg/day instead of the glucocorticoid. After 1 month, her liver function tests rose about seven-fold and her prolactin concentrations by three-fold. She was again given a glucocorticoid and the azathioprine was continued. Six weeks later she was in remission, but her prolactin concentration was still high. There was no galactorrhea or amenorrhea, and the hyperprolactinemia was thought to have been be caused by azathioprine (1A ).

Hematologic The short-term and long-term toxicity of mercaptopurine has been investigated in 410 patients with inflammatory bowel disease treated for 20 years. There was significant leukopenia (3.5 × 109 /l or less) in 11% (2M ). Gastrointestinal Azathioprine can cause severe small-bowel villous atrophy, diarrhea, and malabsorption, reversible after withdrawal. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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• A 20-year-old man with autoimmune hepatitis developed severe small-bowel villous atrophy and chronic diarrhea after taking azathioprine 50 mg/day (3A ). The diarrhea was unresponsive to oral pancreatic enzymes or a gluten-free diet, and severe malabsorption required parenteral nutrition for more than 1.5 years, until the association with azathioprine was identified. Within 2 weeks after withdrawal, the diarrhea resolved completely and parenteral nutrition was discontinued. Mucosal biopsies before and 4 months after azathioprine withdrawal showed complete reversal of severe duodenal villous atrophy and marked upregulation of mucosal dipeptidyl peptidase IV and PepT1 messenger RNA. The patient subsequently maintained normal liver function tests on low-dose prednisone alone, with normal stools and stable nutritional status for more than 4 years.

Pancreas Azathioprine has previously been linked to subsequent acute pancreatitis. In Denmark, 1317 patients redeemed a total of 15 811 prescriptions for azathioprine during 1991 and 2000. The incidence rate for acute pancreatitis was one per 659 treatment year. The risk increased with presence of gallstone disease, alcohol-related diseases, inflammatory bowel disease, and the use of glucocorticoids. Thus, the relative risk of acute pancreatitis is increased in azathioprine users (4M ). Immunologic Azathioprine hypersensitivity has been reported in two patients (5A ). Both had vasculitis with anti-neutrophil cytoplasmic antibodies (ANCA), each mimicking a relapse of vasculitis or a septic complication of immunosuppression. A hypersensitivity reaction to azathioprine was also described in a patient with a demyelinating polyneuropathy (6A ). In 410 patients with inflammatory bowel disease treated with mercaptopurine for 20 years, the incidence of early drug-related allergic reactions was 3.9% (2M ). Desensitization to either

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mercaptopurine or azathioprine is often successful with the same or the other drug (2M , 7c , 8A , 9A ).

in conception failures (defined as spontaneous abortion), abortion secondary to a birth defect, major congenital malformations, neoplasia, or infections among patients taking mercaptopurine compared with controls (RR = 0.85; 95% CI = 0.47, 1.55). The authors concluded that the use of mercaptopurine before or at conception or during pregnancy appears to be safe and that withdrawal before and during pregnancy is not indicated. The risk of adverse birth outcomes in 11 women who took up prescriptions for azathioprine or mercaptopurine during pregnancy was examined in a Danish cohort study (14c ). To examine the risk of congenital malformations, nine pregnancies exposed up to 30 days before conception or during the first trimester were included. To examine perinatal mortality, the frequency of premature births, and low birth weight, 10 pregnancies exposed during the entire pregnancy were included. Outcomes were compared with those of 19 418 pregnancies in which no drugs were prescribed. Of the exposed women, 55% had inflammatory bowel disease and 45% other diseases. Adjusted odds ratios were 6.7 (95% CI = 1.4, 32) for congenital malformations, 20 (2.5, 161) for perinatal mortality, 6.6 (1.7, 26) for premature births, and 3.8 (0.4, 33) for low birth weight. In conclusion, children born to women treated with azathioprine or mercaptopurine during pregnancy had increased risks of congenital malformations, perinatal mortality, and premature birth. However, more data are needed to determine whether the associations are causal or occur through confounding.

Drugs that act on the immune system

Infection risk Disseminated Varicella zoster infection is rare among patients with inflammatory bowel disease, despite the frequent use of azathioprine. • An 18-year-old woman developed severe Varicella zoster pneumonia 9 months after starting to take azathioprine for Crohn’s disease. She recovered after prompt treatment with aciclovir and withdrawal of azathioprine (10A ).

In 410 patients with inflammatory bowel disease, infectious complications occurred at different times during treatment with mercaptopurine in 14%, including pneumonia in 3.9% and Herpes zoster in 3% (2M ). Tumorigenicity There are concerns about whether azathioprine could predispose to malignancy in patients with inflammatory bowel disease. • A 39-year-old non-smoker with Crohn’s disease who had taken azathioprine for 3 years with developed a lingual ulcer (11A ). A biopsy showed a squamous cell carcinoma, a tumor that has not previously been associated with Crohn’s disease. • An invasive cancer of the cervix has been reported in a woman with Crohn’s disease treated by mercaptopurine (12A ).

Over 20 years, lymphoma developed in three of 410 patients with inflammatory bowel disease taking mercaptopurine; however, this incidence was not greater than in the overall population of patients with inflammatory bowel disease (2M ). Teratogenicity Data on azathioprine and mercaptopurine regarding toxicity associated with pregnancy are lacking, raising both patients’ and physicians’ concerns and sometimes resulting in elective abortion. Two recent studies have reported controversial data. Pregnancies in patients with inflammatory bowel disease were analysed to determine whether the patient had taken mercaptopurine before or at the time of conception; they were compared with pregnant women with inflammatory bowel disease who had their pregnancies before taking mercaptopurine (13M ). There was no statistical difference

Drug interactions Infliximab The interaction of infliximab with azathioprine has been studied in 32 patients with Crohn’s disease (15c ). The mean concentration of 6-tioguanine nucleotide was comparable before and 3 months after the first infusion, but there was a significant increase within 1–3 weeks after the first infusion. In parallel, there was a significant fall in leukocyte count and an increase in mean corpuscular volume. These changes normalized 3 months after infusion. An increase in 6-tioguanine nucleotide concentration of more than 400 pmol/8 × 108 erythrocytes was strongly related to good tolerance and a favourable response to infliximab, with a predictive value of 100%.

452 Susceptibility factors Genetic Azathioprine and mercaptopurine can cause life-threatening hemotoxicity in patients who are deficient in thiopurine S-methyltransferase (TPMT), because of accumulation of cytotoxic 6-thioguanine nucleotides (6-TGN). Thus, the use of azathioprine and mercaptopurine is not recommended in patients with TPMT deficiency. However, azathioprine was used in three patients with Crohn’s disease and low TPMT activity, and toxicity was avoided by carefully titrating the dose (16A ). A range of optimal mercaptopurine metabolite concentrations has been defined, as has an association of metabolite concentrations with medication-induced toxicity and the genotype of TPMT (17R ). Measurement of mercaptopurine metabolite concentrations and TPMT molecular analysis provide clinicians with useful tools for optimizing the therapeutic response to mercaptopurine or azathioprine, as well as identifying individuals at increased risk of drug toxicity. In patients with rheumatoid arthritis, the presence of TPMT alleles associated with reduced or absent activity of TPMT might guide the use of azathioprine. TPMT genotype was analysed in 111 patients with rheumatoid arthritis including 40 patients taking azathioprine; TPMT3A [G(460) → A, A(719) → G], the most common mutant allele, was detected in seven of 111 patients (6.3%). Azathioprine was withdrawn in six patients because of adverse effects and in 26 patients because of lack of efficacy. Three patients with moderate adverse effects were homozygous for the wild type TPMT allele, and the other three, who developed severe nausea and vomiting, were TPMT3A carriers. Absence of response, probably due to the low-dose scheme used, was the major cause of azathioprine withdrawal. TPMT genotyping may allow the use of high doses of azathioprine in patients with normal TPMT alleles to improve efficacy (18M ). Azathioprine-induced fatal myelosuppression has been reported in a kidney recipient who carried heterozygous TPMT∗ 1/∗ 3C (19A ). Adverse effects related to TPMT enzyme activity and genotype were analysed in 50 patients with inflammatory bowel disease and azathioprine- or mercaptopurine-related adverse effects. The TPMT genotype ∗ 1/∗ 3 was detected in five patients, genotype ∗ 3/∗ 3 in one,

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and the wild type genotype ∗ 1/∗ 1 in 44. The patient with genotype ∗ 3/∗ 3 had severe pancytopenia. In the control group, three of 50 patients had genotype ∗ 1/∗ 3 and the rest genotype ∗ 1/∗ 1. There was no significant correlation between TPMT mutations and adverse reactions, and most patients with reactions did not have gene mutations (20M ).

Ciclosporin (SED-14, 1286; SEDA-25, 441; SEDA-26, 404; SEDA-27, 374) Cardiovascular Major cardiovascular risk factors have been analysed and the risk of coronary artery disease estimated in a comparative 6-month study of microemulsified ciclosporin (n = 271) versus tacrolimus (n = 286) concomitant with azathioprine and glucocorticoids (21C ). The primary endpoints were the incidence of and time to acute rejection. Blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose were measured at baseline and at months 1, 3, and 6. The 10-year risk of coronary heart disease was estimated according to the Framingham risk algorithm. Tacrolimus lowered serum cholesterol and mean arterial blood pressure, but in a higher summary measure of blood glucose than ciclosporin. Serum triglycerides were not different between tacrolimus and ciclosporin. The mean 10-year coronary artery disease risk estimate was significantly lowered in men who took tacrolimus, but was unchanged in women. Erythromelalgia is a symptom complex of painful inflammatory vasodilatation of the extremities, often regarded as the inverse of Raynaud’s phenomenon. It is usually idiopathic or due to thrombocythemia, and rarely caused by calcium channel blockers. • A 37-year-old man took ciclosporin 150 mg/day for psoriasis and after 4 weeks developed marked erythema, edema, and tenderness over the fingers and toes (22A ). His symptoms increased with warmth and were partly relieved by cold compresses. His full blood count, serum biochemistry, urine analysis, and collagen profile were normal. Ciclosporin was withdrawn and the lesions regressed within 1 week but recurred when ciclosporin was restarted.

Nervous system Ciclosporin-associated neurotoxicity is common but poorly understood.

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• A ten-year-old boy with beta-thalassemia underwent autologous stem cell transplantation followed by ciclosporin 1 mg/kg/day (23A ). The trough ciclosporin concentration on day 14 was 392 ng/ml and the patient subsequently had a generalized tonic-clonic seizure. Ciclosporin was withdrawn, phenytoin was started, and the patient recovered. Six weeks later, a control brain MRI scan showed nearly complete resolution of multifocal high signal abnormalities on T2-weighted sequences in the cortex and subcortical white matter.

Metabolism The effect of long-term ciclosporin on glucose metabolism was analysed in heart transplant recipients who developed posttransplant hyperglycemia, 102 with impaired glycemic control and 20 with clinical diabetes (27c ). There was a significant negative correlation between ciclosporin concentration and insulin in both groups, a significant negative correlation between ciclosporin concentration and proinsulin, C-peptide blood concentration in those with impaired glycemic control and a significant positive correlation between ciclosporin and glucose blood concentration in both groups.

Drugs that act on the immune system

Three patients underwent hemopoietic stem cell transplantation for thalassemia. Prophylaxis of graft-versus-host disease included ciclosporin, prednisolone, and methotrexate. All developed status epilepticus with cortical signal alterations mainly in the occipital regions on T2-weighted MRI. The neurological symptoms and radiographic findings completely disappeared without withdrawing ciclosporin. Children with thalassemia receiving busulfan or cyclophosphamide as a preparative regimen seem to be especially susceptible to ciclosporinassociated seizures (24A ). Reversible cortical blindness is a rare manifestation of ciclosporin toxicity and occurred in a lung transplant recipient (25A ). Endocrine Life-threatening hypothyroidism associated with ciclosporin was reported in a patient treated with reduced-intensity hemopoietic stem cell transplantation for metastatic renal-cell carcinoma (26A ). • A 26-year-old woman with metastatic renal cell carcinoma underwent reduced-intensity hemopoietic stem cell transplantation after having had a right nephrectomy, pelvic radiotherapy, interferon, and conditioning with busulfan, fludarabine, and antithymocyte globulin. Ciclosporin 3 mg/kg was added and graft-versus-host disease occurred on day 54 after ciclosporin was tapered. Ciclosporin 2 mg/kg was restarted intravenously and she developed malaise and hepatorenal dysfunction. The symptoms resolved after withdrawal of ciclosporin on day 62. One week later, ciclosporin 2 mg/kg was given orally and she developed fatigue, lethargy, and paralytic ileus. Thyroid-stimulating hormone, free triiodothyronine, and free thyroxine were undetectable; thyroid function had previously been normal. A thyrotropin-releasing hormone test showed secondary hypothalamic dysfunction.

The authors suggested that ciclosporin had suppressed the hypothalamic-pituitary axis.

Mouth Gingival hyperplasia is a well-documented adverse effect of ciclosporin, but severe lip enlargement occurs less often. This can lead to a poor body image, low self-esteem, and non-adherence to therapy, especially in older children and adolescents. Two pediatric kidney recipients developed marked lip hypertrophy as a consequence of ciclosporin treatment; it resolved after conversion to tacrolimus (28A ). Gastrointestinal Ciclosporin-induced achalasia-like esophageal dysmotility occurred in a liver transplant recipient (29A ). • A 59-year-old liver recipient took ciclosporin 250 mg/day, azathioprine 75 mg/day, and prednisolone, with pantoprazole 40 mg/day as ulcer prophylaxis. Dysphagia and retrosternal pain occurred 3 months after transplantation. The symptoms gradually worsened, with vomiting and severe dysphagia for liquids. Esophageal manometry showed achalasia, with inadequate relaxation of the lower sphincter. Immunosuppression was converted from ciclosporin to tacrolimus resulting in amelioration of the esophageal symptoms.

Urinary tract Ciclosporin-induced renal damage has been described in recipients of solid organs and in patients treated for autoimmune diseases (30R ). The biochemical basis of toxicity due to calcineurin inhibitors and their toxicodynamic interaction with inhibitors of mTOR, such as tacrolimus, is still poorly understood. However, there is evidence that nephrotoxicity is caused by drug-induced mitochondrial dysfunction and that inhibitors of mTOR enhance the negative effects of calcineurin inhibitors on cell energy metabolism (31E ). The effect of microemulsion ciclosporin and tacrolimus on the development of renal allograft

454 fibrosis has been evaluated in a randomized trial in 102 kidney recipients randomized to either microemulsion ciclosporin 15 mg/kg/day (trough concentration range 200–300 ng/ml) or tacrolimus 0.2 mg/kg/day (trough concentration range 8–15 ng/ml) in conjunction with glucocorticoids, or at a lower dose (ciclosporin 7 mg/kg/day and tacrolimus 0.1 mg/kg/day), with the addition of azathioprine for recipients of non-heart-beating kidneys (32C ). There was a significant increase in allograft interstitial fibrosis in the patients who used microemulsion ciclosporin compared with tacrolimus. There was no significant difference in the demographic characteristics between the patients or in the incidence of acute rejection (ciclosporin 36% versus tacrolimus 35%) or glucocorticoidresistant rejection (both 10%). The incidence of insulin resistance was higher with tacrolimus, but this was not significant. Ciclosporin was associated with significant increases in total cholesterol and low-density lipoprotein concentrations, which persisted throughout the study. In 44 patients randomized 3 months after kidney transplantation to ciclosporin + sirolimus + prednisolone (group I) or to sirolimus + prednisolone (group II), baseline graft biopsy showed a higher degree of renal damage in group II (33c ). At 1 year after transplantation, chronic allograft nephropathy was diagnosed in 55% of the patients, of whom 64% were in group I and 36% in group II. Lesions of chronic allograft nephropathy were scored as moderate to severe in 90% of group I patients but only 32% of group II patients. There was a vascular score greater than or equal to 2 in 90% of group I patients and in 38% of group II patients. Group I patients had significantly worse kidney graft function (serum creatinine 177 versus 115 µmol/l). The authors suggested that early withdrawal of ciclosporin is a safe option that allows significant reduction of chronic histological damage, particularly vascular injury, to cadaveric kidney allografts. Kidney recipients (n = 31) with biopsyconfirmed chronic allograft nephropathy were prospectively randomized to receive a 40% ciclosporin dosage reduction either with sirolimus 2 mg/day (n = 16) or without (control, n = 15) (34c ). Sirolimus did not improve functional, molecular, or histological outcomes in patients with chronic allograft nephropathy after ciclosporin dosage reduction.

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Although the pathogenesis of ciclosporin nephrotoxicity is not completely defined, there is evidence that suggests a role of reactive oxygen species. In numerous in vivo and in vitro experiments ciclosporin caused renal insufficiency and increased the synthesis of reactive oxygen species, thromboxane, and lipid peroxidation products in the kidney. Furthermore, it modified the expression and activity of several renal enzymes (cyclo-oxygenase, superoxide dismutase, catalase, and glutathioneperoxidase). Antioxidant nutrients (for example vitamins E and C) can neutralize some of the effects that ciclosporin produces in the kidney (35R ). Thus, vitamin E inhibited the synthesis of reactive oxygen species and thromboxane and the lipid peroxidation process induced by ciclosporin. Antioxidants can also improve renal function and histological damage produced by ciclosporin. Although there are few data in humans taking ciclosporin, it is possibility that antioxidants also neutralize ciclosporin nephrotoxicity and LDL oxidation. Thus, antioxidant nutrients could have a therapeutic role in transplant patients taking ciclosporin. Skin Pseudoporphyria is a generic term that is used to describe photoaggravated bullous dermatoses similar to those of porphyria cutanea tarda (36A ). • A 50-year-old man with a history of chronic hepatitis C, alcoholism, and liver transplantation, taking ciclosporin, developed tender blisters and erosions on the backs of both hands. Skin biopsy was consistent with porphyria cutanea tarda. Urinary excretion of δ-aminolevulinic acid, porphobilinogen, uroporphyrins, hepatocarboxyporphyrin, and hexacarboxylporphyrin were within normal limits. Coproporphyrin and total porphyrin concentrations were raised. Ciclosporin was switched to tacrolimus and the blisters resolved within 3 weeks. Nevertheless, liver function progressively worsened.

Sebaceous glands Ciclosporin can cause sebaceous gland hyperplasia and hyperplastic folliculitis (37A , 38A ). Musculoskeletal Before kidney transplantation 31 of 82 patients (38%) had joint pain and 17 of 82 (21%) after transplantation (39c ). Six (7.3%) and three (3.7%) patients developed arthritis before and after transplantation. Joint pain significantly correlated with serum ciclosporin concentrations over 200 ng/ml. Muscle pain can be related to ciclosporin.

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• A 61-year-old man with incomplete Behçet’s disease developed weakness and muscle pain. He had not responded fully to colchicine and ciclosporin was added (40A ). About 1 year later he noticed weakness of the proximal limb muscles. Within 3 months, he developed progressive severe generalized muscle pain and numbness in his hands. There were rises in serum muscle enzymes, creatinine, and hepatic transaminases. Electromyography and nerve conduction studies suggested a myopathy and a mild polyneuropathy. Colchicine was withdrawn, but the severe muscle pain continued. The dose of ciclosporin was then reduced and 7 days later the weakness and muscle pain disappeared and the laboratory findings improved markedly.

postulated, but ciclosporin toxicity was excluded because of low ciclosporin blood trough concentrations before and throughout the episode, in the presence of relatively stable renal function.

Drugs that act on the immune system

Irinotecan In 37 patients with fluorouracilrefractory metastatic colorectal cancer, irinotecan clearance was reduced from 13 to 5.8 l/h/m2 and AUC0-tn was increased 2.2-fold by coadministration of ciclosporin 5 mg/kg bd for 3 days; the AUCs of the irinotecan metabolites SN38 and SN38G were increased 2.2-fold and 2.3-fold respectively (44c ).

This clinical course suggested that the patho- Itraconazole After kidney transplantation, genesis of neuromyopathy in this case was eight patients took itraconazole solution 400 closely related to either colchicine or ciclosporin. mg/day over about 3 months in combination with ciclosporin (45A ). A 48% reduction in Tumorigenicity Primary cutaneous CD30+ the mean total daily dose of ciclosporin was anaplastic large T cell lymphoma has pre- necessary to maintain target ciclosporin trough viously been reported in patients taking ci- concentrations. closporin for various reasons, but not in those Orlistat There are reports that both probucol taking it for psoriasis. and orlistat can reduce the systemic availability • A 61-year-old woman developed an anaplastic of ciclosporin (46M ). CD30+ cutaneous T cell lymphoma while taking ciclosporin for recalcitrant psoriasis (41A ). Two months after withdrawal the lymphoma resolved clinically and histologically. Three years later extracutaneous involvement of the lymphoma was detected.

It is not clear in this case whether the association between ciclosporin and the lymphoma was casual. Pregnancy Ciclosporin should be used with extreme caution in pregnancy and the postnatal period (42r ). • A woman had fulminant glucocorticoid-refractory ulcerative colitis during pregnancy and refused ciclosporin. After emergency cesarean section, she was given intravenous ciclosporin and 2 days later developed severe hypertension with hypertensive encephalopathy and seizures.

Drug interactions Colchicine Multiorgan failure has been described in cases of colchicine poisoning and in patients after taking usual doses of colchicine during ciclosporin therapy after kidney transplantation. • A renal transplant recipient developed multiorgan failure after taking appropriate doses of colchicine in combination with ciclosporin (43A ). An interaction between colchicine and ciclosporin was

• An overweight 56-year-old man with type II diabetes on peritoneal dialysis took orlistat for some months until he received a living-unrelated kidney transplant (47A ). Despite oral ciclosporin for 48 hours before transplantation and much larger doses after, it was very difficult to achieve adequate ciclosporin blood concentrations for the first week. After he opened his bowels on day 7 and had been given intravenous ciclosporin for 3 days, adequate ciclosporin blood concentrations were achieved and then maintained with conventional oral doses.

The authors believed that this provided evidence of an important interaction of ciclosporin with orlistat. Orlistat may reduce blood ciclosporin concentrations by interfering with its absorption in the small intestine (48A ), although the effect may be mediated indirectly by via reduced fat absorption rather than a direct drug– drug interaction (49A ). Co-administration of orlistat with ciclosporin is not recommended. However, if concomitant use is unavoidable, ciclosporin blood concentrations should be monitored more often, both after the addition of orlistat and on withdrawal. St John’s wort An interaction of ciclosporin with a herbal tea containing St John’s wort (Hypericum perforatum) has been reported (50A ). The effects of a Hypericum extract 600

456 mg/day for 14 days on the pharmacokinetics and metabolism of ciclosporin have been investigated in an open study in 11 patients after kidney transplantation taking regular ciclosporin (51c ). After 2 weeks dose-corrected AUC0-12 , Cmax , and Cmin of ciclosporin fell significantly by 46%, 42%, and 41% respectively. Ciclosporin doses were increased from a median of 2.7 mg/kg/day at baseline to 4.2 mg/kg/day at day 15, and the first dose adjustment was required only 3 days after the start of treatment with St John’s wort. Dose-corrected AUCs of the metabolites AM1, AM1c, and AM4N fell significantly by 59%, 61%, and 23% compared with baseline. The AUCs of AM9 and AM19 were unchanged. After the increase in ciclosporin dose, the AUC of AM9, AM19, and AM4N increased by 47, 51, and 20% and the Cmax by 57, 90, and 43% respectively. These substantial alterations in the kinetics of the metabolites of ciclosporin caused by St John’s wort could affect the toxicity of ciclosporin. Sibutramine An interaction of ciclosporin with sibutramine has been reported (52A ). Like ciclosporin, sibutramine is metabolized by CYP3A4, and a competitive inhibitory interaction is suggested. Sirolimus Sirolimus and ciclosporin are used together after kidney transplantation. Both are taken orally and have common intestinal and hepatic metabolism and intestinal transport mechanisms. There is therefore the potential for pharmacokinetic drug interactions. In an open, randomized, crossover study in 15 healthy men and six women the systemic availability of a single oral dose of sirolimus 10 mg was markedly increased by microemulsion ciclosporin 300 mg taken at the same time (53c ). Cmax , tmax , and AUC increased 116%, 92%, and 230% respectively. However, when sirolimus was taken 4 hours after ciclosporin, the increases in sirolimus Cmax , tmax , and AUC were only 37%, 58%, and 80% respectively. Ciclosporin did not affect the half-life or mean residence time. The systemic availability of ciclosporin was not altered. The authors concluded that ciclosporin markedly increases the systemic availability of sirolimus, perhaps due to a large intestinal and hepatic first-pass effect.

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Statins Ciclosporin and most statins (lovastatin, simvastatin, atorvastatin, and pravastatin) are metabolized by CYP3A4. Thus, a pharmacokinetic interaction is possible. • A 53-year-old renal transplant recipient taking ciclosporin, azathioprine, and prednisone developed rhabdomyolysis within 32 days of starting to take simvastatin (54A ). She had profound muscle pain and weakness, with a rise in serum creatine kinase to 60 000 IU/l and serum creatinine to 147 µmol/l. Simvastatin was withdrawn and the dose of ciclosporin reduced, and 10 days later she was asymptomatic, with serum creatine kinase 67 IU/l and serum creatinine within the reference range.

The mechanism of this interaction does not seem to be solely inhibition of CYP3A4; it probably also partly results from inhibition of statin transport in the liver (46M ). The suggested mechanism of the interaction of cerivastatin with ciclosporin is inhibition of transporter-mediated uptake of the statin in the liver, which is partly mediated by an organic anion transporting polypeptide-2 (55E ).

Cyclophosphamide

(SED-14, 1283; SEDA-25, 443; SEDA-26, 406; SEDA-27, 375)

Liver Hepatotoxicity caused by high-dose myeloablative therapy leads to significant morbidity after hemopoietic cell transplantation. It is hypothesized that hepatotoxicity after cyclophosphamide and total body irradiation is caused by metabolism of cyclophosphamide to toxic metabolites. Cyclophosphamide 60 mg/kg was infused over 1–2 hours on each of 2 consecutive days, followed by total body irradiation in 147 patients (56c ). Hepatotoxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin concentrations. The hazards of liver toxicity, non-relapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as AUC). Of 147 patients, 23 (16%) developed moderate or severe veno-occlusive disease. The median peak serum bilirubin concentration to day 20 was 44 (range 9–700) µmol/l. Metabolism of cyclophosphamide was highly

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variable, particularly for the metabolite Ocarboxyethylphosphoramide mustard, whose AUC varied 16-fold. Exposure to this metabolite was significantly related to veno-occlusive disease, a raised bilirubin, non-relapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of O-carboxyethylphosphoramide mustard exposure had a 5.9-fold higher risk of non-relapse mortality than patients in the lowest quartile. Engraftment and tumor relapse were not significantly related to cyclophosphamide metabolite exposure.

2–3 weeks until the white cell count fell to 3.0 × 109 /l, followed by a rest until a white cell count of at least 4.0 × 109 /l was reached again. This was repeated for up to six cycles. No other immunosuppressants besides glucocorticoids were allowed. The disease improved in 70% of cases. There was transient leukopenia in each patient in a regular pattern during the cycles. There were no deaths or cases of septicemia. There were mild to moderate infections, mainly in the respiratory tract, but they resolved with adequate treatment without sequelae.

Drugs that act on the immune system

Drug interactions The combination called CBV, cyclophosphamide + carmustine (BCNU) + etoposide (VP16-213), has been studied in 18 adults with non-Hodgkin lymphoma, followed by allogeneic hemopoietic stem cell transplantation (57c ). CBV resulted in 2-year estimated relapse-free and overall survival rates of 56 and 79% respectively. Four patients died of Aspergillus infection (n = 2), lymphoma (n = 1), or interstitial pneumonitis (n = 1). Adverse events included acute graft-versus-host disease 17%, chronic graft-versus-host disease 22%, veno-occlusive disease 17%, relapse 23%, and interstitial pneumonitis 6%. The authors concluded that CBV is a safe and effective alternative to total body irradiation before allogeneic hemopoietic stem cell transplantation for nonHodgkin lymphoma.

Deoxyspergualin Deoxyspergualin is a synthetic analogue of the immunosuppressive anti-tumor antibiotic spergualin. It contains the polyamine spermidine as part of its structure and has similar properties and mechanisms of action to ciclosporin and the calcineurin inhibitors. Observational studies The efficacy and safety of deoxyspergualin has been assessed in an open multicenter trial in patients with antineutrophil cytoplasmic antibody-associated vasculitis (19 with Wegener’s granulomatosis and one with microscopic polyangiitis) who were either unresponsive or had contraindications to standard immunosuppressants (58c ). Deoxyspergualin 0.5 mg/kg/day was given for

Everolimus (SDZ-RAD) (SEDA-26, 406) Susceptibility factors Genetic The pharmacokinetics of everolimus 0.75 or 1.5 mg bd in 731 patients were characterized over the first 6 months after kidney transplantation in patients who were also taking ciclosporin and prednisolone; in black patients exposure to everolimus was on average 20% lower than in white patients (59c ).

Glatiramer acetate Glatiramer acetate is a synthetic mixture of four amino acids, approved worldwide for the treatment of relapsing multiple sclerosis. Local injection-site reactions occur in 90% of patients and can result in erythema, induration, and sometimes pain. About 15% of patients have an immediate post-injection reaction; these occur randomly and are not usually an indication for withdrawal. Immunologic Almost all patients develop binding antibodies to glatiramer within 3–4 months after the start of therapy, and these do not interfere with efficacy (60M ).

Leflunomide

(SED-14, 1296)

Skin Leflunomide can cause toxic epidermal necrolysis (61A ).

458 • A woman with rheumatoid arthritis had taken glucocorticoids and methotrexate for 2 years when the methotrexate was replaced by leflunomide. Three weeks later she developed progressive generalized erythema with blisters, fever, chills, and erosive lesions on the lips and oral mucosa. The palmar and plantar surfaces had edema, erythema, and pulpitis with epidermolysis. Histology showed necrotic keratinocytes and epidermal spongiosis. After high-dose prednisolone and topical treatment she recovered within 14 days.

Mycophenolate mofetil (SED-14, 1303; SEDA-25, 445; SEDA-26, 407; SEDA-27, 376) Mycophenolate mofetil is a non-competitive reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). It is rapidly converted to its active metabolite mycophenolic acid by enteral esterases after oral application. It is widely used in autoimmune diseases and after solid organ transplantation. Gastrointestinal disorders, bone marrow toxicity, and infection are its major adverse events. Observational studies Of 191 patients who took mycophenolate after liver transplantation, gastrointestinal disorders or bone marrow toxicity occurred in 60 (31%); however, the incidence of infections did not increase (62c ). Of 54 patients taking mycophenolate mofetil for systemic lupus erythematosus, 21 had 28 gastrointestinal adverse events, 24 had 37 infections, and leukopenia occurred three times but never required dosage adjustment. Adverse events occurred at a similar rate at all doses. Mycophenolate was withdrawn in 16 cases because of adverse events (n = 9), lack of efficacy (n = 3), pregnancy (n = 2), and for administrative reasons (n = 2). A range of doses was tolerated and was associated with clinical improvement, suggesting that a flexible dosing schedule should be considered when using mycophenolate in patients with systemic lupus erythematosus (63c ). Hematologic The Transplant European Survey on Anemia Management (TRESAM) has documented the prevalence and management of anemia in 4263 kidney transplant recipients (64C ). At enrollment, 39% were anemic. Therapy with angiotensin-converting enzyme (ACE)

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inhibitors, angiotensin II receptor antagonists, mycophenolate mofetil, or azathioprine was associated with a higher likelihood of anemia. There was severe anemia in four of 30 kidney transplant patients in the early posttransplantation period (65c ). Immunosuppression consisted of glucocorticoids, ciclosporin, mycophenolate mofetil, and antithymocyte globulin. All four patients received iron and erythropoietin. Blood loss, deficiencies, hemolysis, drug interactions, and viral infections were excluded. Bone marrow biopsy showed pure red cell aplasia, which was ascribed to mycophenolate mofetil. Withdrawal or reduction of mycophenolate was followed by hematological improvement after 5–9 days. Mycophenolate mofetil may have a broader antiproliferative effect than its proposed lymphocyte-specific effect. Three transplant patients acquired mycophenolate-induced reversible Pelger–Huet anomaly, a form of deficient nuclear segmentation and abnormal chromatin condensation of polymorphonuclear neutrophil leukocytes (66A ). Mycophenolate is a necessary but not sufficient condition for the development of the anomaly. There was a dose-response relation between plasma mycophenolate concentration and the severity of neutrophil dysplasia. Except for one slightly raised value, the patients’ plasma mycophenolate concentrations were within the target range. None of the patients developed infections. Previous graft rejection episodes were identified as a potential predisposing factor for the development of Pelger–Huet anomaly. In one patient, withdrawal of mycophenolate led to normalization of polymorph morphology. In the other two patients, the left shift disappeared after the dose of mycophenolate was reduced; in these two patients, there was a form of desensitization to the effect of mycophenolate on neutrophils when the dose of mycophenolate was again increased. Gastrointestinal Diarrhea is the most common adverse event in transplant patients taking mycophenolate. Of 26 recipients with persistent afebrile diarrhea, all but one had an erosive enterocolitis and 70% had malabsorption (67c ). Infective diarrhea was demonstrated in 60% and successfully treated with antimicrobial agents without changes in the immunosuppressive regimen. In 40% of patients without infections, there was a Crohn’s disease-like pattern

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of inflammation. These patients also had less pronounced bile-acid malabsorption but a significant faster colonic transit time, correlating with the trough concentration of mycophenolic acid. However, withdrawal was associated with allograft rejection in one-third of these patients. Because dosage reduction or withdrawal was the only effective therapy, mycophenolic acid or one of its metabolites may have been the cause. Colonic biopsies from 20 kidney recipients with mycophenolate-related diarrhea were compared with colonic biopsies from patients with acute graft-versus-host disease (n = 10) or inflammatory bowel disease or infectious colitis (n = 10), and with colonic biopsies from renal transplant patients not taking mycophenolate (n = 8) (68c ). Normal colonic segments from surgical specimens served as controls (n = 5). Colonic biopsies from patients with mycophenolate-related diarrhea showed prominent crypt cell apoptosis and reactive/reparative changes, including enterocyte atypia, increased neuroendocrine cells, and distortion of the glandular architecture. The changes were similar, although of milder degree to those seen in patients with acute intestinal graft-versus-host disease. This pattern of injury was not seen in controls or in biopsies from transplant patients not taking mycophenolate, and it was markedly different from that seen in idiopathic inflammatory or infectious colitis. The severity of histological changes correlated significantly with the endoscopic degree of colitis. There was no statistically significant correlation between histological damage and the dose of mycophenolate. Mycophenolate-related colitis is a distinct entity that displays histological features remarkably similar to the ones associated with intestinal graft-versus-host disease. This form of injury could be related to either direct toxicity or an “innocent by-stander” phenomenon secondary to alteration of the immunological microenvironment of the colon.

III) ciclosporin + azathioprine + prednisolone (n = 193), the cumulative percentages of all wound-healing problems were not significantly different. Obesity and delayed graft function were significant risk factors for delayed wound healing.

Drugs that act on the immune system

Skin During a 10-year period marked by changing recipient demographics, the introduction of mycophenolate and sirolimus did not result in a significant increase in transplant wound-healing complications (69M ). Of 513 consecutive adult kidney recipients who took one of three regimens, sirolimus + mycophenolate + prednisolone (n = 152), ciclosporin + mycophenolate + prednisolone (n = 168), or

Immunologic The immune status of 138 kidney and 14 pancreas/kidney transplant recipients has been assessed by measurement of lymphocyte subsets, mitogen-induced T cell proliferative responses, neutrophil phagocytic capacity, and generation of reactive oxygen species (70c ). The most common abnormality was B cell lymphopenia (85%), followed by reduced neutrophil production of reactive oxygen species (63%), NK cell lymphopenia (50%), reduced lymphocyte mitogen response (49%), and reduced CD4 cell number (23%). The abnormalities were unrelated to the duration of immunosuppression (up to 15 years), and variable combinations of ciclosporin, azathioprine, prednisolone, and mycophenolate mofetil, except for a consistent reduction in lymphocyte mitogen response in patients taking mycophenolate. A retrospective comparison of infective episodes showed a significantly higher index of infections in patients with the worst score compared with a normal score. Infection risk Immunoglobulin deficiency has been compared in kidney recipients taking azathioprine (n = 17) or mycophenolate mofetil (n = 24). Immunoglobulin concentrations were measured before and every month after kidney transplantation for 6 months (71c ). Concentrations of IgG, IgM, and IgA fell significantly after 6 months in those taking mycophenolate but not in those taking azathioprine. The mean numbers of infection episodes in each patient were 1.3 (mycophenolate) and 0.5 (azathioprine). There were recurrent urinary tract infections in eight patients, seven of whom were taking mycophenolate and had low immunoglobulin concentrations. After 6 months, these seven patients were switched from mycophenolate to azathioprine; in six cases immunoglobulin concentrations normalized within 3 months. Conversion from mycophenolate to azathioprine may be an alternative for patients with low immunoglobulin concentrations and recurrent urinary tract infections.

460 Virus infections Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase, which has in vitro antiviral properties against flaviviruses, suggesting the possibility that it might also inhibit the hepatitis C virus. The antiviral effects of mycophenolate mofetil on hepatitis C viral replication have been studied in 30 patients with chronic hepatitis C infection (72c ). During oral treatment with mycophenolate over 8 weeks (2000 mg/day, 1000 mg/day, 500 mg/day, or a matched oral placebo) did not affect hepatitis C viral RNA. Specifically, no subject became hepatitis C negative or had a one-log reduction in virus titer. Serum transaminases did not normalize. The most common adverse effects were headache, nausea, and diarrhea. Thus, mycophenolate mofetil alone does not appear to have a significant antiviral or biochemical effect in patients with chronic hepatitis C. Susceptibility factors The pharmacokinetics of oral mycophenolate mofetil 2 g/day have been studied in patients after kidney transplantation (n = 16) and patients with autoimmune diseases (n = 16) (73c ). Mycophenolic acid trough concentrations were higher in the patients with autoimmune diseases, but peak concentrations were lower. Mycophenolic acid AUC was comparable between the groups. Drug interactions Ciclosporin In stable lung transplant recipients, mycophenolic acid trough concentrations fell by 50% during therapy with mycophenolate + ciclosporin compared with mycophenolate + tacrolimus. In addition, patients with cystic fibrosis required 30% higher doses of mycophenolate to achieve the same target concentrations as in recipients without cystic fibrosis (74c ).

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Monitoring therapy The need for pharmacokinetic monitoring of mycophenolate mofetil is controversial (76R ). Mycophenolic acid can be readily measured in plasma, and relations between the incidence of rejection and mycophenolic acid predose concentrations and mycophenolic acid AUC have been reported after kidney transplantation. However, the relation between pharmacokinetics and adverse events in renal and cardiac transplant patients is unclear. There is large inter- and intrapatient variability in the pharmacokinetics of mycophenolic acid and in some patient changes in protein binding, concomitant diseases, or interactions with concurrent immunosuppressants can cause further changes. Future directions for research include determining a practical limited sampling strategy for mycophenolic acid AUC; clarifying the relation between free mycophenolic acid concentrations, efficacy, and toxicity; and defining the pharmacodynamic relation between activity of inosine monophosphate dehydrogenase and risk of rejection or adverse effects.

Pimecrolimus In a small observational study the most frequent adverse effect of topical pimecrolimus was initial discomfort at the site of application, in 20% of patients (77c ). There were no systemic adverse events, which was consistent with low pimecrolimus blood concentrations.

Sirolimus (rapamycin)

Valaciclovir Valaciclovir is often used for prophylaxis of cytomegalovirus infection after organ transplantation.

(SED-14, 1304; SEDA-25, 446; SEDA-26, 408; SEDA-27, 377)

• A woman taking mycophenolate mofetil and valaciclovir developed neutropenia (75A ). The duration of valaciclovir treatment exactly corresponded with the duration of the neutropenia, and the mycophenolic acid trough concentrations increased with the neutrophil count.

Cardiovascular In a large multicenter trial, pre-emptive sirolimus therapy was evaluated after liver transplantation. The incidence of hepatic artery thrombosis was six of 110 patients taking sirolimus + tacrolimus and one of 112 taking tacrolimus monotherapy. Whether the increased incidence of hepatic artery thrombosis can be attributed to sirolimus is unclear, but the Food and Drug Administration released a mandated drug warning (78MS ).

Mycophenolate can increase intracellular concentrations of valaciclovir, which may explain this interaction, which needs to be confirmed.

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Respiratory The FDA has received 35 reports of sirolimus-related interstitial pneumonitis (78MS ). Four of 15 consecutive lung transplant patients, taking sirolimus + tacrolimus + prednisone, a statin, and prophylaxis for cytomegalovirus and Pneumocystis jiroveci, had significant airway complications within 6 months, including 3 deaths (79c ). Enrolment in the study was therefore terminated and the study population was compared retrospectively with 83 consecutive lung recipients treated with ciclosporin (n = 64) or tacrolimus (n = 19), mycophenolate mofetil, and prednisone. This confirmed an increased incidence of airway dehiscence and reduced survival in those taking sirolimus.

have been several reports of deterioration of renal function associated with sirolimus, and the combination of sirolimus + tacrolimus can cause nephrotoxicity in some patients by mechanisms that are presently unexplained (82A ). After living-donor kidney transplantation in two African-American men, acute renal insufficiency developed after exposure to sirolimus + tacrolimus. Both patients received similar doses of sirolimus and tacrolimus to achieve target concentrations of 5–15 ng/ml and prednisone in tapering doses. Although both kidneys functioned immediately, acute oliguric renal insufficiency developed about 2 weeks after kidney transplantation, and graft biopsy showed acute tubular necrosis in one patient. Sirolimus and tacrolimus were withdrawn and temporary hemodialysis was required. Graft function returned 2 weeks later and was normal 2 months after kidney transplantation on tacrolimus + mycophenolate. After heart transplantation, two patients taking sirolimus developed renal insufficiency (83c ). Sirolimus has been used as a primary immunosuppressant after transplantation in patients with a history of hemolytic-uremic syndrome and also as rescue therapy in patients with calcineurin inhibitor-associated thrombotic microangiopathy. In four cases there was significant thrombotic microangiopathy in the context of contemporaneous or contiguous use of a calcineurin inhibitor and sirolimus. The intrarenal ciclosporin concentration is thought to be significantly raised by sirolimus; this mandates caution when co-administering them.

Drugs that act on the immune system

Metabolism The incidence, severity, and predisposing factors for dyslipidemia among renal transplant patients on ciclosporin with sirolimus (n = 280) or without sirolimus (n = 118) has been investigated in a retrospective study (80c ). During the first 6 months after kidney transplantation there was hypercholesterolemia in 80% versus 46% and hypertriglyceridemia in 78% versus 43%. However, there was no significant difference in the incidence of cardiovascular events within 4 years after transplantation in the two groups. Thus, sirolimus-associated dyslipidemia does not seem to represent a major risk factor for the early emergence of cardiovascular complications. In a pilot study after coronary angioplasty in 22 patients, sirolimus was given orally in a loading dose of 6 mg followed by 2 mg/day over 4 weeks. Sirolimus was withdrawn after an average of 15 days in 11 patients because of adverse effects, including hypertriglyceridemia (n = 3), leukopenia (n = 3), raised liver function tests, stomatitis, acne, flu-like symptoms, and physician preference (n = 1 each). The rate of coronary restenosis was 87%. Sirolimus did not benefit patients with recalcitrant stenosis and adverse effects were frequent (81c ). Fluid balance The incidence of sirolimusrelated peripheral edema/swelling is 55–64% (78M ). Urinary tract Sirolimus is thought to be non-nephrotoxic. However, inhibitors of mTOR enhance the negative effects of calcineurin inhibitors on cell energy metabolism (32E ). There

• A 26-year-old woman, who had hemolytic-uremic syndrome at the age of 3 years, underwent kidney transplantation (84A ). Immunosuppression consisted of ciclosporin 200 mg bd, azathioprine, and glucocorticoids. Allograft dysfunction occurred after 6 weeks. A graft biopsy showed thrombotic microangiopathy, acute rejection (Banff 1a), and ciclosporin toxicity. The hemoglobin concentration was 9.7 g/dl. Ciclosporin was replaced by mycophenolate mofetil and sirolimus 2 mg/day. A repeat biopsy showed continuing rejection and thrombotic microangiopathy. The platelet count fell to 100 × 109 /l and the lactate dehydrogenase activity rose to 831 U/l. She was given antithymocyte globulin for 10 days and her symptoms improved. After 5 months, her serum creatinine rose from 168 to 247 µmol/l during immunosuppression with sirolimus 8 mg/day and mycophenolate mofetil 1.5 g/day. The platelet count fell to 66 × 109 /l, the hemoglobin fell to 7.7 g/dl,

462

•

•

•

•

and the lactate dehydrogenase activity rose to 1178 U/l. Fragments were seen in a blood film. A graft biopsy showed mild acute rejection and severe thrombotic microangiopathy. She developed cytomegalovirus pneumonia and sirolimus was withdrawn. Despite ganciclovir, plasma exchange, intravenous immunoglobulin, and dialysis she died soon afterwards. An 11-year-old girl with a kidney transplant was given sirolimus 2 mg/day for chronic allograft nephropathy, and the dose of ciclosporin was reduced to 25% (84A ). She developed a thrombotic microangiopathy 6 weeks later. Sirolimus trough concentrations were 10–12 ng/ml and the ciclosporin trough concentration was 121 µg/ml. Ciclosporin was withdrawn and her symptoms improved. A 44-year-old kidney recipient taking sirolimus 2 mg/day and ciclosporin 8 mg/kg/day developed thrombotic microangiopathy 51 days after kidney transplantation (84A ). Ciclosporin was replaced by mycophenolate mofetil, and 12 months later the graft had excellent function. A 47-year-old African-American woman underwent kidney transplantation, but because of preexisting graft nephrosclerosis never received a calcineurin inhibitor and was always maintained on sirolimus; a diagnosis of transplant thrombotic microangiopathy was verified histologically (85A ). A 21-year-old woman with IgA nephropathy underwent kidney transplantation (84A ). After 6 weeks ciclosporin was switched to tacrolimus because of hirsutism. Her platelet count fell from 481 × 109 /l to 181 × 109 /l within 2 weeks after conversion to tacrolimus and there was evidence of tacrolimus toxicity in a renal biopsy and tacrolimus trough concentrations of 6–22 ng/ml. After conversion from tacrolimus to sirolimus 2 mg/day (sirolimus trough concentration 17 ng/ml after 7 days), the platelet count improved briefly, but fell again to 32 × 109 /l after 2 weeks. A repeat kidney biopsy showed plentiful glomerular and arteriolar microthrombi. Sirolimus was withdrawn and mycophenolate mofetil was added. Cytomegalovirus infection resolved with intravenous ganciclovir. The platelet count recovered to 259 × 109 /l by 4 weeks after withdrawal of sirolimus.

The last case suggests thrombotic microangiopathy associated with tacrolimus, and deterioration during sirolimus therapy. Mouth Oral ulceration has been reported in association with sirolimus in a randomized, multicenter trial in 33 kidney transplant recipients (86c ). The patients took oral tacrolimus + mycophenolate mofetil and then at 1 year after transplantation continued to take tacrolimus (trough concentrations 5–10 ng/ml) and mycophenolate 1000–1500 mg/day (n = 18) or converted from tacrolimus to sirolimus 15

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mg/day initially, thereafter adjusted to target trough concentrations of 10–15 ng/ml (n = 15). The study was stopped prematurely when nine patients taking sirolimus developed painful oral ulcers, which did not occur in the control group. Possible explanations were overimmunosuppression during the period of conversion from tacrolimus to sirolimus without antiviral prophylaxis, and the use of an oral emulsion instead of tablets. However, in another study, 19 patients developed oral aphthous ulcers whether they used sirolimus suspension or tablets (78M ). Two of 29 kidney recipients who took sirolimus monotherapy after alemtuzumab induction developed oral ulcers, which resolved after lowering the dose of sirolimus or switching to a calcineurin inhibitor (87c ). Skin Dermatitis has been reported in 21 patients at different times during sirolimus therapy; rash and acne have also been reported, resembling seborrheic dermatitis and most commonly seen on the face and scalp (78M ). Musculoskeletal Polyarthralgia and peripheral edema were more frequent in patients taking sirolimus after heart transplantation (83c ). Sirolimus can also cause a myopathy (88A ). Of 17 kidney recipients with joint pains, 13 also had peripheral edema; the joint pains resolved over several weeks or months with dosage reduction or withdrawal (78M ). Infection risk In an open, randomized study of patients with graft atherosclerosis after heart transplantation, sirolimus (n = 22) was compared with continued current immunosuppression (controls, n = 24) (83c ). Infection was the most common indication for readmission and occurred in nine patients taking sirolimus and seven controls. Trauma In a study of surgical wound complications after kidney transplantation sirolimus + prednisone + tacrolimus or ciclosporin (study group; n = 15) were compared with tacrolimus + prednisone + mycophenolate mofetil (control group; n = 15) (89c ). More than one surgical wound complication occurred in 35% of the study group and 7% of the control group. The incidences of repeat laparotomy were 33% and 7% respectively. Four graft losses were related to chronic rejection (n = 1) or deaths with functioning grafts (n = 3, two in the study group).

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Those who took sirolimus had a significantly higher surgical wound complication rate, but graft and patient survival were not affected. In 39 patients treated with tacrolimus + sirolimus, the rate of wound problems requiring surgical intervention was 22% (90c ).

Nervous system The pathogenesis of tacrolimus-related neurotoxicity is unclear.

Drugs that act on the immune system

Fertility Sirolimus has been reported to cause oligospermia, the risk of which should be considered when sirolimus is given to young men (91r ). • A 36-year-old previously fertile man underwent kidney transplantation. He took ciclosporin 200 mg/day, sirolimus 2 mg/day, and prednisolone 10 mg/day over 3 months and was then switched to sirolimus 7 mg/day and prednisolone 10 mg/day for the next 33 months. Sirolimus trough concentrations were 10–15 ng/ml. His wife failed to become pregnant and a sperm analysis showed a very low sperm count, a low percentage of normalshaped sperm heads, and poor sperm motility. Sirolimus was switched to tacrolimus 5 mg/day and sperm analysis after 6 months was normal.

Drug interactions In a retrospective study, the initial use of sirolimus 2 or 5 mg/day in combination with a calcineurin inhibitor (31 ciclosporin, 10 tacrolimus) was investigated (92c ). Of 41 kidney transplant recipients, five died and 15 were withdrawn because of adverse events. Deaths were caused by thrombotic thrombocytopenic purpura (n = 2), mucormycosis (n = 1), B cell lymphoma (n = 1), and small bowel perforation (n = 1). Sirolimus was associated with significant hyperlipidemia. Calcineurin inhibitor toxicity occurred in 36% and mild thrombocytopenia in 23%.

Tacrolimus (SED-14, 1304; SEDA-25, 446; SEDA-26, 408; SEDA-27, 377) The common adverse effects of tacrolimus ointment include sensations of stinging, soreness, burning, or itching at the site of application, although these are usually short-lived and rarely require withdrawal of treatment. Less common adverse effects include folliculitis, acne, headache, and flu-like symptoms. Herpes zoster infections, tinea incognito, and impetigo have only rarely been reported. Systemic absorption is negligible and skin atrophy does not occur (93r ).

• A 22-year-old man with tacrolimus neurotoxicity had increased signal intensities in both parietooccipital lobes on diffusion-weighted MRI T2weighted images and apparent diffusion coefficient maps (94A ).

These findings suggest that vasogenic edema rather than cytotoxic edema plays a pivotal role in the pathogenesis of tacrolimus neurotoxicity. The prognosis of tacrolimus-related leukoencephalopathy is good after withdrawal or dosage reduction, but complete recovery can occur with continued therapy (95A , 96A ). • A 37-year-old man developed a leukoencephalopathy 12 weeks after heart transplantation and recovered after stabilization of metabolism and arterial blood pressure (96A ).

The findings in this case support the hypothesis that tacrolimus-associated neurotoxicity is severely increased by impairment of the blood– brain barrier. Withdrawal of tacrolimus was not necessary while other causes of endothelial injury were treated successfully. Tacrolimus-associated posterior reversible encephalopathy syndrome occurred in 10 patients (median age 36, range 19–57, years) after autologous hemopoietic stem cell transplantation (97A ). Changes in mental status, cognitive deficits, seizures, and lethargy were the most common findings. Eight patients had characteristic findings of hyperintensity of the white matter on MRI T2-weighted images. Serum tacrolimus concentrations were within the target range in most cases. Tacrolimus was continued (n = 4) or temporarily withdrawn (n = 7) for 1–14 days. One patient was switched to ciclosporin. In most cases subsequent treatment with tacrolimus was well tolerated without recurrence of neurotoxicity. • A 5-year-old girl with Philadelphia chromosomepositive chronic myelogenous leukemia developed two episodes of electrical status epilepticus while taking tacrolimus and then ciclosporin for treatment of graft-versus-host disease (98A ). MRI, including diffusion weighted MRI of the brain, showed abnormalities in the hippocampus and posterior white matter.

While posterior white matter injury has been described with both of these calcineurin inhibitors, no previous report has described hippocampal injury from either drug. The authors

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suggested that the MRI changes in the hippocampus suggested increased susceptibility to hippocampal injury with tacrolimus. Psychological After kidney transplantation, 15 of 20 children tolerated tacrolimus after switching from ciclosporin for immunological reasons or adverse effects (99A ). The most frequent adverse effects were neuropsychological and behavioral symptoms in three children, ranging from anorexia nervosa-like symptoms, with weight loss, amenorrhea, depression, and school problems, to severe insomnia and in one child aggressive and anxious behavior. Only the last child was exposed to toxic tacrolimus blood concentrations. All the adverse effects were fully reversible after withdrawal. • A 5-year-old girl developed speech arrest, agitation, tremor, ataxia, and deviation of downward gaze 13 days after liver transplantation (100A ). The tacrolimus trough concentration was 44 ng/ml. Three days after dosage reduction, she could say a few words and her extra-ocular movements returned to normal. Four months later, she continued to have reduced fluency, dysarthria, and ataxia. One year later, the reduced fluency and mild ataxia persisted.

Rapid identification of speech loss linked to tacrolimus may be important, because dosage reduction or withdrawal may be associated with reverse of speech loss. Pancreas (101Ar ).

Tacrolimus can cause pancreatitis

• A 52-year-old African-American woman took tacrolimus and azathioprine after kidney transplantation. She developed abdominal pain accompanied by vomiting of bilious material. The blood amylase was 2631 U/l and lipase 4494 U/l. Azathioprine was withdrawn and tacrolimus was temporarily stopped because of persistent hyperglycemia and hyperkalemia. Her general condition improved. Tacrolimus was restarted and mycophenolate mofetil was added. After discharge, her symptoms recurred, but with normal amylase and lipase activities. She died after 148 days from cardiopulmonary arrest. Autopsy showed sepsis secondary to necrotizing pancreatitis secondary to immunosuppression.

Urinary tract Tacrolimus-associated hemolytic-uremic syndrome was studied in 16 transplant recipients (102M ). In seven cases renal transplantation was needed. The average time from the first dose of tacrolimus to the onset of

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the syndrome was 7 months. Tacrolimus trough concentrations did not predict the prognosis. Seven patients had improved graft function after treatment, five died, and four lost their graft. Mortality risk factors for transplant recipients with tacrolimus-associated hemolytic-uremic syndrome included lower peak serum creatinine concentrations, liver dysfunction, and higher serum LDH concentrations. Renal tubular acidosis secondary to tacrolimus is a rare complication after liver transplantation. • A 6-month-old girl was treated with tacrolimus after living-donor liver transplantation for fulminant hepatitis (103A ). After 17 days, she developed hyperkalemia and metabolic acidosis and hyperkalemic distal renal tubular acidosis with aldosterone deficiency (type IV). After correction of the acidosis, tacrolimus trough concentrations gradually fell, and the hyperkalemia and metabolic acidosis improved.

Renal tubular acidosis due to tacrolimus is reversible in mild cases when appropriately treated. However, the mechanism is not known. Treatment for acidosis and hyperkalemia should be started as soon as renal tubular acidosis is diagnosed, and tacrolimus dosage should also be reduced if possible. Skin Topical tacrolimus ointment improves atopic dermatitis. In three double-blind, randomized, vehicle-controlled studies, a total of 631 adult and 352 pediatric patients with moderate to severe atopic dermatitis used 0.03% or 0.1% tacrolimus ointment twice daily for up to 12 weeks (104M ). Common adverse events were pruritus, “skin burning”, erythema, infection, and skin tingling in the head and neck. The overall prevalence of adverse events at the site of application fell rapidly during the first few days of treatment. Infection risk The number of reported cases of polyomavirus-associated nephropathy after kidney transplantation has recently increased, and new potent drugs, such as tacrolimus and mycophenolate mofetil, have been implicated as risk factors. When renal transplant biopsies taken between 1999 and 2001 were screened, polyomavirus-associated nephropathy was found in 11 of 1276 biopsies (<1%) and in seven (1%) of 638 patients (105C ). Four of those seven had taken triple immunosuppression, including tacrolimus and mycophenolate.

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This immunosuppressive regimen had an eight times higher incidence and a 13 times higher risk of polyomavirus-associated nephropathy compared with the control group.

(110c ). Tacrolimus trough concentrations were not affected by cerivastatin. The mean cerivastatin AUC at 3 months was 35% higher than after the first dose.

Drug interactions Chloramphenicol A serious interaction was reported between tacrolimus and chloramphenicol in a kidney–pancreas transplant recipient (106A ).

Voriconazole Tacrolimus trough concentrations increased in patients who took voriconazole for invasive mycosis (111A ).

Drugs that act on the immune system

Pomelo Grapefruit juice inhibits CYP3A4 and similar effects have been observed with pomelo (107A ). Prednisone The effect of prednisone on the pharmacokinetics of tacrolimus was studied in a randomized trial after kidney transplantation (108c ). The recipients took tacrolimus + mycophenolate mofetil and either daclizumab (n = 31) or prednisone for 3 months (n = 34). The tacrolimus dose-adjusted predose concentrations were 42% and 29% lower at months 1 and 2 compared with month 4 in those who took prednisone. Rifampicin Information on the extent, duration, and potency of the interaction of rifampicin with tacrolimus is limited. • A 40-year-old Asian woman received a cadaveric renal transplant for end-stage renal disease due to IgA nephropathy and was given tacrolimus, thymoglobulin, mycophenolate mofetil, and prednisone, along with diltiazem for hypertension (109A ). On postoperative day 5, donor bronchioalveolar lavage revealed active tuberculosis. She was given rifampicin 600 mg/day, and the dose of diltiazem was increased. Over the next 12 days, the dose of tacrolimus was increased to 32 mg/day to achieve a target trough concentration of 10–15 ng/ml. She then received a course of fluconazole 100 mg/day and clarithromycin 1000 mg/day. Despite this, there was no increase in tacrolimus concentrations. Rifampicin was withdrawn, after which therapeutic tacrolimus concentrations were finally reached with usual doses.

Rifampicin is a potent inducer of tacrolimus metabolism, sufficient in this case to overcome the inhibitory effects of diltiazem, fluconazole, and clarithromycin. Statins Ten kidney recipients taking tacrolimus with stable kidney graft function and serum LDL cholesterol concentrations over 2.8 mmol/l took cerivastatin 0.2 mg/day over 3 months

6-Thioguanine Thioguanine is a thiopurine analogue that is closely related to mercaptopurine and azathioprine. It is being increasingly used as an alternative in patients with inflammatory bowel disease and azathioprine/mercaptopurine intolerance. Thioguanine 40 mg/day for 24 weeks was evaluated in 37 patients with chronic active Crohn’s disease (112c ). Adverse events included headache (n = 17), minor infections (n = 11), nausea (n = 10), eczema (n = 4), pruritus (n = 3), arthralgia (n = 3), alopecia (n = 3), leukopenia (n = 2), vomiting (n = 2), photoallergic reactions (n = 2), rashes (n = 2), raised transaminases (n = 2), dysesthesia (n = 1), erythema nodosum (n = 1), rotavirus infection (n = 1), anemia (n = 1), thrombocytopenia (n = 1), and pancreatitis (n = 1). Treatment with withdrawn in six patients because of leukopenia (n = 2), headache (n = 2), mild pancreatitis (n = 1), or pneumonia (n = 1). Thioguanine was more effective in azathioprine-intolerant than in azathioprinerefractory patients. In 32 patients with inflammatory bowel disease intolerant of azathioprine/mercaptopurine, thioguanine 20 mg/day (n = 19) or 40 mg/day (n = 13) had to be withdrawn in six because of adverse effects, including nausea, diarrhea, malaise, fever, arthralgia, stomach cramps, and rigid fingers (113c ). Two patients taking thioguanine 40 mg/day developed joint pains that resolved after dosage reduction. Liver Thioguanine caused laboratory abnormalities in 29 of 111 patients with inflammatory bowel disease (114C ). Raised liver enzymes and reduced platelet counts (below 200 × 109 /l) were most commonly observed. Male sex (OR = 2.9; 95% CI = 1.1, 7.3) and preferential

466 6-methylmercaptopurine production after the administration of mercaptopurine/azathioprine (OR = 3.0; 95% CI = 1.2, 7.4) were independently associated with laboratory abnormalities. There was no association with duration of thioguanine treatment, cumulative dose, or thioguanine nucleotide concentrations. The median increases in transaminase and alkaline phosphatase activity were 39, 30, and 75 U/l respectively and the median reduction in platelet count was 115 × 109 /l. Nodular regenerative hyperplasia occurred in 76% of the patients with abnormal liver function tests who underwent biopsy compared with and 33% of those who did not have abnormal liver function tests. Nodular regenerative hyperplasia is therefore common in thioguanine-treated patients with inflammatory bowel disease and its progression and reversibility are unknown. Thioguanine should therefore not be used in patients with inflammatory bowel disease. A patient taking thioguanine for a flare of Crohn’s disease developed abnormal liver func-

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tion tests in the absence of other offending agents (115A ). • A 27-year-old man with a 10-year history of Crohn’s disease, intolerance of azathioprine and infliximab, and failure to respond to methotrexate and prednisone was given thioguanine 40 mg/day. After 2 weeks, he complained of lower abdominal pain. The erythrocyte thioguanine nucleotide concentration was 1.156 pmol/8 × 108 cells and 6-methylmercaptopurine was undetectable. After 4 weeks the alanine transaminase activity peaked at 803 IU/l and thioguanine was withdrawn. The alanine transaminase returned to normal within 1 month. The TPMT activity was 7.9 U/ml of erythrocytes, consistent with a heterozygote genotype for TPMT.

Immunologic Thioguanine hypersensitivity occurred in four of 21 patients with inflammatory bowel disease and azathioprine/mercaptopurine intolerance, including two with gastroenteritis-like syndromes and two with nausea and flu-like symptoms (116c ).

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69. Flechner SM, Zhou L, Derweesh I, Mastroianni B, Savas K, Goldfarb D, Modlin CS, Krishnamurthi V, Novick A. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidneytransplant recipients. Transplantation 2003; 76: 1729–34. 70. Hutchinson P, Chadban SJ, Atkins RC, Holdsworth SR. Laboratory assessment of immune function in renal transplant patients. Nephrol Dial Transplant 2003; 18: 983–9. 71. Keven K, Sahin M, Kutlay S, Sengul S, Erturk S, Ersoz S, Erbay B. Immunoglobulin deficiency in kidney allograft recipients: comparative effects of mycophenolate mofetil and azathioprine. Transplant Infect Dis 2003; 5: 181–6. 72. Firpi RJ, Nelson DR, Davis GL. Lack of antiviral effect of a short course of mycophenolate mofetil in patients with chronic hepatitis C virus infection. Liver Transpl 2003; 9: 57–61. 73. Neumann I, Haidinger M, Jäger H, Grützmacher H, Griesmacher A, Müller MM, Bayer PM, Meisl FT. Pharmacokinetics of mycophenolate mofetil in patients with autoimmune disease compared renal transplant recipients. J Am Soc Nephrol 2003; 14: 721–7. 74. Gerbase MW, Fathi M, Spiliopoulos A, Rochat T, Nicod LP. Pharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: longterm monitoring in stable lung recipients with and without cystic fibrosis. J Heart Lung Transplant 2003; 22: 587–90. 75. Royer B, Zanetta G, Berard M, Davani S, Tanter Y, Rifle G, Kantelip JP. A neutropenia suggesting an interaction between valacyclovir and mycophenolate mofetil. Clin Transplant 2003; 17: 158–61. 76. Cox VC, Ensom MH. Mycophenolate mofetil for solid organ transplantation: does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003; 25: 137–57. 77. Allen BR, Lakhanpaul M, Morris A, Lateo S, Davies T, Scott G, Cardno M, Ebelin ME, Burtin P, Stephenson TJ. Systemic exposure, tolerability and efficacy of pimecrolimus cream 1% in atopic dermatitis patients. Arch Dis Child 2003; 88: 969–73. 78. Neff GW, Montalbano M, Tzakis AG. Ten years of sirolimus therapy in orthotopic liver transplant recipients. Transplant Proc 2003; 35 Suppl 3A: 209S–216S. 79. King-Biggs MB, Dunitz JM, Park SJ, Kay Savik S, Hertz MI. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003; 75: 1437–43. 80. Chueh SC, Kahan BD. Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen: incidence, risk factors, progression, and prognosis. Transplantation 2003; 76: 375–82. 81. Brara PS, Moussavian M, Grise MA, Peilly JP, Fernandez M, Schatz RA, Teirstein PS. Pilot trial of oral rapamycin for recalcitrant restenosis. Circulation 2003; 107: 1722–4. 82. Lawsin L, Light JA. Severe acute renal failure after exposure to sirolimus-tacrolimus in two living

donor kidney recipients. Transplantation 2003; 75: 157–60. 83. Mancini D, Pinney S, Burkhoff D, LaManca J, Itescu S, Burke E, Edwards N, Oz M, Marks AR. Use of rapamycin slows disease progression of cardiac transplantation vasculopathy. Circulation 2003; 108: 48–53. 84. Robson M, Cote I, Abbs I, Koffman G, Goldsmith D. Thrombotic micro-angiopathy with sirolimus-based immunosuppression: potentiation of calcineurin-inhibitor-induced endothelial damage? Am J Transplant 2003; 3: 324–7. 85. Barone GW, Gurley BJ, Abul-Ezz SR, Gokden N. Sirolimus-induced thrombotic microangiopathy in a renal transplant recipient. Am J Kidney Dis 2003; 42: 202–6. 86. Van Gelder T, ter Meulen CG, Hene R, Weimar W, Hoitsma A. Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil. Transplantation 2003; 75: 788–91. 87. Rao V, Pirsch JD, Becker BN, Knechtle SJ. Sirolimus monotherapy following Campath-1H induction. Transplant Proc 2003; 35 Suppl 3A: 128S– 130S. 88. Josef F, Marina K, Alois W. Sirolimus myopathy. Transplantation 2003; 76: 1773–4. 89. Troppmann C, Pierce JL, Gandhi MM, Gallay BJ, McVicar JP, Perez RV. Higher surgical wound complication rates with sirolimus immunosuppression after kidney transplantation: a matched-pair pilot study. Transplantation 2003; 76: 426–9. 90. Lo A, Egidi MF, Gaber LW, Gaber AO. Observations on the use of sirolimus and tacrolimus in high-risk renal transplant recipients. Transplant Proc 2003; 35 Suppl 3A: 105S–108S. 91. Bererhi L, Flamant M, Martinez F, Karras A, Thervet E, Legendre C. Rapamycin-induced oligospermia. Transplantation 2003; 76: 885–6. 92. Masterson R, Leikis M, Perkovic V, Nicholls K, Walker R. Sirolimus: a single center experience in combination with calcineurin inhibitors. Transplant Proc 2003; 35 Suppl 3: 99S–104S. 93. Abramovits W, Goldstein A, Stevenson L. Changing paradigms in dermatology: topical immunomodulators within a permutational paradigm for the treatment of atopic and eczematous dermatitis. Clin Dermatol 2003; 21: 383–91. 94. Ahn KJ, Lee JW, Hahn ST, Yang DW, Kim PS, Kim HJ, Kim CC. Diffusion-weighted MRI and ADC mapping in FK506 neurotoxicity. Br J Radiol 2003; 76: 916–19. 95. Schuuring J, Wesseling P, Verrips A. Severe tacrolimus leukoencephalopathy after liver transplantation. Am J Neuroradiol 2003; 24: 2085–8. 96. Kaczmarek I, Groetzner J, Meiser B, Mueller M, Landwehr P, Ueberfuhr P, Bruning R, Reichart B. Impairment of the blood-brain barrier can result in tacrolimus-induced reversible leucoencephalopathy following heart transplantation. Clin Transplant 2003; 17: 469–72. 97. Wong R, Beguelin GZ, de Lima M, Giralt SA, Hosing C, Ippoliti C, Forman AD, Kumar AJ, Champlin R, Couriel D. Tacrolimus-associated posterior reversible encephalopathy syndrome after al-

Drugs that act on the immune system

470 logeneic haematopoietic stem cell transplantation. Br J Haematol 2003; 122: 128–34. 98. Yoshida Y, Shimada H, Mori T, Yoshihara H, Takeoka M, Takahashi T. FK506-associated limbic injury following umbilical cord blood transplantation. Bone Marrow Transplant 2003; 32: 523–5. 99. Kemper MJ, Sparta G, Laube GF, Miozzari M, Neuhaus TJ. Neuropsychologic side-effects of tacrolimus in pediatric renal transplantation. Clin Transplant 2003; 17: 130–4. 100. Sokol DK, Molleston JP, Filo RS, Van Valer J, Edwards-Brown M. Tacrolimus (FK506)-induced mutism after liver transplant. Pediatr Neurol 2003; 28: 156–8. 101. Ogunseinde BA, Wimmers E, Washington B, Iyob M, Cropper T, Callender CO. A case of tacrolimus (FK506)-induced pancreatitis and fatality 2 years postcadaveric renal transplant. Transplantation 2003; 76: 448. 102. Lin CC, King KL, Chao YW, Yang AH, Chang CF, Yang WC. Tacrolimus-associated hemolytic uremic syndrome: a case analysis. J Nephrol 2003; 16: 580–5. 103. Ogita K, Takada N, Taguchi T, Suita S, Soejima Y, Suehiro T, Shimada M, Maehara Y. Renal tubular acidosis secondary to FK506 in living donor liver transplantation: a case report. Asian J Surg 2003; 26: 218–20. 104. Kang S, Paller A, Soter N, Satoi Y, Rico MJ, Hanifin JM. Safe treatment of head/neck AD with tacrolimus ointment. J Dermatolog Treat 2003; 14: 86–94. 105. Mengel M, Marwedel M, Radermacher J, Eden G, Schwarz A, Haller H, Kreipe H. Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs. Nephrol Dial Transplant 2003; 18: 1190–6. 106. Bakri R, Breen C, Maclean D, Taylor J, Goldsmith D. Serious interaction between tacrolimus FK506 and chloramphenicol in a kidney-pancreas transplant recipient. Transplant Int 2003; 16: 441– 3. 107. Egashira K, Fukuda E, Onga T, Yogi Y, Matsuya F, Koyabu N, Ohtani H, Sawada Y. Pomeloinduced increase in the blood level of tacrolimus in a renal transplant patient. Transplantation 2003; 75: 1057.

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108. Hesselink DA, Ngyuen H, Wabbijn M, Gregoor PJ, Steyerberg EW, Van Riemsdijk IC, Weimar W, Van Gelder T. Tacrolimus dose requirement in renal transplant recipients is significantly higher when used in combination with corticosteroids. Br J Clin Pharmacol 2003; 56: 327–30. 109. Bhaloo S, Prasad GV. Severe reduction in tacrolimus levels with rifampin despite multiple cytochrome P450 inhibitors: a case report. Transplant Proc. 2003; 35: 2449–51. 110. Renders L, Haas CS, Liebelt J, Oberbarnscheidt M, Schocklmann HO, Kunzendorf U. Tacrolimus and cerivastatin pharmacokinetics and adverse effects after single and multiple dosing with cerivastatin in renal transplant recipients. Br J Clin Pharmacol 2003; 56: 214–19. 111. Fortun J, Martin-Davila P, Sanchez MA, Pintado V, Alvarez ME, Sanchez-Sousa A, Moreno S. Voriconazole in the treatment of invasive mold infections in transplant recipients. Eur J Clin Microbiol Infect Dis 2003; 22: 408–13. 112. Herrlinger KR, Kreisel W, Schwab M, Schoelmerich J, Fleig WE, Ruhl A, Reinshagen M, Deibert P, Fellermann K, Greinwald R, Stange EF. 6-Thioguanine – efficacy and safety in chronic active Crohn’s disease. Aliment Pharmacol Ther 2003; 17: 503–8. 113. Derijks LJJ, de Jong DJ, Glissen LPL, Engels LGJB, Hooymans PM, Jansen JMBJ, Mulder CJJ. 6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term saftey assessment. Eur J Gastroenterol Hepatol 2003; 15: 63–7. 114. Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T, Martin P, Vierling JM, Geller SA, Targan SR, Poordad FF. 6thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 2003; 125: 298–303. 115. Rulyak SJ, Saunders MD, Lee SD. Hepatotoxicity associated with 6-thioguanine therapy for Crohn’s disease. J Clin Gastroenterol 2003; 36: 234–7. 116. Dubinsky MC, Feldman EJ, Abreu MT, Targam SR, Vasiliauskas EA. Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine. Am J Gastroenterol 2003; 98: 1058–63.

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Editor’s note: In this chapter adverse effects arising from the oral or intravenous administration of glucocorticoids are covered in the section on systemic glucocorticoids. Other routes of administration are dealt with in the section after that, apart from inhalation and nasal administration, which are dealt with in Chapter 16, and topical administration, which is covered in Chapter 14.

SYSTEMIC GLUCOCORTICOIDS (SED-14, 1369; SEDA-25, 465; SEDA-26, 427; SEDA-27, 414) Cardiovascular The benefit of glucocorticoid therapy is often limited by several adverse reactions, including cardiovascular disorders such as hypertension and atherosclerosis. Plasma volume expansion due to sodium retention plays a minor role, but increased peripheral vascular resistance, due in part to an increased pressor response to catecholamines and angiotensin II, plays a major role in the pathogenesis of hypertension induced by glucocorticoid excess. However, the molecular mechanism remains unclear. A study has been undertaken to clarify whether glucocorticoid excess affects endothelium-dependent vascular relaxation in glucocorticoid treated patients and whether dexamethasone alters the production of hydrogen peroxide and the formation of peroxynitrite, a reactive molecule between nitric oxide and superoxide, in cultured human umbilical endothelial cells (1E ). Glucocorticoid excess impaired endothelium-dependent vascular relaxation in vivo and enhanced the production of reactive oxygen species to cause increased production of peroxynitrite in vitro. Glucocorticoid-induced © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

reduction in nitric oxide availability may cause vascular endothelial dysfunction, leading to hypertension and atherosclerosis. Sensory systems Intravitreal triamcinolone acetonide is non-toxic to the human retina, and has been advocated as a treatment for refractory cystoid macular edema and other ocular problems. Infectious endophthalmitis can occur after intraocular injection, but it is extremely rare when appropriate sterile technique is practised. Seven patients developed a clinical picture simulating endophthalmitis after intravitreal injection of triamcinolone (2A ). The authors believed that this effect was a toxic reaction to the injected material and explained that the differential diagnosis of infectious endophthalmitis in eyes that have been injected with triamcinolone under sterile conditions includes a sterile toxic endophthalmitis that requires careful monitoring, perhaps every 8–12 hours, in order to determine whether the inflammation is worsening or improving. Resolution occurs spontaneously, and in the absence of eye pain unnecessary intervention can be avoided. Psychiatric Use of glucocorticoids is associated with adverse psychiatric effects, including mild euphoria, emotional lability, panic attacks, psychosis, and delirium. Although high doses increase the risks, psychiatric effects can occur after low doses and different routes of administration. Of 92 patients with systemic lupus erythematosus (78 women, mean age 34

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472 years) followed between 1999 and 2000, psychiatric events occurred in six of those who were treated with glucocorticoids for the first time or who received an augmented dose, an overall 4.8% incidence (3C ). The psychiatric events were mood disorders with manic features (delusions of grandiosity) (n = 3) and psychosis (auditory hallucinations, paranoid delusions, and persecutory ideas) (n = 3). Three patients were first time users (daily prednisone dose 30–45 mg/day) and three had mean increases in daily prednisone dose from baseline of 26 (range 15–33) mg. All were hypoalbuminemic and none had neuropsychiatric symptoms before glucocorticoid treatment. All the events occurred within 3 weeks of glucocorticoid administration. In five of the six episodes, the symptoms resolved completely after dosage reduction (from 40 mg to 18 mg) but in one patient an additional 8-week course of a phenothiazine was given. In a multivariate regression analysis, only hypoalbuminemia was an independent predictor of psychiatric events (HR = 0.8, 95% CI = 0.60, 0.97). Pancreas Glucocorticoids have been implicated in cases of acute pancreatitis. A new case with rechallenge that provides direct evidence that hydrocortisone can cause acute pancreatitis in a patient with ulcerative colitis has been published (4c ). • An 18-year-old youth was admitted with a history of large bowel diarrhea off and on for 6 months before admission. There was a history of passage of blood mixed with stools for the same duration. There was no history of fever, arthralgias, jaundice, or red eyes. At the time of admission he was passing 10–12 stools in 24 hours, and 6–7 of them contained blood. His pulse rate was 100/minute and there was pallor and minimal pedal edema. He was tender in the flanks with exaggerated bowel sounds. Sigmoidoscopy showed ulceration, erythema, friability, and loss of vascular pattern in the rectum and sigmoid colon, suggestive of ulcerative colitis. A rectal biopsy showed crypt atrophy, crypt abscesses, a mixed cellular infiltrate, goblet cell depletion, and submucosal edema. He was given intravenous fluids and injectable hydrocortisone 100 mg six times an hour. Injections of ofloxacin and metronidazole were added later, because his leukocyte count was 15.6 × 109 /l. On the second day of treatment he developed epigastric pain radiating to the back. The pain was continuous, associated with vomiting, and relieved by sitting in the knee-chest position. Acute pancreatitis was corroborated by a serum lipase activity of 650 units/l and high serum amylase activity (550

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units/l). Ultrasonography showed a bulky, heterogeneous pancreas with ill defined margins, suggestive of pancreatitis. There were no gallstones. Hydrocortisone was withdrawn and the rest of the treatment continued. Mesalazine was added after 1 day. The pancreatitis resolved in 48 hours, as did the diarrhea. After 1 month the patient was readmitted with a relapse of ulcerative colitis. This time his stool frequency was 4–5 stools in 24 hours, and most contained some blood. There was no fever and his total leukocyte count was normal. He was given mesalazine enemas and injectable hydrocortisone. On the second day after admission, he had a similar bout of acute pancreatitis. Hydrocortisone was withdrawn and he recovered.

Musculoskeletal Acute spontaneous rupture of the Achilles tendon has been attributed to glucocorticoids (5A ). • A 69-year-old man with newly diagnosed giant cell arteritis was given prednisone 30 mg bd, and 2 weeks later developed severe pain along his Achilles tendons bilaterally; 1 week later the left tendon ruptured. Despite immobilization his pain worsened. The prednisone was gradually tapered and the symptoms abated, with complete recovery.

In the previous literature this adverse reaction was described in patients taking glucocorticoids for from 4 months to several years. Among the adverse effects of pulse glucocorticoid therapy, joint manifestations are rare. A woman with systemic lupus erythematosus and nephritis developed transient bilateral knee effusions during pulse therapy with high doses of glucocorticoids (6c ). • A 62-year-old woman was admitted to hospital with lupus nephritis. A kidney biopsy showed a mesangioproliferative glomerulonephritis (WHO class III). After 4 months of inadequate response to traditional treatment, she started monthly pulse glucocorticoid therapy (methylprednisolone 1 g for 3 days) before immunosuppressive drugs. After 2 days of pulse glucocorticoid therapy she complained of pain and flexion discomfort in both knees, which were swollen. At arthrocentesis synovial fluid was aspirated (5 ml from the right knee and 6 ml from the left). The fluid was colorless, with a high viscosity and excellent mucin clot formation. There was only 1 mononuclear cell/mm3 in the right knee synovial fluid and no cells in the left. There were no crystals. Inflammatory laboratory measurements carried out simultaneously were unchanged. X-rays of the affected joints were normal. The effusion resolved with arthrocentesis and did not recur.

The author proposed that raised arterial pressure, which is an adverse effect of high dose

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glucocorticoid treatment, and low oncotic pressure due to a low protein plasma concentration in a patient with nephrotic syndrome, could have increased trans-synovial fluid flow at a lower arterial pressure than normal.

of prednisolone under 130 mg, the adjusted risk (OR) was 0.96 (95% CI = 0.89, 1.04); for 130–499 mg the OR was 1.17 (1.01, 1.35); for 500–1499 mg the OR was 1.36 (1.19, 1.56); and for 1500 mg or more the OR was 1.65 (1.43, 1.92). There was an also increased risk when the study population was stratified according to sex, age, and type of glucocorticoid (systemic or topical). This study showed that even a limited daily dose of glucocorticoids (more than an average dose of prednisolone of about 71 micrograms/day) was associated with an increased risk of hip fracture.

Glucocorticoid-induced osteoporosis and fractures Glucocorticoid therapy is associated with bone loss resulting in osteoporosis and an increase in fracture risk. These effects have been found after the administration of oral and inhaled glucocorticoids. Dose is an important factor, but these adverse effects have been described after low doses. The risk of hip fracture associated with glucocorticoid use has been studied in Denmark in a population-based casecontrol study in 6660 subjects with hip fractures and 33 272 age-matched population controls (7C ). Data on prescriptions for glucocorticoid within the last 5 years before the index date were retrieved from a population-based prescription database. Doses were recalculated to prednisolone equivalents. Cases and controls were grouped according to cumulative glucocorticoid dose: 1. not used; 2. under 130 mg (equivalent to prednisolone 30 mg/day for 4 days given for an acute exacerbation of asthma); 3. 130–499 mg (equivalent to a short course of prednisolone of 450 mg) for acute asthma; 4. 500–1499 mg (equivalent to prednisolone 7.5 mg/day for 6 months or 800 micrograms/day of inhaled budesonide for 1 year); 5. 1500 mg or more (equivalent to more than 4.1 mg day for 1 year, a long-term high dose). A conditional logistic regression was used and adjusted for potential confounders including sex, redeemed prescriptions for hormone replacement therapy, antiosteoporotic, anxiolytic, antipsychotic, and antidepressant drugs. Compared with never users, there was an increased risk of hip fracture in glucocorticoid users, with increasing cumulative doses of any type of drug used during the preceding 5 years. For doses

Prevention with bisphosphonates Bisphosphonates, such as alendronate and risedronate, are effective in the prevention and treatment of glucocorticoid-induced osteoporosis when given for 1 or 2 years. Current oral bisphosphonates are given either daily or weekly. Intermittent administration with oral, intravenous, or intramuscular formulations is being studied. Clodronate 100 mg by intramuscular route once a week was effective in the prevention of glucocorticoid-induced bone loss and fractures in patients with arthritis compared with calcium 1000 mg/day and vitamin D 800 mg/day (8C ). Ibandronate is a new bisphosphonate that can be given intravenously every 3 months. Its efficacy has been demonstrated in men and women with established glucocorticoidinduced osteoporosis in 115 subjects who were randomly assigned to daily calcium supplements (500 mg) plus either ibandronate injections 2 mg every 3 months or daily oral alfacalcidol 1 microgram for up to 3 years (9C , 10C ). After 3 years, intermittent intravenous ibandronate produced significantly greater increases than daily oral alfacalcidol in mean bone mineral density in the lumbar spine (13% versus 2.6%), and femoral neck (5.2% versus 1.9%). However, there were no differences between the groups with respect to fractures. Intermittent etidronate has been evaluated in a randomized controlled trial in 102 Japanese patients who had taken over 7.5 mg/day of prednisolone for at least 90 days (11C ). They were randomized to etidronate disodium 200 mg/day for 2 weeks plus calcium lactate 3.0 g/day and alfacalcidol 0.75 micrograms/day or control (calcium lactate 3.0 g and alfacalcidol 0. 75 micrograms/day). Bone mineral density in the lumbar spine and the rate of new

474 vertebral fractures at 48 and 144 weeks were evaluated. With etidronate the mean lumbar spine bone mineral density increased by 3.7% and 4.8% at 48 and 144 weeks respectively. In the control group, the mean lumbar spine bone mineral density increased by 1.5% and 0.4% at 48 and 144 weeks respectively. Of three subgroups, men, premenopausal women, and postmenopausal women, the postmenopausal women had the greatest benefit. Two control patients had new vertebral fractures, whereas there were no fractures with etidronate. No data are available about the effects on bone mineral density of withdrawing bisphosphonates. Of 183 patients who participated in a randomized, placebo-controlled trial of the efficacy of alendronate 5 and 10 mg/day on the prevention and treatment of glucocorticoidinduced osteoporosis during 1 year 90 participated in a follow-up study for 3.3–4.6 years (12c ). In the subgroup that continued to take a glucocorticoid (more than 6 mg/day of prednisone or equivalent for more than 1 year) and took alendronate for less than 90 days (n = 11), there was bone loss after the end of the trial (−5.1% at the lumbar spine to −9.2% at the femoral neck). In the subgroup that continued to take glucocorticoids and alendronate for more than 300 days (n = 31), there was a small gain in the lumbar spine (+0.1%) and no significant loss in the femoral neck (−0.1%). Although the study had limitations, particularly loss to follow-up of a considerable number of patients, the results suggested that sustained treatment with alendronate maintains bone mineral density, and that patients who discontinue alendronate and continue to take glucocorticoids lose bone mass in the femoral neck and lumbar spine. Prevention with parathyroid hormone Parathyroid hormone (parathormone) is an anabolic osteotrophic agent. Randomized controlled trials have shown the efficacy of human parathormone, hPTH (1–34), in improving bone mass and reducing the risk of fractures in postmenopausal osteoporosis. In 51 women who had been postmenopausal for at least 3 years and who had taken both glucocorticoids (mean dose of prednisone 5–20 mg/day or equivalent for at least 1 year) and hormone replacement therapy (HRT; Premarin 0.625 mg/day or equivalent) were randomized to either HRT +

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parathormone 40 micrograms/day for 1 year or HRT only (13c ). Vertebral cross-sectional area increased by 4.8%, and 1 year after treatment was withdrawn it was still 2.6% higher than at baseline. In the control group there was no change. In addition, estimated vertebral compressive strength increased by more than 200% over baseline with parathormone and there was no change in the control group. Immunologic Immunological reactions to glucocorticoids have been reviewed (14R ). Reactions can be of types I, III, or IV. Immediate reactions usually occur in patients with asthma and in those who have to use glucocorticoids repeatedly. Other susceptibility factors include female sex and hypersensitivity to acetylsalicylic acid. Often excipients are implicated (succinates, sulfites, and carboxymethylcellulose). Cross-reactivity does not necessarily occur; patients with immediate reactions to hydrocortisone and methylprednisolone can often tolerate prednisone and prednisolone and second-generation compounds, such as dexamethasone and betamethasone. To date, there have been about 100 published reports of immediate hypersensitivity reactions after oral and parenteral administration of glucocorticoids. Although there is evidence that glucocorticoids themselves can cause these reactions, there is debate about the mechanism. • A 75-year-old man developed triamcinoloneinduced anaphylaxis and dose-related positive prick skin tests to triamcinolone, suggesting that an IgE-mediated hypersensitivity mechanism may have played a part (15AR ).

Skin prick tests and intradermal tests to hydrocortisone and methylprednisolone, intradermal tests to betamethasone and dexamethasone, and oral challenge tests to betamethasone and deflazacort were performed in 10 patients with adverse reactions to systemic hemisuccinate esters of hydrocortisone and methylprednisolone (16c ). The skin prick tests and intradermal tests results suggested the possibility of an IgE-mediated mechanism for allergic reactions to hydrocortisone and methylprednisolone. The authors hypothesized that this mechanism is probably due, at least in part, to a glucocorticoid-glyoxal compound, a degradation product of cortisol, which in aqueous solution may be responsible for presenting

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steroid carbon rings to the immune system. They suggested that betamethasone and deflazacort could be reserved for emergency use in patients with adverse reactions to other glucocorticoids. Allergy to topical glucocorticoids in inflammatory bowel disease has been reported (17c ).

• Cryptoccocus neoformans meningitis occurred in a 15-year-old child with acute lymphoblastic leukemia (19A ). The clinical signs, headache, and a sixth nerve palsy on the right side, occurred at the end of the maintenance therapy when complete remission had been obtained (after 100 weeks of maintenance therapy, including multiple intermittent doses of dexamethasone). Culture of the cerebrospinal fluid confirmed cryptoccocal meningitis, and antifungal therapy produced a complete clinical response.

• A 57-year-old Caucasian man with inflammatory bowel disease was given prednisolone metasulfobenzoate sodium enemas twice daily and oral mesalazine 800 mg tds for about 5 months, without improvement. He stopped using the prednisolone enemas but continued to take mesalazine. Within 48 hours of stopping prednisolone his symptoms resolved completely. The theoretical possibility of contact allergy was entertained. Patch tests with a standard battery of contact allergens, including tixocortol pivalate and budesonide, were ++ positive with budesonide. At follow up 3 months later he was symptom free.

The authors advised that allergy to topical glucocorticoids should be considered in patients using rectal steroids whose condition unexpectedly fails to improve or in whom there is unexpected deterioration. Infection risk Patients taking glucocorticoids have an increased risk of infections, including those produced by opportunistic and rare pathogens, and inhaled glucocorticoids can cause oral candidiasis. The frequency of oral candidiasis has been studied in 143 asthmatic patients using inhaled glucocorticoids (96 fluticasone and 47 beclomethasone dipropionate), 11 asthmatic patients not using inhaled glucocorticoids, and 86 healthy volunteers (18c ). Quantitative fungal cultures were performed by aseptically obtaining a retropharyngeal wall swab. The growth of Candida species was significantly greater in asthmatic patients taking inhaled glucocorticoids. The presence of Candida was also significantly greater in patients with oral symptoms than in asymptomatic patients, and in patients using fluticasone (26%) compared with those using beclomethasone (11%). The presence of Candida correlated with the dose of fluticasone but not with the inhaled dose of beclomethasone. Candida species were rarely found in asthmatic patients not using glucocorticoids or in healthy volunteers. Gargling with a 1 : 50 dilution of amphotericin was effective in most of the patients with candidiasis.

In a retrospective study that included 163 consecutive recipients of allogenic hemopoietic stem cell transplants with invasive fungal infections, the possible role of glucocorticoid therapy was evaluated. The administration of high-dose glucocorticoids (2 mg/kg/day or more) was associated with an increased risk of mold infection (HR = 4.0, 95% CI = 1.7, 9.6) and an increased risk of mold infection-related death (1 year survival 11% compared with 44% when patients took doses less than 2 mg/kg/day) (20A ). In a retrospective study, postoperative infectious complications were evaluated in 159 patients with inflammatory bowel disease undergoing elective surgery (21c ). Immunosuppression consisted of glucocorticoid monotherapy (n = 56), a glucocorticoid + azathioprine or mercaptopurine (n = 52), and neither a glucocorticoid nor azathioprine or mercaptopurine (n = 51). The adjusted odds ratios for any infection and major infections in patients who took glucocorticoid were 3.69 and 5.54 respectively, and in patients who took azathioprine or mercaptopurine 1.68 and 1.20. Thus, preoperative use of glucocorticoid in patients with inflammatory bowel disease increased the risk of postoperative infectious complications. Pregnancy A single course of a glucocorticoid given to women at risk of preterm delivery promotes fetal lung maturation, reduces the incidence of respiratory distress syndrome, and reduces neonatal morbidity and mortality. In a retrospective analysis of 306 infants of gestational age under 34 weeks, there was an association between glucocorticoid use and gastroesophageal reflux (22C ). In this series, 71% of the neonates (216/306) received antenatal glucocorticoids. More babies who received antenatal glucocorticoids had clinical evidence of gastroesophageal reflux (27% versus 12%).

476 There was a significant increase in the incidence of gastroesophageal reflux with increasing courses of antenatal steroids: no course 12%, one course 25%, and two or more courses 32%. Drug formulations The development of adverse effects has been evaluated after switching from conventional glucocorticoids to a pH-modified release formulation, Eudragit Lcoated budesonide, in 178 patients with Crohn’s disease who had taken 5–30 mg/day of prednisolone equivalents for at least 2 weeks (23c ). The percentage of patients with glucocorticoidrelated adverse effects fell from 65% at entry to 43% at the end of the study. The total number of glucocorticoid-related adverse effects fell significantly from 269 to 90. In conclusion, switching from conventional glucocorticoids to budesonide leads to a significant reduction in glucocorticoid-related adverse effects in patients with Crohn’s disease without causing rapid deterioration of the disease. Drug dosage regimen Pulsed glucocorticoid therapy for moderately severe ulcerative colitis, given on an out-patient basis, can induce remission more quickly than conventional oral glucocorticoid therapy (24c ). There were no serious adverse effects in 11 patients given pulsed glucocorticoids or in eight treated conventionally. The two regimens were equally efficacious. Drug administration route The safety of nasal glucocorticoids in the treatment of allergic rhinitis has been reviewed (25R , 26R ). Drug interactions Aprepitant Aprepitant is a neurokinin-1 receptor antagonist that, in combination with a glucocorticoid and a 5HT3 receptor antagonist, is very effective in preventing chemotherapy-induced nausea and vomiting. At therapeutic doses it is also a moderate inhibitor of CYP3A4. Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma glucocorticoid concentrations (27c ). These findings suggest that the dose of these glucocorticoids should be adjusted when aprepitant is given. HIV protease inhibitors Cushing’s syndrome can be caused by the co-administration of a glucocorticoid and inhibitors of CYP3A4, such as HIV protease inhibitors, resulting in increased plasma glucocorticoid concentrations.

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• Cushing’s syndrome occurred in a 44-year-old HIV-positive patient who used inhaled fluticasone (500 micrograms qds) for severe asthma for 2 years (28A ). Stavudine and nevirapine were replaced by abacavir and ritonavir + lopinavir and 2 months later he developed the typical features of Cushing syndrome.

In this case an interaction of ritonavir + lopinavir with fluticasone was suspected, because fluticasone is metabolized by CYP3A4, which ritonavir inhibits. Itraconazole Cushing’s syndrome of rapid onset occurred during combined treatment with inhaled budesonide and itraconazole (29A ). • A 4-year-old boy with cystic fibrosis developed persistent bronchospasm. Allergic bronchopulmonary aspergillosis was suspected and he was given oral itraconazole 100 mg bd, inhaled formoterol 12 micrograms/day, and inhaled budesonide 200 micrograms bd. After 2 weeks his respiratory symptoms had improved but he had a moon face and swollen abdomen, his blood pressure was 121/75 mmHg, and his weight had increased by 1.5 kg. A morning sample showed low cortisol concentrations (under 3 ng/ml) and a reduced plasma ACTH (12 pg/ml). Itraconazole was withdrawn and budesonide was reduced and withdrawn after 2 weeks. He was given hydrocortisone to prevent acute adrenal insufficiency. He recovered over the next 3 months.

This adverse effect could have been due to inhibition of the metabolism of budesonide by itraconazole.

PROSTAGLANDINS

(SED-14, 1396; SEDA-25, 472; SEDA-26, 430; SEDA-27, 417)

Alprostadil (prostaglandin E1 ) Respiratory Bilateral pleural effusions have been associated with alprostadil (30c ). • After surgery to re-attach an amputated hand, a 75year-old man was given urokinase 240 000 U/day and heparin 20 000 U/day, each for 6 days, and alprostadil 120 micrograms/day for 12 days. From day 7 he started to have respiratory distress, which progressed gradually. A chest X-ray and CT on day 12 showed bilateral pleural effusions and a pericardial effusion. There was mild peripheral edema. The total protein was 52 g/l, albumin 22 g/l, and hemoglobin 7.6 g/dl. Analysis of the pleural

Corticotrophins, corticosteroids, and prostaglandins fluid showed that it was an exudate, with a positive Rivalta reaction, carcinoembryonic antigen 1.7 ng/ml, glucose 6.3 mmol/l; total protein 29 g/l, lactate dehydrogenase 129 U/l, total cholesterol 0.8 mmol/l, and no acid-fast bacilli. Alprostadil was withdrawn, and after 8 days the pleural effusion disappeared and the respiratory distress improved.

The mechanism of pleural effusion in the present case was suspected to be increased capillary permeability due to alprostadil; hypoalbuminemia probably also contributed.

Latanoprost Sensory systems Latanoprost can cause darkening of the color of the eye, particularly in hazel-colored eyes. It has been suggested that this darkening is produced by increased melanin content in stromal melanocytes in the iris. The effects of latanoprost on iris structure were assessed in 17 patients with bilateral primary open-angle glaucoma. In each case an iridectomy was performed in one eye, which served as a control. The other eye was then treated with latanoprost for 6 months followed by iridectomy. Light and electronic microscopy showed no evidence of early ultrastructural changes in the latanoprost-treated eyes (31c ). An iris cyst has been attributed to latanoprost (32c ). • A 67-year-old woman with advanced chronic angle-closure glaucoma was treated with laser iridotomy on both eyes followed by pilocarpine 2% and a beta-blocker. Later she used latanoprost instead, and intraocular pressures were maintained at 12–15 mmHg. There were no abnormal responses except mild hyperemia of the conjunctivae. After about 9 months she developed an iris pigment epithelial cyst on the posterior iris surface. Latanoprost was withdrawn and dorzolamide and a beta-blocker used instead. The iris cyst gradually shrank and completely disappeared from the pupil margin within 5 months. During follow-up for 4 months there was no recurrence.

Drug interactions Latanoprost induces the formation of endogenous prostaglandins including prostaglandin E2 (dinoprostone), which could affect extracellular matrix metabolism

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in ciliary smooth muscle cells. It has therefore been hypothesized that latanoprost ophthalmic solution may reduce intraocular pressure by either direct signal transduction through prostaglandin F2α receptors and by an indirect action through induced endogenous prostaglandins. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the induction of endogenous prostaglandins by suppressing the activity of cyclo-oxygenases. Moreover, recent studies have shown that some NSAIDs also inhibit the formation of latanoprost-induced endogenous prostaglandins. Thus, NSAIDs may oppose intraocular pressure reduction by latanoprost. In a prospective observer masked study of the effects of bromfenac sodium hydrate eye-drops on latanoprost-induced intraocular pressure reduction in 13 volunteers (33c ). Latanoprost significantly reduced intraocular pressure by about 5.7 mmHg, and this effect was attenuated by about 1.5 mmHg by co-administration of bromfenac. Bromfenac on its own did not affect intraocular pressure.

Misoprostol Reproductive system The effects of vaginal misoprostol for third trimester cervical ripening or induction of labor has been reviewed (34M ). Drug administration route The pharmacokinetics of misoprostol 600 mg after oral and rectal administration have been compared in 20 women after delivery (35C ). After rectal administration there was a higher AUC, but lower Cmax and a later tmax ; these findings are consistent with a slower speed but a greater extent of absorption. In 275 women randomized to oral misoprostol 600 micrograms or rectal misoprostol 400 or 600 micrograms after delivery, shivering was reported by 76% of the patients given oral misoprostol and 55% of those given rectal misoprostol. Thus, rectal misoprostol is associated with less toxicity than oral misoprostol.

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REFERENCES 1. Iuchi T, Akaike M, Mitsui T, Ohshima Y, Shintani Y, Azuma H, Matsumoto T. Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ Res 2003; 92: 81–7. 2. Roth DB, Chieh J, Spirn MJ, Green SN, Yarian DL, Chaudhry NA. Noninfectious endophthalmitis associated with intravitreal triamcinolone injection. Arch Ophthalmol 2003; 121: 1279–82. 3. Chau SY, Mok CC. Factors predictive of corticosteroid psychosis in patients with systemic lupus erythematosus. Neurology 2003; 61: 104–7. 4. Khanna S, Kumar A. Acute pancreatitis due to hydrocortisone in a patient with ulcerative colitis. J Gastroenterol Hepatol 2003; 18: 1010–11. 5. Bunch TJ, Welsh GA, Miller DV, Swaroop VS. Acute spontaneous Achilles tendon rupture in a patient with giant cell arteritis. Ann Clin Lab Sci 2003; 33: 326–8. 6. Schiavon F. Transient joint effusion: a forgotten side effect of high dose corticosteroid treatment. Ann Rheum Dis 2003; 62: 491–2. 7. Vestergaard P, Olsen ML, Paaske Johnsen S, Rejnmark L, Sorensen HT, Mosekilde L. Corticosteroid use and risk of hip fracture: a populationbased case-control study in Denmark. J Intern Med 2003; 254: 486–93. 8. Frediani B, Falsetti P, Baldi F, Acciai C, Filippou G, Marcolongo R. Effects of 4-year treatment with once-weekly clodronate on prevention of corticosteroid-induced bone loss and fractures in patients with arthritis: evaluation with dual-energy X-ray absorptiometry and quantitative ultrasound. Bone 2003; 33: 575–81. 9. Ringe JD, Dorst A, Faber H, Ibach K, Preuss J. Three-monthly ibandronate bolus injection offers favorable tolerability and sustained efficacy advantage over two years in established corticosteroidinduced osteoporosis. Rheumatol (Oxf) 2003; 42: 743–9. 10. Ringe JD, Dorst A, Faber H, Ibach K, Sorenson F. Intermittent intravenous ibandronate injections reduce vertebral fracture risk in corticosteroidinduced osteoporosis: results from a long-term comparative study. Osteoporos Int 2003; 14: 801– 7. 11. Sato S, Ohosone Y, Suwa A, Yasuoka H, Nojima T, Fujii T, Kuwana M, Nakamura K, Mimori T, Hirakata M. Effect of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis in Japanese patients with connective tissue disease: 3 year follow up. J Rheumatol 2003; 30: 2673–9. 12. Emkey R, Delmas PD, Goemaere S, Liberman UA, Poubelle PE, Daifotis AG, Verbruggen N, Lombardi A, Czachur M. Changes in bone mineral density following discontinuation or continuation of alendronate therapy in glucocorticoid-treated patients: a retrospective, observational study. Arthritis Rheum 2003; 48: 1102–8.

13. Rehman Q, Lang TF, Arnaud CD, Modin GW, Lane NE. Daily treatment with parathyroid hormone is associated with an increase in vertebral cross-sectional area in postmenopausal women with glucocorticoid-induced osteoporosis. Osteoporos Int 2003; 14: 77–81. 14. Ventura MT, Muratore L, Calogiuri GF, Dagnello M, Buquicchio R, Nicoletti A, Altamura M, Sabba C, Tursi A. Allergic and pseudoallergic reactions induced by glucocorticosteroids: a review. Curr Pharm Des 2003; 9: 1956–64. 15. Karsh J, Yang WH. An anaphylactic reaction to intra-articular triamcinolone: a case report and review of the literature. Ann Allergy Asthma Immunol 2003; 90: 254–8. 16. Ventura MT, Calogiuri GF, Matino MG, Dagnello M, Buquicchio R, Foti C, Di Corato R. Alternative glucocorticoids for use in cases of adverse reaction to systemic glucocorticoids: a study on 10 patients. Br J Dematol 2003; 148: 139–41. 17. Monk BE, Skipper D. Allergy to topical corticosteroids in inflammatory bowel disease. Gut 2003; 52: 597. 18. Fukushima C, Matsuse H, Tomari S, Obase Y, Miyazaki Y, Shimoda T, Kohno S. Oral candidiasis associated with inhaled corticosteroid use: comparison of fluticasone and beclomethasone. Ann Allergy Asthma Immunol 2003; 90: 646–51. 19. Mavinkurve-Groothuis AMC, Bokkerink JPM, Verweij PE, Veerman AJP, Hoogerbrugge PM. Cryptococcal meningitis in a child with acute lymphoblastic leukemia. Pediatr Infect Dis J 2003; 22: 576. 20. Fukuda T, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, Martin PJ, Storb RF, Marr KA. Risks and outcomes of invasive fungal infections in recipients of allogenic hematopoietic stem cell transplants after nonmyeloablative conditioning. Blood 2003; 102: 827–33. 21. Aberra FN, Lewis JD, Hass D, Rombeau JL, Osborne B, Lichtenstein GR. Corticosteroids and immunomodulators: postoperative infectious complication risk in inflammatory bowel disease patients. Gastroenterology 2003; 125: 320–7. 22. Chin S-OS, Brodsky NL, Bhandari V. Antenatal steroid use is associated with increased gastroesophageal reflux in neonates. Am J Perinatol 2003; 20: 205–13. 23. Andus T, Gross V, Caesar I, Schulz HJ, Lochs H, Strohm WD, Gierend M, Weber A, Ewe K, Scholmerich J; German/Austrian Budesonide Study Group. Replacement of conventional glucocorticoids by oral pH-modified release budesonide in active and inactive Crohn’s disease: results of an open, prospective, multicenter trial. Dig Dis Sci 2003; 48: 373–8. 24. Oshitani N, Kamata N, Ooiso R, Kawashima D, Inagawa M, Sogawa M, Iimuro M, Jinno Y, Watanabe K, Higuchi K, Matsumoto T, Arakawa T. Outpatient treatment of moderately severe active ulcerative colitis with pulsed steroid therapy and

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conventional steroid therapy. Dig Dis Sci 2003; 4: 1002–5. 25. Mehle ME. Are nasal steroids safe? Curr Opin Otolaryngol Head Neck Surg 2003; 11: 201–5. 26. Salib RJ, Howarth PH. Safety and tolerability profiles of intranasal antihistamines and intranasal corticosteroids in the treatment of allergic rhinitis. Drug Saf 2003; 26: 863–93. 27. McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, Hesney M, Lines CR, Petty KJ, Deutsch PJ, Murphy MG, Gottesdiener KM, Goldwater DR, Blum RA. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 2003; 74: 17–24. 28. Rouanet I, Peyriere H, Mauboussin JM, Vincent D. Cushing’s syndrome in a patient treated by ritonavir/lopinavir and inhaled fluticasone. HIV Med 2003; 4: 149–50. 29. De Wachter E, Vanbesien J, De Schutter I, Malfroot A, De Schepper J. Rapidly developing Cushing syndrome in a 4-year-old patient during combined treatment with itraconazole and inhaled budesonide. Eur J Pediatr 2003; 162: 488–9.

30. Watanabe H, Anayama S, Horiuchi T, Sato E, Hamada Y, Ishihara H. Pleural effusion caused by prostaglandin E1 preparation. Chest 2003; 123: 952–3. 31. Pfeiffer N, Grierson I, Goldsmith H, Appleton P, Hochgesand D, Winkgen A. Fine structural evaluation of the iris after unilateral treatment with latanoprost in patients undergoing bilateral trabeculectomy (the Mainz II study). Arch Ophthalmol 2003; 121: 23–31. 32. Lai IC, Kuo MT, Teng IMC. Iris pigment epithelial cyst induced by topical administration of latanoprost. Br J Ophthalmol 2003; 87: 366. 33. Kashiwagi K., Tsukahara S. Effect of nonsteroidal anti-inflammatory ophthalmic solution on intraocular pressure reduction by latanoprost. Br J Ophthalmol 2003; 87: 297–301. 34. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev 2003; (1): CD000941. 35. Khan RU, El-Refaey H. Pharmacokinetics and adverse-effect profile of rectally administered misoprostol in the third stage of labor. Obstet Gynecol 2003; 101: 968–74.

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GONADOTROPINS AND OVULATION-INDUCING DRUGS (SED-14, 1464; SEDA-25, 478; SEDA-26, 434; SEDA-27, 420) Metabolism What may be the first case in which an attack of acute porphyria was triggered by gonadotropic stimulation of the ovary has been reported (1A ). • A 36-year-old woman who had undergone a standard course of gonadotropin treatment for infertility developed severe pelvic pain and hyponatremia. She had a family history of porphyria and it was thought that the treatment had fired an acute attack of the condition.

This case once more underlines the need to take a complete personal history before using this or any other form of intensive hormonal therapy. It also recalls the instances in which porphyria or pseudoporphyric incidents have been triggered by oral contraceptives. Reproductive system Various means have been developed to predict ovarian hyperstimulation by gonadotropins; one of them involves rheometry (2r ). In 25 volunteers using a damped oscillation rheometer for blood measurements before and during administration of a regimen of human menopausal gonadotropin + human chorionic gonadotropin (hGM + hCG) there were detectable changes in blood rheometry well before the onset of frank changes in blood coagulation (3c ). © 2005 Published by Elsevier B.V. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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A German group has described two patients in whom severe ovarian hyperstimulation occurred, with severe and persistent ascites. In both cases it became necessary to terminate the early pregnancy, but because the grossly enlarged ovaries made laparoscopic termination impossible, mifepristone had to be used. In one case it was unsuccessful and had to be followed by curettage. In both cases ascites persisted for many months. This is not a familiar complication of ovarian hyperstimulation, and it is possible that the use of mifepristone at least aggravated and prolonged the ascites (4A ). A technique known as “coasting” has been developed over the last 20 years to reduce the incidence of severe ovarian hyperstimulation. It involves withdrawing exogenous gonadotropins and postponing hCG administration if the patient’s serum estradiol concentration becomes “dangerous”; treatment is resumed once the concentration is again acceptable (5r ). A full description of the various techniques used would go beyond the scope of this review, but it is important to realize that in principle they do considerably reduce the risk of hyperstimulation (6R ). Finally, as recombinant luteinizing hormone (rLH) becomes more widely available it will be important to determine whether, as has been suggested, it is less likely to lead to ovarian hyperstimulation than are the chorionic gonadotropins used up to now, in view of its shorter half-life (7r ). However, a recent examination of the clinical data submitted for registration of rLH in France showed no evidence to date that it is any safer in this respect that human chorionic gonadotropin; the usual precautions to avoid ovarian hyperstimulation still need to be adopted (8M ). Tumorigenicity The possibility that gonadotropins used for the treatment of infertility

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might in later life lead to an increased risk of breast cancer has been examined in the USA using findings from the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study (9C ). The investigators identified a population of 4575 patients with primary invasive breast cancer and 4682 healthy control subjects from the same environment, and examined their medical histories. A history of infertility drug use was not associated with a risk of breast cancer. However, compared with women who had never used any fertility medication, women who had used human menopausal gonadotropin for 6 months or more, or for at least six cycles, had a relative risk of breast cancer of 2.7–3.8. The authors therefore considered that long-term use of certain infertility drugs could increase the risk of breast cancer, but they pointed out that additional confirmatory studies are needed.

ESTROGENS

(SED-14, 1448; SEDA-25, 478; SEDA-26, 436; SEDA-27, 422) The discovery of the estrogen receptors in different organs stimulated intensive research into the development of more selective agents with hormonal or antihormonal effects in specific systems. Not all of the selective estrogen receptor modulators (SERMs) developed to date have lived up to expectations, but more are on the way or undergoing testing. There is also interest in the possible neuroprotective effects of estrogens on the nervous system, since estrogen may act as an antiapoptotic agent, an antioxidant, or a neurotrophic modulating agent, promoting cross-talk with neurotrophic factors (10R ). This could in theory prove helpful in the treatment of conditions such as Parkinsonism, but no selective agent with such usefulness, and devoid of unwanted effects on other systems, has so far emerged. In the meantime, tibolone, sometimes described as a “gonadomimetic” agent, because of its ability to stimulate certain estrogen receptors selectively, has been used, although without any clear success, in the hope of potentiating the effects of fluoxetine on major depression (11c ).

Immunologic Angioedema and urticaria have often been attributed to food allergy, in the absence of any other explanation. In 26 young

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women in whom these conditions had been attributed to food allergy there was reason to believe that estrogens in oral contraceptives were in fact responsible (12A ). All the patients had a deficiency of C1 esterase inhibitor. Withdrawal of oral contraception caused an increase in C1 esterase inhibitor concentrations and activity, associated with recovery or marked improvement in the symptoms that had formerly been attributed to food allergy. The relatively high frequency of women taking cyproterone acetate in this population was striking. Replacement of the initial contraception containing ethinylestradiol by a progestogen-only regimen maintained or even accentuated these good therapeutic results. Tumorigenicity Weak evidence from interview studies conducted in the past suggested that the risk of non-Hodgkin’s lymphoma might be increased by estrogen treatment. A casecontrol study in a total population of some 300 000 adults in the Netherlands, using primary discharge diagnoses and pharmacy dispensing records now appears to have discounted this supposed risk (13C ). Drug administration route Well-designed studies of local, topical, and intradermal forms of estrogen as a means of attaining a general systemic effect have tended to show that when doses are therapeutically equivalent to those used orally the adverse effects are similar (14c ). However, this is a complex issue, which is discussed more extensively in connection with hormone replacement therapy later in this chapter. For the relief of purely local symptoms in the lower genital tract, an intravaginal estrogen can have advantages. It has long been accepted that some urogenital symptoms in women can be relieved by intravaginal administration of estrogens in doses too low to produce troublesome systemic effects. This continues to be confirmed, as in a study of micronized estradiol vaginal tablets 25 micrograms or placebo in 1612 women, with assessment at 4 and 12 months; the estrogen did not increase serum estrogen concentrations or stimulate endometrial growth (15c ). In a placebo-controlled study in the “urge syndrome” in 40 menopausal women an implant of 17-beta-estradiol 25 mg had no therapeutic effect, but nine women had vaginal bleeding (16c ).

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Nylestriol Nylestriol is a new estriol derivative (cyclopentylethinylestriol), which has been tested in animals in combination with levonorgestrel as a potential agent for the treatment of postmenopausal osteoporosis. In a preliminary placebo-controlled study over 1 year using nylestriol 0.5 mg + levonorgestrel 0.15 mg once weekly in 119 patients, the combination produced no adverse effects on the uterus or breasts and there was no uterine bleeding (17c ).

Diethylstilbestrol (stilbestrol, DES) Hematologic The risk of thromboembolic complications when diethylstilbestrol is used in treating prostatic cancer is well documented, but there has been some doubt as to the mechanisms involved. Oral diethylstilbestrol diphosphate 300 mg/day has been compared with LR-RH agonist therapy or no treatment in 35 patients with prostatic cancer (18c ). Diethylstilbestrol reduced the concentrations of protein S to below the lower limit of normal in 24 of the 35 cases. There was also some reduction in antithrombin III concentrations. These results were consistently confirmed in a followup group of eight further patients who took diethylstilbestrol. Since these very low concentrations of protein S are virtually the same as those found in congenital deficiency, it seems likely that this plays a role in the development of cardiovascular complications during diethylstilbestrol treatment. Liver Liver damage has again been attributed to diethylstilbestrol (19A ). • A 65-year-old man started to take diethylstilbestrol 1 mg bd for prostatic cancer (Gleason grade 3). After 11 years of treatment without metastasis he was switched to treatment with an LH-RH analogue, which was regarded as safer, but at this time his liver function tests were found to be seriously deranged. Biopsy showed established cirrhosis with steatohepatitis. He had no history of excessive alcohol intake, and it seemed likely that the diethylstilbestrol was the cause of the liver disorder.

A Japanese paper of 1989 reported six similar cases, but no others appear to be on record.

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Pregnancy The long and tragic tale of the complications resulting from the use of diethylstilbestrol in pregnancy between 1948 and 1975 has still not yet been fully told. The methodological errors made by OW Smith in the 1948 paper that launched this dangerous and ineffective treatment have been reviewed as a striking example of the need for critical clinical studies in any field (20R ). Although the use of diethylstilbestrol in pregnancy fortunately ended in much of the world more than 30 years ago, cases are still being reported of women who were exposed to the drug during their prenatal life and later developed severe reproductive problems. There have been various cases of rupture of the uterus in mid-pregnancy, and a rupture of a previously unscarred uterus during the first trimester has now also bee reported (21A ). • A 28-year-old woman undergoing her first pregnancy developed a uterine rupture in the anterior fundal area of the uterus during the first trimester. Both tubes were normal.

The event presumably reflected thinness of the uterine wall, which has been described before in women who were exposed to diethylstilbestrol before birth. Third-generation effects Even more disconcerting than the second-generation effects in women exposed to diethylstilbestrol during pregnancy is the possibility of third-generation effects. There is no certainty regarding these, but worrying cases have been reported at intervals over the last thirty years or more (SED-14, 1449). • Ovarian carcinoma occurred in an adolescent girl with a suggestive history. The tumor was a smallcell carcinoma of the ovary, which is excessively rare in childhood and adolescence (22A ). Her grandmother had taken diethylstilbestrol when she was pregnant with her mother. Her mother had in later life undergone hysterectomy for a cervical dysplasia, another condition that could have been due to exposure to diethylstilbestrol.

A current hypothesis is that in utero exposure to diethylstilbestrol leads to genetic or epigenetic changes in the primordial oocytes that are formed in the first trimester of gestation in the daughter. These changes can then be inherited by grandchildren.

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Hormone replacement therapy (HRT) (SED-14, 1457; SEDA-25, 479; SEDA-26, 436; SEDA-27, 423) It is not always pleasant to be proved right. A quarter of a century and more ago these volumes were stressing the need for weighing critically the adverse effects of hormonal replacement therapy alongside the doubts that had already arisen as to its necessity and efficacy (SEDA-2, 328). The problems of the post-menopausal period, especially that of osteoporosis, affect many women, and there was genuine hope that hormone replacement could develop into a form that would provide widespread benefit without undue risks. That hope has receded as one large study after another has presented its conclusions. The desirability of limiting treatment to the minority of women who really need it is now regularly echoed (23R , 24r –27r ). As has been stressed in a brief review (28r ) the Women’s Health Initiative study was stopped because of safety concerns regarding combined treatment with estrogens + progestogens, and it was an entirely fair conclusion that the risks of the treatment outweighed the benefits. The outcome of the Women’s Health Initiative has had drastic consequences for the acceptance of hormone replacement therapy among women who have been informed of the findings (29c ). All the same, the risks were difficult to express in exact terms, and this has led to criticism of the work and its conclusions (30r ). There was undoubtedly an increase in breast cancer among users, but no greater than the increase reported in observational studies; there was an increase in vascular events, but many of the women in the study had risk factors for cardiovascular disease. Since no further long-term trials of combined hormone replacement therapy appear to be in progress, the ultimate truth regarding the benefit to harm balance may remain in doubt for very long time. “Hormone replacement therapy can still be prescribed for menopausal symptoms and for osteoporosis prevention, but the need for continued use should be reviewed annually” (28r ), and “a consensus is growing that postmenopausal women may be treated with HRT only . . . for disturbing symptoms of the ovarian hormone insufficiency syndrome, rather than . . . for menopause per se” (31R ).

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A number of groups continue to stress the possibility, raised in the Nurses Health Study and elsewhere, that by reducing the dosages used in hormonal replacement one might eliminate the risks while retaining efficacy (32r ), but so long as this has not been shown to be true it will not provide a way ahead. The Million Women Study in the UK (33C ), extensively discussed in SEDA-27, has been criticized on various grounds by some proponents of hormone replacement therapy, notably because in their view the number of deaths from breast cancer was too small and the follow-up too short to justify the belief that HRT increases the risk of death from breast cancer; discrepancies between this and other studies have also been stressed (34r ). The interpretation of the study in the editorial that accompanied it has also been criticized as being unduly pessimistic. However, the fact remains that the study is not the only source of serious doubts about the benefit to harm balance of hormone replacement therapy. With such disagreements and doubts it can be difficult to provide a woman with the properly balanced information which she needs if “informed consent” to hormonal replacement treatment is to be meaningful (35r ). Cardiovascular Hormone replacement therapy can cause prolongation of the QT interval on the electrocardiogram. In a recent prospective study set of the incidence and extent of this effect 3103 women were followed at intervals over 9 years and data were collected on their use of hormonal replacement and the QT interval, prolongation being defined as an increase of not less than 10% (36C ). The QTc interval was moderately but significantly longer in users of hormone replacement therapy, the risk of QT prolongation being nearly twice that in neverusers. The consequences of these changes for the user’s health could not be assessed and merit further study. Metabolism The unfavorable effects of estrogens on blood lipids are particularly serious in women with hypertriglyceridemia. The changes in women with previously raised lipids have been quantified (37c ). In 56 women, median age 52 years, with serum triglyceride concentrations over 4.5 mmol/l (400 mg/dl) despite diet and drug treatment, or with a history of hypertriglyceridemic acute pancreatitis. Of the 56

484 women, 23 had taken some form of hormone replacement therapy and one had been treated with selective estrogen receptor modulators; in these women at entry the median fasting triglyceride concentration averaged 1270 mg/dl and in the previously untreated women 1087 mg/dl. After baseline testing, the hormonal treatment was withdrawn and they received a very low fat diet, gemfibrozil 1.2–1.5 mg/day, and omega3-fatty acids 4–12 g/day. After 2–4 weeks of this treatment, the median triglyceride concentration in those who had taken hormones fell from 1270 to 284 mg/dl and in the non-hormone group from 1087 to 326 mg/dl. The authors stressed the seriousness of the lipid complications that can occur with estrogens when women already have a tendency, familial or otherwise, to hypertriglyceridemia. Triglycerides must be measured before beginning hormone therapy; hormone therapy is contraindicated in women with a triglyceride concentration of 500 mg/dl or more. Triglyceride-lowering diets and drugs are likely to fail as long as hormones are being given. Gastrointestinal Since hormone status could be involved in the occurrence of irritable bowel syndrome, the risk has been examined in women using hormone replacement therapy (38C ). A population of women aged 50–69 years old with at least one prescription for HRT were identified from Britain’s General Practice Research Database, and a cohort of 50 000 women who had never used HRT was sampled from the same source population. The incidence of irritable bowel syndrome per 1000 person-years was 1.7 in the cohort of never-users and 3.8 among HRT users. Both current and past users of HRT had an increased risk of irritable bowel syndrome compared with non-users, after adjusting for co-morbidity and consultation patterns. The increased risk was unaffected by treatment duration, regimen, or route of administration. This result suggests that HRT is associated with an increased risk of irritable bowel syndrome similar to that observed among younger premenopausal women with endogenous estrogenic activity. Reproductive system The incidence of endometrial hyperplasia in a large series of women using different forms of HRT over 12 months has been examined (39C ). Subgroups each

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received one of six blinded norethindrone acetate + ethinylestradiol combinations (0/5 mg, 0.25/5 mg, 1/5 mg, 0/10 mg, 0.5/10 mg, or 1/10 mg) or open conjugated equine estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg. Endometrial hyperplasia, assessed by biopsy, developed in 26 subjects, 23 of these being in the subgroup who took ethinylestradiol 10 micrograms without norethindrone acetate. Norethindrone acetate thus appears to have protected the endometrium from estrogen-induced hyperplasia and changes in proliferative status. Those who took norethindrone acetate + ethinylestradiol had significantly less endometrial proliferation than those who took conjugated equine estrogens + medroxyprogesterone acetate. Tumorigenicity Breast cancer There is today no reasonable doubt that hormone replacement therapy increases the risk of breast cancer. As always, however, the devil is in the detail, and argument continues as to nature and extent of the risk and the approaches or dosage schemes that might be relatively safe. The epidemiological figures continue to be interpreted in a manner much influenced by the writer’s optimism or pessimism. The most useful estimates are still those from the 1997 analysis of 51 epidemiological studies (a 2% risk for each year of use) and from the Women’s Health Initiative (a relative risk of 1.26 when combined therapy is compared with placebo). More subtle approaches are now estimating the risk by histological type. Tumor registry data from three eastern states in the USA, suggested that lobular carcinoma was associated with estrogen therapy within the last 2 years (OR = 1.8) and recent use of combined therapy (OR = 3.6), whereas ductal carcinoma showed no correlation with either type of HRT (40C ). A recent prospective population study in Sweden has looked further into the question of how the incidence of breast cancer during HRT might be influenced by the type of replacement therapy used, i.e. with or without a progestogen (41C ). From 1995 onwards, data were collected on 6586 women aged 50–64 years in the Lund area of Sweden, with no reported breast cancer on inclusion. Information on their use of HRT during the period from December 1995 to February 2000 was obtained by questionnaire. Between their inclusion in the study and December

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2001, 101 developed breast cancer. Only everuse of the continuous combined estrogen + progestogen formula differed significantly between cases and controls (45% versus 24%). Compared with never-users, exclusive users of combined estrogen + progestogen had the highest age-adjusted hazard ratio (HR = 3.3; 95% CI = 1.9, 5.6), followed by users of combined estrogen + progestogen in addition to other HRT formulas (HR = 2.8; 95% CI = 1.4, 5.5). There was no significant increase in women who exclusively used other HRT formulas. On this evidence it can be concluded that women who used combined estrogen + progestogen had over three times the risk of breast cancer compared with never-users and twice the risk compared with users of other types of HRT. Precisely because a careful watch has to be kept for signs of malignant change in the breast in users of HRT, it is important to recognize the possible influence of the hormonal treatment itself on the breast, even in the absence of cancerous change. In the past an increase in parenchymal density, ranging from 11% to 52% has been described. In a new prospective study of this issue in Turkey, 182 menopausal women were given HRT (estrogen alone, sequential use of progestogens + estrogens, continuous use of both types of hormone, or tibolone alone) (42C ). Breast examinations and mammography were carried out at the outset and repeated after a mean of 11.6 months. The parenchymal density of the breast was increased by an average of some 18% in all cases; the effect was most marked in women who took the combined product continuously (a 25% increase in density) and least in the users of tibolone (a 5.5% increase). The increase in density was particularly striking in obese women and was twice as severe in women with a family history of breast cancer; in the series as a whole, it ran parallel with an increase in breast tenderness. However, there was no atypia, and the changes were therefore not considered to constitute a contraindication to continued HRT. In a relatively small but meticulously designed study of not only actual breast cancer but all possible forms of breast changes in 300 women aged 30–50 years, of whom 120 had taken HRT and 180 had never been exposed to it, the women were divided into four categories: those with normal breast tissue, those with fibrocystic disease, those with cellular atypia, and those with breast cancer (43C ).

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Another group of women were also identified who had breast implants. Changes in breast tissue were determined using breast-enhanced scintigraphy. The breasts were “normal” in 122 (40%), of whom 84 (69%) had not taken HRT. This accounted for 47% of the women not taking hormone therapy (84 of 180), while only 32% of the women taking HRT (38 of 120) had normal breasts. This difference was statistically significant. There was a greater overall incidence of breast abnormality in women taking HRT and a lower incidence in pathology among women not taking HRT when cumulatively analysed for FCD, cellular atypia, and breast cancer. This difference was statistically significant for women with breast cancer, of whom 63% (10 of 16) were taking HRT. This work suggests that the initial empirical observations of a higher incidence of HRT among women with breast cancer may have a relation to underlying changes in breast tissue that are associated with differences in mitochondrial content and activity. Perhaps one should stress that this paper was concerned primarily with defining the entire spectrum of changes that can occur in the breast during HRT; it did not address the question of existing evidence about the association between HRT and breast cancer. Breast tumors that develop in HRT users have prognostically favorable histological features, but it is unclear if this is the case for both short-term and long-term use. In 2000 women aged over 55 years with invasive breast cancer diagnosed over 7 years short-term users of HRT (5 years or less) were about 50% less likely to develop poorly differentiated breast tumors or node-positive tumors than non-users (44C ). Longer term users of HRT were also less likely to develop poorly differentiated tumors, but the incidence of node-positive tumors was not reduced compared with controls. Tumor size was not significantly related to the duration of treatment. Other malignancies While the incidence of some tumors is increased in HRT users, that of other tumors seems to be reduced, the reduced incidence of colorectal cancer having been documented. The authors of a review brought together data on this issue from a series of casecontrol studies conducted in Italy between 1983 and 1999 involving a total of 537 cancers occurring in ever-users and 6439 reported in neverusers; there was a control group of 6976 women

486 with acute, non-neoplastic conditions (45M ). In the overall analysis there was an inverse relation between HRT and the occurrence of cancer of the colon (OR = 0.7), rectum (OR = 0.5) and liver (OR = 0.2). There were excess risks for cancers of the gallbladder (OR = 3.2), breast (OR = 1.1), endometrium (OR = 3.0), and urinary bladder (OR = 2.0). There was also a non-significant increase in the risk of ovarian cancer. The very small increase in breast cancer risk in this study is striking when one sets these findings against other work, cited above. Drug withdrawal Sudden withdrawal of estrogen replacement therapy can result in very rapid bone loss, and patients who abandon this treatment should be carefully monitored and provided with alternative care to avoid a serious risk of fractures (46r ). Susceptibility factors The choice of an optimal and reasonably safe dose of a hormonal product varies with race and population, at least because of variations in body weight and possibly also differences in metabolic processes. Dosage studies, for example with very low-dose estrogen treatment, must therefore of necessity be conducted in different populations. In menopausal Chinese women, a daily dose of 1 mg of estradiol has been found to be as effective as 2 mg in reducing the risk of osteoporosis (47c ), but it would be unwise to accept these conclusions as being valid for typical European or American women. Drug administration route The oftenrepeated hypothesis that transdermal hormone therapy might be safer than oral treatment in equivalent doses has been put to the test in several studies. It seems possible that certain effects of estrogens will vary with the route of administration because of first-pass metabolism in the liver. On the other hand, when comparing the effects of oral and transdermal treatment one has to be sure that the concentrations reaching the system by the two routes are truly therapeutically equivalent before one can draw any conclusion regarding such a dissociation of effect. Oral post-menopausal estrogen replacement therapy increases circulating concentrations of C-reactive protein, but in 68 women who took a combination of transdermal 17-beta-estradiol

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and micronized progesterone there was no significant effect of transdermal estrogen on Creactive protein concentrations compared with placebo (48c ). Another study, in the Netherlands, looked primarily at effects of various types and routes of replacement therapy on the hemostatic variables associated with venous thrombosis (49C ). In a double-blind, randomized, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received 13 monthly cycles of placebo, transdermal 17-beta estradiol (50 micrograms/day), oral estradiol 1 mg, or a combination of oral estradiol + gestodene 25 micrograms/day. In all the actively treated groups, there were increases in resistance to activated protein C, which were more marked in those who took oral treatment. The effect was not explained by changes in protein S, protein C, or prothrombin, but it could contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy. This is not the first study in which increases in activated protein C have been observed with HRT; they seem to occur irrespective of the progestogen used. However, these new results contrast with some earlier work in which transdermal estradiol was actually claimed to reduce resistance to activated protein C, an effect that might be favourable as regards clotting. There is other evidence that transdermal estrogen replacement therapy has relatively little effect on hemostasis. In a case control study, 155 consecutive patients with a first documented episode of idiopathic venous thromboembolism, 92 of whom had a pulmonary embolism and 63 a deep venous thrombosis, were compared with 381 healthy matched controls (50C ). Overall, 32 (21%) of the cases and 27 (7%) of the controls were current users of oral estrogen replacement therapy, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal estrogen replacement therapy. After adjustment for potential confounding variables, the odds ratios for venous thromboembolism in current users of oral and transdermal estrogen replacement therapy compared with non-users were 3.5 (95% CI = 1.8, 6.8) and 0.9 (0.5, 1.6) respectively. Estimated risk for venous thromboembolism in current users of oral estrogen replacement therapy compared with transdermal users was 4.0 (1.9, 8.3). Because C-reactive protein is synthesized in the liver, It has been hypothesized that the

Sex hormones and related compounds, including hormonal contraceptives

estrogen-induced rise in C-reactive protein is related to first-pass hepatic metabolism (51C ). In a randomized, crossover, placebo-controlled study in 21 postmenopausal women, transdermal estradiol had no effect on C-reactive protein or on concentrations of the anti-inflammatory growth factor IGF-1, whereas oral conjugated estrogens for 8 weeks caused a more than twofold increase in C-reactive protein and a significant reduction in IGF-1. The magnitude of increase in C-reactive protein was inversely correlated to the fall in IGF-1. Neither transdermal estradiol nor oral conjugated estrogens had any effects on the plasma concentrations of cytokines that promote the synthesis of C-reactive protein. The authors concluded that in postmenopausal women, oral but not transdermal estrogen increased C-reactive protein by a firstpass hepatic effect. Because C-reactive protein is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, they considered that the route of administration may be an important consideration in minimizing the adverse effects of estrogens on cardiovascular outcomes. The various forms of transdermal hormone formulations have been reviewed (52R ). The authors concluded that while the transdermal route offers various practical advantages, adverse effects are about the same as with oral products. Clearly, not all doubts on the issue are yet resolved. Food–drug interactions It has sometimes been suspected that food might interfere sufficiently with the availability of progestogen + estrogen combinations, especially low-dose formulations, to impair the effects of treatment. One crossover study in 18 women taking a lowdose combination (containing norethindrone acetate 1 mg and ethinylestradiol 10 micrograms) showed that a single high-fat meal, while changing the absorption pattern, did not affect it to a sufficient degree to interfere with the effects of the combination (53c ).

HORMONAL CONTRACEPTIVES (SED-14, 1405; SEDA-25, 484; SEDA-26, 442; SEDA-27, 426) Hematologic The judicial conclusion cited in SEDA-27 that with third-generation oral con-

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traceptives the risk of thromboembolic complications is substantially raised compared with that of second-generation products, continues to be corroborated in authoritative literature (54R ). Yet despite all the evidence, there is a surprising degree of optimism in some quarters, especially when results rely only on one or two measurements. Hypercoagulability has been assessed using thromboelastography in 43 women taking low-dose oral contraceptives (ethinylestradiol 35 micrograms or less, combined with various progestogens) for 3 months (55c ). The 3-month R time (a thromboelastographic parameter) was significantly reduced compared with pre-treatment values, although the authors argued that the magnitude of this change was not characteristic of hypercoagulability. The outcome was not affected by the type of progestogen used. The small size and limited duration of the study, and the limited range of measures used, inevitably throw some doubt on the significance of the findings. Skin Pseudoporphyria has been described in a woman taking an oral contraceptive (56A ). • A 40-year-old white woman with skin type II who for 4 months had been taking a low-dose combined oral contraceptive based on levonorgestrel and ethinylestradiol developed skin fragility on her sun-exposed forearms, with blisters, erosions, and scars. Histology led to a diagnosis of pseudoporphyria, since porphyrin concentrations were not raised. After the oral contraceptive was withdrawn the lesions healed slowly, despite continuing sun exposure.

Although there have been no previous reports attributing pseudoporphyria to oral contraceptives, in earlier reports of this condition (for example in users of sun-ray beds) a fair proportion of the women were in fact taking estrogens or oral contraceptives. One is also reminded of cases in which true porphyria was precipitated by hormonal treatment. Reproductive system When a woman with polycystic ovary syndrome requires treatment with flutamide and metformin, the question arises whether the effects of this treatment could be deranged by simultaneous use of an oral contraceptive. In 36 women with polycystic ovary syndrome, of whom 12 were also taking a low-dose oral contraceptive the beneficial effects of flutamide 125 mg/day and metformin

488 1275 mg/day on hyperandrogenemia, hyperinsulinemia, and dyslipidemia were maintained when an oral contraceptive (ethinylestradiol 20 micrograms + gestodene 75 micrograms) was used, and in the latter there was an additional increase in sex hormone-binding globulin, and thus a further fall in the free androgen index (57c ). These workers concluded that in such patients combined treatment is in fact ideal. Immunologic According to anecdotal reports published over the years, recurrent angioedema has sometimes been associated with the use of oral contraceptives and hormone replacement therapy. In a recent study the supposed link was investigated (58C ). Of 516 women with recurrent angioedema, 228 (44%) had used oral contraceptives or hormone replacement therapy, and of this group 103 (45%) had urticariarelated angioedema, while 50 (22%) had idiopathic angioedema, 39 (17%) had hereditary angioedema type III, and 32 (14%) had hereditary angioedema type I. Oral contraceptives or hormone replacement therapy led to attacks of angioedema in 46 women (20%), including 20 (63%) of the women with hereditary angioedema type I, 24 (62%) of those with hereditary angioedema type III, and 2 (4%) of those with idiopathic angioedema. These 46 women included 26 in whom symptoms occurred for the first time after the use of these medications and 20 in whom pre-existing recurrent angioedema worsened considerably. However, it should be remembered that these conditions are not contraindications; many women with these diseases tolerate these medications without any effects on their angioedema. Tumorigenicity Breast cancer Contradictory impressions and conclusions as to the risk of breast cancer in users of oral contraceptives continue to be published, and one hesitates to revise existing judgement in the light of a single new study. However, what does seem reasonably apparent is that, as one would expect, the lower the dose of the hormonal components the less the risk of this complication, as has been shown in a population based case-control study in the USA in some 3000 women (59C ); the design of the study was originally described in 1995 (60C ). Women who had recently used oral contraceptives containing more than 35 micrograms of ethinylestradiol per tablet were at a

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significantly higher risk of breast cancer than users of lower dose formulations and at both doses the risk was higher than among neverusers (respective relative risks of 1.99 and 1.27). The relation was particularly marked among women under 35 years of age, In whom the respective relative risks were 3.62 and 1.91. The authors also found significant trends of increasing breast cancer risk for tablets with higher progestogen and estrogen potencies, and these were again most pronounced among women under 35. The preponderance of evidence on breast cancer relates to the occurrence of invasive carcinoma, and until recently no study had looked specifically at the risk of non-invasive breast carcinoma, i.e. breast carcinoma in situ. That particular aspect was studied in Connecticut in 2003 by examining data on 875 cases of ductal carcinoma in situ registered between 1994 and 1998, as well as data on 999 controls. The risk of ductal carcinoma in situ was not increased in women who had ever used oral contraceptives compared with women who had never used them; nor was it significantly increased in any subgroup of ever-users (61C ). Drug dosage regimens There has long been a belief that a woman who intends to use oral contraception should wait for her next menstrual period before beginning the treatment, since by attuning the treatment to the existing cyclical rhythm the bleeding pattern will be more physiological. An alternative approach is to begin treatment immediately it is prescribed, whatever the menstrual phase. From recent randomized controlled work it now seems clear that either approach is acceptable; immediately starting treatment does not produce a less acceptable pattern of vaginal bleeding (62C ). Drug interactions Omeprazole Since hormonal contraceptives are potent inhibitors of some CYP isozymes, they can interfere with the metabolic breakdown of various drugs and thus potentiate their effects. The possibility that a contraceptive containing ethinylestradiol 40 micrograms + levonorgestrel 75 micrograms or levonorgestrel 60 micrograms only, given for 10 days, might interfere with the metabolism of omeprazole has been investigated (63c ). The progestogen alone did not cause any interaction but the combined product led to a 38%

Sex hormones and related compounds, including hormonal contraceptives

increase in the AUC of omeprazole, which is metabolized by CYP2C19, in all 10 subjects studied. There was no interference with the following stage of elimination, which is mediated by CYP3A4. The authors did not comment on the possible clinical consequences, but one would expect the degree of interaction to be sufficient to reduce the dose of omeprazole needed for an optimal effect.

Emergency post-coital contraception Data on experience with emergency post-coital contraception in the field emerge only very slowly, because of the fact that so much is concealed by a veil of secrecy; patients may not wish to admit to using the method and doctors may not be aware of their having used it (SEDA-27, 429). The “progestogen only” form of emergency post-coital contraception appears to share some of the problems of the progestogen-only precoital products: some 35 years after its initial introduction, the “progestogen-only pill” remains a contraceptive of limited merit, because it is less reliable than progestogen + estrogen combinations and because of the rather higher risk that any pregnancy that occurs will be ectopic. Essentially the same applies when a progestogen-only product is taken after coitus as a form of emergency contraception (the “morning after pill”). The most widely used product of this type comprises two tablets of levonorgestrel 0.75 mg, which was approved for sale in various countries in 1999. The main study available at that time related to 976 women; there were 11 failures, but all the resulting pregnancies were intrauterine. However, ectopic pregnancy has been previously reported after failure of post-coital progestogen treatment and there have been other unpublished cases among the “spontaneous reports” reaching the regulatory authorities (64Ar ). There were 12 such reports from the UK and others from the USA, New Zealand, and Sweden. There have since been three more cases of ectopic pregnancy after use of levonorgestrel for emergency contraception (65A ). It is impossible to estimate the degree of risk, but it is probably higher in women who

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have had ectopic pregnancies in the past. Regulatory authorities are now ensuring that users of emergency post-coital contraceptives are warned, through package inserts, of the possibility of ectopic pregnancy, and they should consult a physician if they have a history of ectopic pregnancy or if they start to have abdominal or pelvic pain (66r ). With the estrogen + progestogen type of emergency post-coital product (commonly norgestrel 500 micrograms + ethinylestradiol 50 micrograms) estrogenic complications can occasionally arise. Stroke has been reported after this type of oral contraception (67A , 68A ) and there were earlier isolated cases of retinal vein thrombosis (69A ) and occlusion of the right common carotid artery. For the reasons sketched above, one cannot possibly calculate the risks of emergency post-coital contraception but complications clearly do occur.

Transdermal contraception Just as with estrogens and hormone replacement therapy, it has sometimes been suggested that the metabolic effects of estrogen + progestogen contraceptives administered transdermally are qualitatively different in one way or another from those of the equivalent oral products. A study by the Johnson and Johnson company using its contraceptive patch (which delivers norelgestromin 150 micrograms and ethinylestradiol 20 micrograms to the circulation in the course of a week) was performed primarily to examine the effects on blood lipids (70c ). There was a double-blind comparison with a placebo patch. At cycles 3, 6, and 9, there were increases from baseline in high density lipoprotein cholesterol, HDL3 cholesterol, total cholesterol, and total triglycerides, and reductions in the concentrations of low density lipoprotein and HDL. These findings were very similar to those seen with oral contraceptives based on norgestimate + ethinylestradiol.

Contraceptive implants The two principal implants that release levonorgestrel, i.e. the six-capsule Norplant and

490 the two-rod Jadelle are now considered by authoritative reviewers to have essentially equal rates of drug release, pregnancy, and adverse events over 5 years of use (71R ). Adverse effects of levonorgestrel implants are similar to those observed with progestogen only and combined oral contraceptives. The risks of ectopic pregnancy, other pregnancy complications, and pelvic inflammatory disease are reduced in comparison with those in women who use copper or non-medicated intrauterine devices. The risks of gallbladder disease and frank or borderline hypertension, although small, are respectively about 1.5 and 1.8 times greater in women using levonorgestrel implants than in women not using hormonal contraception. Other serious diseases do not occur significantly more often in users of levonorgestrel implants than in women not using hormonal contraception. The great majority of levonorgestrel implant users have menstrual problems, but serious bleeding problems are not more frequent than in controls. In 16 000 women other health problems reported more frequently by users of levonorgestrel implants than by women not using hormonal contraception included skin conditions, headache, upper limb neuropathies, dizziness, nervousness, malaise, minor visual disturbances, respiratory conditions, arthropathies, weight change, anxiety, and non-clinical depression. Clinical depression is stated to be no more frequent in women using implants compared with those not using hormonal contraception (i.e. intrauterine devices or sterilization), but one must doubt this; certain women with a tendency to depression do experience triggering or aggravation of their condition with hormonal contraceptives, and it is not clear how this could differ between the various products. Problems with removing the device appear to be less frequent with Jadelle than with Norplant. Skin Three women developed severe acne vulgaris within several weeks to a few months after either insertion of a levonorgestrel IUCD (two women, aged 27 and 33 years) or subcutaneous implantation of etonogestrel (a 26-yearold woman) (72A ).

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ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) (SED-14, 1466; SEDA-25, 489; SEDA-26, 445; SEDA-27, 429)

Anastrozole and the aromatase inhibitors The development of newer antiestrogens continues in the hope of attaining a better benefit to harm balance, particularly in the adjuvant treatment of early breast cancer after the menopause (73R ). An aromatase inhibitor in the same class as letrozole, anastrozole, is regarded as a “pure anti-estrogen” (74R ) and could hold promise for breast cancer prevention, but it is still not entirely clear how unique it will prove in practice. Findings with anastrozole seem at present to be positive, as demonstrated by a first analysis of the ATAC (“Arimidex, Tamoxifen Alone or in Combination”) trial, with a median followup of 33 months and a safety analysis after as many as 37 months of treatment (75C ). The latest safety analysis seemed to confirm that endometrial cancer vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flushes all occurred less often in the anastrozole group, whereas musculoskeletal disorders and fractures continued to occur less often in the tamoxifen group. However, with no more than 3 years of follow-up data so far available, the debate about whether anastrozole has significant advantages over tamoxifen is still in full swing; proponents of anastrozole argue that it is associated with fewer adverse effects (including endometrial cancer as well as those listed above) compared with tamoxifen (76r ). These third-generation aromatase inhibitors, of which this is probably only the advance guard, could bear considerable promise if their very specific and potent endocrine effects translate into increased therapeutic benefit (77R ).

Idoxifene Idoxifene is another of the newer selective estrogen receptor modulators (SERMs), and pre-

Sex hormones and related compounds, including hormonal contraceptives

clinical data show that it has greater antiestrogenic activity than tamoxifen but lower estrogenic activity. It is not yet clear whether this affects its degree of usefulness or safety when it is used, for example, in cases of metastatic breast cancer. In comparisons of the two drugs in such patients the desired effects were similar and the incidence of adverse effects was essentially the same (78c ).

Raloxifene Raloxifene has again been reviewed (79r , 80r ). Current work seems to show an altogether positive effect of raloxifene (for example 60 mg/day) on bone metabolism and serum lipids in post-menopausal women on chronic hemodialysis, without significant adverse effects in the short term. However, even the authors of very promising work in this connection point to the difficulty in assessing the long-term safety of the treatment in such women (81C ). Longerterm work elsewhere has pointed particularly to the occurrence of thromboembolic disease, but also of hot flushes, influenza-like symptoms, peripheral edema, and leg cramps. With the exception of thromboembolism these are unpleasant rather than serious, but they still need to be recorded and studied in this very susceptible group of users. Cardiovascular The effects of raloxifene on the vascular endothelium have been studied in 19 subjects who underwent endothelial function testing at baseline and after treatment with placebo or raloxifene (60 mg/day for 6 weeks) (82c ). The findings in this small short-term study were entirely positive. Brachial artery diameter change (flow-mediated dilatation) increased 5.0% with placebo and 8.6% with raloxifene in response to a hyperemic stimulus. The ratio of AUC response to AUC reference with the use of laser Doppler measures was 1.18 for placebo and 1.28 for raloxifene. Flowmediated dilatation and AUC ratio correlated significantly. The authors concluded that raloxifene enhanced endothelial-mediated dilatation in brachial arteries and digital vessels in these women, and they discussed the drug’s possible cardioprotective effect.

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Reproductive system Raloxifene is now the subject of some massive international multicenter studies. In one of the largest it was found that, compared with combined hormone replacement therapy (with 17-beta-oestradiol 2 mg + norethisterone acetate 1 mg) 12 months of raloxifene treatment at 60 mg/day was not associated with increased endometrial thickness or uterine volume (83C ). Susceptibility factors Genetic Most clinical work with raloxifene 60 mg/day for the treatment of osteoporosis and lipid disorders in the menopause has been performed in Western populations. A multinational multicenter study in 483 Asian women (and a similar placebo control group) treated for 1 year has now confirmed that the efficacy and the adverse effects of the treatment are very similar to those in western populations (84C ). Drug interactions Estrogens Because raloxifene acts as an estrogen receptor antagonist on some genitourinary tissues, one might expect it to block the vaginal effects of local estrogen therapy. A multicenter placebo-controlled US study in 91 post-menopausal women set out to determine whether oral raloxifene (60 mg/day), such as is used to counter post-menopausal osteoporosis, might interfere with the efficacy of a low-dose estradiol-releasing vaginal ring used to relieve vaginal atrophy in women of a similar age. During the 6 months of treatment the signs of vaginal atrophy were assessed both objectively (vaginal histology and pH) and subjectively. There was no evidence of interference with local estrogen treatment (85C ). A very similar conclusion was reached In another study of a possible interaction between raloxifene 60 mg/day and a conjugated estrogen cream used locally to treat vaginal atrophy (86c ). Levothyroxine An interaction of raloxifene with levothyroxine has been described (87A ). • In a 79-year-old woman raloxifene 60 mg/day significantly interfered with the absorption of levothyroxine. The problem was observed clinically when it became necessary to raise her dose of levothyroxine progressively from 150 micrograms/day to 300 micrograms/day to maintain euthyroidism.

The interaction was later confirmed by specific testing but the mechanism is unclear.

492

Tamoxifen With evidence accumulating from major studies in several countries (88R ), there is still considerable optimism regarding the use of tamoxifen or its analogues to prevent breast cancer in high-risk groups, although the results of various studies are not consistent and much detail needs to be filled in (89C , 90C ). A short report has been published on the Italian Randomized Trial of Tamoxifen in 2700 women, which is intended to assess the success of the drug set against placebo, used in 2708 women, in preventing breast cancer in a population of hysterectomized post-menopausal women (91C ). After a median 81 months of follow-up, breast cancers had developed in 34 women in the tamoxifen group and 45 in the placebo group. The effect was highly significant in a subgroup of women considered, in the light of their reproductive and hormonal characteristics, as being at high risk of breast cancer, but was dubious in low-risk women, in whom the risk of cancer may actually have been marginally increased. However, the authors stressed that whatever usefulness the drug proves to have for this purpose must be set against Its adverse effects, such as endometrial cancer and thromboembolic complications. As currently published, the findings did not indicate the incidence of these complications in the study itself. High doses of tamoxifen are sometimes used in non-hormonal cancers, in the hope of enhancing the effect of cytostatic drugs. The question is then whether any enhancement of effect might also bring with it enhanced toxicity. In a small study in the Mayo Clinic the acceptability of using tamoxifen alongside intravenous cisplatin was examined in 15 patients with lung cancer (92CR ). Daily doses in various patients were 160 mg/m2 , 200 mg/m2 , or 250 mg/m2 for 7 days. Grade 3 anemia occurred in one patient only, at the 200 mg/m2 dose, while another patient, with an unfavorable cardiovascular history, had an embolic stroke 20 days after completing the course. On the basis of this small trial, the Clinic proposed to continue using high doses of tamoxifen alongside cisplatin in such patients. On present evidence from this and other centers, tamoxifen potentiates the cytostatic effects of cisplatin without clearly increasing the toxicity of the regimen;

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various mechanisms to explain this apparently useful interaction are being debated. Metabolism Tamoxifen has favorable effects on lipid and lipoprotein profiles, reducing concentrations of total and low-density lipoprotein cholesterol. However there is also evidence that it can cause increased serum triglyceride concentrations, which in some cases have risen dangerously. A Taiwan group has sought to determine whether this adverse effect might be avoided by using lower but still effective doses of the drug in women with early breast cancer (93C ). They found that in 115 patients with breast cancer taking tamoxifen 20 mg bd the serum triglyceride concentration rose significantly after 15 months of therapy, although the increase was only clinically dangerous (400 mg/dl or more) in 14 cases. In these patients the dose was halved to 10 mg/day, and in 10 of the 14 women the triglycerides fell markedly; in the other four they did not, and antilipemic therapy was needed. The authors did not evaluate the efficacy of lower doses, but there is some earlier literature that seems to show that efficacy is attainable at this level. Hematologic There is some evidence that one might be able to maintain the therapeutic benefits of tamoxifen in breast cancer at much lower doses (for example 1 mg/day and 5 mg/day) than those generally used (20 mg/day), thus perhaps avoiding the risks associated with thrombogenesis (94R ). In a non-randomized study, all three doses were studied in 120 women with estrogen receptor-positive breast cancer, comparing the outcome over a 4-week period with that in controls. Expression of the tumor expression marker Ki-67 fell to a similar degree in all three tamoxifen dosage groups, with no difference in the magnitude of reduction among the different dosages. Effects on various blood markers (including insulin-like growth factor-I, sex hormone-binding globulin, low-density lipoprotein cholesterol, ultrasensitive C-reactive protein, fibrinogen, and antithrombin III concentrations) were too variable to draw clear conclusions about whether the lower doses were indeed safer, but they provide a reasonable basis for further examination of the matter (95C ).

Sex hormones and related compounds, including hormonal contraceptives

Liver Tamoxifen can cause hepatic steatosis in certain patients, and the frequency and course of this complication has been studied using CT scans in 76 patients with breast cancer who took tamoxifen for 5 years (96C ). In all 29 women developed hepatic steatosis during the first 2 years, four to a severe degree. The liver:spleen ratio returned to normal within a mean of 1.2 years after the end of treatment in 23 of these women. The authors stressed that hepatic dysfunction can occur with tamoxifen, and that it is vital to differentiate the condition from hepatic metastases. Reproductive system Endometrial polyps, which not uncommonly become malignant, are the most common endometrial pathology described in association with post-menopausal tamoxifen exposure. The susceptibility factors that predispose to polyps have been sought In 64 patients with polyps (97C ). The combination of shorter tamoxifen exposure before the diagnosis of primary polyps, lower parity, lower menopausal age at the time of diagnosis of primary polyps, and greater duration of tamoxifen treatment significantly increased the risk of recurrent endometrial polyps. One additional year of tamoxifen treatment increased the risk of recurrent polyps five-fold. A Japanese study of DNA extracted from endometrial polyps in women treated with tamoxifen showed a three-fold increase in K-ras mutations compared with the incidence in cases of spontaneous endometrial hyperplasia. These findings could support the hypothesis that the endometrial polyps will prove an early indicator for the development of endometrial carcinoma in such patients (98c ). Not only can endometrial polyps that arise during tamoxifen treatment undergo malignant degeneration, but in some cases they may be the site of metastases from the original breast cancer. Such polyps must always undergo thorough histological sampling to distinguish the two possibilities. Two cases with metastases from lobular breast carcinoma to a polyp have been described (99A ). Tumorigenicity A variety of uterine tumors have been associated with tamoxifen, Levine et al have now presented what is probably the first report of Tamoxifen-associated uterine liposarcoma has now been observed in a 62year-old woman (100A ). The tumor cells were

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immunoreactive to vimentin, estrogen receptors, and S-100. Surgery was performed, but the tumor recurred 9 months later.

PROGESTOGENS (SED-14, 1468; SEDA-26, 447; SEDA-27, 433) Levonorgestrel Immunologic Hypersensitivity to steroids used for contraceptive purposes has very occasionally been reported for many years. • A 42-year-old woman who used the Mirena system to relieve heavy periods and spasmodic dysmenorrhea developed an itchy eruption on her shins on the day after insertion of the system, later spreading to her thighs, chest, and arms (101A ). A diagnosis of “autoimmune progesterone dermatitis” was made, although one is bound to wonder whether the reaction was to progesterone itself or to levonorgestrel. Treatment with glucocorticoids and antihistamines provided only temporary relief, and the Mirena system had to be removed.

Drug administration route Levonorgestrel is used in the form of an intrauterine device (for example Mirena) both as a contraceptive and to treat menorrhagia. It is effective, but critical reviewers continue to point to the need to be alert to the possible development of pain and hypermenorrhea, and to warn patients of the possibility of expulsion or perforation (102r ). In a study of the long-term acceptability of Mirena, 165 women were examined during and after 6 and 36 months of use. There were changes in menstrual bleeding pattern in 161 women (98%), with cessation or transient absence of menstruation in 75 (47%) and 14 (9%) women respectively. As in many other studies, amenorrhea was considered by most women (81%) as a welcome effect. The device had no disturbing effects on the women or their partners during sexual intercourse (103c ). The fact that the Mirena system induces intermenstrual bleeding within the first few months after insertion is puzzling. It has been suggested that it is due to changes in vascular development, and a randomized study in 48 women using hysterectomy specimens has shown that the system has a localized effect on some vessels within the superficial endometrium. The cross-sectional diameters of

494 the largest vascular lumina were significantly increased after treatment. However, there was no difference in the median values of vessel diameter or the vascular surface density (104c ). This may not necessarily be the only explanation for early intermenstrual bleeding during such treatment. Other authors have concluded that intrauterine levonorgestrel induces a decrease in expression of vascular endothelial growth factor but increased expression of adrenomedullin in the endometrial glands and stroma after 3 months of therapy (105c ). Any intrauterine device can very occasionally perforate the uterine wall and enter the peritoneal cavity. When the device releases an active pharmacological agent it is relevant to know whether this is likely to cause adhesions. An investigation in Israel looked into this issue, examining the files of all patients with an intraperitoneal intrauterine device over a twelveyear period (106c ). Eight such cases were identified, four of them involving a levonorgestrelcontaining device and four a copper intrauterine device. Laparoscopy for removal of the intrauterine device disclosed mild local peritoneal adhesions between the omentum and the pelvic organs in all cases. There was no difference between the two devices as regards the appearance of the peritoneum. These few cases suggest that the potential of the levonorgestrel system to adhere to the peritoneum is low and similar to that of the copper-bearing device. The Fibroplant system provides an alternative to Mirena; this miniature intrauterine delivery device releases levonorgestrel 14 micrograms/day and is used for hormonal substitution therapy, contraception, and treatment in peri- and post-menopausal women (107C ). A 1year study of the system in a mixed population of 141 peri- and post-menopausal women, including women with heavy or post-menopausal bleeding and women needing contraception, was too small and too heterogeneous to justify firm conclusions, and most of the women were in any case also using percutaneous 17beta-estradiol 1.5 mg/day). However, the results suggested that this regimen is well tolerated.

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in medical treatment by its synthetic analogues, because of their superior oral absorption. However, it can be administered in other ways, particularly as a vaginal suppository, and the hypothesis has long existed that it might be more effective or better tolerated than the synthetic agents. In a double-blind, placebo-controlled, randomized study a Swedish group examined the mental effects of progesterone in 36 women with climacteric symptoms (108C ). All received estradiol 2 mg/day during three 28-day cycles. Vaginal progesterone suppositories (400 or 800 mg/day) or placebo were added sequentially for 14 days per cycle. Women without a history of premenstrual syndrome had cyclical variations in both negative mood and physical symptoms while taking progesterone 400 mg/day, but not the higher dose or the placebo. Women without a history of premenstrual syndrome had more physical symptoms on progesterone treatment compared with placebo. Women with prior premenstrual syndrome reported no progesteroneinduced symptom cyclicity. The authors concluded that in women without prior premenstrual syndrome natural progesterone caused negative mood effects similar to those induced by synthetic progestogens, but the dose-effect relation was complex. Drug administration route Natural progesterone in the form of vaginal suppositories or gels is also used to provide luteal support for in vitro fertilization. Two different formulations for this purpose have been compared in 60 patients at risk of ovarian hyperstimulation (109C ). Cyclogest vaginal suppositories 400 mg bd and Crinone 8% vaginal gel od, both for 14 days were compared. Perineal irritation was reported by some 20% of patients in each group. Significantly more patients using the suppositories graded inconvenience of administration, leakage, and interference with coitus as moderate or severe.

PROGESTERONE ANTAGONISTS (SED-14, 1471; SEDA-25, 492; SEDA-26, 448; SEDA-27, 433)

Progesterone

Mifepristone

Psychological Progesterone, the physiological progestogen, has long been overshadowed

The use of mifepristone and misoprostol for termination of pregnancy was approved relatively

Sex hormones and related compounds, including hormonal contraceptives

late in the USA, and only now is American experience with this mode of treatment accumulating. With data on some 80 000 courses to hand, experience is characterized as favourable (110C ). Thirteen patients required blood transfusions, 10 were treated with antibiotics for infections, and six had a generalized allergic reaction. In 50 patients the pregnancy continued despite treatment, and in 48 of these suction curettage was carried out; 39 other patients required suction curettage for heavy or prolonged vaginal bleeding. Reproductive system Since the contraceptive properties of low-dose mifepristone result from its antiprogestogenic properties, with no effect on follicular development, the user’s endometrium remains exposed for long periods to unopposed estrogen. In 90 European and Asian (Chinese) women taking mifepristone 2 or 5 mg/day for 120 days the endometrial thickness increased significantly in the Europeans but decreased in the Asians (111C ). There were proliferative or cystic changes, with dense stroma and a significant reduction in markers of proliferation, i.e. mitotic index and Ki67 staining. It is not at all clear why the findings differed by race, although some earlier work pointed to a difference in the secretion or metabolism of estrogens between Caucasians and Chinese; the findings could also have reflected differences in body weight (and thus in relative dosage), but the absence of signs of hyperplasia or atypia led the authors to suggest that in this respect the product is safe. Tumorigenicity A rare case of a non-metastatic gestational trophoblastic tumor after induction of early abortion with mifepristone and misoprostol has been reported (112A ). • Ultrasound before induction of an abortion suggested that the pregnancy was abnormal. The abortion was successfully induced and recovery appeared normal up to day 16, after which the patient declined further surveillance and was lost to follow-up. Sixty days after the initial treatment, she presented to a hospital with a history of intermittent bleeding and underwent curettage, revealing a complete hydatidiform mole. Chemotherapy was instituted when concentrations of human chorionic gonadotrophin plateaued. Complete gonadotrophin regression occurred after three weekly injections of methotrexate, and up to the time of writing surveillance was uneventful.

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ANABOLIC STEROIDS, ANDROGENS, AND RELATED COMPOUNDS (SED-14, 1471; SEDA-25-493; SEDA-26, 449; SEDA-27, 434)

Androgen replacement therapy The concept of the andropause, demanding testosterone replacement, remains disputed. As in the case of estrogen replacement in women, there is no real doubt that a perhaps small minority of men require substitution; disagreement relates primarily to the benefit to risk balance in others. A recent thorough review of the literature has turned up much evidence for the benefit of short-term testosterone treatment in selected subjects, provided prostate cancer can be excluded, but also marked reservations regarding the safety or otherwise of longterm use. Potential risks include erythrocytosis, edema, gynecomastia, and prostate stimulation. The possibility of significantly increased risks of prostate cancer and cardiovascular disease has been considered (113R ).

Anabolic androgenic steroids Anabolic steroids should have disappeared from the drug scene at least a generation ago. Their supposed dissociation of anabolic and androgenic effects was based on a misleading animal model and was largely disproved. The benefits that they were thought to confer in conditions such as aplastic anemia and uremia were minimal or dubious, and their adverse effects were pronounced. There are still those who would argue for the use of anabolic steroids, alongside erythropoietin, in renal anemia (114r ), but this practice is now unusual. Yet as they disappeared from pharmacy shelves, the anabolic steroids began to return anew through largely surreptitious channels. The western literature on the use and effects of performance-enhancing drugs as a whole suggests that anabolic-androgenic steroids are currently used in up to 1% of women, 0.5–3% of high school girls, 1–5% of men, 1–12% of high school boys, and up to 67% of some groups of elite athletes, often alongside other agents reputed to enhance physical development or performance (115r ).

496 Psychological In the late 1980s various reports seemed to show that the use of anabolic steroids was linked to aggressive behavior and mood changes, even to the extent of inducing or potentiating violent crime (116c , 117A ). During the decade that followed, a series of other papers similarly linked high circulating concentrations of testosterone to increased degrees of aggression and related changes in mood. Undoubtedly, some of these findings are wellfounded, but one must always be alert to the fallacy that individuals with particular pre-existent personality traits might be more susceptible than others to become bodybuilders, to use anabolic steroids, or to take testosterone. This possibility remains open after the completion of a thorough study of weightlifters at various American academic centers. In 20 male weightlifters, 10 of whom were taking anabolic steroids (metandrostenolone, testosterone, and nandrolone), supranormal testosterone concentrations were associated with increased aggression (118c ). Users tended to have a greater degree of depression, agitation, psychic or somatic anxiety, hypochondriasis, and hopelessness on the Hamilton Depression Scale; on the Modified Manic State Rating Scale, users showed more talkativeness, restlessness, threatening language, irritability, and sexual preoccupation. However, the results of the Personality Disorder Questionnaire suggested that this finding, while valid, was to some extent confounded by the personality disorder profile of the steroid users. The latter showed “cluster B” personality disorder traits for antisocial, borderline, and histrionic personality disorder, significantly differing in this respect from non-users. Endocrine Although concerns regarding the risk of anabolic steroids usually relate primarily to their peripheral and organic adverse effects, the fact that serious hypothalamic-pituitary dysfunction can occur, and can be slow to recover, is often overlooked. • A 37-year-old bodybuilder developed gynecomastia and severe acne, together with headaches and weight gain. Sexual function and desire were much reduced (119A ). For two periods of 18 weeks in each year he had been taking cocktails containing methylandrostenediol, stanozolol, mesterolone, metenolone enanthate, trebolone acetate, androlone laurate, and drostanolone propionate, surely a record in anabolic steroid polypharmacy. Circulating concentrations of luteinizing

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hormone and follicle stimulating hormone were undetectable and plasma testosterone was critically low. A hypothalamic function test with LH-RH showed an inadequate response. He was treated effectively with high doses of LH-RH 200 micrograms/day for 3 days, and normal function progressively returned.

Liver It is possible that anabolic steroids might have some usefulness in treating physical wasting in cases of AIDS, but to use substances with such a potential for adverse effects in patients who are so seriously ill raises medical and ethical questions. In a double-blind placebocontrolled study in Germany, oxymetholone 50 mg bd or tds in 52 such patients for 16 weeks led to improvements in appetite and well-being and weight gain. However, there was marked derangement of liver function tests in 27% of patients taking the lower dose and 35% of those taking the higher dose (120c ). Liver damage has always been problematic with drugs in this class, and in such patients it might very well prove to outweigh any benefit on general physical state. One should add that any useful effects that may emerge in patients with HIV could just as well be obtained with plain androgens, for example small doses of testosterone (121r ). Fertility Not surprisingly, azoospermia is a classic consequence of intensive use of anabolic androgenic steroids, and it can be reflected in sterility. A well-documented case has shown that in at least some cases the condition can be reversed and fertility restored by treatment with gonadotropins (HMG and HCG) (122A ).

Danazol Cardiovascular A 42-year-old woman, with no history of smoking, had an acute myocardial infarct 2 months after she had started to take danazol 100 mg/day (123A ). There have been occasional reports of thrombosis during danazol treatment, possibly because of effects on lowdensity lipoprotein cholesterol, raised glucose concentrations, or an increase in the platelet count. It would at all events seem wise to avoid danazol in patients at particular risk of coronary artery disease.

Sex hormones and related compounds, including hormonal contraceptives

Liver Use of the very weak androgen danazol for advanced, recurrent, or persistent endometrial cancer not amenable to other means of treatment has proved disappointing. At a dose of 100 mg qds, treatment had to be withdrawn in five cases because of toxicity, four with hepatic complications (124A ). A further case of danazol-induced hepatocellular carcinoma has been reported (125A ), to add to three described before. • A 37-year-old woman with refractory idiopathic thrombocytopenic purpura, who had responded dramatically to danazol 600 mg/day after the failure of other forms of treatment, developed a multinodular well-differentiated trabeculovesicular hepatocellular tumor after 5 years. There were no metastases and no invasion of the lymph nodes, and after chemoembolization she received an orthoptic liver transplant. A year later she remained in good condition.

Testosterone Despite the availability of specific agents for the treatment of erectile dysfunction, there is continued interest in the use of testosterone in elderly men, particularly when there is evidence of hypogonadism on various fronts. The use of transdermal testosterone products, such as gels and scrotal or non-scrotal dermal patches, has become popular. Proponents of these methods claim that they have a good safety profile (126R ). Transdermal testosterone replacement certainly improves bone mass and lean body mass, reduces fat mass, and improves mood and sexual function. There are said to be no harmful effects on the prostate and lipids. Acne, polycythemia, and gynecomastia are stated to be less common with this form of therapy than with the intramuscular esters. To date these claims must be regarded with some reservations; it is not at all clear that in equieffective doses the local or topical forms of administration dissociate wanted and unwanted effects. Drug administration route Testosterone gel is certainly effective transdermally, although a report on its use in the form of AA2500 (trade name), which releases 50 or 100 mg/day, points to an unusually high incidence of local sensitivity reactions; it is not clear whether this is due to testosterone itself or to excipients absent from the placebo comparator (127c ).

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ANTIANDROGENS

(SED-14, 1475; SEDA-25, 494; SEDA-26, 451; SEDA-27, 435)

Antiandrogens are widely used for benign prostatic hyperplasia, but there is a tendency for patients to abandon treatment early. A Dutch group has sought to develop optimal treatment strategies for lower urinary tract symptoms suggestive of benign prostatic hyperplasia (128C ). Within a large general practice database all men aged 45 years and over with new diagnoses of benign prostatic hyperplasia were followed up; 26% discontinued therapy; discontinuation was not in the first place due to adverse reactions. The probability of early discontinuation was higher if the patients were primarily concerned by symptoms related to voiding, postmicturition, or storage rather than if they experienced a range of symptoms. The risk of early discontinuation was higher if patients had a normal prostate-specific antigen concentration. Older age and a higher chronic disease score protected against early treatment discontinuation. Reproductive system It is possible to reduce the incidence of gynecomastia in men taking antiandrogens by prophylactic irradiation of the breast. In a major randomized clinical study of antiandrogen use in Scandinavia, breast irradiation, generally using single-fraction electrons (12 to 15 Gy), was given to 174 (69%) of 253 patients (129C ). After 1 year physician evaluations suggested some form of gynecomastia in 71% and 28% of the non-irradiated and irradiated patients respectively, some form of breast enlargement in 78% and 44%, and some degree of breast tenderness in 75% and 43%.

Finasteride In the normal daily dose of 1 mg, which is sufficient to treat male pattern hair loss, finasteride is well tolerated over long periods. There is a very slightly higher incidence of impaired sexual function in users compared with placebo (130r ). In women too, low doses of finasteride (2.5 mg/day) are well tolerated when used to treat hirsutism (131R ). In a Spanish systematic review of the world literature there were firm conclusions about the

498 value of finasteride in reducing the symptoms of benign prostatic hyperplasia in doses that are well tolerated in all respects (132R ). A major field of use for finasteride is its long-term administration in men past middle age, in the hope of preventing prostatic cancer. However, there has been sufficient doubt about the efficacy and safety of this treatment to justify long-term, randomized, placebo-controlled comparisons, notably the Prostate Cancer Prevention Trial in the USA. In 9060 men who had participated in this trial for 7 years, taking finasteride 5 mg/day or placebo finasteride either prevented or delayed the appearance of prostatic cancer, with an overall reduction in cancer incidence of 25 percent (133C ). However, of the 757 tumors that occurred in the finasteridetreated group, no less than 37% were classified as relatively malignant (Gleason grades 7, 8, 9, or 10), whereas in the placebo group of 1068 tumors only 22% received this grading. The absolute number of high grade tumors was also rather higher in the finasteride group (n = 280) than in the placebo group (n = 237). Sexual adverse effects (reduced volume of ejaculate, erectile dysfunction, loss of libido, gynecomastia) were also significantly more common in the treated group than in those taking placebo, but in the finasteride group urinary problems, such as prostatic hyperplasia or problems with micturition, were markedly reduced. The authors suggested that “physicians can use these results to counsel men regarding the use of finasteride” but it is hard to see that it provides a simple choice. Reproductive system Reports of gynecomastia in users of finasteride continue to appear. Some of these relate to doses as low as 1 mg/day; the condition can be painful and bilateral (134A ). Sexual function Very long-term treatment of prostatic enlargement with finasteride, for example over 10 years, continues to be sufficiently well tolerated, although adverse effects, mostly relating to sexual function, do occur (135C , 136C ). The incidence and nature of these adverse effects has been well documented in The Proscar Long-term Efficacy and Safety Study (PLESS), a 4-year, randomized, double-blind, placebo-controlled trial in 3040 men, all of whom took finasteride 5 mg/day (137C ). At

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screening, 46% of all the patients reported some history of sexual dysfunction. During the first year of the study, 15% of the finasteride-treated patients and 7% of the placebo-treated patients had sexual adverse events that were considered drug related; during years 2–4, there was no between-group difference in the incidence of new sexual adverse events (7% in each group). Sexual adverse events resolved while continuing therapy in 12% of those taking finasteride and 19% of those taking placebo. The incidence of erectile dysfunction induced by finasteride is difficult to estimate, since in many users of the drug other causes are present; they include advanced age, heart disease, diabetes, hypertension, smoking, and hypercholesterolemia. Benign prostatic hyperplasia itself can also aggravate or even induce erectile dysfunction. Analysis of a questionnaire study in New Jersey suggested that such pathological factors can have a greater role in inducing erectile dysfunction than drugs such as finasteride and alpha-blockers, although the latter can clearly contribute (138c ).

Flutamide Skin Cutaneous adverse effects of flutamide, which as a whole are common, include some cases of photosensitivity. • A 70-year-old man who had taken flutamide for 4 months for prostatic carcinoma photosensitivity was associated with a positive rechallenge test (139Ar ). The authors provided evidence that this might have represented an early form of lupus erythematosus. The theory was supported by histology and by the fact that in the literature there is at least one case of flutamide-induced lupus.

Combined androgen deprivation treatment Hematologic The use of androgen blockade in the treatment of prostatic cancer is, at least for a period, highly effective, but it commonly causes anemia or aggravates the anemia that is often already present in such patients. The onset and degree of the anemia in such cases has been studied in 42 patients with

Sex hormones and related compounds, including hormonal contraceptives

adenocarcinoma of the prostate, stage C, who underwent combined androgen blockage using LH-RH-A and antiandrogen treatment (leukopride acetate 3.75 mg intramuscularly every month plus oral flutamide 250 mg every 8 hours) (140c ). Patients who developed severe symptomatic anemia were treated with erythropoietin. Observations continued over 6 months. The mean hemoglobin concentration fell significantly from 14.2 g/dl at the start to 12.7 g/dl at 6 months, but there was severe and clinically evident anemia (less than 11 g/dl) in only six patients (14%). The development of severe anemia did not correlate with testosterone baseline values, age, or clinical stage. Its approach was detectable by the third month. The condition was readily correctable with recombinant erythropoietin.

MISCELLANEOUS COMPOUNDS Various pharmacological treatments for benign prostatic hyperplasia are in use, and their efficacy and safety have been reviewed (141M ). Certain alpha-adrenoceptor blockers can improve erectile function in such patients, but with one of these agents (tamsulosin) there is failure of ejaculation in some 4–18% of cases, rising to 30% with long-term use.

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In addition, treatment with the 5-alphareductase inhibitor finasteride is associated with problems with ejaculation (in an incidence here estimated at 2.1–7.7%), erection (4.9–16%), and libido (3.1–5.4%). Such significant and undesirable complications in relation to sexual function produce a well-documented negative impact on quality of life.

Tibolone

(SEDA-27, 437)

Tibolone has now been in use for some 30 years to treat bone loss in post-menopausal women, and some long-term studies (for example over 10 years) appear to have confirmed its safety and relative freedom from adverse effects (142C ). In particular there is little or no increase in thrombotic events and the incidence of breast tenderness is low. Drug interactions Two patients taking oral anticoagulants developed excessive anticoagulant activity shortly after they had begun to take a course of tibolone (143Ar ). This seems to be a specific interaction, apparently similar to that seen with more potent estrogens, and the dose of anticoagulant may need to be reduced when tibolone is taken; the problem did not seem to arise consistently with other hormone replacement formulations.

REFERENCES 1. Seiden WB, Kelly LP, Ali R. Acute intermittent porphyria associated with ovarian stimulation: a case report. J Reprod Med 2003; 48: 201–3. 2. Braude P, Rowell P, Taylor A. ABC of subfertility. Assisted conception. III—Problems with assisted conception. Ovarian hyperstimulation syndrome. Br Med J 2003; 327: 920. 3. Watanabe T. Early prediction of ovarian hyperstimulation syndrome during gonadotropin therapy by means of a damped oscillation rheometer. Biorheology 2002; 39: 767–86. 4. Gnoth C, Halbe E, Freundl G. Persistent ascites after ovarian hyperstimulation syndrome and administration of mifepristone (RU 486) for the termination of pregnancy. Arch Gynecol Obstet 2003; 268: 65–8. 5. Levinsohn-Tavor O, Friedler S, Schachter M, Raziel A, Strassburger D, Ron-El R. Coasting—what is the best formula? Hum Reprod 2003; 18: 937–40.

6. Al-Shawaf T, Grudzinskas JG. Prevention and treatment of ovarian hyperstimulation syndrome. Best Pract Res Clin Obstet Gynaecol 2003; 17: 249–61. 7. Ludwig M, Westergaard L.G, Diedrich K, Andersen CY. Developments in drugs for ovarian stimulation. Best Pract Res Clin Obstet Gynecol 2003; 17: 231–47. 8. Anonymous. Lutropin alfa: combined with follitropin for follicular development: no better than menotropin. Prescrire Int 2003; 12: 91–2. 9. Burkman R, Tang M-TC, Malone KE, Marchbanks PA, McDonald JA, Folger SG, Norman SA, Strom BL, Bernstein L, Ursin G, Weiss LK, Daling JR, Simon MS, Spirtas R. Infertility drugs and the risk of breast cancer: Findings from the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study. Fertil Steril 2003; 79: 844–851.

500 10. Saunders-Pullman R. Estrogens and Parkinson disease: neuroprotective, symptomatic, neither, or both? Endocrine 2003; 21: 81–7. 11. Berlanga C, Mendieta D, Alva G, Del Carmen Lara M. Failure of tibolone to potentiate the pharmacological effect of fluoxetine in postmenopausal major depression. J Women’s Health 2003; 12: 33– 9. 12. Andre F, Veysseyre-Balter CE, Rousset H, Descos L, Andre C. Exogenous oestrogen as an alternative to food allergy in the aetiology of angioneurotic oedema. Toxicology 2003; 185: 155–60. 13. Beiderbeck AB, Holly EA, Sturkenboom MCJM, Coebergh JW, Stricker BHCh, Leufkens HGM. No increased risk of non-Hodgkin’s lymphoma with steroids, estrogens and psychotropics (Netherlands). Cancer Causes Control 2003; 14: 639–44. 14. Al-Azzawi F, Buckler HM. Comparison of a novel vaginal ring delivering estradiol acetate versus oral estradiol for relief of vasomotor menopausal symptoms. Climacteric 2003; 6: 118– 27. 15. Simunic V, Banovic I, Ciglar S, Jeren L, Pavicic Baldani D, Sprem M. Local estrogen treatment in patients with urogenital symptoms. Int J Gynaecol Obstet 2003; 82: 187–97. 16. Rufford J, Hextall A, Cardozo L, Khullar V. A double-blind placebo-controlled trial on the effects of 25 mg estradiol implants on the urge syndrome in postmenopausal women. Int Urogynecol J Pelvic Floor Dysfunct 2003; 14: 78–83. 17. Liao E-Y, Luo X-H, Deng X-G, Wu X-P, Liao H-J, Wang P-F, Mao J-P, Zhu X-P, Huang G, Wei QY. The effect of low dose nylestriol-levonorgestrel replacement therapy on bone mineral density in women with post-menopausal osteoporosois. Endocr Res 2003; 29: 217–26. 18. Hayashi N, Wada T, Ikemoto I, Oishi Y, Suzuki H, Ueda M. Decrease in anticoagulant factors in patients with prostate cancer treated with diethylstilbestrol diphosphate. Nippon Hinyokika Gakkai Zasschi 2003; 94: 420–7. 19. Cooper L, Palmer M, Oien K. Cirrhosis with steatohepatitis following longterm stilboestrol treatment. J Clin Pathol 2003; 56: 639. 20. Bamigboye AA, Hofmeyr GJ, Morris J. Diethylstilbestrol—haunting lessons. S Afr Med J 2003; 93: 346–7. 21. Porcu G, Courbiere B, Sakr R, Carcopino X, Gamerre M. Spontaneous rupture of a firsttrimester gravid uterus in a woman exposed to diethylstilbestrol in utero: a case report. J Reprod Med 2003; 48: 744–6. 22. Blatt J, Van Le L, Weiner T, Sailer S. Ovarian carcinoma in an adolescent with transgenerational exposure to diethylstilbestrol. J Pediatr Hematol/Oncol 2003; 25: 635–6. 23. Kaweski S; Plastic Surgery Educational Foundation DATA Committee. Anti-aging medicine. Part I. Hormone replacement therapy in women. Plast Reconstr Surg 2003; 111: 935–8. 24. Gabriel-Cox K. Hormone replacement therapy and primary prevention: alas, again. Prev Cardiol 2003; 6: 61–2.

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25. Michels KB, Manson JE. Postmenopausal hormone therapy: a reversal of fortune. Circulation 2003; 107: 1830–3. 26. Grady D Postmenopausal hormones—therapy for symptoms only. New Engl J Med 2003; 348: 1835–7. 27. Cranney A, Wells GA. Hormone replacement therapy for postmenopausal osteoporosis. Clin Geriatr Med 2003; 19: 361–70. 28. MacLennan AH, Sturdee D. Is hormone therapy still an option for the management of osteoporosis? Climacteric 2003; 6: 89–91. 29. Lawton B, Rose S, McLeod D, Dowell A. Changes in use of hormone replacement therapy after the report from the Women’s Health Initiative: cross sectional survey of users. Br Med J 2003; 327: 845–6. 30. La Vecchia C. Menopause, hormone therapy and breast cancer risk. Eur J Cancer Prev 2003; 12: 437–8. 31. Verhaeghe J. Turbulent times for hormone replacement therapy: is there a way out? Gynecol Obstet Invest 2003; 56: 43–50. 32. Sanada M, Higashi Y, Nakagawa K, Tsuda M, Kodama I, Kimura M, Chayama K, Ohama K. A comparison of low-dose and standard-dose oral estrogen on forearm endothelial function in early postmenopausal women. J Clin Endocrinol Metab 2003; 88: 1303–9. 33. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419–27. 34. Gambacciani M, Genzzani AR. The study with a million women (and hopefully fewer mistakes). Gynecol Endocrinol 2003; 17: 359–62. 35. Hendrix SL. Menopausal hormone therapy informed consent. Am J Obstet Gynecol 2003; 189: S31–2; discussion S32–6. 36. Carnethon MR, Anthony MS, Cascio WE, Folsom AR, Rautaharju PM, Liao D, Evans GW, Heiss G. A prospective evaluation of the risk of QT prolongation with hormone replacement therapy: the atherosclerosis risk in communities study. Ann Epidemiol 2003; 13: 530–6. 37. Goldenberg NM, Wang P, Glueck CJ. An observational study of severe hypertriglyceridemia, hypertriglyceridemic acute pancreatitis, and failure of triglyceride-lowering therapy when estrogens are given to women with and without familial hypertriglyceridemia. Clin Chim Acta 2003; 332: 11–19. 38. Ruigomez A, Garcia Rodriguez LA, Johansson S, Wallander M-A. Is hormone replacement therapy associated with an increased risk of irritable bowel syndrome? Maturitas 2003; 44: 133–40. 39. Portman DJ, Symons JP, Wilborn W, Kempfert NJ. A randomized, double-blind, placebocontrolled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone. Am J Obstet Gynecol 2003; 188: 334–42. 40. Newcomer LM, Newcomb PA, Potter JD, Yasui Y, Trentham-Dietz A, Storer BE, Longnecker MP, Baron JA, Daling JR. Postmenopausal hormone therapy and risk of breast cancer by histologic

Sex hormones and related compounds, including hormonal contraceptives type (United States). Cancer Causes Control 2003; 14: 225–33. 41. Jernstrom H, Bendahl P-O, Lidfeldt J, Nerbrand C, Agardh C-D, Samsioe G. A prospective study of different types of hormone replacement therapy use and the risk of subsequent breast cancer: the women’s health in the Lund area (WHILA) study (Sweden). Cancer Causes Control 2003; 14: 673– 80. 42. Bulbul NH, Ozden S, Dayicioglu V. Effects of hormone replacement therapy on mammographic findings. Arch Gynecol Obstet 2003; 268: 5–8. 43. Fleming RM. Do women taking hormone replacement therapy (HRT) have a higher incidence of breast cancer than women who do not? Integr Cancer Ther 2003; 2: 235–7. 44. Gertig DM, Erbas B, Fletcher A, Amos A, Kavanagh AM. Duration of hormone replacement therapy, breast tumour size and grade in a screening programme. Breast Cancer Res Treatment 2003; 80: 267–73. 45. Fernandez E, Gallus S, Bosetti C, Franceschi S, Negri E, La Vecchia C. Hormone replacement therapy and cancer risk: a systematic analysis from a network of case-control studies. Int J Cancer 2003; 105: 408–12. 46. Miller E. Therapeutic options: an evidencebased approach to prevention and treatment of osteoporosis. Int J Fertil Women’s Med 2003; 48: 122–6. 47. Haines CJ, Yim SF, Chung TKH, Lam CWK, Lau EWC, Ng MHL, Chin R, Lee DTS. A prospective, randomized, placebo-controlled study of the dose effect of oral estradiol on bone mineral density in postmenopausal Chinese women. Maturitas 2003; 45: 169–73. 48. Lacut K, Oger E, Le Gal G, Blouch M-T, Abgrall J-F, Kerlan V, Scarabin P-Y, Mottier D. Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on Creactive protein. Thromb Haemost 2003; 90: 124– 31. 49. Post MS, Thomassen MCLGD, Van der Mooren M.J, Van Baal WM, Rosing J, Kenemans P, Stehouwer CDA. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arterioscl Thromb Vasc Biol 2003; 23: 1116–21. 50. Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogenreplacement therapy with venous thromboembolism risk. Lancet 2003; 362: 428–32. 51. Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol 2003; 41: 1358–63. 52. Henzl MR, Loomba PK. Transdermal delivery of sex steroids for hormone replacement therapy and contraception: a review of principles and practice. Reprod Med 2003; 48: 525–40. 53. Boyd RA, Zegarac EA, Eldon MA. The effect of food on the bioavailability of norethindrone and

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ethinyl estradiol from norethindrone acetate/ethinyl estradiol tablets intended for continuous hormone replacement therapy. J Clin Pharmacol 2003; 43: 52–8. 54. Bloemenkamp KWM, Helmerhorst FM, Rosendaal FR, Vandenbroucke JP. Thrombophilias and gynaecology. Best Pract Res Clin Obstet Gynaecol 2003; 17: 509–28. 55. Zahn CM, Gonzalez Jr DI, Suto C, Kennedy S, Hines JF. Low-dose oral contraceptive effects on thromboelastogram criteria and relationship to hypercoagulability. Am J Obstet Gynecol 2003; 189: 43–7. 56. Silver EA, Silver AH, Silver DS, McCalmont TH. Pseudoporphyria induced by oral contraceptive pills. Arch Dermatol 2003; 139: 227–8. 57. Ibanez L, De Zegher F. Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome. J Hum Reprod (Oxf) 2003; 18: 57–60. 58. Bork K, Fischer B, Dewald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003; 114: 294–8. 59. Althuis MD, Brogan DR, Coates RJ, Daling JR, Gammon MD, Malone KE, Schoenberg JB, Brinton LA. Hormonal content and potency of oral contraceptives and breast cancer risk among young women. Br J Cancer 2003; 88: 50–7. 60. Brinton LA, Daling JR, Liff JM, Schoenberg JB, Malone KE, Stanford JL, Coates RJ, Gammon MD, Hanson L, Hoover RN. Oral contraceptives and breast cancer risk among younger women. J Natl Cancer Inst 1995; 87: 827–35. 61. Claus EB, Stowe M, Carter D. Oral contraceptives and the risk of ductal breast carcinoma in situ. Breast Cancer Res Treat 2003; 81: 129–36. 62. Westhoff C, Morroni C, Kerns J, Murphy PA. Bleeding patterns after immediate vs. conventional oral contraceptive initiation: a randomized, controlled trial. Fertil Steril 2003; 79: 322–9. 63. Palovaara S, Tybring G, Laine K. The effect of ethinyloestradiol and levonorgestrel on the CYP2C19-mediated metabolism of omeprazole in healthy female subjects. Br J Clin Pharmacol 2003; 56: 232–7. 64. Vinson DR. Emergency contraception and risk of ectopic pregnancy: is there need for extra vigilance? Ann Emerg Med 2003; 42: 306–7. 65. Sheffer-Mimouni G, Pauzner D, Maslovitch S, Lessing J.B, Gamzu R. Ectopic pregnancies following emergency levonorgestrel contraception. Contraception 2003; 67: 267–9. 66. Harrison-Woolrych M, Woolley J. Progestogenonly emergency contraception and ectopic pregnancy. J Fam Plann Reprod Health Care 2003; 29: 5–6. 67. Sanchez-Guerra M, Valle N, Blanco LA, Combarros O, Pascual J. Brain infarction after postcoital contraception in a migraine patient. J Neurol 2002; 249: 774. 68. Hamandi K, Scolding NJ. Emergency contraception and stroke. J Neurol 2003; 250: 615–16.

502 69. Lake SR, Vernon S. Emergency contraception and retinal vein thrombosis. Br J Ophthalmol 1999; 83: 630–1. 70. Creasy GW, Fisher AC, Hall N, Shangold GA. Transdermal contraceptive patch delivering norelgestromin and ethinyl estradiol: effects on the lipid profile. J Reprod Med 2003; 48: 179–86. 71. Sivin I. Risks and benefits, advantages and disadvantages of levonorgestrel-releasing contraceptive implants. Drug Saf 2003; 26: 303–35. 72. Cohen EB, Rossen NN. Acne vulgaris bij gebruik van progestagenen in een hormoonspiraal of een subcutaan implantaat. Ned Tijdschr Geneeskd 2003; 147: 2137–9. 73. Powles TJ. Anti-oestrogenic chemoprevention of breast cancer—the need to progress. Eur J Cancer 2003; 39: 572–9. 74. Smith RE, Good BC. Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others. Endocr Relat Cancer 2003; 10: 347–57. 75. Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, Sahmoud T; the ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98: 1802–10. 76. Aapro MS, Forbes JF. Three years’ follow-up from the ATAC trial is sufficient to change clinical practice: a debate. Breast Cancer Res Treat 2003; 80: S3–11. 77. Miller WR, Jackson J. The therapeutic potential of aromatase inhibitors. Exp Opin Invest Drugs 2003; 12: 337–51. 78. Arpino G, Krishnan MN, Dinesh CD, Bardou VJ, Clark GM, Elledge RM. Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer. Ann Oncol 2003; 14: 233–41. 79. Heringa M. Review on raloxifene: profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther 2003; 41: 331–45. 80. Cosman F. Selective estrogen-receptor modulators Clin Geriatr Med 2003; 19: 371–9. 81. Hernandez E, Valera R, Alonzo E, BajaresLilue M, Carlini R, Capriles F, Martinis R, BellorinFont E, Weisinger JR. Effects of raloxifene on bone metabolism and serum lipids in postmenopausal women on chronic hemodialysis. Kidney Int 2003; 63: 2269–74. 82. Sarrel PM, Nawaz H, Chan W, Fuchs M, Katz DL. Raloxifene and endothelial function in healthy postmenopausal women. Am J Obstet Gynecol 2003; 188: 304–9. 83. Neven P, Lunde T, Benedetti-Panici P, Tiitinen A, Marinescu B, De Villiers T, Hillard T, Cano A, Peer E, Quail D, et al (89 other authors). A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol

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and norethisterone acetate. Br J Obstet Gynaecol 2003; 110: 157–67. 84. Kung AWC, Chao H-T, Huang K-E, Need AG, Taechakraichana N, Loh F-H, Gonzaga F, Sriram U, Ismail NMN, Farooqi A, Rachman IA, Crans GG, Wong M, Thiebaud D. Efficacy and safety of raloxifene 60 milligrams/day in postmenopausal Asian women. J Clin Endocrinol Metab 2003; 88: 3130– 6. 85. Pinkerton JV, Shifren JL, La Valleur J, Rosen A, Roesinger M, Siddhanti S. Influence of raloxifene on the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women. Menopause 2003; 10: 45–52. 86. Parsons A, Merritt D, Rosen A, Heath III H, Siddhanti S, Plouffe Jr L. Effect of raloxifene on the response to conjugated estrogen vaginal cream or nonhormonal moisturizers in postmenopausal vaginal atrophy. Obstet Gynecol 2003; 101: 346–52. 87. Siraj ES, Gupta MK, Reddy SSK. Raloxifene causing malabsorption of levothyroxine. Arch Intern Med 2003; 163: 1367–70. 88. Sacchini V. The European Tamoxifen Trials 2003; 6: 21–9. 89. Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, Boyle P. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003; 361: 296–300. 90. Rastogi P, Vogel VG. Update on breast cancer prevention. Oncology (Huntingdon) 2003; 17: 799– 805. 91. Veronesi U, Maisonneuve P, Rotmensz N, Costa A, Sacchini V, Raviglini R, D’Aiuto G, Lovison F, Gucciardo G, Muraca MG. Pizzichetta MA, Conforti S, Decensi A, Robertson C, Boyle P, and the Italian Tamoxifen Study Group. Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst 2003; 95: 160–5. 92. Perez EA, Gandara DR, Edelman MJ, O’Donnell R, Lauder IJ, DeGregorio M. Phase I trial of high-dose tamoxifen in combination with cisplatin in patients with lung cancer and other advanced malignancies. Cancer Invest 2003; 21: 1–6. 93. Liu C-L, Yang T-L. Sequential changes in serum triglyceride levels during adjuvant tamoxifen therapy in breast cancer patients and the effect of dose reduction. Breast Cancer Res Treat 2003; 79: 11–16. 94. Wu K, Brown P. Is low-dose tamoxifen useful for the treatment and prevention of breast cancer? J Natl Cancer Inst 2003; 95: 766–7. 95. Robertson C, Viale G, Pigatto F, Johansson H, Kisanga ER, Veronesi P, Torrisi R, Cazzaniga M, Mora S, Sandri MT, Pelosi G, Luini A, Goldhirsch A, Lien EA, Veronesi U. A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 2003; 95: 779–90. 96. Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high

Sex hormones and related compounds, including hormonal contraceptives frequency of involvement and rapid reversal after completion of tamoxifen therapy. Am J Radiol 2003; 180: 129–34. 97. Biron-Shental T, Tepper R, Fishman A, Shapira J, Cohen I. Recurrent endometrial polyps in postmenopausal breast cancer patients on tamoxifen. Gynecol Oncol 2003; 90: 382–6. 98. Hachisuga T, Miyakawa T, Tsujioka H, Horiuchi S, Emoto M, Kawarabayashi T. K-ras mutation in tamoxifen-related endometrial polyps. Cancer 2003; 98: 1890–7. 99. Houghton JP, Ioffe OB, Silverberg SG, McGrady B, McCluggage WG. Metastatic breast lobular carcinoma involving tamoxifen-associated endometrial polyps: report of two cases and review of tamoxifen-associated polypoid uterine lesions. Mod Pathol 2003; 16: 395–8. 100. Levine PH, Wei X-J, Gagner J-P, Flax H, Mittal K, Blank SV. Pleomorphic liposarcoma of the uterus. Case report and literature review. Int J Gynecol Pathol 2003; 22: 407–11. 101. Pereira A, Coker A. Hypersensitivity to Mirena—a rare complication. J Obstet Gynaecol 2003; 23: 81. 102. Anonymous. Arzneimittelnebenwirkungen aktuell. Intern Praxis 2003; 43: 405. 103. Baldaszti E, Wimmer-Puchinger B, Loschke K. Acceptability of the long-term contraceptive levonorgestrel-releasing intrauterine system Mirena: a 3-year follow-up. Contraception 2003; 67: 87–91. 104. McGavigan C.J, Dockery P, Metaxa-Mariatou V, Campbell D, Stewart CJR, Cameron IT, Campbell S. Hormonally mediated disturbance of angiogenesis in the human endometrium after exposure to intrauterine levonorgestrel. Hum Reprod 2003; 18: 77–84. 105. Laoag-Fernandez JB, Maruo T, Pakarinen P, Spitz IM, Johansson E. Effects of levonorgestrelreleasing intra-uterine system on the expression of vascular endothelial growth factor and adrenomedullin in the endometrium in adenomyosis. Hum Reprod 2003; 18: 694–9. 106. Haimov-Kochman R, Doviner V, Amsalem H, Prus D, Adoni A, Lavy Y. Intraperitoneal levonorgestrel-releasing intrauterine device following uterine perforation: the role of progestins in adhesion formation. Hum Reprod 2003; 18: 990– 993. 107. Wildemeersch D, Schacht E, Wildemeersch P. Performance and acceptability of intrauterine release of levonorgestrel with a miniature delivery system for hormonal substitution therapy, contraception and treatment in peri- and postmenopausal women. Maturitas 2003; 44: 237–45. 108. Andreen L, Bixo M, Nyberg S, SundstromPoromaa I, Backstrom T. Progesterone effects during sequential hormone replacement therapy. Eur J Endocrinol 2003; 148: 571–7. 109. Ng EHY, Miao B, Cheung W, Ho P-C. A randomised comparison of side effects and patient inconvenience of two vaginal progesterone formulations used for luteal support in in vitro fertilisation cycles. Eur J Obstet Gynecol Reprod Biol 2003; 111: 50–4.

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110. Hausknecht R. Mifepristone and misoprostol for early medical abortion: 18 months experience in the United States. Contraception 2003; 67: 463–5. 111. Baird DT, Brown A, Critchley HOD, Williams AR, Lin S, Cheng L. Effect of long-term treatment with low-dose mifepristone on the endometrum. Hum Reprod 2003; 18: 61–8. 112. Lichtenberg ES. Gestational trophoblastic tumor after medical abortion. Obstet Gynec 2003; 101: 1137–9. 113. Tan RS, Culberson JW. An integrative review on current evidence of testosterone replacement therapy for the andropause. Maturitas 2003; 45: 15– 27. 114. Navarro JF. In the erythropoietin era, can we forget alternative or adjunctive therapies for renal anaemia management? Nephrol Dial Transplant 2003; 18: 2222–6. 115. Boyce EG. Use and effectiveness of performance-enhancing substances. J Pharm Pract 2003; 16: 22–36. 116. Pope Jr HG, Katz DL Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 1988; 145: 487–90. 117. Conacher GN, Workman DG. Violent crime possibly associated with anabolic steroid use. Am J Psychiatry 1989; 146: 679. 118. Perry PJ, Kutscher EC, Lund BC, Yates WR, Holman TL, Demers L. Measures of aggression and mood changes in male weightlifters with and without androgenic anabolic steroid use. J Forensic Sci 2003; 48, 646–51. 119. Van Breda E, Keizer HA, Kuipers H, Wolffenbuttel BHR. Androgenic anabolic steroid use and severe hypothalamic-pituitary dysfunction: a case study. Int J Sports Med 2003; 24: 195–6. 120. Hengge UR, Stocks K, Faulkner S, Wiehler H, Lorenz C, Jentzen W, Hengge D, Ringham G. Oxymetholone for the treatment of HIV-wasting: a double-blind, randomized, placebo-controlled phase III trial in eugonadal men and women. AIDS 2003; 17: 699–710. 121. Dobs A. Role of testosterone in maintaining lean body mass and bone density in HIV-infected patients. Int J Impot Res 2003; 15: S21–5. 122. Menon DK. Successful treatment of anabolic steroid-induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Fertil Steril 2003; 79: 1659–61. 123. Boos CJ, Dawes M, Jones R, Farrell T. Danazol treatment and acute myocardial infarction. J Obstet Gynecol 2003; 23: 327–8. 124. Covens A, Brunetto VL, Markman M, Orr Jr JW, Lentz SS, Benda J. Phase II trial of danazol in advanced, recurrent, or persistent endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2003; 89: 470–4. 125. Confavreux C, Seve P, Broussolle C, Renaudier P, Ducerf C. Danazol-induced hepatocellular carcinoma. Quart J Med 2003; 96: 317–18. 126. Basaria S, Dobs AS. New modalities of transdermal testosterone replacement. Treatments Endocrinol 2003; 2: 1–9.

504 127. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003; 88: 2673–8. 128. Verhamme KMC, Dieleman JP, Bleumink GS, Bosch JLHR, Stricker BHCh, Sturkenboom MCJM. Treatment strategies, patterns of drug use and treatment discontinuation in men with LUTS suggestive of benign prostatic hyperplasia: the Triumph project. Eur Urol 2003; 44, 539–45. 129. Widmark A, Fossa SD, Lundmo P, Damber J-E, Vaage S, Damber L, Wiklund F, Klepp O. Does prophylactic breast irradiation prevent antiandrogen-induced gynecomastia? Evaluation of 253 patients in the randomized Scandinavian trial SPCG-7/SFUO-3. Urology 2003; 61: 145–51. 130. Whiting DA, Olsen EA, Savin R, Halper L, Rodgers A, Wang L, Hustad C, Palmisano J. Efficacy and tolerability of finasteride 1 mg in men aged 41 to 60 years with male pattern hair loss. Eur J Dermatol 2003; 13, 150–60. 131. Bayram F, Muderris I, Guven M, Ozcelik B, Kelestimur F. Low-dose (2.5 mg/day) finasteride treatment in hirsutism. Gynecol Endocrinol 2003; 17: 419–22. 132. Jimenez Cruz JF, Quecedo Gutierrez L, Del Llano Senaris J. Finasterida: Diez anos de uso clinico. Revision sistematica de la literatura. Actas Urol Esp 2003; 27: 202–15. 133. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman Jr CA. The influence of finasteride on the development of prostate cancer. New Engl J Med 2003; 349: 215– 24. 134. Kim BJ, Kim YJ, Ro BI. Two cases of reversible bilateral painful gynecomastia induced by 1 mg oral finasteride (Propecia). Korean J Dermatol 2003; 41: 232–4. 135. Lam JS, Romas NA, Lowe FC. Long-term treatment with finasteride in men with symptomatic

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benign prostatic hyperplasia: 10-year follow-up. Urology 2003; 61: 354–8. 136. Lowe FC, McConnell JD, Hudson PB, Romas NA, Boake R, Lieber M, Elhilali M, Geller J, Imperto-McGinely J, Andriole GL, Bruskewitz RC, Walsh PC, Bartsch G, Nacey JN, Shah S, Pappas F, Ko A, Cook T, Stoner E, Waldstreicher J. Longterm 6-year experience with finasteride in patients with benign prostatic hyperplasia. Urology 2003; 61: 791–6. 137. Wessells H, Roy J, Bannow J, Grayhack J, Matsumoto AM, Tenover L, Herlihy R, Fitch W, Labasky R, Auerbach S, Parra R, Rajfer J, Culbertson J, Lee M, Bach MA, Waldstreicher J. Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia. Urology 2003; 61: 579–84. 138. Sadeghi-Nejad H, Sherman N, Lue J. Comparison of finasteride and alpha-blockers as independent risk factors for erectile dysfunction. Int J Clin Pract 2003; 57: 484–7. 139. Kaur C, Thami GP. Flutamide-induced photosensitivity: is it a forme fruste of lupus? Br J Dermatol 2003; 148: 603–4. 140. Bogdanos J, Karamanolakis D, Milathianakis C, Repousis P, Tsintavis A, Koutsilieris M. Combined androgen blockade-induced anemia in prostate cancer patients without bone involvement. Anticancer Res 2003; 23: 1757–62. 141. Carbone Jr DJ, Hodges S. Medical therapy for benign prostatic hyperplasia: Sexual dysfunction and impact on quality of life. Int J Impot Res 2003; 15: 299–306. 142. Rymer J, Robinson J, Fogelman I. Tiz even keresztul naponta 2.5 mg dozisban adagolt tibolon hatasa a csontvesztesre postmenopauzas nokben. Magyar Nöorvosok Lapja 2003; 66: 101–8. 143. McLintock LA, Dykes A, Tait RC, Walker ID. Interaction between hormone replacement therapy preparations and oral anticoagulant therapy. Br J Obstet Gynaecol 2003; 110: 777–9.

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Thyroid hormones and antithyroid drugs

THYROID HORMONES (SED-14, 1485; SEDA-25, 503; SEDA-26, 45; SEDA-27, 442) Thyroid hormones are among the most commonly prescribed drugs in the developed world, with a prevalence of prescription of 5–10% in the over 60 age group (1c , 2c ). Since about 25% of those who use thyroxine (T4) take doses sufficient to suppress serum TSH (2c , 3C ), much attention has focussed on potential adverse effects of this degree of over-treatment. Musculoskeletal Many studies have examined the effect of thyroxine in TSH-suppressive doses on measurements of bone mineral density. A meta-analysis of such studies has suggested a small but statistically significant adverse effect on bone mineral density, especially in post-menopausal women (4M ). However, few studies have examined the effect of thyroxine on the clinically relevant end-point, fractures. A case-control study has examined the association between the use of thyroid hormone and hip fractures in women aged 65 years and over: 501 women with hip fractures in Northern California and 533 age-matched controls without hip fractures (5c ). There was no difference in the ever use or duration of use of exogenous thyroid hormone between cases and controls (OR = 1.1, 95% CI = 0.8, 1.6), although hip fractures were associated with visual impairment, prior use of glucocorticoids, and falls, as might be expected. These findings are in agreement with the results of another study of hip fracture rates in a large number of subjects in the UK taking thyroxine with those not taking © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

thyroxine (6C ). There was no association between the use of thyroxine and the occurrence of fractures in women, although there was an independent association in the smaller number of men taking thyroxine. Overall, these data are reassuring, given the prevalence of thyroxine prescription, especially among women. Immunologic Hypersensitivity reactions to thyroid hormones have not been convincingly reported. • A patient with a history of an immediate, severe, hypersensitivity reaction at the start of thyroxine therapy subsequently developed a systemic reaction after open challenge with thyroxine (7A ). Later blinded challenges with both intravenous and oral thyroxine were uneventful, and the final diagnosis was psychogenic vocal cord dysfunction.

This case illustrates the need to verify apparently severe reactions to thyroxine, since such reactions are physiologically unlikely, given that exogenous thyroxine is structurally identical to that produced endogenously. Drug interactions Many patients using thyroid hormones take other medications, but the incidence of important drug interactions appears to be relatively low. It is well recognized that estrogens and selective estrogen receptor modulators, such as tamoxifen citrate and raloxifene hydrochloride, can affect tests of thyroid function by their ability to increase the serum concentration of thyroxine binding globulin, leading to a rise in serum concentrations of total thyroxine and triiodothyronine (T3), although serum free T4, free T3, and TSH concentrations remain unchanged. However, in subjects with treated hypothyroidism it has been reported that exogenous estrogen, given as hormone replacement therapy, can lead to increased thyroxine dosage requirements (8C ).

505

506 • A 79-year-old woman taking long-term thyroxine 150 micrograms/day developed a raised TSH and symptoms of hypothyroidism after the introduction of raloxifene hydrochloride 60 mg/day for osteopenia (9A ). Ingestion of thyroxine and raloxifene at the same time resulted in biochemical hypothyroidism, but not if ingestion they were separated by 12 hours. A 6-hour absorption test showed blunting of the rise in serum total thyroxine after ingestion of 100 micrograms of thyroxine co-administered with raloxifene.

While an effect of raloxifene on circulating thyroxine-binding globulin is well recognized, this case suggests an additional effect on thyroxine absorption.

IODINE Health Canada has advised consumers against using some products containing iodine (SEAVITE Premium Atlantic Kelp tablets), since these products, when consumed according to the label instructions, can provide 25 times the recommended daily allowance (RDA) of iodine for adults; this could lead to serious adverse health consequences (10S ). The RDA for iodine ranges from 90 micrograms/day for children aged 1–8 years to 150 micrograms/day for adults. Excessive iodine intake could lead to thyroid disorders and in turn to heart problems. Three reports of serious adverse events have been associated with the use of these products; one patient required hospitalization. The excessive iodine can cause hypothyroidism or hyperthyroidism. Individuals who are especially sensitive to the toxic effect of excess iodine include fetuses, children of all ages, pregnant women, breast fed babies, and people who are or have been those under supervision for thyroid disease. Anyone taking amiodarone may also be at increased risk.

ANTITHYROID DRUGS (SED-14, 1489; SEDA-25, 503; SEDA-26, 458; SEDA-27, 442) Hematologic Drug-induced agranulocytosis is a life-threatening disorder with a mortality of 5–15%. Outcomes have been reported in a consecutive series of 91 patients hospitalized

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with non-chemotherapy drug-induced agranulocytosis from 1985–2000 (11c ). All but two survived. Antithyroid drugs were the cause of agranulocytosis in 20% of cases. Univariate and multivariate analyses failed to reveal a specific effect of antithyroid drugs on the time to neutrophil recovery. In contrast, hemopoietic growth factor treatment was associated with speedier hematological recovery. In a study in the UK drug prescribing data recorded on the General Practice Research Database were used to identify the incidences of idiosyncratic neutropenia and agranulocytosis in England and Wales, which were estimated to be 120 and 7 cases per million per year respectively (12C ). Current users of drugs classed as “thyroid inhibitors” had the highest adjusted odds ratios for neutropenia (adjusted OR = 35; 95% CI = 12–100) and for agranulocytosis (OR = 21; 95% CI = 3.3–∞) compared with other classes of drug associated with this complication. The increase in risk of neutropenia was highest in those who had received two or three prior prescriptions (OR = 58; 7.4, 454), compared with one prior prescription (OR = 14; 1.6, 119) or those who had received four or more prior prescriptions (OR = 34; 7.7, 154). The increased risk of neutropenia specifically associated with carbimazole was higher in those who were taking 20 mg/day or more (OR = 33; 8.0, 136), compared with those taking 5–15 mg/day (OR = 17; 4.2, 72). These findings support the view that agranulocytosis is the most important complication of antithyroid drugs (remembering that neutropenia may in part reflect underlying hyperthyroidism rather than an adverse drug reaction), and extrapolation of data from those with neutropenia confirms a dose relation in terms of risk. Liver Both carbimazole and propylthiouracil can cause liver damage. Two further cases of fatal fulminant hepatic failure have been described in previously healthy women aged 30 and 32 years who presented with jaundice 4 and 5 months respectively after starting to take propylthiouracil for Graves’ hyperthyroidism (13A ). Another case of fatal fulminant liver failure with cholestatic jaundice 2 weeks after the start of treatment with propylthiouracil 100 mg tds has been described (14A ).

Thyroid hormones and antithyroid drugs

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Teratogenicity The issue of whether antithyroid drug administration in early pregnancy is associated with congenital abnormalities remains unclear. Aplasia cutis congenita and choanal atresia have been reported in association with maternal carbimazole therapy, suggesting a causative link either with the drug or with underlying hyperthyroidism. • Choanal atresia with scalp aplasia cutis, umbilical hernia, sacral pilonidal sinus, limb hypertonia, and down-slanting palpebral fissures affected the child of a woman who took methimazole 10 mg/day until the 8th week of gestation (15A ). • Aplasia cutis affected one of twin boys born to a mother with Graves’ disease, drug addiction, and psychosis, who had taken methimazole 40 mg/day, propranolol, and haloperidol (with poor compliance) (15A ). • Fatal gastroschisis occurred in a child born to a mother who had taken high-dose carbimazole (60 mg/day) during the first trimester of pregnancy (16A ).

These cases highlight a possible link between carbimazole, or its active metabolite methimazole, and congenital abnormalities, especially aplasia cutis and choanal atresia, and suggest that propylthiouracil should be the drug of choice in early pregnancy.

IODINE AND THE IODIDES (SED-14, 1492; SEDA-25, 505; SEDA-26, 459) Complications of iodine applied to the skin are well recognized and reflect absorption through the skin, especially in neonates. Two case reports have highlighted the fact that, even in adults, topical administration of povidone iodine can be associated with serious toxicity. • A 45-year-old man with mediastinitis and renal and hepatic dysfunction was treated with mediastinal irrigation with povidone iodine (17A ). He developed toxic plasma iodine concentrations and clinical deterioration; hemodialysis and hemofiltration were effective in reducing plasma iodine concentrations. • A 68-year-old man was treated for a subcutaneous infection of the thigh by subcutaneous irrigation with povidone iodine (18A ). Toxic plasma and urinary iodine concentrations were associated with abnormalities of cardiac conduction, lactic acidosis, acute renal insufficiency, hypocalcemia, and thyroid dysfunction.

These cases suggest that topical povidone iodine should be used with caution in patients in whom significant absorption can occur, especially in the presence of renal impairment.

REFERENCES 1. Kaufman SC, Gross TP, Kennedy DL. Thyroid hormone use: trends in the United States from 1960 through 1988. Thyroid 1991; 1: 285–91. 2. Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract 1993; 43: 107–9. 3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160: 526–34. 4. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 1996; 81: 4278–89. 5. Van Den Eeden SK, Barzilay JI, Ettinger B, Minkoff J. Thyroid hormone use and the risk of hip fracture in women > or = 65 years: a case-control study. J Womens Health (Larchmt) 2003; 12: 27– 31. 6. Sheppard MC, Holder R, Franklyn JA. Levothyroxine treatment and occurrence of fracture of the hip. Arch Intern Med 2002; 162: 338–43.

7. Nugent JS, Nugent AL, Whisman BA, White K, Hagan LL. Levothyroxine anaphylaxis? Vocal cord dysfunction mimicking an anaphylactic drug reaction. Ann Allergy Asthma Immunol 2003; 91: 337–41. 8. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. New Engl J Med 2001; 344: 1743–9. 9. Siraj ES, Gupta MK, Reddy SS. Raloxifene causing malabsorption of levothyroxine. Arch Intern Med 2003; 163: 1367–70. 10. Anonymous. Iodine. Some products contain more than the RDA. WHO Pharm Newslett 2003; 3: 2. 11. Maloisel F, Andres E, Kaltenbach G, Noel E, Koumarianou A. Prognostic factors of hematologic recovery in nonchemotherapy drug-induced agranulocytosis. Haematologica 2003; 88: 470–1. 12. Van Staa TP, Boulton F, Cooper C, Hagenbeek A, Inskip H, Leufkens HG. Neutropenia and agranulocytosis in England and Wales: incidence and risk factors. Am J Hematol 2003; 72: 248–54.

508 13. Ruiz JK, Rossi GV, Vallejos HA, Brenet RW, Lopez IB, Escribano AA. Fulminant hepatic failure associated with propylthiouracil. Ann Pharmacother 2003; 37: 224–8. 14. Chan AO, Ng IO, Lam CM, Shek TW, Lai CL. Cholestatic jaundice caused by sequential carbimazole and propylthiouracil treatment for thyrotoxicosis. Hong Kong Med J 2003; 9: 377–80. 15. Ferraris S, Valenzise M, Lerone M, Divizia MT, Rosaia L, Blaid D, Nemelka O, Ferrero GB, Silengo M. Malformations following methimazole exposure in utero: an open issue. Birth Defects Res A Clin Mol Teratol 2003; 67: 989–92.

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16. Guignon AM, Mallaret MP, Jouk PS. Carbimazole-related gastroschisis. Ann Pharmacother 2003; 37: 829–31. 17. Kanakiriya S, De Chazal I, Nath KA, Haugen EN, Albright RC, Juncos LA. Iodine toxicity treated with hemodialysis and continuous venovenous hemodiafiltration. Am J Kidney Dis 2003; 41: 702–8. 18. Labbe G, Mahul P, Morel J, Jospe R, Dumont A, Auboyer C. Intoxication a l’iode apres irrigations sous-cutanées de povidone iodée. Ann Fr Anesth Reanim 2003; 22: 58–60.

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42

Insulin, glucagon, and oral hypoglycemic drugs

INSULIN

(SED-14, 1501; SEDA-25, 507; SEDA-26, 461; SEDA-27, 446) Sensory systems Acute angle closure glaucoma has been reported as rare complication of rapid insulin therapy for hyperglycemic nonketotic coma (1A ). It was postulated that raised glucose concentrations in the lens leads to increased sorbitol and water influx. The osmotic changes in the lens are not immediately corrected when the glucose concentration in aqueous humor is lowered, and this can lead to obstruction of the canal of Schlemm and increased intraocular pressure. Metabolism Hypoglycemia Autoimmune insulin hypoglycemia is rare, and is most often seen in East Asia. Patients have low concentrations of insulin and C-peptides, but insulin can be released from the insulin antibody complex or receptor antibodies can stimulate the message in the receptor.

• A 72-year-old woman with type 2 diabetes was treated with insulin but developed repeated attacks of hypoglycemia, with blood glucose concentrations below 2.2 mmol/l (2A ). She stopped taking insulin, but the attacks continued, causing disorientation, loss of consciousness, palpitation, and sweating. Her HbA1c concentration was raised at 6.3%. There were insulin antibodies 58% and also insulin receptor antibodies. Treatment with prednisone and glucose tablets resolved the hypoglycemic episodes within 48 hours.

Therapy with high-dose glucocorticoids, plasmapheresis, and alkylating agents produces variable results. The frequency and nature of episodes of hypoglycemia have been quantified in a retrospective survey of 215 patients with type 2 © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

diabetes treated with insulin (3C ). More than 90% used a mixture of short-acting or rapidacting insulin plus an intermediate acting insulin twice daily, six used NPH insulin twice daily, and 13 used three or more injections per day. In the preceding year 32 of them had 60 periods of severe hypoglycemia (requiring assistance), 0.28 episodes/patient/year. One patient with 13 episodes had impaired awareness. The frequency increased with age, duration of insulin therapy, and duration of diabetes, but not with a lower concentration of HbA1c or a higher dose of insulin. There was mild hypoglycemia in 64%. In those with mainly autonomic symptoms the occurrence of symptoms was inversely related to age. The neuroglycopenic symptoms were more frequent with increasing duration of insulin therapy. Hypoglycemia can cause dysesthesia. • A 26-year-old woman had numbness and tingling in her hands and feet on awakening (4A ). They were most pronounced in the hands and resolved within minutes. Her insulin regimen had recently been changed from NPH 50 U in the morning to 35 NPH and 5 regular in the morning and 8 NPH and 5 regular before dinner. The morning glucose concentrations averaged 3.3 mmol/l. One month after reducing the dose of insulin the symptoms of hypoglycemic neuropathy had disappeared and low morning glucose concentrations were rare.

Hypoglycemic neuropathy has also been described in association with an insulinoma (5c ). Liver When giving insulin for diabetic ketoacidosis an increase in liver enzymes can occur. These patients have often higher concentrations of HbA1c , glucose, and triglycerides, need more insulin, and have more fat disposition in the liver during treatment of the acute phase (6C ). Hepatic dysfunction can contribute to insulin edema.

509

510 • A 68-year-old woman developed marked insulin insensitivity during acute liver dysfunction due to autoimmune hepatitis treated with prednisolone 40 mg/day (7A ). Her recently diagnosed diabetes had been treated with diet only and her HbA1c was 6.2%. Prednisolone reversed her anorexia and general malaise and improved her liver function tests. However, even 112 units of insulin per day could not control her blood glucose adequately, notwithstanding the fact that she was producing a substantial amount of her own insulin (C peptide excretion in the urine was 70 µg/day). She gained 8.5 kg in weight and developed pitting edema, pleural effusions, and ascites. Diuretic therapy and salt restriction eliminated fluid retention and restored insulin sensitivity in 4 weeks.

Immunologic Skin reactions to insulin are rare and treatment is complicated. • A 21-year-old woman with a history of allergy, in whom coconuts and penicillin had caused laryngeal edema, had uncontrolled diabetes and subcutaneous allergy for insulin (8A ). Treatment with an antihistamine was not effective. Intradermal tests with animal and human insulins, regular and NPH insulins, and protamine were all positive. No rapid-acting analogues were tested. Gradual desensitization with small doses of insulin was impossible, as she needed larger doses for metabolic control. When she was given a pump with insulin lispro, used food with a low glycemic index, and temporarily increased basal infusion rates instead of pre-meal boluses, no reactions were seen. HbA1c fell from 13.5% to 8.2% after 3 months and 7.5–8.0% after 6 months. She had only two minor episodes of hypoglycemia. • A 64-year-old man with type 2 diabetes used premixed regular and NPH insulin and after 14 months noticed local wheal-and-flare reactions accompanied by sweating and slight dyspnea for 1 hour (9A ). Notwithstanding treatment with an antihistamine his symptoms became worse. Glibenclamide and metformin caused abnormal liver function tests. Rapid-acting analogues, regular insulin, NPH insulin, and insulin-like growth factor-I gave positive reactions on intradermal testing. Crystalline zinc insulin (Novolin® U), which contains no monomeric insulin, gave no reaction. However, the first subcutaneous injection of zinc insulin provoked an itchy wheal-and-flare reaction within 10 minutes and lasted for 1 hour. The addition of prednisolone 0.07 mg per unit of insulin, starting with a low dose and increasing the dose every other day, produced improvement. When a dose of 34 U/day was reached regulation was still not optimal. Glimepiride 6 mg/day improved HbA1c to below 7.0% and the prednisolone was tapered. With insulin 30 U/day and glimepiride 6 mg/day he remained well regulated.

It may be that the exposure time to monomeric insulin plays a role in allergic effects. Pumps

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with extra short acting insulin give a short contact of monomeric insulin with the body. The same may be true for zinc insulin; the released monomers are only for a short period in the circulation. Infection risk The risk of infection from insulin injection sites is small, but infections can give problems in diagnosis and treatment, especially when they are atypical. • A 43-year-old woman with a 23-year history of poorly controlled diabetes (HbA1c 14%) developed abscesses at injection sites on the thighs and abdomen (10A ). Repeated treatment with flucloxacillin had no effect and cultures were sterile. From aspirated pus, cultured for 6 weeks, Mycobacterium chelonae was isolated and clarithromycin and ciprofloxacin were effective.

Repeated episodes of catheter obstruction by fibrin clots or omental encapsulation can be a problem during continuous peritoneal insulin infusion from implanted pumps (SEDA 20, 397). In the encapsulated tissue, collagen fibrosis, inflammatory reactions with lymphocytes, and amyloid-like deposits reacting to antiinsulin antibodies can occur; higher macrophage chemotaxis may also promote these processes. • A 54-year-old woman and a 62-year-old man with catheter blockages both developed aseptic peritonitis (11A ). In both cases clots had earlier been removed by laparoscopy, which also showed diffuse thickening around the tip and in the peritoneal fat, with fluid accumulation or inflammation and whitish urticaria-like plaques. The tissue was granulomatous, with histiocytes, fibrosis, and pseudoamyloid material that could not be labeled by anti-insulin antibodies. The peritoneal fluid contained a lot of fibrin, monocytes, lymphocytes, and macrophages, but no bacteria or cancer cells.

Drug misuse Some body-builders misuse insulin to manipulate the effects of diet. • A 31-year-old healthy man who used insulin as an adjunct for body-building became unconscious (12A ). His blood glucose was 0.6 mmol/l and he had a respiratory acidosis and dehydration. He recovered with 50 ml of intravenous dextrose 50%. He admitted that he used insulin three times per week and glucocorticoids to support his diet before competitions. This time he had used a fast-acting insulin.

Drug tolerance Insulin-induced lipohypertrophy can cause reduced efficacy of insulin, which should prompt review of injection technique and injection sites (13A ).

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Drug administration route Continuous subcutaneous insulin infusion Continuous subcutaneous insulin infusion (CSII) often gives a better quality of life (14c ). There has been a systematic review of 11 studies of at least 10 weeks duration, comparing soluble insulin with the analogs lispro and, in one case, aspart in pumps (15M ). The analog produced a small, significant improvement in HbA1c . There were no differences in hypoglycemia. Ketosis, hyperglycemia, and clogging were not common. In 132 patients with type 2 diabetes using insulin randomly assigned to continuous subcutaneous insulin infusion (with insulin aspart) or multiple daily injections of insulin aspart and NPH insulin for 16 weeks, after 8 weeks training to establish optimal dosages (16C ) there were more episodes of hyperglycemia (blood glucose over 19.4 mmol/l) with multiple daily injections. HbA1c was identical. Most of the patients who expressed a view (93%) wanted to stay on the pump. In 40 patients aged 4–25 years with type 1 diabetes who were given continuous subcutaneous insulin infusion for 6 months the number of episodes of hypoglycemia was reduced by a half (17C ). There were two episodes of diabetic ketoacidosis. In 10 patients lipohypertrophy developed at the insertion site and three patients had signs of skin redness, which improved with local antibiotic treatment. Continuous subcutaneous insulin infusion in 23 children, aged 9.4–13.9 years, was compared with multiple daily insulin injections in a randomized crossover study of two periods of 3.5 months (18C ). Insulin dosage requirements fell during continuous infusion and increased with multiple injections. Episodes of mild diurnal and nocturnal hypoglycemia were the same. There was one severe episode of nocturnal hypoglycemia during continuous infusion and three (two nocturnal) during multiple injections. Diabetic ketoacidosis did not occur; episodes of mild ketosis were related to problems with infusion sets. There were 12 minor infections at infusion sites, 16 blockages, and 42 dislodgements. Three patients developed intercurrent infections, two during continuous infusion and one during injection therapy. • A 56-year-old man was given a continuous subcutaneous insulin infusion because of frequent

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episodes of hypoglycemia of which he was unaware and he had four separate episodes of profound ketoacidosis (19A ). Multiple daily injections produced less flexibility in his mealtimes, more episodes of hypoglycemia, and the need for more injections. However, injecting 60% of his basal needs as insulin glargine once daily in combination with continuous subcutaneous infusion prevented further episodes of diabetic ketoacidosis.

Non-injection routes Non-invasive insulin delivery is still experimental. The various methods (transdermal, nasal, lungs, oral) have been reviewed, with special attention to the various techniques and administration of inhaled insulin, which seems the most promising alternative to injection (20R , 21R ). Inhalation In the AERx® insulin diabetes management system liquid insulin droplets are delivered from an insulin strip to the deep lung only during precise predefined inspiratory flow and volume. In 107 patients with type 2 diabetes randomly assigned during 12 weeks to inhaled fast-acting insulin or subcutaneous fastacting insulin before meals, both with evening NPH insulin the change in HbA1c was identical (22C ). Inhaled insulin caused hypoglycemia in three cases, compared with no episodes in those using injections. Pulmonary function tests were not consistently altered. Breath holding after inhalation for 0, 3, or 10 seconds had no effect on the pharmacokinetics or pharmacodynamics of inhaled insulin (23c ). Oral When variable amounts of insulin (50, 100, 135, or 150 units) were given to healthy volunteers in capsules containing SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) 700 mg insulin was absorbed in the proximal part of the gut (24c ). SNAC had no adverse effects in animals and a single dose of 2800 mg in was not problematic in healthy volunteers during follow-up for 8 weeks. Drug formulations Stability of insulin solutions Two patients, who measured their blood glucose concentration four times a day and used glargine (Lantus® ) insulin bottles for 2 months and 40 days respectively, observed that in the last 25% of the bottles the activity of the insulin was reduced (25S ). This prompted an enquiry at the manufacturers about the stability of their products. Insulin loses up to 1% of its potency over 30 days when stored at room temperature

512 but only up to 0.03% when refrigerated. No insulin should ever be frozen; it must than be discarded. Unopened vials can be kept for at least 24 months when stored at 2–8◦ C. When kept in an open vial, of which some insulin was taken out every day and kept at 5 or 25◦ C, insulin met all stability criteria after 28 days. After that time it is recommended that insulin be discarded. Prefilled syringes kept at 5◦ C became turbid in 2–3 days depending on the type of syringe. Lantus® (Aventis) should always be kept out of the light. Other manufacturers, such as Lilly and NovoNordisk advise keeping unopened vials and cartridges refrigerated (at 2–8◦ C). They can than be used until the expiry date. Vials and pens in use should be kept at room temperature to prevent local injection site reactions to cold insulin. The maximum-use period for opened vials and pen syringes is 28– 30 days. For the mix Flex pen, which contains 70% insulin aspart protamine and 30% insulin aspart, the maximal period is 14 days. The 2003 guidelines of the American Diabetes Association state that if uncertain over the potency of insulin in a vial, that vial should be replaced with another of the same type (26S ). Drug interactions Alcohol and hypoglycemia have additive effects on cognitive performance. This makes it even more important that people with type 1 diabetes refrain from alcohol when driving (27r ). Thiazolidinediones When thiazolidinediones are combined with insulin, edema can develop if there is cardiac dysfunction (28S ). Recreational drugs In London an anonymous confidential postal questionnaire was sent to 158 young adults (15–30 years) attending an urban diabetes clinic (29c ). Of 85 respondents 25 admitted using street drugs; 12 told their friends or performed extra blood tests. Only 23% of the users and non-users were aware of effects of recreational drugs on diabetes. Two had become hypoglycemic after cannabis and two had developed ketoacidosis after using ecstasy and cannabis. Street drugs affect diabetes in various ways. Amphetamines stimulate catecholamine release. Ecstasy creates a syndrome of inappropriate antidiuretic hormone release (hyponatremia and cerebral edema). Cocaine causes hyperglycemia via α-adrenoceptors. Withdrawal of opiates can cause ketoacidosis.

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NEW ULTRASHORT-ACTING INSULINS (SED-14, 1506; SEDA-25, 509; SEDA-26, 463; SEDA-27, 449) Metabolism Hypoglycemia In a comparison of insulin lispro and soluble insulin during a crossover study over 24 weeks in prepubertal children (7–11 years), there were no differences in HbA1c or mean insulin doses (30C ). Insulin lispro produced a lower mean blood glucose concentration in the evening (18–22 hours), higher blood glucose in the early night (22–04 hours), and later identical concentrations. Episodes of hypoglycemia were most frequent in the afternoon and less than half occurred at night. They were less frequent with insulin lispro, but this was not statistically significant. In 42 children (aged 6–12 years) and 34 adolescents (aged 13–17 years) in two crossover periods of 6 weeks there was no difference in fructosamine or HbA1c concentrations; only blood glucose 2 hours after breakfast was significantly lower in the postprandial period (31C ). The risk of hypoglycemia was not different and there were no differences between the age groups. In a 6-month comparison of three times daily regular insulin + NPH at night versus premeal insulin lispro + NPH at lunch and at night, HbA1c fell more in the second group and glucose concentrations 2 hours after a meal were lower (32C ). The frequencies of episodes of hypoglycemia were not significantly different. • A 42-year-old woman and a 39-year-old woman who were transferred from preprandial regular insulin to insulin lispro, without a reduction in the total dose of insulin, developed postprandial hypoglycemia (33A ).

This has been reported before (SEDA-22, 475). Lipodystrophy Lipoatrophy due to insulin lispro during pump therapy has been reported before (SEDA-25, 510; SEDA-27, 449). • A 35-year-old woman transferred from regular insulin to insulin lispro, as she had developed unawareness of hypoglycemia (34A ). After 23 months she developed a circumscribed area of lipoatrophy about 3 cm in diameter at an injection site on the right thigh. Her anti-insulin antibodies were

Insulin, glucagon, and oral hypoglycemic drugs

Chapter 42

high (50%). Six months later incipient lipoatrophy was seen in the same area in the contralateral thigh and the first lesion remained unchanged, although no more insulin had been injected there. She was transferred to insulin aspart, which caused no changes over 6 months. The anti-insulin antibodies were then 31%.

Immunologic Switching from ordinary insulin to insulin lispro can reduce the production of insulin antibodies. • A 54-year-old woman with type 2 diabetes had poor metabolic control, despite using 60–80 units of short-acting and long-acting human insulins for 10 years (35A ). Transfer to insulin lispro reduced the daily amount of insulin to 28 units. Insulin specific antibodies fell from 2.7 to 0.3% and crossreactive antibodies, binding both human insulin and insulin lispro, fell from 44 to 16%. Specific insulin lispro antibodies rose from 0 to 0.3%. HbA1c fell from 9.1% to 6.8% and body mass index from 30 to 27, probably because of the reduced dose of insulin.

Drug dosage regimens It is still a matter of debate what the optimal timing is for injecting insulin lispro, specifically when postprandial glucose is taken into account. Insulin lispro acts so rapidly that it must be injected just before a meal, which is more convenient for the patient. Some physicians advise injecting the new shortacting insulins after a meal. However, when insulin lispro was injected postprandially in 31 patients in a random crossover design during two alternating periods of 3 months, mean HbA1c increased, mean postprandial blood glucose was higher, and mean preprandial blood glucose was lower in those who injected postprandially (36C ). There was no difference in episodes of hypoglycemia.

NEW LONG-ACTING INSULINS (SEDA-26, 463; SEDA-27, 450) Clinical studies of new long-acting insulins, have been reviewed, mainly with reference to insulin glargine (37M ). The author concluded that these new analogues have efficacy and safety advantages over NPH insulin.

513

Insulin detemir The pharmacokinetic profile of detemir does not differ in various age groups, including children. The profile is less variable than that of NPH insulin (38C ).

Insulin glargine In a 24-week, randomized, open, multicenter study NPH insulin + insulin glargine was compared with oral hypoglycemic drugs alone in 764 overweight patients with type 2 diabetes; HbA1c and fasting plasma glucose were reduced to the same extent (39C ). The target HbA1c was 7.0% or less. When this goal was reached, nocturnal hypoglycemia was less frequent with insulin glargine (33 versus 27%) and other categories of symptomatic hypoglycemia (such as symptomatic events or confirmed events at various glucose concentrations) were 21–48% less frequent with insulin glargine. In a comparison of combinations of glimepiride (3 mg/day) and NPH insulin at bedtime or insulin glargine in the morning or at bedtime in 695 patients for 24 weeks both morning and bedtime insulin glargine reduced nocturnal hypoglycemia and morning insulin glargine provided better glycemic control than bedtime NPH and bedtime insulin glargine (40C ). In 82 patients transferred from once or twice daily NPH to insulin glargine once daily (and unchanged usual short-acting insulin) to reduce nocturnal hypoglycemia and to improve fasting glucose the first effect was a reduction in HbA1c of about 0.3% (41C ). Patients with a high HbA1c or pre-supper glucose concentrations were given insulin glargine twice daily (n = 20). The 62 patients who took a single dose of insulin glargine had an improved HbA1c of 0.6% and the patients who used a split regimen had a final mean HbA1c 0.5% lower than the starting value.

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GLUCAGON AND GLUCAGON-LIKE PEPTIDE-1 (SED-14, 1508; SEDA-25, 510; SEDA-26, 466; SEDA-27, 451)

Glucagon Glucagon infusions in the treatment of tumorinduced hypoglycemia can cause adverse effects comparable to the effects of a glucagonoma (hyperglycemia, necrolytic migratory erythema, weight loss, anemia, angular cheilitis, and venous thrombosis), as reported in three patients (42A ). • A 38-year-old woman developed erythematous dermatitis, in a skin biopsy consistent with necrolytic migratory erythema, and angular cheilitis, which disappeared after withdrawal of glucagon infusion after 2 months. • After 5 months of glucagon treatment a 38-yearold man developed an erythematous scaly rash and angular cheilitis, which subsided dramatically after withdrawal of the glucagon. • A 57-year-old man developed massive thrombosis, which resolved after removal of glucagon infusion and medical therapy.

Hyponatremia and thrombocytopenia during glucagon infusion (SEDA-26, 466) prompted a retrospective investigation in 2045 preterm infants (before 37 weeks of gestation), of whom 28 had received glucagon infusion (43C ). One had severe hyponatremia but it was easily corrected and it was considered to be dilutional. There were no cases of thrombocytopenia.

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Glucagon-like peptide-1 is quickly degraded and therefore long-acting glucagon-like peptide receptor agonists and oral inhibitors of dipeptidyl peptidase IV (DPP-IV), which inhibit the degradation of glucagon-like peptide1, and glucose-dependent insulinotropic peptide (GIP) are being developed and have been reviewed (46R ). The agonists can cause nausea and vomiting, but have more potency for glucose lowering than DPP-IV inhibitors. Exenatide (synthetic exendin-4, from the saliva from a lizard), which has a 53% overlap with glucagon-like peptide-1 and which also binds to the glucagon-like peptide-1 receptor, has been investigated in a placebo-controlled study for 28 days in 116 patients with type 2 diabetes in addition to a sulfonylurea or metformin (47C ). The most common adverse effects were nausea (mostly only in the first week) and mild to moderate hypoglycemia, for which no treatment was needed.

ORAL HYPOGLYCEMIC DRUGS (SED-14, 1508; SEDA-25, 510; SEDA-26, 466; SEDA-27, 452)

ALPHA-GLUCOSIDASE INHIBITORS (SED-14, 1513; SEDA-24, 495; SEDA-25, 513; SEDA-26, 466; SEDA-27, 452)

Acarbose Glucagon-like peptide-1 Glucagon-like peptide-1 is a proglucagon derivative, secreted in the small intestinal mucosa. It inhibits glucagon secretion and gastric emptying and stimulates insulin secretion. It is given subcutaneously. No hypoglycemia was seen when it was given to lean people with type 2 diabetes (44c ). When glucagon-like peptide-1 was given as a continuous subcutaneous infusion for 12 weeks to patients who stopped taking oral therapy or without withdrawing oral therapy, one patient had fatigue and dry eyes during the study and two had nausea during the first week (45C ). There were no episodes of hypoglycemia.

Alpha-glucosidase inhibitors have been used to prevent or delay the onset and development of diabetes (impaired glucose tolerance). One of the goals is to reduce cardiovascular risk and hypertension, as was found in the STOPNIDDM trial of acarbose (48C ). However, in this study almost a quarter of the participants withdrew early, and the main cause of early withdrawal was gastrointestinal adverse effects. Reduction of insulin resistance in impaired glucose tolerance, as found in a Chinese multicenter study (49C ), can be another incentive to start treatment with α-glucosidase inhibitors. Various studies of the effects of α-glucosidase inhibitors on hyperglycemia and insulin resistance in type 2 diabetes and impaired glucose tolerance have been reviewed (50R ).

Insulin, glucagon, and oral hypoglycemic drugs

Chapter 42

Gastrointestinal The author of a review of the use of acarbose concluded that acarbose is safe in both monotherapy and combination therapy (51R ). The most common adverse effects are: mild to moderate gastrointestinal symptoms, such as flatulence, meteorism, diarrhea, soft stools, abdominal discomfort, and pain. As glucose oxidase increases in the small intestine during therapy, it is advisable to start with a low dose so that the gut can adapt to acarbose. In a post-marketing surveillance study of 1142 patients in whom acarbose was added to insulin therapy for type 2 diabetes mellitus, HbA1c improved by 0.9% and there were 108 adverse effects in 6.9% of the patients (52C ). Most of the complaints were gastrointestinal (flatulence, abdominal pain, diarrhea) and more than half were reported in the first week of acarbose therapy. Skin Skin adverse effects of acarbose are rare. Erythema multiforme was once reported (SEDA-24, 496). • A 43-year-old man developed generalized exanthema pustulosis 48 hours after the start of acarbose therapy (53A ). The lesions disappeared within 1 week after stopping acarbose. He was not retested.

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BIGUANIDES

(SED-14, 1512; SEDA-25, 513; SEDA-26, 467; SEDA-27, 453)

Buformin Metabolism Three further cases of lactic acidosis induced by buformin have been reported. • In Spain a 69-year-old woman with a dilated cardiomyopathy and poor inferior ventricular function developed lactic acidosis after an increase in the dose of buformin (pH 7.1, lactate 18 mmol/l). After withdrawal of buformin and infusion of sodium bicarbonate her renal function and electrolyte disturbances were corrected (55A ). • Two other cases were reported in Japan. One developed in a patient with type 2 diabetes without any underlying disease (56A ). The other case was caused by suicide (57A ).

Buformin is no longer registered in many countries.

Metformin Metformin has been reviewed, with special attention to therapy in combination with other hypoglycemic drugs (58M ). The general conclusions were that it can effectively lower HbA1c concentrations, Improve lipid profiles, and improve vascular and hemodynamic indices.

Contraindications to metformin AMYLIN ANALOGUES (SEDA-27, 453)

Pramlintide In 19 patients with type 1 diabetes using regular insulin and 21 using insulin lispro, who injected pramlintide 60 micrograms or placebo before a standardized breakfast in addition to their normal insulin treatment, there was a marked reduction in the postprandial blood glucose excursion; mild hypoglycemia (25%) and mild nausea (18%) were the most frequent adverse events (54C ).

Contraindications to the use of metformin have been debated (59r ), in relation to the reduced number of cardiovascular events seen in the obese patients treated with metformin in the UK prospective diabetes study (UKPDS) (60R ). The authors stated inter alia that lactic acidosis is rare (1–5 cases per 100 000) and that in the absence of renal insufficiency accumulation of metformin is rare. Moreover, the authors of a Cochrane systematic review concluded that treatment with metformin was not associated with an increased risk of lactic acidosis (61M ). Tissue hypoxia is often the trigger for metformin accumulation. Many physicians do not comply with the official British contraindications. The author suggested the following necessary precautionary measures:

516 • withdraw the drug during periods of suspected tissue hypoxia (myocardial infarction and sepsis); • withdraw the drug during 3 days after the administration of an iodine-containing contrast medium and 2 days before general anesthesia; • check renal function in both cases before metformin is restarted; • serum creatinine over 150 µmol/l is a contraindication. To this one could add that drugs that compromise renal function should not be combined with metformin. Others have stated that metformin is contraindicated when serum creatinine concentrations are over 133 µmol/l (1.5 mg/dl) in men or 124 µmol/l (1.4 mg/dl) in women (58M ). However, creatinine is sometimes a poor predictor of renal function. For example, it must be related to muscular mass and the “normal” serum creatinine may be too high in a person of 50 kg and little muscle. It is therefore better to use creatinine clearance below 60 ml/min as a criterion. For some reactions the usefulness of withdrawing metformin before operations, except in emergency, cardiac, and vascular surgery and in operations requiring deliberate hypotension, has been discussed (62r ) and the creatinine threshold value has been discussed (63r ). Reconsideration of contraindications has also been proposed in a prospective study in patients with serum creatinine concentrations of 130–220 µmol/l and coronary heart disease (n = 226), congestive heart failure (n = 94) and chronic obstructive pulmonary disease (n = 91). Half of the patients continued to take metformin and the other half stopped (64C ). Bodyweight and HbA1c increased over 4 years in those who stopped taking metformin. Lactic acid concentrations were similar in the two groups. Deaths were similar in the two groups (62 and 64 respectively). The incidences of myocardial infarction, all cardiovascular events, and cardiovascular mortality were the same. Changes in additional therapy were only significant for insulin (30% versus 45% respectively) and diet (25% versus 0% respectively). Nervous system Two cases of encephalopathy, which improved after metformin was withdrawn, have been reported (65A ).

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• One week after starting to take metformin 850 mg in divided dose a 74-year-old man became confused and disoriented and had speech abnormalities and bilateral horizontal gaze-evoked nystagmus. Electroencephalography suggested a toxic-metabolic encephalopathy. Metformin was withdrawn, he became alert and oriented, and the electroencephalogram normalized. • A 67-year-old man took metformin for 4 years after which repaglinide 3 mg/day was added. After 3 weeks he became confused and had general diffuse myoclonic jerks and bilateral asterixis. The electroencephalogram showed a general slowing. He improved after stopping both hypoglycemic drugs and became asymptomatic within 3 days. Metformin was reinstituted, as repaglinide was considered to have caused the changes. However, within 2 days the same clinical picture evolved. After withdrawal of metformin he normalized progressively and he had no confusion over the next year.

Metabolism Further cases of lactic acidosis have been reported in patients taking metformin. • An 82-year-old man and a 76-year-old man with normal renal function developed increased lactate concentrations (3.6 mmol/l and 3.2 mmol/l respectively) a few weeks after starting to take metformin (66A ). Both had a low bicarbonate concentration and high anion gap. The second patient was also taking ciprofloxacin for a urinary tract infection. In both patients lactate reached normal values after metformin was withdrawn. • A 40-year-old man taking metformin 850 mg bd developed severe metabolic acidosis (pH 6.62, base deficit 31 mmol/l, anion gap 37 mmol/l, lactate over 20 mmol/l) and hypoglycemia (1.9 mmol/l) (67A ).

In contrast to the numerous reports of lactic acidosis in patients taking metformin, a systematic review has shown no evidence of an association (61M ). This highlights a problem of comparing randomized controlled trials with anecdotal reports from real-life therapy. An effect that occurs only in people with a particular susceptibility may be missed in even very large randomized trials and may therefore only be reported anecdotally. Absence of evidence from a meta-analysis in such circumstances is not evidence against an effect in susceptible individuals. Nutrition Metformin can cause reduced vitamin B12 absorption, reducing serum B12 concentrations and causing megaloblastic anemia (68A ), the prevalence of which was 9% in 600

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patients with type 2 diabetes taking biguanides (phenformin or metformin) for a mean of 12 years (69c ). In 353 patients with type 2 diabetes, treated with insulin, who took metformin for 16 weeks in a placebo-controlled study, metformin increased serum homocysteine concentrations by 4% and reduced serum folate by 7% and vitamin B12 by 14% (70C ). Gastrointestinal At the start of therapy watery diarrhea, nausea, abdominal bloating, flatulence, anorexia and dyspepsia are common, but they resolve mostly within a few weeks (58M ). The use of metformin in polycystic ovarian syndrome, which is often accompanied by insulin resistance or other aspects of the metabolic syndrome, has been systematically reviewed (71M ). Metformin was therapeutically less effective than weight loss. Adverse effects were nausea, vomiting, and gastrointestinal disturbances. Drug formulations Modified-release formulations of metformin allow once daily dosage. In a double-blind, parallel-group comparison of an immediate-release and an extended-release formulation in 191 patients for 24 weeks (72C ) adverse events did not differ between the groups. Drug overdose Two reports of metformin overdose have appeared. • A 70-year-old man survived a suicidal attempt with metformin 63 g (73A ). His serum lactate concentration was 24 mmol/l and creatinine 216 µmol/l. He received bicarbonate hemodialysis, blood pressure support, and active warming for hypothermia. After 6 hours lactate and creatinine normalized. • A 48-year-old man successfully committed suicide with metformin and alcohol (74c ). The authors used a simplified, rapid, and sensitive HPLC assay, with no interference from other drugs or toxic substances, which determined metformin extracted from blood and various tissues both ante-mortem and post-mortem. The serum metformin concentration on admission was 141 µg/ml.

Pregnancy A trial of metformin in pregnancy has been announced (75r ), although the safety of metformin in pregnancy has not been established. Drug interactions Nucleoside analogue reverse transcriptase inhibitors can rarely cause lactic acidosis with hepatic steatosis and might potentiate the effect of metformin.

517

• A 52-year-old man with advanced HIV infection taking many medicines took metformin 500 mg bd for 6 days (76A ). He became increasingly unwell, with nausea, vomiting, abdominal pain, lethargy, and jaundice. His pH was 7.28 and lactic acid 15 mmol/l. Antiviral drugs and metformin were withdrawn, but he died after 30 hours.

Orlistat A possible interaction of orlistat with metformin has been reported. • A 59-year-old obese woman with normal renal function, taking metformin 500 mg tds, took orlistat 120 mg tds for 3 months (77A ). She developed abdominal pain and diarrhea, for which she was given cimetidine, and became weak and dizzy, with blurred vision, reduced consciousness, agitation, and confusion. Her pH was 6.5, bicarbonate 2 mmol/l, base deficit 38 mmol/l, and lactate 21 mmol/l. She required rehydration, bicarbonate, inotropic support and renal replacement therapy.

The authors suggested that chronic diarrhea induced by orlistat could have led to impaired renal function or that orlistat could have increased the absorption of metformin by reducing fat absorption. Rofecoxib Lactic acidosis in a patient taking metformin and rofecoxib has been attributed to renal damage by the latter. • A 58-year-old woman with type 2 diabetes taking metformin 500 mg bd took rofecoxib for 1 month for osteoarthritis of the knees and developed lactic acidosis (78A ).

Warfarin A complication of warfarin therapy contributed to lactic acidosis. • A 73-year-old woman taking metformin 1000 mg bd and warfarin 5 mg/day developed epistaxis, hematuria, gingival bleeding, a retroperitoneal hematoma, and bilateral perinephric blood with obstruction of both collecting systems (79A ). She received fresh frozen plasma, vitamin K1 10 mg, and packed erythrocytes. In the next 8 hours she developed a metabolic acidosis (pH 7.06, lactate 16.5 mmol/l). She had a cardiopulmonary arrest, was resuscitated, and recovered with sodium bicarbonate, additional fresh frozen plasma, vitamin K1 , and hemodialysis. Serum metformin was 7.3 µg/ml (usual target range 1–2).

Interference of warfarin by metformin has been described before (SED-14, 1513).

518

MEGLITINIDES

(SEDA-25, 512; SEDA-26, 468; SEDA-27, 455)

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SULFONYLUREAS

(SED-14, 1508; SEDA-25, 511; SEDA-26, 469; SEDA-27, 456)

Cardiovascular In 1970 the University Group Diabetes Program (UGDP) study appeared to Nateglinide (and perhaps repaglinide) reduces show that a fixed dose of tolbutamide caused the excretion of glycated insulin, which has im- more cardiovascular deaths than placebo or paired biological activity, from the islets (80c ). a fixed or variable dose of insulin. This reThis may contribute to the anti-hyperglycemic sult generated vigorous debate on the outcome and the methods used (SED-8, 917; SEDA-1, action of nateglinide. 317), and the results of the UGDP study are now widely regarded as impossible to be unanimously interpreted. However, the question of whether sulfonyRepaglinide lureas have a negative effect during myocardial Gastrointestinal When repaglinide 4 mg tds infarction and survival during infarction has and glimepiride 160 mg bd were used in combi- lingered. New data on the sulfonylurea recepnation with bedtime NPH insulin for 13 weeks tor as part of the ATP-dependent potassium in 80 patients, one patient had severe diarrhea channel (SUR-1 in the beta pancreatic cells, and fecal incontinence which subsided after involved in insulin secretion, and SUR-2 in the myocardium, involved in cardiac adaptastopping repaglinide (81C ). tion during ischemia) has still not yielded a Liver In the same study (81C ) a patient de- definitive answer. The available experimental veloped abnormal liver function tests, which and clinical data have been systematically renormalized after withdrawal of repaglinide. He viewed (84M ). The conclusion was that experimentally the effects of sulfonylureas on heart was not retested. muscle are both deleterious and protective for Susceptibility factors Genetic When the phar- glibenclamide while tolbutamide, glimepiride, macokinetics of repaglinide 0.5, 1.0, and 2.0 mg and gliclazide have no effects. There seem to were studied in healthy men, 15 Caucasians and be no adverse cardiac consequences of chronic 12 Japanese, AUC and Cmax were higher in the treatment with sulfonylureas. Japanese (82c ). Hypoglycemic reactions were more common at the highest dose, and were Metabolism In a retrospective study 400 doctors in Germany were asked to compare the more common in the Japanese men. characteristics of severe hypoglycemia in paDrug interactions CYP3A4 is involved in tients in acute care induced by glimepiride and the metabolism of repaglinide. Preadministra- glibenclamide (85C ). Only 24 responded (6%). tion of ketoconazole (an inhibitor of CYP3A4) There were no differences in clinical characterin healthy subjects increased the AUC of a sin- istics or time course. gle dose of repaglinide 2 mg by 15% and the Cmax by 7%; conversely, preadministration of rifampicin (an inducer of CYP3A4) reduced the AUC of a single dose of repaglinide 4 mg by Chlorpropamide 31% and the Cmax by 26% (83c ). Ethinylestradiol + levonorgestrel (a po- Chlorpropamide is no longer recommended for tential inhibitor of CYP3A4), nifedipine, or treatment of type 2 diabetes. However, in 1993 simvastatin (both of which are often given to and 1994, of 3050 older Mexican Americans, of whom 36 patients with type 2 diabetes) had no signifi- 365 used inappropriate medicines, C ). In a comparable used chlorpropamide (86 cant effects on the availability of repaglinide. Repaglinide did not alter the kinetics of nifedip- study of 5734 patients over 65 years old, hosine, ethinylestradiol, or levonorgestrel. When pitalized in 81 geriatric and internal medicine repaglinide was given, the major adverse effect wards in Italy during 2 different months in 1997 and 1998, 17 patients (0.3%) were still using was hypoglycemia (in non-diabetic subjects). chlorpropamide (87C ).

Nateglinide

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Glibenclamide When 51 recently diagnosed patients with type 2 diabetes were treated with mixed insulin (30% soluble + 70% NPH) twice daily or glibenclamide in doses that kept HbA1c no more than 1% above the upper normal concentration for 1 year, early insulin treatment prolonged endogenous insulin secretion and improved metabolic control. Adverse effects and quality of life were not different (88C ). This differs from the UKPDS, in which early institution of insulin made no difference in metabolic control. Liver Glibenclamide can cause liver damage. • After increasing his dose of glibenclamide from 2.5 to 5 mg/day for 1 month a 55-year-old man developed jaundice and liver dysfunction, which improved after withdrawal for 2 months (89A ). Retreatment caused an exacerbation. Liver function became normal after complete withdrawal.

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• A 50-year-old obese woman taking glipizide 5 mg/day who had been drinking a bottle of rum daily for 2 months developed an acute hepatitis and died (92A ). The viral hepatitis profile was negative. At autopsy the liver weighed 1800 g and there was focal necrosis without evidence of autoimmune or alcoholic hepatitis. There was no brain edema.

The picture was characteristic of subfulminant hepatic failure, possibly caused by glipizide and potentiated by excessive alcohol consumption. Drug formulations The effects of an immediate-release formulation of glipizide up to 20 mg bd, glipizide GITS up to 20 mg before breakfast, and nateglinide 120 mg tds on postprandial blood glucose have been compared during three admissions with intervals of 1 week (93C ). The three formulations gave equivalent control of postprandial hyperglycemia and there were no episodes of severe hypoglycemia. One person taking glipizide 10 mg had one episode of hypoglycemia before lunch and one taking glipizide GITS 15 mg had hypoglycemia 30 minutes before and 15 minutes after lunch.

Gliclazide Drug formulations A once-daily modifiedrelease formulation of gliclazide has been reviewed (90R ). It has a low tendency to cause hypoglycemia in all patients, including the elderly and patients with mild renal insufficiency. Arthralgia, arthritis, back pain, and bronchitis are its most commonly reported adverse effects, although it is not clear whether they are all related to gliclazide.

Glimepiride Glimepiride has been reviewed (91M ). It can be given once a day and causes less hypoglycemia than other sulfonylureas. It is not recommended in patients with liver disease.

Glipizide Liver The combination of alcohol abuse and glipizide may have caused fatal hepatic failure.

THIAZOLIDINEDIONES (GLITAZONES) (SED-14, 1514; SEDA-25, 515; SEDA-26, 471; SEDA-27, 457) Cardiovascular Thiazolidinediones have been implicated in cardiovascular problems • A 74-year-old man with long-standing type 2 diabetes and compensated systolic dysfunction taking glibenclamide was given rosiglitazone 4 mg/day, increasing to 8 mg/ml after 1 month (94c ). After 2 weeks he had weight gain of 5 kg, increased jugular venous pressure, shortness of breath, bibasal crackles, and a gallop rhythm. Subsequently he had a total weight gain of 17 kg and worse symptoms. When rosiglitazone was withdrawn his weight fell within 12 days to the pretreatment weight and the edema disappeared.

Cardiac dysfunction increases insulin resistance, suggesting that thiazolidinediones, which reduce insulin resistance might be a good choice in patients with diabetes and cardiac dysfunction. However, this case suggests that they can worsen fluid retention, perhaps by vasodilatation (95c ).

520 The American Heart Association and the American Diabetes Association have published a consensus statement in which they stated that in patients with signs or symptoms of NYHA class III or IV cardiac failure thiazolidinediones should not be used and in class I or II they should be used cautiously, starting with a very low dosage (rosiglitazone 2 mg or pioglitazone 15 mg) (28S ). Gradual dose escalation is warranted, with careful observation to identify weight gain, edema, or exacerbation of cardiac failure. Even if there are no signs of chronic heart failure, it can develop when thiazolidinediones are begun. When thiazolidinediones are combined with insulin, edema is more common. In a retrospective study in diabetic patients taking various oral hypoglycemic agents from January 1995 to March 2001 in a large insurance company there were 5441 thiazolidinedione users and 28 103 non-thiazolidinedione users (96C ). Those taking thiazolidinediones were younger but more likely to have coronary artery disease or complications of diabetes. The adjusted incidence of heart failure after 40 months was 8.2% in those taking thiazolidinediones and 5.3% in those not taking thiazolidinediones. The validity of the conclusion was discussed (97r ) but other commentators supported the need to be vigilant for heart failure when prescribing thiazolidinediones (98r ). In 40 ambulatory hemodialysis patients, 25 of whom were taking pioglitazone and 15 rosiglitazone, there were no increases in intravascular volume, anemia, edema, or chronic heart failure in a retrospective study (99c ). It may be that dialysis obviates any increase in intravascular volume. The use of these drugs during dialysis seems to be safe, although there were reductions in systolic and diastolic blood pressures. Endocrine Exacerbation of thyroid eye disease, stable and inactive for more than 2 years, by pioglitazone in a 57-year-old man was explained by the effect of PPARγ agonists on preadipocytes from orbits in thyroid eye disease or from neck fat during Graves’ disease in hormone/agonist induced models (100AE ). The agonists increased adipogenesis 2–13 times and PPARγ antagonists reduced adipogenesis 2–7 times, suggesting that thiazolidinediones may have a direct effect on fat proliferation in thyroid eye disease.

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Susceptibility factors Renal impairment A single dose of rosiglitazone or a single or repeated doses of pioglitazone reduced the glucose AUC in patients with moderate or severe renal impairment (101c , 102c ). Both drugs are primarily metabolized in the liver and their tolerability and adverse effects were the same in patients with normal renal function or with renal impairment. In a post-hoc analysis of three studies in which rosiglitazone or placebo was added for 6 months to a sulfonylurea regimen in 824 patients, 301 of whom had mild to moderate renal impairment (creatinine clearance 30–80 ml/minute) HbA1c and fasting glucose improved to the same extent in those with renal impairment as in those without (103C ). Weight increase, edema (not serious), and mild hypoglycemia did not differ between the groups.

Pioglitazone In 244 patients with type 2 diabetes who took pioglitazone 30 or 45 mg/day for 20 weeks or 30 mg/day for 12 weeks and then 45 mg/day for 8 weeks, blood pressure, liver enzymes, and lipid profile improved and HbA1c fell by 1% (104C ). There was one serious adverse effect related to pioglitazone: severe headache and severe weight gain in a patient taking 30 mg/day, which required drug withdrawal. In a post-marketing surveillance study in 8760 patients for 16 weeks the most common serious adverse effect was weight gain, followed by edema of the legs, nausea, headache, and dizziness (105C ). When pioglitazone 30 mg/day was added to acarbose or acarbose with a sulfonylurea for 16 weeks in 20 patients, there were reductions in HbA1c , fasting plasma glucose, and postprandial glucose (106C ). There were edema, mild hypoglycemia, and increases in lactate dehydrogenase and creatine kinase activities. Two patients, who had angina pectoris before entry, had myocardial infarctions. An almost identical study in 20 patients for 16 weeks gave the same results and adverse effects (107C ). Cardiovascular Of 143 patients (108C ) studied retrospectively, eight stopped taking treatment because of significant peripheral edema,

Insulin, glucagon, and oral hypoglycemic drugs

Chapter 42

one had an exacerbation of cardiac failure, and one reported myalgia. HbA1c , lipid profiles, and blood pressure improved. In 38 patients taking pioglitazone brain natriuretic peptide, which may play a role in fluid retention, did not rise (109c ). Metabolism Insulin resistance in type 2 diabetes contributes to reduced efficacy of both endogenous and exogenous insulin. When metformin and pioglitazone were compared in patients who had not taken previous drug therapy, they were equally efficacious in glycemic control, but parameters of insulin sensitivity increased much more with pioglitazone (110C ). Highly active antiretroviral therapy (HAART) can increase insulin resistance and cause lipodystrophy (loss of subcutaneous fat and increased intra-abdominal fat). In patients with lipodystrophy associated with HAART pioglitazone 30 mg/day was given for 3 months and than increased to 45 mg/day for another 3 months (111c ). There was a significant increase in total and leg fat mass. However, insulin resistance was prevented only partially or not at all. Cholesterol and triglycerides did not change. The serum leptin concentration was low and did not increase during treatment. There were no effects on liver function tests. The results on insulin resistance and lipid profiles were opposite to those found in a comparable study with rosiglitazone (112c ).

521

patients with lipodystrophy associated with HAART rosiglitazone 8 mg/day for 24 weeks had no effect on body weight, subcutaneous or intra-abdominal fat, total body fat, anthropometry, or serum leptin concentrations (112c ). However, it reduced percentage liver fat and serum insulin concentrations and normalized liver function tests. During the first 12 weeks serum triglycerides rose from 3.5 to 6.5 mmol/l and serum cholesterol from 6.0 to 7.8 mmol/l. The results on insulin resistance and lipid profiles were opposite to those found in a comparable study with pioglitazone (111c ). Liver Changes in liver enzymes have been attributed to rosiglitazone. • Rosiglitazone 8 mg/day increased liver enzymes (114A ) in a very obese 41-year-old woman (body mass index 36), who had intractable diarrhea on metformin. She already had increased liver enzymes (alanine transaminase 60 IU/l, γ -glutamyl transpeptidase 299 IU/l, alkaline phosphatase 189 IU/l), supposedly related to hepatic steatosis. Eight weeks later she had severe malaise and the alanine transaminase was 12 times higher, γ -glutamyl transpeptidase three times higher, and alkaline phosphatase twofold higher. After withdrawal of rosiglitazone, the liver enzymes reached pretreatment concentrations in 30 days.

Drug interactions In 10 healthy volunteers gemfibrozil increased the plasma concentrations of rosiglitazone, probably by inhibiting CYP2C8 (115c ).

Rosiglitazone The addition of rosiglitazone 2 mg bd (n = 215), 4 mg bd (n = 210), or placebo (n = 105) to sulfonylurea therapy in Chinese patients, of whom 56% were seropositive for hepatitis B and/or C, caused a significant fall in HbA1c (113C ). There were more respiratory infections, weight gain, edema of the legs, hyperlipidemia, and episodes of hypoglycemia in those who took rosiglitazone. In all groups there were a few cases of slight increases in transaminases, but no signs of hepatotoxicity. Metabolism Highly active antiretroviral therapy (HAART) can increase insulin resistance and cause lipodystrophy (loss of subcutaneous fat and increased intra-abdominal fat). In 30

Combinations of hypoglycemic drugs Studies of drug combinations in the therapy of diabetes mellitus are regularly reported (SEDA27, 458). When combinations improve HbA1c , minor episodes of hypoglycemia are more common. Biguanides plus glitazones The combination of metformin + thiazolidinediones (glitazones) is contraindicated or not recommended in patients taking therapy for cardiac failure. In a retrospective study of 12 505 and 13 158 patients with cardiac failure and diabetes in two different years (1998/9 and 2000/1) (116C )

522 7.1% (later 11.%) had a prescription for metformin, 7.2% (16.%) for thiazolidinediones and 14% (24%) for both drugs added to cardiac drugs. This suggests that many patients with heart failure are taking hypoglycemic drugs, notwithstanding contraindications. Biguanides plus meglitinides The combination of nateglinide + metformin for 3–4 months reported caused mild adverse events in 2.9% of patients, the most common being gastrointestinal complaints (117C ). Biguanides plus sulfonylureas or glitazones plus sulfonylureas The combination of metformin with various sulfonylurea derivatives has been extensively reviewed (58M ). When metformin or pioglitazone were added to sulfonylureas in patients with type 2 diabetes who were poorly controlled, those with reduced pancreatic beta cell function responded better to metformin, while those with greater insulin resistance responded better to pioglitazone (118C ). Combination tablets containing metformin + glibenclamide (250 + 1.25 mg) were compared with monotherapy with metformin 500 mg/day or glibenclamide 2.5 mg/day for 16 weeks in 486 patients (119C ). The total daily doses were adjusted depending on fasting plasma glucose. The final mean doses with combined therapy were lower than with monotherapy. Gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and abdominal pain, were significantly more frequent with metformin monotherapy than with either combined therapy or glibenclamide monotherapy. Hypoglycemia was most frequent in those who took combination therapy and least with metformin monotherapy, but finger-stick glucose concentrations under 2.8 mmol/l were rare with metformin monotherapy and equally common with glibenclamide monotherapy and combination therapy. Glitazones plus meglitinides In 246 patients pioglitazone 30 mg/day, repaglinide (optimal dosage), or pioglitazone + repaglinide were compared over 12 weeks after an initial 12 weeks to establish dosages in an open study (120C ). There were no episodes of major hypoglycemia or raised transaminases. HbA1c changed in the three groups by −0.18%,

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+0.32%, and −1.76% respectively. Fasting glucose improved most in the combined group. There were minor episodes of hypoglycemia in 8%, 3%, and 5% respectively. There were weight gains of 0.3, 2.0, and 5.5 kg respectively. The main reason for discontinuation before the end of the trial (41%, 58% and 15%) respectively was insufficient effect. The combination of rosiglitazone + repaglinide during 24 weeks (121C ) in 252 patients with HbA1c over 7.0% produced one major episode of hypoglycemia. Minor episodes occurred in 9% of those taking combined therapy, 6% of those taking repaglinide, and 2% of those taking rosiglitazone. There was peripheral edema in 4% of those taking combined therapy and 3% of those taking rosiglitazone. Weight gain was +4.4 kg in those taking combined therapy, 2.3 kg in those taking rosiglitazone, and 1.6 kg in those taking repaglinide. Glitazones plus sulfonylureas Rosiglitazone 8 mg/day + glibenclamide 7.5 mg/day were compared with glibenclamide alone (maximum 15 mg/day) in 335 patients over 26 weeks (122C ). HbA1c fell by 0.81% with combination therapy. One patient taking combination therapy had a single episode of serious hypoglycemia; mild to moderate hypoglycemia was reported in 19% of the patients taking combination therapy and 4.1% in those taking glibenclamide alone. There was edema in 9.5% versus 2.9%, weight gain of 3.1 kg versus 0.14 kg, and reduced hemoglobin in those taking combination therapy. Insulin plus oral hypoglycemic drugs In a multicenter, open, parallel-group study in USA, 188 patients responded insufficiently to two oral hypoglycemic drugs (HbA1c over 8.0%) and received either a third oral drug or metformin with insulin 70/30 mix twice a day (123C ). HbA1c and fasting plasma glucose did not differ between the groups and neither did minor episodes of hypoglycemia. Weight gain was 3.5 and 2.9 kg respectively. Lack of efficacy or adverse effects prompted withdrawal in 13% of those taking triple therapy and 2% of those taking insulin + metformin. In those taking insulin + metformin cholesterol and triglycerides fell and the mean cost was $10.40 for the triple group and $3.20 for the insulin + metformin group.

Insulin, glucagon, and oral hypoglycemic drugs

Chapter 42

When repaglinide 4 mg tds and glimepiride 160 mg bd in combination with bedtime NPH insulin were compared for 13 weeks in 80 patients, there were no differences in improvement

523

of glycemic control, hypoglycemia, or weight gain, except in one patient taking gliclazide + NPH, who needed third party help for hypoglycemia (81C ).

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13. Chowdhury TA, Escudier V. Poor glycaemic control caused by insulin induced lipohypertrophy. Br Med J 2003; 327: 383–4. 14. Kamoi K, Miyakoshi M, Maruyama R. A quality-of-life assessment of intensive insulin therapy using insulin lispro switched from short-acting insulin and measured by an ITR-QOL questionnaire: a prospective comparison of multiple daily insulin injections and continuous insulin infusion. Diabetes Res Clin Pract 2004; 64: 19–25. 15. Colquitt J, Royle P, Waugh N. Are analogue insulins better than soluble in continuous subcutaneous insulin infusion? Results of a meta-analysis. Diabetic Med 2003; 20: 863–6. 16. Raskin P, Bode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB, Peterson GE, Mudaliar SR, Reinhardt RR. Continuous subcutaneous insulin infusion treatment and multiple daily injection therapy are equally effective in type 2 diabetes. Diabetes Care 2003; 26: 2598–603. 17. Sulli N, Shashaj B. Continuous subcutaneous insulin infusion in children and adolescents with diabetes mellitus: decreased HbA1c with low risk of hypoglycemia. J Pediatr Endocrinol Metab 2003; 16: 393–9. 18. Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G, Lilos P, Dickerman Z, Phillip M. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: a randomized open crossover trial. Pediatrics 2003; 112: 559–64. 19. Phillips BD, Aurand LA, Bedwell MM, Levy JR. A novel approach to preventing diabetic ketoacidosis in a patient treated with an insulin pump. Diabetes Care 2003; 26: 2960–1. 20. Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabetic Med 2003; 20: 886–98. 21. Cefalu WT. Concepts, strategies, and feasibility of noninvasive insulin delivery. Diabetes Care 2004; 27: 239–46. 22. Hermansen K, Rönnemaa T, Petersen AH, Bellaire S, Adamson U. Intensive therapy with inhaled insulin via the AERx insulin diabetes management system. Diabetes Care 2004; 27: 162–7. 23. An B, Reinhardt RR. Effects of different duration of breath holding after inhalation of insulin using the AERx® insulin diabetes management system. Clin Ther 2003; 25: 2233–44. 24. Kidron M, Dinh S, Menachem Y, Abbas R, Variano B, Goldberg M, Arbit E, Bar-On H. A novel per-oral insulin formulation: proof of concept study

524 in non-diabetic subjects. Diabetic Med 2004; 21: 354–7. 25. Grajower MM, Fraser CG, Holcombe JH, Daugherty ML, Harris WC, De Felippis MR, Santiago OM, Clark NG. How long should insulin be used once a vial is started? Diabetes Care 2003; 26: 2665–9. 26. ADA Clinical Practice Recommendations. Insulin administration. Diabetes Care 2003; 26 Suppl 1: S121–4. 27. Cheyne EH, Sherwin RS, Lunt MJ, Cavan DA, Thomas PW, Kerr D. Influence of alcohol on cognitive performance during mild hypoglycemia; implications for type 1 diabetes. Diabetic Med 2004; 21: 230–7. 28. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Winter ML, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. Thiazolidinedione use, fluid retention and congestive heart failure. Diabetes Care 2004; 27: 256–63. 29. Ng RSH, Darko DA, Hillson RM. Street drug use among young patients with type 1 diabetes in the UK. Diabetic Med 2004; 21: 295–6. 30. Ford-Adams ME, Murphy NP, Moore EJ, Edge JA, Ong KL, Watts AP, Acerini CL, Dunger DB. Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young children with diabetes mellitus. Diabetic Med 2003; 20: 656–60. 31. Danne T, Amna J, Schober E, Deiss D, Jacobsen JL, Friberg HH, Jensen LH. A comparison of postprandial administration of insulin aspart in children and adolescents with type 1 diabetes. Diabetes Care 2003; 26: 2359–64. 32. Sargin H, Sargin M, Altuntas Y, Sengul AM, Orbay E, Seber S, Ucak S, Yayla A. Comparison of lunch and bedtime NPH insulin plus mealtime insulin lispro therapy with premeal regular insulin plus bedtime NPH insulin therapy in type 2 diabetes. Diabetes Res Clin Pract 2003; 62: 79–86. 33. Fujiwara M, Baba T, Neugebauer S, Hasegawa K, Hosoya E, Tanaka K, Shimada K, Yamada D, Watanabe T. Postprandial hypoglycaemia due to insulin lispro. Diabetic Med 2004; 21: 297–8. 34. Arranz A, Andia V, López-Gúzman A. A case of lipoatrophy with lispro insulin without insulin pump therapy. Diabetes Care 2004; 27: 625–6. 35. Asai M, Kodera T, Ishizeki K, Uebori S, Kashiwaya T, Itoh H, Makino I. Insulin lispro reduces insulin antibodies in a patient with type 2 diabetes with immunological insulin resistance. Diabetes Res Clin Pract 2003; 61: 89–92. 36. Schenthaner G, Wein W, Shnawa N, Bates PC, Birkett MA. Preprandial vs. postprandial lispro—a comparative crossover trial in patients with type 1 diabetes. Diabetic Med 2004; 21: 279–84. 37. Barnett AH. A review of basal insulins. Diabetic Med 2003; 20: 873–85. 38. Danne T, Lüpke K, Walte K, Von Schuetz W, Gall M-A. Insulin detemir is characterized by a consistent pharmacokinetic profile across agegroups in children, adolescents, and adults with type 1 diabetes. Diabetes Care 2003; 26: 3087–92. 39. Riddle MC, Rosenstock J, Gerich J. The treat to target trial; randomized addition of glargine or hu-

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man NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26: 3080–6. 40. Fritsche A, Schweitzer MA, Häring H-U, 4001 Study group. Glimepiride, combined with morning insulin glargine, bedtime neutral protamine Hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. Ann Intern Med 2003; 138: 952–9. 41. Albright ES, Desmond R, Bell DSH. Efficacy of conversion from bedtime NPH insulin injection to once- or twice-daily injections of insulin glargine in type 1 diabetic patients using basal/bolus therapy. Diabetes Care 2004; 27: 632–3. 42. Case CC, Vassilopoulou R. Reproduction of features of the glucagonoma syndrome with continuous intravenous glucagon infusion as therapy for tumor-induced hypoglycemia. Endocrine Pract 2003; 9: 22–5. 43. Chrasha DS, McKinley PS, Whitfield JM. Glucagon infusion for treatment of hypoglycemia: efficacy and safety in sick, premature infants. Pediatrics 2003; 111: 220–1. 44. Knop FK, Vilsbøll T, Larsen S, Madsbad S, Holst JJ, Krarup T. No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis. Diabetes Care 2003; 26: 2581–7. 45. Meneilly GS, Greig N, Tildesley H, Habener JF, Egan JM, Elahi D. Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care 2003; 26: 2835–41. 46. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003; 26: 2929–40. 47. Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A, Kim D, Baron AD. Effect of glycemic control of exenatide (synthetic exendine4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 2003; 26: 2370–7. 48. Chiasson J-L, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. J Am Med Assoc 2003; 290: 486–94. 49. Pan C-Y, Gao Y, Chen J-W, Luo B-Y, Fu Z-Z, Lu J-M, Guo X-H, Cheng H. Efficacy of acarbose in Chinese subjects with impaired glucose tolerance. Diabetes Res Clin Pract 2003; 61: 183–90. 50. Cheen AJ. Is there a role for alpha-glucosidase inhibitors in the prevention of type 2 diabetes mellitus? Drugs 2003; 63: 933–51. 51. Breuer H-WM. Review of acarbose therapeutic strategies in the long-term treatment and in the prevention of type 2 diabetes. Int J Clin Pharmacol Ther 2003; 41: 421–40. 52. Klocke KR, Stauch K, Landen H. Effect of addon acarbose to insulin therapy in routine clinical practice. Clin Drug Invest 2003; 23: 621–7. 53. Poszepczynska-Guigné E, Viguier M, Assier H, Pinquier L, Hochedez P, Dubertret L. Acute generalized exanthema pustulosis induced by drugs

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with low-digestive absorption: acarbose and nystatin. Ann Dermatol Venereol 2003, 130, 439–42. 54. Weyer C, Gottlieb A, Kim DD, Lutz K, Schwartz S, Gutierrez M, Wang Y, Ruggles JA, Kolterman OG, Maggs DG. Pramlintide reduces postprandial glucose excursions when added to regular insulin or insulin lispro in subjects with type 1 diabetes. Diabetes Care 2003; 26: 1074–9. 55. Montero Alonso M, Salvador Cervelló G, Perelló Rosso A, Roig Osca MA. Acidosis láctica asociada al uso de buformina. Rev Clin Esp 2003; 203: 216. 56. Tamura Y, Tsukamoto K, Yakamoto N, Ishibashi S, Kadowaki T, Kimura S. A case of buformin treated type 2 diabetes mellitus without any other underlying disease complicated by acute renal failure, lactic acidosis, subsequent diarrhea and vomiting [in Japanese]. Tonyobyo 2003; 46: 325–7. 57. Kurita S, Muramoto S, Okabe G. A case of lactic acidosis acute renal failure caused by taking a lot of buformin for suicide [in Japanese]. Tonyobyo 2003; 46: 329–31. 58. Setter SM, Iltz JL, Thams J, Campbell RK. Metformin hydrochloride in the treatment of type 2 diabetes mellitus: a clinical review with a focus on dual therapy. Clin Ther 2003; 25: 2991–306. 59. Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. Br Med J 2003; 326: 4–5. 60. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998, 352: 854–65. 61. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2003; 2: CD002967. 62. Jones P, Yate P. Blanket banning of metformin two days before surgery may not be a good idea. Br Med J 2003; 326: 5. 63. Elder AT. Age and creatinine clearance need to be taken in consideration. Br Med J 2003; 326: 4. 64. Rachmani R, Slavachevski I, Levi Z, Zadok BS, Kedar Y, Ravid M. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Int Med 2002; 13: 428–33. 65. Vander T, Hallevy H, Ifergane G, Herishanu YO. Metformin-induced encephalopathy without lactic acidosis. Diabetic Med 2003; 21: 194–5. 66. Khan JK, Pallaki M, Tolbert SR, Hornick TR. Lactic acidemia associated with metformin. Ann Pharmacother 2003; 37: 66–9. 67. Edwards CMB, Barton MA, Snook J, David M, Mak VHF, Chowdhury TA. Metformin-associated lactic acidosis in a patient with liver disease. Quart J Med 2003; 96: 315–18. 68. Fujita H, Narita T, Yoshioka N, Hosoba M, Ito S. A case of megaloblastic anemia due to vitamin B12 deficiency precipitated in a totally gastrectomized type II diabetic patient following the introduction of metformin therapy. Endocr J 2003; 50: 483–4.

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69. Filioussi K, Bonovas S, Katsaros T. Should we screen diabetic patients using biguanides for megaloblastic anaemia? Aust Fam Physician 2003; 32: 383–4. 70. Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van den Burg B, Donker AJM, Stehouwer CDA. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med 2003; 254: 455–63. 71. Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. Br Med J 2003; 327: 351–5. 72. Fujioka K, Pans M, Joyal S. Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation. Clin Ther 2003; 25: 515–29. 73. Gjedde S, Christiansen A, Pedersen SB, Rungby J. Survival following a metformin overdose of 63 g: a case report. Pharmacol Toxicol 2003; 93: 98–9. 74. Moore KA, Levine B, Titus JM, Fowler DR. Analysis of metformin in antemortem serum and postmortem specimens by a novel HPLC method and application to an intoxication case. J Anal Toxicol 2003; 27: 592–4. 75. Hague WM, Davoren P, Oliver J, Rowan J. Metformin may be useful in gestational diabetes. Br Med J 2003; 236: 762–3. 76. Worth L, Elliott J, Anderson J, Sasadeusz J, Street A, Lewin S. A cautionary tale: fatal lactic acidosis complicating nucleoside analog and metformin therapy. Clin Infect Dis 2003; 37: 315–16. 77. Dawson D, Conlon C. Case study: metformin associated lactic acidosis; could orlistat be relevant? Diabetes Care 2003; 26: 2471–2. 78. Price G. Metformin lactic acidosis, acute renal failure and rofecoxib. Br J Anaesth 2003; 91: 909– 10. 79. Schier JG, Hoffman RS. Metformin acidosis due to a warfarin adverse drug event. Ann Pharmacother 2003; 37: 1145. 80. Lindsay JR, McKillop AM, Mooney MH, O’Harte FPM, Flatt PR, Bell PM. Effect of nateglinide on the secretion of glycated insulin and glucose tolerance in type 2 diabetes. Diab Res Clin Pract 2003; 61: 167–73. 81. Furlong NJ, Hulme SA, O’Brien SV, Hardy KJ. Comparison of repaglinide vs gliclazide in combination with bedtime NPH insulin in patients with type 2 diabetes inadequately controlled with oral hypoglycaemic agents. Diabetic Med 2003; 20: 935–41. 82. Thomsen MS, Chassard D, Evène E, Nielsen KK, Jørgensen M. Pharmacokinetics of repaglinide in healthy Caucasian and Japanese subjects. J Clin Pharmacol 2003; 43: 23–8. 83. Hatorp V, Kristian TH, Thomsen MS. Influence of drugs interacting with CYP3A4 on the pharmacokinetics, phamacodynamics, and safety of the prandial glucose regulator repaglinide. J Clin Pharmacol 2003; 43: 649–60.

526 84. Riveline JP, Danchin N, Ledru F, Varroud-Vial M, Charpentier G. Sulfonylureas and cardiovascular effect: from experimental data to clinical use. Available data in humans and clinical applications. Diabetes Metab 2003; 29: 207–22. 85. Holstein A, Plaschke A, Hammer C, Egberts E-H. Characteristics and time course of severe glimiperide- versus glibenclamide-induced hypoglycemia. Eur J Clin Pharmacol 2003; 59: 91–7. 86. Raji MA, Ostir GV, Markides KS, Espino DV, Goodwin JS. Potentially inappropriate medication use by elderly Mexican Americans. Ann Pharmacother 2003; 37: 1197–202. 87. Onder G, Landi F, Cesari M, Gambassi G, Carbonin P, Bernabei R. Inappropriate medication use among older adults in Italy: results from the Italian group of pharmacoepidemiology in the elderly. Eur J Clin Pharmacol 2003; 59: 157–62. 88. Alvarsson M, Sundkvist G, Lager I, Henricsson M, Berntorp K, Fernqvist-Forbes E, Steen L, Westermark G, Westermark P, Örn T, Grill V. Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients. Diabetes Care 2003; 26: 2231–7. 89. Ichimyya Y, Furuya K, Hasegawa A, Nishimura M. Dose related glibenclamide–induced hepatitis; a case report. J Japan Diab Soc 2003; 46: 241–5. 90. Schernthaner G. Gliclazide modified release: a critical review of pharmacodynamic, metabolic, and vasoprotective effects. Metabolism 2003; 52 Suppl 1: 29–34. 91. Massi-Benedetti M. Glimiperide in type 2 diabetes mellitus: a review of the worldwide therapeutic experience. Clin Ther 2003; 25: 799–816. 92. Ilario MJ-M, Turyan HV, Axiotis CA. Glipizide treatment with short-term alcohol abuse resulting in subfulminant hepatic failure. Virchows Arch 2003; 443: 104–5. 93. Carroll MF, Gutierrez A, Castro M, Tsewang D, Schade DS. Targeting postprandial hyperglycemia: a comparative study of insulinotropic agents in type 2 diabetes. J Cin Endocrinol Metab 2003; 88: 5248– 54. 94. Page II RL, Gozansky WS, Ruscin JM. Possible heart failure exacerbation associated with rosiglitazone: case report and literature review. Pharmacotherapy 2003; 23: 945–54. 95. Walker AB, Naderali EK, Chattington PD, Buckingham RE, Williams G. Differential vasoactive effects of the insulin sensitizers rosiglitazone (BRL 49653) and troglitazone on human small arteries in vitro. Diabetes 1998; 47: 810–14. 96. Delea TE, Edelsberg JS, Hagiwara MH, Oster G, Phillips LS. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes; a retrospective cohort study. Diabetes Care 2003; 26: 2983–9. 97. Karter AJ, Ahmed AT, Liu J, Moffet HH, Parker MM, Ferrara A, Selby JV. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes; a retrospective cohort study. Diabetes Care 2004; 27: 850–1. 98. Delea TE, Edelsberg JS, Hagiwara MH, Oster G, Phillips LS. Use of thiazolidinediones and

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risk of heart failure in people with type 2 diabetes; a retrospective cohort study. Diabetes Care 2004; 27: 852. 99. Manley HJ, Allcock NM Thiazolidinedione safety and efficacy in ambulatory patients receiving hemodialysis. Pharmacotherapy 2003; 23: 861–5. 100. Starkey K, Heufelder A, Baker G, Joba W, Evans M, Davies S, Ludgate M. Peroxisome proliferator activated receptor-gamma in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab 2003; 88: 55–9. 101. Budde K, Neumayer H-H, Fritsche L, Sulowicz W, Stompôr T, Eckland D. The pharmacokinetics of pioglitazone in patients with impaired renal function. Br J Clin Pharmacol 2003; 55: 368–74. 102. Chapelski MC, Thompson-Culkin K, Miller AK, Sack M, Blum R, Freed MI. Pharmacokinetics of rosiglitazone in patients with various degrees of renal insufficiency. J Clin Pharmacol 2003; 43: 252–9. 103. Agrawal A, Sautter MC, Jones NP. Effects of rosiglitazone maleate when added to a sulfonylurea regimen in patients with type 2 diabetes mellitus and mild to moderate renal impairment: a post hoc analysis. Clin Ther 2003; 25: 2754–64. 104. Gerber P, Lübben G, Heusler S, Dodo A. Effects of pioglitazone on metabolic control and blood pressure: a randomized study in patients with type 2 diabetes mellitus. Curr Med Res Opin 2003; 6: 532–9. 105. Schöfl C, Lübben G. Postmarketing surveillance study of the efficacy and tolerability of pioglitazone in insulin-resistant patents with type 2 diabetes mellitus in general practice. Clin Drug Invest 2003; 23: 725–34. 106. Hayashi Y, Miyachi N, Takeuchi T, Takeuchi Y, Kamiya F, Kato T, Imaeda K, Okayama N, Shimizu M, Itoh M. Clinical evaluation of pioglitazone in patients with type 2 diabetes using alpha-glucosidase inhibitor and examination of its efficacy profile. Diabetes Obesity Metab 2003; 5: 58–65. 107. Seino H, Yamaguchi H, Misaki A, Sakata Y, Kitagawa M, Yarnazaki T, Kikuchi H, Abe R. Clinical effect of combination therapy of pioglitazone and an alpha-glucosidase inhibitor. Curr Med Res Opin 2003; 8: 676–82. 108. Jun JK, Gong WC, Mathur R. Effects of pioglitazone on diabetes related outcomes in Hispanic patients. Am J Health-Syst Pharm 2003; 60: 469– 73. 109. Igarashi M, Jimbu, Y, Hirato A, Yamaguchi H, Kato T, Tominaga M. Effect of pioglitazone on the plasma concentration of brain natriuretic peptide in patients with type 2 diabetes. Ther Res 2003; 24: 1873–81. 110. Pavo I, Jermendi G, Varkonyi TT, Kerenyi Z, Gymesi A, Shoustov S, Shestakova M, Herz M, Johns D, Schluchter BJ, Festa A, Tan MH. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 1637– 45.

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111. Calmy A, Hirschel B, Hans D, Karsegard VL, Meier CA. Glitazones in lipodystrophy syndrome induced by highly active antiretroviral therapy. AIDS 2003; 17: 770–2. 112. Sutinen J, Häkkinen A-M, Westerbacka J, Seppälä-Lindroos A, Vehkavaara S, Halavaara J, Järvinen A, Ristola M, Yki-Järvinen H. Rosiglitazone in the treatment of HAART-associated lipodystrophy—a randomized double-blind placebo-controlled study. Antiviral Ther 2003; 8: 199– 207. 113. Zhu X-X, Pan C-Y, Li G-W, Shi H-L, Tian H, Yang W-Y, Jiang J, Sun X-C, Davies C, Chow W-H. Addition of rosiglitazone to existing sulfonylurea treatment in Chinese patients with type 2 diabetes and exposure to hepatitis B or C. Diabetes Technol Ther 2003; 5: 33–42. 114. Nag S, McCulloch A. Liver enzymes and rosiglitazone. Br J Diabetic Vasc Dis 2003; 3: 62–3. 115. Niemi M. Backman JT, Granfors M, Laitila J, Neuvonen M, Neuvonen PJ. Gemfobrizil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 2003; 46: 1319–23. 116. Masoudi FA, Wang Y, Inzucchi SE, Setaro JF, Havranek EP, Foody JM, Krumholz HM. Metformin and thiazolidinedione use in Medicare patients with heart failure. J Am Med Assoc 2003; 290: 81–5. 117. Schatz H, Schoppel K, Lehwalder D, Schandry R. Efficacy, tolerability and safety of nateglinide in combination with metformin. Results

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from a study under general practice conditions. Exp Clin Endocrinol Diabetes 2003; 111: 262–6. 118. Nagasaka S, Aiso Y, Yoshiwaza K, Ishibashi S. Comparison of pioglitazone and metformin efficacy using homeostasis model assessment. Diabetic Med 2004; 21: 136–41. 119. Garber AJ, Donovan Jr DS, Dandona P, Bruce S, Park J-S. Efficacy of glyburide/metformin tablets compared with initial monotherapy in type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 3598– 604. 120. Javanovic L, Hassman DR, Gooch B, Jain R, Greco S, Khutoryansky N, Hale PM. Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone. Diabetes Res Clin Pract 2004; 63: 127–34. 121. Raskin P, McGill J, Saad MF, Cappleman JM, Kaye W, Khutoryansky N, Hale PM. Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone. Diabetic Med 2004; 21: 329–35. 122. Kerenyi Z, Samer H, James R, Yan Y Stewart M. Combination therapy with rosiglitazone and glibenclamide compared with upward titration of glibenclamide alone in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2004; 63: 213–23. 123. Schwartz S, Sievers R, Strange P, Lyness WH, Hollander P. Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs. Diabetes Care 2003; 26: 2238–43.

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Miscellaneous hormones

Gonadotropin-releasing hormone (GnRH, gonadorelin) and analogues (SED-14, 1523;

Reproductive system One of 66 women randomized to receive goserelin acetate for uterine fibroids withdrew from the study owing to severe pelvic pain (4c ).

SEDA-25, 520; SEDA-26, 477; SEDA-27, 465) Endocrine Following reports of autoimmune thyroid disease in association with gonadorelin analogues (SEDA 27, 465) further reports have appeared (1A ). • A 49-year-old woman developed Graves’ disease after receiving buserelin acetate for 4 months. • A 41-year-old woman developed painless thyroiditis after receiving leuprolide acetate for 4 months. • A 29-year-old woman developed Graves’ disease 4 months after starting to receive buserelin acetate.

Hematologic The relation between androgens and erythropoiesis is well known. In 42 patients with adenocarcinoma of the prostate, leuprolide acetate and flutamide (an antiandrogen) were used in combination (2c ). Hemoglobin concentrations fell by more than 25% in six patients who developed symptomatic anemia. Checking the hemoglobin at 3 months was thought to be useful in predicting those who would become symptomatic.

Growth hormone (human growth hormone, hGH, somatotropin) (SED-14, 1520; SEDA-25, 521; SEDA-26, 479; SEDA- 27, 466) The potential immediate and long-term hazards in athletes who use growth hormone in supraphysiological doses have been reviewed (5R ). They were: Acute: • exacerbation of lipolysis and increasing lactate production during exercise, which could impair an athlete’s performance; • reduced glycogen storage in muscle and liver, which would make exercise recovery more difficult; • increased fatty acid concentrations, with a possible risk of cardiac dysrhythmias. Chronic:

Musculoskeletal Children with precocious puberty treated with gonadorelin receptor agonists recovered their bone mineral density when therapy was withdrawn (SEDA-27, 465). Of 25 girls with idiopathic precocious puberty, 11 had not been treated and 14 had received leuprolide acetate monthly for at least 1 year; they were compared with 19 healthy controls (3c ). There was no significant difference between the groups. There was no osteopenia or osteoporosis after therapy. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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• poor exercise tolerance; • evidence of reduced fat; although muscle appears better defined it can show myopathic features. Cardiovascular The use of growth hormone other than in growth hormone-deficient people continues to be investigated. In 80 postmenopausal women with osteoporosis aged 50–70 years, two doses of growth hormone, 1.0 U/day (n = 28) or 2.5 U/day (n = 27) for 3 years, were compared with placebo (6c ). Plasma fibrinogen increased in both growth hormone groups at 4 years only; the significance of this finding is uncertain. Fibrinogen

Miscellaneous hormones

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concentrations are raised in acromegaly and since fibrinogen is a risk factor for cardiovascular disease, especially stroke, people with acromegaly have an increased risk of cardiovascular disease. Respiratory In 31 elderly frail women, mean age 86 years, who were randomized to receive growth hormone or placebo for 14 days after surgery for hip fracture, there was an excess of thromboembolic events and chest infections; the mechanism was not clear (7c ). It has previously been shown that patients in intensive care receiving growth hormone have an excess mortality (SEDA-24, 504). Musculoskeletal Of 21 of 151 patients who were treated with growth hormone for growth hormone deficiency for 2–12 years, some developed acromegalic features: eight had a foot size greater than the 97th centile and four had a jaw length greater than +2 standard deviations (8c ). In 85 Japanese children with various skeletal dysplasias there was no gain in height from growth hormone therapy in those with pseudochondroplasia (n = 4) or congenital spondyloepiphyseal dysplasia (n = 4) (9c ). Patients with spondyloepiphyseal dysplasia in particular found that when growth was promoted weakness in their ligaments resulted in worsening kyphosis and lordosis. • Avascular necrosis of the femoral head and another of slipped capital femoral epiphysis with avascular necrosis have been reported in two children with growth hormone deficiency receiving growth hormone (10A ).

In a North American register of patients with chronic renal insufficiency and end-stage renal disease there was no excess of cases of slipped capital femoral epiphysis or avascular necrosis in those receiving growth hormone (11c ). Reproductive system A change in prostate size has been reported in patients receiving growth hormone, but no change in the concentration of prostate-specific antigen (12c ). Tumorigenicity The cancer risk of growth hormone has been reviewed (13R ). In 1848 patients treated with growth hormone during childhood there was an 11-fold increase in the

incidence of colorectal cancer after a mean 16 years of follow-up and a 15-fold increase in mortality from colorectal cancer and Hodgkin’s disease after 21 years of follow-up. However, there were too few deaths to draw any firm conclusions. The Pharmacia (originally Pharmacia & Upjohn) International Metabolic Surveillance (KIMS) study is following adult patients receiving growth hormone for growth hormone deficiency. A higher incidence of intracranial neoplasia has been reported; however, this could be an effect of increased surveillance (14R ).

Growth hormone receptor antagonists Pegvisomant is a new genetically engineered growth hormone analogue that acts as a growth hormone receptor antagonist. Its role in managing acromegaly is evolving (15R ). Nervous system In 112 patients with active acromegaly who received pegvisomant in a 12 week, randomized, double-blind study of three different daily subcutaneous doses of pegvisomant (10, 15, and 20 mg), headache was reported in the placebo group as often as in the active treatment groups (12%) (16c ). In a longer follow-up study for up to 18 months, 26% of 160 patients had headache, but there was no control group for comparison (17c ). Endocrine Two patients receiving pegvisomant had significant growth of their pituitary tumors after several months, requiring further therapy. There was no control group to show if this was significant, but regular assessment of the pituitary anatomy is recommended (17c ). Pegvisomant inhibits the action of growth hormone at its receptor, reducing serum IGF-1 concentrations. Growth hormone concentrations increase and appear to plateau by 6 months (17c ). Whether a Nelson’s syndrome-like effect will occur in patients receiving pegvisomant requires long-term follow up.

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Gastrointestinal In a 12-week study there was diarrhea in four of 29 patients taking pegvisomant 20 mg/day compared with one patient taking placebo (16c ). One patient taking 10 mg/day and none taking 15 mg/day reported diarrhea. In a longer follow-up study (18 months) 14% reported diarrhea (17c ).

Respiratory Octreotide has been used in premature neonates for closure of enterocutaneous fistulae complicating necrotizing enterocolitis. Two cases of oxygen desaturation have been reported (21A ). The authors suggested that the effect may relate to pre-existing hyaline membrane disease.

Liver Two patients developed significantly abnormal liver function tests after receiving pegvisomant for 12 weeks (16c , 17c ). Transaminase activities rose to more than 10-fold the upper limits of the reference ranges and returned to normal after withdrawal. One of the two was treated for autoimmune hepatitis (18R ). Monitoring of liver enzymes every 4–6 weeks is recommended for 6 months or if symptoms of hepatitis develop.

Metabolism Somatostatin analogues can also cause hypoglycemia possibly through their effects on reducing counter-regulatory hormones, such as growth hormone and glucagon.

Skin In a placebo-controlled study, six of 80 patients taking pegvisomant had injection site reactions, which were mild, erythematous, and self-limiting and did not require treatment (16c ).

The authors suggest that in patients at risk of hypoglycemia, short-acting somatostatin may be useful to assess response (22A ).

Growth hormone release-inhibiting hormone (somatostatin) and analogues (SED-14, 1522; SEDA-25, 522; SEDA-26, 480; SEDA-27, 467) Metabolism In 24 patients with acromegaly, glucose homeostasis was assessed before and after 6 months of either 2-weekly lanreotide (n = 14) or monthly octreotide (n = 10) (19c ). Insulin resistance and triglyceride concentrations improved. Glucose homeostasis, measured by HBA1c , deteriorated. This was probably due to impaired insulin secretion. There were no distinct differences between the analogues, but the numbers were small.

Octreotide A review of octreotide LAR has suggested that the most common adverse effects are gastrointestinal effects and injection site reactions (20R ). Injection site pain is also common and dose related. The cardiovascular, biliary, and glucose metabolism effects were also reviewed.

• A 62-year-old woman with multiple carcinoid hepatic metastases was given octreotide LAR 20 mg and developed severe hypoglycemia 6 hours later. Parenteral dextrose was continued for a month. Prednisolone was needed to discontinue the dextrose.

Gastrointestinal Radiolabelled isotopes of somatostatin analogues are used in managing patients with neuroendocrine gastroenteropancreatic tumors. The somatostatin analogue (DOTA0,Tyr3)octreotate has been radiolabelled with 177 Lu and used in 35 patients (23c ). Nausea and vomiting within the first 24 hours of administration were common (up to 30%) and abdominal pain occurred in 11%. Liver There have been isolated reports of hepatic dysfunction due to octreotide (24A ). • A 41-year-old woman with hepatocellular carcinoma was treated with chemotherapy. Octreotide 100 micrograms bd and LAR 20 mg was added to her therapy to control symptoms of diarrhea, but 10 days later she developed severe abdominal pain and 10-fold increases in transaminases, which returned to normal 6 weeks after octreotide was withdrawn.

Hair Scalp hair loss occurred in three patients receiving octreotide for acromegaly (25A ). • Hair loss in a 36-year-old man began after 1 month of octreotide. Therapy was changed to lanreotide after 6 months and hair loss reversed. This may have been coincidental.

Four patients who developed hair loss whilst receiving octreotide found that the loss stopped after 3–6 months (20R ). Hair loss has also been reported with lanreotide (SEDA-24, 505).

Miscellaneous hormones

Melatonin

531

Chapter 43

(SEDA-25, 523)

Nervous system Asperger’s disease is a rare neuropsychiatric disorder classified among the spectrum of autistic disorders. Its cause is unknown, but it is thought to be associated with genetic and neurodevelopment factors (26R ). Sleep disturbances are common in patients with Asperger’s disease. Although these sleep problems often persist and can significantly impair the child’s daytime well-being, no treatment studies have been reported. In an open trial, the effectiveness of melatonin 3 mg/day for 14 days was studied in 15 children (13 boys) with Asperger’s disease aged 6–17 years (27c ). Sleep patterns improved in all the children, and half of them had excellent responses. However, one child suffered from excessive tiredness, dizziness, and headache. This was surprising, because in another study 100 children with sleep-related problems took melatonin with no adverse effects (28c ). Drug overdose A 14-year-old girl with major depressive disorder had drowsiness, dizziness, blurred vision, and confusion after taking an overdose of melatonin (24–36 mg) (29A ).

In 238 women with post-menopausal osteoporosis randomly assigned to subcutaneous parathormone(1-84) plus placebo, parathormone plus alendronate, or alendronate plus placebo, there was a significant increase in mean serum uric acid concentrations in those taking parathormone (31c ). Three women had gout, one in the parathormone-only group and two in the combination group. Mineral balance Patients randomly assigned to parathormone(1-84) at doses of 50 micrograms/day (n = 50), 75 micrograms/day (n = 52), 100 micrograms/day (n = 51), or to placebo (n = 53) had a dose-related increase in serum total calcium concentrations. This effect was most evident in the first 6 months and appeared to improve at 6–12 months. There was transient hypercalcemia in 24 patients, of whom 11 were taking 100 micrograms/day (32c ). There was hypercalcemia in 12% of 119 patients taking parathormone(1-84) 100 micrograms/day with daily calcium and vitamin D and in 14% of 59 taking additional alendronate. After stopping the calcium supplements only two women needed a dosage reduction of parathormone (31c ). Skin Injection site reactions are common and do not appear to be dose-related (32c ).

Oxytocin (SED-14, 1523; SEDA-26, 481; SEDA-27, 468) Immunologic Anaphylactoid reactions to oxytocin have been described (30A ).

VASOPRESSIN AND ANALOGUES (SED-14, 1522;

• A 41-year-old woman treated for shock after a septic abortion received an intravenous infusion of oxytocin 40 mU/minute. Just after the infusion started she developed tachypnea, bronchospasm, and laryngeal stridor. Her symptoms disappeared only when the oxytocin was withdrawn.

SEDA-25, 525; SEDA-26, 482; SEDA-27, 469)

Parathyroid hormone (PTH)

Gastrointestinal When arginine vasopressin is used in high single doses (4–16 IU), to control upper gastrointestinal tract bleeding, gut ischemia has been reported (33R ). Continuous infusions at lower doses have shown changes suggestive of splanchnic hypoperfusion.

Skin In a retrospective analysis of 63 pa(SED-14, 1520; SEDA-25, 525; SEDA-26, 481; tients treated with arginine vasopressin for catecholamine resistant vasodilatory shock, 30% SEDA-27, 468) developed ischemic skin lesions (34c ). Preexisting peripheral arterial occlusive disease Metabolism Most studies of parathormone and septic shock were independent susceptibilhave involved parathormone(1-34) (teriparatide). ity factors.

532

Desmopressin (N-deamino-8-D-arginine vasopressin, DDAVP) Electrolyte balance Hyponatremia has often been reported with desmopressin. • A 55-year-old woman with Von Willebrand’s disease was found comatose (35A ). She had received desmopressin as prophylaxis for bleeding several times before without problems. On this occasion she had also received ibuprofen as a pain killer. She was hyponatremic.

NSAIDs inhibit prostaglandin synthesis. This can potentiate the effect of water reabsorption in the renal tubules of vasopressin. In 224 women aged 20–89 years, desmopressin 0.1–0.4 mg/day was used for treating nocturia (36c ). There were five adverse events, four of which were reported in the dose-titration period. Of these four events, two were deaths

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that were not thought to be due to hyponatremia and two were due to serious hyponatremia. The fifth case occurred during the double-blind period in the placebo group. In 27 patients serum sodium concentrations were below the reference range and in 13 they were less than 130 mmol/l; 11 of the 13 were aged 65 years or older.

Terlipressin A review has suggested that terlipressin has fewer adverse effects than vasopressin; however, the studies on which this was based were rated as low in quality (37R ). Gastrointestinal It has been suggested that terlipressin also has vasoconstrictor activity within the splanchnic vascular territory (38A ).

REFERENCES 1. Amino N, Hidaka Y, Takano T, Tatsumi K, Izumi Y, Nakata Y. Possible induction of Graves’ disease and painless thyroiditis by gonadotrophin-releasing hormone analogues. Thyroid 2003; 8: 815–18. 2. Bogdanos J, Karamanolakis D, Milathianakis C, Repousis P, Tsintavis A, Koutsilieris M. Combined androgen blockade-induced anemia in prostate cancer patients without bone involvement. Anticancer Res 2003; 23: 1757–62. 3. Unal O, Berberoglu M, Evliyaoglu O, Adiyaman P, Aycan Z, Ocal G. Effects of bone mineral density of gonadotropin releasing hormone analogs used in the treatment of central precocious puberty. J Pediatr Endocrinol Metab 2003; 16: 407–11. 4. Donnez J, Vivancos BH, Kudela M, Audebert A, Jadoul P. A randomised placebo-controlled, doseranging trial comparing fulvestrant with goserelin in premenopausal patients with uterine fibroids awaiting hysterectomy. Fertil Steril 2003; 79: 1380–9. 5. Rennie MJ. Claims for the anabolic effects of growth hormone: a case of the Emperor’s new clothes? Br J Sports Med 2003; 37: 100–5. 6. Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson BA. Growth hormone increases bone mineral content in postmenopausal osteoporosis: A randomised placebo-controlled trial. J Bone Mineral Res 2003; 18: 393–405. 7. Yeo AL, Levy D, Martin FC, Sonksen P, Sturgess I, Wheeler MM, Young A. Frailty and the biochemical effects of recombinant human growth hormone

in women after surgery for hip fracture. Growth Hormone IGF Res 2003; 13: 361–70. 8. Carvalho LR, Justamante de Faria ME, Osorio MGF, Estefan V, Jorge AAL, Arnhold IJP, Mendonca BB. Acromegalic features in growth hormone (GH)-deficient patients after long-term GH therapy. Clin Endocrinol 2003; 59: 788–92. 9. Kanazawa H, Tanaka H, Inoue M, Yamanaka Y, Namba N, Seino Y. Efficacy of growth hormone therapy for patient with skeletal dysplasia. J Bone Mineral Metab 2003; 21: 307–10. 10. Smida M, Nouri H, Kandara H, Jalel C, Ghachem MB. Bone diseases in children receiving growth hormone. Acta Orthopaed Belg 2003; 69: 458–62. 11. Fine RN, Ho M, Tejani A, Blethen S. Adverse events with rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease. J Pediatr 2003; 142: 539–45. 12. Colao A, Di Somma C, Spiezia S, Filippella M, Pivonello R, Lombardi G. Effect of growth hormone (GH) and/or testosterone replacement on the prostate in GH-deficient adult patients. J Clin Endocrinol Metab 2003; 88: 88–94. 13. Murray RD. Adult growth hormone replacement: current understanding. Curr Opin Pharmacol 2003; 3: 642–9. 14. Monson JP. Long-term experience with GH replacement therapy: efficacy and safety. Eur J Endocrinol 2003; 148: S9–14. 15. Rowles S, Paisley A, Trainer PJ. Somastatin analogue versus growth-hormone antagonist treat-

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ment for acromegaly: who should get what? Curr Opin Endocrinol Diabetes 2003; 10 265–71. 16. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, Van der Lely AJ, Dimarki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Maldonado M, Rose DR, Clemmons DR, Johannson G, Bengtsson B-A, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, Davis RJ. Treatment of acromegaly with growth hormonereceptor antagonist pegvisomant. New Engl J Med 2000; 342: 1171–7. 17. Van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, Klibnaski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart PM, Friend KE, Clemmons DR, Johannsson G, Stavrou S, Cook DM, Phillips LS, Strasburger CJ, Hacker S, Zib KA, Davis RJ, Scarlett JA, Thorner MO. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 2001; 358: 1754–9. 18. Melmed S, Vance ML, Barkan AL, Bengtsson B-A, Kleinberg D, Klibanski A, Trainer PJ. Current status and future opportunities for controlling acromegaly. Pituitary 2002; 5: 185–96. 19. Baldelli R, Battista C, Leonetti F, Ghiggi MR, Ribaudo M-C, Paoloni A, D’Amico E, Ferretti E, Baratta R, Liuzzi A, Trishitta V, Tamburrano G. Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment. Clin Endocrinol 2003; 59: 492–9. 20. McKeage K, Cheer S, Wagstaff AJ. Octreotide long-acting release (LAR) a review of its use in management of acromegaly. Drugs 2003; 63: 2473– 99. 21. Arevalo RP, Bullabh P, Krauss AN, Auld PAM, Spigland N. Octreotide-induced hypoxemia and pulmonary hypertension in premature neonates. J Pediatr Surg 2003; 38: 251–3. 22. Sari H, Altunbas H, Ozdogan M, Gurer EI, Karayalcin U. Severe and prolonged hypoglycemia triggered by long-acting octreotide in a patient with malignant mesenchymal tumor: case report. J Chemother 2003; 15: 85–8. 23. Kwekkeboom DJ, Bakker WH, Kam BL, Teunissen JJM, Kooij PPM, Herder WW, Feelders RA, Eijck CHJ, Jong M, Srinivasan A, Erion JL, Krenning EP. Treatment of patients with gastroentero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue (177Lu-DOTA0, Tyr3)octreotate. Eur J Nucl Med Mol Imaging 2003; 30: 417–22. 24. Uygur-Bayramicli O, Gemici C. Is liver disease an octreotide side effect? J Clin Gastroenterol 2003; 37: 86–7. 25. Lami M-C, Hadjadj S, Guillet G. Hair loss in three patients with acromegaly treated with octreotide. Br J Dermatol 2003; 149: 655–6.

533 26. Gilberg C. Disorders of empathy: autism and autism spectrum disorders (including childhood onset schizophrenia). In: Clinical Child Neuropsychiatry. Gillberg C (editor). Cambridge: Cambridge University Press, 1995: 54–111. 27. Paavonen EJ, Nieminen-von Wendt T, Vanhala R, Aronen ET, Von Wendt L. Effectiveness of melatonin in the treatment of sleep disturbances in children with Asperger disorder. J Child Adolesc Psychopharmacol 2003; 13: 83–95. 28. Jan JE, O’Donnell ME. Use of melatonin in the treatment of paediatric sleep disorders. J Pineal Res 1996; 21: 193–9. 29. Balentine J, Hagman J. More on melatonin. J. Am Acad Child Adolesc Psychiatry 1997; 36: 1013–18. 30. Cabestrero D, Perez-Paredes C, Fernandez-Cid R, Arribas MA. Bronchospasm and laryngeal stridor as an adverse effect of oxytocin treatment. Crit Care 2003; 7: 392. 31. Black DM, Greespan SL, Ensrud KE, Palmero L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. New Engl J Med 2003; 349: 1207–15. 32. Hodsman AB, Hanley DA, Ettinger MP, Bolognese MA, Fox J, Metcalfe AJ, Lindsay R. Efficacy and safety of human parathyroid hormone (1-84) in increasing bone mineral density in postmenopausal osteoporosis. J Clin Endocrinol Metab 2003; 88: 5212–20. 33. Dunser MW, Wenzel V, Mayr AJ, Hasibeder WR. Management of vasodilatory shock defining the role of arginine vasopressin. Drugs 2003; 63: 237–56. 34. Dunser MW, Mayr AJ, Tur A, Pajk W, Barbara F, Knotzer H, Ulmer H, Hasibeder WR. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 2003; 31: 1394–8. 35. Garcia EBG, Ruitenberg A, Madrestsma GS, Hintzen RQ. Hyponatraemic coma induced by desmopresssin and ibuprofen in a woman with von Willebrand’s disease. Haemophilia 2003; 9: 232–4. 36. Lose G, Lalos O, Freeman RM, Van Kerrebroeck P, the Nocturia study group. Efficacy of desmopressin (Minirin) in the treatment of nocturia: a double-blind placebo-controlled study in women. Am J Obstet Gynecol 2003; 189: 1106–13. 37. Ioannou GN, Doust J, Rockey DC. Systematic review: terlipressin in acute oesophageal variceal haemorrhage. Aliment Pharmacol Ther 2003; 17: 53–64. 38. Fellahi JL, Benard P, Daccache G, Mourgeon E, Gerard JL. Vasodilatory septic shock refractory to catecholamines: is there a role for terlipressin? Ann Fr Anesth Reanim 2003; 22: 631–4.

I. Aursnes

44 Ezetimibe

Drugs that affect lipid metabolism (SEDA-27, 473)

Ezetimibe is an inhibitor of cholesterol absorption, which selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. In 432 patients included in a pooled analysis of two phase 2 studies, both lasting for 12 weeks, ezetimibe was well tolerated, with an adverse events profile similar to that of placebo (1c ). Drug interactions In 668 patients ezetimibe was given with simvastatin and adverse effects were similar to those experienced with simvastatin alone (2C ). Ezetimibe plus atorvastatin was also well tolerated in 628 patients, with a safety profile similar to that of atorvastatin alone and to placebo. When co-administered with atorvastatin, ezetimibe provided significant incremental reductions in LDL cholesterol and triglycerides and increased HDL cholesterol (3C ).

Fibrates

(SED-14, 1527; SEDA-25, 533; SEDA-26, 486; SEDA-27, 473)

Metabolism Fenofibrate and bezafibrate were associated with hyperhomocysteinemia, which is a risk factor for coronary heart disease. In a review, the underlying causes for this adverse effect were discussed (4R ). The authors suggested using gemfibrozil instead or adding vitamin B12 and folic acid. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

534

Drug interactions Repaglinide Possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide have been investigated in a randomized crossover study in 12 healthy volunteers who took gemfibrozil 600 mg bd, itraconazole 100 mg/day (first dose 200 mg), both gemfibrozil and itraconazole, or placebo, each for 3 days (5c ). On day 3 they took a single dose of repaglinide 0.25 mg. Plasma drug and blood glucose concentrations were followed for 7 hours and serum insulin and C peptide concentrations for 3 hours after the dose. Gemfibrozil increased the AUC of repaglinide 8 (range 5.5–15) times and prolonged its half-life from 1.3 to 3.7 hours. Although itraconazole alone increased the AUC of repaglinide only 1.4 (1.1–1.9) times, the combination of gemfibrozil + itraconazole increased it 19 (13–25) times and prolonged the halflife of repaglinide to 6.1 hours. The plasma repaglinide concentration at 7 hours was increased 29 times by gemfibrozil and 70 times by the combination of gemfibrozil + itraconazole. Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide. Concomitant use of gemfibrozil and repaglinide is best avoided. Rosiglitazone Gemfibrozil increases plasma concentrations of rosiglitazone, probably by inhibiting the metabolism of rosiglitazone by CYP2C8. Co-administration of gemfibrozil, or another potent inhibitor of CYP2C8, and rosiglitazone could increase the efficacy of rosiglitazone, but could also increase the risk of adverse effects (6C ). Warfarin Fibrates can potentiate the anticoagulant effects of warfarin (SED-14, 1529). From such reports and two additional cases with fenofibrate, a 20% reduction in warfarin

Drugs that affect lipid metabolism

dosage, followed by close INR monitoring, has been suggested (7C ).

Fish oil

535

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(SED-14, 534)

Fish oil is effective and generally well tolerated in patients with very high serum triglyceride concentrations and can be used as either alternative or adjunctive therapy when conventional treatments become ineffective or intolerable. Liver Two individuals with serum triglyceride concentrations over 11.3 mmol/l (1000 mg/dl) were referred to a pharmacist-managed lipid clinic by their primary-care provider because of either treatment failure or intolerance of conventional therapies (8A ). Fish oils were used in one case in lieu of and in the other in addition to conventional treatments. Although fish oil has not been reported to cause hepatotoxicity, both of these patients had increased transaminases while taking fish oil. Whether fish oil truly causes hepatic injury remains to be elucidated.

HMG-CoA reductase inhibitors (SED-14, 1530; SEDA-25, 533; SEDA-26, 487; SEDA-27, 473) Psychological Emerging data associate statins with a reduced risk of Alzheimer’s disease; however, two women had significant cognitive impairment temporally related to statin therapy (9A ). One took atorvastatin, and the other first took atorvastatin then simvastatin. Cognitive impairment and dementia as potential adverse effects associated with statins has been reviewed (10R ). When the MedWatch drug surveillance system of the Food and Drug Administration (FDA) from November 1997 to February 2002 was searched for reports of statin-associated memory loss, 60 patients were identified; 36 had taken simvastatin, 23 atorvastatin, and one pravastatin (10R ). About a half of the patients noted cognitive adverse effects within 2 months of therapy and 14 of 25 patients noted improvement when the statin was withdrawn. Memory

loss recurred in four patients who were rechallenged. The current literature is conflicting with regard to the effects of statins on memory loss. Experimental studies support links between cholesterol intake and amyloid synthesis; however, observational studies suggest that patients taking statins have a reduced risk of dementia. However, available prospective studies show no cognitive or antiamyloid benefits of any statin. Musculoskeletal Chinese red rice products include natural HMG CoA reductase inhibitors (primarily lovastatin) and are used as cholesterol-lowering agents. • A 50-year-old man presented with joint pain and muscle weakness in his upper right arm (11A ). His history was unremarkable, except for the fact that he had started taking a Chinese red rice preparation 3 months earlier, 1 month before the onset of symptoms. He was instructed to stop taking this medicine, and 3 weeks later his symptoms had completely resolved.

Drug interactions Rhabdomyolysis was associated with third-degree atrioventricular block in a patient taking atorvastatin with esomeprazole and clarithromycin. • A 51-year-old white woman developed severe weakness, near syncope, shortness of breath, and chest pain. She had complete heart block. The creatine kinase activity was over 7000 U/l. She had taken atorvastatin for more than 1 year, esomeprazole for 6 weeks, and three doses of clarithromycin 500 mg just before the episode. Her symptoms coincided with starting to take esomeprazole.

The pharmacokinetic profiles of these agents suggested that esomeprazole had inhibited P glycoprotein, reducing the normal first-pass clearance of atorvastatin (12C ). Rhabdomyolysis has been attributed to the combination of fusidic acid with statins. • A 71-year-old man developed nausea, abdominal discomfort, and myalgia after taking fusidic acid for 4 weeks. The next day he had myoglobinuria. Simvastatin, which he had taken for 8 years, was withdrawn. Prompt clinical improvement followed (13C ).

Atorvastatin Nervous system Peripheral neuropathy has occasionally been reported in patients taking

536 statins (SEDA-24, 510; SEDA-27, 473) and in a case-control study (14C ). • A 57-year-old man in good health took atorvastatin 5 mg and aspirin 75 mg/day and had progressive numbness and burning in both feet for 6 months (15C ). Muscle punch biopsies showed a neuropathic process affecting small-caliber sensory nerve fibers. The symptoms resolved 3 months after withdrawal of atorvastatin.

Liver Acute hepatitis has been attributed to statins. • A 65-year-old woman developed fatigue, jaundice, and altered liver function tests while taking atorvastatin (20 mg/day for some weeks) (16A ). On the basis of clinical, serological, and histological findings, a diagnosis of autoimmune hepatitis was made.

The authors suggested that atorvastatin may have unmasked an underlying autoimmune hepatitis. Immunologic Hypersensitivity reactions have been seen with statins (SED-14, 1531; SEDA27, 474). • A patient developed atorvastatin-induced severe autoimmune hepatitis and a lupus-like syndrome. Although the drug was immediately withdrawn, the disease persisted and deteriorated to a fulminant form with acute hepatic failure. There was no response to conventional immunosuppression with glucocorticoids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery. The patient had the HLA haplotypes DR3 and DR4, which are wellknown genetic factors associated with autoimmune diseases.

This case is the first report of drug-induced lupus-like syndrome concomitant with severe autoimmune hepatitis in a genetically predisposed patient (17C ). Drug interactions CYP3A4 activates clopidogrel and atorvastatin competitively inhibits this activation. It has therefore been suggested that the use of a statin that is not metabolized by CYP3A4 and platelet function testing are warranted in patients taking clopidogrel (18C ). However, this predicted interaction was not observed in a post hoc analysis of a placebocontrolled study (19C ). The comments of others show that this question is not yet settled (20r ).

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Simvastatin Skin A generalized exanthematous pustulosis was believed to have been due to simvastatin 20 mg/day for 2 weeks, in that oral rechallenge produced pustular lesions within 3 hours in a 57-year-old man (21A ). • A 63-year-old man took simvastatin for hypercholesterolemia for 2 months and 1 month later developed a pruriginous and bullous lichenoid eruption (22C ). Histological and direct immunofluorescent features were consistent with the diagnosis of lichen planus pemphigoides. Western blot analysis showed antibodies against a 180 kDa antigen. All the lesions disappeared gradually after simvastatin was withdrawn.

Drug interactions Concomitant treatment with simvastatin and bosentan (the first orally active endothelin receptor antagonist) reduces exposure to simvastatin by about 40%, suggesting that in vivo bosentan is a mild inducer of CYP3A4 (23C ). A potential drug interaction between simvastatin and danazol, causing rhabdomyolysis and acute renal insufficiency, has been reported (24A ). Rhabdomyolysis can occur with all statins when they are used alone and particularly when they are combined with other drugs that are themselves myotoxic or that increase the concentration of the statin. Statins are particularly susceptible to the latter effect because of their metabolism by the CYP450 system and their low oral systemic availability.

NICOTINIC ACID DERIVATIVES (SED-14, 1533; SEDA-25, 531; SEDA-27, 475)

Nicotinic acid The effects and adverse reactions of nicotinic acid (niacin) have been reviewed (25R ). Standard nicotinic acid from an immediate-release formulation is metabolized primarily by conjugation, which results in a high frequency of flushing. Long-acting nicotinic acid is metabolized through the nicotinamide pathway, which results in less flushing but increases the risk of hepatotoxicity. Extended-release nicotinic acid, on the other hand, has a more balanced metabolism and causes fewer of both types of adverse effects.

Drugs that affect lipid metabolism

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REFERENCES 1. Bays HE, Moore PB, Drehobl MA, Rosenblatt S, Toth PD, Dujovne CA, Knopp RH, Lipka LJ, LeBeaut AP, Yang B, Mellars LE, Cuffie-Jackson C, Veltri EP, for the Ezetimibe Study Group. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther 2001; 23: 1209–30. 2. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S, Veltri EP. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40: 2125–34. 3. Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, Le Beaut AP, Sager PT, Veltri EP, for the Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003; 107: 2409–15. 4. Dierkes J, Westphal S, Luley C. Fenofibrateinduced hyperhomocysteinemia: clinical implications and management. Drug Saf 2003; 26: 81–91. 5. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46: 347–51. 6. Niemi M. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 2003; 46: 1319–23. 7. Kim KY, Mancano MA. Fenofibrate potentiates warfarin effects. Ann Pharmacother 2003; 37: 212– 15. 8. Caron MF, Nguyen IT, Folstad JE. Treatment of very high triglycerides with fish oils: a review of 2 cases. J Pharm Technol 2003; 19: 14–18. 9. King DS. Cognitive impairment associated with atorvastatin and simvastatin. Pharmacotherapy 2003; 23: 1663–7. 10. Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 1920; 23: 871–80. 11. Smith DJ, Olive EO. Chinese red rice-induced myopathy. South Med J 2003; 96: 1265–7.

12. Sipe BE, Jones RJ, Bokhart GH. Rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction. Ann Pharmacother 2003; 37: 808–11. 13. Yuen SL, McGarity B. Rhabdomyolysis secondary to interaction of fusidic acid and simvastatin. Med J Aust 2003; 179: 172. 14. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology 2002; 58: P1333–7. 15. Silverberg C. Atorvastatin-induced polyneuropathy. Ann Int Med 2003; 139: 792–3. 16. Pelli N. Autoimmune hepatitis revealed by atorvastatin. Eur J Gastroenterol Hepatol 2003; 15: 921–4. 17. Graziadei IW. Drug-induced lupus-like syndrome associated with severe autoimmune hepatitis. Lupus 2003; 12: 409–12. 18. Lau WC. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003; 107: 32–7. 19. Saw J. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 2003; 108: 921–4. 20. Serebruany VL. Are antiplatelet effects of clopidogrel inhibited by atorvastatin? A research question formulated but not yet adequately tested. Circulation 2003; 107: 1568–9. 21. Oskay T. Acute generalized exanthematous pustulosis induced by simvastatin. Clin Exp Dermatol 2003; 28: 558–9. 22. Stoebner P. Lichen plan pemphigoide induit par la simvastatine. Ann Dermatol Venereol 2003; 130: 187–90. 23. Dingemanse J. Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet 2003; 42: 293–301. 24. Andreou ER. Potential drug interaction between simvastatin and danazol causing rhabdomyolysis. Can J Clin Pharmacol 2003; 10: 172–4. 25. McKenney J. Niacin for dyslipidemia: considerations in product selection. Am J Health-Syst Pharm 2003; 60: 995–1005.

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45

Cytostatic drugs

Editor’s note: The wide range of cytostatic drugs, the multitude of their adverse effects, and the fact that they are generally used in combinations of several agents all make it impossible to provide as detailed a review of the adverse effects of all the drugs in this field as the Annual gives in others. This year most of this chapter is devoted to a special review of the adverse effects of the vinca alkaloids, by Drs Lipp and Hartmann. The rest of the chapter is by Dr Stanley, who thanks those clinicians and researchers who have sent him copies of their original research papers. Previous special reviews in this chapter have been as follows: • • • • •

Anthracyclines (SEDA-25, 533) Fluorouracil (SEDA-23, 476) Inhibitors of topoisomerase I and topoisomerase II (SEDA-27, 477) Paclitaxel (SEDA-21, 463) Platinum compounds (SEDA-26, 490)

Vinca alkaloids From among nearly 30 different alkaloids that have been isolated from the periwinkle Catharanthus roseus (Apocynaceae), vincristine and vinblastine have been assessed to have the highest antitumor activity. Both have a large dimeric asymmetric structure composed of a dihydroindole nucleus (vindoline ring) and an indole nucleus, linked by a carbon-carbon bond. In contrast, the derivatives vindesine (deacetyl vinblastine amide sulfate) and vinorelbine are semisynthetic (1R , 2R , 3E ). Finally, vinflunine represents the latest semisynthetic vinca alkaloid. This fluorinated derivative is still under clinical investigation and has a different inhibitory action than other vinca alkaloids. Preliminary results suggest that this congener may be less toxic on the peripheral and autonomic nervous systems (4R ). Vincristine Vincristine is part of many chemotherapeutic regimens, based on its lack of © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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myelosuppressive toxicity. It is used, for example, in the treatment of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), lymphomas, neuroblastoma, brain tumors, and Wilms’ tumor. The generally recommended dose in adults is 1.4 mg/m2 /week intravenously (5R ). Some clinicians have recommended an absolute upper limit of 2 mg, but this limitation is still a matter of debate (6r ). The usual pediatric dosage is 1.5–2 mg/m2 , but for children weighing 10 kg or less or who have a body surface area less than 1 m2 , the manufacturers recommend that treatment should be begun at 0.05 mg/kg once a week (5R ). Vinblastine Vinblastine is used in combination with other cytotoxic agents for the treatment of disseminated Hodgkin’s disease stages III and IV, non Hodgkin’s lymphoma, histiocytic lymphoma, and advanced carcinoma of the testis. It has also been used for the treatment of bladder cancer, melanoma, and renal cell cancer. The usual adult dosage is 3–6 mg/m2 intravenously for the treatment of testicular germ cell tumors and Hodgkin’s disease (1R , 2R ).

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Vindesine Vindesine (deacetyl vinblastine amide sulfate, DVAS) was the first semi-synthetic vinca alkaloid derivative introduced into clinical oncology. It differs solely from vinblastine in the nature of the substituted functional group attached to the vindoline ring. Vindesine was most extensively studied in the treatment of non-small cell lung cancers. A randomized study showed that vindesine (3 mg/m2 intravenously) was substantially better than vincristine (1.4 mg/m2 intravenously) both given weekly for 4 weeks, then every 2 weeks for 1 months, then monthly. However, another study showed that vindesine may be inferior to the structurally related vinorelbine in the treatment of advanced non-small cell lung cancers, with overall response rates of 9% and 29% respectively. Vindesine has also been used in patients with advanced malignant melanomas. Potential indications that have been studied with vindesine include head and neck cancer, acute lymphocytic leukemia, lymphomas, and breast cancer. However, its precise role and clinically relevant advantages to other available vinca alkaloids needs further investigation (7R , 8R , 9E , 10E ). Vinorelbine Vinorelbine has become the principal agent for treating adjuvant non-small cell lung cancer (stages IB–III) and the palliative treatment of non-small cell lung cancer (stages IIIB and IV), sometimes in combination with drugs like cisplatin. In addition, vinorelbine plays an important part in the treatment of advanced and metastatic breast cancer. Its role in the treatment of advanced cervical cancer is still under investigation. The usual intravenous dosage is 20–30 mg/m2 (vinorelbine base) given once a week. In contrast to the other congeners, vinorelbine can also be taken orally, based on its absolute systemic availability of about 44% after administration as a capsule. Oral dosages of 60 mg/m2 and 80 mg/m2 have been said to be pharmacokinetically and clinically equivalent to intravenous dosages of 25 mg/m2 and 30 mg/m2 respectively (2R , 11c , 12c ). Mechanism of action All four vinca alkaloids block mitosis with metaphase arrest. Their antitumor activity is based on their high binding affinity to intracellular tubulin, which is the protein subunit of the spindle microtubules.

539 The binding constants of vincristine, vinblastine, and vindesine for tubulin are 8 nmol/l, 6 nmol/l, and 3.3 nmol/l respectively (9E , 10E ). The formation of complexes between the vinca alkaloids and tubulin prevents the polymerization of the tubulin subunits to microtubules, which results in depolymerization of microtubules and inhibition of microtubule assembly. Based on the fact that microtubule assemblies also play a pivotal role in the movement of neurotransmitter substances along neuronal axons, vinca alkaloids can cause neurotoxicity, particularly at higher concentrations (9E , 10E ). Pharmacokinetics After intravenous administration, plasma concentrations of vinca alkaloids fall triphasically with an initial rapid phase. All four congeners are extensively distributed into peripheral compartments, but passage across the blood-brain-barrier is limited (11c , 12c ). In addition to tissue binding, vinca alkaloids binding to blood constituents like human platelets and lymphocytes. Binding to plasma proteins has been estimated to be from about 80% to more than 90%, with an unbound fraction of about 0.10–0.20. Binding to whole blood is usually higher than in serum, which reflects substantial binding to platelets (11c , 12c ). All four congeners are extensively metabolized in the liver and excreted in the bile (13c ). Their metabolic biotransformation is primarily mediated by CYP3A. Deacetylvinorelbine, the primary metabolite of vinorelbine, has remarkable antitumor activity; however, the amounts detected in blood after conventional doses of vinorelbine are very low, which suggests that this metabolite does not contribute significantly to the overall antitumor activity of vinorelbine (14c , 15r ). Based on the pivotal role of CYP3A isozymes during the catabolism of vinca alkaloids, care is warranted when using concomitant drugs that inhibit these isozymes (16E , 17E ). The half-lives of vinblastine, vindesine, and vinorelbine are all about 24 hours; vincristine has a much longer half-life of about 3.5 days (5R ). Because biliary and fecal drug excretion is of major quantitative importance during the elimination of vinca alkaloids, patients with impaired hepatic clearance and increased bilirubin concentrations may need dosage modification in order to avoid critical drug accumulation. CYP3A4 activity measurement (for

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example by the monoethylglycinexylidide test) would be the most appropriate method to assess the individual capacity to metabolize drugs like vinorelbine; however, such methods have not yet been routinely established in most cancer centers. Empirically, it is prudent to reduce doses by about 50% in patients with liver volume replacement by tumor that exceeds 75% (18C ). Vinorelbine is the only vinca congener that can also be used orally. Its oral availability is not affected by food (19C ). The interpatient variability in blood concentrations is in the same range as after intravenous administration (15r ). General adverse effects The most important adverse effects of vinca alkaloids include nervous system disorders, hematological effects, and gastrointestinal discomfort. Respiratory and cardiovascular adverse effects have to be particularly considered during combination chemotherapy. All the vinca alkaloids are tissue irritants, and extravasation without any adequate supportive management can result in severe local ulceration (1R , 2R , 5R , 8R , 20c ).

with ischemic heart disease than other cancer chemotherapeutic agents. Whether druginduced platelet activation, altered clotting, or endovascular damage are responsible for vascular toxicity is still unclear. The risk of ischemic heart disease must therefore be kept in mind when patients receive a combination of doxorubicin and vincristine, especially when potential risk factors have been identified. Whether the structural similarity between vinca alkaloids and ergot alkaloids, which are vasospastic, is relevant, is highly speculative. After administration of vinorelbine, chest pain occurs in up to 5% of patients. However, subsequent analysis showed that most patients had underlying cardiovascular disease or a tumor in the chest, making interpretation difficult (2R , 20c ).

Respiratory Acute shortness of breath and bronchospasm have been reported after the administration of vinca alkaloids, for example vinblastine and vindesine (24A –28A ). The respiratory effects, including abrupt onset of progressive dyspnea, non-productive cough, pleuritic chest pain, profound wheezing, and Cardiovascular Vinca alkaloid-associated my- diffuse basal crackles, were more common when ocardial infarction, angina pectoris, and tran- mitomycin was used concomitantly. The onsient electrocardiographic changes related to set of symptoms can be rapid (for example coronary ischemia are limited to case reports a few minutes to 1–5 hours after adminis(21A –23A ). In addition, patients with these tration) or subacute (for example up to 2 adverse effects received combination cancer weeks). If patients have pre-existing pulmonary chemotherapy containing drugs, such as bleo- dysfunction, intensified treatment including glumycin and cisplatin, which both have been cocorticoids may be indicated. Most reports of suggested to cause cardiovascular adverse ef- vinca alkaloid-associated pulmonary toxicity have related to vinblastine, usually in combifects. nation with other known pneumotoxic agents or • A 64-year-old Japanese man developed chest pain thoracic irradiation. Patients receiving combiwith concomitant lateral ST segment depression af- nation chemotherapy including vinca alkaloids ter treatment with intravenous cisplatin 70 mg/m2 , vincristine 1.2 mg/m2 , and bleomycin 12 units/m2 . should be monitored carefully for pulmonary There was no history of predisposing factors and symptoms. The underlying mechanism of vinca the symptoms disappeared quickly with glyceryl alkaloid pulmonary toxicity is unclear, but may trinitrate. During the following cycle containing involve a hypersensitivity reaction. cisplatin and verapamil as an antianginal agent, chest pain did not reoccur (22A ). • A 46-year-old man developed a Q wave inferior and a right ventricular myocardial infarct with post-infarction angina after the third cycle of vincristine + doxorubicin for multiple myeloma (23A ). He had no hyperviscosity nor any risk factors for ischemic heart disease, except for a positive smoking history.

There is some evidence that both vincristine and doxorubicin are more often associated

Nervous system The most commonly reported dose-limiting toxic effect of vinca alkaloids is a mixed sensorimotor polyneuropathy (29R ). Vincristine has been associated with highest incidence of sensorimotor polyneuropathy, followed by vindesine and vinblastine; vinorelbine causes less neurotoxicity than the other congeners (2R , 5R , 8R , 30A ). The neurotoxic effects of vinca alkaloids are reversible (5R ).

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The vinca alkaloids can have synergistic effects on the nervous system. Among 17 patients with metastatic breast cancer given a four-drug combination, vincristine + vinblastine + doxorubicin + cyclosphosphamide, there was a high incidence of acute neurotoxicity at half the usual therapeutic dose of vincristine and vinblastine (31c ). Nerve palsies Cranial nerve palsies can occur with the vinca alkaloids (32A –35A ). Peripheral neuropathy The features of vinca alkaloid-induced polyneuropathy include early loss of tendon reflexes at the ankles and distal paresthesia, followed by loss of touch, pain, and vibration sensations. Other symptoms include headache, malaise, weakness, dizziness, severe face and jaw pain, and vocal cord paralysis. The first symptoms usually occur a few days after drug administration (30A , 36A ). Gastrointestinal discomfort, particularly constipation, abdominal pain, and adynamic ileus, can occur through an autonomic neuropathy (5R , 37A ). Higher drug concentrations during monotherapy (possibly related to impaired drug excretion in patients with hepatic dysfunction) or prolonged periods of treatment are important predisposing factors for more severe forms of neurotoxicity. The same is true of concomitant use of potent CYP3A inhibitors, such as erythromycin, itraconazole, or quinupristin + dalfopristin, which can increase plasma vinca alkaloid drug concentrations (5R ). The pathogenesis of vincristine-induced neuropathy has not been fully elucidated, but very probably altered axoplasmic transport processes are of major importance, since neurons treated with vincristine lose portions of their axonal microtubules (29R ). There is marked interindividual variability in sensitivity to this toxic effect, partly based on different predisposing factors, for example diabetes mellitus, pre-treatment with other potentially neurotoxic agents (such as cisplatin and taxanes), or familial disorders (such as Charcot–Marie– Tooth syndrome) (31c , 38A , 39A ). Several drugs have been proposed to be neuroprotective, including folinic acid, vitamin B1 , vitamin B6 , glutamic acid, Org 2766, insulinlike growth factor (IGF-1), and nerve growth factor. However, most drugs have been studied in experimental systems and there are only a few case reports suggesting clinical benefit. In contrast, folinic acid and vitamins B1 , B6 ,

541 and B12 , which were promising in experimental systems, failed to provide protection from vincristine-induced neuropathy. In the case of L-glutamic acid, which can be given orally, there was some neuroprotective activity; however, more information is needed to exclude any impairment of vincristine-induced antineoplastic activity, when both agents are used together on the same day (5R ). The ACTH analogue Org 2766 was studied in a randomized, double-blind, placebocontrolled trial as a neuroprotective agent in patients receiving vincristine (40c ). In spite of positive results, the study design was later criticized because of a significantly higher number of younger patients in the Org 2766 group. In addition, there are contradictory results on the potential effect of Org 2766 on the overall antineoplastic activity of vincristine. During recent years more attention has been paid to nerve growth factor as a neuroprotective agent, since it may induce microtubule assembly, especially during neurite outgrowth. For instance, patients with a sensory neuropathy related to the use of cancer chemotherapy including paclitaxel, vincristine, or cisplatin, had a significant reduction in plasma nerve growth factor concentrations (5R ). Acetyl-L-carnitine has been considered for neuroprotection because it increases nerve growth factor expression. However, as in the case of L-glutamine or Org 2766, more information is needed to evaluate any potential effect on vincristine antitumor efficacy. Finally, the aminothiol amifostine has been proposed to be effective in preventing vincristine-induced neurotoxicity; however, clinical data are still lacking to assess its role as a neuroprotective agent in terms of vinca alkaloids (5R ). Myeloencephalopathy Central nervous system toxicity is unusual with vinca alkaloids, because they do not readily cross the blood–brain barrier. However, fatal myeloencephalopathy can occur a few hours after accidental intrathecal drug administration (41A , 42A ), with severe bilateral leg pain and over the next 36 hours progressive leg weakness, urinary retention, meningism, fever, and somnolence. Other effects include absence of deep tendon and gag reflexes and disappearance of rectal tone. In spite of high-dose folinic acid rescue, patients became comatose, for example by the fourth day

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after injection, with loss of brain stem function a few days later. Seizures Seizures associated with intravenous use of vinca alkaloids are very rare (43A –45A ). Some cases may have been due to SIADH-associated hyponatremia. Other forms include tumor-related effects, nervous system infections, or cerebral hemorrhage, which often make direct causal relations between drug exposure and nervous system adverse effects very difficult. • An 8-year-old girl with leukemia had tonic–clonic convulsions and life-threatening encephalopathy after intravenous vincristine. After the second dose (1.5 mg/m2 in combination with prednisone) she developed seizures and bilateral translucencies on CT scan. When vincristine was withdrawn in subsequent cycles, the symptoms disappeared (44A ).

Four of 350 patients without a history of seizures developed generalized seizures 5–6 days after the first, second, and eleventh doses of intravenous vincristine. However, seizures did not recur in later cycles. It is difficult to implicate vincristine as a cause of these adverse effects (45A ). Tonic–clonic seizures were only reported in four patients 7 days after vindesine administration. All patients had preexisting cerebral deposits of melanoma possibly mimicking nervous system adverse effects (8R ). Sensory systems Eyes Reversible visual damage has been attributed to vincristine. • An 18-year-old man with lymphocytic leukemia became completely blind for 6 months after a fifth 10-day cycle of therapy with vincristine 2 mg intravenously followed by cyclophosphamide 600 mg orally for 5 days with prednisolone 100 mg orally for 5 days (46A ). • A 15-year-old girl developed bilateral optic atrophy after treatment with weekly vincristine, posterior craniectomy, and whole neuraxis radiation therapy (47A ). Withdrawal resulted in recovery of visual function.

Of 50 patients, ptosis and diplopia related to vincristine occurred in 16 (47A ). The exact pathomechanism of this vincristine-related side effect has not been elucidated. Ears Vinca alkaloids can have ototoxic effects, such as tinnitus and transient hearing loss. In addition, vestibular disorders can cause dizziness, nystagmus, and vertigo (48R , 49c , 50A ).

• A 29-year-old man with recurrent Hodgkin’s disease was treated with the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) (50A ). He complained of tinnitus after each treatment cycle, with an onset of about 6 hours and a duration of 7–10 days. These symptoms interfered with reading, watching television, and general concentration. Audiography, performed before and several hours after several cycles, showed evidence of mild sensorineural hearing loss in the high-decibel range 48 and 72 hours after drug administration. Six months after the completion of cancer chemotherapy, there was still some mild high-frequency sensorineural hearing loss in the left ear.

The authors concluded that vinblastine may have been responsible, because the other agents have not yet been associated with ototoxicity and because vincristine can cause ototoxicity too. The mechanism of this adverse effect is unclear but may involve vinca alkaloid-associated damage to the eighth cranial nerve. This means that care should be taken when vinca alkaloids are used together with platinum compounds, especially cisplatin. Endocrine A rare but well-known adverse effect of vinca alkaloids, including vinorelbine, is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (51A –53A ). The diagnosis is usually based on clinical and laboratory findings. There are falls in plasma sodium (below 120 mmol/l), chloride (below 90 mmol/l) and osmolality (below 230 mosm/kg). Further features include lethargy, anorexia, nausea, listlessness, and rarely coma, particularly when serum sodium falls below 110 mmol/l. Treatment is based on withdrawal of the causative agent and the administration of NaCl 0.9% and potassium (for example 40 mmol/l) at an infusion rate of 200 ml/hour. Further treatment strategies include demeclocycline (for example 300 mg bd), which can be continued for the duration of further vinca alkaloid-containing cycles. In one case demeclocycline prevented SIADH during further courses of vinorelbine (53A ). Asian patients have been proposed to be at higher risk of SIADH during treatment with vincristine. Between 1983 and 1999, 76 cases of hyponatremia and/or SIADH related to the use of vincristine were reported to the global adverse event database of Eli Lilly and Company. The average age of the patients was 36 years (range 2 weeks to 86 years) and 62%

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were male. Most of the patients had received vincristine for leukemia or lymphomas. Of the 76 reports, 39 included background information on race: 35 patients were Asian, three were Caucasian, and one was black. The authors concluded that there may be a correlation between race and vinca alkaloid-associated SIADH/hyponatremia; however, the reasons are still unclear (54r ). Hematologic The most frequent adverse effect of vinblastine, vindesine, and vinorelbine is hematological toxicity (1R , 2R , 5R , 7R , 8R ). Leukopenia, particularly neutropenia, occurs more often than thrombocytopenia or anemia. The nadir in the leukocyte count after vinblastine occurs 4–10 days after administration, with recovery within another 7–14 days. Blood counts should generally be measured weekly and before the administration of each dose, in order to avoid severe forms of myelosuppression, neutropenic fever, or infections (20c ). Oral vinorelbine is also associated with neutropenia. In one small study in patients with breast cancer treated with 50–160 mg/week the incidence of grade 3 to 4 neutropenia was 32% (14c ). The incidence of severe neutropenia is higher with vinorelbine than the other vinca alkaloids. However, mean recovery (about 9 days) appears to be somewhat shorter with vinorelbine than with compounds vinblastine and vindesine (average 14–21 days) (1R , 2R ). Gastrointestinal Constipation is common when vinca alkaloids cause an autonomic neuropathy. Laxatives such as lactulose or polyethylene glycol-containing solutions can prevent adynamic subileus during treatment courses containing vinca alkaloids (37A , 55A ). In contrast to constipation, nausea and vomiting are neither frequent nor dose-limiting adverse effects of vinca alkaloids. The regular use of antiemetics, such as 5HT3 receptor antagonists in combination with dexamethasone, is not recommended. However, oral vinorelbine has been associated with more severe forms of nausea and vomiting, with a frequency that is higher than after intravenous administration; in these patients and in particular those with predisposing factors for nausea and vomiting, metoclopramide and 5HT3 receptor antagonists are justified (56C ).

543 Skin Vinca alkaloids are potential vesicants (57R , 58A , 59r ) and accidental drug extravasation can cause severe soft tissue ulceration. The initial symptoms include marked pain, erythema, and local swelling for several hours up to a day; later effects include blisters and severe painful skin ulcers, several days and 3 weeks after extravasation respectively. The lesions usually heal very slowly and sometimes require surgical intervention. Because vinca alkaloid extravasation can have severe effects, the use of antidotes is highly recommended when extravasation is suspected. In addition, venous irritation can be worsened if the vinca alkaloid is infused over at least 20–30 minutes rather than 6–10 minutes. Among several antidotes for the treatment of vinca alkaloid extravasation, hyaluronidase is the most effective (60c ). Seven patients with extravasation of vincristine, vinblastine, or vinorelbine received hyaluronidase 250 units diluted in 6 ml of NaCl 0.9%, through the indwelling needle or, when the needle had been already removed, as six subcutaneous injections around the extravasation site. None developed skin necrosis. Local mild skin warming in order to produce local vasodilatation may have an additional beneficial effect, but should be avoided when simultaneous extravasation of a vinca alkaloid and an anthracycline is suspected, because local warming can worsen the anthracycline-associated local reaction, whereas local cooling, which is generally beneficial in anthracycline-related extravasation alone, can worsen skin necrosis due to vinca alkaloids (57R ). Hair Vinca alkaloids are associated with a low incidence of alopecia. In about 10% of patients, there can be gradual thinning of hair, but very few patients develop total hair loss (1R , 5R , 7R ). Reproductive system Based on comparative studies of the relative gonadal toxicity of several antineoplastic agents in experimental models and humans, the vinca alkaloids vinblastine and vincristine have negligible potency for killing stem cells. Permanent recovery of sperm counts and preserved ovarian function, depending on the patient’s age at the time of treatment and the total cumulative dose, can be expected after treatment with vinca alkaloids (61R , 62R , 63A ).

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Drug tolerance Resistance to vinca alkaloids can be mediated by glycoprotein B, a transmembrane pump that is part of the multidrug resistance (MDR) phenotype (5R ). Mutagenicity Vinca alkaloids are less mutagenic than other cytotoxic agents like the NLost derivatives or bleomycin. Positive or negative results in mutagenicity tests depend on the test system used. For instance, vinorelbine significantly increased the frequencies of micronuclei in binucleate lymphocytes (64E ). In Chinese hamster ovary cells vinorelbine arrested cells at the first metaphase and caused an increase in abnormal anaphases, containing chiefly lagging chromosomes and multipolar spindles (65E ). These results suggest that vinorelbine does not directly damage DNA, but acts on spindle microtubules, altering chromosome movement and causing aneuploidy. However, it has no mutagenic effects in the Ames test. Carcinogenicity In the International Agency for Research and Treatment of Cancer (IARC) the vinca alkaloids were classified in group 3, which means that they cannot yet be classified in group 1 (proven human carcinogens), 2A (probably carcinogenic), or 2B (possibly carcinogenic) (66R , 67R ). Teratogenicity There is evidence that vinca alkaloids are teratogenic. Vinblastine caused malformations after first trimester administration (68A , 69A , 70ES ). However, since vinca alkaloids are often combined with other cytotoxic drugs, it is difficult to relate any teratogenic effect to the vinca alkaloid alone (68A ). In mice and rabbits vinblastine was embryotoxic and fetotoxic (70ES ). However, it is unclear whether vinca alkaloids can cross the placenta because of their high molecular weights (about 1000 g/mol). Two pregnant women with breast cancer received two or three courses of intravenous vinorelbine 20–30 mg/m2 and fluorouracil 500– 750 mg/m2 at 24, 28, and 29 weeks of gestation; there were no adverse effects in the two newborns (69A ). A third patient also had epirubicin and cyclophosphamide and her infant, who had been exposed to the 4-drug regimen, developed transient anemia at 21 days of age which resolved spontaneously. All three infants were developing normally at 2–3 years of age.

According to the FDA classification the potential therapeutic benefits of vinca alkaloids have to be outweighed with the potential teratogenic risks (FDA classification D). All women of child-bearing potential should be advised to avoid becoming pregnant while receiving cytotoxic cancer chemotherapy (61R ). Drug interactions Vinca alkaloids are primarily metabolized by CYP3A4, inducers and inhibitors of which can significantly change vinca alkaloid pharmacokinetics (16E , 17E , 71A ). Potent inhibitors of CYP3A4 include itraconazole, ketoconazole, and voriconazole, quinupristin + dalfopristine, and erythromycin and some other macrolide antibiotics. In contrast, potent CYP3A4 inducers, such as carbamazepine and phenytoin, increase the clearance of vincristine and related compounds. Asparaginase Asparaginase and vincristine should not be used together on the same day, since simultaneous administration can cause increased vincristine toxicity. It has been suggested that this is due to a deleterious effect of asparaginase on hepatic function, reducing the metabolism of vincristine (5R ). Antiepileptic drugs In a small pharmacokinetic study the clearance of vincristine was 65% greater than in patients who were not taking carbamazepine or phenytoin and the half-life and AUC of vincristine were reduced by 35% and 43% respectively (72c ). Erythromycin Towards the end of a phase I study of vinblastine plus oral ciclosporin to reverse multidrug resistance, three patients also received erythromycin to raise their ciclosporin concentrations; all developed severe toxicity consistent with a much higher dose of vinblastine than was actually given (73A ). Itraconazole The concomitant use of itraconazole with vincristine increased the incidence of neurotoxicity in children and adults with acute lymphocytic leukemia (74A , 75A ). • A 19-year-old woman developed severe abdominal pain and constipation 28 days after starting to take itraconazole as antifungal prophylaxis when receiving vincristine for acute lymphocytic leukemia (75A ). She had hypertension, marked abdominal distension and tenderness, and absent bowel sounds. Withdrawal of itraconazole resulted in resolution of symptoms and vincristine was continued. • A 72-year-old patient developed painful oral mucositis and constipation 3 days after being given

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vinorelbine and itraconazole (76A ). Further complications included neutropenia and hypoxia and he died.

Concomitant use of itraconazole 2.5 mg/kg/ day and vincristine in five children receiving vincristine resulted in hypertension, paralytic ileus, and SIADH (74A ).

GENERAL One of the difficulties in attributing adverse effects to individual cytotoxic drugs is the common use of multidrug or multi-intervention studies. A Phase I Study of Foscan-Mediated Photodynamic Therapy and Surgery in Patients with Mesothelioma is a good example of this. The authors could not separate the toxic effects, which were considerable and included local burns, cardiotoxicity, and hepatotoxicity (77c ). Metabolism A rise in body mass index has been reported in young patients with teratomas treated with chemotherapy, still apparent 14 years after the end of treatment (78M ). Hematologic In 85 older patients over 60 years of age with chemotherapy-induced febrile neutropenia there were similar rates of infections and outcomes to younger patients (79c ). This contradicts the popular belief that older patients have more infections with a worse outcome. Reproductive system Ten women with osteosarcoma were followed up for between 1–14 years. All of the women who had normal menstrual function before chemotherapy had amenorrhea (80c ). Nine had normal ovarian function, but only when their gonadotropin concentrations had normalized, which took several years. Tumorigenicity Of 688 patients treated with topical chemotherapy in the Stanford Clinical in the USA between 1958 and 1999, said to be the world’s largest series of patients with mycosis fungoides treated with topical therapy, only eight developed secondary cutaneous malignancies and none could be attributed directly to the topical chemotherapy (81M ).

Susceptibility factors Age The view that older patients do not tolerate chemotherapy as well as younger patients has been disproved in a pilot study of 60 patients aged 70 years or more (82c ). Drug formulations A modified-release formulation of cytarabine, DepoCyt, which is given every 2 weeks, lead to similar toxicity to the immediate-release formulation but for longer (83c ).

Anthracyclines Cardiovascular In 630 patients who received cumulative anthracycline doses of 550 mg/m2 , 164 (26%) had congestive heart failure compared with the literature estimate of 7%. Age was a critical risk factor after a cumulative dose of 400 mg/m2 , and patients over 65 years of age had a greater incidence rate (84M ). In 184 children (101 with acute lymphoblastic leukemia and 83 with Wilms’ tumors) the cumulative anthracycline dose was reduced to under 250 mg/m2 , followed by serial echocardiograms over 10 years. In children who were given less than this dose there was no deterioration of left ventricular function (85c ).

Asparaginase Cardiovascular The susceptibility factors for venous thromboembolism have been reviewed; the risk in patients with cancer is increased by the use of asparaginase (86r ).

Bleomycin Skin Bleomycin-induced flagellate hyperpigmentation has been reported after a single intralesional dose of 14 000 IU. Whilst this toxic effect is well documented for intravenous bleomycin, often with doses of 100 000 IU or more and rarely with intrapleural administration, this case was unusual in occurring after local administration (87A ).

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Capecitabine Gastrointestinal An association has been described between the AUC of capecitabine metabolites and adverse effects on the bowel and liver (88R ).

Cisplatin Nervous system In 400 patients (203 men and 197 women) receiving cisplatin (70–85 mg/m2 ), neurotoxicity greater than grade 1 was associated with older age, female smokers, hypoalbuminemia, and co-administration of paclitaxel (89M ).

Cyclophosphamide Liver Of 147 patients, 23 (16%) developed moderate or severe hepatic sinusoidal obstruction syndrome after being given cyclophosphamide 60 mg/kg over 1–2 hours on each of 2 consecutive days, followed by total body irradiation. The median peak serum bilirubin concentration on day 20 was 44 µmol/l (2.6 mg/dl) (90c ). The metabolism of cyclophosphamide was highly variable, particularly for the metabolite o-carboxyethyl-phosphoramide mustard, whose AUC varied 16-fold. Exposure to this metabolite was significantly related to sinusoidal obstruction syndrome, raised bilirubin concentration, non-relapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk of non-relapse mortality than patients in the lowest quartile. Engraftment and tumor relapse were not significantly related to cyclophosphamide metabolite exposure.

• A 3-year-old girl developed a ventral polyradiculopathy 15 days after receiving intrathecal cytarabine (91A ). • A 44-year-old man with leukemia developed a myelopathy 4 weeks after receiving intrathecal cytarabine (92A ).

Fluorouracil In 1470 patients with gastrointestinal cancers receiving protracted venous infusion of fluorouracil stomatitis occurred more rapidly than diarrhea or palmar-plantar erythema (93M ). Female sex, better performance status, raised bilirubin, early grade 1 palmar plantar erythema, and early grade 1 diarrhea were independent prognostic factors for the development of grade 2 or worse palmar-plantar erythema. Female sex, increased age, raised alanine transaminase and urea, and early grade 1 palmar plantar erythema were significant independent prognostic factors for the development of grade 2 or worse stomatitis. Early grade 1 diarrhea predicted grade 2 or worse diarrhea. Cardiovascular In three patients with angina pectoris due to fluorouracil the prophylactic use of transdermal nitrates allowed continuation of fluorouracil without angina (94A ). Nervous system A 63-year-old man developed a peripheral neuropathy after receiving a cumulative dose of fluorouracil of 13 200 mg/m2 and leucovorin 2000 mg/m2 . He had pronounced numbness of fingers and toes, and only his toes recovered at 10 weeks after withdrawal (95A ). Sensory systems Fluorouracil can enter the anterior chamber of the eye when injected subconjunctivally and has reportedly caused cataract. • A 51-year-old man developed a cataract after bleb needling and subconjunctival fluorouracil; the cataract took 7 months to resolve (96c ).

Cytarabine Hydroxyurea Nervous system Cytarabine is commonly given intrathecally as part of leukemia and lymphoma protocols, and can cause nervous system damage.

Hydroxyurea has been used in combination with didanosine and stavudine, since it has an antiretroviral effect in this combination by

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altering purine metabolism. The reduction in cellular purine concentrations not only explains the antiviral action of hydroxyurea, but also the high frequency of mitochondrial toxicity with this combination. The safety and efficacy of hydroxyurea 1000 mg/day + didanosine 200 mg bd + stavudine 40 mg bd for 16 weeks has been investigated in 31 patients who had already taken NRTIs. Adverse effects (neutropenia, pancreatitis, and peripheral neuropathy) occurred in four subjects and resolved on withdrawal. (97c ).

Imatinib Skin Severe skin reactions have previously been reported with imatinib, and in another four patients the duration and severity of the cutaneous eruptions were strongly dose-related (98c ). The authors therefore suggested that and the eruptions represented a toxic effect rather than a hypersensitivity reaction, which has also been reported with imatinib.

Methotrexate Tumor lysis syndrome has been attributed to methotrexate. • A 14-year-old girl receiving large-dose methotrexate for Burkitt’s lymphoma developed tumor lysis syndrome, which progressed to renal insufficiency and cutaneous vasculitis of the palms and soles (99A ).

Liver There has been a report of 14 cases of hepatotoxicity in 68 patients when methotrexate 10 mg/week was given chronically. Liver biopsies showed hepatic changes after about 1 g of cumulative treatment given over 2 years (100c ).

Mitomycin Urinary tract In a meta-analysis of 11 trials involving 2749 patients treated intravesically with either BCG or mitomycin, whilst BCG was superior in the prevention of recurrence,

its toxic effects in terms of cystitis were significantly more common. However, the cystitis did not get worse during maintenance treatment with BCG (101M ).

Platinum-containing cytotoxic drugs Immunologic Hypersensitivity reactions to both cisplatin and carboplatin are well documented and have also now been reported with oxaliplatin. Two patients developed erythema, fever, and mild dyspnea after oxaliplatin, nine doses in one case and 11 in the other. Both reactions occurred about 25 minutes into the infusion, but re-challenge was uneventful when they were premedicated with glucocorticoids and histamine H1 and H2 receptor antagonists (102A ). Of 124 patients, 17 developed oxaliplatin hypersensitivity. The reactions were unpredictable, with no relation to cumulative dose or time of exposure to oxaliplatin. When six of the 17 patients were re-exposed after glucocorticoid premedication, only one did not have another reaction (103C ). Ten patients with moderate to severe hypersensitivity to carboplatin were re-exposed to cisplatin 60 mg/m2 and then received 2– 5 cycles of cisplatin. This was achieved by using a pre-medication regimen of dexamethasone 20 mg intravenously, ranitidine 50 mg intravenously, and promethazine intramuscularly, 30 minutes before the cisplatin (104c ).

Taxanes Cardiovascular In 58 patients with breast cancer there were no significant changes in cardiac function after a single dose of docetaxel 100 mg/m2 , but supraventricular extra beats occurred in those who received docetaxel 75 mg/m2 and epirubicin 75 mg/m2 (105c ). However, the authors were unable to attribute any real clinical significance to these observations.

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Drug dosage regimens Weekly (106c ) and bimonthly (107c ) regimens of docetaxel have been compared with conventional 3-weekly schedules. As a broad rule the shorter the treatment interval, i.e. the lower the individual dose, the less the hematological toxicity, but the

greater the non-hematological toxicity, particularly the nail and “tearing” adverse effects. Thus the patient’s quality of life will be potentially worse but the treatment will be less life-threatening.

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TYPES OF CONTRAST AGENTS Iodinated water soluble contrast media are of four types: (a) high-osmolar ionic monomers (e.g. diatrizoate, iothalamate, metrizoate); (b) low-osmolar ionic dimers (e.g. ioxaglate); (c) low-osmolar non-ionic monomers (e.g. iopitridole, iohexol, iomeprole, iopamidole, iopromide, ioversol); (d) iso-osmolar non-ionic dimers (e.g. iodixonal, iotrolan). They are mainly used intravascularly, but can also be injected into body cavities particularly the low-osmolar contrast agents. They are also suitable for oral or rectal administration. The high-osmolar water soluble contrast agent Gastrografin (diatrizoate preparation) is suitable only for oral or rectal administration. Barium formulations, widely used for imaging different parts of the gastrointestinal tract, are based on barium sulfate, which is not absorbed. Several additives are used in commercial barium formulations to enhance the properties of the suspension to image the gastrointestinal tract and improve taste for oral use. The barium formulations are generally safe, with a low incidence of adverse effects. There are also contrast agents to enhance the diagnostic information provided by ultrasound scanning and magnetic resonance imaging. The latter are mainly gadolinium-based, but new non-gadolinium paramagnetic contrast agents have recently become available. Ultrasound contrast agents are microbubbles that provide acoustic enhancement. Adverse reactions to contrast media are generally few, and serious reactions are uncommon. Ultrasound contrast agents are particularly safe. © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

552

Water-soluble intravascular iodinated contrast agents (SEDA-25, 557; SEDA-26, 512; SEDA-27, 496) Adverse reaction to intravascular iodinated contrast agents can be minor, intermediate, or severe and life-threatening. All types of reactions to low-osmolar contrast media are at least five times less common than reactions to highosmolar contrast media. The selective use of low-osmolar agents in computed tomography (CT) has been investigated in a total of 19 834 contrast-enhanced CT examinations (1C ). Contrast was injected with a power injector and large venous catheter, 20 gauge for an injection rate of 2–3 ml and 18 gauge for an injection rate of 3–5 ml. Highosmolar agents were used in 13 670 patients (71%), mean age 55 (range 16–91) years, 61% men and 39% women. The low-osmolar agents were used in 5884 (29%) patients, mean age 62 (range 13 to 97) years), 65% men and 35% women. The guidelines for the use of low-osmolar agents included cardiac dysfunction, severe pulmonary impairment, a history of allergy, or a previous moderate reaction to high-osmolar agents and severe debilitation. Before the injection of a high-osmolar agent, metoclopramide 10 mg (Primperan, Delagrange Quetigny, France) was administered, in order to reduce nausea and vomiting. In the high-osmolar group there were 304 minor or mild adverse reactions (2.2%), and 10 severe adverse reactions (0.08%). In the low-osmolar group there were 34 mild or moderate adverse reactions (0.6%) and three severe adverse reactions (0.05%). There were significant differences in the incidence of mild adverse reactions between the low-osmolar and high-osmolar agents. However, there were no significant differences in severe adverse reactions. The authors concluded that selective use of low-osmolar agents in CT is safe and results in a substantial reduction in costs.

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The safety and efficacy of the low-osmolar agent iobitridol (Xenetix) has been assessed in 61 754 patients from 1996 to 2000 (2C ). There were adverse events in 2.3% of the examinations, but nearly half of them (1.1%) presented with a “feeling of warmth” as the only symptom. Of the adverse events, 0.2% were nontransient, and one patient died. The authors concluded that iobitridol is an efficient contrast agent for radiological procedures and is associated with a low rate of adverse events. Immunologic In an epidemiological study of severe anaphylactic and anaphylactoid reactions among hospital patients there was an intermediate risk of anaphylaxis with contrast media: 71 per 100 000 procedures with highosmolar agents and 35 with low-osmolar agents per 100 000 procedures (3C ). An allergic reaction to a small intra-arterial dose of a non-ionic contrast material that was administered during cerebral angiography in a patient premedicated with steroids and antihistamines has been reported (4A ). • A 23-year-old man had cerebral angiography performed before temporal lobectomy for the treatment of epilepsy. He had asthma and had bronchospasm during an intravenous injection of contrast medium for urography a few years before. He was therefore premedicated with oral prednisolone 50 mg, three doses in the 24 hours before angiography, and diphenhydramine 50 mg about 2 hours before the procedure. During cerebral angiography 3 ml of iohexol (a low-osmolar agent, 300 mgI/ml) was injected into the right common carotid artery. Within minutes he complained of a tight sensation in the throat, difficulty in breathing, and itching. A papular rash developed over the face and hands. The procedure was halted, and he was given inhaled salbutamol and oxygen. His vital signs, including blood pressure and heart rate, were stable, and oxygen saturation was normal. He recovered fully within 5 minutes. The procedure was then continued with a gadolinium-based contrast material (Omniscan; Nycomed; 287 mg/ml) instead of iohexol. No further complications occurred.

Allergic reactions to intravenous contrast agents are more common in individuals with a history of bronchial asthma or an allergic reaction to contrast material as and in those who are debilitated or medically unstable. These reactions can occur even with a small dose of a low-osmolar agent and despite the use of prophylactic premedication.

Delayed reactions to iodinated water-soluble contrast media (SEDA-25, 558; SEDA-26, 513, SEDA-27, 497) 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; however, delayed skin reactions are usually attributable. Delayed skin reactions tend to be commoner with non-ionic dimers compared with other types of contrast media (SEDA-22, 499). Delayed reactions are generally benign, although not always. Early (before 24 hours) and late (1–7 days) reactions after the use of iopamidol 340 (a nonionic monomer), iomeprol 350 (a non-ionic monomer), and iodixanol 320 (a non-ionic dimer) have been investigated in 2108 patients who underwent cardiac catheterization (5C ). Early reactions were relatively common (7.4%), but there were no significant differences among the three agents. Late skin reactions, excluding reactions solely at the site of the arterial puncture and continuations of early urticarial reactions, were also relatively common (5.4%), but the incidences differed among the three agents: in 2.7% of those who received iopamidol 340, 3.5% of those who received iomeprol 350, and 10.4% of those who received iodixanol 320. The study confirmed previous observations that late skin reactions are significantly more common with the non-ionic dimers compared with the non-ionic monomers. A prospective survey of delayed adverse reactions to iohexol, a non-ionic iodinated contrast medium, has been carried out in 7505 in-patients who underwent intravenous urography or contrast-enhanced computed tomography (6C ). To explore the relevant risk factors, the relation between the occurrence of adverse reactions to iohexol and 17 different variables was evaluated by logistic regression analysis. The prevalence of delayed adverse reactions was 2.8%. Multivariate analysis showed that six parameters had a significant influence on delayed adverse reactions to iohexol, including a history of allergy, the season (during the pollination period), the radiographic procedure, age, concomitant surgery or other invasive procedures, and concomitant medications.

554 The nature of both immediate and delayed adverse reactions induced by contrast media is still unclear. However, it has been suggested that delayed skin reactions could be T cellmediated. The possibility of using released cytokines as surrogate markers for allergic or pseudoallergic responses in patients who have been given contrast media has been investigated. Interleukin-1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, tumor necrosis factor-alpha, plasma histamine concentration, and anaphylatoxin C5a were measured by enzyme-linked immunosorbent assay in nine patients (mean age 58, range 36–74 years) who received the non-ionic dimeric iodinated contrast medium iotrolan (280 mgI/ml, dose 80 or 100 ml) during routine CT scanning (7C ). None of the patients had a history of allergic reactions. Serum samples were collected before, 1 hour, 6 hours, and 24 hours after iotrolan injection. Kinetic studies showed a trend to an early increase in IL-2 (1 hour after injection), followed by a delayed increase in IL-4 and IL-6. Histamine fell significantly after iotrolan injection and C5a increased 6 hours after injection in parallel with IL-6. IL-1beta fell (the lowest value being found 6 hours after injection), and tumor necrosis factor-alpha did not show any trend. The authors concluded that even in patients without obvious adverse effects, contrast media injection can cause slight changes in cytokine release. The released cytokines initially had T helper 1 (IL-2 after 1 hour), and later T helper 2 patterns (IL-4, IL-5, and IL-6) suggesting a T helper 1/T helper 2 switch. The only patient who developed late adverse reactions (skin reactions, itching, arthralgia) had a T helper 1 to T helper 2 shift and had the highest histamine concentrations. Respiratory Aspiration of barium sulfate into the lungs during barium meal examination can cause significant respiratory embarrassment, particularly in patients with a poor general condition and poor respiratory function. Inhalation of thick barium paste occludes small bronchi and can cause fatal asphyxiation. Aspiration of barium can also cause fatal pneumonia. Persistent alveolar deposition of the barium sulfate on the chest radiograph, with only a slight improvement compared with the initial X-ray, will be observed.

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• In a 73-year-old woman, studied by high-resolution computed tomography 1 year after the event there were thickened interlobular septa, subpleural lines, subpleural cysts, and centrilobular micronodules, along with barium particles in a subpleural distribution (8A ).

These findings suggest that barium can cause mild clinically silent pulmonary fibrosis. Nervous system Contrast neurotoxicity after coronary angiography mimicking subarachnoid hemorrhage has been reported (9A ). • An 82-year-old woman received 500 ml of the non-ionic contrast medium iomeprol (350 mgI/ml) during coronary angioplasty. Before and during the procedure she had no neurological deficits. However, 30 minutes after the procedure she became disoriented and drowsy. During the next 4 hours she became aphasic and developed a right hemiparesis. Cranial CT showed hyperdense material filling the sulci of both brain hemispheres, which was diagnosed as subarachnoid hemorrhage. However, lumbar puncture yielded normal cerebrospinal fluid, with no evidence of bleeding. An MRI scan showed no significant abnormality and excluded intracranial hemorrhage. Spontaneous recovery occurred within 40 hours of the procedure and a repeat CT scan showed no abnormality. She remained free of neurological symptoms after discharge from the hospital.

Ataxia as a delayed adverse reaction to contrast medium for intravenous urography has been reported (10A ). • A 4-year-old girl underwent intravenous urography with 20 ml of iopamidol (a non-ionic contrast medium, 300 mgI/ml) 2 weeks after an attack of acute pyelonephritis, which was treated successfully with antibiotics. She developed an ataxic gait and dizziness 20 hours later. Her temperature was normal and laboratory tests were within the reference ranges. A CT scan of the brain showed no abnormality. She developed an erythematous maculopapular rash on her arms, legs, and trunk 24 hours later. The rash, dizziness, and ataxia resolved within 2 days, with no further complications.

Endocrine Hyperthyroidism and hypothyroidism have both been reported to be precipitated by the administration of iodinated contrast media (SEDA-21, 478; SEDA-23, 497; SEDA-25, 559; SEDA-26, 515). The authors of a recent report have re-emphasized the possibility of inducing thyrotoxic crisis after the intravascular use of iodinated contrast media in patients with thyroid carcinoma and thyrotoxicosis (11A ).

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Hematologic The incidence of peripheral blood eosinophilia associated with gastrointestinal administration of water-soluble iodinated contrast media (diatrizoate meglumine and diatrizoate sodium) has been investigated in 110 patients (aged 18–79 years) undergoing abdominal CT. A control group of 65 patients (aged 24–82 years) underwent single-contrast barium upper gastrointestinal or enema examinations (12C ). White blood cell and eosinophil counts were determined about 24 hours before the examination and every 24 hours thereafter for 9 days. Eosinophilia was detected in 16% of the patients after gastrointestinal administration of iodinated contrast media. The prevalence of eosinophilia after the administration of iodinated contrast media was statistically significantly different compared with the 65 controls, of whom none had eosinophilia. Eosinophilia was detected 48 hours after the use of the iodinated contrast agents and lasted for 6 days, with a peak on day 5. The prevalence of eosinophilia was independent of dose or the type of iodinated contrast medium. Eosinophilia in all cases was asymptomatic. The authors concluded that eosinophilia can be caused by gastrointestinal administration of iodinated contrast media but that it is transient and clinically silent. The mechanism is not clear. The effect of the radiographic contrast medium iopamidol (a non-ionic monomer) on hemostasis has been investigated in 30 patients (7 men, 23 women; mean age 51, range, 17– 79 years) undergoing coronary angiography or cardiac catheterization (13C ). Blood samples were drawn before and 3 minutes after the injection of 120–300 ml of iopamidol 370 mgI/ml. Complete blood count and coagulation profile (bleeding time, clotting time, clot retraction time, euglobulin lysis time, prothrombin and partial thromboplastin times, coagulation factor I concentration, platelet factor 3 availability), and the natural coagulation inhibitors protein C, protein S, and antithrombin III were measured. The re were significant falls in hemoglobin, white blood cell count, and platelet count after the administration of iopamidol but remained within the reference ranges. Mean concentrations of protein C, protein S, and antithrombin III did not change significantly. Bleeding time did not change. Although platelet factor 3 availability was prolonged in both groups, the changes were not statistically significant. The

555 authors concluded that although hemostasis remained grossly intact after the injection of non-ionic contrast material, the coagulation system may have been affected by the accelerated consumption of coagulation factor I and platelets. The affected variables were platelets, clot retraction time, euglobulin lysis time, and the natural coagulation inhibitors (protein C, protein S, and antithrombin III). Although the natural coagulation inhibitors remained within the reference ranges, there were significant correlations. These changes in hemostasis affected the vascular phase. If the vascular compartment, especially the endothelium, remains intact, the infusion of non-ionic agents in low concentrations might be safe for angiography and other procedures. Salivary glands Sialadenitis (“iodide mumps”) following peripheral angiography in a peritoneal dialysis patient has been reported (14A ). • A 62-year-old man on peritoneal dialysis for endstage renal disease underwent peripheral angiography for ischemic vascular disease of the legs. Several hours after the procedure, in which 120 ml of iopromide (300 mgI/ml, non-ionic monomer) was used, the patient developed swelling of the parotid and submandibular glands accompanied by a fever of 38.9◦ C. The salivary gland swelling and the fever resolved spontaneously within 36 hours.

Salivary gland dysfunction is common after the use of high-dose radioactive iodine in the treatment of thyroid cancer and is also recognized as an uncommon delayed adverse reaction to the intravascular use of iodinated contrast media. This adverse effect is caused by concentration of iodine by the salivary glands. The amount of free iodine in contrast media is very small and so sialadenitis after contrast medium injection is rare, even in patients with chronic renal insufficiency, in whom contrast medium elimination from the body is delayed. Pancreas Computed tomography enhanced with intravenous injection of iodinated contrast medium is widely used to diagnose acute pancreatitis. However, iodinated contrast media lengthen the duration of pancreatitis and can increase the incidence of local or systemic complications. Total parenteral nutrition, including intravenous lipid emulsion, plays an important

556 role in the management of patients with pancreatitis. Induction of pancreatitis by intravenous lipid emulsion is exceedingly rare. An association of pancreatitis with the administration of contrast medium and intravenous lipid emulsion in a patient with AIDS has been reported (15A ). • A 30-year-old patient with AIDS and mild pancreatitis underwent CT scanning of the abdomen with intravenous and oral contrast enhancement (the doses were not reported). The serum lipase activity increased from 405 to 1489 3 days after the scan, suggesting worsening of the pancreatitis. On day 6 the patient received intravenous lipid emulsion. This was followed by a rise in serum lipase to 2265. The lipid infusion was stopped but restarted on day 13 to provide essential fatty acids. This was also accompanied by a rise in serum lipase activity. The lipid emulsion infusion was withdrawn, followed again by a fall in serum lipase.

This is the first case to have implicated intravenous lipid emulsion in the exacerbation of pancreatitis in a patient with acquired immunodeficiency syndrome and normal baseline triglyceride concentrations. The authors suggested that caution must be exercised in the use of contrast medium and intravenous lipids in the diagnosis and management of acute pancreatitis.

Contrast medium-induced nephrotoxicity Contrast medium nephrotoxicity is a condition in which an impairment in renal function (an increase in serum creatinine of more than 25% or 44 µmol/l) occurs within 3 days of the intravascular administration of a contrast medium in the absence of an alternative cause. Susceptibility factors The susceptibility factors for contrast medium nephrotoxicity include pre-existing renal insufficiency, particularly if it is secondary to diabetes mellitus, dehydration, multiple exposures to contrast media within a short space of time (72 hours), congestive heart failure, and the concurrent administration of nephrotoxic drugs such as non-steroidal antiinflammatory drugs. The impact of sex on the incidence and outcomes of contrast-induced nephropathy after

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percutaneous coronary intervention has been investigated in 8628 patients, who were followed for 1 year (16C ). Contrast nephropathy was present in 24% of the women compared with 17% of the men. Multivariate analysis showed that female sex, pre-existing chronic renal insufficiency, diabetes mellitus, age, and hypertension were independent predictors of contrast nephropathy. Among patients without chronic renal insufficiency who developed contrast nephropathy, the women (n = 465) had higher rates of 1-year mortality and major adverse cardiac events than the men (n = 710) (14% vs. 10% mortality, 36% vs. 30% major adverse cardiac events). In patients with chronic renal insufficiency who developed contrast nephropathy there was no significant sex difference in 1-year clinical events (37% vs. 36% mortality, 42% vs. 45% major adverse cardiac events). By multivariate analysis only baseline chronic renal insufficiency, diabetes, age, and severe congestive heart failure (NYHA class IV) were identified as independent predictors of 1-year mortality in patients with contrast nephropathy after percutaneous coronary intervention. The authors concluded that being female is an independent predictor of contrast nephropathy after percutaneous coronary intervention and a marker of worse 1-year mortality after contrast nephropathy in patients without baseline chronic renal insufficiency. After the development of nephropathy, pre-existing chronic renal insufficiency, diabetes mellitus, age, and severe heart failure, but not sex are independent predictors of 1-year mortality. Frequency The occurrence of contrast nephropathy has been examined retrospectively in 302 consecutive lower limb angiography and angioplasty procedures (17C ). Serum creatinine 1 and 3 days after the procedure was used to identify cases of contrast nephropathy, defined as a 25% increase above baseline. Of 267 patients, 224 had diagnostic procedures and 78 interventional procedures. Of these, 46% had pre-existing renal impairment (creatinine over 118 µmol/l), of whom 11% were on dialysis; the dialysis patients were excluded from the analysis of changes in serum creatinine. Repeat creatinine measurements were taken after 191 procedures. Contrast nephropathy occurred after 15 procedures; nine died and six recovered. Of these patients, 11 were

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taking potentially nephrotoxic drugs and nine had renal impairment. Precautions to avoid contrast nephropathy were taken in only two cases. Of the nine deaths, six were associated with severe underlying disease processes, but three occurred as a direct result of contrast nephropathy. Two of these three patients received the iso-osmolar dimer iodixanol (dose not reported), which is said to be less nephrotoxic than low-osmolar non-ionic monomers (SEDA-27, 501). Baseline serum creatinine was 332 µmol/l in one patient (95 years old) and 127 µmol/l in the other (72 years old). The incidence of contrast nephropathy in this series was 8%. Death from renal insufficiency was relatively rare, with an incidence of 1%. The authors concluded that precautionary measures should be observed and that alternatives to conventional angiography should be considered particularly where there is pre-existing renal impairment and other co-morbidities. Prevention Several strategies have been advocated to reduce the incidence of contrast medium nephrotoxicity. The lowest possible dose of a low-osmolar non-ionic agent should be used in patients at high risk; high-osmolar agents and large doses should be avoided. In addition, intravenous hydration with saline (1 ml/kg/hour for 4–6 hours before contrast injection and for 12 hours afterwards) should be given (SEDA-27, 501). The value of pharmacological manipulation using renal vasodilators or cytoprotective drugs in preventing contrast nephropathy is uncertain. Fenoldopam mesylate is a specific agonist at dopamine D1 receptors and enhances renal blood flow. The effectiveness of fenoldopam mesylate in the prevention of contrast-induced nephropathy has been investigated in 315 patients, mean age 70 years, mean baseline creatinine clearance 29 ml/min (range 7.5–57), undergoing invasive cardiac procedures; 49% had diabetes mellitus (18C ). The mean volume of non-ionic contrast medium used per procedure was 157 ml and 10% of the patients received the non-ionic dimer iodixanol. The patients were hydrated with 1–1.5 ml of 0.45% saline for 2–12 hours before contrast administration and were randomized to either intravenous fenoldopam (0.05 µg/kg/minute titrated to 0.10 µg/kg/minute) or matching placebo, starting 1 hour before angiography

557 and continuing for 12 hours. Contrast-induced nephropathy occurred in 34% of the patients assigned to fenoldopam versus 30% assigned to placebo. The incidence of contrast nephrotoxicity in patients who received the iso-osmolar dimer iodixanol was 33% compared with 25% with other types of low-osmolar agents. This is at variance with a recent report (the NEPHRIC study), in which there was a low incidence of contrast nephrotoxicity (3%) with iodixanol in patients with pre-existing renal impairment and diabetes undergoing angiographic procedures (SEDA-27, 502). The authors concluded that fenoldopam mesylate does not prevent further renal function deterioration after contrast administration in patients with chronic renal insufficiency. Another drug that has been recommended to reduce the risk of contrast nephrotoxicity is the antioxidant N-acetylcysteine. Acetylcysteine (600 mg bd for 2 days starting the day before the examination) in addition to hydration reduced the incidence of contrast nephrotoxicity in some but not all studies (SEDA-27, 502). The protective effect of acetylcysteine against contrast-induced renal impairment could be by effects on nitric oxide metabolism and oxidative stress. In a recent study patients with a serum creatinine concentration above 106 µmol/l undergoing coronary angiography (using a nonionic monomeric agent, 300 mgI/ml, mean dose 140 ml/procedure) were randomly assigned to receive either acetylcysteine 1 g (n = 24, mean age 68 years) or placebo (n = 29, mean age 66 years) twice daily 24 hours before and after angiography with 0.45% saline hydration in a double-blind study (19C ). Creatinine clearance was calculated and urinary nitric oxide and F2-isoprostane excretion were measured at baseline, 24 hours, and 96 hours after angiography. Acetylcysteine significantly improved the effect of contrast media on creatinine clearance; maximal beneficial effect was observed 24 hours after angiography. Creatinine clearance was respectively 60, 65, and 59 ml/minute at baseline, 24, and 96 hours after angiography in the acetylcysteine group, and 65, 52, and 54 ml/minute in the placebo group. Acetylcysteine prevented the reduction in urinary nitric oxide after angiography. The urinary nitric oxide/creatinine ratio was respectively 0.0058, 0.0057, and 0.0052 µmol/mg at baseline, 24,

558 and 96 hours after angiography in the acetylcysteine group, and 0.0057, 0.0031, and 0.0039 in the placebo group. Acetylcysteine had no significant effect on urinary F2-isoprostanes. The authors concluded that acetylcysteine has renoprotective effect in patients with mild chronic renal insufficiency undergoing coronary angiography, which may be partly mediated by increased nitric oxide production. The role of acetylcysteine in preventing acute deterioration of renal function after elective coronary angiography and intervention has been investigated in 200 Chinese patients (mean age 68 years) with stable moderate renal insufficiency (creatinine clearance below 60 ml/min) who were undergoing elective coronary angiography with or without intervention (20C ). They were randomly assigned to oral acetylcysteine (600 mg bd; n = 102) or matching placebo (n = 98) on the day before and the day of angiography. All received low-osmolar non-ionic monomeric agents (mean dose 125 ml/procedure). Twelve control patients (12%) and four acetylcysteine patients (4%) developed contrast nephropathy. Acetylcysteine treatment significantly increased creatinine clearance from 45 to 59 ml/minute 2 days after contrast administration. The increase was not significant in the control group (from 42 to 44 ml/minute). The benefit of acetylcysteine was consistent among various patient subgroups and persisted for at least 7 days. There were no major treatment-related adverse events. The authors concluded that acetylcysteine protects patients with moderate chronic renal insufficiency from contrast-induced deterioration in renal function after coronary angiography, with minimal adverse effects and at a low cost. In a further study the protective effect of acetylcysteine in reducing the incidence of acute renal dysfunction has been investigated in 55 patients undergoing coronary angiography and 55 historical controls, well matched apart from a lower baseline serum creatinine (159 vs. 177 µmol/l) (21C ). All received intravenous hydration before and after cardiac catheterization and the patients received three doses of acetylcysteine before. There was no difference in the amount (mean dose 139 ml/procedure) or type of contrast used. The mean change in creatinine after 48 hours was a drop of 44 µmol/l in the treated group and an increase of 88 µmol/l in the controls. The authors concluded that

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prophylactic use of acetylcysteine prevented reduction of renal function after coronary angiography. A rapid protocol for the prevention of contrast-induced renal dysfunction using intravenous acetylcysteine has been investigated in 80 patients with stable renal dysfunction undergoing cardiac catheterization/intervention who were prospectively randomized to a rapid protocol of intravenous acetylcysteine (150 mg/kg in 500 ml of isotonic saline over 30 minutes immediately before contrast followed by 50 mg/kg in 500 ml of isotonic saline over 4 hours, n = 41, mean age 67 years, mean volume of contrast medium used 238 ml/procedure) or intravenous hydration (1 ml/kg/hour of isotonic saline for 12 hours before and after contrast, n = 39, mean age 71 years, mean volume of contrast medium used 222 ml/procedure) (22C ). Contrast-induced nephropathy occurred in two of the 41 patients who were given acetylcysteine (5%) and in eight of the 39 patients who were hydrated (21%). In the acetylcysteine group, mean serum creatinine fell from 164 to 156 µmol/l at 24 hours and to 158 µmol/l at 48 hours and 4 days after contrast. In the hydration group, serum creatinine increased from 155 to 160 µmol/l at 48 hours and to 159 µmol/l at 4 days after contrast. Acetylcysteine infusion was withdrawn after the bolus in three patients (7%) because of flushing, itching, or a transient rash. The authors concluded that the administration of intravenous acetylcysteine should be considered in all patients at risk of contrast nephropathy before contrast exposure when time constraints preclude adequate oral prophylaxis, provided the patient is able to tolerate this degree of volume loading. Although several studies have shown a protective effect, others have shown that oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. The prophylactic administration of oral acetylcysteine 600 mg bd plus intravenous hydration in the prevention of contrast nephropathy has been investigated in 73 patients with chronic renal insufficiency (mean age 66 years; mean serum creatinine 177 µmol/l) undergoing cardiac catheterization and receiving moderate to high doses of intravenous contrast (over 1 ml/kg) (23C ). The controls were 106 patients (mean age 65 years) who received hydration alone. The volume of contrast used was similar in the two

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groups (mean 2.2 ml/kg). There was a mean change in serum creatinine of 15 µmol/l in the acetylcysteine group versus 17 µmol/l in the controls at 48 hours. The incidence of contrast nephropathy was 13% in those given acetylcysteine versus 12% in the controls. The authors concluded that in patients with chronic renal insufficiency, oral acetylcysteine 600 mg bd before and after cardiac catheterization, along with intravenous fluids, is as effective as fluids alone in the prevention of contrast nephropathy when moderate to high doses of contrast are used. However, in another open study acetylcysteine 400 mg tds for 2 days did not prevent contrast nephropathy in 91 patients with moderate to severe renal insufficiency (serum creatinine concentration 149–400 µmol/l) undergoing coronary procedures (24c ). There were no significant differences between the two groups in baseline characteristics or the mean volume of contrast agent administered (128 ml/procedure). Six patients (13%) in the control group and eight (17%) in the acetylcysteine group developed contrast nephropathy. Serum creatinine concentrations increased from 201 to 217 µmol/l in the acetylcysteine group and from 210 to 212 µmol/l in the controls. The authors concluded that oral acetylcysteine did not prevent contrast nephropathy in patents with moderate to severe renal insufficiency undergoing coronary angiography or interventions. Several meta-analyses of studies of the protective effect of acetylcysteine against contrast nephropathy have been carried out to clarify the inconsistency of published reports. In one meta-analysis of randomized controlled comparisons of acetylcysteine and hydration with hydration alone in patients with chronic renal insufficiency seven trials (805 patients) were analysed (25M ). The overall incidence of contrast nephropathy varied between 8% and 28%. Since there was significant heterogeneity a random-effects model was used. Compared with periprocedural hydration alone, acetylcysteine plus hydration significantly reduced the relative risk of contrast nephropathy by 56% in patients with chronic renal insufficiency. The authors concluded that acetylcysteine with hydration significantly reduces the risk of contrast nephropathy in patients with chronic renal insufficiency. In a meta-analysis of group data extracted from previously published studies of the effect of

559 acetylcysteine in preventing contrast nephropathy in patients with pre-existing chronic kidney disease, eight randomized controlled trials (885 patients) published in full-text articles were analysed (26M ). The results suggested that acetylcysteine reduces the risk of contrast nephropathy. A systematic review of published studies of acetylcysteine in the prevention of contrast nephropathy produced highly mixed results; five were dramatically positive, and eight others had no demonstrable efficacy at all (27M ). The authors concluded that considering the inconsistency of the published reports a definitive study on the efficacy of acetylcysteine in prevention of contrast nephropathy is required. In a systematic review and meta-analysis of 15 studies (1776 patients) to assess the efficacy of acetylcysteine in preventing contrast nephropathy after intravascular administration of contrast media, the authors concluded that acetylcysteine may reduce the incidence of acutely increased serum creatinine after intravascular administration of contrast media, but this finding was of borderline statistical significance and there was significant heterogeneity between trials (28M ). They suggested that before acetylcysteine becomes the standard of care for all patients receiving intravascular contrast media, new randomized trials evaluating its effect on clinically relevant outcomes are required. Hemofiltration has recently been recommended for preventing contrast nephropathy in patients with marked renal impairment (creatinine clearance below 30 ml/minute). The role of hemofiltration, compared with hydration with isotonic saline, in preventing contrast-induced nephropathy in patients with renal insufficiency undergoing coronary interventions has been studied in 114 patients with chronic renal insufficiency (serum creatinine concentration over 177 µmol/l) who were undergoing coronary interventions (mean volume of contrast medium used 252 ml/procedure) (29C ). The patients were randomly assigned to hemofiltration in an intensive care unit (58 patients, mean age 69 years, mean serum creatinine concentration 265 µmol/l) or hydration with isotonic saline 1 ml/kg/hour given in a step-down unit (56 patients, mean age 69 years, mean serum creatinine concentration 274 µmol/l). Hemofiltration (fluid replacement rate 1000 ml/hour

560 without weight loss) and saline hydration were begun 4–8 hours before the coronary intervention and were continued for 18–24 hours after the procedure was completed. The following were the results (hemofiltration group first): (a) an increase in serum creatinine concentration of more than 25% from baseline after coronary intervention: 5% versus 50%; (b) requirement for temporary renal replacement therapy (hemodialysis or hemofiltration): 3% versus 25%; (c) in-hospital events: 9% versus 52%; (d) in-hospital mortality: 2% versus 14%; (e) cumulative 1-year mortality: 3% versus 10%. The authors concluded that in patients with chronic renal insufficiency who are undergoing percutaneous coronary interventions, periprocedural hemofiltration given in an ICU prevents deterioration in renal function due to contrastagent-induced nephropathy and is associated with improved in-hospital and long-term outcomes. The authors of a recent review of the subject of preventing contrast-induced nephrotoxicity highlighted the importance of identifying patients at risk through the use of screening questionnaires (history of renal disease, proteinuria, prior kidney surgery, hypertension, gout, or diabetes) and renal function measurement (serum creatinine) (30CR ). They recommended that patients at risk who require an injection of contrast medium for important clinical indications should receive a small dose of either a non-ionic iso-osmolar dimeric or a non-ionic low-osmolar monomeric agent and hydration (intravenous infusion of 1 ml/kg/hour of isotonic saline starting 4 hours before contrast medium injection and continuing for at least 12 hours afterwards). The authors also suggested that prophylactic hemodialysis does not lower the risk of contrast nephropathy but that hemofiltration for several hours before and after contrast medium injection offers good protection in patients with advanced renal disease. They also emphasized the inconsistency of effective protection against contrast nephropathy by pharmacological manipulation (renal vasodilators, such as calcium channel blockers, dopamine, atrial natriuretic peptide, fenoldopam, and prostaglandin E1,

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non-selective adenosine receptor antagonists, such as theophylline, non-selective endothelin receptor antagonists, and the antioxidant acetylcysteine). Drug administration route Extravasation of contrast material is a well-known complication of contrast-enhanced imaging studies. Automated power injection can result in extravasation of a large volume, which can cause severe tissue damage. Infants, young children, and unconscious and debilitated patients are particularly at risk of extravasation. High-osmolar contrast media can cause significant tissue damage. The management of this complication is contentious. Fortunately, in most cases of extravasation results in minimal swelling or erythema, with no long-term sequelae. However, skin necrosis and ulceration can occur. Compartment syndrome can be associated with extravasation of large volumes. Conservative management is often adequate, and in serious cases the advice of a plastic surgeon is recommended. The Contrast Media Safety Committee of The European Society of Urogenital Radiology has produced guidelines on the prophylaxis and management of extravasation injuries due to contrast media (Table 1) (31S ). Compartment syndrome of the hand caused by extravasation of contrast medium during computed tomography examination has been reported (32A ). • A 51-year-old woman underwent abdominal CT scanning with contrast enhancement for assessment of liver metastases using 100 ml of the lowosmolar contrast medium iopromide injected intravenously into the dorsum of the hand with a rapid injector system. The agent infiltrated the subcutaneous tissues and the patient reported severe pain and swelling. She had a tense swollen hand with reduced sensation. Capillary refill was sluggish in all fingers. Compartment syndrome was diagnosed and she underwent fasciotomy. At operation the muscles of the hand were swollen but necrosis was not found macroscopically. The skin incisions were left open, and after 2 days the swelling had abated, allowing closure of the incisions. She made a full recovery, with no residual damage.

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Table 1. Simple guidelines for prevention and management of extravasation of contrast media (31S ) Look for

(a) Infants and small children (b) Unconscious patients (c) Patients receiving chemotherapy (d) Debilitated patients (e) Patients with arterial insufficiency (f) Patients with compromised lymphatic and venous drainage

Do

• Intravenous injection should be carried out in the above mentioned patients with utmost care using non-ionic contrast agents • Avoid administration of contrast media in indwelling intravenous catheters with suspected thrombophlebitis • Careful intravenous technique should always be implemented, preferably using plastic catheters • Avoid injections in the leg (specifically the foot or ankle) and less optimal intravenous sites, including the back of the hand, the wrist, and sites adjacent to major tendons or nerves • Close monitoring of the injection site during power injection of contrast medium is mandatory (video monitoring, extravasation detection device)

Management

• • • • •

Conservative management is adequate in most cases Limb elevation Cold or heat compression Careful monitoring If in doubt, seek the advice of a plastic surgeon

MRI CONTRAST MEDIA Gadolinium salts

(SEDA-25, 562; SEDA-26, 520, SEDA-27, 504)

Nephrotoxicity of gadolinium salts and their use in patients with impaired renal function DoTS classification: Reaction: renal damage from gadolinium salts Dose relation: toxic reaction Time course: intermediate Susceptibility factors: impaired renal function The use of gadolinium-based contrast media for radiographic examination as an alternative to iodinated contrast media in order to avoid contrast nephrotoxicity in patients with impaired renal function has been erroneously endorsed by several published reports. However, at equimolar concentrations gadolinium-based contrast media are more nephrotoxic than iodinated contrast media, and at equivalent X-ray attenuation gadolinium based contrast media are also more nephrotoxic than iodinated contrast media. Gadolinium-based contrast media should not be given intravascularly at a dose

above 0.3 mmol/kg. In radiographic examinations a dose above 0.3 mmol/kg will be required to produce diagnostic studies. At such a dose gadolinium based contrast medium can induce significant nephrotoxicity particularly in patients with pre-existing renal impairment (SEDA-27, 504). The safety of gadobenate dimeglumine infusion has been evaluated in 32 patients (mean age 56 years) with severe or moderate chronic renal insufficiency in a randomized, doubleblind, placebo-controlled study (33C ). Renal insufficiency was defined as severe if creatinine clearance was 10–29 ml/min, and as moderate if it was 30–60 ml/min. Serum creatinine concentrations and 24-hour urine samples for creatinine clearance were measured daily for 7 days after the administration of either gadobenate dimeglumine 0.2 mmol/kg or a saline infusion. No patient had a significant change in renal function, defined as an increase in serum creatinine concentration greater than 44 µmol/l over baseline, and no patient required hospitalization or dialysis during the study period. The authors concluded that gadobenate dimeglumine at a dose of 0.2 mmol/kg is well tolerated in patients with moderate to severe renal insufficiency. The efficacy and safety of four different doses of gadobenate dimeglumine (0.025, 0.05,

562 0.1, and 0.2 mmol/kg) for contrast-enhanced three-dimensional MR angiography of the abdominal aorta and renal arteries have been studied in 94 patients (mean age 58 years) (34C ). There was a significant change in the total diagnostic quality score from unenhanced to contrast-enhanced MR angiography at all doses. The change increased with increased dose, plateauing at the 0.1 mmol/kg dose. All the doses were well tolerated and there were no significant changes in safety parameters. The authors concluded that gadobenate dimeglumine is effective and safe for contrast-enhanced MR angiography of the abdominal aorta and renal arteries. A dose of 0.1 mmol/kg of body weight appears to be the most suitable. In a study of the effect of gadolinium arteriography on renal function and its diagnostic accuracy in patients with uremia with suspected renovascular disease, catheter-based digital subtraction arteriography was performed on 25 occasions in 21 patients (mean age 64 years) with uremia (mean serum creatinine 265 µmol/l) to evaluate renal arterial circulation (35C ). Gadodiamide 287 mg/ml was the only contrast medium used and the dose of gadolinium was 40–264 ml (mean 124 ml). Serial determinations of renal function were performed in all patients. Arteriography was undertaken 20 times after prior renal revascularization, seven times as a routine postoperative follow-up study, nine for increasing uremia, three for worsening hypertension, and once for evaluation of known renal artery stenosis in patient with an abdominal aortic aneurysm. Three additional arteriograms were performed to evaluate suspected renovascular hypertension. The two other arteriograms were performed in patients with known aortic aneurysms in whom renal artery stenosis was suspected. No adverse changes in renal function followed gadolinium arteriography. Prearteriography serum creatinine values were 141–804 µmol/l, compared with postangiography values of 106–743 µmol/l. All 38 renal arteries evaluated were adequately imaged; 21 showed no abnormalities, including six of seven reconstructed arteries subjected to early postoperative evaluation; 12 showed significant disease, including seven with stenoses and five that had become occluded. Among five other renal arteries studied, two had obstructing thrombus, two had dissections, and one had

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a kinked aortorenal bypass graft. The authors concluded that catheter-based arteriography in patients with uremia with gadolinium as a contrast agent is safe and effective in evaluating the renal arterial circulation. They erroneously recommended preferential use of gadolinium in lieu of iodinated contrast agents for catheterbased arteriography in patients with uremia. Patients with end-stage renal disease receiving peritoneal dialysis or hemodialysis may have prolonged clearance of gadolinium-based contrast media. Adverse effects can occur because of in vivo dissociation of the gadolinium– ligand complex into the metal ion and ligand. This phenomenon is thought to launch a ligand competition reaction and metal ion exchange (transmetallation). There has been very little discussion of the clinical significance of the transmetallation process in patients with endstage renal disease. Previous reports have suggested that it is safe to inject gadolinium-based contrast media at doses up to 0.3 mmol/kg in patients with end-stage renal disease who are receiving hemodialysis or peritoneal dialysis (36C ). A recent report documented severe iron intoxication with life-threatening serum iron concentrations in a hemodialysis patient after MRI with Gd-DTPA (37A ). • A 19-year-old man with end-stage renal disease due to reflux nephropathy on hemodialysis had a history of multiple blood transfusions for severe autoimmune hemolytic anemia. He developed arthralgia and fever 1 day after MRI examination with intravenous Gd-DTPA to investigate recurrent abdominal pain. A chest X-ray was normal and blood cultures were negative. Blood tests showed no significant abnormalities, with the exception of raised liver enzyme activities (aspartate transaminase and lactate dehydrogenase) and evidence of iron overload (serum iron concentration 13.8 µg/ml and ferritin concentration over 30 000 ng/ml). The liver enzymes returned to normal within 4 days and the iron concentration dropped to baseline after three consecutive hemodialysis sessions within a week. All of his symptoms resolved.

The authors concluded that Gd-DTPA may have an iron mobilizing effect in specific conditions of iron overload. They hypothesized that the combination of iron overload and lack of adequate clearance of Gd chelates may cause massive liberation of iron with dangerous elevation of free serum iron. They recommended

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that after gadolinium contrast studies, patients with end-stage renal disease and probable iron overload should undergo prompt and intensive hemodialysis to prevent this serious complication. Interference with diagnostic routines Gadodiamide and gadoversetamide can cause spurious hypocalcemia, particularly at doses of 0.2 mmol/kg or higher in patients with renal insufficiency. The contrast medium interferes with calcium measurements obtained by using Arsenazo III dye and ortho-cresolphthalein (OCP) colorimetric assays. The false measurements do not occur with use of gadopentetate dimeglumine or gadoteridol. A study of the prevalence of spurious hypocalcemia after gadodiamide-enhanced MR imaging in 896 patients with available serum calcium data obtained before and after gadodiamide-enhanced MR imaging showed that changes in serum calcium correlated with gadodiamide dose, renal function, and time between gadodiamide administration and phlebotomy (38C ). Following 42 gadodiamide-enhanced examinations, serum calcium spuriously fell by more than 0.5 mmol/l, resulting in laboratory reports of “critical” hypocalcemia (i.e. calcium concentration below 1.5 mmol/l) in 25 examinations. These reduced calcium measurements were correlated with serum creatinine concentration, gadodiamide dose, and time between gadodiamide injection and phlebotomy. Spurious reductions in calcium after the administration of gadodiamide 0.1 mmol/kg or 0.2 mmol/kg were greater in patients with renal insufficiency than in those with normal renal function. Patients with renal insufficiency had spuriously low calcium measurements up to 4.5 days after gadodiamide administration. Seven patients were inappropriately treated with intravenous calcium and 11 with oral calcium in response to false-positive laboratory reports of critical hypocalcemia. No patient had characteristic symptoms of hypocalcemia or injuries attributed to the inappropriate medical treatment. The authors concluded that gadodiamide administration causes spurious hypocalcemia, particularly at doses of 0.2 mmol/kg or higher in patients with renal insufficiency. Awareness of this effect on calcium measurements by some MRI contrast agents is important, in order to avoid improper treatment,

which could be hazardous to the patient. Biochemical assays are better performed before contrast injection or delayed for at least 24 hours afterwards or longer in patients with renal impairment. Urgent laboratory tests performed on specimens collected shortly after contrast media injection should be carefully assessed. Accuracy of unexpected abnormal results should be questioned and discussed with colleagues from the hospital laboratories.

Gadobenate dimeglumine Gadobenate dimeglumine (Multihance, GDBOPTA) is a gadolinium-based contrast agent that has been approved for MRI examinations. Gadobenate dimeglumine has a capacity for weak and transient interaction with serum albumin, which increases in vivo T1 relaxivity by a factor of two compared with conventional extracellular gadolinium chelates. In addition, unlike other gadolinium-based contrast agents, which are excreted exclusively by glomerular filtration through the kidneys, it undergoes both renal and hepatobiliary elimination. Clinical trials of the safety of this agent in 2540 adults and children have been reviewed (39R ). Adverse events potentially related to the administration of gadobenate dimeglumine were mainly mild, transient, and self-resolving. The most common were headache, injection site reactions, nausea, and taste disturbances, which occurred with a frequency of 1.0–2.6%. Serious adverse events potentially related to gadobenate dimeglumine were reported in 0.2% of patients. Controlled studies showed no differences between gadobenate dimeglumine and other gadolinium chelates or placebo in the incidence and type of adverse events, including studies in children and subjects with renal or liver insufficiency. Nervous system The safety and diagnostic efficacy of gadobenate dimeglumine in the central nervous system have been evaluated in a double-blind, multicenter, phase III trial in 205 patients (mean age 50 years) at 16 sites in the USA (40C ). They were randomized to one of three incremental dosing regimens. Gadodiamide (Omniscan) (0.1 and 0.3 mmol/kg) was compared with gadobenate dimeglumine (0.05

564 and 0.15 mmol/kg and 0.1 and 0.2 mmol/kg). The amount of diagnostic information from gadobenate dimeglumine at 0.1 mmol/kg was equivalent to that with gadodiamide at the same dose. The cumulative doses of gadobenate dimeglumine were well tolerated and as safe as gadodiamide. The authors concluded that gadobenate dimeglumine is comparable to gadodiamide in terms of safety and efficacy for imaging of nervous system lesions. The safety of a total gadobenate dimeglumine dose of 0.3 mmol/kg, given as three sequential bolus injections of 0.1 mmol/kg, at 10-minute intervals over a 20-minute period has been investigated in 74 adults with proven intracranial metastatic lesions (41C ). Cumulative dosing produced significant dose-related increases in lesion-to-brain ratio and lesion signal intensity enhancement. Significantly more lesions were noted after the first injection compared with unenhanced images, and after a second injection compared with the first, but no further increase in lesion detection was observed with the third injection. No safety concerns were identified in this study.

Gadobutrol Gadobutrol is an MRI contrast agent that displays high relaxivity at a concentration of 1 mmol/ml and that has an osmolality (1603 mosm/kg) lower than that of other MRI contrast agents at a concentration of 0.5 mmol/ml. The safety of intravenous gadobutrol has been investigated in 435 patients (mean age 61 years) undergoing contrast-enhanced MR angiography. Gadobutrol was given as an intravenous bolus injection (mean dose 0.15 mmol/kg) followed by saline 20–40 ml (42C ). There was good tolerability, with only 4.6% “possibly related” adverse reactions and no clinically important changes in blood and urine samples, including no transmetallation effect on serum zinc concentrations. There was no effect on renal function, irrespective of pre-existing renal impairment. Electrocardiography (rhythm analysis, pace-setting disturbances, conduction disturbances, and time interval measurements, including uncorrected and corrected QT intervals) showed no clinically important effect

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on the cardiac conduction system. The authors concluded that intravenous injection of gadobutrol at a dose of up to 0.3 mmol/kg is safe.

Gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) Gadolinium-DTPA is a widely used MRI contrast agent with a good safety record after intravascular administration (SEDA-25, 558). Its clinical pharmacology, safety, and diagnostic efficacy in direct intra-articular injection before MRI examination have been assessed in a meta-analysis of clinical trials published between 1987 and 2001 (43M ). The best concentration for intra-articular administration is 2 mmol/l. After passive complete diffusion from the joint within 6–24 hours, there is complete and rapid renal elimination. Local safety is excellent and almost no systemic adverse effects have been reported. However, the same safety considerations apply for intra-articular administration as for intravenous injection. The authors concluded that the diagnostic efficacy of intra-articular MR arthrography in most clinical conditions affecting major joints is greater than that of plain MRI. Given sterile administration, the intra-articular administration of Gd-DTPA in a concentration of 2 mmol/l before MRI is safe.

Superparamagnatic iron oxide particles (SPIO) MRI contrast agents (SEDA-25, 564; SEDA-26, 522) Ferucarbotran (Resovist) is a 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. Iron oxide has a strong susceptibility effect that causes loss of MRI signal intensity, especially on T2 and T1 weighted images. The contrast between the lesions and the surrounding tissues is therefore increased because of loss of signal in the healthy tissues. The diagnostic efficacy and safety of ferucarbotran has been

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reviewed (44R ). Safety data obtained during clinical phases I–III showed a total of 75 adverse events classified as possibly, probably, or definitely drug related. Most of the events occurred within the first 3 hours and were mild. Ferucarbotran significantly improves the detection of hypovascular focal liver lesions. The authors concluded that ferucarbotran can be regarded as safe and well tolerated.

Mangafodipir trisodium Mangafodipir trisodium (Mn-DPDP, Teslascan) is a contrast agent developed for MR imaging of the hepatobiliary system. Its safety and efficacy have been evaluated in 923 patients, mean age 60 years, including 180 patients with cirrhosis and 743 without (45M ). They received mangafodipir trisodium 5 µmol/kg in 11 prospective randomized European clinical trials. There were mild adverse events (headache, nausea, vomiting, abdominal pain, flushing, taste disturbances, back pain, and a feeling of warmth) in 7%. The authors concluded that mangafodipir trisodium is safe and well tolerated in patients with cirrhosis

Thorotrast

(SEDA-23, 500; SEDA-24, 530, SEDA-27, 506) Thorotrast was widely used between 1928 and 1955 as an X-ray contrast medium. It contains thorium dioxide with a radioactive half-life of about 400 years. After intravascular injection Thorotrast is retained mainly in the reticuloendothelial system, especially of the liver, spleen, and bone marrow. Thorotrast recipients often develop hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, or leukemia 20 years or more after the injection. Peripheral cholangiocarcinoma was reported in a patient 48 years after exposure to Thorotrast (46A ).

• A 70-year-old man developed right hypochondriac pain. Clinical examination and laboratory evaluations were normal. He had undergone angiography with Thorotrast 48 years before. An unenhanced CT scan of the abdomen showed increased density of the liver and spleen, with high-density foci in the splenic hilum and porta hepatis. There was retroperitoneal lymphadenopathy in the upper abdomen. An MRI scan showed a large lobulated mass in the right lobe of the liver. Hepatic resection was performed and histological examination showed cholangiocarcinoma. He made a good recovery and left hospital 10 days after the operation.

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cardiac catheterization. J Invasive Cardiol 2003; 15: 133–8. 6. Munechika H, Hiramatsu Y, Kudo S, Sugimura K, Hamada C, Yamaguchi K, Katayama H. A prospective survey of delayed adverse reactions to iohexol in urography and computed tomography. Eur Radiol 2003; 13: 185–94. 7. Bohm I, Speck U, Schild H. Cytokine profiles after nonionic dimeric contrast medium injection. Invest Radiol 2003; 38: 776–83. 8. Voloudaki A, Ergazakis N, Gourtsoyiannis N. Late changes in barium sulfate aspiration: HRCT features. Eur Radiol 2003; 13: 2226–9. 9. Velden J, Milz P, Winkler F, Seelos K, Hamann GF. Nonionic contrast neurotoxicity after coronary angiography mimicking subarachnoid hemorrhage. Eur Neurol 2003; 49: 249–51. 10. Watanabe T. Ataxia as a delayed reaction to contrast medium for an intravenous pyelography. Pediatr Nephrol 2003; 18: 303.

566 11. Owen PJ, Lazarus JH, Morse RE. Unusual complications of thyroid carcinoma. Postgrad Med J 2003; 79: 55–6. 12. Plavsic BM, Newman AC, Reuther WL, Terry JA, Drnovsek VH. Peripheral blood eosinophilia associated with gastrointestinal administration of iodinated contrast media. Am J Roentgenol 2003; 180: 751–3. 13. Kilinc Y, Sasmaz I, Bozkurt A, Antmen B, Acarturk E. Effect of the radiographic contrast material iopamidol on hemostasis: an observational study in thirty cardiac patients. Curr Ther Res 2003; 64: 461–72. 14. Magen E, Korzets Z. Sialadenitis (“iodide mumps”) following peripheral angiography in a peritoneal dialysis patient. Peritoneal Dial Int 2003; 23: 303–4. 15. Kasi VS, Estrada CA, Wiese W. Association of pancreatitis with administration of contrast medium and intravenous lipid emulsion in a patient with the acquired immunodeficiency syndrome. South Med J 2003; 96: 66–9. 16. Iakovou I, Dangas G, Mehran R, Lansky AJ, Ashby DT, Fahy M, Mintz GS, Kent KM, Pichard AD, Satler LF, Stone GW, Leon MB. Impact of gender on the incidence and outcome of contrastinduced nephropathy after percutaneous coronary intervention. J Invasive Cardiol 2003; 15: 18–22. 17. Srodon P, Matson M, Ham R. Contrast nephropathy in lower limb angiography. Ann R Coll Surg Engl 2003; 85: 187–91. 18. Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, Wang A, Chu AA, Schaer GL, Stevens M, Wilensky RL, O’Neill WW. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. J Am Med Assoc 2003; 290: 2284–91. 19. Efrati S, Dishy V, Averbukh M, Blatt A, Krakover R, Weisgarten J, Morrow JD, Stein MC, Golik A. The effect of N-acetylcysteine on renal function, nitric oxide, and oxidative stress after angiography. Kidney Int 2003; 64: 2182–7. 20. Kay J, Chow WH, Chan TM, Lo SK, Kwok OH, Yip A, Fan K, Lee CH, Lam WF. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. J Am Med Assoc 2003; 289: 553–8. 21. Tadros GM, Mouhayar EN, Akinwande AO, Campbell B, Wood C, Blankenship JA. Prevention of radiocontrast-induced nephropathy with Nacetylcysteine in patients undergoing coronary angiography. J Invasive Cardiol 2003; 15: 311–14. 22. Baker CSR, Wragg A, Kumar S, De Palma R, Baker LRI, Knight CJ. A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. J Am Coll Cardiol 2003; 41: 2114– 18. 23. Boccalandro F, Amhad M, Smalling RW, Sdringola S. Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. Catheter Cardiovasc Interventions 2003; 58: 336–41. 24. Fung JW, Szeto CC, Chan WW, Kum LC, Chan AK, Wong JT, Wu EB, Yip GW, Chan JY, Yu CM,

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Woo KS, Sanderson JE. Effect of N-acetylcysteine for prevention of contrast nephropathy in patients with moderate to severe renal insufficiency: a randomized trial. Am J Kidney Dis 2004; 43: 801–8. 25. Birck R, Krzossok S, Markowetz F, Schnulle P, Van der Woude FJ, Braun C. Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet 2003; 362: 598–603. 26. Alonso A, Lau J, Jaber BL, Weintraub A, Sarnak MJ. Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials. Am J Kidney Dis 2004; 43: 1–9. 27. Fishbane S, Durham JH, Marzo K, Rudnick M. N-acetylcysteine in the prevention of radiocontrastinduced nephropathy. J Am Soc Nephrol 2004; 15: 251–60. 28. Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int 2004; 65: 1366– 74. 29. Marenzi G, Marana I, Lauri G, Assanelli E, Grazi M, Campodonico J, Trabattoni D, Fabbiocchi F, Montorsi P, Bartorelli AL. The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. New Engl J Med 2003; 349: 1333– 40. 30. Morcos SK. Prevention of contrast media nephrotoxicity—the story so far. Clin Radiol 2004; 59: 381–9. 31. Bellin M-F, Jakobsen JA, Tomassin I, Thomsen HS, Morcos SK, Almen T, Aspelin P, Clauss W, Flaten H, Grenier N, Idee J-M, Krestin GP, Stacul F, Webb JAW; Contrast Media Safety Committee of The European Society of Urogenital Radiology. Contrast medium extravasation injury: guidelines for prevention and management. Eur Radiol 2002; 12: 2807–12. 32. Stein DA, Lee S, Raskin KB. Compartment syndrome of the hand caused by computed tomography contrast infiltration. Orthopedics 2003; 26: 333–4. 33. Townsend RR, Cohen DL, Katholi R, Swan SK, Davies BE, Bensel K, Lambrecht L, Parker J. Safety of intravenous gadolinium (Gd-BOPTA) infusion in patients with renal insufficiency. Am J Kidney Dis 2000; 36: 1207–12. 34. Kroencke TJ, Wasser MN, Pattynama PM, Barentsz JO, Grabbe E, Marchal G, Knopp MV, Schneider G, Bonomo L, Pennell DJ, del Maschio A, Hentrich HR, Dapra M, Kirchin MA, Spinazzi A, Taupitz M, Hamm B. Gadobenate dimeglumineenhanced MR angiography of the abdominal aorta and renal arteries. Am J Roentgenol 2002; 179: 1573–82. 35. Ailawadi G, Stanley JC, Williams DM, Dimick JB, Henke PK, Upchurch Jr GR. Gadolinium as a nonnephrotoxic contrast agent for catheter-based arteriographic evaluation of renal arteries in patients with azotemia. J Vasc Surg 2003; 37: 346–52. 36. Morcos SK, Thomsen HS, Webb JAW; Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR). Dialysis and contrast media. Eur Radiol 2002; 12: 3026–30. 37. Vorobiov M, Basok A, Tovbin D, Shnaider A, Katchko L, Rogachev B. Iron-mobilizing properties

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of the gadolinium-DTPA complex: clinical and experimental observations. Nephrol Dial Transplant 2003; 18: 884–7. 38. Prince MR, Erel HE, Lent RW, Blumenfeld J, Kent KC, Bush HL, Wang Y. Gadodiamide administration causes spurious hypocalcemia. Radiology 2003; 227: 639–46. 39. 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. 40. 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 MultiHance (gadobenate dimeglumine) and Omniscan (gadodiamide) in magnetic resonance imaging in patients with central nervous system pathology. Invest Radiol 2001; 36: 65–71. 41. Schneider G, Kirchin MA, Pirovano G, Colosimo C, Ruscalleda J, Korves M, Salerio I, La Noce A, Spinazzi A. Gadobenate dimeglumine-enhanced magnetic resonance imaging of intracranial metastases: effect of dose on

567 lesion detection and delineation. J Magn Reson Imaging 2001; 14: 525–39. 42. Balzer JO, Loewe C, Davis K, Goyen M, Leiner T, Meaney JF, Pockler-Schoniger C, SchulteAltedorneburg G, Tombach B, Vosshenrich R, Wegener R. Safety of contrast-enhanced MR angiography employing gadobutrol 1.0 M as contrast material. Eur Radiol 2003; 13: 2067–74. 43. Schulte-Altedorneburg G, Gebhard M, Wohlgemuth WA, Fischer W, Zentner J, Wegener R, Balzer T, Bohndorf K. MR arthrography: pharmacology, efficacy and safety in clinical trials. Skeletal Radiol 2003; 32: 1–12. 44. Reimer P, Balzer T. Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications. Eur Radiol 2003; 13: 1266–76. 45. Marti-Bonmati L, Fog AF, De Beeck BO, Kane P, Fagertun H. Safety and efficacy of mangafodipir trisodium in patients with liver lesions and cirrhosis. Eur Radiol 2003; 13: 1685–92. 46. Sahani D, Prasad SR, Tannabe KK, Hahn PF, Mueller PR, Saini S. Thorotrast-induced cholangiocarcinoma: case report. Abdom Imaging 2003; 28: 72–4.

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Drugs used in ocular treatment

ANTIALLERGIC DRUGS Ketotifen

(SED-14, 495)

Ketotifen fumarate acts as an antihistamine and also has other anti-inflammatory effects, including mast cell stabilization. Ketotifen fumarate 0.025% ophthalmic solution is indicated for the treatment of allergic conjunctivitis and several well-designed placebo-controlled studies have shown it to be efficacious and well tolerated (1C –4C ).

ANTICHOLINERGIC DRUGS (SED-14, 1640)

Cyclopentolate As surgical treatment of refractive errors and measurement of cycloplegic refraction using cyclopentolate become more frequent, ophthalmologists, optometrists, and orthoptists should be aware of acute toxic events. • A 56-year-old woman was evaluated for surgical correction of hyperopia (+3.0 diopters) (5A ). Two drops of cyclopentolate 1% were instilled in both eyes for measurement of the cycloplegic refraction and wavefront analysis. Immediately after the second instillation she reported drowsiness, dizziness, nausea, and fatigue and 10 minutes later developed stimulatory central nervous system symptoms: restlessness, cheerfulness, and a 20 minute long roar of laughter, interrupted by a new sedative phase. Examination was unremarkable, except for gait ataxia. Four hours later the examination was continued uneventfully.

© 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

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ACETYLCHOLINE RECEPTOR AGONISTS (SED-14, 1642) Pilocarpine is an agonist at acetylcholine receptors, used topically to treat narrow-angle glaucoma. However, oral pilocarpine has been advocated for the treatment of ocular symptoms in patients with Sjögren’s syndrome. In a 12-week, randomized, controlled study 29 patients with primary Sjögren’s syndrome were randomly assigned to receive oral pilocarpine 5 mg bd, 28 only artificial tears, and 28 inferior puncta occlusion (6C ). The patients who took oral pilocarpine and those with inferior puncta occlusion also used artificial tears. Subjective and objective global assessments of dry eyes were made at baseline and throughout the study. Pilocarpine 10 mg/day had a beneficial effect on subjective as well as on objective eye symptoms, as measured by the rose Bengal test; however, Schirmer’s test showed no differences between the treated groups. Commonly reported adverse effects were headache, increased sweating, nausea, and vomiting in the pilocarpine group, while one patient in the inferior puncta occlusion group had blepharitis and was withdrawn from the study. • A 31-year-old female physician with bilateral myopia had myopic laser in situ keratomileusis in the right eye (7A ). She was overcorrected by the initial treatment and had two subsequent hyperopic treatments, resulting in central corneal irregularity. She had Sjögren’s syndrome with marked keratoconjunctivitis sicca, anisometropia, aniseikonia, and monocular diplopia, and was unable to tolerate contact lenses. Oral pilocarpine was prescribed, which improved salivation, lacrimation, and keratoconjunctivitis sicca. As a beneficial side effect, she was then able to tolerate rigid gas-permeable contact lenses to achieve 20/20 visual acuity in both eyes and regain binocular vision.

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ADRENOCEPTOR AGONISTS

and glucocorticoid treatment (10C ). Recently four patients have been described who had clinical and fluorescein angiographic evidence of central serous chorioretinopathy, had psychogenic stress, and were using high dosages of oxymetazoline, pseudoephedrine, or 3,4methylenedioxymetamfetamine. In all cases resolution of the central serous chorioretinopathy coincided with withdrawal of the medication (11A ). Patients with central serous chorioretinopathy should be notified about its possible association with sympathomimetic medications.

Drugs used in ocular treatment

(SED-14, 1643; SEDA-27, 509) Adrenoceptor agonists are widely used in medications available over the counter and can have significant toxic effects, especially in children. Physicians, pharmacists, and the public should be educated about adverse effects of over-thecounter formulations. Those with potent pharmacological properties should be stored out of the reach of children, and manufacturers should package these products in childproof containers.

Tetrahydrozoline (Visine) Visine, an over-the-counter tetrahydrozoline topical ophthalmic decongestant, has central and peripheral alpha-adrenergic properties. Accidental pediatric oral exposure with resultant neurological and cardiovascular complications has been reported (8A ). Visine is not marketed in childproof containers, despite the potential severity of accidental ingestion.

Naphazoline Naphazoline, an alpha2 -adrenoceptor agonist, is used as non-prescription eye-drops and nosedrops because of its vasconstrictive and decongestive properties. Overdose and/or systemic adverse effects due to absorption can quickly cause severe central nervous system depression and cardiovascular adverse effects, especially in children. In a 7-year-old boy naphazoline intoxication was diagnosed by toxicological analysis (9A ). The case was also of forensic interest, because the naphazoline mixture had been prepared in a pharmacy in a concentration 80 times more than the recommended dosage for children.

Oxymetazoline Sensory systems Central serous chorioretinopathy or diffuse retinal pigment epitheliopathy has been associated with psychogenic stress

Phenylephrine

(SED-14, 1643)

Gastrointestinal Cyclopentolate + phenylephrine eye-drops are commonly used for mydriasis during routine screening for retinopathy of prematurity in preterm infants. Although systemic absorption is usually minimal, it can result in adverse effects. Two cases of transient paralytic ileus associated with transient oxygen desaturation and hypertension following the use of cyclopentolate + phenylephrine eye drops have been reported (12A ). Urinary tract Renal insufficiency has been attributed to phenylephrine eye-drops. • A girl of low birth weight with a history of renal insufficiency underwent fundoscopy 29 days after birth (13A ). Eye-drops containing phenylephrine were instilled several times, and additional drops were instilled during fundoscopy using an eyelid retractor, resulting in a raised blood concentration of phenylephrine, sufficient to contract the renal vessels and ultimately inducing renal insufficiency.

Since the use of mydriatic eye-drops in infants of low birth weight could induce renal insufficiency, the following points should be considered (13A ): 1. Mydriatic eye-drops should be used with caution, with monitoring of mydriasis and avoiding excessive instillation. 2. After instillation, the lacrimal region should be compressed to prevent the flow of mydriatic drops into the nasolacrimal duct. 3. Vital signs should be monitored to check for adverse reactions for 12 hours after fundus examination.

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BETA-ADRENOCEPTOR ANTAGONISTS (SED-14, 1639; SEDA-26, 525) Skin Beta-blockers in eye-drops are associated with local stinging, burning, itching, eyelid dermatitis, and periocular hyperpigmentation. In general, however, patch testing with a patient’s own eye-drops is often unsuccessful (14r , 15r ). Dermatitis from beta-blocker eye-drops was associated with a negative ROAT and a positive use test (16r ). • An 87-year-old non-atopic woman used betaxolol eye-drops for several years for open-angle glaucoma and then developed severe itching dermatitis of the eyelids. A patch test with Betoptic suspension showed a positive reaction. The Betoptic was withdrawn and the dermatitis healed in 2 weeks. A ROAT was performed and was negative. She then put one drop of Betoptic solution into each eye, and several hours later developed erythematous edematous plaques on her lower eyelids, which resolved in 3 days. A test with a specially prepared ophthalmic solution containing all the excipients that the commercial product contained in the same concentrations, but without betaxolol, twice daily did not produce a reaction.

GLUCOCORTICOIDS AND NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) (SED-14, 1640) Topical steroids and non-steroidal anti-inflammatory drugs are used to reduce ocular inflammation after lens extraction. The efficacy and ocular adverse effects of prednisolone acetate, ketorolac, and fluorometholone acetate have been compared in a prospective, investigatormasked, randomized, controlled trial in 120 eyes (17C ). Each drug was prescribed 4 times a day for 28 days. All three drugs were effective in reducing postoperative inflammation: ketorolac was less effective than glucocorticoids but did not cause ocular hypertension. A burning sensation was often reported by those who used ketorolac. Some studies have suggested that ophthalmic NSAIDs reduce the pain associated with corneal

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abrasions without impairing healing. An evidence-based emergency medicine critical search suggested that NSAIDs provide greater pain relief and improvement of other subjective symptoms compared with placebo (18R ). The use of NSAIDs in eye-drops may reduce the need for sedating analgesics. Ophthalmic NSAIDs appear to be useful for reducing pain in patients with corneal abrasions who must return to work immediately, particularly when potential opioid-induced sedation is intolerable.

Ketorolac Patients using chronic topical ketorolac, especially those with ocular surface abnormalities, can present with severe complications, such as corneal melting. • A 78-year-old man developed two discrete areas of sterile corneal melting associated with chronic use of topical ketorolac after uneventful clear corneal phacoemulsification; he was treated successfully with tissue adhesive application (19A ).

CARBONIC ANHYDRASE INHIBITORS (SED 14, 1644) Acetazolamide Skin Stevens–Johnson syndrome has been attributed to acetazolamide (20A ). • A 53-year-old man with glaucoma took acetazolamide for 7 days and developed diffuse erythematous papules on both forearms and hands with multiple erosive lesions on his lips and genitalia. Stevens–Johnson syndrome was diagnosed and he was treated with systemic prednisolone with no sequelae.

Dorzolamide Adverse effects associated with systemic carbonic anhydrase inhibitors have adversely affected adherence to treatment in patients with glaucoma, obviating their long-term use. The

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tolerability and efficacy of dorzolamide, a topical carbonic anhydrase inhibitor, has been studied in a selected group of 39 patients with glaucoma and ocular hypertension, who were intolerant of systemic carbonic anhydrase inhibitors in a 3-month prospective study (21c ). The patients were evaluated on the day of switching from systemic carbonic anhydrase inhibitor to dorzolamide and at five more visits. Within 4 weeks after switching the mean health assessment scores improved significantly in seven of the eight categories of the SF-36 questionnaires, used to evaluate changes in well-being and quality of life. There were no significant differences between the mean intraocular pressure on day 0 and subsequent measurements. In patients with glaucoma who are intolerant of systemic carbonic anhydrase inhibitors, topical treatment with dorzolamide offers similar efficacy and better tolerability.

MISCELLANEOUS Acetylcysteine Skin Contact dermatitis has been attributed to acetylcysteine eye-drops (22r ). • A 30-year-old woman with lifelong atopic eczema had a 10-year history of peri-orbital eczema, associated with severe atopic keratoconjunctivitis and keratoconus. Topical glucocorticoids had resulted in early cataracts and glaucoma. She was using fluorometholone and sodium cromoglicate eye-drops and hypromellose and acetylcysteine drops as tear replacement. She was patch tested with an extended European standard series, a facial series, a medicament series, an ophthalmic series including 1% ethylenediamine tetra-acetate and 0.05% phenylmercuric acetate, and her own eye-drops, and was positive to acetylcysteine, phenylmercuric acetate, fragrance mix, and Myroxylon pereirae resin (balsam of Peru). Patch testing with acetylcysteine was negative in 14 controls. There was a marked reduction in redness and itching of the eyes within 1 week of withdrawal of the acetylcysteine eye-drops, with maintained improvement at 4 months.

REFERENCES 1. Ganz M, Koll E, Gausche J, Detjen P, Orfan N. Ketotifen fumarate and olopatadine hydrochloride in the treatment of allergic conjunctivitis: a realworld comparison of efficacy and ocular comfort. Adv Ther 2003; 20: 79–91. 2. Greiner JV, Mundorf T, Dubiner H, Lonsdale J, Casey R, Parver L, Kapik BM, Shams NB, Abelson MB. Efficacy and safety of ketotifen fumarate 0.025% in the conjunctival antigen challenge model of ocular allergic conjunctivitis. Am J Ophthalmol 2003; 136: 1097–105. 3. Kidd M, McKenzie SH, Steven I, Cooper C, Lanz R. Australian Ketotifen Study Group. Efficacy and safety of ketotifen eye drops in the treatment of seasonal allergic conjunctivitis. Br J Ophthalmol 2003; 87: 1206–11. 4. Horak F, Stubner P, Zieglmayer R, Kawina A, Moser M, Lanz R. Onset and duration of action of ketotifen 0.025% and emedastine 0.05% in seasonal allergic conjunctivitis. Clin Drug Invest 2003; 23: 329–37. 5. Mirshahi A, Kohnen T. Acute psychotic reaction caused by topical cyclopentolate use for cycloplegic refraction before refractive surgery. Case report and review of the literature. J Cataract Refract Surg 2003, 29: 1026–30. 6. Tsifetaki N, Kitsos G, Paschides CA, Alamanos Y, Eftaxias V, Voulgari PV, Psilas K, Drosos AA.

Oral pilocarpine for the treatment of ocular symptoms in patients with Sjögren’s syndrome: a randomised 12 week controlled study. Ann Rheum Dis 2003; 62: 1204–7. 7. Bhamra J, Wong J, Gohill J. Oral pilocarpine for the treatment of keratoconjunctivitis sicca with central corneal irregularity. J Cataract Refract Surg 2003; 29: 2236–8. 8. Daggy A, Kaplan R, Roberge R, Akhtar J. Pediatric Visine (tetrahydrozoline) ingestion: case report and review of imidazoline toxicity. Vet Hum Toxicol 2003; 45: 210–12. 9. Musshoff F, Gerschlauer A, Madea B. Naphazoline intoxication in a child—a clinical and forensic toxicological case. Forensic Sci Int 2003; 134: 234– 7. 10. Polak BCP, Baarsma GS, Snyers B. Diffuse retinal pigment epitheliopathy complicating corticosteroid treatment. Br J Ophthalmol 1995; 79: 922–5. 11. Michael JC, Pak J, Pulido J, De Venecia G. Central serous chorioretinopathy associated with administration of sympathicomimetic agents. Am J Ophthalmol 2003; 136: 182–5. 12. Lim DL, Batilando M, Rajadurai VS. Transient paralytic ileus following the use of cylopentolate– phenylephrine eye drops during screening for

572 retinopathy of prematurity. J Paediatr Child Health 2003; 39: 318–20. 13. Shinomiya K, Kajima M, Tajika H, Shiota H, Nakagawa R, Saijyou T. Renal failure caused by eyedrops containing phenylephrine in a case of retinopathy of prematurity. J Med Invest 2003; 50: 203–6. 14. Carriere M, Giordano-Labadie F, Schwarze HP, Loche F, Bazex J. Difficulties in the interpretation of patch test reactions to ophthalmic beta-blockers. Contact Dermatitis 1998; 39: 319–20. 15. Wilkinson SM. False-negative patch test with levobunolol. Contact Dermatitis 2001; 44: 264. 16. Sánchez-Pérez J, Jesus Del Rio M, FernándezVillalta MJ, Garcia-Diez A. Positive use test in contact dermatitis from betaxolol hydrochloride. Contact Dermatitis 2002; 46: 313–14. 17. Trinavarat A, Surachatkumtonekul T, Atchaneeyasakul L-O. Comparison of topical prednisolone acetate, ketolorac tromethamine and fluorometholone acetate in reducing inflammation after phacoemulsification. J Med Assoc Thailand 2003; 86: 143–50.

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18. Weaver CS, Terrell KM. Update. Do ophthalmic nonsteroidal anti-inflammatory drugs reduce the pain associated with simple corneal abrasion without delaying healing? Ann Emerg Med 2003; 41: 134–40. 19. Marcon AS, Rapuano CJ, Tabas JG. Tissue adhesive to treat 2-site corneal melting associated with topical ketorolac use. J Cataract Refract Surg 2003; 29: 393–4. 20. Ha JH, Song JY, Kim HO, Kim JW. A case of Stevens–Johnson syndrome caused by acetazolamide. Korean J Dermatol 2003; 41: 248–50. 21. Nesher R, Ticho U. Switching from systemic to the topical carbonic anhydrase inhibitor dorzolamide: effect on the quality of life of glaucoma patients with drug-related side effects. Israel Med Assoc J 2003; 5: 260–3. 22. Davison SC, Wakelin SH. Allergic contact dermatitis from N-acetylcysteine eyedrops. Contact Dermatitis 2002; 47: 238.

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Treatments used in complementary and alternative medicine

Given the increasingly high level of popularity of complementary and alternative medicine, many experts now realize the importance of studying the safety of the treatments involved. However, pharmacovigilance in this area is still in its infancy (1R ). Since complementary medicines are by no means risk-free, it is mandatory to advise consumers responsibly. Unfortunately, reliable advice is exceedingly hard to come by. Advice provided in Canadian health food stores often proved to be wanting (2R ). Similarly, advice volunteered by vendors via the Internet has been shown to be unreliable (3R ). Perhaps most worryingly, advice obtained from practitioners can also be misleading to the point of endangering the health of consumers (4R , 5R ).

therapists suggested that only 17% of these professionals had ever noted an adverse reaction to a herbal treatment (7C ). Several authors have cautioned that herbal medicines may not be safe during pregnancy and lactation (8R , 9R ), in children and adolescents (10R , 11M ), or elderly people (12A ). Herbal medicines can also damage specific organ systems, such as the liver (13C , 14M ), the nervous system (15M ), or the cardiovascular system (16M ). Other problems include adulteration with prescription drugs (17R ), and herb– drug interactions (18R –23R ). Thus, the need for adequate pharmacovigilance of herbal medicine is obvious (24R ) and guidance for safety assessment has been provided (25R ). The inadequacy of regulation of herbal medicines has repeatedly been stressed (26R ), and guidance for better safety assessments has been provided (25R ).

HERBAL MEDICINES (SED-14, 1651; SEDA-25, 399; SEDA-26, 528; SEDA-27, 512) Survey data have repeatedly shown that adverse effects of herbal medicines are more frequent than is generally appreciated. A large US study involving 11 poison centers showed that one-third of the events reported in association with intake of dietary supplements were “greater than mild severity” (6C ). They included myocardial infarction, liver failure, bleeding, and death. Most frequently implicated were Ma Huang (Ephedra), guaraná, ginseng, and St John’s wort. A survey of 2203 Australian © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

Asian herbal medicines Chinese herbal medicines have a long tradition and are increasingly popular in the West. A survey of all patients seen in a German hospital specializing in traditional Chinese medicine included 1036 patients, in 6.5% of whom adverse events (mostly of minor severity) were recorded (27C ). Several severe adverse events were also noted; they included paralysis of the tibialis anterior muscle, paresthesia, and raised liver enzymes. Cardiovascular Severe hypotension has been attributed to a Chinese herbal mixture (28A ). • A 57-year-old man developed nausea, epigastric pain, dizziness, and diarrhea 4 hours after taking a decoction made of 14 Chinese herbs. On admission his blood pressure was 77/46 and his pulse 6

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574 per minute. He was given intravenous fluids and the hypotension normalized within hours.

The authors pointed out that seven of the 14 herbal constituents are known to have vasodilatory effects. They therefore believed that this herbal mixture synergistically caused the hypotensive crisis. Liver Japanese authors have reported 12 cases of acute liver damage associated with Chaso or Onshido, two Chinese herbal aids to weight loss (29c ). Both supposedly herbal medicines actually contained N-nitroso-fenfluramine. Most patients made a full recovery, but one died and one required liver transplantation. A health warning about these medicines was issued in Japan, and subsequently 474 further cases of hepatotoxicity induced by herbal aids to weight loss came to light. The nature of the liver injury and its exact cause is not entirely clear. The pathology was consistent with toxic hepatitis. • A 31-year-old woman developed severe hepatotoxicity while taking the Chinese drug OnshidouGenbi-Kounou for weight loss (30A ). Her condition improved after withdrawal of the remedy. Other possible causes were excluded.

The authors believed that the Chinese medicine had caused the hepatitis. Drug contamination When British dermatologists analysed 24 Chinese herbal creams used by their patients for eczema they found that all but four of these samples were adulterated with glucocorticoids (31E ). The Chinese patent medicine Hua Fo-Vigor Max is marketed for erectile dysfunction. It was shown by Canadian authorities to contain the prescription drug tadalafil, which is used to treat erectile impotence (32E ). Health Canada required the importer to remove the product from the market and issued a “Customs Alert” to stop importation of the product. The regulatory authorities in New Zealand have ordered the withdrawal of 11 Chinese medicines (33S ). They were adulterated either with Aristolochia species, which causes severe kidney damage, or prescription drugs such as sildenafil, diclofenac, chlorphenamine, paracetamol, glibenclamide, ketoconazole, clobetasol, albendazole, and ephedrine. One remedy was contaminated with arsenic.

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Drug interactions Quilinggao, a popular Chinese mixture that contains a multitude of herbal ingredients (including Fritillaria cirrhosa and other Fritillaria species, Paeoniae rubra, Lonicera japonica, and Poncirus trifoliata, in many different brands), has been reported to enhance the actions of warfarin (34A ). • A 61-year-old man taking stable warfarin therapy developed gum bleeding, epistaxis, and skin bruising 5 days after taking Quilinggao. His international normalized ratio was above 6 (usual target 2–3). His warfarin was withdrawn and the international normalized ratio normalized. Days later he tried taking Quilinggao again with a similar result.

The authors pointed out that several herbs in this mixture have anticoagulant activity.

Allium sativum

(SED-14, 1652; SEDA-26, 529; SEDA-27, 515) Drug interactions The potential interactions between garlic and prescribed drugs have been reviewed (35R ). The medicines that might thus be affected include ritonavir, saquinavir, paracetamol, warfarin, and chlorpropamide. The effect of garlic on cytochrome P450 enzymes has been studied in 14 subjects, using the probe substances dextromethorphan and alprazolam (36C ). The results suggested that garlic extracts are unlikely to alter the disposition of co-administered medications whose metabolism primarily depends on CYP2D6 or CYP3A4. Garlic has anti-platelet activity and can therefore reduce the effects of the anticoagulant fluindione (37A ).

• An 82-year-old man developed a reduced international normalized ratio after he started to take garlic tablets while also taking fluindione. He had started taking fluindione 1 year earlier because of chronic atrial fibrillation; his co-medications included enalapril, furosemide, and pravastatin. His international normalized ratio remained between 2 and 3 during 1 year of fluindione treatment and then suddenly decreased. Despite an increase in fluindione dosage (mean dose 6.6–10 mg) it remained below 2 for 12 consecutive days. Garlic was withdrawn and the international normalized ratio returned to its previous level within 4 days.

Treatments used in complementary and alternative medicine

Aristolochia species (SED-14, 1654; SEDA-25, 568; SEDA-26, 529; SEDA-27, 515) Tumorigenicity Urothelial tumors have previously been reported in patients taking Aristolochia (38c ). • A 69-year-old woman developed invasive urothelial cancer and later died after taking a Chinese herbal medicine containing aristolochic acid for weight loss (39A ). Her cancer was diagnosed 9 years after taking about 189 g of Aristolochia fangchi in total. Examination of tissue samples showed significant concentrations of specific aristolochic acid DNA adducts.

Unusually, the patient had not suffered from renal impairment before developing cancer. Drug contamination When 42 samples of Chinese herbal slimming aids were analysed in Switzerland four were found to contain the nephrotoxic aristolochic acid I and a further two were suspected to contain aristolochic acid derivatives (40E ). The authors called for the immediate removal of these products from the Swiss market.

Camelia sinensis Liver The French and Spanish Advisory Boards have suspended the marketing authorization of Exolise, an ethanolic extract of green tea (Camelia sinensis), because of several reports of hepatic disorders (41S ). There have been 13 reports of hepatic disorders (nine in France and four in Spain). All were women, aged 27–69 years, with a time to onset of 9 days to 5 months. Five of the patients had not taken any other medications. Viral serology was negative in eight cases. Rechallenge was positive in eight cases.

Centella asiatica Skin

Centella asiatica can cause rashes.

• An 18-year-old woman presented with a pruritic eczematous eruption that developed after topically applying an ointment containing hydrocortisone acetate, neomycin sulfate and Centella asiatica. She was positive to all three ingredients of the ointment (42A ).

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Chelidonium majus The Australian Complementary Medicines Evaluation Committee (CMEC) has advised that all oral products containing Chelidonium majus (greater celandine) should contain a label with the warning that they should be used under the supervision of health-care professionals; consumers with a history of liver disease should seek advice from a health-care professional before starting to use such a product and to stop using it if particular symptoms occur (43S ). This recommendation follows the CMEC’s careful examination of all available evidence linking ingestion of Chelidonium majus with moderate to severe reversible acute hepatitis in a relatively small number of individuals worldwide. The mechanism underlying the hepatotoxic effect needs to be elucidated. Pending further information, the Therapeutic Goods Administration (TGA) has advised health-care professionals to watch for signs of liver toxicity associated with the use of Chelidonium majus, which has traditionally been used to treat a range of conditions, including liver disorders, and is available internationally.

Cimicifuga racemosa

(SEDA-27, 516)

A systematic review of all clinical data on the safety of Cimicifuga racemosa (black cohosh) found only a slight risk of mild, transient adverse effects (44M ). The authors concluded that, taken for a limited length of time, this remedy is reasonably safe. Liver Severe liver damage has been associated with black cohosh (45A ). • A 52-year-old woman was hospitalized with acute liver failure. She had taken a herbal mixture containing Cimicifuga racemosa, ground ivy, and three other medicinal herbs for 3 months. She had no risk factors for hepatitis and had taken no other medicines. Her condition deteriorated and she developed hepatic encephalopathy as well as hepatorenal failure. She underwent liver transplantation with an uneventful postoperative course. Analysis of the herbal mixture revealed no undeclared constituents.

The authors discuss that either Cimicifuga racemosa or ground ivy could have caused this adverse event.

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Crataegus oxyacantha

Eleutherococcus senticosus

Drug interactions The interaction between hawthorn (Crataegus extract 450 mg bd for 21 days) and digoxin 0.25 mg was tested in a randomized crossover trial in eight healthy volunteers (46C ). Hawthorn had no effect on the pharmacokinetics of digoxin.

Drug interactions In 12 healthy volunteers the probe substrates dextromethorphan and alprazolam were given to test the effects of Siberian ginseng on the activity of CYP2D6 and CYP3A4 (50C ). The results showed that Siberian ginseng is unlikely to alter the disposition of co-administered medications whose metabolism primarily depends on CYP2D6 or CYP3A4.

Commiphora mukul Metabolism Guggulipid is a standardized extract from Commiphora mukul, often used in traditional Indian medicine for circulatory problems. The results of several studies have suggested that it lowers cholesterol concentrations. However, a placebo-controlled study showed that it increased LDL cholesterol by 4% (300 mg/day of guggulipid) and 5% (600 mg/day of guggulipid) (47C ).

Curcuma longa Because of its bright yellow color, this plant (turmeric) is sometimes used as a food coloring agent; in Ayurvedic medicine turmeric has a long history as a medicine for a wide range of conditions for both topical and internal use. A systematic review of all human trials found only six studies (48M ). The dosage of curcumin was 1125–2500 mg/day. Serious adverse events were not reported, and the authors conclude that curcumin “has been demonstrated to be safe”.

Echinacea (SED-14, 1658; SEDA-25, 569; SEDA-26, 531, SEDA-27, 516) Immunologic Sjögren’s syndrome has been attributed to Echinacea. • A 36-year-old woman developed generalized muscle weakness (49A ). She was found to have hypokalemia, which was treated with electrolyte replacement. Her muscular complaints disappeared but she then complained of joint stiffness, dry mouth, and dry eyes. The diagnosis of Sjögren’s syndrome was confirmed by laboratory tests. She had been taking a herbal mixture that included Echinacea, which is known to stimulate the immune system, and the authors speculated that Echinacea had aggravated a pre-existing autoimmune disease.

Ginkgo biloba (SED-14, 631, 1658; SEDA-23, 214; SEDA-26, 531; SEDA-27, 517) Hematologic Some studies (but not all) have shown that Ginkgo biloba inhibits platelet aggregation. It could therefore theoretically cause bleeding, particularly when used in combination with other antiplatelet drugs. • A 71-year-old man had a fatal stroke due to intracerebral bleeding (51A ). His medical history was unremarkable, except for the fact that he had taken 40 mg bd of a ginkgo extract for 2.5 years. Four weeks before his death he started taking ibuprofen (600 mg/day).

Whether this association was causal is speculative. A rare case of retrobulbar hemorrhage was associated with chronic intake of Ginkgo biloba (52A ). • A 65-year-old woman was admitted for routine lens implantation. Immediately after injection of 5 ml of local anesthetic, there was sudden proptosis, bruising of her lower lid, pain, and reduced vision. The problems turned out to be caused by retrobulbar bleeding. She had taken 3 × 40 mg of Ginkgo biloba extract daily for 2 years. Her blood count, prothrombin time, and partial thromboplastin time were normal.

Drug interactions Gingko biloba extracts are increasingly being linked to a bleeding tendency, owing to an inhibitory action on platelet activating factor-mediated platelet aggregation. The danger is that over-the-counter herbal medicines are not taken into consideration when other drugs with antiplatelet effects, such as ibuprofen, are prescribed. A fatal incident has illustrated the problem (53A ).

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• A 71-year-old man in good health had taken a concentrated extract of Gingko biloba for at least 2.5 years because of occasional dizziness. He then took ibuprofen for osteoarthritic hip pain. Ibuprofen inhibits thromboxane-dependent platelet aggregation. Four weeks later, he suffered a fatal massive intracranial bleeding.

Drug interactions The potential of liquorice to interact with prescribed drugs has been reviewed (58R ). The list of implicated comedications includes prednisolone, aspirin, antibiotics, diuretics, cardiac glycosides, NSAIDs, oral contraceptives, antidiabetic drugs, antithrombotic drugs, and antidepressants.

Glycyrrhiza species

Hypericum perforatum

(SED-14, 1659; SEDA-25, 569; SEDA-26, 531, SEDA-27, 517) Liquorice is often used as a flavoring agent in sweets and as a medicine in traditional Chinese medicine. It causes adverse effects by its aldosterone-like actions.

Cardiovascular Liquorice can cause hyperaldosteronism and hence hypertension. • A 52-year-old woman had high blood pressure that had previously been resistant to antihypertensive drugs (54A ). Her history was unremarkable and her blood pressure readings varied between 140/70 and 200/80 mmHg without apparent reason. On detailed questioning she admitted to eating two bars of an unnamed liquorice sweet daily. Discontinuation of this habit normalized her blood pressure within 1 month without the need for any other medical intervention.

Electrolyte balance Liquorice can cause hyperaldosteronism and hence hypokalemia. • A 56-year-old woman developed severe hypokalaemic myopathy and pseudoaldosteronism (55A ). Her hypokalemia was corrected with an infusion of potassium chloride and all her symptoms resolved swiftly. The cause of the problem remained elusive until it was noted that she had eaten large amounts of Pontefract cakes, which contained 15 g of pure liquorice, per day to treat chronic constipation.

Endocrine Of 34 Japanese patients with diabetes and chronic hepatitis, 18 were given glycyrrhizin 240–525 mg for over 1 year (56c ). This resulted in a significant lowering of total testosterone concentrations and increased arteriosclerotic plaque formation. The authors suggested that glycyrrhizin treatment was an independent risk factor for arteriosclerosis. The testosterone lowering effect of liquorice has been confirmed in another trial (57c ).

(SED-14, 1660; SEDA-25, 570; SEDA-26, 532; SEDA-27, 517) Drug withdrawal Like most antidepressants Hypericum perforatum (St John’s wort) can cause withdrawal symptoms. • A 58-year-old woman had taken a hypericum extract 1800 mg tds for 32 days when she decided to stop taking it because of a photosensitivity reaction (which is a rare adverse effect of hypericum) (59A ). Within 24 hours, she developed nausea, anorexia, dizziness, dry mouth, thirst, cold chills, and extreme fatigue. These symptoms peaked on day 3 and gradually improved until they abated on day 8.

The authors believed that these symptoms had been caused by the withdrawal of St John’s wort, similar to withdrawal from conventional antidepressants. Drug interactions St John’s wort interacts with a range of prescription drugs through activation of the drug metabolizing enzyme CYP3A and the efflux transporter P glycoprotein. These mechanisms make it conceivable that it may lower the blood concentrations of oral estrogens (60A ). • A 36-year-old woman who had taken St John’s wort 1700 mg/day for 3 months for depression became pregnant despite regularly taking the combined oral contraceptive Valette® . A therapeutic abortion was carried out which revealed a healthy 17-week-old 144 g male fetus.

The authors believed that this pregnancy was related to an interaction of hypericum with ethinylestradiol. They also mentioned four similar cases that had been reported to the German regulatory authorities. In 12 healthy volunteers the effects of St John’s wort on CYP3A4 using dextromethorphan 30 mg and alprazolam 2 mg while taking

578 3 × 300 mg hypericum extract for 14 days resulted in a two-fold reduction in AUC and a two-fold increase in drug clearance, consistent with the known enzyme inducing effect of St John’s wort (61C ). The effect of hypericum extract 600 mg/day for 14 days on the pharmacokinetics of tacrolimus and mycophenolate mofetil has been studied in 10 renal transplant recipients who had received their transplant at least 2 years before and who were taking stable immunosuppressive therapy (62C ). The plasma concentrations of both drugs were significantly reduced. In 11 renal transplant patients taking stable doses of ciclosporin, all required a ciclosporin dosage adjustment 3 days after the introduction of hypericum 600 mg/day (63C ). After 10 days the median daily dose of ciclosporin was increased from 2.7 to 4.2 mg/kg/day to maintain ciclosporin blood concentrations in the target range. The pattern of ciclosporin metabolism was also altered by hypericum as the relative concentrations of the individual ciclosporin metabolites were also changed. In a controlled study, 18 women (aged 18– 35 years) took ethinylestradiol + desogestrel 0.02/0.15 mg/day alone or in combination with hypericum 300 mg bd (cycle A) or tds (cycle B) (64C ). There was no evidence of ovulation during concomitant hypericum and oral contraceptive use; however, significantly more patients reported mid-cyclic bleeding during cycles A (76%) and B (88%) than during the control cycle (35%), and the AUC of 3-ketodesogestrel fell significantly during cycles A and B compared with the control cycle.

Melaleuca alternifolia Skin Melaleuca alternifolia (tea tree oil) is popular, for example, as a topical treatment for skin infections, but can cause rashes. • An 18-year-old woman developed linear IgA bullous dermatosis after applying tea tree oil to her umbilical region after piercing (65A ). Patch testing was positive to tea tree oil. She was treated with topical clobetasol and recovered fully after 5 days.

Immunologic Anaphylaxis has been attributed to topical tea tree oil.

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• A 38-year-old man applied tea tree oil to psoriatic lesions on his legs and immediately developed erythema at the sites of application (66A ). Within minutes he developed throat constriction and generalized pruritus and subsequently all the signs of anaphylaxis. He was treated accordingly and made a swift, full recovery.

Myristica fragrans Psychological Nutmeg is the dried kernel of the evergreen tree Myristica fragrans. At sufficiently high doses it has psychoactive effects. • A 23-year-old man developed delusions and hallucinations (67A ). His medical history was unremarkable. For several months he had been regularly taking nutmeg 5 g/day. He improved after withdrawal of nutmeg and was treated with olanzapine. After 6 months he was still taking antipsychotic medication but could resume work.

Panax ginseng Drug interactions In 20 healthy volunteers who took 100 mg of an extract of Panax ginseng standardized to 4% ginsenosides twice daily for 14 days no effects on CYP3A were detected and this result was confirmed in in vitro studies (68CE ). • A 58-year-old anticoagulated man with a mechanical bi-leaflet aortic valve prosthesis was hospitalized with an acute anteroseptal myocardial infarction and diabetic ketoacidosis (69A ). His international normalized ratio on admission was 1.4 and there were no other factors that could have interfered with warfarin. Thrombosis of the artificial valve was diagnosed and removed surgically.

The authors suspected that the thrombosis had been caused by an interaction of ginseng with warfarin.

Piper methysticum (SED-14, 1663; SEDA-25, 571; SEDA-26, 533; SEDA-27, 518) Safety issues involving herbal medicines: kava as a case study Kava or awa (Piper methysticum) is a plant that grows in the South Pacific Islands. Eight

Treatments used in complementary and alternative medicine

species have been identified by the local cultivators on the basis of its habitat, such as mountainous versus lowland, in shade versus in full sun. In the Pacific Islands kava has been widely consumed as a traditional ceremonial beverage and for its mood-altering and stress relieving properties (70R ). Traditional preparations use aqueous emulsions of the crushed or dried roots or lower stems of the kava shrub, and its pharmacological properties have been attributed to a group of components collectively know as kava pyrones or kava lactones. However, in the last 10 years there has been an expanding global market for herbal formulations containing lipid kava extracts in the west, largely evolving in Germany and spreading to the American and European markets. In the UK, three licensed medicines and a large number of unlicensed herbal remedies containing kava were available until they were banned in 2004. These products were marketed for the treatment of anxiety, insomnia, premenstrual syndrome, and stress, and were sold over the counter as complementary medicines or as dietary supplements and nutraceuticals. Since 1999, several cases of severe hepatotoxicity in people using kava-containing herbal products were reported in Europe and the USA. By late 2002 there were 10 reports of patients requiring liver transplants (eight in Europe and two in the USA; one died after transplantation) after hepatic failure associated with the use of kava-containing products. This led to various worldwide regulatory measures, ranging from a total ban of kava-containing products to consumer advisory warnings about the adverse effects of kava. The WHO Global Database for Adverse Drug Reactions has received altogether 23 case reports of liver injury in suspected connection with the use of kava from the UK, Switzerland, Germany, the USA, and Canada; most have come from Germany. In addition, the database contains 26 reports of a variety of hypersensitivity reactions. The mechanism of kava toxicity remains to be elucidated, but it may be caused by a compound that is extracted in lipid extracts and not in aqueous extracts or a metabolite of such a compound (71E ). Histological studies have shown portal inflammation with lymphocytes and eosinophils. An idiosyncratic immune response to a reactive metabolite has been suggested as a possible cause. Genetic differences

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in liver metabolism of kava lactones also need to be examined. Liver Piper methysticum (kava kava) has been associated with about 70 cases of liver damage, in some cases severe. It was therefore withdrawn in several countries. In an analysis of the 19 German reports it was concluded that a probably causal relation could be established in only one patient (72R ). In a review of 29 cases reported between 1990 and 2002, nine patients developed fulminant liver failure and three died; the rest made full recoveries (73c ). The authors considered that immunoallergic and idiosyncratic factors had been responsible. Meanwhile further cases of severe liver damage have been associated with the use of kava (74A ).

Polygonum multiflorum Liver Polygonum multiflorum (witch hazel) is often recommended for topical use but in traditional Chinese medicine it is also used orally. • An 18-year-old man developed liver failure during long-term use of the herbal mixture “RespirActin” which contained numerous herbs, including witch hazel (75A ). He required a liver transplant and made a good recovery.

The causality between witch hazel consumption and liver damage was speculative in this case.

Salix species Immunologic Anaphylaxis has been attributed to willow bark. • A 25-year-old woman developed anaphylaxis after taking a herbal slimming aid containing willow bark, which is rich in salicylates (76A ). She had a history of salicylate allergy. She made a full recovery in intensive care.

Serenoa repens Immunologic Allergic contact dermatitis has been attributed to Serenoa repens (saw palmetto).

580 • A 24-year-old woman developed allergic contact dermatitis while taking minoxidil and again while taking Serenoa repens solution for androgenic alopecia (77A ).

Drug interactions In 12 healthy volunteers Serenoa repens (saw palmetto) at generally recommended doses did not alter the disposition of co-administered medications whose metabolism primarily depends on CYP2D6 or CYP3A4 (78C ).

Silybum marianum Drug interactions In 10 healthy volunteers taking silymarin 160 mg tds for 17 days there was no evidence of an interaction with indinavir 800 mg tds (79C ).

Soy Drug interactions In 20 healthy volunteers who took soy extract containing 50 mg of isoflavones twice daily for 2 weeks there was no evidence of induction of CYP3A, although in vitro studies showed inhibition of all of the CYPs tested (68CE ).

Tripterygium wilfordii Endocrine Tripterygium wilfordii (thundergod vine) is often used in traditional Chinese medicine, for instance to treat arthritis. • A 36-year-old woman developed vaginal dryness, reduced libido, and hot flushes after taking Tripterygium for 3 months to treat psoriasis (80A ). Her follicle stimulating hormone and luteinizing hormone concentrations were abnormally high, while her 17-beta-estriadol concentration was abnormally low. Her signs and symptoms normalized after the herbal remedy was withdrawn.

The authors suggested that thundergod vine has suppressive effects on both male and female gonads.

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Zingiber officinale Pregnancy Zingiber officinale (ginger) is often used for morning sickness. It is therefore important to define its safety in pregnancy. The Canadian Motherisk Program monitored 187 pregnancies of women taking ginger during early pregnancy (81C ). There were 181 live births, two stillbirths, three spontaneous abortions, one elective termination, and three malformations. Compared with non-ginger taking mothers, these data were not significantly different. The authors therefore argued that ginger does not appear to increase the rates of major malformations. However, the sample size may well have been too small to draw such a conclusion with certainty.

Dietary supplements Drug contamination The dietary supplement “Vinarol” is promoted in the USA as a treatment for erectile dysfunction (82S ). It was recalled after illegal adulteration with sildenafil was noted.

Probiotics Infection risk Lactobacilli and bifidobacteria are promoted for a range of intestinal complaints. In rare cases they can cause infections, particularly in immunocompromised individuals. However, according to a review of the safety of probiotics, the infection risk is negligible (83R ).

Proprietary mixtures Liver Hepatitis can complicate the use of many herbal medicines. • A 52-year-old woman developed liver damage resembling chronic hepatitis while taking the herbal weight loss aid “Be Petite” (84A ). After withdrawal of the product her signs and symptoms improved, and at 4 months follow-up she had recovered fully.

Treatments used in complementary and alternative medicine

In the absence of other risk factors, the authors believed that “Be Petite” may have caused this hepatotoxic event. • When a 37-year-old woman was admitted for elective surgery her liver enzymes and prothrombin time were found to be abnormal (85A ). The most plausible reason for this was that she was taking Chinese herbal mixtures containing a total of 61 different herbal ingredients. She was operated on after withdrawal of the herbal medicines for 4 days and developed a vaginal vault hematoma postoperatively. She was discharged free of symptoms on day 17.

Urinary tract Nephritis can complicate the use of herbal medicines. • A 52-year-old woman developed left-sided abdominal pain, diarrhea, and a hematoma after taking the herbal remedy CKLS for 5 days (86A ). Renal biopsy confirmed acute tubulointerstitial nephritis.

CKLS which is marketed as a “kidney purifier” contains multiple herbal ingredients, including aloe vera, cascara, and chaparral. The authors suggested that the nephritis was most likely due to aloe vera and cascara, both of which contain anthraquinone glycosides.

ACUPUNCTURE

(SED-14, 1673; SEDA-25, 573; SEDA-26, 535; SEDA-27, 520)

A German survey of 29 acupuncturists included 409 patients who received 3535 acupuncture sessions (87R ). In 11.4% of these there were adverse events, which were usually mild and transient: slight bleeding (2.9%), hematoma (2.2%), and dizziness (1%). There were no serious events and the authors concluded that acupuncture is safe. Others have pointed out after reviewing the relevant literature that serious complications are infrequent but “responsible clinicians practicing acupuncture and seeing patients who use acupuncture should be aware of the adverse events associated with it” (88R ). Respiratory The most common serious adverse effect of acupuncture is pneumothorax, through puncturing the lung with an acupuncture needle. A fatal case of acupuncture-induced pneumothorax has been reported (89A ). The patient developed dyspnea and chest pain directly

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after the treatment and died before adequate medical help was available. At autopsy ecchymoses were noted on the parietal pleura, suggesting that needles had been inserted into the thoracic cavity and had perforated the lungs. Microscopically many black spots were seen on the parietal pleura along the vertebral column. The authors interpreted them as traces from previous acupuncture treatments, which had been dangerously close to causing pneumothorax. • A 25-year-old woman had a bilateral pneumothorax with pericardial and peritoneal effusions during acupuncture treatment (90A ). She was successfully resuscitated and made a full recovery.

The Japanese press reported a similar case (91A ), but in this instance the life of the patient was not saved. Nervous system Several reports have illustrated that acupuncture needles can cause nerve damage. • A 62-year-old woman developed left drop foot, anterior leg pain, and numbness (92A ). The symptoms occurred after acupuncture for sciatica. Radiographs showed a needle-like object near the fibular head; it was removed surgically. • A 68-year-old woman developed symptoms consistent with spinal stenosis (93A ). Microscopic examination showed a chronic inflammatory epidural granuloma compressing the lumbar fourth nerve and dural sac. Her history suggested that it had been caused by acupuncture. Surgical excision of the granuloma led to a full recovery. • When a 67-year-old woman was investigated for pancytopenia, multiple needle fragments were noted on an X-ray along the anterior and posterior thoracic and abdominal walls (94A ). They had probably originated from acupuncture 17 years before, when she had “Hari” acupuncture, which involves leaving small gold needles permanently at acupuncture points. She did not seem to have had any symptoms from these remnants.

The authors of the last report cautioned that such fragments may be mistaken for calcified organs at X-ray. Infection risk A systematic review of 15 mostly Asian epidemiological studies has assessed the risk of hepatitis infection through non-sterile acupuncture needles (95M ). Five studies reported associations between acupuncture and seropositivity to hepatitis C virus. In those studies, acupuncture increased the risk only modestly.

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Skin Skin lesions can result from acupuncture needles. • An 83-year-old woman developed intense pruritus and pigmented particles were noted in the dermis on her lower back (96A ). It turned out that she had acupuncture 20 years before, when silver needles had been implanted in her skin. She had developed argyria, which had caused the pruritus. • A 58-year-old immunosuppressed woman developed tender, red, suppurating subcutaneous nodules in the skin of her abdomen 3 months after having acupuncture for obesity (97A ). Histological examination of the nodules showed chronic inflammatory cells with abscess and necrosis. Culture grew Mycobacterium chelonae. She was treated with antibiotics and recovered fully.

HOMEOPATHY

(SED-14, 1668;

SEDA-25, 573) In its highly diluted form, arsenic is used as a homeopathic remedy. Three cases of chronic arsenic poisoning were associated with the use of homeopathic arsenic (98A ). In all instances, the dilution was not sufficiently high to render the remedies non-toxic.

SPINAL MANIPULATION (SED-14, 1674; SEDA-25, 575; SEDA-26, 536; SEDA-27, 521) Spinal manipulation is a therapeutic technique used by chiropractors, osteopaths, physiotherapists, doctors, and other health-care professionals, mostly but not exclusively for the treatment of spinal pain syndromes. It can cause serious complications, particularly when it involves the cervical spine. Over a 5 year period, US neurologists from one single group practice treated 22 patients with adverse effects after cervical manipulation (99c ). The complications included radiculopathy (n = 21), myelopathy (n = 11), Brown– Séquard syndrome (n = 2) and vertebral artery dissection (n = 1); 17 of these patients made a good recovery while the rest had persistent neurological deficits. Based on prevalence data for usage of chiropractic spinal manipulation in

E. Ernst

their area, the authors calculated that the frequency of irreversible complications is about 1 per 850 patients undergoing a series of cervical manipulations – a figure that is dramatically different from those usually proposed by chiropractors. Cardiovascular In a US nested case-control study, all patients under 60 years of age with cervical arterial dissection and transient ischemic attacks or strokes from 2 stroke centers were reviewed (100C ). In a multivariate analysis, vertebral arterial dissections were independently associated with spinal manipulation within 30 days (OR = 6.62; 95% CI = 1.4, 30). In a series of 126 German patients with cervical arterial dissection, potential susceptibility factors for this condition were assessed (101c ). Chiropractic cervical manipulation had been performed before diagnosis in 16% of these cases. Vertebral arterial dissection was noted in 30% of these cases. • A 34-year-old previously healthy man had bilateral internal carotid and vertebral arterial dissections after spinal manipulation from a chiropractor (102A ). He developed severe neck pain while still on the chiropractic table. MRI and MRA studies showed an acute right thalamic infarct and arterial dissection. Catheter angiography showed a dissecting pseudoaneurysm at the craniocervical junction. • A 46-year-old woman developed tinnitus in her left ear (103A ). The carotid arteriogram showed dissection of the left internal carotid artery. She had chiropractic neck manipulation 6 weeks earlier for neck pain. • Spanish doctors described the case of a young patient with incomplete Wallenberg’s syndrome hours after receiving cervical manipulation from a chiropractor (104A ). MRI confirmed the diagnosis of vertebral arterial dissection.

Nine Taiwanese patients developed acute vertigo after cervical manipulation by chiropractors (105c ). MRI scans showed abnormalities in the vertebral arteries, such as occlusion, stenosis, and slow blood flow. Dextran infusions restored all the patients to good health. Nervous system Subdural bleeding can result from spinal manipulation. • After being treated with cervical manipulation by a German chiropractor a 40-year-old woman experienced sharp pain followed by nausea and vomiting 24 hours later and double vision 6 days later (106A ). Lumbar puncture showed intracranial hypotension and a subdural effusion with a leak of

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chronic hepatitis. J Gastroenterol Hepatol 2003; 18: 999–1000. 85. Critchley LAH, Chen DQ, Chu IT, Fok BS, Yeung C. Pre-operative hepatitis in a woman treated with Chinese medicines. Anaesthesia 2003; 58: 1096–100. 86. Adesunloye BA. Acute renal failure due to the herbal remedy CKLS. Am J Med 2003; 115: 506–7. 87. Ernst G, Strzyz H, Hagmeister H. Incidence of adverse effects during acupuncture therapy—a multicentre survey. Complement Ther Med 2003; 11: 93–7. 88. Chung A, Bui L, Mills E. Adverse effects of acupuncture. Can Fam Phys 2003; 49: 985–9. 89. Iwadate K, Ito H, Katsumura S, Matsuyama N, Sato K, Yonemura I, Ito Y. An autopsy case of bilateral tension pneumothorax after acupuncture. Leg Med (Tokyo) 2003; 5: 170–4. 90. Cantan R, Milesi-Defrance N, Hardenberg K, Vernet M, Messant I, Freysz M. Pneumothorax bilatéral et tamponnade après acupuncture. Presse Med 2003; 32: 311–12. 91. Ananova. Woman dies after acupuncture needle pierces lung. http://www.ananova.com/news/story/ sm_573168.html?menu=. [Accessed 9 May 2003.] 92. Sato M, Katsumoto H, Kawamura K, Sugiyama H, Takahashi T. Peroneal nerve palsy following acupuncture treatment. J Bone Joint Surg 2003; 85A: 916–18. 93. Ha K-Y, Kim Y-H. Chronic inflammatory granuloma mimics clinical manifestations of lumbar spinal stenosis after acupuncture: a case report. Spine 2003; 28: E217–20. 94. Vassiou K, Kelekis NL, Fezoulidis IV. Multiple retained acupuncture needle fragments. Eur Radiol 2003; 13: 1188–9. 95. Ernst E, Sherman KJ. Is acupuncture a risk factor for hepatitis? Systematic review of epidemiological studies. J Gastroenterol Hepatol 2003; 18: 1231–6. 96. Kakurai M, Demitsu T, Umemoto N, Ohtsuki M, Nakagawa H. Activation of mast cells by silver particles in a patient with localized argyria due to implantation of acupuncture needles. Br J Dermatol 2003; 148: 822. 97. Ara M, de Santamaria CS, Zaballos P, Yus C, Lezcano MA. Mycobacterium chelonae infection with multiple cutaneous lesions after treatment with acupuncture. Int J Dermatol 2003; 42: 642–4. 98. Chakraborti D, Mukherjee SC, Saha KC, Chowdhury UK, Rahman MM, Sengupta MK. Arsenic toxicity from homeopathic treatment. J Toxicol Clin Toxicol 2003; 41: 963–7. 99. Malone DG, Baldwin NG, Tomecek TJ, Boxell CM, Gaede SE, Covington CG, Kugler KK. Complications of cervical spine manipulation therapy: 5-year retrospective study in a single-group practice. Neurosurg Focus 2002; 13: 1–11. 100. Smith WS, Johnston SC, Skalabrin EJ, Weaver M, Azari P, Albers GW, Gress DR. Spinal manipulative therapy is an independent risk factor for vertebral artery dissection. Neurology 2003; 60: 1424–8. 101. Dziewas R, Konrad C, Dräger B, Evers S, Besselmann M, Lüdemann P, Kuhlenbäumer

586 G, Stögbauer F, Ringelstein EB. Cervical artery dissection—clinical features, risk factors, therapy and outcome in 126 patients. J Neurol 2003; 250: 1179–84. 102. Nadgir RN, Loevner LA, Ahmed T, Moonis G, Chalela J, Slawek K, Imbesi S. Simultaneous bilateral internal carotid and vertebral artery dissection following chiropractic manipulation: case report and review of the literature. Diagnostic Neuroradiology 2003; 45: 311–14. 103. Wojcik W, Pawlak JK, Knaus R. Doctor! I can’t stand the noise in my ear! Can J Diagnosis 2003; April: 55–9.

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104. Menendez Gonzalez M, Garcia C, Suarez E, Fernandez Diaz D, Blazquez Menes B. Wallenberg’s syndrome caused by chiropractic manipulation. Rev Neurol 2003; 37: 837–9. 105. Young Y-H, Chen C-H. Acute vertigo following cervical manipulation. Laryngoscope 2003; 113: 659–62. 106. Beck J, Raabe A, Seifert V. Intracranial hypotension after chiropractic manipulation of the cervical spine. J Neurol Neurosurg Psychiatry 2003; 74: 820–6.

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Errors in drug administration Errors in drug administration are not uncommon (1A –3A ). Some are related to the fact that brand and generic drug names and appearances can be very similar (sound-alike or lookalike drugs) (4A , 5R , 6R ). Anecdotal reports Anecdotal reports of drug errors appear at regular intervals and often involve hypoglycemic drugs (SEDA-19, 395; SEDA-21, 443; 7R ), although by no means exclusively (7R , 8R ). • A father brought his 6-year-old son to an emergency department after realized that the boy had been given the wrong medication for 3 months (9A ). He had asthma, for which he had used inhaled fluticasone twice daily and inhaled salbutamol as required for 4 years, and his physician had then prescribed montelukast 5 mg/day orally. The pharmacist had mistakenly dispensed alendronate 5 mg/day, without drug information. The parents had complied with the directions and had given the child alendronate each night. The child often complained of epigastric pain and heartburn in the hours after taking the medication. Night-time vomiting occurred once or twice a week. The asthma symptoms neither improved nor deteriorated.

Alendronate and montelukast are produced by the same pharmaceutical company and have very similar types of packaging. Similar packaging complicated by similar dosing explained this dispensing error. In some pharmacies, drugs are stored by manufacturers’ names, resulting in medications with look-alike packages being placed side-by-side on the shelves; this should obviously be avoided. It has elsewhere © 2005 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 28 J.K. Aronson, ed.

been suggested that drugs that are commonly involved in dispensing errors, particularly hypoglycemic drugs, should be kept in a separate area of the pharmacy, rather than in alphabetical order (7R ). Abbreviations used by manufacturers to distinguish products, such as DS, SR, and XL, can result in confusion and also cause errors. Pharmacists and nurses can incorrectly prepare, dispense, and administer medications appropriately ordered by physicians. Incorrect physician orders can go undetected and result in disastrous consequences for the patient. Another cause for error is similar packaging of products by pharmaceutical companies (10R ). • In three patients near misses in drug administration resulted from confusion between ketamine and suxamethonium chloride, after a change in the color of the ampoule of the latter (11A ).

Observational studies Intravenous administration The incidence and the severity of intravenous drug preparation and administration errors have been studied in one pharmacy in Britain with a traditional ward pharmacy service and two in Germany, one with a traditional ward stock supply and one with a satellite pharmacy service with unit doses (12c ). The preparation error rates were: 22% (CI = 13–3%), 23% (16–3%) and 31% (23–39%) respectively. The administration error rates were 27% (16– 3%), 49% (39–58%) and 22% (14–30%) respectively. In 10 wards in a teaching and non-teaching hospital in the UK 249 errors in intravenous drug administration were identified (13c ). At least one error occurred in 212 of 430 intravenous drug doses (49%, 95% CI = 45–54%). Three doses (1%) had potentially severe errors, 126 (29%) had potentially moderate errors, and

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588 83 (19%) had potentially minor errors. Most errors occurred when giving bolus doses or making up drugs that required multiple steps in their preparation. Cardiology Among 14 983 US pharmacist interventions, 4768 were related to medication errors, or 24 medication errors per 100 admissions (14c ). The most common errors involved the wrong drug (36%) or wrong dose (35%), and cardiovascular medications were involved in 41% of the errors. Prescribers were associated with most of the errors, and the transition from out-patient to in-patient was the most common point in the system for the occurrence of these errors. There were more errors during the transition period of house staff, and the total number of errors increased during the study period (September 1995 to February 2000). Obstetrics In a postal survey of 240 lead obstetric anesthetists in all consultant-led maternity units in the UK about drug errors and the measures taken to reduce or prevent them of the 179 (75%) who responded, 70 (39%) knew of at least one drug error that had occurred in their unit during the last year, and 28 of them (40%) knew of more than one (15c ). Of the most recent errors, giving the wrong drug was the most common error, occurring in 27 units (15%). This most commonly involved the use of thiopental instead of antibiotics or vice versa (n = 14), or suxamethonium instead of Syntocinon (n = 8), or other drugs (n = 4). Errors involving epidural/spinal analgesia/anesthesia (including drugs intended for these routes but given via other routes) occurred in 20 cases. Only 36 respondents (20%) described protocols for checking anesthetic drugs. Methods described for reducing drug errors were the use of colored labels (20%) or pre-filled labelled syringes (6%), limiting the range of drugs available (6%), and keeping drugs in separate trays once drawn up (6%). In obstetric hospital in-patients from December 1996 to November 2001 there were 164 medication errors, which led to adverse drug reactions; 154 were of class 1 (no harm), 10 of class 2 (additional therapy but no additional harm), and none of class 3 (permanent harm) (16c ). Omissions and incorrect timing of drug administration were the most common reasons. The rate of class 1 adverse drug reactions was lower in the labor and delivery suites than on the ward (0.8 versus 1.4 per 1000 patient days).

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Overdosage with intravenous magnesium sulfate was the most common class 2 event. Oncology Typical errors in cytotoxic drug therapy have been reviewed (17R ). Sources of errors include unintentional intrathecal injection, confusion between total and single doses, errors in calculation and preparation, errors in operation of infusion pumps; platinum compounds and anthracyclines are often involved. Pediatrics The incidence and types of medication errors, severity of events, patient outcomes, and categories of drugs involved have been studied retrospectively in the largest pediatric hospital in Thailand over 15 months (18c ). Medication errors occurred in 1% of admissions (322 errors in 32 105 admissions). The most common type of error was prescription error (35%). Most of the errors were detected and prevented before the drugs were administered (77%). There was one case of permanent brain damage and no deaths. The most common drugs involved in medication errors were antibiotics and the most common route of administration was oral. Psychiatry Potential adverse drug reactions due to medication errors were analysed in 132 units in 44 Japanese psychiatric hospitals in October and November 2000 (19c ). There were 221 reports from 85 units in 44 hospitals, 25% of which were intercepted before reaching the patients. The frequency of monitoring of patients by staff in response to medication errors increased by 8.1%. Wrong drug administration, i.e. giving a drug that was not prescribed for that patient, was the most common type of incident (36%) and occurred more often on units with either fewer registered nurses or when there were two or more patients with the same (or similar) names in the same unit. Patients with allergies Of 340 adult patients, 50 (15%) had an allergy that was documented in the hospital computer system but 133 patients (39%) reported allergies to at least one drug (20c ). Allergies to beta-lactams, sulfonamides, and opioid narcotics were reported in 43, 31, and 49 patients respectively. There were 70 errors in which patients were given drugs to which they were allergic; most involved betalactam antibiotics, with an overwhelming number due to piperacillin–tazobactam (36 errors). Other drugs involved were ampicillin (n = 7), other beta-lactams (n = 17), opioids (n = 7), and sulfonamides (n = 3). Most of the errors

Miscellaneous drugs and materials, medical devices and techniques

occurred because the prescribing physician was unaware of the allergy. Medication errors in Australia have been reviewed based on systematic literature reviews and reports from data collections of the Australian Bureau of Statistics, the Institute of Health and Welfare, the Council for Health Care Standards, and the Patient Safety Foundation (21R ). Errors occurred in 15–20% of drug administrations when ward stock systems were used and 5–8% when individual patient systems were used. Previous allergic reactions to drugs were recorded more than 75% of the time. Contributory factors In a survey of 156 US hospitals, a multivariate logistic regression model showed increased reporting of medication errors in hospitals with 24-hour pharmacy services, presumably because of better error reporting systems. When the number of occupied beds was included, the final model showed that bed size was the only statistically significant factor (22C ). In two UK hospitals there were 265 intravenous drug errors during observation of 483 drug preparations and 447 administrations (23c ). The most common type of error was deliberate violation of guidelines when injecting bolus doses faster than the recommended speed of 3–5 minutes. Causes included a lack of perceived risk, poor role models, and available technology. Mistakes occurred when drug preparation or administration involved uncommon procedures, such as the preparation of very small volumes or the use of unusual drug vial presentations. Causes included a lack of knowledge of preparation or administration procedures and complex design of equipment. Underlying problems were the cultural context, allowing unsafe drug use, failure to teach practical aspects of drug handling, and design failures. MEDMARX is an Internet-accessible, anonymous medication error reporting program in the USA. Of 154 816 medication error reports that were submitted to MEDMARX in 1999– 2001 about two-thirds of the errors reported affected the patient, but relatively few caused harm, although there were 19 deaths (24C ). Errors of omission and improper dose/quantity were the most commonly reported. Performance deficit and procedure/protocol not followed were consistently identified as causes of error.

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Distractions and workload increase were often cited as contributing factors. Detection The use of a review team and selfreporting in detecting different types of medication errors have been compared in a state psychiatric hospital (25c ). T he team reviewed 31 patient records over a total of 1448 patient-days and identified 2194 medication errors, compared with nine self-reported errors. Administration errors accounted for more than half of the total (66%), followed by transcription errors (23%), prescription errors (11%), and dispensing errors (less than 1%); 19% of the errors were rated as having a low risk of harm, 23% as having a moderate risk, and 58% as having a high risk. Prevention To prevent such errors, healthcare practitioners need to reduce or eliminate the possibility of errors, make errors visible, and minimize the consequences of errors. Surveillance systems and methods of preventing errors are being reviewed increasingly often (26R –36R ). In one institution (37c ) medication administration errors were reduced by: • becoming intimately familiar with the errors, including where, when, why, and how they were occurring, by interviewing those who were directly involved in occurrences; • establishing a non-punitive environment and encouraging reporting of errors, including near-miss errors; • using error report data to identify areas of concentrated errors in the medication use process; • simplifying and standardizing process steps; • selecting the right technology to address error-prone steps in the hospital’s systems. Medication errors in discharge orders from an ICU were eliminated by a process called medication reconciliation, in which medications were reviewed by the admitting nurse within 24 hours of admission to ICU and by the charge nurse on discharge (38c ). In a pediatric nephrology ward two dispensing schemes were compared: handwritten prescription plus ward stock distribution, and computerized prescription plus unit-dose drug dispensing (39C ). The computerized prescription error rate was 11% (419 of 3943) and the

590 handwritten prescription error rate was 88% (518 of 589). The total administration error rate was 24% (1077 of 4589), including wrong administration time, and 12% (538 of 4589) excluding administration time. The administration error rate, including administration associated with time errors, was 23% (888 of 3943) for computerized prescriptions, compared with 29% (189 of 646) for handwritten prescriptions. Excluding administration associated with time errors, the administration error rates were 9.7% and 24% respectively. In a prospective cohort study of 1020 children, 10 778 medication orders contained 616 errors (40c ). Of these, 120 (19% of errors, 1.1% of orders) were classified as potentially harmful, including 115 potential adverse drug events and five preventable adverse drug effects. Most errors occurred at the ordering stage (74%) and involved errors in dosing (28%), route (18%), or frequency (9%). Of the interventions studied, three were effective: computerized physician order entry with clinical decision support systems (76%); ward-based clinical pharmacists (81%); and improved communication among physicians, nurses, and pharmacists (86%). One of the easiest measures in preventing errors is for pharmacists to avoid storing similarly packaged or named drug products side by side (7R ). Work-system redundancy can also help to prevent dispensing errors. An example of system redundancy in the hospital pharmacy setting is independent verification of dispensed drugs by different personnel. Empowering the patient may be beneficial (41R ). In the community, patients should be encouraged to read the label, because they are the last to view it before administration of the drug. Such dispensing errors are often found when the patient is renewing the prescription. A bar-coding system can prevent pharmacists from putting a label on the wrong medication (42c ). Furthermore, dispending of more than one package should be discouraged in order for an error to be detected as early as possible. Lastly, it is not uncommon for a patient to receive no written information about the drug just prescribed for them unless they are instructed to read the monograph or gather information through other sources, such as the Internet. Patient-oriented information including, possibly, a picture of the medication or verbal counselling can provide system redundancy and help circumvent errors (43R ).

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The role of managed care in preventing medication errors (44R ) and in managing their aftermath has been reviewed (45R ). Computerized physician order entry also has the potential to reduce medication errors. In a retrospective cohort study in a tertiary-care pediatric hospital there were 804 medication errors in 36 103 discharges and 179 183 patient days, resulting in 18 adverse reactions (46c ). The overall medication error rate was 4.49 per 1000 patient days and computerized physician order entry reduced it by 40%, although it had no effect in the number of adverse reactions.

Arachis (peanut) oil Immunologic All practising doctors in the UK have recently been alerted by the Chief Medical Officer to the risks of topical medicines that contain arachis oil (47S ). Products are clearly labelled as containing this refined ingredient. The alert highlighted a study in children that suggested sensitization to peanuts may be caused by the application of creams containing arachis oil to inflamed skin (48C ). It also mentioned an earlier study that showed that small amounts of allergenic protein persist in peanut oil despite refinement (49E ). Although the UK’s Committee on Safety of Medicines has determined that there is insufficient evidence to conclude that exposure to topical medicines containing arachis oil leads to sensitization to peanut protein, it has issued a precautionary recommendation that patients with known peanut allergy should avoid such medicines, and the labelling of these products is to be updated with new warnings. All this is highly relevant to practising otorhinolaryngologists, because a widely prescribed product, Naseptin nasal cream, contains peanut oil.

Bisphosphonates Sensory systems Pamidronic acid has been associated with ocular inflammation, including uveitis, non-specific conjunctivitis, episcleritis, and scleritis, and similar ocular adverse effects have been reported with alendronic acid,

Miscellaneous drugs and materials, medical devices and techniques

clodronic acid, etidronic acid, and risedronic acid. Health Canada has received 27 reports of bisphosphonate-associated ocular and visual disorders; 13 of these reports involved alendronic acid, five etidronic acid, six pamidronic acid, and three risedronic acid (50c ). They have recommended that patients who have visual loss or ocular pain during bisphosphonate therapy should be referred to an ophthalmologist, and that if scleritis occurs bisphosphonate therapy must be withdrawn. They added that more than one ocular adverse effect can occur at the same time, and in some cases the bisphosphonate may need to be withdrawn for the ocular inflammation to resolve. Skin An urticarial eruption has been reported in a patient taking alendronate (51A ). • A 72-year-old woman who had taken alfacalcidol 500 nanograms/day and alendronate sodium hydrate 5 mg/day for 3 years for osteoporosis developed many red papules and petechiae on the legs (52A ).

Musculoskeletal Increasingly, bisphosphonates are being administered to children and have been reported to improve clinical outcomes and augment bone mass in conditions such as osteogenesis imperfecta, juvenile osteoporosis, and fibrous dysphasia, although controlled studies in children are lacking. Genetic defects that abrogate the action of osteoclasts cause osteopetrosis, which is characterized by dense, poorly formed, and brittle skeletal tissue. Acquired osteopetrosis, or marble bone disease, could therefore result from treatment with bisphosphonates during growth. • During prolonged pamidronate therapy (a minimum of about 2800 g over about 3 years) for osteoporosis in a 12-year-old boy changes developed in the long bones (53A ). The metaphyses were dense with club-shaped deformities, indicating osteopetrosis. The base of the skull became sclerotic. There was no family history of skeletal disease or consanguinity. Neither his parents nor his sister had hyperphosphatasemia. Genetic studies showed no mutation in the genes for transforming growth factor beta-1, osteoprotegerin, chloride channel 7, or alkaline phosphatase or its promoter.

The amount of pamidronate this child had taken was more than four times the amount that is typically administered during the same time to children with osteogenesis imperfecta and

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other disorders (54c ). Had the cumulative dose been taken over a longer period, the changes would most likely have been less pronounced. However, bisphosphonates are often taken for years and therapeutic end-points are unclear (55R ). In a study of the effect of bisphosphonate therapy on bone mineral density, 40 postmenopausal women (mean age 70 years) with primary hyperparathyroidism were randomized to receive alendronate 10 mg/day or placebo for 48 weeks, followed by withdrawal for 24 weeks (56C ). The mean changes in bone mineral density at the femoral neck and lumbar spine were significantly higher with alendronate at 48 weeks. Serum calcium was reduced by alendronate. Serum bone-specific alkaline phosphatase activity was lower with alendronate from 12 weeks on and increased at 24 weeks after withdrawal. At recruitment a significant proportion of patients had musculoskeletal symptoms (60%), gastrointestinal symptoms (23%), and systemic symptoms (25%). However, symptoms did not change in either group during the study. There were 25 adverse events with alendronate, and 24 with placebo; most were upper respiratory tract infections. There were two serious adverse events in patients taking alendronate. One patient was hospitalized because of dizziness and a fall, another developed hemolytic anemia attributed to methyldopa. There were three serious adverse events in patients taking placebo. One patient fractured a humerus after a fall, one developed first-degree heart block due to a beta-blocker, and one had an ibuprofen-induced gastric ulcer; all were withdrawn from the study.

Caprolactam Caprolactam is a monomer used in the textiles industry in the production of Nylon-6 polyamide, a textile with a high strength-toweight ratio and good chemical and thermal stability and durability. Nylon-6 polyamide is widely used in the manufacture of fishing nets, tyre yarns, sewing threads, industrial drivebelts, in castings and injection molding and extrusion. Skin An allergic skin reaction has been reported with caprolactam (57A ).

592 • A 58-year-old woman developed eczematous lesions at a site on her skin where a thread had been removed from a 10-day-old operation wound. The suture material consisted of blue Nylon-6 polyamide thread. She had already undergone more than 40 surgical operations to remove multiple nevi and two melanomas. A patch test with the thread for 48 hours provoked erythema and unbearable itching lasting for 1 week. Topical clobetasol propionate cream caused resolution within 2 weeks. Later, epicutaneous tests were performed with the European Standard series, hairdressers’ series, and the components of the suture material. At 72 hours, she had ++ reactions to ammonium persulfate, 2,5 diaminotoluene, ε-caprolactam, and acid blue 158. After 96 hours, the dye reaction increased to + + + and lasted 2 weeks. All other compounds in the European standard series and hairdressers’ series were negative. Five controls tested with ε-caprolactam and acid blue 158 were negative.

This patient has worked as a hairdresser for nearly 17 years. Supposedly during this time she had acquired a contact allergy to ammonium persulfate and 2,5-diaminotoluene, which might be considered a cross-reacting precursor, facilitating the acquisition of hypersensitivity to the azo dye acid blue 158.

Dietary supplements Adulteration In the USA two dietary supplement products (Vinarol from Ultra Health Laboratories Inc and Bionate Inc, and Viga from Best Life International) are being voluntarily recalled by their respective manufacturers because of the unlabelled presence of sildenafil, a prescription drug that could have serious health risks if used without medical supervision (58r ). Both products were being sold as dietary supplements, without a prescription, for increasing desire confidence and sexual performance. Consumers who have purchased either of these products are urged to discontinue their use. There has been a similar report from Health Canada who warned against the use of the health products Stamen and Bell Magic Bullet after both were found to contain sildenafil (59S ). Neither product has been approved by Health Canada for sale, and neither are they labelled as containing sildenafil. Health Canada has received one report of an adverse reaction to Stamen but no reports relating to Bell Magic

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Bullet. Health Canada is currently working with the distributors to remove the products from the market and advises consumers who have used the products and have concerns to contact their physicians or health-care providers. Health Canada has warned consumers not to use Hua Fo VIGOR-MAX Tablets, a Chinese herbal product that contains tadalafil (60S ), which is not approved for sale in Canada. Health Canada issued a previous warning in February 15, 2002 concerning Hua Fo, when it was found to contain sildenafil; at the time, Health Canada required the importer to remove the product from the shelves (59S ). Health Canada is again directing the importer to remove Hua Fo VIGOR-MAX from the market and has issued a Customs Alert to stop its further importation (60S ).

Disulfiram (SED-14, 1697; SEDA-25, 580; SEDA-26, 541) Of 33 patients with alcoholism and severe mental illness (70% with schizophrenia or a schizoaffective disorder) who had taken disulfiram seven reported adverse effects, but there were no psychiatric complications (61c ). The most common adverse effects were upset stomach and skin rash, followed by nausea and vomiting (Table 1). Although most of the patients (76%) used alcohol while taking disulfiram, only a minority reported adverse reactions, the most common of which were vomiting and a flushed face. Only two received treatment for these reactions. Only six patients continued to take disulfiram when the chart review was conducted. The most common reasons for stopping treatment were that the patient began to drink again, became sober, or was non-compliant.

Glycerol Glycerol has been widely used in medical practice, as for example in patients with inner ear disorders or as an osmotic agent for treatment of cerebral edema (62R ). The effect of glycerol on the inner ear is probably due to the fact that it increases plasma osmolality, resulting in withdrawal of water from the extravascular spaces.

Miscellaneous drugs and materials, medical devices and techniques Table 1. Adverse effects of disulfiram and reactions to alcohol (n = 33) (61c ) Adverse effects

Number

Upset stomach Skin rash Nausea Vomiting Peculiar taste Palpitation Chest pain Headache Drowsiness Shakiness Alcohol use while taking disulfiram Reactions to alcohol while taking disulfiram (n = 25) Vomiting Flushed face Tachycardia Headache Treatment for alcohol-disulfiram reactions Stopped taking disulfiram Began drinking again Obtained sobriety Non-compliance Adverse effects Hospitalized Moved out of area Fear of adverse effects Other

3 3 2 2 1 1 1 1 1 1 25 7 4 3 2 1 2 27 7 4 4 3 3 2 1 3

However, dehydration is also the primary cause of its adverse effects. Glycerol taken orally can cause headache, nausea, and vomiting. In 12 patients suspected of having Menière’s disease oral glycerol 0.51 g/kg produced a change of over 10 mosm/kg in all patients while intravenous glycerol 0.30 g/kg produced the same changes in osmolality in only one patient (63c ). The amount of discomfort was consistently higher, with one exception, when glycerol was given orally rather than intravenously. Nervous system Of 20 children with fructose1,6-bisphosphatase deficiency six were given glycerol solution to treat definite or suspected cerebral edema during treatment of hypoglycemia and metabolic acidosis (64c ). Two had no cerebral edema before glycerol, but it developed after. Of 14 patients who were not treated with glycerol none had cerebral edema. The amount of fructose (0.5 g/kg) in one dose of glycerol solution (1.0 g/kg) for cerebral edema is more than the recommended dose of fruc-

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tose (0.2 g/kg) used for diagnosis of the disease. Glycerol should not be used in any patients with hypoglycemia and metabolic acidosis until lactate acidosis is ruled out.

Grapefruit juice Drug interactions The Adverse Drug Reactions Advisory Committee (ADRAC) in Australia has revised its previous advice relating to grapefruit juice interactions (65S ). The committee noted that although there have been no reports of significant clinical problems when grapefruit juice and other drugs are separated by more than a few hours, grapefruit juice can nevertheless interact for up to 3 days after ingestion. ADRAC now considers that “the safest course is to avoid grapefruit and its juice altogether when taking medicines that interact”.

Indocyanine green Sensory systems Staining of the internal limiting membrane with indocyanine green has been used to make the otherwise transparent and barely visible membrane perceptible during removal (66c ). However, there are some concerns about adverse effects of indocyanine green in the retina and especially the retinal pigment epithelium cells, because atrophic changes in the retina have been reported postoperatively (67c ). • A 66-year-old woman with a macular hole underwent vitrectomy with indocyanine green (68A ). Indocyanine green was found in the subretinal space for more than 6 months and there was retinal pigment epithelium atrophy at the site of the lesion.

In addition, in vitro data have suggested that indocyanine green is probably toxic in cultured human retinal pigment epithelium cells (69E ). Contact of indocyanine green with retinal pigment epithelium cells should therefore probably be minimized. The impact of staining of the internal limiting membrane with indocyanine green 0.05% (275 mosmol/l, pH 7.5) on functional outcome in anatomically successful macular hole surgery

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has been studied in 18 consecutive patients compared retrospectively with patients who had not received indocyanine green (70c ). There were no significant differences in the duration of preoperative symptoms and preoperative visual acuity, but there was significantly lower visual acuity after indocyanine green-assisted vitrectomy and nine of the 18 patients had visual field defects. These findings suggest potential damage to the neurosensory retina in association with the intraoperative administration of indocyanine green. Whether this is caused by toxic effects of the dye itself, mechanical trauma to the retina, or other mechanisms is unknown. Although indocyanine green may be useful in distinguishing the internal limiting membrane and other tissues, careful use is required to prevent adverse effects.

Isoparaffin Respiratory Lipoid pneumonia is caused by the aspiration or inhalation of fatty materials (animal, vegetable, or mineral). The prognosis is usually good and fatal cases are exceptional (71A ). • A 66-year-old man with a history of depression voluntarily took about 400 ml of an insecticide composed of methylparathion 5%, isoparaffin 75%, ethoxylated oleic acid 8%, naphtha 6%, 1,2,3-trimethylbenzene 4%, 1,3,5-trimethylbenzene 1%, propylbenzene 0.4%, and xylene 0.3% (72A ). He was conscious and alert and gastric lavage was performed and activated charcoal given. There were no clinical symptoms of organophosphate ingestion, despite reduced erythrocyte and plasma cholinesterase activity. A chest X-ray showed pulmonary infiltrate compatible with aspiration. He developed respiratory failure refractory to treatment and died from multiorgan failure after 23 days. At post-mortem examination there were abundant lipid-laden macrophages and pulmonary fibrosis in the alveolar spaces, with enlargement of the intra-alveolar septa.

Isosulfan blue

(SEDA-26, 543;

SEDA-27, 528) Isosulfan blue is an aniline dye used to stain lymphatic channels before lymphangiography.

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The sentinel lymph node hypothesis is based on the assumption that a tumor metastasis, if it exists, will travel on a direct path from the primary tumor through the efferent lymphatic channels to the first draining lymph node in the regional lymphatic basin, the sentinel node. Respiratory Isosulfan can migrate to tissues other than those into which it is injected. • A 61-year-old woman with breast adenocarcinoma underwent uneventful lumpectomy of the breast mass with sentinel node mapping and axillary node dissection (73A ). On postoperative extubation, the endotracheal tube was stained with about 3 ml of concentrated isosulfan dye. The patient maintained good oxygen saturation and breath sounds. A subsequent chest X-ray ruled out a pneumothorax or pleural effusion. She was admitted overnight and discharged the next morning without incident.

Immunologic Although anaphylactic reactions to patent blue dyes have long been known, the first case of an anaphylactic reaction to isosulfan blue was reported in 1985 (74A ) and cases continue to be reported occasionally (75A ). • A 53-year-old woman was admitted for sentinel lymph node biopsy and excision of a breast carcinoma. Her history included Graves’ disease treated with radioactive iodine and thyroxine. She reported an allergy to penicillin (urticaria). Before incision, the surgeon injected 1% isosulfan blue 4 ml subcutaneously. One minute after the injection, her systolic blood pressure fell to 55 mmHg and then became undetectable. The electrocardiogram showed a nodal rhythm at a rate of 40/minute, with frequent ventricular extra beats. There was a widespread reddish macular rash. She was given adrenaline (300 micrograms subcutaneously and 30 micrograms intravenously), ephedrine (85 mg intravenously), and glycopyrrolate (0.4 mg intravenously), and her heart rate increased to 150/minute. However, the systolic blood pressure remained at 60–70 mmHg over the next 30 minutes despite infusion of adrenaline, dexamethasone (12 mg intravenously), and intravascular volume replacement. Surgery was aborted and within 30 minutes her arterial blood pressure became stable at 90/70 mmHg. Her urine was blue-green and the serum was green. The diffuse rash gradually abated, but her forearms and fingers became markedly swollen with edema, which gradually resolved over the next 24 hours.

Interference with diagnostic tests Isosulfan blue dye can discolor a patient’s serum, making pulse oximetry useless by mimicking true intraoperative hypoxia (76A ).

Miscellaneous drugs and materials, medical devices and techniques

Lauromacrogols

(SEDA-27, 529)

Lauromacrogol 400 (polidocanol) foam has been developed as a sclerosing treatment for varicose veins. Although it is usually well tolerated, some adverse effects have been reported. They are mostly local, but general effects, such as “visual problems”, monocular blindness, and migraine, have been reported (77A , 78R ). Nervous system In four consecutive patients seen in 6 months the injection of Lauromacrogol 400 foam into a non-saphenous varicose vein and telangiectasiae triggered a typical attack of visual migrainous aura (79A ). • A 53-year-old man received an injection of lauromacrogol 400 foam (0.20%) 2 ml for the first time and 3 minutes later noticed central blurring of vision, which turned into a typical scintillating scotoma, spreading to the periphery. The visual symptoms lasted 20 minutes without subsequent headache. • A 45-year-old woman received an injection of lauromacrogol 400 foam (0.15%) 2 ml for the second time, and 10 minutes later saw a white spot in the lower part of her visual field, rapidly expanding, associated with moving broken lines and blurred vision. This lasted 23 minutes and was followed by a bitemporal pulsatile headache for 2 hours. • A 43-year-old woman received an injection of lauromacrogol 400 foam (0.15%) 2 ml for the first time, and 10 minutes later progressively saw as through a kaleidoscope in her left visual field for 30 minutes; she subsequently had a frontotemporal headache. • A 47-year-old woman with a history of migraine with aura had her typical scintillations lasting 25 minutes and followed by a headache for 4 hours 10 minutes after an injection of lauromacrogol 400 foam (0.15%) 2 ml.

The mechanism of this effect is unknown.

Methylthioninium chloride (methylene blue) The administration of intravenous methylthioninium chloride 1 mg/kg to individuals without methemoglobinemia has been associated with nausea and vomiting, tachypnea, chest tightness, tachycardia, apprehension, tremor, mydriasis, blue staining of the skin and mucous membranes, abdominal pain, dizziness, paresthesia, headache, confusion, mild methemoglobinemia

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(up to 7%), and electrocardiographic changes (T wave flattening or inversion) (80A ). These features resolved within 2–12 hours. Rapid intravenous injection of methylthioninium chloride can be painful and extravasation can cause tissue necrosis (81A ). Nervous system Methylthioninium chloride is used intravenously for intraoperative staining of the parathyroid glands (82c ) but has reportedly caused an adverse neurological event. • A 60-year-old woman with a history of anxiety and depression had symptomatic hypercalcemia secondary to a parathyroid adenoma (83A ). She had no known allergies and had one previous general anesthetic for tonsillectomy with no adverse effects. Preoperatively, she was given an infusion of methylthioninium chloride 7.5 mg/kg. She vomited once during its administration and on arrival in the anesthetic room looked very blue but showed no abnormal behavior. Surgery was carried out uneventfully under general anesthesia, during which all her vital signs were normal. Shortly after arrival in recovery, she developed rotatory nystagmus and dilated unreactive pupils; 30 minutes later she began to have rigid, jerky movements of all four limbs and remained very agitated over the next 2 hours. She had increased tone in all four limbs, bilateral extensor plantar reflexes, was sweating profusely, and was flushed above the shoulders, but remained hemodynamically stable. She then became more agitated and aggressive overnight, after which sedation was stopped and she was extubated without incident. She was stained an intense blue and had dark blue urine for 3 days. There was no evidence of hemolysis. Over the next 2 days her speech and neurological status returned to normal. An MRI scan was normal.

Hematologic When administered as a diagnostic dye 5 mg/kg intravenously, methylthioninium chloride caused 7% methemoglobinemia in one case, while in another case 100 mg/kg intravenously caused a transient reduction in pulse oximetry to 82% without any reported change in skin color (84A ). Mutagenicity Vital dyes are being used more and more during routine endoscopic examination (chromoendoscopy) to assist in visualizing preneoplastic and neoplastic lesions. In particular, the thiazine dye methylthioninium chloride has been used in investigating patients with Barrett’s esophagus who are undergoing surveillance because of a high risk of adenocarcinoma. Methylthioninium chloride selectively stains the specialized intestinal metaplasia in

596 Barrett’s esophagus, since it is specifically absorbed by the goblet cells that characterize this preneoplastic tissue type (85Ec ). In 12 men and three women with Barrett’s esophagus (median age 62, range 34–76 years) chromoendoscopy with methylthioninium chloride 0.5% was immediately preceded by spraying with 10 ml of acetylcysteine 10% to remove surface mucus (86c ). Alkaline singlestrand gel electrophoresis (comet assay) was used to assess strand breaks and alkali-labile sites in DNA. DNA damage in individual cells was assessed by measuring the percentage of DNA in the tail of the comet. The amount of DNA damage in each patient increased after chromoendoscopy compared with matched biopsy samples obtained before: the increase in the median amount of DNA damage was 6– 72%. Comparison of matched biopsies from the 15 patients showed significantly more damage to DNA after chromoendoscopy than before. In addition, the proportion of highly damaged cells was more than three times higher after exposure. These finding suggest that chromoendoscopy with methylthioninium chloride at concentrations currently recommended during endoscopy increases the amount of DNA damage in Barrett’s mucosa.

Nicotine Green tobacco sickness is an occupational illness reported by tobacco workers worldwide (87R ). Among farm workers in shade tobacco fields in Connecticut 15% had diagnoses that could be attributed to possible green tobacco sickness (ICD-9) (88c ). Using a stricter case definition, the frequency fell to 4%. Non-smokers were significantly more likely than smokers to report symptoms, particularly isolated symptoms of headache and dizziness. Diagnostic criteria for green tobacco sickness have not been established. The symptoms include dizziness or headache and nausea or vomiting, but can also include abdominal cramps, headache, prostration, difficulty in breathing, abdominal pain, and occasionally fluctuations in blood pressure or heart rate. Green tobacco sickness is normally a selflimiting condition, from which workers recover

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in 2 or 3 days. However, symptoms are sometimes severe enough to result in dehydration and a need for emergency medical care. Although the sickness is widely known among tobacco workers and has been reported in the major tobacco-growing states of the USA, the research literature is sparse. In a prospective longitudinal study susceptibility factors for green tobacco sickness were picking tobacco, working in wet conditions, working later in the season, and not smoking or chewing tobacco (89c ). Although early researchers argued that green tobacco sickness was caused by factors other than nicotine exposure (90R ), it has since been thought that dermal absorption of nicotine from plant surfaces results in the characteristic symptoms (91R ). Of 182 workers 25 had 31 episodes of green tobacco sickness. Among non-smokers, each incremental increase in the natural log of cotinine increased the odds of green tobacco sickness 2.11 times, adjusting for task and wet conditions (89c ). Urinary cotinine concentrations in 80 male tobacco-growing farmers were significantly higher than in 40 healthy men who did not handle wet tobacco leaves in Kelantan, Malaysia (92C ). Farmers with urinary cotinine concentrations of 50 ng/ml/m2 or above had eye symptoms more often than those with lower concentrations. Farmers who did not wear protective equipment had subjective symptoms more often than those who did. Some of the symptoms were more common in organophosphate users than in non-users.

Phosphates

(SEDA-25, 581;

SEDA-27, 529) Endocrine X-linked hypophosphatemic rickets is characterized by defective proximal renal tubular phosphate transport and impaired renal production of 1,25-dihydroxycolecalciferol. These abnormalities lead to renal phosphate wasting, hypophosphatemia with normocalcemia, low plasma 1,25-dihydroxycolecalciferol concentrations, and defective bone mineralization. The clinical features include rickets, skeletal deformities, growth retardation, and dental abscesses (93c ).

Miscellaneous drugs and materials, medical devices and techniques

Anecdotal observations suggest that excessive use of oral phosphates may be a risk factor for the development of tertiary hyperparathyroidism in patients with X-linked hypophosphatemic rickets. Of 13 patients with X-linked hypophosphatemic rickets two developed tertiary hyperparathyroidism and 11 secondary hyperparathyroidism during treatment (94c ). Patients with tertiary hyperparathyroidism had on average earlier and longer treatment and higher doses of phosphates (over 100 mg/kg/day) than the 11 patients with secondary hyperparatyhyroidism. Those who later developed tertiary hyperparathyroidism had very high serum parathormone concentrations (over 42 pmol/l). Mineral balance Severe hypophosphatemia is also associated with the re-feeding syndrome and requires treatment with intravenous phosphate to prevent potentially life-threatening complications (95c ). The effectiveness and safety of intravenous phosphate infusion 50 mmol, given as “Phosphates Polfusor”, for the treatment of severe hypophosphatemia in the re-feeding syndrome were studied in 30 patients treated over 2 years. After treatment, 37% had a normal serum phosphate concentration and 73% had a serum phosphate concentration of over 0.5 mmol/l within 24 hours. Ten patients required more than one infusion of Phosphates Polyfusor. Within 72 hours 93% had achieved a serum phosphate concentration of at least 0.50 mmol/l. No patient developed renal insufficiency. However, three patients developed transient, mild hyperphosphatemia (highest 1.57 mmol/l; reference range, 0.85– 1.40 mmol/l) without complications. Four developed asymptomatic hypercalcemia. In one patient the corrected calcium concentration fell from 2.53 to 2.00 mmol/l (reference range 2.25–2.70 mmol/l), although this was associated with a fall in albumin during rehydration from 22 to under 10 g/l (which makes calcium correction inaccurate). The other three episodes involved a fall in calcium concentration from 2.43 to 2.20, 2.28 to 2.08, and 2.32 to 2.19 mmol/l. None of these episodes was associated with hyperphosphatemia, renal dysfunction, or clinical evidence of hypercalcemia. One patient had a minor episode of phlebitis.

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Plasma/urinary medicinal products Infection risk The UK Committee on Safety of Medicines (CSM) has advised that no human plasma or urine used in the production of medicines should be sourced from a country with one or more endogenous cases of variant Creutzfeldt–Jacob disease (vCJD) (96S ). The CSM continually reviews the safety of medicines that are prepared from human and animal materials, particularly with respect to any potential risk from transmissible spongiform encephalopathies. In 1998 it recommended that human blood plasma sourced from the UK should not be used to prepare medicines, because of the number of cases of variant Creutzfeldt–Jacob disease reported in the UK. Later this restriction was extended to include plasma from all other countries in which at least one indigenous case had been reported. Later, the same precautionary principle was extended to urine-derived products, since the abnormal prion protein was detected in the urine of patients with transmissible spongiform encephalopathies. The CSM has advised that when possible plasma and urine should be sourced from countries with no or low risk of bovine spongiform encephalopathy and that plasma pools for fractionation and urine used for the manufacture of medicines should be restricted to a single country of origin. The use of plasma-derived products in medicines should be limited and recombinant alternatives should be used if available.

Textile dyes Skin Disperse dyes are well-known causes of allergic contact dermatitis. They are chemically either azo or anthraquinone dyes. Azo compounds have been used to color synthetic fibers and in hair dyes, fur dyes, leather processing, printer’s ink, and photographic products. Allergic contact dermatitis from azo dyes can be due to the dye itself or to its metabolic products. Some of the metabolic intermediates formed are similar to paraphenylenediamine or its metabolites, and this may lead to cross-sensitization between paraphenylenediamine and certain azo

598 dyes (97c ). Cross-sensitization between paraphenylenediamine and Disperse Orange 3 has been reported many times, sometimes with a very high concordance rate. In a study of the frequency of simultaneous patch test reactions to paraphenylenediamine and a range of textile dyes in 128 patients who were patch-test positive to paraphenylenediamine and who were also patch tested with textile dyes the dyes that most commonly cross-reacted were Disperse Orange 3 (46%) and Disperse Yellow 3 (22%). Dyes that were least likely to react were Bismarck Brown (0%), Naphthol AS (1.1%), Disperse Yellow 9 (1.1%), Disperse Blue 3 (1.6%), and Disperse Red 11 (2.1%) (98c ). In 102 of these patients, the strength of the reaction to paraphenylenediamine was documented; 44 of the 55 patients who had ++ or stronger reactions to paraphenylenediamine also reacted to Disperse Orange 3.

HEMODIALYSIS Acid-base balance One goal of hemodialysis is to correct chronic acidosis resulting from impaired excretion of hydrogen ions, corrected by the inclusion of a buffer (bicarbonate) in the dialysis fluid. The bicarbonate concentration

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in dialysis fluid for intermittent hemodialysis is usually 32–35 mmol/l. However, the severity of chronic metabolic acidosis secondary to end-stage renal insufficiency is very variable, so that in some patients pre-dialysis acidosis is overcorrected. Hemodynamic tolerance to metabolic alkalosis during intermittent hemodialysis has been analysed in a randomized controlled, single-blind, crossover trial in 26 patients, with a total of 468 dialysis sessions (99C ). The dialysis fluid contained bicarbonate in a concentration of 32 or 26 mmol/l. During high bicarbonate and low bicarbonate dialyses respectively the mean lowest systolic blood pressures were 121 versus 124 mmHg, mean systolic blood pressures were 139 versus 145 mmHg, and the highest heart rate was 74 versus 76. Patients who received the higher dose of bicarbonate had more dialysis sessions with hypotensive episodes (5.6 versus 1.7%) and required more infusions of saline or hypertonic glucose (21 versus 14% of sessions). The authors concluded that mild metabolic alkalosis resulting from standard bicarbonate hemodialysis (32 mmol/l) can cause symptomatic hypotension. While normalizing chronic metabolic acidosis is desirable, reducing bicarbonate concentrations should be considered in cases of significant alkalemia or otherwise untreatable hemodynamic instability.

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Y, Araki S. Assessment of urinary cotinine as a marker of nicotine absorption from tobacco leaves: a study on tobacco farmers in Malaysia. J Occup Health 2003; 45: 140–5; erratum 270. 93. Albright F, Butler AM, Bloom E. Rickets resistant to vitamin D therapy. Am J Dis Child 1937; 54: 529–44. 94. Makitie O, Kooh SW, Sochett E. Prolonged high-dose phosphate treatment: a risk factor for tertiary hyperparathyroidism in X-linked hypophosphatemic rickets. Clin Endocrinol 2003; 58: 163–8. 95. Terlevich A, Hearing SD, Woltersdorf WW, Smyth C, Reid D, McCullagh E, Day A, Probert CSJ. Refeeding syndrome: effective and safe treatment with Phosphates Polyfusor. Aliment Pharmacol Ther 2003; 17: 1325–9. 96. Anonymous. Plasma/urinary medicinal products. Danger of variant Creutzfeldt-Jakob disease. WHO Pharm Newslett 2003; 2: 4. 97. Seidenaris S, Mantovani L, Manzini BM, Pignati M. Cross-sensitization between azo dues and para-amino compound: a study of 236 azo-dyesensitive subjects. Contact Dermatitis 1997; 36: 91–6. 98. Goon ATJ, Gilmour NJ, Basketter DA, White IA, Rycroft RJG, McFadden JP. High frequency of simultaneous sensitivity to Disperse Orange 3 in patients with positive patch tests to paraphenylenediamine. Contact Dermatitis 2003; 48: 248–50. 99. Gabutti L, Ferrari N, Giudici G, Mombelli G, Marone C. Unexpected heamodynamic instability associated with standard bicarbonate haemodialysis. Nephrol Dial Transplant 2003; 18: 2369–76.

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 Dra Mabel Teresa Foppiano Head Tel: +54-1-340 0866 Fax: +54-1-340 0866 E-mail: [email protected] Website: anmat.gov.ar

Administración Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT) Sistema Nacional de Farmacovigilancia Avenida de Mayo 869, piso 11o 1084 Buenos Aires Argentina

Armenia Dr Samvel Azatyan Deputy director Tel: +374-1-584 020, 584 120 Fax: +374-1-542 406 E-mail: [email protected] Website: pharm.am

Department of Pharmacovigilance and Rational Use of Drugs Armenian Drug and Medical Technology Agency 15 Moskowian Street Yerevan 375001 Armenia

Australia Dr John McEwen Principal Medical Advisor Tel: +61-2-6232 8113 Fax: +61-2-6232 8392 E-mail: [email protected] Website: tga.gov.au/adr Austria Eugen Obermayr Head Tel: +43-1-711 00, ext 4638 Fax: +43-1-712 0823 E-mail: [email protected] Website: bmsg.gv.at

602

Therapeutics Goods Administration PO Box 100 Woden ACT 2606 Australia

Federal Ministry for Social Security and Generations Pharmacovigilance Unit VI/A/7 Radetzkystrasse 2 A-1031 Vienna Austria

603

Address list of national centres

Bahrain Ms Layla Abdur-Rahman Director Tel: +973-25 86 68 Fax: +973-25 93 57 E-mail: [email protected] Belarus Mr Godovalnikov Tel: +7-017-289 55 14 Fax: +7-017-289 53 48

Belgium Johan Van Calster Director-General Tel: +32-2-227 5500 Fax: +32-2-227 5528 E-mail: [email protected] Website: afigp.fgov.be

Brazil Dr Anthony Wong Medical Director Tel: +55-11-3088 9431 Fax: +55-11-3088 9431 E-mail: [email protected] Website: ceatox.com.br

Ministry of Health Pharmacy and Drug Control PO Box 28136 Riffa Bahrain

Ministry of Health Center for Examinations and Test Health Service Republican Unitary Enterprise 2-a Tovarishcheskij Per 22 0037 Minsk Belarus

Federal Public Service Public Health Protection Directorate—General Medicinal Products National Centre for Pharmacovigilance Boulevard Bischoffsheim 33, 1st floor B-1000 Brussels Belgium

CEATOX Sao Paulo Regional Poison and Pharmacovigilance Centre Inst. Crianca Reference Centre Av. Dr Enéas de Carvalho Aguiar 647 05403-903 Sao Paulo SP Brazil

Brazil Mr Murilo Freitas Dias Head Tel: +55-61-448 1219 Fax: +55-61-448 1275 E-mail: [email protected] Website: anvisa.gov.br/farmacovigilancia

Pharmacovigilance Unit—UFARM Agencia Nacional de Vigilância Sanitárita ANVISA SEPN 515 Bl.B Ed. Omega 2 Andar, Sala 2 CEP 70770-502 Brasilia DF Brazil

Bulgaria Ms Daniela Encheva Head Tel: +359-2-9446 99 - 356, 944 2368 Fax: +359-2-9434 487 E-mail: [email protected] Website: bda.bg

Bulgarian Drug Agency Department of Pharmacovigilance Eurointegration and Pharmacopoeia 26 Yanko Sakazov Boulevard BG-1504 Sofia Bulgaria

604 Canada 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 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/hpb-dgps/therapeut/

Chile Dra Q F Cecilia Morgado-Cadiz Head Tel: +56-2-239 8769 Fax: +56-2-239 8760 E-mail: [email protected]

China Dr Yixin Chen Division Acting Director Tel: +86-10-6716 4979 Fax: +86-10-6718 4951 E-mail: [email protected] Website: cdr.gov.cn and adr.gov.cn

Congo, the Democratic Republic of the Mr Franck Biayi Kanumpepa Tel: +243-81-8125 838 +243-81E-mail: [email protected]

Costa Rica Dra Jetty Murillo Ocampo Farmacéutica responsable Tel: +506-222 1878 Fax: +506-295 2905 E-mail: [email protected]

Address list of national centres

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 Building, 1st Floor Tunney’s Pasture A/L 0201 C2 Ottawa, Ontario K1A 1B9 Canada

Instituto de Salud Publica de Chile CENIMEF – National Drug Information and Pharmacovigilance Centre Avenida Marathon 1000, 3 piso, Nuñoa-Casilla 48 Santiago Chile

Division of ADR Monitoring Center for Drug Reevaluation, SFDA Building 11, Fa-Hua-Nan-Li Chongwen District Beijing 100061 China

Ministère de la Santé Boulevard dy 30 Juin no 4310 BP 3088 Kinshasa Gombe The Democratic Republic of the Congo

Caja Costarricense de Seguro Social Centro Nacional de Farmacovigilancia Avda. Segunda San José Costa Rica

605

Address list of national centres

Croatia Dr Igor Francetic Head Tel: +385-1-2421 875 Fax: +385-1-2388 279 E-mail: [email protected]

Cyprus Dr Athos Tsinontides Clinical Pharmacist Tel: +357-2-240 7101 Fax: +357-2-233 9623 E-mail: [email protected]

Czech Republic Dr Ivana Koblihova Head Tel: +42-2-7218 5848, 7218 5111 Fax: +42-2-7143 2377, 7218 5816 E-mail: [email protected]

Denmark Ms Margit Handlos Head of Pharmacovigilance Tel: +45-44-88 92 87 Fax: +45-44-88 95 99 E-mail: [email protected] Website: dkma.dk

Egypt Prof Abdulla Molokhia Chairman, NODCAR Tel: +20-2-7484 989 Fax: +20-2-3379 445 E-mail: [email protected]

Eritrea Embaye Andom Tel: +291-1-122 429 Fax: +291-1-122 899 E-mail: [email protected]

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

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

Danish Medicines Agency Medicines Control Division Axel Heides gade 1 DK-2300 Kobenhavn Denmark

Ministry of Health National Organization for Drug Control and Research PO Box 29 51 Wezaret Al-Ziraa, Agouza Cairo Egypt

Ministry of Health Drug Information Unit PO Box 212 Asmara Eritrea

606 Estonia Dr Maia Uusküla Head Tel: +372-7-374 140 Fax: +372-7-374 142 E-mail: [email protected] Website: sam.ee

Ethiopia Mr Abraham Geberegiorgis Tel: +251-1-52 41 22 Fax: +251-1-52 13 92 E-mail: [email protected]

Fiji Mr Peter Zinck Chief Pharmacist Tel: +679-3-315 022 Fax: +679-3-304 199 E-mail: [email protected]

Address list of national centres

Ravimiamet State Agency of Medicines 19 Ravila Str. 50411 Tartu Estonia

Drug Administration and Control Authority of Ethiopia ADR Monitoring & Promotion Control Division PO Box 5681 Addis Ababa Ethiopia

Business and Essential Drugs (BED) Fiji Pharmaceutical Services Ministry of Health Box 106 Suva Fiji

Finland 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 Dr Carmen Kreft Jaïs Head Tel: +33-1-5587 3533 Fax: +33-1-5587 3532 E-mail: [email protected] Website: afssaps.sante.fr

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 Dr Jürgen Beckmann Head Tel: +49-228-207 3311 Fax: +49-228-207 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

607

Address list of national centres

Ghana Dr Alex Dodoo Tel: +233-21-675 885 Fax: +233-21-666 8219 E-mail: [email protected]

Greece 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 Licda. Leticia Vargas de Ponce Tel: +502-471 9842 Fax: +502-440 8267 E-mail: [email protected]

Hungary Dr Mariann Virányi Head Tel: +36-1-266 6073 Fax: +36-1-266 6073 E-mail: [email protected]

Iceland Prof. Magnús Jóhannsson Tel: +354-5-20 2114 Fax: +354-5-61 2170 E-mail: [email protected] Website: lyfjastofnun.is

India Prof Suresh K. Gupta Chief Tel: +91-11-2659 3633 Fax: +91-11-6286 2663 or 652 10 41 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 Av GR-155 62 Athens-Holargos Greece

Coordinadora del Programa Nacional de Farmacovigilancia MSPAS 11 Ave. “A” 11-57 zona 7 Finca La Verbena Guatemala

National Institute of Pharmacy Adverse 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

608 Indonesia Dra Engko Sosialine M. Head Tel: +62-21-4245 459 Fax: +62-21-4243 605 E-mail: [email protected] Website: pom.go.id

Iran, Islamic Republic of Dr Kheirollah Gholami Tel: +98-21-640 4223 Fax: +98-21-641 7252 E-mail: [email protected]

Ireland Ms Niamh Arthur Pharmacovigilance Co-ordinator Tel: +353-1-676 4971 Fax: +353-1-676 7836 E-mail: [email protected] Website: imb.ie Israel Dr Dina Hemo Head Tel: +972-2-568 1219 Fax: +972-2-672 58 20 E-mail: [email protected]

Italy Dr Roberto Raschetti Tel: +39-06-599 41 Fax: +39-06-5994 3554 E-mail: [email protected] Website: ministerosalute.it/medicinali /farmacovigilanza/farmaco Jordan Ms Nancy Ghabboun Tel: +962-6-5660 028 Fax: +962-6-5660 028 E-mail: [email protected]

Address list of national centres

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

Ministry of Health and Medical Education Research and Development Office Iranian ADR Centre Under-secretary for Food and Drug Affairs Building no. 3, Fakhr-e-Razi Street, Enghlab Ave 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 Str. PO Box 1176 Jerusalem 91010 Israel

Ministry of Health Centro Nazionale di Epidemiologia Istituto Superiore di Sanita Viale Regina Elena 299 I-00161 Rome Italy

Drug Directorate Ministry of Health PO Box 86 Amman Jordan

609

Address list of national centres

Korea, Republic of Dr Joon-Shik Chang Tel: +82-2-382 0185, 380 1636 Fax: +82-2-386-0843 E-mail: [email protected] Website: kfda.go.kr Kyrgyzstan Saliya Karimbaeva Tel: +996-312-54 29 40 Fax: +996-312-54 29 10 E-mail: [email protected]

Latvia Dr Inese Studere Head of ADR Monitoring Dpt. Tel: +371-2-707 8442 Fax: +371-2-707 8442 E-mail: [email protected] Website: vza.gov.lv/index.html Lithuania Donatas Stakisaitis Tel: +370-5-2614 552 Fax: +370-5-2614 552 E-mail: [email protected]

Macedonia, the Former Yugoslav Republic of Ms Vesna Nasteska-Nedanovska Tel: +389-2-322 71 95, 323 76 69 Fax: +389-2-323 08 57

Malaysia Ms Abida Haq Bt Syed M. Haq Tel: +60-3-7957 3611 Fax: +60-3-7956 7151 E-mail: [email protected]

Malta Ms Lilian Wismayer Tel: +356-23-43 91 10 Fax: +356-23-43 91 61 E-mail: [email protected]

Korea Food and Drug Administration Pharmaceutical Safety Bureau 5 Nokbun-dong, Eunpyong-ku Seoul 135-793 Republic of Korea

Drug Information Centre Ministry of Health 3rd Liniya Street 720044 Bishkek Kyrgyzstan

State Agency of Medicine of Latvia (SAM) ADR Monitoring Department Jersikas St. 15 LV-1003 Riga Latvia

Division for Preclinical and Clinical Trials State Medicines Control Agency Traku 14 2001 Vilnius Lithuania

Ministry of Health ul. 50 Divizija b.b. 1000 Skopje The Former Yugoslav Republic of Macedonia

National Pharmaceutical Control Bureau Ministry of Health Jalan University PO Box 319 MA-46730 Petaling Jaya Malaysia

Medicines Regulatory Unit 198 Rue D’Argens Gzira Gzr 03 Malta

610 Mexico Dra Carmen Becerril Martinez Head Tel: +52-5203 4378 Fax: +52-5203 4378 E-mail: [email protected]

Moldavia, Republic of Dr Lucia Tsurcan Head Tel: +373-2-73 70 02, 73 87 86 Fax: +373-2-73 70 45 E-mail: [email protected]

Morocco Dr Rachida Soulaymani-Bencheikh Head Tel: +212-37-6110 47 45 (gsm) Fax: +212-37-77 71 79 E-mail: [email protected]

Mozambique Dr Esperanca Julia Sevene Tel: +258-1-32 52 27 / 32 42 10 Fax: +258-1-32 52 55 E-mail: [email protected] Netherlands Dr A.C. van Grootheest Director Tel: +31-73-646 9700 Fax: +31-73-642 6136 E-mail: [email protected] Website: lareb.nl

Address list of national centres

Ministry of Health Monterrey 33 piso 10 Col. Roma Del Cuauthémoc Mexico City DF CP 06700 Mexico

National Centre for Adverse Reaction Monitoring of the Republic of Moldova National Institute of Pharmacy Str. Korolenko 2/1 Chisinau 2028 Republic of Moldavia

Centre Anti Poisons et de Pharmacovigilance Rue Lamfedel Cherkaoui Al Irfane Rabat Institute BP 769 Rabat Morocco

Drug Information Center (CIMed) Av. Salvador Allende n. 702 Maputo Mozambique

Netherlands Pharmacovigilance Centre LAREB Goudsbloemvallei 7 NL-5237 MH’s-Hertogenbosch Netherlands

Netherlands Antilles 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

New Zealand 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

611

Address list of national centres

Nigeria Mrs Ijeoma P.C. Nnani Tel: +234-9-670 28 23 Fax: +234-9-6706 576 E-mail: [email protected]

Norway Ms Ingebjorg Buajordet Head Tel: +47-22-89 77 00 Fax: +47-22-89 77 99 E-mail: [email protected] Website: legemiddelverket.no Oman Dr Sawsan Ahmad Jaffar Head Tel: +968-600 016 Fax: +968-602 287 E-mail: [email protected]

Pakistan Prof Akhlaque Un-Nabi Khan Tel: +92-21-588 2997, 589 2801 Fax: +92-21-588 1444, 589 3062 E-mail: [email protected]

Peru 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

Philippines Mrs Nazarita Lanusa E-mail: [email protected]

National Agency for Food & Drug Administration and Control (NAFDAC) 2023 Olusegun Obasanjo way Zone 7, Wuse Abuja 7 Nigeria

Norwegian Medicines Agency Statens Legemiddelverk Adverse Drug Reaction Section Sven Oftedals vei 8 N-0950 Oslo Norway

Ministry of Health Directorate General of Pharmaceutical Affairs and Drug Control PO Box 393 Muscat, Sultanate of Oman 113 Oman

College of Physicians & Surgeons Pakistan (CPSP) Department of Clinical Pharmacology 7th Central Street Phase II, Defence Housing Authority Karachi 75500 Pakistan

Presidenta del Comite Tecnico Nacional de Farmacovigilancia CENAFIM, DIGEMID Ministerio de Salud Av. Arenales # 1302 - Of. 318-319 Lima, Ministerio de Salud 11 Peru

OIC, Product Service Division Bureau of Food and Drugs Department of Health Filinvest Corporate City, Alabang Muntinlipa City 1770 Philippines

612

Address list of national centres

Poland Dr Agata Maciejczyk Head Tel: +48-22-4520 645 Fax: +48-22-4520 634 E-mail: [email protected] Website: urpl.gov.pl

Pharmacovigilance Unit Office for Medicinal Products Medical Devices and Biocides 30/34 Chelmska Street PL-00725 Warsaw Poland

Portugal 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 Dr Juliana Daniela Stanciu Head Tel: +40-1-224 1102, 224 1710 Fax: +40-1-2243 497 E-mail: [email protected]

National Medicines Agency Str Aviator Sanatescu no 48, Sector 1 R-71 324 Bucuresti Romania

Russian Federation Prof Victor Cheltsov Head Tel: +7-095-1905 427 or 1903 490 Fax: +7-095-434 02 92 E-mail: [email protected]

Department of Clinical Pharmacology Miklukho-Maklay Street 8 117198 Moscow Russian Federation

Serbia and Montenegro Prof Vaso Antunovic Head Tel: +381-11-361 5531 Fax: +381-11-361 56 30

Singapore Ms Chan Cheng Leng Head of Pharmacovigilance Tel: +65-6-325 5604, 325 5610 Fax: +65-6-325 5448 E-mail: [email protected] Website: hsa.gov.sg/hsa/cpa/CPA_pharma_about.htm Slovakia Dr Pavol Gibala Head Tel: +421-2-5293 1735, 5293 1732 Fax: +421-2-5293 1734 E-mail: [email protected] Website: sukl.sk

Clinical Centre of Serbia National Centre for Adverse Drug Reactions Visegradska 26 YU-11000 Belgrade Serbia and Montenegro

Pharmacovigilance, Communications & Research Division Health Sciences Authority No. 2 Jalan Bukit Merah Singapore 169547 Singapore

National Centre for Monitoring Adverse Reactions to Drugs State Institute for Drug Control Kvetná 11 825 08 Bratislava 26 Slovakia

613

Address list of national centres

South Africa Mrs Nanette O’Connor Tel: +27-21-447 1618 Fax: +27-21-448 6181 E-mail: [email protected]

Spain 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 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]

National Adverse Drug Event Monitoring Centre Division of Pharmacology, Medical School University of Cape Town Medical School K45 Old Main Building Groote Schuur Hospital Observatory 7925 South Africa

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

Sweden Dr Gunilla Sjölin-Forsberg Tel: +46-18-17 46 00 Fax: +46-18-54 85 66 E-mail: [email protected] Website: mpa.se

Medical Products Agency Husargatan 8 Box 26 S-751 03 Uppsala Sweden

Switzerland Dr Ruedi Stoller Head Tel: +41-31-322 0348 Fax: +41-31-322 0418 E-mail: [email protected] Website: swissmedic.ch

Swissmedic Schweizerisches Heilmittelinstitut Pharmacovigilance Zentrum Erlachstrasse 8 CH-3000 Bern 9 Switzerland

Tanzania, United Republic of Ms Mary Masanja Head, Drug Information Department Tel: +255-22-245 0512 / 245 07 51 Fax: +255-22-245 0793 E-mail: [email protected]

Tanzania Drug and Toxicology Information Service (TADATIS) Pharmacy Board PO Box 77150 Dar Es Salaam United Republic of Tanzania

614 Thailand Mr Chanchai Uerchakul Director Tel: +66-590 72 81 Fax: +66-591 84 57 E-mail: [email protected]

Tunisia Prof Chalbi Belkahia Head Tel: +216-1-562 098 Fax: +216-1-571 390 or 57 81 96 E-mail: [email protected]

Turkey Dr Seyfullah Dagistanli Head of Department Tel: +90-312-230 2769 Fax: +90-312-230 1610 E-mail: [email protected]

Ukraine Dr Marina Sharayeva Head Tel: +7-380-44268 2500 Fax: +7-380-44268 2500 E-mail: [email protected]

United Kingdom Dr June Raine Head Tel: +44-20-7084 2400 Fax: +44-20-7084 2675 E-mail: [email protected] Website: mhra.gov.uk

United States Dr M. Miles Braun Director Tel: +1-301-827 3974 Fax: +1-301-827 3529 E-mail: [email protected]

Address list of national centres

Thai National ADRM Centre Food and Drug Administration Ministry of Public Health Ti-wa-nondh Road Nonthaburi 11000 Thailand

Centre National de Pharmacovigilance Sis Hôpital Ch Nicolle Bd du 9 Avril Tunis 1006 Tunisia

TADMER Saglik Bakanlikgi Ilac ve Eczacilik Genel Mürdürlügü Ilkiz Sok, No. 4 06410 Sihhiye Ankara Turkey

Pharmacovigilance Department State Pharmacological Center Ministry of Health of Ukraine 18 Chygorina Str. 01042 Kiev Ukraine

Post-licensing Division Medicines and Healthcare Products Regulatory 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 United States of America

615

Address list of national centres

United States Dr Paul Seligman Tel: +1-301-827 6276 Fax: +1-301-827 6276 E-mail: [email protected]

Uruguay Dra Carolina Seade Fournie Tel: +598-2-487 27 02 Fax: +598-2-6226 969 E-mail: [email protected]

Uruguay Dra Mabel Burger Tel: +598-2-480 4000 Fax: +598-2-487 0300, hänvis (31/10-01): 487 5682/AK E-mail: [email protected] Website: ciat.hc.edu.uy Venezuela Dr Jesús Querales Castillo Head Tel: +58-212-6624 797 Fax: +58-212-6624 797, 693 1455

Vietnam Prof Hoang Tich Huy_n Head Tel: +84-4-245 292 Fax: +84-4-823 1253 E-mail: [email protected]

Zimbabwe Mrs Sakhile Dube-Mwedzi Regulatory Officer Tel: +263-4-736981-5 Fax: +263-4-736980 E-mail: [email protected]

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 United States

Depto de Farmacologia Hospital de Clinicas Avda Italia s/n, piso 1 11600 Montevideo Uruguay

Depto de Toxicologia Hospital de Clínicas Avda Italia s/n, piso 7 11600 Montevideo Uruguay

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

Medicines Control Authority of Zimbabwe 106 Baines Ave Bulawayo Zimbabwe

Index of drugs Notes. See both classes and specific drugs. Boldface page numbers refer to main discussions. A abacavir, 332 ABCD see amphotericin B colloidal dispersion (ABCD) abciximab, 396 ABLC see amphotericin B lipid complex (ABLC) acamprosate, 113–114 acarbose gastrointestinal system, 514–515 skin, 515 ACE (angiotensin converting enzyme) inhibitors see also specific drugs, such as captopril; perindopril concomitant aspirin, 124–125 concomitant NSAIDs, 122–123 aceclofenac, 126 acetaminophen see paracetamol acetazolamide fluid balance, 233 hematologic effects, 233 Stevens–Johnson syndrome, 570 acetyl-L-carnitine, 541 acetylcysteine concomitant contrast media, 557–559 contact dermatitis, 571 acetylsalicylic acid (aspirin) cardiovascular effects, 123 concomitant ACE inhibitors, 124 concomitant clopidogrel, 124 concomitant NSAIDs, 118–119, 123 overdose, 123–124 respiratory system, 123 sensory systems, 123 aciclovir psychiatric effects, 328 skin, 328 acitretin, 171 acupuncture infection risk, 581 nervous system effects, 581 respiratory effects, 581 adalimumab immunological effects, 427 infection risk, 427 respiratory system, 426 skin, 426 tumorigenicity, 427

616

urinary tract, 426 adapalene, 171–172 adenosine cardiovascular effects, 204 comparative studies, 203–204 nervous system, 204 observational studies, 203 placebo-controlled studies, 204 adrenaline, 160 ajmaline, 204–205 alatrofloxacin, 276 albumin, 369 alefacept, 168 alemtuzumab administration route, 435 hematological effects, 434 immunological effects, 434 infection risk, 434–435 all-trans retinoic acid, 299 Allium sativum 574 allopurinol, 133 alosetron gastrointestinal system, 402 prescribing criteria, xxxii–xxxiii alprazolam concomitant fluoxetine, 52–53 concomitant fluvoxamine, 52 concomitant SSRIs, 18 general effects, 52 alprostadil (prostaglandin E1 ), 476–477 alteplase, 392 aluminium immunologic effects, 244 nervous system, 244 amalgams, 249 amfebutamone concomitant SSRIs, 14 immunologic effects, 19 nervous system, 18–19 overdose, 15 amfepramone, 7 amfetamine abuse, 5 cardiovascular effects, 4, 28–29 concomitant mefloquine, 5 concomitant triazolam, 6 drug dependence, 5 fetotoxicity, 5 psychiatric effects, 4–5 amifostine, 541 amikacin, 274 aminoglycosides, 274

aminosalicylates, 408 amiodarone cardiovascular effects, 205–206 concomitant loratadine, 181, 208 diagnostic test interference, 208 discontinuation causes, 202 endocrine, 207 interactions, 208 liver, 207–208 observational studies, 205 respiratory system, 206–207 sensory system, 207 skin, 208 systematic reviews, 205 amitriptyline, 304–305 amlodipine, 219 ammonium chelators, 254 amodiaquine, 315 amoxicillin see co-amoxiclav amphotericin B colloidal dispersion (ABCD), 296–297 amphotericin B deoxycholate (DAMB), 295–296 amphotericin B lipid complex (ABLC), 297 anabolic steroids endocrine system, 496 fertility, 496 liver, 496 psychological, 496 usage, 495 anakinra see interleukin-1 receptor antagonist anastrozole, 490 androgen deprivation treatment, 498–499 androgen replacement therapy see testosterone anesthesia, 4; see also specific agents, such as benzocaine; ropivacaine angiotensin converting enzyme inhibitors see ACE inhibitors angiotensin II receptor antagonists, 229; see also specific drugs, such as irbesartan; telmisartan antacids, 401 anthracyclines, 545 anthrax vaccine during pregnancy, 358 sensory systems, 357

617

Index of drugs anti-CD3 antibody, 435 anti-CD40 antibody, 435 antiandrogens, 497 antibiotics, future use of, 265–267; see also specific drugs and classes, such as cephalosporins; minocycline anticholinergic drugs, 166 anticoagulants, 499 antidepressant drugs overdose, 14–15 sexual function, 14 tumorigenicity, 14 antiepileptic drugs see also specific drugs and classes, such as benzodiazepines; gabapentin psychological effects, 86 reproductive function, 88 skin, 87 teratogenicity, 88 vincristine clearance, 544 antihistamines (H1 ), 178; see also specific drugs, such as cetirizine; loratadine antimony, 244–245 antiparkinsonian drugs, 69 antipsychotic drugs cardiovascular effects, 59 diabetes mellitus, 60–64 endocrine system, 60 nervous system, 59–60 sexual function, 64 susceptibility factors, 64 tumorigenicity, 64 antipyrine see phenazone antiretroviral drugs concomitant voriconazole, 299–300 metabolic syndrome, 329–330 antithymocyte globulin general effects, 373 hematologic effects, 374 immunologic effects, 374 infection risk, 374 respiratory system, 374 tumorigenicity, 374–375 antithyroid drugs hematological effects, 506 liver, 506 teratogenicity, 507 appetite suppressants, 6–7 aprepitant concomitant digoxin, 197 concomitant glucocorticoids, systemic, 476 arachis oil see peanut oil arbekacin, 274 argatroban, 393–394 arginine vasopressin, 531 Aristolochia species, 6–7, 575 aromatase, 490 arsenic, 245 artemether concomitant lumefantrine, 320–321

immunologic effects, 320–321 nervous system, 320 artemisinin, 321 artesunate body temperature, 321 efficacy, 320 metabolism, 321 ASA see acetylsalicylic acid ascorbic acid see vitamin C Asian herbal medicines concentration, warfarin, 574 contaminated, with drugs, 574 general effects, 573 hypotension, 573–574 liver, 574 asparaginase concomitant vincristine, 544 venous thromboembolism, 545 aspirin see acetylsalicylic acid atazanavir, 335 atenolol, 217 atorvastatin cognitive impairment, 535 immunologic effects, 536 liver, 536 nervous system, 535–536 rhabdomyolysis, + esomeprazole, 535 atovaquone + proguanil pregnancy, 318 psychological effects, 318 resistance, 317 azathioprine concomitant infliximab, 434, 451 endocrine system, 450 gastrointestinal system, 450 immunological effects, 450 infection risk, 451 pancreas, 450 teratogenicity, 451 tumorigenicity, 451 azelastine, 177 azithromycin cardiovascular effects, 282 concomitant ciclosporin, 282 immunologic effects, 282 psychiatric effects, 282 skin, 282 azole antifungals concomitant second-generation antihistamines, 179 concomitant tacrolimus, 304 B Bacille Calmette–Guérin vaccine, 358 baclofen, 157 barium, 554 basiliximab, 435 BCG see Bacille Calmette–Guérin vaccine beclomethasone, 185 benazapril, 227

benfluorex, 7 benzalkonium compounds, 261 benzimidazoles efficacy, 346–347 skin, 347 susceptibility factors, 348 teratogenicity, 347–348 benzocaine, 150 benzodiazepines, 52 bepridil general effects, 208–209 respiratory system, 219 beta-blockers (ocular), 570 beta-blockers (systemic), 217, 397 beta-carotene, 387 betamethasone see glucocorticoids bevacizumab, 436 BG9588 see anti-CD40 antibody biguanides, 521–522 bismuth, 245 bismuth biskalcitrate + metronidazole + tetracycline + omeprazole, 405 bisphosphonates musculoskeletal effects, 591 skin effects, 591 visual effects, 590–591 black cohosh (Cimicifuga racemosa) safety, 575 bleomycin, 545 blood transfusion, 369 bosentan, 536 botulinum toxin A, 168 brivudine, 328 bromazepam, 300 budesonide angioedema, 186 concomitant itraconazole, 301 buformin, 515 bupivacaine, 150–151 buprenorphine general effects, 112–113 overdose, 44–45, 113 bupropion see amfebutamone buspirone, 52 busulfan, 323–324 C caffeine concomitant HRT, 2 concomitant menthol, 2 nervous system, 1 neuromuscular system, 1 pregnancy, 1–2 calciferol see vitamin D calcipotriol, 169 calcium channel blockers see also specific drugs, such as bepridil; verapamil overdose, 219 skin, 218

618 tumorigenicity, 218–219 calcium dobesilate, 223 calcium salts, 245–246 Camelia sinensis see tea candesartan, 229 cannabinoids cardiovascular effects, 36–37 fetotoxicity, 37–38 immunologic effects, 37 nervous system, 37 psychological effects, 37 susceptibility factors, 38 cannabis, 32, 34 capecitabine, 546 caprolactam, 591–592 carbamazepine cardiovascular effects, 88–89 concomitant valproic acid, 88 immunologic effects, 89 overdose, 89 cardiac drugs, 588 cardiac glycosides, 196–197 carotenoids see vitamin A carvedilol concomitant digoxin, 197 metabolism, 218 caspofungin, 310–311 caudal anesthesia, 146 cefepime, 269 ceftriaxone, 269–270 celandine (Chelidonium majus) liver damage, 575 celecoxib concomitant lithium, 131 concomitant sulfamethoxazole, 322 gastrointestinal system, 130 immunologic effects, 130–131 interactions, 131 skin, 130 urinary tract, 130 celiprolol, 300 Centella asiatica, 575 cephaloporins cross-reacting with penicillins, 267–268 nervous system, 268–269 cetirizine, 178 Chelidonium majus see celandine chemotherapy, 545 Chinese herbal medicines, 7; see also Asian herbal medicines chloramphenicol, 276 chloramphenicol A, 465 chlorhexidine, 261 chloroquine hematologic effects, 315–316 metabolism, 315 musculoskeletal effects, 316 resistance, 315 skin, 316 teratogenicity, 316 urinary tract, 316 chlorphenamine (chlorpheniramine) 177

Index of drugs abuse, 178 concomitant antihistamines, 178 interactions, 178 observational studies, 178 chlorpromazine sexual function, 64–65 chlorpropamide use pattern, 518 cholelitholytic agents gastrointestinal system, 410 hematological effects, 410 interactions, 410 lactation, 410 liver, 410 metabolism, 409–410 skin, 410 teratogenicity, 410 chromium oxidative damage, 246 ciclosporin cardiovascular effects, 452 concentration, + ursodeoxycholic, 410 concomitant azithromycin, 282 concomitant colchicine, 455 concomitant irinotecan, 455 concomitant itraconazole, 300–301, 455 concomitant mycophenolate mofetil, 460 concomitant orlistat, 455 concomitant sibutramine, 9, 455–456 concomitant sirolimus, 456, 461–462 concomitant St. John’s wort, 455–456 concomitant statins, 456 endocrine system, 453 gastrointestinal system, 453 interactions, 455 metabolism, 453 mouth, 453 musculoskeletal system, 454–455 nervous system, 452–453 sebaceous glands, 454 skin, 454 tumorigenicity, 455 urinary tract, 453–454 cidofovir, 326 cimetidine, 302 Cimicifuga racemosa see black cohosh ciprofloxacin concentration, + ursodeoxycholic, 410 concomitant glibenclamide, 277 hematologic effects, 277 immunologic effects, 277 liver, 277 musculoskeletal effects, 277

nervous system, 277 psychiatric effects, 277 skin, 277 urinary tract, 277 cisapride, 401 cisatracurium, 155 cisplatin, 546 clarithromycin concomitant digoxin, 198, 283 formulations, 282–283 immunologic effects, 282 liver, 282 pancreas, 282 respiratory system, 282 sensory systems, 282 clindamycin gastrointestinal effects, 281 pregnancy, 282 skin, 281 clobazam, 53 clonazepam, 53 clonidine, 230 clopidogrel concomitant aspirin, 124 leukopenia, 397 clozapine cardiovascular effects, 65 concentration, + fluvoxamine, 65 concentration. + omeprazole, 68 concomitant lithium, 68 death, 67 formulations, 68 hematologic effects, 66–67 lactation, 67 metabolism, 66 monitoring therapy, 68–69 nervous system, 66 overdose, 68 pancreas, 67 pregnancy, 67 selenium concentration, 66 susceptibility factors, 67–68 co-trimoxazole electrolyte balance, 286 fetotoxicity, 287 gastrointestinal effects, 286 hematologic effects, 286, 322 immunologic effects, 286, 322 liver, 286, 322 metabolism, 322 nervous system, 322 psychiatric effects, 286 sensory systems, 286 skin, 286 susceptibility factors, 287, 322–322 coagulation factor gene therapy, 377 coagulation factors body temperature, 377 cardiovascular effects, 376 immunologic effects, 376 infection risk, 377

619

Index of drugs cocaine cardiovascular effects, 2–3, 38–39 concomitant anesthesia, 4 concomitant opiates, 28 death, 42–43 ear, nose, throat, 3, 40–41 endocrine system, 41–42 fetotoxicity, 4, 43–44 hematologic system, 42 musculoskeletal effects, 42 nervous system, 3, 41 pregnancy, 4 respiratory system, 40 sexual function, 3 colchicine concomitant ciclosporin, 455 dosage regimens, 133 interactions, 133–134 musculoskeletal effects, 133 Commiphora mukul see guggulipid contraceptive implants, 489–490 contrast media concomitant acetylcysteine, 557–559 concomitant fenoldopam mesylate, 557 nephrotoxicity, 556–560 copper, 246 coumarin, 391 COX-2 inhibitors see also celecoxib; rofecoxib cardiovascular effects, 128–129 concomitant lithium, 25 musculoskeletal effects, 129–130 psychiatric effects, 129 sensory systems, 129 susceptibility factors, 130 “crack” see cocaine Crataegus oxyacantha see hawthorn Curcuma longa see turmeric cyclizine, 178 Cyclo 3 fort, 223 cyclopentolate, 568 cyclophosphamide concomitant itraconazole, 301 concomitant suxamethonium, 156–157 hepatic sinusoidal obstruction syndrome, 546 interactions, 457 liver, 456–457 cyproheptadine, 14 cytarabine, 546 cytotoxic drugs see also anthracyclines; chemotherapy hematologic effects, 545 metabolism, 545 reproductive system, 545 susceptibility factors, 545 tumorigenicity, 545

D D4T see stavudine daclizumab, 436 DAMB see amphotericin B deoxycholate (DAMB) danazol cardiovascular effects, 496 concomitant simvastatin, 536 liver, 497 dapsone concentration, + ursodeoxycholic, 410 hematologic effects, 343 immunologic effects, 343 pancreas, 343 daptomycin, 287 darbepoetin alfa, 378 daunorubicin see anthracyclines DDAVP see desmopressin deferiprone, 256 deferoxamine overdose, 256–257 sensory systems, 256 urinary tract, 256 deflazacort see glucocorticoids dental anesthesia, 148–149 deoxyspergualin, 457 desloratadine concomitant fluconazole, 302 interactions, 179 nervous system, 179 desmopressin (DDAVP), 532 dexamethasone see glucocorticoids dexibuprofen, 126 dexketoprofen, 126 dexmedetomidine, 141 dextromethorphan comparative studies, 106 concomitant quinidine, 212 drug dosage regimens, 106 skin, 106 diamorphine see heroin diazepam concomitant phenytoin, 54 teratogenicity, 53–54 diclofenac, 126–127 diethylcarbamazine, 348–349 diethylpropion see amfepramone diethylstilbestrol, 482 digitalis, 198–199 digoxin concentration, + clarithromycin, 283 concomitant aprepitant, 197 concomitant clarithromycin, 198 concomitant dipyridamole, 198 concomitant hawthorn, 197 concomitant polyethoxylated castor oil, 198 concomitant ritonavir, 198 concomitant spironolactone, 199

concomitant teriparatide, 198 concomitant voriconazole, 198, 301 diltiazem, 219 diphenydramine, 179 diphenylcyclopropenone, 169 diptheria-tetanus-acellular pertussis vaccine general effects, 360 vs. Lyme disease vaccine, 359 dipyridamole concomitant digoxin, 198 overdose, 397 dipyrone, 126 dirithromycin, 283 disopyramide, 209 disulfiram, 592, 593 diuretics see specific drugs and classes, such as furosemide; loop diuretics dofetilide, 209 dolasetron, 402 donepezil cardiovascular effects, 9 concomitant maprotiline, 9 concomitant risperidone, 9, 78–79 drug withdrawal, 9 nervous system, 9 dopamine receptor agonists, 162–163 dorzolamide general effects, 570–571 sensory systems, 233 doxorubicin see also anthracyclines ischemic heart disease, + vincristine, 540 doxycycline, 270–271 droperidol, 69 DTaP see diptheria-tetanus-acellular pertussis vaccine dyestuffs, 262 E ecabet, 405 Echinacea species Sjögren’s syndrome, 576 echinocandins, 309–310 ecstasy see MDMA efalizumab, 436–437 efavirenz cholesterol concentration, 330 general effects, 334 Eleutherococcus senticosus, eleuthero root see Siberian ginseng enalapril liver, 227 pancreas, 227 skin, 228 urinary tract, 228 enfuvirtide, 337

620 enoxacin, 277 enoxaparin, 393 entacapone, 165 ephedrine priapism, 3 systemic effects, 161 epidural anesthesia, 146–147 epinephrine see adrenaline epirubicin see anthracyclines eplerenone, 235 epoetin, 378 see also erythropoietin eptifibatide, 398 ergot alkaloids, 224 erythromycin concomitant vinblastine, 544 general effects, 283 lidocaine clearance, 210 erythropoietin and derivatives cardiovascular effects, 378 general effects, 377–378 immunologic effects, 378 sensory systems, 378 tumorigenicity, 378 esomeprazole comparative studies, 403 concomitant atorvastatin, 535 esomeprazole + clarithromycin + metronidazole, 405 estrogens administration route, 481 concomitant raloxifene, 491 immunological effects, 481 tumorigenicity, 481 etanercept hematological effects, 427–428 infection risk, 428 musculoskeletal system, 428 placebo-controlled studies, 427 sensory systems, 427 skin, 428 etherified starches, 371 ethyl alcohol see alcohol ethylene oxide, 262 etomidate, 141 etoricoxib, 131 everolimus, 457 exenatide, 514 ezetimibe, 534 F factor VIII, 376 factor IX concentrate, 376 factor IX inhibitor, 376 famotidine, 403 felbamate, 87 femoral block, 149 fenoldopam mesylate, 557 fentanyl, 108 ferucarbotran, 564–565 fexofenadine, 179–180 fibrates concomitant warfarin, 534 interactions, 534

Index of drugs metabolism, 534 filgrastim see granulocyte colony-stimulating factor finasteride general effects, 169, 497–498 fish oil, 535 flecainide, 209–210 Fleet’s enema, 407 fluconazole concomitant all-trans retinoic acid, 299 concomitant amitriptyline, 304–305 concomitant desloratadine, 302 concomitant nateglinide, 302 concomitant simvastatin, 304 concomitant tretinoin, 174 immunologic effects, 305–306 liver, 305 teratogenicity, 306 urinary tract, 305 flucytosine, 311 fluindione, 574 fluoropyrimidines, 96 fluoroquinolones, 276 fluorouracil cardiovascular effects, 546 concomitant levamisole, 350 general effects, 546 nervous system, 546 sensory systems, 546 fluoxetine concomitant alprazolam, 52–53 concomitant pethidine, 111 reproductive system, 17 flutamide, 498 fluticasone allergic granulomatous vasculitis, 186 esophageal candidiasis, 186 suppression of adrenal gland function, 184–185 fluvoxamine clozapine concentration, 65 concomitant alprazolam, 52 concomitant metamfetamine, 4 concomitant methadone, 109 concomitant tizanidine, 157 folinic acid, 387–388 fondaparinux, 392–393 formoterol, 188–189 fosfomycin gastrointestinal effects, 287 liver, 287 skin, 287 fosmidomycin, 287 furosemide immunologic effects, 234–235 nutrition, 234 salivary glands, 234 sensory systems, 233–234 urinary tract, 234 fusidic acid gastrointestinal effects, 280

hematologic effects, 280 rhabdomyolysis, 535 G gabapentin, 89 gadobenate dimeglumine general effects, 563–564 safety, 561–562 gadobutrol, 564 gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) iron intoxification, 562 safety, 564 gadolinium salts, 561–563 gallium, 246 ganciclovir, 326–327 garenoxacin, 277–278 garlic (Allium sativum), 574 gatifloxacin concomitant glibenclamide, 278 concomitant glipizide, 278 psychiatric effects, 278 susceptibility factors, 278 Gd-DTPA see gadoliniumdiethylenetriamine-pentaacetic acid (Gd-DTPA) gemfibrozil concomitant rosiglitazone, 521 repaglinide concentration, 534 rosiglitazone concentration, 534 gemifloxacin, 278 gemtuzumab, 437 gentamicin immunologic effects, 275 mineral balance, 274 musculoskeletal effects, 275 sensory systems, 274 ginger (Zingiber officinale), 580 Ginkgo biloba concomitant ibuprofen, 127 concomitant SSRIs, 14 hematological effects, 576–577 ginseng (Panax ginseng) concomitant warfarin, 578 glatiramer acetate, 457 glibenclamide concomitant ciprofloxacin, 277 concomitant gatifloxacin, 278 dipyridamole imaging, enhancement, 397 liver damage, 519 gliclazide concomitant rifampicin, 344 general effects, 519 glimepiride, 519 glipizide concomitant gatifloxacin, 278 formulations, 519 hepatic failure, 519 glitazones concomitant biguanides, 521–522

621

Index of drugs concomitant meglitinides, 522 concomitant sulfonylureas, 522 glucagon-like peptide-1, 514 glucocorticoids, inhaled delivery systems, 187–188 safety during pregnancy, 186–187 glucocorticoids, systemic administration route, 476 cardiovascular effects, 471 concomitant aprepitant, 476 concomitant itraconazole, 476 concomitant protease inhibitors, 476 dosage regimens, 476 formulations, 476 immunological effects, 474 infection risk, 475 musculoskeletal system, 472–473 pancreas, 472 pregnancy, 475–476 psychiatric, 471–472 sensory systems, 471 glucocorticoids, topical, 169–170 glyburide see glibenclamide glycerol general effects, 592–593 nervous system effects, 593 glyceryl trinitrate concomitant tadalafil, 218 nervous system, 218 Glycyrrhiza species see liquorice glycyrrhizinic acid, 170 GnRH see gonadrotropin-releasing hormone gold hematologic effects, 247 respiratory system, 246 gonadorelin see gonadrotropin-releasing hormone gonadotropin-releasing hormone (GnRH, gonadorelin) endocrine effects, 528 hematologic effects, 528 musculoskeletal system, 528 reproductive system, 528 gonadotropins metabolism, 480 reproductive system, 480 tumorigenicity, 480–481 goserelin acetate, 528 granisetron, 402 granulocyte colony-stimulating factor (G-CSF) cardiovascular effects, 415 hematological effects, 415 immunological effects, 416 musculoskeletal system, 415–416 pregnancy, 416 skin, 415

tumorigenicity, 416 grapefruit juice, 593 CYP3A4 inhibition, 18 quinine clearance, 319 growth hormone (human growth hormone, hGH, somatotropin) cardiovascular effects, 528–529 musculoskeletal effects, 529 reproductive system, 529 respiratory system, 529 tumorigenicity, 529 growth hormone receptor antagonists see pegvisomant growth hormone release-inhibiting hormone (somatostatin), 530 guggulipid (Commiphora mukul), 576 H haloperidol concentration, + antiparkinsonian drugs, 69 QT interval prolongation, 59 hawthorn (Crataegus oxyacantha), 576 hemodialysis metabolic alkalosis, 598 hemofiltration, 559 Hemophilus influenzae type B vaccine see also influenza vaccine heparins, 391–392 herbal medicines see also Asian herbal medicines general cautions, 573 hepatitis, 580–581 nephritis, 581 heroin infection risk, 107 nervous system, 45–47, 106–107 overdose, 47, 107–108 respiratory system, 45 special senses, 47 withdrawal effects, 107 Herpes simplex virus vaccine, 361 hGH see growth hormone Hib see Hemophilus influenzae type B vaccine histamine hydrochloride, 424 HMG-CoA reductase inhibitors (statins) concomitant ciclosporin, 456 concomitant tacrolimus, 465 interactions, 535 musculoskeletal effects, 535 psychological effects, 535 homeopathy, 582 hormone replacement therapy (HRT) administration route, 486–487 cardiovascular effects, 483 concomitant caffeine, 2

food–drug interactions, 487 gastrointestinal system, 484 metabolism, 483–484 reproductive system, 484 susceptibility factors, 486 tumorigenicity, 484–485 HRT see hormone replacement therapy human growth hormone see growth hormone human papilloma virus vaccine, 361 hyaluronidase, 543 hydralazine, 230–231 hydrocortisone, 472 hydromorphone, 109 hydroxychloroquine see chloroquine hydroxyurea general effects, 546–547 hematologic effects, 170 skin, 170 Hypericum perforatum see St. John’s wort hypochlorite, 262 hypoxia metformin concentration, 515–516 I ibuprofen body temperature, 127 cardiovascular effects, 127 concomitant desmopressin, 127 concomitant Ginkgo biloba, 127 interactions, 127 nervous system, 127 ICL670, 257 idarubicin see anthracyclines idoxifene, 490–491 idraparinux, 393 imatinib, 547 immunoglobulins, intravenous cardiovascular effects, 372 general effects, 372 hematologic effects, 373 immunologic effects, 373 nervous system, 372–373 urinary tract, 373 indinavir biliary tract, 335 cholesterol concentration, 330 concentration with liver impairment, 336 diabetes, 331–332 hematologic effects, 335 insulin resistance, 331–332 susceptibility factors, 336 urinary tract, 336 indocyanine green, 593–594 indometacin, 128 infliximab cardiovascular effects, 429 comparative studies, 429

622 concomitant azathioprine, 434, 451 death, 433 general effects, 428 hematological effects, 430 immunologic effects, 431–432 infection risk, 432 interactions, 434 musculoskeletal system, 431 nervous system, 429 observational studies, 428–429 respiratory system, 429 sensory systems, 429–430 skin, 430–431 teratogenicity, 433–434 tuberculosis, 432–433 tumorigenicity, 433 influenza vaccine see also Hemophilus influenzae type b vaccine concomitant warfarin, 362 nasal administration, 362 nervous system, 362 oculorespiratory syndrome, 361–362 insulin administration route, 511 concomitant oral hypoglycemic drugs, 522–523 formulations, 511–512 infection risk, 510 liver, 509–510 metabolism, 509 misuse, 510 sensory systems, 509 tolerance, 510 insulin detemir, 513 insulin glargine, 513 interferon, 327 interferon alfa, 421 cardiovascular effects, 416–417 endocrine system, 420 hematological effects, 420–421 infection risk, 422 musculoskeletal system, 422 nervous system, 417–418 psychiatric effects, 419–420 respiratory system, 417 sensory systems, 418–419 skin, 421 susceptibility factors, 422 urinary tract, 421 interferon beta endocrine system, 422–423 hematological effects, 423 immunological effects, 423–424 liver, 423 psychiatric effects, 422 urinary tract, 423 interleukin-1 receptor antagonist, 424 interleukin-2 (IL-2), 424 interleukin-6 (IL-6), 302

Index of drugs interleukin-11 (IL-11), 424 interleukin-12 (IL-12), 424–425 intrathecal (spinal) anesthesia, 147–148 intrauterine devices, 246 intravenous drugs, 587–588 intravenous regional anesthesia, 149 iodinated water-soluble contrast media hematologic effects, 555 low- vs. high-osmolar agents, 552 pancreas, 555–556 salivary glands, 555 skin reaction, 554 iodine see also contrast agents, water-soluble iodinated concentration, topical, 507 concomitant amiodarone, 506 thyroid effects, 506 iomeprol, 554 ipratropium bromide, 190 irbesartan, 229 irinotecan, 455 iron, 247 iron chelators, 254–256 isoniazid immunologic effects, 343–344 liver, 343 overdose, 344 isoparaffin, 594 isosulfan blue, 594 isotretinoin cardiovascular effects, 172 metabolic effects, 172 psychiatric effects, 172 sensory systems, 172 skin, 172–173 teratogenicity, 173 itraconazole concomitant bromazepam, 300 concomitant budenoside, 301 concomitant celiprolol, 300 concomitant ciclosporin, 300–301, 455 concomitant cyclophosphamide, 301 concomitant glucocorticoids, 476 concomitant interleukin-6, 302 concomitant omeprazole, 303 concomitant quazepam, 300 concomitant rosuvastatin, 303–304 concomitant vincristine, 305, 544–545 efficacy, 307 electrolyte balance, 307 hematologic effects, 307 immunologic effects, 307–308 nervous system, 307 ivermectin filariasis, 349, 350

scabies treatment, 349–350 J Japanese encephalitis vaccine, 363 josamycin, 283 K kanamycin, 275 kava (Piper methysticum), 578–579 ketamine, 141 ketoconazole concomitant repaglinide, 518 midazolam concentration, 54 ketolides, 281 ketorolac, 570 ketotifen, 568 L L-AmB see liposomal amphotericin L-glutamic acid, 541 lamivudine, 332 lamotrigine concomitant phenytoin, 87–88 concomitant valproate, 90 nervous system, 90 psychiatric effects, 90 skin, 90 lansoprazole, 404 latanoprost, 477 lauromacrogols, 595 lead, 247 leflunomide, 457–458 lepirudin, 394 lercanidipine, 219 leucovorin see folinic acid levalbuterol see levosalbutamol levamisole, 350 levetiracetam dosage regimens, 94 observational studies, 91 psychiatric effects, 93 levobupivacaine, 151–152 levocetirizine, 180–181 levodopa homocysteine, 164 learning performance, 163 susceptibility factors, 164 levofloxacin cardiovascular effects, 278 concomitant quinolone antibiotics, 303 hematologic effects, 278 liver, 278 musculoskeletal effects, 279 urinary tract, 278 levonorgestrel administration route, 493–494 ectopic pregnancy, 489 immunological effects, 493 levosalbutamol (levalbuterol), 189

623

Index of drugs levothyroxine, 505–506, 491 licorice see liquorice lidocaine clearance, + erythromycin, 210 concomitant ropivacaine, 145 seizures, 145 vasospasm, 152 lignocaine see lidocaine linezolid concomitant phenylpropanolamine, 284 concomitant pseudoephedrine, 284 lipid emulsion, 556 liposomal amphotericin (L-AmB) administration route, 298–299 immunologic effects, 298 mineral balance, 297–298 susceptibility factors, 299 urinary tract, 298 liquorice (Glycyrrhiza) cardiovascular effects, 577 electrolyte balance, 577 endocrine system, 577 lisinopril, 228 Litargirio, 247 lithium cardiovascular effects, 24 concentration, + loop diuretics, 235 concomitant celecoxib, 131 concomitant clozapine, 68 concomitant COX-2 inhibitors, 25 endocrine system, 24 fetotoxicity, 25 monitoring therapy, 25–26 nervous system, 24 overdose, 25 therapeutic studies, 23–24 urinary tract, 24–25 local anesthetics, 145 lomefloxacin, 279 loperamide, 406 lopinavir, 336 loratadine concomitant amiodarone, 181, 208 interactions, 181 skin, 181 lorazepam, 54 lornoxicam, 127 losartan, 229 loxapine, 69–70 lumbar plexus block, 149 lumefantrine, 320–321 Lyme disease vaccine, 358–359 M Ma-huang see ephedrine macrolides see also specific drugs, such as josamycin; spiramycin concomitant voriconazole, 302

magnesium, 248 mangafodipir trisodium, 565 manganese, 248 mannitol blood–brain barrier, 237–238 bowel cleansing, 238 cardiopulmonary bypass, 240 cardiovascular effects, 240 diarrhea diagnosis, 239–240 intracranial pressure, 236–237 musculoskeletal effects, 241 nephrotoxicity, + cisplatin, 240 radiocontrast medium, 239 respiratory system, 240 sensory systems, 240 urinary tract, 240 maprotiline, 9 marijuana see cannabinoids MDMA (ecstasy, methylenedioxymetamfetamine) cardiovascular effects, 32 concomitant cannabis, 32, 34 concomitant moclobemide, 15, 36 death, 36 electrolyte balance, 35 mouth, 35 nervous system, 32 nutrition, 34–35 psychiatric effects, 33–34 psychological effects, 32–33 toxicity, 31–32 urinary tract, 35 measles-mumps-rubella (MMR) vaccine, 363–365 mefloquine, 316–317 meglitinides, 522 Melaleuca alternifolia see tea tree oil meloxicam, 128 meningococcal vaccine, 359–360 menthol, 2 mepacrine see quinacrine meperidine see pethidine mercaptopurine hematological effects, 450 infection risk, 451 teratogenicity, 451 tumorigenicity, 451 mercury see also thiomersal immunologic effects, 249 nervous system, 248 psychological effects, 249 mesalazine (mesalamine) gastrointestinal system, 408 nervous system, 408 pancreas, 408 pregnancy and teratogenicity, 408–409 respiratory system, 408 metamfetamine cardiovascular effects, 29 concomitant fluvoxamine, 4 concomitant morphine, 28, 110

concomitant nicotine, 31 death, 30 fetotoxicity, 30–31 nervous system, 29 psychiatric effects, 29–30 psychological effects, 29–30 metformin concomitant orlistat, 517 contraindications, 515–516 formulations, 517 gastrointestinal system, 517 hypoxia, 515–516 metabolism, 516 nervous system, 516 nutrition, 516–517 overdose, 517 pregnancy, 517 methadone abuse, 48 cardiovascular effect, 47–48 cardiovascular effects, 108–109 concomitant fluvoxamine, 109 concomitant St. John’s wort, 109 death, 109 dosage regimens, 109 nervous system, 48 methotrexate, 547 methylene-dioxymetamfetamine see MDMA methylphenidate, 6 methylprednisolone see glucocorticoids methylthioninium chloride (methylene blue) general effects, 595 hematologic effects, 595 mutagenicity, 595–596 nervous sytem effects, 595 metronidazole metabolism, 323 nervous system, 323 psychiatric effects, 323 skin, 323 midazolam, 54 mifepristone (RU 486) efficacy, 494–495 reproductive system, 495 tumorigenicity, 495 milk thistle (Silybum marianum) safety, 580 milrinone safety, 199–200 minocycline cytotoxity, 270 musculoskeletal effects, 271–272 nervous system, 271 psychiatric effects, 271 skin, 271 minoxidil cardiovascular effects, 170 endocrine system, 170 hair, 170–171

624 pregnancy, 171 safety, 170 mirtazapine nervous system, 19 overdose, 15 misoprostol, 477 mitomycin, 547 mivacurium, 155 MMR see measles-mumps-rubella (MMR) vaccine moclobemide concomitant MDMA, 36 overdose, 15 montelukast, 191 morphine comparative studies, 110 concomitant metamfetamine, 28, 110 interactions, 110 nervous system, 110 observational studies, 109 placebo-controlled studies, 110 susceptibility factors, 110 mosapride, 402–403 moxidectin, 350–351 moxifloxacin cardiovascular effects, 279 concomitant warfarin, 279 gastrointestinal effects, 279 skin, 279 mumps vaccine see measles-mumps-rubella (MMR) vaccine mupirocin, 285 muromonab-CD3 biliary tract, 438 comparative studies, 438 dosage regimens, 438–439 general effects, 437 nervous system, 438 tumorigenicity, 438 mycophenolate mofetil concomitant ciclosporin, 460 gastrointestinal system, 458–459 hematological effects, 458 immunological effects, 459 infection risk, 459–460 interactions, 460 observational studies, 458 skin, 459 Myristica fragrans see nutmeg N N-deamino-8-d-arginine vasopressin see desmopressin nafcillin, 220 naftidrofuryl, 223 naloxone, 113 naltrexone concomitant acamprosate, 114 concomitant heroin, 114 general effects, 113–114

Index of drugs naphazoline, 569 narcotic antagonists, 106 natalizumab, 439 nateglinide concomitant fluconazole, 302 concomitant rifampicin, 344 general effects, 518 nefazodone, 54 nelfinavir, 336 neomycin hypersensitivity, 171 immunologic effects, 275 neuroleptic drugs, 25 nevirapine liver, 334 skin, 334–335 susceptibility factors, 335 niacin see nicotinic acid nickel, 249 nicotine, 31 nicotinic acid, 536 nifedipine concomitant nafcillin, 220 concomitant phenobarbital, 220 extended-release formulation, 220 nimesulide, 132–133 nisoldipine, 220 nitrate derivatives concomitant phosphodiesterase type V inhibitors, 224 headache, 218 nitrendipine, 220 nitrofurantoin concomitant vitamin B6 , 388 liver, 284 pancreas, 284 respiratory system, 284 nitroglycerin see glyceryl trinitrate nitronaproxen, 128 nitrosofenfluramine, 7 nitrous oxide, 140 nizatidine, 403 non-steroidal anti-inflammatory drugs see NSAIDs norfloxacin, 279 novobiocin, 287 NRTI see nucleoside analogue reverse transcriptase inhibitors NSAIDs (non-steroidal anti-inflammatory drugs) see also specific drugs, such as ketoprofen concentrated latanoprost, 477 concomitant ACE inhibitors, 122–123 concomitant aspirin, 118, 123 concomitant coumarin, 391 concomitant SSRIs, 16 dyspepsia, 120 gastrointestinal effects, 120 tumorigenicity, 123 nucleoside analogue reverse transcriptase inhibitors (NRTI)

fat wasting, 330 lactic acidosis, 330 mitochondria, 330 nutmeg (Myristica fragrans), 578 nylestriol, 482 O obstetric drugs, 588 octreotide gastrointestinal effects, 530 hair, 530 liver, 530 metabolism, 530 respiratory system, 530 ocular anesthesia, 150 ofloxacin, 279 olanzapine body temperature, 73 cardiovascular effects, 71 comparative studies, 70–71 diabetes mellitus, 61 gastrointestinal system, 72 hematologic effects, 72 liver, 72 metabolism, 72 nervous system, 71–72 observational studies, 70 placebo-controlled studies, 71 smoking, 73 susceptibility factors, 73 weight gain, 62 olprinone, 200 omeprazole clozapine concentration, 68 concomitant itraconazole, 303 concomitant oral contraceptives, 488–489 concomitant troleandomycin, 283–284 concomitant voriconazole, 303 duodenal scars, 403 electrolyte balance, 404 formulations, 404 gastrointestinal system, 404 immunological system, 404 respiratory system, 404 susceptibility factors, 404 omeprazole + azithromycin + amoxicillin or tinidazole, 405 omeprazole + clarithromycin + tinidazole, 405 oncology drugs, 588 ondansetron, 402 opiates, 28 opioid analgesics, 106 oprelvekin see interleukin-11 (IL-11) oral bowel preparation electrolyte balance, 407 gastrointestinal system, 407 general effects, 406 mineral balance, 407 oral contraceptives

625

Index of drugs concomitant omeprazole, 488–489 dosage regimens, 488 hematological effects, 487 immunological effects, 488 proguanil concentration, 318 reproductive system, 487–488 skin, 487 tumorigenicity, 488 oral hypoglycemic drugs, 522–523 oral rehydration therapy, 406 Org 2766, 541 orlistat concomitant ciclosporin, 455 concomitant metformin, 517 oseltamivir, 337 oxaliplatin, 547 oxazolidinones, 284 oxcarbazepine electrolyte balance, 94 liver, 94–95 nervous system, 94 nutrition, 94 skin, 95 oxicams, 128 oxycodone concomitant clonazepam, 53 death, 110–111 oxymetazoline, 569 oxytocin, 531 P Panax ginseng see ginseng paracetamol, 125 parathyroid hormone (PTH) concomitant digoxin, 198 general effects, 531 paravertebral block, 150 parenteral nutrition biliary tract, 384–385 metabolism, 383 metal metabolism, 384 nutrition, 383–384 pancreas, 385 paroxetine breast cancer, 14 fetotoxicity, 17 reproductive system, 17 parvovirus vaccine, 365 peanut oil, 590 pediatric drugs, 588 pefloxacin, 279 pegfilgrastim see granulocyte colony-stimulating factor pegvisomant gastrointestinal effects, 530 liver, 530 nervous system, 529 penicillamine fetotoxicity, 259 nervous system, 257–258 skin, 258–259 teratogenicity, 259

urinary tract, 258 penicillins, 267–268 perfluorocarbons cardiovascular effects, 370 immunologic effects, 370–371 infection risk, 371 liver, 370 perindopril, 228 pethidine 5-HT syndrome, 18 concomitant fluoxetine, 111 nervous system, 111 phenazone, 126 phenobarbital concomitant nifedipine, 220 fetotoxicity, 95 phenolic compounds, 263 phenylephrine, 569 phenylpropanolamine cardiovascular effects, 7–8 concomitant linezolid, 284 nervous system, 161–162 phenytoin concomitant diazepam, 54 concomitant fluoropyrimidines, 95 concomitant lamotrigine, 87–88 concomitant voriconazole, 303 nervous system, 95 skin, 95 phosphate, 383 phosphate enema, 406 phosphates, 596–597 phosphodiesterase type V inhibitors, 224 phototherapy, 171 phytomenadione see vitamin K pimecrolimus, 460 pioglitazone cardiovascular effects, 520–521 general effects, 520 metabolism, 521 Piper methysticum see kava piribedil, 163 pivmecillinam, 269 plasma derivatives (human), 597 pneumococcal vaccine, 360–361 polidocanol see lauromacrogols poliomyelitis vaccine see also DTP vaccines tumorigenicity, 365 polyethoxylated castor oil, 198 polygeline, 371–372 Polygonum multiflorum see witch hazel polymyxins, 285 polystyrene sulfonates, 259 polyvinylpyrrolidone endocrine effects, 263 nervous system, 262–263 skin, 263 urinary tract, 263 pomelo, 465

post-coital contraception, 489 potassium salts death, 250 neuromuscular effects, 249 pramipexole behavioral changes, 163 distortion of color vision, 163 hallucinations, 162 pramlintide, 515 pranlukast, 192 praziquantel lactation, 352 teratogenicity, 351–352 tolerance, 352 prednisolone see glucocorticoids prednisone see also glucocorticoids Achilles tendon rupture, 472 concomitant tacrolimus, 465 pregabalin, 56 pristinamycin, 285 probenecid, 334 probiotics, 580 procainamide, 210–211 prochlorperazine, 73 progesterone, 494 proguanil see atovaquone + proguanil promazine, 73–74 propafenone liver, 211 overdose, 211–212 placebo-controlled studies, 211 propofol comparative studies, 142 genotoxicity, 143 metabolism, 143 nervous system, 143 observational studies, 142 respiratory system, 142–143 propyphenazone, 125 prostaglandin E see alprostadil protease inhibitors concentration, + ritonavir, 336 concomitant glucocorticoids, systemic, 476 diabetes mellitus, 332 protirelin see thyrotropin-releasing hormone (TRH) proton pump inhibitors, 403 prulifloxacin, 279 pseudoephedrine see also ephedrine concomitant linezolid, 284 psychiatric drugs, 588 PTH see parathyroid hormone (PTH) pyrazinamide, 344 pyrazinamide + sulfadoxine, 318 pyrazolone derivatives, 125 pyridoxine see vitamin B6

626 Q quazepam concomitant itraconazole, 300 nervous system, 55 quinacrine, 320 quinidine, 212 quinine concomitant rifampicin, 344 hematologic system, 318–319 quinolone antibiotics, 303 quinupristin/dalfopristin, 285 R rabeprazole, 404 rabeprazole + amoxicillin + clarithromycin, 405 rabeprazole + amoxicillin + metronidazole, 406 rabeprazole + levofloxacin + rifabutin, 406 racecadotril, 406 raloxifene cardiovascular effects, 491 concomitant estrogens, 491 concomitant levothyroxine, 491, 505–506 reproductive system, 491 susceptibility factors, 491 ramipril pancreas, 228 skin, 229 ramoplanin, 288 rapamycin see sirolimus (rapamycin) reboxetine, 15 recombinant activated protein C, 369 recombinant factor VIIa, 375 recombinant factor VIII, 376 remifentanil, 111–112 repaglinide concentration, + gemfibrozil, 534 concomitant gemfibrozil + itraconazole, 302–303 concomitant ketoconazole, 518 concomitant rifampicin, 518 gastrointestinal system, 518 liver, 518 susceptibility factors, 518 retinol see vitamin A ribavirin concomitant interferon, 327 susceptibility factors, 327–328 ribavirin + interferon nervous system, 327 skin, 327 urinary tract, 327 rifampicin concomitant glicazide, 344 concomitant nateglinide, 344 concomitant quinine, 344 concomitant repaglinide, 518

Index of drugs concomitant tacrolimus, 304, 465 interactions, 344 quinine clearance, 319 risperidone cardiovascular effects, 76 comparative studies, 74 concomitant donepezil, 9, 78–79 concomitant SSRIs, 78 concomitant topiramate, 74 endocrine system, 60, 77 metabolism, 77–78 musculoskeletal effects, 78 nervous system, 76 observational studies, 74 placebo-controlled studies, 74–75 psychiatric effects, 77 sexual function, 78 stroke, 76–77 ritonavir concomitant digoxin, 198 indinavir concentration, 335 protease inhibitor concentration, 336 rhabdomyolysis, 336 rituximab hematological effects, 439–440 immunological effects, 440 infection risk, 440–441 nervous system, 439 rofecoxib cardiovascular effects, 131 gastrointestinal system, 131–132 hematologic effects, 131 lactic acidosis, 517 nervous system, 131 observational studies, 131 skin, 132 urinary tract, 132 ropinirole, 162 ropivacaine cardiac arrest, 152–153 concomitant lidocaine, 145 rosiglitazone, 521 rosuvastatin, 303–304 rotavirus vaccine, 365 roxithromycin, 283 RU 486 see mifepristone rubella vaccine see measles-mumps-rubella vaccine rufloxacin, 280 S salbutamol metabolism, 189 Salix species see white willow bark salmeterol, 190 saquinavir, 336–337 saridon, 125

saw palmetto (Serenoa repens), 579–580 sclerosant injections, 410 second-generation antihistamines, 179 secretin, 409 selective serotonin re-uptake inhibitors see SSRIs selegiline, 164–165 selenium concentration, + clozapine, 66 general effects, 250 Serenoa repens see saw palmetto serotonin (5-HT2 ) receptor antagonists, 14 sertraline, 17 sevoflurane cardiovascular effects, 139 gastrointestinal system, 139–140 genogenicity, 140 nervous system, 139 Siberian ginseng (Eleutherococcus senticosus), 576 sibutramine comparative studies, 8 concomitant ciclosporin, 9, 456 placebo-controlled studies, 8 skin, 8 susceptibility factors, 8 sildenafil, 580, 592 silver, 250 Silybum marianum see milk thistle simvastatin concomitant bosentan, 536 concomitant danazol, 536 concomitant fluconazole, 304 concomitant verapamil, 221 skin, 536 sirolimus (rapamycin) cardiovascular effects, 460–461 concomitant ciclosporin, 456, 461–462 fertility, 463 fluid balance, 461 infection risk, 462 interactions, 463 metabolism, 461 mouth, 462 musculoskeletal system, 462 respiratory system, 461 skin, 462 trauma, 462–463 urinary tract, 461–462 sitafloxacin, 280 smallpox vaccine, 365–366 sodium fusidate see fusidic acid somatostatin see growth hormone release-inhibiting hormone somatotropin see growth hormone sotalol discontinuation causes, 202

627

Index of drugs torsade de pointes, 218 soy, 580 sparfloxacin, 280 spinal manipulation cardiovascular effects, 582 nervous system effects, 582–583 spiramycin, 283 spironolactone concomitant digoxin, 199 skin, 235 urinary tract, 235 SSRIs (selective serotonin re-uptake inhibitors) concomitant alprazolam, 18 concomitant amfebutamone, 14 concomitant cyproheptadine, 14 concomitant Ginkgo biloba, 14 concomitant NSAIDs, 16 concomitant risperidone, 78 concomitant selegiline, 165 concomitant serotonin (5-HT2 ) receptor antagonists, 14 fetotoxicity, 17 gastrointestinal system, 16 lactation, 17–18 liver, 17 nervous system, 15–16 overdose, 15 psychiatric effects, 16 reproductive system, 17 sexual disfunction, 14 St. John’s wort (Hypericum perforatum) concomitant ciclosporin, 455–456 drug withdrawal, 577 interactions, 577–578 statins see HMG-CoA reductase inhibitors stavudine lipoatrophy, 331 nervous system, 322–333 streptokinase, 392 sulfamethoxazole, 322; see also co-trimoxazole sulfonamide antimicrobials, 234 sulfonylureas cardiovascular effects, 518 concomitant biguanides, 522 concomitant glitazones, 522 metabolism, 518 sultiame, 96 suramin, 352–353 suxamethonium concomitant cyclophosphamide, 156 dosage regimens, 156 interactions, 156 T T3/4.A see anti-CD3 antibody tacrolimus

concentration, + chloramphenicol, 276 concomitant azole antifungals, 304 concomitant chloramphenicol A, 465 concomitant pomelo, 465 concomitant prednisone, 465 concomitant rifampicin, 304, 465 concomitant statins, 465 concomitant voriconazole, 465 infection risk, 464–465 interactions, 465 nervous system, 463–464 pancreas, 464 psychological effects, 464 skin, 464 urinary tract, 464 tadalafil, 218, 592 tamoxifen concomitant levothyroxine, 505–506 hematological effects, 492 liver, 493 metabolic effects, 492 reproductive system, 493 tumorigenicity, 493 taxanes, 547 Td vaccine see diptheria-tetanus-acellular pertussis vaccine tea (Camelia sinensis), 575 tea tree oil (Melaleuca alternifolia), 578 teicoplanin, 280 telmisartan immunologic effects, 229 teratogenicity, 230 temazepam, 55 tenofovir, 333–334 terbinafine immunologic effects, 295 liver, 294 skin, 294–295 susceptibility factors, 295 teriparatide see parathyroid hormone (PTH) terlipressin, 532 testosterone, 497 tetracyclines, 270 tetrahydrozoline, 568 textile dyes, 597–598 theophylline, 2 thiazide diuretics, 226 musculoskeletal effects, 233 thiazolidinediones cardiovascular effects, 519–520 endocrine system, 520 susceptibility factors, 520 thimerosal see thiomersal 6-thioguanine, 465–466 thiomersal see also mercury autism, 363–365

safety, 356 Thorotrast, 565 thundergod vine (Tripterygium wilfordii), 580 thyroid hormones, 505 thyrotropin see thyroid stimulating hormone thyroxine see levothyroxine tibolone, 499 tiotropium bromide, 190–191 titanium, 250–251 tizanidine, 157 tobramycin administration route, 275 respiratory system, 275 sensory systems, 275 susceptibility factors, 276 tocopherols see vitamin E tolterodine, 165 topiramate body temperature, 98 concomitant risperidone, 74 general effects, 96–97 nervous system, 97 psychiatric effects, 98 psychological effects, 97–98 sensory systems, 97 susceptibility factors, 98 urinary tract, 98 tosufloxacin, 280 tramadol, 112 transdermal contraception, 489 trazodone, 19 tretinoin concomitant fluconazole, 174 hematologic effects, 173 immunologic effects, 174 interactions, 174 nervous system, 173 skin, 173–174 triamcinolone, 471 triazolam concomitant amfetamine, 6 nervous system, 55–56 overdose, 56 tribavirin see ribavirin trichloroethylene, 140 tricyclic antidepressants, 15 trimethoprim see also co-trimoxazole hematologic effects, 285–286 uric acid concentration, 322 urinary tract, 285 troleandomycin, 283–284 tropisetron, 402 trovafloxacin, 276 TSH see thyroid stimulating hormone tumor necrosis factor antagonists cardiovascular effects, 425 immunological effects, 425 infection site, 425–426 tumorigenicity, 426 turmeric (Curcuma longa), 576

628 U ultrashort-acting insulins, 512–513 urethral anesthesia, 150 urine derivatives (human), 597 V vaccines, 356 valaciclovir, 328–329 valdecoxib, 132 valproate cardiovascular effects, 99 concomitant lamotrigine, 90 concomitant pivmecillinam, 269 immunologic effects, 100 metabolism, 99 nervous system, 99 pancreas, 100 reproductive system, 100 sexual function, 100 valproic acid concomitant carbamazepine, 88 concomitant zolpidem, 57 vancomycin hematologic effects, 281 immunologic effects, 281 sensory systems, 280–281 skin, 281 venlafaxine abuse, 20 endocrine system, 20 nervous system, 20 overdose, 15 psychiatric effects, 20 respiratory system, 19–20 verapamil, 220–221 vigabatrin, 101 vinblastine, 538 concomitant erythromycin, 544 vinca alkaloids carcinogenicity, 544 cardiovascular effects, 540 ears, 542 endocrine effects, 542 gastrointestinal effects, 543

Index of drugs general effects, 540 hair, 543 hematologic effects, 543 interactions, 544 mechanism of action, 539 mutagenicity, 544 nervous system, 540–541 pharmacokinetics, 539–540 reproductive system, 543 respiratory system, 540 seizures, 542 sensory systems, 542 skin, 543 teratogenicity, 544 tolerance, 544 vincristine, 538 clearance, antiepileptic drugs, 544 concomitant asparaginase, 544 concomitant biocin, 287 concomitant itraconazole, 305, 544–545 vindesine, 539 vinorelbine, 539 virginiamycin, 288 Visine see tetrahydrozoline vitamin A, 386 vitamin B6 , 388 vitamin C, 285, 387 vitamin D (calciferol) cardiovascular effects, 388 endocrine, 388–389 skin, 389 susceptibility factors, 389 vitamin E, 285, 387 voriconazole concomitant antiretroviral drugs, 299–300 concomitant cimetidine, 302 concomitant digoxin, 198, 301 concomitant macrolides, 302 concomitant omeprazole, 303 concomitant phenytoin, 303 concomitant tacrolimus, 465 concomitant warfarin, 305 general effects, 308

liver, 309 W warfarin concomitant fibrates, 534 concomitant ginseng, 578 concomitant influenza vaccine, 362 concomitant moxifloxacin, 279 concomitant voriconazole, 305 lactic acidosis, 517 white willow bark (Salix species), 579 witch hazel (Polygonum multiflorum), 579 X xenon, 140 ximelagatran comparative studies, 394–395 hematological system, 395 liver, 395 placebo-controlled studies, 395 susceptibility factors, 395–396 Y yellow fever vaccine, 366 Z zafirlukast acute renal insufficiency, 192 liver damage, 191 zaleplon, 56 zanamivir, 337 ZD0473 zidovudine, 333 zinc, 251 Zingiber officinale see ginger ziprasidone cardiovascular effects, 79–80 nervous system, 80 overdose, 80 sexual function, 80 zolpidem, 56–57 zonisamide, 101–102

Index of adverse effects 5-HT syndrome pethidine, 18 risperidone + SSRIs, 78 venlafaxine, 20 5-HT toxicity moclobemide + SSRIs, 15 A abdominal bloating metformin, 517 abdominal cramps quinine, 318 abdominal discomfort acarbose, 515 mebendazole, 346 polyethylene glycol, 407 pranlukast, 192 rabeprazole + amoxicillin + clarithromycin, 405 sennoside calcium, 407 vitamin B6 + nitrofurantion, 388 abdominal fullness zolpidem, 56 abdominal pain antimony, 245 atovaquone + proguanil, 317 azithromycin, 282 castor oil, 407 ceftriaxone, 270 cholelitholytic agents, 410 clarithromycin, 283 clindamycin, 281, 282 co-trimoxazole, 286 dapsone, 343 diethylcarbamazine, 348 interleukin-12, 425 itraconazole, 306 levetiracetam, 91 liposomal amphotericin, 298 mangafodipir trisodium, 565 mannitol, 238 moxifloxacin, 279 nucleoside reverse transcriptase inhibitors, 330 oxamniquine, 351 praziquantel, 351 quinine, 319 sodium phosphate, 407 voriconazole, 309 abnormal liver function tests isotretinoin, 172 abnormal meibum secretion isotretinoin, 172 abnormal thoughts levetiracetam, 91

abnormal vision topiramate, 96 voriconazole, 308 abnormalities, neonatal telmisartan, 230 abscess interferon alfa, 422 interleukin-1 receptor antagonist, 424 accidental injury levetiracetam, 91 acetylation genetic variation, 342 aches, body diethylcarbamazine, 348 Achilles tendon rupture prednisone, 472 acidosis antiretroviral drugs, 330 benazapril, 227 isoniazid, 344 liposomal amphotericin, 298 MDMA, 31 metamfetamine, 30 quinine, 319 tenofovir, 333 acne anabolic steroids, 496 sirolimus, 462 tacrolimus, 463 acne vulgaris contraceptive implants, 490 acquired hemophilia interferon beta, 423 acromegalic features growth hormone, 529 acromelia cocaine, 43 activated protein C (increase) HRT, 486 acute coronary dissection cocaine, 39 acute coronary syndrome amfetamine, 4 cocaine, 39 granulocyte colony-stimulating factor, 415 metamfetamine, 29 acute generalized exanthematous pustulosis clindamycin, 281 pristinamycin, 285 spiramycin, 283 acute respiratory distress syndrome (ARDS) antithymocyte globulin, 374

lithium, 24 addiction cocaine, 41–42 adhesions levonorgestrel, 494 administration errors causes and cures, 587–590 adult respiratory distress syndrome interferon alfa, 417 adverse reactions components, xxvii dose relation, xxvii–xxviii susceptibility factors, xxxi affective disorders levetiracetam, 93 topiramate, 98 ageusia interferon alfa, 419 aggression anabolic steroids, 496 clonazepam, 53 efavirenz, 334 levetiracetam, 91, 92, 93 oxcarbazepine, 95 agitation aciclovir, 328 amfebutamone, 15 anabolic steroids, 496 cefepime, 269 cocaine, 41 famotidine, 403 gatifloxacin, 278 levetiracetam, 91, 93 naltrexone, 114 sevoflurane, 139 tacrolimus, 464 topiramate, 98 vancomycin, 281 venlafaxine, 15 agranulocytosis antithyroid drugs, 506 calcium dobesilate, 223 clozapine, 66 co-trimoxazole, 286 dapsone, 343 rituximab, 439 suramin, 353 airway dehiscence sirolimus, 461 airway responsiveness, increased mannitol, 240 akathisia droperidol, 69 haloperidol, 60

629

630 olanzapine, 70 risperidone, 75 akinesia parenteral nutrition, 384 akinetic mutism muromonab-CD3, 438 allergic contact dermatitis minoxidil, 170 allergic granulomatous vasculitis fluticasone, 186 allergic rash buprenorphine, 112 allergic reaction amiodarone, 205 coagulation factors, 375 diphtheria-tetanus-acellular pertussis vaccine, 360 erythropoietin and derivatives, 377 etherified starches, 371 folinic acid, 387 gentamicin, 275 influenza vaccine, 362 intravenous immunoglobulins, 373 iron, 247 nickel, 249 oral contraceptives, 481 polyvinylpyrrolidone, 263 sclerosant injections, 410 tiotropium bromide, 191 allergic reaction, type I furosemide, 234 allergic sensitization heroin, 45 allergy drug administration, 588–589 infliximab, 429 lepirudin, 394 allodynia morphine, 110 allograft interstitial fibrosis ciclosporin, 454 allograft nephropathy ciclosporin, 454 alopecia 6-thioguanine, 465 acitretin, 171 interferon alfa, 418, 421 interferon beta, 422 isotretinoin, 172 Lyme disease vaccine, 358 octreotide, 530 vinca alkaloids, 543 altered conciousness chloroquine, 316 altered metabolism of thyroid hormones polyvinylpyrrolidone, 263 alveolar hemorrhage liposomal amphotericin (L-AmB), 298 alveolar infiltrates

Index of adverse effects gold, 246 alveolar rupture cocaine, 40 alveolar ventilation naloxone, 113 amenorrhea antiepileptic drugs, 88 copper IUCD, 246 cytotoxic drugs, 545 interferon alfa, 420 risperidone + topiramate, 74 tacrolimus, 464 amnesia levetiracetam, 91 MDMA, 32 midazolam, 54 polyvinylpyrrolidone, 263 triazolam, 56 anaphylactic reaction antithymocyte globulin, 373 ceftriaxone, 267 cephalosporins, 267 chlorhexidine, 259 ciprofloxacin, 277 coagulation factors, 376 etherified starches, 371 intravenous immunoglobulins, 373 muromonab-CD3, 437 sulfamethoxazole + celecoxib, 322 tosufloxacin, 280 anaphylactic shock basiliximab, 436 omeprazole, 404 anaphylactic transfusion reaction blood transfusion, 370 anaphylactoid reaction etherified starches, 371 folinic acid, 387 oxytocin, 531 polygeline, 371 anaphylactoid shock iron, 247 anaphylaxis fluoroquinolones, 276 gentamicin, 275 glucocorticoids, systemic, 474 iodinated water-soluble contrast media, 553 isoniazid, 343–344 Japanese encephalitis vaccine, 363 lepirudin, 394 Melaleuca alternifolia, 578 polyvinylpyrrolidone, 263 rofecoxib, 131 Salix species, 579 anaplastic CD-30+ cutaneous T cell lymphoma ciclosporin, 455 ANCA see antineutrophil cytoplasmic antibodies (ANCA)

anemia 6-thioguanine, 465 ammonium chelators, 254 androgen deprivation treatment, 498–499 chloroquine, 316 co-trimoxazole, 286, 322 dapsone, 343 glucagon, 514 gonadotropin-releasing hormone, 528 hydroxyurea, 170 interferon alfa, 421 interleukin-12, 425 intravenous immunoglobulins, 373 linezolid, 284 manganese, 248 mycophenolate mofetil, 458 quinine, 319 suramin, 353 tamoxifen, 492 vinca alkaloids, 543 zidovudine, 333 anger interferon alfa, 419 levetiracetam, 93 topiramate, 98 angina see also cardiac ischemia fluorouracil, 546 ketamine, 139, 141 metamfetamine, 29 vinca alkaloids, 540 angioedema budesonide, 186 estrogens, 481 interferon alfa, 421 itraconazole, 308 Japanese encephalitis vaccine, 363 oral contraceptives, 488 ramipril, 229 rofecoxib, 131 telmisartan, 229 vancomycin, 281 angioedema, facial furosemide, 234 angiosarcoma thorotrast, 565 angle-closure glaucoma insulin, 509 topiramate, 97 angular cheilitis glucagon, 514 nickel, 249 annular actinic granulomata doxycycline, 271 annular crystalline keratopathy intravenous immunoglobulins, 372 anorexia atovaquone + proguanil, 317 benazapril, 227

631

Index of adverse effects co-trimoxazole, 286 droperidol, 69 famotidine, 403 felbamate, 87 levetiracetam, 91 mercury, 249 metformin, 517 spironolactone, 235 topiramate, 97 vinca alkaloids, 542 vitamin D (calciferol), 388 anorexia nervosa-like symptoms tacrolimus, 464 anorgasmia gabapentin, 89 anosmia amikacin, 274 anterior ischemic optic neuropathy interferon alfa, 418 anterior uveitis etanercept, 427 anti-alefacept antibodies alefacept, 168 anti-entanercept antibodies etanercept, 427 anticonvulsant hypersensitivity syndrome valproate, 100 antigenicity perfluorocarbons, 370–371 antineutrophil cytoplasmic antibodies (ANCA) cocaine, 3 antinuclear antibodies infliximab, 431 antiphospholipid antibody syndrome procainamide, 210–211 antisocial reactions levetiracetam, 91 anuria anti-CD3 antibody, 435 ceftriaxone, 270 enalapril, 228 mannitol, 240 metamfetamine, 30 anxiety alprazolam, 52 anabolic steroids, 496 azithromycin, 282 clindamycin, 281 contraceptive implants, 490 droperidol, 69 interferon alfa, 419 levetiracetam, 91, 93 MDMA, 31 reboxetine, 15 topiramate, 98 venlafaxine, 20 aortic inflammation cocaine, 40 aortic regurgitation

Aristolochia fangchi, 6–7 aortic thrombus cocaine, 39–40 apathy levetiracetam, 91 aphagia intrathecal (spinal) anesthesia, 148 aphasia heroin, 46 ivermectin, 349 rituximab, 440 aphonia intrathecal (spinal) anesthesia, 148 aphthous ulcers interferon alfa, 421 sirolimus, 462 aplasia cutis congenita antithyroid drugs, 506 aplastic anemia chloramphenicol, 276 etanercept, 427 apnea clonidine, 230 ocular anesthesia, 150 propofol, 142 apoptosis of neutrophils clozapine, 66–67 appetite increase alprazolam, 52 risperidone, 75 appetite loss buspirone, 52 interferon alfa, 419 methylphenidate, 6 naftidrofuryl, 223 application site discomfort pimecrolimus, 460 aqueous humor protein concentration, increased mannitol, 240 arachnoiditis intrathecal (spinal) anesthesia, 148 ARDS see acute respiratory distress syndrome argyria silver, 250 arousal, reduced antidepressant drugs, 14 arterial thrombosis COX-2 inhibitors, 129 arteriosclerosis cocaine, 39 arteriosclerotic plaque formation Glycyrrhiza species, 577 arthralgia 6-thioguanine, 465 antimony, 245 ciprofloxacin, 277 erythropoietin and derivatives, 377

gliclazide, 519 intravenous immunoglobulins, 372 minocycline, 272 quinupristin/dalfopristin, 285 arthritis efalizumab, 437 gliclazide, 519 Lyme disease vaccine, 358 arthropathy contraceptive implants, 490 ascites gonadotropins, 480 insulin, 510 interleukin-12, 425 aseptic meningitis intravenous immunoglobulins, 372 metronidazole, 323 muromonab-CD3, 438 rofecoxib, 131 sulfamethoxazole, 322 trimethoprim, 322 aseptic meningoencephalitis co-trimoxazole, 322 aseptic peritonitis insulin, 510 aspergillosis alemtuzumab, 434 tumor necrosis factor antagonists, 426 asphyxia barium, 554 triazolam, 56 aspirated mucus clonazepam + oxycodone, 53 aspiration pneumonia heroin, 46 asterixis aciclovir, 328 metformin, 516 asthma aspirin, 123 inhaled glucocorticoids, 186 asymmetry of facial expression botulinum toxin A, 168 asystole olanzapine, 71 ataxia clobazam, 53 diazepam + phenytoin, 54 gabapentin, 90 heroin, 46 iomeprol, 554 lamotrigine, 90 levetiracetam, 91, 92 lithium, 24 metronidazole, 323 rituximab, 440 valproate + lamotrigine, 90 venlafaxine, 20 ataxic gait MDMA, 31 atherosclerosis glucocorticoids, systemic, 471

632 athletic effects growth hormone, 528 atopic dermatitis etanercept, 428 atopic dermatitis-like eruption infliximab, 430 atrial fibrillation cardiac glycosides, 196 MDMA, 32 penicillamine, 258 tiotropium bromide, 191 verapamil, 220–221 atrium, heart see entries at heart atrophic gastritis interferon alfa, 421 atrophy mesalazine, 408 attention deficit metamfetamine, 5, 30 atypical central visual processing changes lorazepam, 54 auditory acuity, reduced interferon alfa, 418 auditory disturbance see entries at hearing auditory hallucinations cefepime, 269 glucocorticoids, systemic, 472 mefloquine, 316 autism measles-mumps-rubella (MMR) vaccine, 363–365 mercury, 248–249 thiomersal, 363–365 autoimmune arthritis Lyme disease vaccine, 358 autoimmune hemolytic anemia infliximab, 431 levofloxacin, 278 rituximab, 439 autoimmune hepatitis pegvisomant, 530 autoimmune thyroid disease gonadotrophin-releasing hormone, 528 autonomic function aluminium, 244 axonal injury heroin, 46 axonal polyneuropathy vitamin D (calciferol), 388 azoospermia anabolic steroids, 496 B B cell lymphopenia mycophenolate mofetil, 459 sirolimus, 463 babesiosis blood transfusion, 370 back pain gliclazide, 519

Index of adverse effects levetiracetam, 91 mangafodipir trisodium, 565 quinine, 319 back spasms iron, 247 backache intravenous immunoglobulins, 372 bacterial infections tumor necrosis factor antagonists, 425 ballismus amfebutamone, 19 behavioral changes levetiracetam, 93 pramipexole, 163 behavioral problems levetiracetam, 92 zonisamide, 101 Bell’s palsy interferon alfa, 418 benign intracranial hypertension doxycycline, 270 mesalazine, 408 minocycline, 271 bezoars polystyrene sulfonates, 259 bilirubin concentration itraconazole, 306 liposomal amphotericin (L-AmB), 297 parenteral nutrition, 385 binding antibodies glatiramer acetate, 457 binocular depth perception cannabinoids, 37 binuria ribavirin + interferon, 327 birth, premature antimony, 245 birth weight, reduced atenolol, 217 bitter taste azelastine, 177 rabeprazole + amoxicillin + clarithromycin, 405 secnidazole, 346 bladder cancer HRT, 486 bladder irritation suramin, 353 bladder spasm suramin, 353 bleeding abciximab, 396 acupuncture, 581 aspirin, 124 clindamycin, 281 enoxaparin, 393 estrogens, 481 fondaparinux, 392 Ginkgo biloba, 576–577 lepirudin, 394

nizatidine, 403 recombinant activated protein C, 369 ximelagatran, 394, 395 blepharoconjunctivitis isotretinoin, 172 blisters penicillamine, 258 terbinafine, 295 vinca alkaloids, 543 blood transmission of vCJD blood transfusion, 370 blue-grey pigmentation minocycline, 271 blurred vision amiodarone, 205 interferon alfa, 418 melatonin, 531 minocycline, 271 quinine, 318 risperidone, 75 body mass index, rise in cytotoxic drugs, 545 body sway zolpidem, 56 bone abnormalities vitamin A, 386 bone loss HRT, 486 bone marrow aplasia interferon alfa, 420–421 bone marrow depression chloramphenicol, 276 bone marrow suppression zinc, 251 bone marrow toxicity mycophenolate mofetil, 458 bone mineral density thyroxine, 505 bone mineralization inhaled glucocorticoids, 185 bone pain granulocyte colony-stimulating factor, 415–416 bone resorption vitamin A, 386 bone turnover rate risperidone, 78 bony abnormalities lisinopril, 228 bowel perforation copper IUCD, 246 bradycardia adrenaline, 161 amiodarone, 205, 206 amphotericin B deoxycholate (DAMB), 295 calcium channel blockers, 219 mannitol, 238 nifedipine, 220 phenytoin, 96 potassium salts, 250 propofol, 142, 143 verapamil, 221

633

Index of adverse effects bradydysrhythmia donepezil, 8 bradykinesia heroin, 46 manganese, 248 olanzapine, 70 brain atrophy valproate, 99 brain injury heroin, 46–47 brain stem stroke olanzapine, 71 branch artery occlusion inhibitors of phosphodiesterase type V, 224 breast cancer antidepressant drugs, 14 calcium channel blockers, 219 ethylene oxide, 262 gonadotropins, 481 HRT, 484–485 oral contraceptives, 488 breast enlargement SSRIs, 17 breathing, difficulty in leucovorin, 387 bronchiolitis obliterans organizing pneumonia benzalkonium compounds, 261 liposomal amphotericin, 298 bronchitis gliclazide, 519 infliximab, 428 bronchospasm etherified starches, 371 heroin, 45 Japanese encephalitis vaccine, 363 mivacurium, 155 propofol, 143 tobramycin, 275 vinca alkaloids, 540 Brugada syndrome ajmaline, 204–205 epidural anesthesia, 147 bruising botulinum toxin A, 168 penicillamine, 258 bullous lichenoid eruptions simvastatin, 536 bullous pemphigoid penicillamine, 258 burning acitretin, 171 adapalene, 172 beta-blockers (ocular), 570 tacrolimus, 463, 464 tretinoin, 174 vancomycin, 281 vitamin B6 + nitrofurantion, 388 burns cytotoxic drugs, 545

C C-reactive protein HRT, 486 cancer beta-carotene, 387 ethylene oxide, 262 growth hormone, 529 poliomyelitis vaccine, 365 candidiasis clindamycin, 282 famotidine, 403 glucocorticoids, systemic, 475 infliximab, 432 tiotropium bromide, 191 capillary leak granulocyte colony-stimulating factor, 416 carcinogenicity coagulation factor gene therapy, 377 trichloroethylene, 140 carcinoma antithymocyte globulin, 375 calcium channel blockers, 219 coagulation factors, 376 thorotrast, 565 cardiac see also entries at coronary; heart cardiac arrest see also myocardial infarction amfebutamone, 15 amfetamine, 29 digoxin, 197 lidocaine + ropivacaine, 145 nifedipine, 220 potassium salts, 250 ropivacaine, 152–153 cardiac death clozapine, 67 cardiac dysrhythmia amfebutamone, 15 metamfetamine, 4 methadone, 109 phenytoin, 96 venlafaxine, 15 cardiac failure, exacerbation of pioglitazone, 521 thiazolidinediones, 520 cardiac output, reduced mannitol, 240 cardiac syncope donepezil, 8 cardiogenic shock verapamil, 220–221 cardiomyopathy amphotericin B deoxycholate, 295 cardiopulmonary arrest potassium salts, 250 cardiorespiratory arrest tramadol, 112 cardiovascular collapse bupivacaine, 151

iron, 247 cardiovascular complications infliximab, 429 tetrahydrozoline, 569 cardiovascular defects co-trimoxazole, 287 cardiovascular malformations diazepam, 53 carnitine depletion cephalosporins, 269 pivalic acid, 269 valproate, 269 cartilage toxicity ciprofloxicin, 277 cataract fluorouracil, 546 inhaled glucocorticoids, 184 catheter associated masses intrathecal (spinal) anesthesia, 148 catheter misplacement paravertebral block, 150 CD4 cell count mycophenolate mofetil, 459 cell proliferation, inhibited gentamicin, 275 cellular rejection terbinafine, 294 cellulitis infliximab, 428 central nervous system depression naphazoline, 569 central serous chorioretinopathy oxymetazoline, 569 centrilobular cholestasis terbinafine, 294 centrilobular hepatocyte necrosis enalapril, 227 cephalalgia zolpidem, 56 cerebellar ataxia levamisole, 350 cerebellar atrophy phenytoin, 95 cerebellar toxicity metronidazole, 323 cerebral blood flow, impaired MDMA, 32 cerebral dysfunction mefloquine, 316 cerebral toxoplasmosis etanercept, 428 cerebrovascular events anastrozole, 490 risperidone, 75 cervical subcutaneous emphysema cocaine, 40 changes in pigmentation diphenylcyclopropenone, 169 cheerfulness

634 cyclopentolate, 568 cheilitis acitretin, 171 chemical cystitis gentian violet, 262 chest infection growth hormone, 529 chest pain anti-CD40 antibody, 435 cannabinoids, 36 cocaine, 2–3, 38, 39, 42 deferoxamine, 257 dirithromycin, 283 gold, 246 isoniazid, 343 liposomal amphotericin, 298 metamfetamine, 4 polygeline, 372 vancomycin, 281 venlafaxine, 20 vinca alkaloids, 540 vitamin D (calciferol), 388 chills alefacept, 168 anti-CD3 antibody, 435 anti-CD40 antibody, 435 bevacizumab, 436 efalizumab, 437 intravenous immunoglobulins, 372 ivermectin, 349 Japanese encephalitis vaccine, 363 quinine, 319 rituximab, 439 sertraline, 17 vancomycin, 281 Chinese herb nephropathy aristolochic acid, 6–7 choanal atresia antithyroid drugs, 506 cholangiocarcinoma thorotrast, 565 cholangitis quinacrine, 320 cholelithiasis indinavir, 335 cholestasis co-trimoxazole, 286 cholestatic hepatitis enalapril, 227 propafenone, 211 terbinafine, 294 cholestatic jaundice prochlorperazine, 73 cholestatic liver disease parenteral nutrition, 384 cholesterol concentration Commiphora mukul, 576 chorea lamotrigine, 90 choreoathetosis lithium, 24 choroidal detachment

Index of adverse effects dorzolamide, 233 choroidal thickening interferon alfa, 419 chronic allograft nephropathy ciclosporin, 454 chronic atrophic gastritis interferon alfa, 421 chronic fatigue aluminium, 244 Churg-Strauss syndrome montelukast, 191 pranlukast, 192 cirrhosis amiodarone, 208 diethylstilbestrol, 482 clumsiness heroin, 46 coagulapathy quinine, 319 coagulation quinine, 318 coccidioidomycosis infliximab, 432 cognition, disturbed aciclovir, 328 cognitive adverse effects topiramate, 97 cognitive impairment antiepileptic drugs, 86 atorvastatin, 535 cannabinoids, 37 MDMA, 33 metamfetamine, 30 risperidone + topiramate, 74 cold feet ergot alkaloids, 224 colicky abdominal pain ceftriaxone, 270 colitis alosetron, 402 NSAIDs, 120 collagenous colitis celecoxib, 130 collapse suramin, 353 collapsed lung clonazepam + oxycodone, 53 collateral reactions characteristics, xxix, xxvii–xxviii color vision disturbance pramipexole, 163 voriconazole, 308 colorectal cancer growth hormone, 529 coma aciclovir, 328 ergot alkaloids, 224 gabapentin, 89 isoniazid, 344 MDMA, 32 phenytoin, 96 polyvinylpyrrolidone, 263 compartment syndrome

contrast media, 560 complex-partial seizures MDMA, 34 complex visual hallucinations zonisamide, 101 complicated sepsis etanercept, 428 concentration, impaired efavirenz, 334 zolpidem, 56 conciousness, altered cefepime, 269 chloroquine, 316 conduction disturbances bupivacaine, 151 confusion aciclovir, 328 cefepime, 269 COX-2 inhibitors, 129 droperidol, 69 gatifloxacin, 278 infliximab, 428 ivermectin, 349 levetiracetam, 91 melatonin, 531 metronidazole, 323 morphine, 109 parenteral nutrition, 384 quinine, 319 topiramate, 97 congenital abnormalities diazepam, 53 congenital defects cocaine, 43 congenital malformations azathioprine, 451 mercaptopurine, 451 congestive heart failure anthracyclines, 545 infliximab, 428 tumor necrosis factor antagonists, 425 vitamin D (calciferol), 388 conjunctivitis voriconazole, 308 connective tissues disorders penicillamine, 259 constipation alosetron, 402 calcium salts, 245 erythropoietin and derivatives, 378 levetiracetam, 91 olanzapine, 70 opioid analgesics, 106 risperidone, 74 sibutramine, 8 tiotropium bromide, 191 vinca alkaloids, 543 contact dermatitis acetylcysteine, 570 neomycin, 275 polyvinylpyrrolidone, 263 Serenoa repens, 579–580

635

Index of adverse effects vitamin D (calciferol), 389 convulsions cephalosporins, 268 Japanese encephalitis vaccine, 363 levetiracetam, 93 Lyme disease vaccine, 358 metronidazole, 323 theophylline, 2 coprolalia methadone, 48 corneal melting ketorolac, 570 corneal opacities isotretinoin, 172 corneal precipitate ciprofloxicin, 277 coronary see also entries at cardi-; heart coronary artery disease carbamazepine, 88–89 penicillamine, 258 coronary artery spasm amfetamine, 28–29 coronary dissection cocaine, 39 coronary microvascular resistance cocaine, 39 coronary restenosis sirolimus, 461 coronary syndrome cocaine, 39 metamfetamine, 29 coronary vasoconstriction cocaine, 38 corrosion gallium, 246 cotton wool spots doxycycline, 270 cough artemether + lumefantrine, 321 atovaquone + proguanil, 317 benzalkonium compounds, 261 bepridil, 219 cocaine, 40 nitrofurantoin, 284 omeprazole, 404 parenteral nutrition, 385 phenolic compounds, 263 venlafaxine, 20 vinca alkaloids, 540 zanamivir, 337 cough, dry gold, 246 coughing fentanyl, 108 crackles parenteral nutrition, 385 thiazolidinediones, 519 vinca alkaloids, 540 cramps copper IUCD, 246 mannitol, 238

crampy abdominal pain deferoxamine, 257 creatine kinase activity, raised MDMA, 31 creatinine concentration liposomal amphotericin, 297 critical site bleeding ximelagatran, 395 Crohn’s disease, exacerbation interleukin-1 receptor antagonist, 424 crusting cocaine, 40 crying, persistent meningococcal vaccine, 360 crypt cell apoptosis mycophenolate mofetil, 459 cryptoccocal meningitis glucocorticoids, systemic, 475 crystalline keratopathy intravenous immunoglobulins, 372 crystalluria indinavir, 336 sultiame, 96 Cushing’s syndrome budenoside + itraconazole, 301 glucocorticoids, 169 glucocorticoids, systemic + itraconazole, 476 itraconazole, 476 protease inhibitors, 476 protease inhibitors + glucocorticoids, systemic, 476 cutaneous elastosis penicillamine, 257 cutaneous eruptions imatinib, 547 cutaneous lupus erythematosus nifedipine, 220 nitrendipine, 220 terbinafine, 295 cutaneous necrotizing vasculitis chloroquine, 316 cutaneous reaction ivermectin, 349 cutaneous vasculitis rofecoxib, 132 cutis laxa penicillamine, 259 cyanosis chloroquine, 316 cystitis gentian violet, 262 cytolytic hepatis quinacrine, 320 cytomegalovirus infection antithymocyte globulin, 373, 374 cytopenia alemtuzumab, 434 gentamicin, 275

D darkening of the iris latanoprost, 477 De Clérambault’s syndrome venlafaxine, 20 death abacavir, 332 anti-CD40 antibody, 435 antimony, 244–245 antithymocyte globulin, 374 aspirin, 124 blood transfusion, 369 clonazepam + oxycodone, 53 clozapine, 67 cocaine, 41 dapsone, 343 desmopressin, 531 droperidol, 69 gold, 246 heroin, 45 interferon alfa, 417 ipratropium bromide, 190 Japanese encephalitis vaccine, 363 lepirudin, 394 MDMA + moclobemide, 36 methadone, 48 morphine + metamfetamine, 110 nifedipine, 220 nizatidine, 403 penicillamine, 257–258 perfluorocarbons, 370 risperidone, 74 suramin, 353 telmisartan, 230 tenofovir, 333 triazolam, 56 verapamil, 221 voriconazole + antiretroviral drugs, 299–300 ximelagatran, 395 decomposition of liver function cholelitholytic agents, 410 deep vein thrombosis intravenous immunoglobulins, 372 dehydration infliximab, 430 insulin, 510 ivermectin, 349 parenteral nutrition, 383 delayed psychotic syndrome levetiracetam, 92 delirium amfebutamone, 15 azithromycin, 282 co-trimoxazole, 286 cocaine, 41 gatifloxacin, 278 glucocorticoids, systemic, 471 itraconazole, 307 ketamine, 141 metronidazole, 323

636 sevoflurane, 139 delusional symptoms interferon beta, 422 delusions levetiracetam, 91 mefloquine, 316 delusions of grandiosity glucocorticoids, systemic, 472 delusions of love venlafaxine, 20 dementia ibuprofen, 127 sodium phosphate, 407 demyelination infliximab, 428 interferon alfa, 418 depersonalization levetiracetam, 91 minocycline, 271 depigmentation chloroquine, 316 depression anabolic steroids, 496 contraceptive implants, 490 efavirenz, 334 gatifloxacin, 278 histamine hydrochloride, 424 interferon alfa, 419 interferon beta, 422 isotretinoin, 172 levetiracetam, 91, 93 MDMA, 33 risperidone, 74 tacrolimus, 464 depression of hemopoiesis flucytosine, 311 dermatitis see also contact dermatitis; eczematous dermatitis; exfoliative dermatitis beta-blockers (ocular), 570 betadine, 250 dapsone, 343 diphenylcyclopropenone, 169 neomycin, 275 sirolimus, 462 suramin, 353 dermatosis epoetin, 378 dermopathy penicillamine, 258 desire, reduced antidepressant drugs, 14 deviation of downward gaze tacrolimus, 464 diabetes hypertension control, 226–227 indinavir, 331 diabetes insipidus tenofovir, 333 diabetes mellitus antipsychotic drugs, 60–64 carvedilol, 218 olanzapine, 61–62

Index of adverse effects protease inhibitors, 332 stavudine, 331–332 diabetes mellitus, type 1 interferon alfa, 420 diabetic ketoacidosis antipsychotic drugs, 63 insulin, 511 diagnostic routines, interference with gadolinium salts, 563 diarrhea 6-thioguanine, 465 acarbose, 515 amiodarone, 205 anti-CD3 antibody, 435 antithymocyte globulin, 373 atovaquone + proguanil, 317 azathioprine, 450 cholelitholytic agents, 410 clarithromycin, 283 clindamycin, 281, 282 co-trimoxazole, 286 ergot alkaloids, 224 esomeprazole + clarithromycin + metronidazole, 405 fluorouracil, 546 fusidic acid, 280 ICL670, 257 indinavir, 335 intravenous immunoglobulins, 372 itraconazole, 306 ivermectin, 349 ketolides, 281 levetiracetam, 91 levofloxacin, 278 lithium, 25 mannitol, 239 metformin, 517 moxifloxacin, 279 mycophenolate mofetil, 458–459 naltrexone, 114 pegvisomant, 530 pranlukast, 192 pristinamycin, 285 quinine, 319 repaglinide, 518 risperidone, 74 suramin, 353 valaciclovir, 329 venlafaxine, 20 diarrhea, chronic cyclo 3 fort, 223 diffuse abdominal cramp quinine, 318 diffuse destructive lesions cocaine, 41 diffuse erythema co-trimoxazole, 286 diffuse retinal pigment epitheliopathy oxymetazoline, 569 diffuse spinal myoclonus

interferon alfa, 417 digital ulcerations interferon alfa, 417 dilated cardiomyopathy amphotericin B deoxycholate (DAMB), 295 dilated pupils pethidine, 111 diplopia cocaine, 41 diazepam + phenytoin, 53 levetiracetam, 91 oxcarbazepine, 94 rituximab, 440 topiramate, 96 vinca alkaloids, 542 dipyridamole imaging beta-blockers, 397 glibenclamide, 397 disc swelling doxycycline, 271 discoloration of the skin, blue-grey amiodarone, 208 silver, 250 discomfort botulinum toxin A, 168 dislocation cisapride, 401 disorientation naltrexone, 114 disseminated encephalomyelitis Japanese encephalitis vaccine, 363 disseminated intravascular coagulation quinine, 318 disseminated lobular capillary hemangioma granulocyte colony-stimulating factor, 415 disseminated vasculitis levamisole, 350 disseminating papulovesicles heparins, 392 distal embolization abciximab, 396 distortion of color vision pramipexole, 163 voriconazole, 308 disturbed dreaming ketamine, 141 dizziness acupuncture, 581 alprazolam, 52 antiepileptic drugs, 86 atovaquone + proguanil, 317 benzimidazoles, 346 cannabinoids, 37 contraceptive implants, 490 cyclopentolate, 568 daptomycin, 287 diethylcarbamazine, 348 efavirenz, 334

637

Index of adverse effects ergot alkaloids, 224 gabapentin, 90 garenoxacin, 277 gatifloxacin, 278 histamine hydrochloride, 424 intravenous immunoglobulins, 372 iron, 247 ketolides, 281 levetiracetam, 91, 93 melatonin, 531 metronidazole, 323 moxidectin, 351 olanzapine, 70 oxamniquine, 351 oxcarbazepine, 94 pioglitazone, 520 praziquantel, 351 pregabalin, 56 risperidone + topiramate, 74 topiramate, 97 tramadol, 112 vancomycin, 281 vinca alkaloids, 542 dopamine transporters metamfetamine, 29 dosing adverse drug reactions, xxvii–xxviii DoTS classification described, xxvii uses, xxxii–xxiii double aortic arch anomaly cocaine, 43 dream disturbance ketamine, 141 dreams, abnormal efavirenz, 334 DRESS see drug rash with eosinophilia and systemic symptoms drowsiness alprazolam, 52 baclofen, 157 cyclopentolate, 565 melatonin, 531 morphine, 110 olanzapine, 70 oxamniquine, 351 praziquantel, 351 tramadol, 112 drug extravasation vinca alkaloids, 543 drug hypersensitivity syndrome co-trimoxazole, 286 drug rash with eosinophilia and systemic symptoms (DRESS) spironolactone, 235 dry cough gold, 246 parenteral nutrition, 385 dry eyes glucagon-like peptide-1, 514 isotretinoin, 172

dry mouth alprazolam, 52 anticholinergic drugs, 166 olanzapine, 70 risperidone, 75 sibutramine, 8 dry skin indinavir, 335, 336 dryness adapalene, 172 ductopenia enalapril, 227 ductopenic hepatitis candesartan, 229 duodenal scars omeprazole, 403 dysarthria aciclovir, 328 heroin, 46 ivermectin, 349 lithium, 24 metronidazole, 323 parenteral nutrition, 384 penicillamine, 257 tacrolimus, 464 dysesthesia 6-thioguanine, 465 dental anesthesia, 148 insulin, 509 mesalazine, 408 dysgraphia parenteral nutrition, 384 dyshidrotic dermatitis infliximab, 431 dyskinesia cisapride, 401 olanzapine, 70 phenytoin, 95 risperidone, 74 dyslipidemia sirolimus, 461 dysmetria metronidazole, 323 dyspepsia antimony, 245 atovaquone + proguanil, 317 fosfomycin, 287 levetiracetam, 91 metformin, 517 dysphagia celecoxib, 130 ciclosporin, 453 cocaine, 41 infliximab, 432 metronidazole, 323 dysphonia MDMA, 31 perindopril, 228 dyspnea alemtuzumab, 435 anti-CD3 antibody, 435 antimony, 245 benzalkonium compounds, 261 cocaine, 38

furosemide, 234 gold, 246 infliximab, 432 intravenous immunoglobulins, 372 iron, 247 liposomal amphotericin (L-AmB), 298 nitrofurantoin, 284 phenolic compounds, 263 vancomycin, 281 venlafaxine, 20 vinca alkaloids, 540 dysrhythmia adrenaline, 160 droperidol, 69 methadone, 47 quinine, 319 roxithromycin, 283 voriconazole, 309 dystonia cisapride, 401 cyclizine, 178 olanzapine, 70, 71 risperidone, 74, 75 dysuria risperidone, 78 E ear infection infliximab, 428 ecchymotic rash quinine, 319 ectopic pregnancy levonorgestrel, 489 eczema 6-thioguanine, 465 ribavirin + interferon, 327 eczema-like toxiderma infliximab, 430 eczematous purpura of Doucas and Kapetenakis infliximab, 430 eczematous reactions interferon alfa, 421 edema ciclosporin, 452 cocaine, 41 etherified starches, 371 gentian violet, 262 granulocyte colony-stimulating factor (G-CSF), 415 influenza vaccine, 361 insulin, 510 insulin + thiazolidinediones, 512 metamfetamine + morphine, 28 minocycline, 272 olanzapine, 70, 71, 72 rosiglitazone, 521 spironolactone, 235 testosterone, 495 thiazolidinediones, 520 edema, facial

638 antiepileptic drugs, 87 edema, pulmonary heroin, 47 efalizumab antibodies efalizumab, 437 effusions etanercept, 428 parenteral nutrition, 383 ejaculation dysfunction finasteride, 499 risperidone, 75, 78 ejaculatory inhibition antidepressant drugs, 14 electrocardiographic changes see also QT interval prolongation isotretinoin, 172 lithium, 24 electrolyte abnormalities liposomal amphotericin, 297 emesis see vomiting emotional instability levetiracetam, 91 emotional lability glucocorticoids, systemic, 471 levetiracetam, 91, 93 emphysema cocaine, 40 empyema-like eosinophilic pleural effusion cocaine, 40 encephalitis Japanese encephalitis vaccine, 363 parenteral nutrition, 384 yellow fever vaccine, 366 encephalomyelitis Japanese encephalitis vaccine, 363 encephalopathy ceftriaxone, 269 ciclosporin, 455 erythropoietin and derivatives, 377 glyceryl trinitrate, 218 Japanese encephalitis vaccine, 363 metamfetamine, 29 metformin, 516 metronidazole, 323 penicillamine, 258 encephalopathy-like syndrome isoniazid, 344 end-stage renal failure anti-CD40 antibody, 435 endometrial cancer anastrozole, 490 antipsychotic drugs, 64 HRT, 486 endometrial hyperplasia HRT, 484 endothelial dysfunction cocaine, 39

Index of adverse effects engraftment syndrome granulocyte colony-stimulating factor (G-CSF), 416 enlarged deep cervical lymph nodes metamfetamine + morphine, 28 enteritis moxidectin, 351 enterocolitis carbamazepine, 89 enterocyte atypia mycophenolate mofetil, 459 enteroviral meningoencephalitis rituximab, 440 enuresis norclozapine, 67 enzyme increases perfluorocarbons, 370 eosinophilia clarithromycin, 282 fluconazole, 305 iodinated water-soluble contrast media, 555 moxidectin, 351 nevirapine, 334 spironolactone, 235 terbinafine, 294 eosinophilic empyema cocaine, 40 eosinophilic pneumonia diclofenac, 126 meloxicam, 128 epigastric discomfort iron, 247 epileptic seizure pethidine, 111 epiretinal membrane interferon alfa, 418 epistaxis bevacizumab, 436 coumarin, 391 manganese, 248 Epstein-Barr virus infection antithymocyte globulin, 373 erectile dysfunction antidepressant drugs, 14 beta-blockers, 217 finasteride, 498 risperidone, 75 erosive enterocolitis mycophenolate mofetil, 458 erosive stomatitis sibutramine, 8 erotomania venlafaxine, 20 erythema adapalene, 172 adjuvants, 357 buprenorphine, 112 ciclosporin, 452 deferoxamine, 256 diphenylcyclopropenone, 169 erythropoietin and derivatives, 377

glatiramer acetate, 457 minocycline, 272 tacrolimus, 464 tretinoin, 174 vinca alkaloids, 543 erythema elevatum diutinum epoetin, 378 erythema multiforme acarbose, 515 co-trimoxazole, 286 phenazone, 126 pyrazolone derivatives, 125 terbinafine, 294 erythema multiforme-like bullous lesions sibutramine, 8 erythema multiforme-like eruption adalimumab, 426 erythema nodosum 6-thioguanine, 465 erythematous maculopapular eruptions aciclovir, 328 ribavirin + interferon, 327 erythematous plaques heparins, 392 erythematous rash vancomycin, 281 erythematous generalized rash fluconazole, 305 erythrocytosis cocaine, 42 testosterone, 495 erythrocyturia indinavir, 336 erythroderma spironolactone, 235 erythrodermic mycosis fungoides phenytoin, 88 erythromelagia ciclosporin, 452 erythropoiesis, inhibition of angiotensin II receptor antagonists, 229 Escherichia coli overgrowth mannitol, 239 esophageal candidiasis fluticasone, 186 esophageal disorders clindamycin, 281 esophageal dysmotility ciclosporin, 453 esophagitis celecoxib, 130 esotropia heroin, 47 estrogens concentration Hypericum perforatum, 577 euphoria glucocorticoids, systemic, 471 levetiracetam, 91 exanthems

639

Index of adverse effects diltiazem, 219 excess facial hair minoxidil, 170–171 exercise intolerance parenteral nutrition, 385 exfoliation phenytoin, 95 exfoliative dermatitis dapsone, 343 suramin, 353 extrapyramidal movement disorders amfebutamone, 19 extrapyramidal symptoms olanzapine, 70 risperidone, 74 risperidone + topiramate, 74 ziprasidone, 79 extrapyramidal syndrome rituximab, 440 extravasation contrast media, 560–561 eye movements, abnormal lamotrigine, 90 eye pain interferon alfa, 418 mannitol, 237 voriconazole, 308 eyes, rolling back potassium salts, 250 F facial edema influenza vaccine, 361 facial swelling minocycline, 272 failure to thrive cisapride, 401 fainting sodium phosphate, 407 falls risperidone, 75 false thrombocytopenia valproate, 100 fasciculation suxamethonium, 156 fasting glucose concentrations olanzapine, 70 fasting triglyceride concentrations olanzapine, 70 fat accumulation protease inhibitors, 332 fatigue aciclovir, 328 aluminium, 244 anti-CD40 antibody, 435 cyclopentolate, 568 glucagon-like peptide-1, 514 interferon alfa, 416 ivermectin, 349 levetiracetam, 92 naftidrofuryl, 223 naltrexone, 114

oxcarbazepine, 94 parenteral nutrition, 384 polyvinylpyrrolidone, 263 risperidone, 75 suramin, 353 topiramate, 96 valaciclovir, 329 vitamin D (calciferol), 388 febrile episodes diptheria-tetanus-acellular pertussis vaccine, 360 febrile neutrophilic dermatosis isotretinoin, 172–173 febrile reactions intravenous immunoglobulins, 372 febrile seizures diptheria-tetanus-acellular pertussis vaccine, 360 fecal incontinence olanzapine, 72 repaglinide, 518 fecal urgency azithromycin, 282 feeling cold alprazolam, 52 feet, cold ergot alkaloids, 224 festoon formation botulinum toxin A, 169 fetal growth retardation caffeine, 1 fever 6-thioguanine, 465 alemtuzumab, 435 amfebutamone, 19 anti-CD3 antibody, 435 anti-CD40 antibody, 435 antiepileptic drugs, 87 antithymocyte globulin, 373, 374 benzalkonium compounds, 261 blood transfusion, 369 caspofungin, 310 co-trimoxazole, 322 coagulation factors, 377 cocaine, 40 dapsone, 343 daptomycin, 287 diethylcarbamazine, 348 efalizumab, 437 erythropoietin and derivatives, 377 fluconazole, 305 gold, 246 granulocyte colony-stimulating factor, 416 infliximab, 430, 432 intravenous immunoglobulins, 372 Japanese encephalitis vaccine, 363 MDMA, 31, 35 muromonab-CD3, 437

olanzapine, 72 parenteral nutrition, 385 phenytoin, 95 pneumococcal vaccine, 360 probenecid, 326 quinine, 318, 319 rituximab, 439 sibutramine, 8 smallpox vaccine, 366 spironolactone, 235 vancomycin, 281 vinca alkaloids, 541 fibrosis nitrofurantoin, 284 first-degree atrioventricular block amiodarone, 205 fixed drug eruption celecoxib, 130 co-trimoxazole, 286 dextromethorphan, 106 histamine hydrochloride, 424 loratadine, 181 flaccid paralysis cisatracurium, 155 potassium salts, 249 flagellate hyperpigmentation bleomycin, 545 flank pain liposomal amphotericin (L-AmB), 298 flatulence acarbose, 515 metformin, 517 flexion contractures parenteral nutrition, 383 flu-like symptoms alemtuzumab, 435 botulinum toxin A, 168 erythropoietin and derivatives, 377 interferon alfa, 416, 422 interferon beta, 422 Lyme disease vaccine, 358 perfluorocarbons, 370 phenolic compounds, 263 raloxifene, 491 sclerosant injections, 410 sirolimus, 461 tacrolimus, 463 fluid retention granulocyte colony-stimulating factor (G-CSF), 415 flushing liposomal amphotericin (L-AmB), 298 mangafodipir trisodium, 565 nicotinic acid, 536 sulfamethoxazole + celecoxib, 322 suramin, 353 topiramate, 96 focal proliferative glomerulonephritis hydralazine, 231

640 focal segmental sclerosing glomerulopathy penicillamine, 258 foggy thinking risperidone, 75 folliculitis infliximab, 431 tacrolimus, 463 fracture healing COX-2 inhibitors + NSAIDs, 129 levofloxacin, 279 trovafloxacin, 276 fractures anastrozole, 490 antiretroviral drugs, 330 glucocorticoids, systemic, 473 tricyclic antidepressants, 15 fuliminant heptic failure propylthiouracil, 506 fulminant hepatic necrosis tramadol, 112 fulminant liver failure co-trimoxazole, 322 fungal infections tumor necrosis factor antagonists, 426 G gait ataxia cyclopentolate, 568 gait disorder diamorphine, 107 heroin, 46–47 gait disturbance metronidazole, 323 parenteral nutrition, 384 galactorrhea risperidone, 77 venlafaxine, 20 gallbladder cancer HRT, 486 gallbladder disease contraceptive implants, 490 gallbladder sludge ceftriaxone, 269–270 gallop rhythm thiazolidinediones, 519 gambling pramipexole, 163 gangrene interferon alfa, 417 gastric blood loss etoricoxib, 131 gastritis atovaquone + proguanil, 317 interferon alfa, 421 gastroenteritis benazapril, 227 gastroesophageal reflux glucocorticoids, systemic, 475 gastrointestinal abnormalities interferon alfa, 422 gastrointestinal bleeding

Index of adverse effects bevacizumab, 436 coumarin, 391 penicillamine, 258 SSRIs, 17 gastrointestinal disease Lyme disease vaccine, 358 gastrointestinal disorders daptomycin, 287 mycophenolate mofetil, 458 gastrointestinal disturbances abacavir, 332 clindamycin, 282 deferiprone, 256 diethylcarbamazine, 348 fusidic acid, 280 itraconazole, 306 Japanese encephalitis vaccine, 363 levamisole, 350 oseltamivir, 337 quinine, 319 risperidone, 75 risperidone + topiramate, 74 gastrointestinal motility, altered cyclo 3 fort, 223 gastroschisis carbimazole, 506 gaze paresis heroin, 45 generalized exanthematous pustulosis acarbose, 515 simvastatin, 536 generalized pustular eruptions terbinafine, 295 generalized rash fluconazole, 305 generalized tonic-clonic seizure haloperidol + promethazine, 54 topiramate, 97 genetic susceptibility drug metabolism, 342–343 genital ulceration tretinoin, 173 gestational trophoblastic tumor mifepristone (RU 486), 495 giddiness rabeprazole + amoxicillin + clarithromycin, 405 gingival hyperplasia ciclosporin, 453 gingivitis MDMA, 35 glaucoma topiramate, 97 glomerulonephritis hydralazine, 231 glossitis co-trimoxazole, 286 glycosuria lithium, 24 tenofovir, 333 goiter interferon beta, 423

Goodpasture’s syndrome penicillamine, 258 gout parenteral nutrition, 383 graft-vs.-host disease cyclophosphamide, 457 grand mal seizures see tonic-clonic seizures granulocytopenia co-trimoxazole, 286 fusidic acid, 280 granuloma annulare infliximab, 430 granulomata parenteral nutrition, 386 granulomatosis mercury, 249 granulomatous interstitial nephritis levofloxacin, 278 ground-glass opacities gold, 246 parenteral nutrition, 385 growth restriction metamfetamine, 5 growth retardation atenolol, 217 glucocorticoids, 169 Guillain–Barré syndrome influenza vaccine, 362 interferon alfa, 418 suramin, 353 gut ischemia arginine vasopressin, 531 guttate psoriasis etanercept, 427 gynecomastia amlodipine, 219 anabolic steroids, 496 antiandrogens, 497 finasteride, 169, 498 SSRIs, 17 testosterone, 495 H Haber’s Law described, xxviii hair discoloration interferon alfa, 421 hair loss see alopecia hallucinations aciclovir, 328 cefepime, 269 COX-2 inhibitors, 129 efavirenz, 334 glucocorticoids, systemic, 472 levetiracetam, 91 MDMA, 32, 34, 35 mefloquine, 316 metronidazole, 323 morphine, 109 pramipexole, 162 zonisamide, 101 hallucinations (visual)

641

Index of adverse effects zolpidem, 57 hangover effects quazepam, 55 hard palate perforation cocaine, 40 hard palate resorption cocaine, 3 headache 6-thioguanine, 465 all-trans retinoic acid + fluconazole, 299 anabolic steroids, 496 anti-CD3 antibody, 435 anti-CD40 antibody, 435 benzimidazoles, 346 bevacizumab, 436 buspirone, 52 co-trimoxazole, 322 contraceptive implants, 490 daptomycin, 287 diazepam + phenytoin, 53 diethylcarbamazine, 348 diphenylcyclopropenone, 169 doxycycline, 270 efalizumab, 437 ergot alkaloids, 224 esomeprazole + clarithromycin + metronidazole, 405 famotidine, 403 gadobenate dimeglumine, 563 garenoxacin, 277 gatifloxacin, 278 histamine hydrochloride, 424 ICL670, 257 intravenous immunoglobulins, 372 iron, 247 ivermectin, 349 Japanese encephalitis vaccine, 363 levetiracetam, 91, 92 mangafodipir trisodium, 565 MDMA, 32, 34 melatonin, 531 metronidazole, 323 minocycline, 271 moxidectin, 351 oxamniquine, 351 oxcarbazepine, 94 pegvisomant, 529 pioglitazone, 520 polyvinylpyrrolidone, 263 praziquantel, 351 probenecid, 326 quinine, 319 ribavirin + interferon, 327 risperidone, 74 risperidone + donepezil, 79 rituximab, 440 smallpox vaccine, 366 sodium phosphate, 407 tacrolimus, 463 topiramate, 97 tramadol, 112

valaciclovir, 329 vancomycin, 281 zolpidem, 56 hearing loss epidural anesthesia, 147 furosemide, 233–234 gentamicin, 274 interferon alfa, 419 tobramycin, 275 vancomycin, 280–281 vigabatrin, 101 heart see also coronary; entries at cardiheart beat see cardiac dysrhythmias; tachycardia; specific conditions, such as sinus node dysfunction heart failure clonazepam + oxycodone, 53 heart rate, changes levosalbutamol (levalbuterol), 189 heartburn diethylcarbamazine, 348 heat bumps topiramate, 96 heat intolerance topiramate, 98 helplessness MDMA, 32 hemangioma erythropoietin, 378 hemarthrosis aspirin, 124 hematemesis quinine, 319 hematoma abciximab, 396 acupuncture, 581 coumarin, 391 gentian violet, 262 gold, 247 hematuria abciximab, 396 antithymocyte globulin, 374 cocaine, 39 gentian violet, 262 hydralazine, 230 indinavir, 335 lepirudin, 394 hemiplegia metamfetamine, 29 hemoglobinuria perfluorocarbons, 370 hemolysis intravenous immunoglobulins, 373 quinine, 318 hemolytic anemia chloroquine, 316 cholelitholytic agents, 410 co-trimoxazole, 286, 322

dapsone, 343 intravenous immunoglobulins, 373 nimesulide, 133 suramin, 353 hemolytic transfusion reaction blood transfusion, 370 hemolytic-uremic syndrome interferon alfa, 421 quinine, 318 tacrolimus, 464 hemophagocytic syndrome infliximab, 430 hemopoietic cancers ethylene oxide, 262 hemoptysis abciximab, 396 lepirudin, 394 penicillamine, 258 hemorrhage coumarin, 391 doxycycline, 270–271 lepirudin, 394 liposomal amphotericin, 298 penicillamine, 258 hemorrhage, retinal minocycline, 271 hemorrhage, subarachnoid MDMA, 32 hemorrhagic blisters penicillamine, 258 hemorrhagic stroke alteplase, 392 streptokinase, 392 hemorrhagic telangiectasia manganese, 248 Henoch–Schõnlein purpura clarithromycin, 282 hepatsee also entries at liver hepatic artery thrombosis sirolimus, 460 hepatic disorders Camelia sinensis, 575 hepatic dysfunction caspofungin, 310 octreotide, 530 polyvinylpyrrolidone, 263 hepatic encephalopathy penicillamine, 258 valproate, 100 hepatic failure dapsone, 343 glipizide + alcohol, 519 hepatic necrosis tramadol, 112 hepatic sinusoidal obstuction syndrome cyclophosphamide, 546 hepatic steatosis metformin + nucleoside analogue reverse transcriptase inhibitors, 517 tamoxifen, 493

642 hepatic toxicity levamisole + fluorouracil, 350 hepatic veno-occlusive disease terbinafine, 294 hepatitis acupuncture, 581 antiepileptic drugs, 87 Asian herbal medicines, 574 atorvastatin, 536 candesartan, 229 dapsone, 343 enalapril, 227 herbal medicines, 580–581 inhibitors of phosphodiesterase type V, 224 levofloxacin, 278 olanzapine, 72 pegvisomant, 530 quinacrine, 320 saridon, 125 SSRIs, 17 terbinafine, 294 hepatitis B reactivation infliximab, 433 rituximab, 440 hepatitis C infection coagulation factors, 377 hepatocellular carcinoma coagulation factors, 376 danazol, 497 thorotrast, 565 hepatocellular-cholestatic reactions co-trimoxazole, 286 hepatocellular injury co-trimoxazole, 322 hepatocellular necrosis co-trimoxazole, 322 hepatomegaly antiepileptic drugs, 87 infliximab, 430 hepatorenal syndrome valproate, 100 hepatotoxicity candesartan, 229 Chinese herbal medicines, 7 co-trimoxazole, 286 cytotoxic drugs, 545 fluconazole, 305 isoniazid, 343 methotrexate, 547 nevirapine, 334 nimesulide, 132 paracetamol, 125 terbinafine, 294 trovafloxacin, 276 herpes encephalitis adalimumab, 427 herpes labialis interferon alfa, 421 herpes simplex infection alemtuzumab, 434 infliximab, 433 herpes simplex mucositis

Index of adverse effects valaciclovir, 329 herpes zoster infections tacrolimus, 463 Herxheimer reaction diethylcarbamazine, 348 hiccups famotidine, 403 hip fracture tricyclic antidepressants, 15 hippocampal dysfunction MDMA, 33 hippocampal injury tacrolimus, 463–464 histamine release amphotericin B deoxycholate, 295 histopathology penicillamine, 258 histoplasmosis adalimumab, 427 infliximab, 432 tumor necrosis factor antagonists, 426 HIV infection cannabinoids, 38 hoarseness perindopril, 228 Hodgkin’s disease growth hormone, 529 homicidal behavior haloperidol, 60 homocysteine levodopa, 164 hormone suppression Tripterygium wilfordii, 580 Horner’s syndrome epidural anesthesia, 147 hostility interferon alfa, 419 levetiracetam, 91, 92, 93 topiramate, 98 hot flushes anastrozole, 490 raloxifene, 491 humeral “bifurcation” cocaine, 43 hydatidiform mole mifepristone (RU 486), 495 hydrogen gas accumulation mannitol, 239 hydronephrosis gentian violet, 262 hyperactivity clonazepam, 53 MDMA + cannabis, 34 hyperaldosteronism Glycyrrhiza species, 577 hyperammonemia parenteral nutrition, 384 valproate, 99 hyperamylasemia ribavirin + interferon, 327 hyperandrogenism valproate, 100

valproic acid, 88 hyperbilirubinemia atazanavir, 335 gemtuzumab, 437 hypercalcemia calcium salts, 245 parathyroid hormone, 531 vitamin A, 386 vitamin D (calciferol), 388, 389 hypercalciuria indinavir, 336 vitamin D (calciferol), 388 hyperchloremia benazapril, 227 hypercoagulability oral contraceptives, 487 hypergastrinemia interferon alfa, 421 hyperglycemia carvedilol, 218 formoterol, 189 gatifloxacin, 278 gatifloxacin + glibenclamide, 278 gatifloxacin + glipizide, 278 glucagon, 514 MDMA, 31 hyperhomocysteinemia fibrates, 534 hyperkalemia antacids, 401 co-trimoxazole, 286 eplerenone, 235 erythropoietin and derivatives, 377 MDMA, 31 omeprazole, 404 potassium salts, 249, 250 tacrolimus, 464 hyperkinesia risperidone, 74 hyperlipidemia isotretinoin, 172 protease inhibitors, 332 rosiglitazone, 521 sirolimus, 463 hypermenorrhea levonorgestrel, 493 hypernatremia liposomal amphotericin (L-AmB), 298 oral rehydration therapy, 406 hyperosmolality mannitol, 240 hyperoxaluria indinavir, 336 hyperparathyroidism lithium, 24 hyperphosphatemia liposomal amphotericin, 297–298 phosphate, 383 sodium phosphate, 407 hyperpigmentation of the skin and tongue

643

Index of adverse effects interferon alfa, 421 hyperplastic folliculitis ciclosporin, 454 hyperprolactinemia antiepileptic drugs, 88 antipsychotic drugs, 64 azathioprine, 450 risperidone, 60, 77 hyper-reflexia pethidine, 111 hypersensitivity 6-thioguanine, 466 abacavir, 332 allopurinol, 133 artemether + lumifantrine, 320–321 atorvastatin, 536 azathioprine, 450 dapsone, 343 fluconazole, 305–306 furosemide, 234–235 glucocorticoids, systemic, 474 glycyrrhizinic acid, 170 histamine hydrochloride, 424 insulin, 510 iron, 247 itraconazole, 307–308 Japanese encephalitis vaccine, 363 josamycin, 283 levonorgestrel, 493 mercury, 249 neomycin, 171 oxaliplatin, 547 penicillamine, 257 Piper methysticum, 579 rituximab, 440 suramin, 353 hypersensitivity skin reactions antiepileptic drugs, 87 hypersensitivity syndrome carbamazepine, 89 phenytoin + lamotrigine, 87–88 hypersusceptibility reactions characteristics, xxix, xxvii hypertension adrenaline, 160 amphotericin B deoxycholate, 295 anti-inflammatory drugs, 118 atenolol, 217 bevacizumab, 436 carbamazepine, 89 ciclosporin, 455 contraceptive implants, 490 doxycycline, 270 erythropoietin and derivatives, 377, 378 glucocorticoids, systemic, 471 Glycyrrhiza species, 577 ibuprofen, 127 iron, 247 minocycline, 271 olanzapine, 71

perfluorocarbons, 370 quinine, 318 reboxetine, 15 hypertensive encephalopathy erythropoietin and derivatives, 377 hyperthermia caffeine, 1 chlorphenamine, 177 cocaine, 41 MDMA, 31, 32 metamfetamine, 30 metamfetamine + morphine, 28 morphine, 110 topiramate, 98 venlafaxine, 15 hyperthyroidism amiodarone, 207 interferon alfa, 420 interferon beta, 422–423 iodinated water-soluble contrast media, 554 iodine, 505 hypertonia olanzapine, 70 hypertriglyceridemia HRT, 483–484 sirolimus, 461 hyperuricosuria indinavir, 336 hyperventilation heroin, 46 hyperzincemia zinc, 251 hypoacusis clindamycin, 281 hypoalbuminemia glucocorticoids, systemic, 472 hypoaldosteronism benazapril, 227 hypocalcemia gentamicin, 274 phosphate, 383 sodium phosphate, 407 hypochondriasis anabolic steroids, 496 hypocitraturia indinavir, 336 hypogammaglobulinemia carbamazepine, 89 hypoglycemia artesunate, 321 cannabis, 512 chloroquine, 315 clindamycin, 281 cocaine, 512 ecstasy, 512 exenatide, 514 gatifloxacin, 278 insulin, 509 octreotide, 530 pramlintide, 515 rosiglitazone, 521 SSRIs, 17

ultrashort-acting insulins, 512 hypokalemia caspofungin, 310 formoterol, 189 Glycyrrhiza species, 577 itraconazole, 307 sodium phosphate, 407 tenofovir, 333 hypokinesia olanzapine, 70 hypolipidemic effect metronidazole, 323 hypomagnesuria indinavir, 336 hyponatremia desmopressin, 531 glucagon, 514 mannitol, 236, 240 MDMA, 35 oxcarbazepine, 94 hyponatremic coma ibuprofen, 127 hypophosphatemia tenofovir, 333 hypopigmentation chloroquine, 316 hypopituitarism interferon alfa, 420 hypoplasia cocaine, 43 hypopnea lithium, 25 hypoproliferative anemia zidovudine, 333 hyposmia interferon alfa, 419 hypotension adrenaline, 161 amiodarone, 205, 206 amphotericin B deoxycholate (DAMB), 295 anti-CD3 antibody, 435 Asian herbal medicines, 573–574 blood transfusion, 369 calcium channel blockers, 219 candesartan, 229 donepezil, 8 eptifibatide, 398 furosemide, 234 gabapentin, 90 histamine hydrochloride, 424 intravenous immunoglobulins, 372 isoniazid, 344 ivermectin, 349 mannitol, 238 MDMA, 31 nifedipine, 220 phenytoin, 96 potassium salts, 250 propofol, 142, 143 ropinirole, 162 sulfamethoxazole + celecoxib, 322

644 temazepam, 55 vancomycin, 281 vasodilators + nitrate derivatives, 224 hypothalamic amenorrhea antiepileptic drugs, 88 hypothalamic-pituitary-adrenal axis dysregulation cocaine withdrawal, 41 hypothalamic-pituitary dysfunction anabolic steroids, 496 hypothermia clonidine, 230 ibuprofen, 127 MDMA, 35 olanzapine, 73 phenytoin, 95 SSRIs, 17 hypothyroidism ciclosporin, 453 interferon alfa, 420 interferon beta, 423 iodinated water-soluble contrast media, 554 iodine, 505 polyvinylpyrrolidone, 263 hypotonic paresis heroin, 45 hypouricemia parenteral nutrition, 383 hypovolemia anti-CD3 antibody, 435 hypoxemia propofol, 142 hypoxia liposomal amphotericin (L-AmB), 298 metformin concentration, 515–516 phenolic compounds, 263 hypoxic damage heroin, 45–46

I ileitis Bacille Calmette-Guérin vaccine, 357 immune disease aluminium, 244 immune thrombocytopenia diclofenac, 126 immune thrombocytopenic purpura interleukin-12, 425 immunological abnormalities coagulation factors, 376–377 immunomorphology penicillamine, 258 immunosuppression antithymocyte globulin, 374 impaired consciousness valproate, 99

Index of adverse effects impaired sexual function finasteride, 497 impetigo tacrolimus, 463 impotence diamorphine, 107 heroin, 47 impulsivity MDMA + cannabis, 34 incomplete muscle paralysis botulinum toxin A, 168 incontinence heroin, 47 levetiracetam, 91 midazolam, 54 phosphate enema, 406 risperidone, 78 incontinence, fecal olanzapine, 72 increased heart rate olprinone, 200 increased seizure frequency levetiracetam, 92 topiramate, 97 induration adjuvants, 357 deferoxamine, 256 glatiramer acetate, 457 infarction see cerebral infarction; myocardial infarction infection cocaine, 41 efalizumab, 436 infliximab, 429 levetiracetam, 91 moxidectin, 351 mycophenolate mofetil, 458 infectious endophthalmitis triamcinolone, 471 infective endocarditis metamfetamine, 4, 30 infiltrative lung disease SSRIs, 20 inflammation clindamycin, 281 cocaine, 41 inflammation, local suramin, 351 influenza ICL670, 257 information processing impairment risperidone, 77 infusion-related reactions caspofungin, 311 infliximab, 428, 432 liposomal amphotericin (L-AmB), 298 infusion site irritation factor IX concentrate, 376 infusion site pain quinupristin/dalfopristin, 285 infusion site reaction

intravenous immunoglobulins, 372 ingrown toenails indinavir, 335 inhibitor development coagulation factors, 376 inhibitors against factor XI coagulation factors, 376 injection site erythema erythropoietin and derivatives, 377 injection site infection insulin, 510 injection site reaction daptomycin, 287 diptheria-tetanus-acellular pertussis vaccine, 360 enfuvirtide, 337 gadobenate dimeglumine, 563 glatiramer acetate, 457 heparins, 391, 392 Herpes simplex virus vaccine, 361 histamine hydrochloride, 424 interferon beta, 422 interleukin-1 receptor antagonist, 424 Japanese encephalitis vaccine, 363 meningococcal vaccine, 360 parathyroid hormone, 531 pegvisomant, 530 injury levetiracetam, 91 risperidone, 75 INR prolongation moxifloxacin + warfarin, 279 insomnia atovaquone + proguanil, 317 benzimidazoles, 346 COX-2 inhibitors, 129 daptomycin, 287 efavirenz, 334 gatifloxacin, 278 infliximab, 428 levetiracetam, 91, 92 methylphenidate, 6 tacrolimus, 464 insulin antibodies ultrashort-acting insulins, 513 insulin resistance indinavir, 331 protease inhibitors, 332 intermenstrual bleeding levonorgestrel, 493–494 interstitial fibroedema tenofovir, 333 interstitial fibrosis penicillamine, 258 interstitial lung disease mesalazine, 408 interstitial lung edema influenza vaccine, 362 interstitial nephritis celecoxib, 130

645

Index of adverse effects ciprofloxicin, 277 levofloxacin, 278 interstitial pneumonia bepridil, 219 cyclophosphamide, 457 gold, 246 interstitial pneumonitis bepridil, 209 interferon alfa, 417 nitrofurantoin, 284 sirolimus, 461 intestinal perforation polystyrene sulfonates, 259 intoxication metamfetamine, 30 phenytoin, 96 intra-alveolar hemorrhage penicillamine, 258 intracerebral hemorrhage eptifibatide, 398 NSAIDs, 119–120 intracranial hematoma cocaine, 3 intracranial hemorrhage alteplase, 392 metamfetamine, 29 phenylpropanolamine, 161–162 streptokinase, 392 intracranial hypertension doxycycline, 270 mannitol, 236 mesalazine, 408 minocycline, 271 intracranial neoplasia growth hormone, 529 intracranial pressure mannitol, 236–237 intraocular pressure nitrous oxide, 140 intravascular coagulation quinine, 318 intravascular hemolysis intravenous immunoglobulins, 373 quinine, 318 intussusception rotavirus vaccine, 365 invasive aspergillosis infliximab, 432 involuntary facial movements interferon alfa, 417–418 iris cyst latanoprost, 477 iron deficiency manganese, 248 iron intoxication gadolinium salts, 562 irreversible aplastic anemia chloramphenicol, 276 irritability clonazepam, 53 famotidine, 403 levetiracetam, 92, 93 mercury, 249

irritable bowel syndrome HRT, 484 irritant dermatitis vitamin D (calciferol), 389 ischemic colitis alosetron, 402 ischemic heart disease doxorubicin + vincristine, 540 ischemic ocular complications inhibitors of phosphodiesterase type V, 224 ischemic optic neuropathy inhibitors of phosphodiesterase type V, 224 interferon alfa, 418 ischemic skin lesions arginine vasopressin, 531 itching beta-blockers (ocular), 570 deferoxamine, 256, 257 diethylcarbamazine, 348 furosemide, 234 heparins, 391 ivermectin, 349 tacrolimus, 463 tramadol, 112 vancomycin, 281 itching of the feet infliximab, 428 J jaundice atazanavir, 335 candesartan, 229 chloroquine, 316 co-trimoxazole, 322 enalapril, 227 fluconazole, 305 interferon beta, 423 naftidrofuryl, 223 parenteral nutrition, 385 perfluorocarbons, 370 suramin, 353 terbinafine, 294 jerky movements penicillamine, 257 jitteriness clonazepam + paroxetine, 53 SSRIs, 17 joint pain 6-thioguanine, 465 ciclosporin, 454 ICL670, 257 ivermectin, 349 joint swelling parenteral nutrition, 383 K karyomegaly tenofovir, 333 keratopathy intravenous immunoglobulins, 372–373 kidney

see also entries at nephro-; renal kidney damage chloroquine, 316 kidney disease lithium, 24–25 kidney failure dapsone, 343 kidney function impairment penicillamine, 258 polyvinylpyrrolidone, 263 spironolactone, 235 kidney stones ceftriaxone, 270 indinavir, 336 topiramate, 96–97, 97 knee effusions glucocorticoids, systemic, 472 kyphosis growth hormone, 529 L lacrimation disturbances voriconazole, 308 lactic acidosis antiretroviral drugs, 330 buformin, 515 metformin, 516 propofol, 143 quinine, 319 rofecoxib, 517 rofecoxib + metformin, 517 salbutamol, 189 tenofovir, 333 warfarin, 517 warfarin + metformin, 517 language skills cocaine, 44 laryngospasm propofol, 142 laughter cyclopentolate, 568 lead poisoning Litargirio, 247 learning performance levodopa, 163 left bundle branch block calcium channel blockers, 219 left ventricular decompensation flecainide, 210 leg amputation thiazides, 233 leg complaints zolpidem, 56 leg cramps raloxifene, 491 leg edema vitamin D (calciferol), 388 leg pain liposomal amphotericin (L-AmB), 298 leg ulcers hydroxyurea, 170 leg weakness vinca alkaloids, 541

646 leptin concentration clozapine, 63 lesions aciclovir, 328 antiepileptic drugs, 87 arginine vasopressin, 531 chloroquine, 316 co-trimoxazole, 286 cocaine, 40, 41 heparins, 391 heroin, 46, 47 nifedipine, 220 nitrendipine, 220 phenytoin, 95 lethargy aciclovir, 328 gabapentin, 90 infliximab, 430 MDMA, 35 moxidectin, 351 rabeprazole + amoxicillin + clarithromycin, 405 vinca alkaloids, 542 leukemia antithymocyte globulin, 374 coagulation factor gene therapy, 377 thorotrast, 565 leukemia, childhood Hemophilus influenzae type b vaccine, 358 leukocytoclastic vasculitis azithromycin, 282 leukocytosis antiepileptic drugs, 87 moxidectin, 351 olanzapine, 72 tretinoin, 173 leukocyturia indinavir, 336 leukoencephalopathy diamorphine, 107 heroin, 45 tacrolimus, 463 leukopenia 6-thioguanine, 465 ammonium chelators, 254 clopidogrel, 397 clozapine, 65 deoxyspergualin, 457 ganciclovir, 327 hydroxyurea, 170 interferon beta, 422 itraconazole, 307 levamisole + fluorouracil, 350 linezolid, 284 mercaptopurine, 450 moxidectin, 351 mycophenolate mofetil, 458 oxcarbazepine, 94 penicillamine, 257 sirolimus, 461 vinca alkaloids, 543 libido, reduced

Index of adverse effects interferon alfa, 420 risperidone, 75 lichen planus ribavirin + interferon, 327 lichenoid dermatitis infliximab, 430 lichenoid eruptions enalapril, 228 infliximab, 431 lightheadedness alprazolam, 52 gatifloxacin, 278 limb deficiencies diazepam, 53 linear erythema aciclovir, 328 linear immunoglobulin A bullous disease vancomycin, 281 lipase activity parenteral nutrition, 385 lipid concentration transdermal contraception, 489 lipoatrophy stavudine, 331 lipodystrophy nucleoside analogue reverse transcriptase inhibitors (NRTI), 330–331 ultrashort-acting insulins, 512–513 lipodystrophy syndrome described, 329 lipohypertrophy insulin, 510, 511 Listeria infections tumor necrosis factor antagonists, 426 listeriosis infliximab, 432 listlessness vinca alkaloids, 542 livedo reticularis interferon alfa, 421 liver see also entries at hepatliver damage amiodarone, 207–208 anabolic steroids, 496 Chelidonium majus, 575 cimicifuga racemosa, 575 ephedrine, 161 glibenclamide, 519 paracetamol, 125 Piper methysticum, 579 verapamil, 221 zafirlukast, 191 liver disease parenteral nutrition, 384 liver dysfunction manganese, 248 liver failure clarithromycin, 282 nimesulide, 133

penicillamine, 258 Polygonum multiflorum, 579 liver injury ciprofloxicin, 277 co-trimoxazole, 322 pranlukast, 192 liver involvement dapsone, 343 liver necrosis nitrofurantoin, 284 liver toxicity voriconazole, 309 Loa loa encephalopathy ivermectin, 349 local events pneumococcal vaccine, 360 local reactions deferoxamine, 256 long QT syndrome adrenaline, 161 loose bowel motions rabeprazole + amoxicillin + clarithromycin, 405 loose stools cyclo 3 fort, 223 pristinamycin, 285 lordosis growth hormone, 529 loss of libido finasteride, 498 low birth weight cocaine, 44 lowered diastolic blood pressure olprinone, 200 lung cancer beta carotene, 387 lung damage amiodarone, 206–207 lung edema influenza vaccine, 362 lungs, collapsed clonazepam + oxycodone, 53 lupus erythematosus nifedipine, 220 nitrendipine, 220 terbinafine, 295 lupus erythematosus-like eruptions terbinafine, 295 lupus-like syndrome adalimumab, 427 atorvastatin, 536 celecoxib, 130–131 etanercept, 425 infliximab, 425, 428, 431 tumor necrosis factor antagonists, 425 lymph node enlargement diphenylcyclopropenone, 169 lymphadenopathy antiepileptic drugs, 87 dapsone, 343 Lyme disease vaccine, 358 lymphangitis smallpox vaccine, 366

647

Index of adverse effects lymphedema botulinum toxin A, 169 lymphoblastic leukemias Hemophilus influenzae type b vaccine, 358 lymphocytic colitis cyclo 3 fort, 223 lymphocytosis deferiprone, 256 inhibitors of phosphodiesterase type V, 224 lymphoma mercaptopurine, 451 lymphoproliferative disorder antithymocyte globulin, 374 muromonab-CD3, 438 lymphoproliferative malignancies infliximab, 433 M macrocytosis parenteral nutrition, 384 macropapular eruptions antiepileptic drugs, 87 macrophage activation syndrome etanercept, 428 infliximab, 432 macrophagic myofasciitis aluminium, 244 macular rash terbinafine, 294 maculopapular allergic lesions irbesartan, 229 maculopapular rash amfebutamone, 19 azithromycin, 282 co-trimoxazole, 286 diltiazem, 219 itraconazole, 308 josamycin, 283 maculopathy degeneration deferoxamine, 256 malabsorption azathioprine, 450 mycophenolate mofetil, 458 malaise 6-thioguanine, 465 ciclosporin, 453 contraceptive implants, 490 dapsone, 343 fluconazole, 305 Japanese encephalitis vaccine, 363 lithium, 24 MDMA, 35 quinine, 319 suramin, 353 malignancy titanium, 251 malignant hyperthermia caffeine, 1 mammary tumors

SSRIs, 14 tricyclic antidepressants, 14 manganese intoxication parenteral nutrition, 384 mania efavirenz, 334 metamfetamine, 4 ziprasidone, 80 manic reactions levetiracetam, 91 mask-like face manganese, 248 parenteral nutrition, 384 melanoma phototherapy, 171 melena interleukin-12, 425 quinine, 319 membranous glomerulopathy celecoxib, 130 memory impairment lormetazepam, 56 MDMA, 33 memory loss clobazam, 53 tolterodine, 165 meningism vinca alkaloids, 541 meningitis glucocorticoids, systemic, 475 metronidazole, 323 menstrual abnormalities valproate, 100 menstrual disorders valproic acid, 88 mental changes calcium salts, 245 mental retardation mercury, 248 Merkel cell carcinoma antithymocyte globulin, 375 metabolic acidosis benazapril, 227 isoniazid, 344 metamfetamine, 30 parenteral nutrition, 384 tenofovir, 333 metabolic alkalosis hemodialysis, 598 metabolic syndrome antipsychotic drugs, 64 described, 329 meteorism acarbose, 515 mannitol, 239 metered-dose inhalers, replacements inhaled glucocorticoids, 186–187 methemoglobinemia benzocaine, 150 dapsone, 343 methemoglobinia chloroquine, 315

MI see myocardial infarction microangiopathic hemolytic anemia interferon alfa, 421 micronucleus metamfetamine, 31 minor infections 6-thioguanine, 465 miosis epidural anesthesia, 147 mitochondrial damage heroin, 45–46 stavudine, 332–333 mitochondrial DNA depletion stavudine, 330 zidovudine, 330 mold infection glucocorticoids, systemic, 475 monocular scotoma interferon alfa, 418 monocytosis moxidectin, 351 mood changes aluminium, 244 anabolic steroids, 496 levetiracetam, 93 mood disorders glucocorticoids, systemic, 472 mood problems topiramate, 97 motor activity impairment risperidone, 77 motor asymmetries cocaine, 44 motor skill development metamfetamine, 5 motor tics methadone, 48 mouth, dry sibutramine, 8 movement coordination aluminium, 244 movement disorders cisapride, 401 interferon alfa, 417 mucocutaneous effects isotretinoin, 172 mucormycosis sirolimus, 463 mucositis valaciclovir, 329 mucus, aspirated clonazepam + oxycodone, 53 multi-organ failure spironolactone, 235 multifocal fixed drug eruption histamine hydrochloride, 424 multifocal septic arthritis etanercept, 428 multiorgan failure ciclosporin + colchicine, 455 interferon alfa, 417 valproate, 100

648 yellow fever vaccine, 366 multiple sclerosis interferon alfa, 418 muscle atrophy mesalazine, 408 muscle contractions, involuntary risperidone, 74 muscle pain aluminium, 244 ciclosporin, 454–455 daptomycin, 287 verapamil + simvastatin, 221 muscle weakness colistin, 285 fluconazole + simvastatin, 304 vitamin D (calciferol), 388 musculoskelatal disorders pefloxacin, 279 mutism muromonab-CD3, 438 olanzapine, 73 propofol, 143 myalgia aluminium, 244 antimony, 245 co-trimoxazole, 322 efalizumab, 437 intravenous immunoglobulins, 372 isotretinoin, 172 Japanese encephalitis vaccine, 363 minocycline, 271 quinine, 319 quinupristin/dalfopristin, 285 myasthenia gravis, exacerbated ketolides, 281 Mycobacterium pneumonia alemtuzumab, 434 Mycobacterium tuberculosis infliximab, 428 mycolonic jerks metformin, 516 mycotic emboli metamfetamine, 30 mydriasis heroin, 46 MDMA, 34, 35 myelitis rituximab, 450 myelodysplastic syndrome antithymocyte globulin, 374 myeloencephalopathy vinca alkaloids, 541–542 myelopathy diamorphine, 107 zinc, 251 myelosuppression azathioprine, 452 linezolid, 284 mannitol, 237 mercaptopurine, 452 myocardial damage

Index of adverse effects NSAIDs, 118–119 promazine, 73–74 myocardial infarction see also cardiac arrest amfetamine, 4, 28–29 anti-CD40 antibody, 435 cocaine, 2, 38–39 danazol, 496 dipyridamole, 397 ephedrine, 161 granulocyte colony-stimulating factor, 415 interferon alfa, 416–417 intravenous immunoglobulins, 372 metamfetamine, 29 pioglitazone, 520 vinca alkaloids, 540 myocardial injury phenylpropanolamine, 7–8 myocardial ischemia adrenaline, 160 myocarditis aspirin, 124 intravenous immunoglobulins, 373 myoclonus aciclovir, 328 etomidate, 141 venlafaxine, 15, 20 myofasciitis aluminium, 244 myoglobinuria MDMA, 31 myoglobinuric acute renal insufficiency cocaine, 43 myopathy antiretroviral drugs, 330 chloroquine, 316 colchicine, 133 minocycline, 271 sirolimus, 462 myopia co-trimoxazole, 286 isotretinoin, 172 topiramate, 97 N nasal reflux cocaine, 41 nasocutaneous fistula cocaine, 41 nasopharyngitis valaciclovir, 329 nausea 6-thioguanine, 465 alemtuzumab, 435 alprazolam, 52 amiodarone, 205 antimony, 245 antithymocyte globulin, 373 atovaquone + proguanil, 317 baclofen, 157

benazapril, 227 buprenorphine, 113 calcium salts, 245 clindamycin, 281, 282 co-trimoxazole, 286 cocaine, 39 cyclopentolate, 568 daclizumab, 436 dolasetron, 402 efalizumab, 437 erythropoietin and derivatives, 378 exenatide, 514 fentanyl, 108 fosfomycin, 287 gabapentin, 90 gadobenate dimeglumine, 563 glucagon-like peptide-1, 514 ICL670, 257 indinavir, 335 interferon beta, 422 intravenous immunoglobulins, 372 iron, 247 isoniazid, 343 itraconazole, 306 ivermectin, 349 ketolides, 281 levetiracetam, 91 levofloxacin, 278 lithium, 25 mangafodipir trisodium, 565 mannitol, 237, 238, 239 MDMA, 32 methylphenidate, 6 moxidectin, 351 moxifloxacin, 279 ondansetron, 402 opioid analgesics, 106 oxcarbazepine, 94 pioglitazone, 520 polyethylene glycol, 407 polyvinylpyrrolidone, 263 pramlintide, 515 praziquantel, 351 probenecid, 326 quinine, 318, 319 risperidone, 74 sennoside calcium, 407 sertraline, 17 sevoflurane, 140 smallpox vaccine, 366 sodium phosphate, 407 suramin, 353 terbinafine, 294 topiramate, 96 tramadol, 112 tropisetron, 401 valaciclovir, 329 venlafaxine, 20 vinca alkaloids, 542 vinorelbine, 543 voriconazole, 309 neck spasms

649

Index of adverse effects iron, 247 necrolytic migratory erythema glucagon, 514 necrosis aspirin, 124 enalapril, 227 suramin, 351 tramadol, 112 necrotizing fasciitis infliximab, 432 NSAIDs, 121–122 necrotizing ulcerative lesions cocaine, 40 neonatal neutropenia penicillamine, 259 neonatal renal insufficiency lisinopril, 228 neonatal syndrome SSRIs, 17 neoplasia muromonab-CD3, 437 nephrsee also entries at kidney; renal nephritis herbal medicines, 581 nephrogenic diabetes insipidus liposomal amphotericin, 298 lithium, 24, 25 tenofovir, 333 nephrolithiasis ceftriaxone, 270 furosemide, 234 indinavir, 335 nephropathy tenofovir, 333 nephrotic syndrome adalimumab, 426 factor IX inhibitor, 376 interferon beta, 423 nephrotoxicity arbekacin, 274 caspofungin, 310 cidofovir, 326 colistin + polymyxin, 285 contrast media, 556–560 gadolinium salts, 561–563 gentamicin, 275 tenofovir, 333 nerve damage acupuncture, 581 nerve fiber injury trovafloxacin, 276 nerve palsies vinca alkaloids, 541 nervousness contraceptive implants, 490 levetiracetam, 92 risperidone + donepezil, 79 topiramate, 97 neural tube defects co-trimoxazole, 287 neurobehavioral deficits trichloroethylene, 140 neurobehavioral parameters

aluminium, 244 neurocognitive impairment amfetamine, 5 mercury, 249 neurodevelopmental disorders mercury, 248–249 neuroleptic malignant syndrome antipsychotic drugs, 59–60 clozapine, 66 lithium, 24, 25 lithium + neuroleptic drug, 25 olanzapine, 71–72 risperidone, 76 neurological deterioration penicillamine, 257 neuromuscular dysfunction potassium salts, 249 neuromuscular hyperexcitability magnesium, 248 neuromuscular weakness magnesium, 248 neuronal processing cocaine, 41 neuropathy antiretroviral drugs, 330 contraceptive implants, 490 Lyme disease vaccine, 358 metronidazole, 323 neuropsychiatric disturbance aciclovir, 328 cefepime, 269 efavirenz, 334 interferon alfa, 420, 422 neurosis levetiracetam, 91 neurotoxic symptoms cefepime, 269 neurotoxicity aciclovir, 328 cisplatin, 546 iomeprol, 554 itraconazole, 307 muromonab-CD3, 437 valproate + lamotrigine, 90 neurotropic disease yellow fever vaccine, 366 neutralizing antibodies interferon beta, 423 neutropenia antiepileptic drugs, 87 antithymocyte globulin, 373, 374 antithyroid drugs, 506 cytotoxic drugs, 545 ganciclovir, 326–327 hydroxyurea, 547 interleukin-12, 425 intravenous immunoglobulins, 373 levamisole, 350 mycophenolate mofetil + valaciclovir, 460

olanzapine, 72 penicillamine, 259 phototherapy, 171 rituximab, 439 suramin, 353 valproate, 99 vinca alkaloids, 543 neutrophilic dermatosis see Sweet’s syndrome new-onset seizures baclofen, 157 nitrate derivatives headache, 218 NK cell lymyphopenia mycophenolate mofetil, 459 nocardiosis infliximab, 432 nocturnal hematuria antithymocyte globulin, 374 non-axillary sweating botulinum toxin A, 169 non-cardiogenic pulmonary edema heroin, 47 non-cytomegalovirus infections antithymocyte globulin, 374 non-Hodgkin’s lymphoma adalimumab, 427 infliximab, 433 NSAIDs, 123 non-oliguric renal insufficiency aminoglycosides, 274 non-traumatic rhabdomyolysis cocaine, 42 normoglycemic glycosuria tenofovir, 333 nuchal rigidity MDMA, 32 numbness acupuncture, 581 insulin, 509 vitamin D (calciferol), 388 nystagmus diazepam + phenytoin, 53 metronidazole, 323 morphine, 110 vinca alkaloids, 542 O obesity valproic acid, 88 obtundation ivermectin, 349 occipital headache MDMA, 32 ocular complications interferon alfa, 418 oculorespiratory syndrome influenza vaccine, 361 odynophagia celecoxib, 130 OHSS see ovarian hyperstimulation syndrome

650 olfaction, altered cocaine, 41 olfactory disorders amikacin, 274 oligodactyly cocaine, 43 oligohydramnios lisinopril, 228 telmisartan, 230 oligospermia sirolimus, 463 oliguria enalapril, 228 opacities gold, 246 ophthalmic complications interferon alfa, 418 ophthalmoplegia isotretinoin, 173 parenteral nutrition, 384 opioid analgesia chlorphenamine, 178 opioid toxicity fentanyl, 108 optic atrophy doxycycline, 271 vinca alkaloids, 542 optic nerve atrophy cocaine, 43 optic nerve edema interferon alfa, 418 optic neuritis anthrax vaccine, 357 interferon alfa, 418 optic neuropathy amiodarone, 207 interferon alfa, 418 ocular anesthesia, 150 oral candidiasis glucocorticoids, systemic, 475 oral itching furosemide, 234 oral paresthesia indinavir, 335 oral ulceration sirolimus, 462 orbital symptoms cocaine, 41 organ donors cocaine intoxication, 2 cocaine users, 42–43 organ failure spironolactone, 235 orgasmic inhibition antidepressant drugs, 14 orofacial granulomatosis mercury, 249 orthostatic dysregulation epidural anesthesia, 146 orthostatic hypotension temazepam, 55 osmiophilic lamellated bodies chloroquine, 316 osteoarthritis

Index of adverse effects aspirin, 124 osteolysis titanium, 250–251 osteoporosis acitretin, 171 antiretroviral drugs, 330 glucocorticoids, systemic, 473 heparins, 392 risperidone, 78 osteosarcoma titanium, 251 otitis media carbamazepine, 89 cocaine, 41 ototoxicity kanamycin, 275 ovarian carcinoma diethylstilbestrol, 482 ovarian hyperstimulation syndrome gonadotropins, 480 overanticoagulation argatroban, 394 overdose olanzapine, 71 oxidation genetic variation, 342 oxidative damage chromium, 246 oxygen desaturation isoniazid, 344 octreotide, 530 oxygen saturation etherified starches, 371 P pain aspirin, 124 cocaine, 41 deferoxamine, 256 efalizumab, 437 levetiracetam, 91 levonorgestrel, 493 phosphate enema, 406 titanium, 251 palmar-plantar erythema fluorouracil, 546 palpable crepitation cocaine, 40 palpitation cannabinoids, 36 pancreatic autoantibodies interferon alfa, 420 pancreatic dysfunction antiretroviral drugs, 330 pancreatitis 6-thioguanine, 465 azathioprine, 450 clarithromycin, 282 clozapine, 67 dapsone, 343 enalapril, 227 hydrocortisone, 472 hydroxyurea, 547

iodinated water-soluble contrast media, 555–556 mesalazine, 408 nitrofurantoin, 284 perfluorocarbons, 370 ramipril, 228 ribavirin + interferon, 327 tacrolimus, 464 valproate, 100 pancytopenia infliximab, 430 linezolid, 284 panic attacks alprazolam, 52 glucocorticoids, systemic, 471 MDMA, 32 risperidone, 75 panuveitis interferon alfa, 418 papilledema all-trans retinoic acid + fluconazole, 299 doxycycline, 270–271 minocycline, 271 papular neutrophilic dermatosis epoetin, 378 papular rash mercury, 249 papulosquamous annular eruption nifedipine, 220 paradoxical increase in seizure frequency levetiracetam, 93 paraglobulinemia intravenous immunoglobulins, 372–373 paralyic ileus ciclosporin, 453 loperamide, 406 paralysis donepezil + suxamethonium, 8 Lyme disease vaccine, 358 potassium salts, 249 paralysis of the tibialis anterior muscle Asian herbal medicines, 573 paralytic ileus phenylephrine, 569 paranoia cocaine, 41 efavirenz, 334 paranoid delusions glucocorticoids, systemic, 472 mefloquine, 316 paranoid reactions levetiracetam, 91 paraparesis itraconazole + vincristine, 305 parathyroid hormone glucocorticoid-induced osteoporosis, 474 parenchymal density of the breast, increased

651

Index of adverse effects HRT, 485 paresis heroin, 45, 46 paresthesia Asian herbal medicines, 573 dental anesthesia, 148 diamorphine (heroin), 47, 107 dirithromycin, 283 indinavir, 335 risperidone + topiramate, 74 rituximab, 440 topiramate, 97 vancomycin, 281 Parkinsonism cisapride, 401 manganese, 248 MDMA, 32 Parkinson’s disease cocaine, 3, 41 infliximab, 429 parenteral nutrition, 384 paroxymal nocturnal hematuria antithymocyte globulin, 374 partial thromboplastin time argatroban, 394 parvovirus B19 transmission coagulation factors, 377 peeling tretinoin, 174 Pelger–Huet anomaly mycophenolate mofetil, 458 pelvic cramps copper IUCD, 246 pelvic pain goserelin acetate, 528 pemphigoid terbinafine, 295 pemphigus carbamazepine, 89 enalapril, 228 montelukast, 191 penicillamine, 258 penicillamine dermopathy penicillamine, 258 pericardial effusion interferon alfa, 417 pericarditis interferon alfa, 417 perifascial edema etherified starches, 371 periglomerular inflammatory infiltrates penicillamine, 258 perinatal mortality azathioprine, 451 mercaptopurine, 451 periocular hyperpigmentation beta-blockers (ocular), 570 periosteitis interleukin-11 (IL-11), 424 peripheral edema olanzapine, 71 pioglitazone, 520 raloxifene, 491

sirolimus, 461, 462 peripheral interstitial involvement sclerosant injections, 410 peripheral monocular scotoma interferon alfa, 418 peripheral nerve disease heroin, 47 peripheral neuropathy atorvastatin, 535–536 fluorouracil, 546 hydroxyurea, 547 Japanese encephalitis vaccine, 363 metronidazole, 323 suramin, 353 vinca alkaloids, 541 peritonitis penicillamine, 258 pernicious anemia interferon alfa, 421 perniosis-like eruption infliximab, 430 persistent crying meningococcal vaccine, 360 personality disorder levetiracetam, 91, 92 petechiae gold, 247 quinine, 319 petechial bleeding lepirudin, 394 phantom limb pain lumbar plexus block, 149 pharyngeal pain anti-CD40 antibody, 435 pharyngitis garenoxacin, 277 moxidectin, 351 tiotropium bromide, 191 phlebitis amiodarone, 205 phocomelia cocaine, 43 photoallergic reactions 6-thioguanine, 465 photo-damage calcium channel blockers, 218 photophobia isotretinoin, 172 MDMA, 32 voriconazole, 308 photosensitivity co-trimoxazole, 286 dexketoprofen, 126 flutamide, 498 Hypericum perforatum, 577 phototoxicity enoxacin, 277 fluoroquinolones, 276 lomefloxacin, 279 moxifloxacin, 279 sitafloxacin, 280 pigmentary degeneration

deferoxamine, 256 pinch weakness botulinum toxin A, 168 pituitary gland autoantibodies interferon alfa, 420 pituitary tumors pegvisomant, 529 placental weight, reduced atenolol, 217 plasma fibrinogen, increased growth hormone, 528–529 platelet aggregation ibuprofen, 127 PLERM ivermectin, 349 pleural effusions alprostadil, 476 cocaine, 40 gold, 246 insulin, 510 nitrofurantoin, 284 pleuritic chest pain vinca alkaloids, 540 Pneumocystis jiroveci pneumonia infliximab, 432 pneumomediastinum cocaine, 40 pneumonia 6-thioguanine, 465 barium, 554 benzalkonium compounds, 261 bepridil, 219 dapsone, 343 deferiprone, 256 gold, 246 heroin, 46 infliximab, 428 mercaptopurine, 451 risperidone, 75 venlafaxine, 19–20 pneumonitis infliximab, 429 pneumothorax acupuncture, 581 cocaine, 40 poisoning isoniazid, 344 polyarthralgia sirolimus, 462 polyarticular gout parenteral nutrition, 383 polycystic ovaries antiepileptic drugs, 88 valproate, 100 valproic acid, 88 polydipsia lithium, 24 MDMA, 35 polymorphisms genetic variation, 342–343 polymyosis infliximab, 432 polyneuropathy

652 ciclosporin, 455 stavudine, 332 suramin, 353 zinc, 251 polyomavirus-associated nephropathy tacrolimus, 464–465 polyuria antiretroviral drugs, 330 liposomal amphotericin, 298 lithium, 24 MDMA, 35 poor memory levetiracetam, 92 portosystemic shunts manganese, 248 post-transplant lymphoproliferative disorder antithymocyte globulin, 374 comparison table, 375 post-vaccinal encephalitis yellow fever vaccine, 366 posterior ocular complications interferon alfa, 418 posterior reversible encephalopathy syndrome tacrolimus, 463 posterior synechiae interferon alfa, 418–419 posterior white matter injury tacrolimus, 463 postoperative myalgia suxamethonium, 155–156 postoperative sensitivity gallium, 246 postural asphyxia triazolam, 56 postural hypotension ivermectin, 349 postural instability risperidone, 77 postural syncope cannabinoids, 37 potentiation verapamil, 196 pregnancy dipyrone, 126 Hypericum perforatum + oral contraceptives, 577 premature birth antimony, 245 azathioprine, 451 mercaptopurine, 451 premature epiphyseal closure isotretinoin, 172 premature menopause antiepileptic drugs, 88 priapism chlorpromazine, 64–65 cocaine, 3 risperidone, 78 ziprasidone, 80 primary pulmonary hypertension

Index of adverse effects amfepramone, 7 primary sclerosing cholangitis muromonab-CD3, 438 primary thrombocythemia intravenous immunoglobulins, 372 progressive central vein sclerosis terbinafine, 294 progressive dyspnea venlafaxine, 20 progressive myelopathy heroin, 46–47, 47 prolonged F wave latency heroin, 47 prolonged QT interval see QT interval prolongation property destruction clonazepam, 53 propofol infusion syndrome propofol, 143 proptosis cocaine, 41 prostate cancer finasteride, 498 prostate stimulation testosterone, 495 proteinuria benazapril, 227 celecoxib, 130 cocaine, 39 hydralazine, 230 tenofovir, 333 prothrombin time prolongation influenza vaccine, 362 voriconazole + warfarin, 305 proximal weakness antiretroviral drugs, 330 pruritic blistering eruption terbinafine, 295 pruritic erythematous generalized rash fluconazole, 305 pruritic rash nevirapine, 334 pruritus 6-thioguanine, 465 atovaquone + proguanil, 317 bezafibrate, 409 buprenorphine, 112 cholelitholytic agents, 410 efalizumab, 436 epidural anesthesia, 146 interferon alfa, 421 intravenous immunoglobulins, 372 morphine, 110 ribavirin + interferon, 327 tacrolimus, 464 vancomycin, 281 pseudoacromegaly minoxidil, 170 pseudolithiasis ceftriaxone, 269–270

pseudolymphoma antiepileptic drugs, 87 carbamazepine, 259 penicillamine, 259 Pseudomonas septicemia valproate, 100 pseudomycosis fungoides carbamazepine, 259 penicillamine, 259 pseudoporphyria ciclosporin, 454 oral contraceptives, 487 pseudotumor cerebri tretinoin, 173 psoas abscess femoral block, 149 psoriasis etanercept, 427 rofecoxib, 132 psychiatric disorders rufloxacin, 280 topiramate, 96 psychiatric syndromes aciclovir, 328 psychoactive effects Myristica fragrans, 578 psychomotor impairment temazepam, 55 topiramate, 97 zaleplon, 56 psychomotor performance mirtazapine, 19 psychosis ciprofloxicin, 277 co-trimoxazole, 286 ephedrine, 161 glucocorticoids, systemic, 471 levetiracetam, 91, 92, 93 MDMA, 34 MDMA + cannabis, 34 mefloquine, 316–317 metamfetamine, 5–6 metronidazole, 323 olanzapine, 71 topiramate, 97 psychotic depression levetiracetam, 91 psychotic disorders topiramate, 98 ptosis botulinum toxin A, 168 epidural anesthesia, 147 vinca alkaloids, 542 pulmonary allergic reaction sclerosant injections, 410 pulmonary barotrauma cocaine, 40 pulmonary edema blood transfusion, 369 granulocyte colony-stimulating factor, 415 heroin, 47 influenza vaccine, 362 muromonab-CD3, 437

653

Index of adverse effects pulmonary embolism basiliximab, 436 clozapine, 65 intravenous immunoglobulins, 372 pulmonary fibrosis barium, 554 pulmonary granulomas adalimumab, 426 pulmonary hypertension amfepramone, 7 interferon alfa, 417 penicillamine, 258 pulmonary hypoplasia lisinopril, 228 pulmonary infiltration granulocyte colony-stimulating factor, 416 pulmonary infiltration with eosinophilia clarithromycin, 282 pulmonary mast cell degranulation heroin, 45 pulmonary nodules venlafaxine, 20 pulmonary thromboembolism risperidone, 76 pulmonary vasculitis interferon alfa, 417 pure red cell aplasia erythropoietin and derivatives, 378 purpura acetazolamide, 233 co-trimoxazole, 286 penicillamine, 258 quinine, 318 PUVA burn phototherapy, 171 pyoderma gangrenosum intravenous immunoglobulins, 373 pyramidal signs heroin, 46 pyramidal syndrome rituximab, 440 pyrexia erythropoietin and derivatives, 378 heroin, 46 sertraline, 17 pytiriasis versicolor interferon alfa, 421 Q QRS complex widening flecainide, 210 QT interval prolongation amfebutamone, 15 amiodarone, 206 amiodarone + loratadine, 208 azithromycin, 282 cisapride, 401

droperidol, 69 epidural anesthesia, 146 flecainide, 210 fluconazole, 279 fluconazole + amitriptyline, 304–305 fluconazole + levofloxacin, 279 fluoroquinolones, 276 grapefruit juice + quinine, 319 haloperidol, 59 HRT, 482 levofloxacin, 278 levofloxacin + quinolone antibiotics, 303 loratadine, 181 methadone, 47, 108 moxifloxacin, 279 olanzapine, 71 sevoflurane, 139 sparfloxacin, 280 summary table, 203 ziprasidone, 79 R rash 6-thioguanine, 465 alemtuzumab, 435 atovaquone + proguanil, 317 azithromycin, 282 bevacizumab, 436 buprenorphine, 112 Centella asiatica, 575 clindamycin, 281, 282 co-trimoxazole, 286, 322 dapsone, 343 daptomycin, 287 diltiazem, 219 efavirenz, 334 fluconazole, 305 gemifloxacin, 278 gentamicin, 275 gold, 246 granulocyte colony-stimulating factor, 416 heparins, 392 ICL670, 257 indinavir, 335 intravenous immunoglobulins, 372 itraconazole, 308 Japanese encephalitis vaccine, 363 levetiracetam, 91, 93 mercury, 249 nevirapine, 334 oxazolidinones, 284 oxcarbazepine, 94, 95 penicillamine, 257 pristinamycin, 285 probenecid, 326 quinine, 319 rabeprazole + amoxicillin + clarithromycin, 405 sirolimus, 462

smallpox vaccine, 366 thiabendazole, 347 valaciclovir, 329 vancomycin, 281 rash, maculopapular amfebutamone, 19 Raynaud’s phenomenon interferon alfa, 417, 421 reactivation of skin damage aciclovir, 328 reactive arthritis infliximab, 431 rectal-anal atresia/stenosis diazepam, 53 recurrent capsule opacities erythropoietin, 378 red eyes influenza vaccine, 361 red man syndrome vancomycin, 281 redness pneumococcal vaccine, 360 reduced arousal antidepressant drugs, 14 naltrexone, 114 reduced desire antidepressant drugs, 14 reduced ejaculate volume finasteride, 169 reduced libido finasteride, 169 reduced visual acuity isotretinoin, 172 refractory hypotension eptifibatide, 398 regulatory decision-making DoTS guidance, xxxii renal see also entries at kidney; nephrrenal glycosuria MDMA, 35 renal impairment ceftriaxone, 270 eptifibatide, 398 gatifloxacin clearance, 278 MDMA, 31 teicoplanin dosage, 280 renal infarction cocaine, 39–40 renal insufficiency aminoglycosides, 274 cardiac glycosides, 196–197 cefepime, 269 ciclosporin, 454 cocaine, 42, 43 deferoxamine, 256 dipyridamole, 397 enalapril, 228 etherified starches, 371 furosemide, 234 hydralazine, 230–231 interferon alfa, 421 intravenous immunoglobulins, 373

654 liposomal amphotericin (L-AmB), 298 lisinopril, 228 lithium, 24 losartan, 229 MDMA, 32 penicillamine, 258 phenylephrine, 569 polymyxin B, 285 polyvinylpyrrolidone, 263 pyrazolone derivatives, 125 quinine, 319 sirolimus, 461 telmisartan, 230 topiramate, 98 renal microcysts lithium, 25 renal papillary necrosis celecoxib, 130 renal tubular acidosis tacrolimus, 464 renal tubular dysfunction antiretroviral drugs, 330 deferoxamine, 256 renal vasculitis hydralazine, 230–231 resistance antibiotic prudence, 265–267 antimony, 244 praziquantel, 351 virginiamycin, 288 respiratory acidosis insulin, 510 parenteral nutrition, 384 respiratory alkalosis phenolic compounds, 263 respiratory arrest MDMA, 36 respiratory depression midazolam, 54 morphine, 109 opioid analgesics, 106 remifentanil, 112 respiratory distress blood transfusion, 369 lithium, 25 ramipril, 229 SSRIs, 17 respiratory infection botulinum toxin A, 168 rosiglitazone, 521 respiratory symptoms influenza vaccine, 361 restless legs syndrome diamorphine, 107 zonisamide, 101 restlessness cyclopentolate, 568 heroin, 45 venlafaxine, 20 retinal damage deferoxamine, 256 retinal hemorrhage minocycline, 271

Index of adverse effects retinal injury trovafloxacin, 276 retinopathy interferon alfa, 418 retrobulbular hemorrhage Ginkgo biloba, 576 retro-orbital headache MDMA, 32 retroperitoneal bleed lepirudin, 394 retropulsion parenteral nutrition, 384 retrosternal pain ciclosporin, 453 reversible bone marrow depression chloramphenicol, 276 reversible QRS complex widening flecainide, 209 rhabdomyolysis atorvastatin + esomeprazole, 535 chlorpheniramine, 177 cocaine, 42 colchicine, 133 diphenydramine, 179 fluconazole + simvastatin, 304 fusidic acid + vastatin, 280 interferon alfa, 422 itraconazole, 307 lopinavir + ritonavir, 336 MDMA, 31 propofol, 143 red rice products, 535 verapamil + simvastatin, 221 rhinitis histamine hydrochloride, 424 olanzapine, 71 right bundle branch block isotretinoin, 172 right-sided infective endocarditis metamfetamine, 30 right-sided phocomelia cocaine, 43 rigid fingers 6-thioguanine, 465 rigidity olanzapine, 72 parenteral nutrition, 384 rigor alemtuzumab, 435 co-trimoxazole, 322 rituximab, 439 rotavirus infection 6-thioguanine, 465 S salivary flow rate, altered furosemide, 234 scalp hair loss octreotide, 530 scleral thickening

interferon alfa, 419 scrotal reactions diethylcarbamazine, 348 sebaceous gland hyperplasia ciclosporin, 454 seborrheic dermatitis interferon alfa, 421 sirolimus, 462 secretory otitis media cocaine, 41 sedation antiepileptic drugs, 86 clobazam, 53 clonazepam + paroxetine, 53 clozapine, 65 mirtazapine, 15, 19 morphine, 109 norclozapine, 67 olanzapine, 70 risperidone, 74, 75 temazepam, 55 seizure amfebutamone, 15 antithymocyte globulin, 373 baclofen, 157 caffeine, 1 chlorphenamine, 177 ciclosporin, 455 ciprofloxicin, 277 clobazam, 53 diptheria-tetanus-acellular pertussis vaccine, 360 erythropoietin and derivatives, 377 gatifloxacin, 278 glyceryl trinitrate, 218 haloperidol + promethazine, 54 heroin, 46 interferon alfa, 417 isoniazid, 344 lidocaine, 145 MDMA, 32, 34, 35, 36 NSAIDs + quinolones, 278 ocular anesthesia, 150 olanzapine, 72 pethidine, 111 polyvinylpyrrolidone, 262–263 topiramate, 97 venlafaxine, 15 vinca alkaloids, 542 seizure exacerbation levetiracetam, 93 selenium deficiency parenteral nutrition, 384 semicircular actinic granulomata doxycycline, 271 semicircular canals, damage to aspirin, 123 sensitivity gallium, 246 sensitization antithymocyte globulin, 373 heroin, 45

655

Index of adverse effects muromonab-CD3, 437 sensorimotor hemiplegia heroin, 45 sensorimotor polyneuropathy mesalazine, 408 vinca alkaloids, 540 sensorineural hearing loss interferon alfa, 419 vancomycin, 280–281 sensory loss metronidazole, 323 sensory neuropathy antiretroviral drugs, 330 vitamin B6 + nitrofurantion, 388 sepsis interferon alfa, 417 rituximab, 439 septal erosion cocaine, 41 septal perforation cocaine, 3, 40 septicemic shock metamfetamine, 30 serotonin syndrome see 5-HT syndrome serum sickness amfebutamone, 19 antithymocyte globulin, 373, 374 rituximab, 440 sex differences cardiac glycoside toxicity, 196 sexual arousal, reduced risperidone, 75 sexual dysfunction clonazepam + paroxetine, 53 risperidone + topiramate, 74 Sézary syndrome phenytoin, 88 shivering misoprostol, 477 sulfamethoxazole + celecoxib, 322 venlafaxine, 20 shock suramin, 353 short-term memory loss tolterodine, 165 shortness of breath amiodarone, 205 calcium channel blockers, 219 calcium salts, 245 cannabinoids, 36 deferoxamine, 257 parenteral nutrition, 385 thiazolidinediones, 519 vinca alkaloids, 540 vitamin D (calciferol), 388 SIADH see syndrome of inappropriate antidiuretic hormone secretion (SIADH) sialadenitis

iodinated water-soluble contrast media, 555 sialorrhea norclozapine, 67 signal abnormalities heroin, 47 sino-nasal inflammatory condition cocaine, 3 sinus bradycardia amiodarone, 205 methadone, 47 sinusitis tiotropium bromide, 191 sinusoidal obstruction syndrome cyclophosphamide, 456 sister chromatid exchange ethylene oxide, 262 metamfetamine, 31 skin, dry indinavir, 335, 336 skin discoloration minocycline, 271 skin discoloration, yellow dipyridamole, 397 skin eruptions ribavirin + interferon, 327 skin flushing suramin, 353 skin fragility penicillamine, 258 skin irritation calcipotriol, 169 erythropoietin and derivatives, 377–378 vitamin D (calciferol), 389 skin lesions aciclovir, 328 antiepileptic drugs, 87 arginine vasopressin, 531 chloroquine, 316 nifedipine, 220 nitrendipine, 220 skin necrosis contrast media, 560 skin reaction epoetin, 378 insulin, 510 iodinated water-soluble contrast media, 553 skin ulcers vinca alkaloids, 543 sleep attacks dopamine receptor agonists, 162–163 entacapone, 165 piribedil, 163 sleep cycle inversion clozapine, 65 sleep disorders levetiracetam, 91 sleep disturbance donepezil, 8

methylphenidate, 6 SSRIs, 15–16 sleep walking see somnambulism sleepiness alprazolam, 52 olanzapine, 71 small-bowel perforation sirolimus, 463 small-bowel villous atrophy azathioprine, 450 small-for-date infants caffeine, 1 metamfetamine, 30–31 soft palate perforations cocaine, 40 somnambulism amfebutamone, 18–19 paroxetine, 15–16 zolpidem + valproic acid, 57 somnolence COX-2 inhibitors, 129 droperidol, 69 efavirenz, 334 famotidine, 403 gatifloxacin, 278 levetiracetam, 91, 92, 93 moxidectin, 351 olanzapine, 70, 71 polyvinylpyrrolidone, 263 pregabalin, 56 risperidone, 75 risperidone + donepezil, 79 risperidone + topiramate, 74 ropinirole, 162 topiramate, 96, 97 vinca alkaloids, 541 ziprasidone, 80 sore throat influenza vaccine, 363 soreness tacrolimus, 463 spasms heroin, 45, 46 iron, 247 spastic paresis heroin, 46 spastic quadriparesis heroin, 46 speech alterations olanzapine, 73 parenteral nutrition, 384 tacrolimus, 464 speech disorders mercury, 248 speech loss tacrolimus, 464 spina bifida aperta valproic acid + carbamazepine, 88 spinal myoclonus interferon alfa, 417 intrathecal (spinal) anesthesia, 148 spleen rupture

656 granulocyte colony-stimulating factor, 415 splenomegaly granulocyte colony-stimulating factor, 415 spongiform degeneration heroin, 45 spongiform leukoencephalopathy heroin, 46 spontaneous acute coronary dissection cocaine, 39 sporotrichosis tumor necrosis factor antagonists, 426 spurious hypocalcemia gadolinium salts, 563 squamous cell carcinoma azathioprine, 451 ST segment depression adenosine, 204 Staphylococcus aureus cocaine, 41 status epilepticus ciclosporin, 453 itraconazole + vincristine, 305 levetiracetam, 93 valproate + lamotrigine, 90 steatohepatitis diethylstilbestrol, 482 sterile cholecystitis tumor necrosis factor antagonists, 425 Stevens-Johnson syndrome aceclofenac, 126 acetazolamide, 570 carbamazepine, 87 ciprofloxicin, 277 co-trimoxazole, 286 metronidazole, 323 metronidazole + mebendazole, 347 oxicams, 128 ribavirin + interferon, 327 rofecoxib, 131 terbinafine, 295 stiffness parenteral nutrition, 383 titanium, 251 stinging beta-blockers (ocular), 570 tacrolimus, 463 tretinoin, 174 stipation tramadol, 112 stocking sensory neuropathy antiretroviral drugs, 330 stomach ache buspirone, 52 methylphenidate, 6 stomatitis co-trimoxazole, 286 fluorouracil, 546

Index of adverse effects sirolimus, 461 suramin, 353 stomatitis, erosive sibutramine, 8 stool abnormalities nelfinavir, 336 stools, loose pristinamycin, 285 stools, loose watery cyclo 3 fort, 223 strabismus heroin, 47 Streptococcus pneumoniae sepsis infliximab, 432 strictures clindamycin, 281 stroke darbepoetin alfa, 378 intravenous immunoglobulins, 372 olanzapine, 71 post-coital contraception, 489 risperidone, 75, 76–77 tamoxifen, 492 stupor aciclovir, 328 ivermectin, 349 levetiracetam, 91 pivmecillinam, 269 subacute lupus erythematosus-like eruptions terbinafine, 295 subarachnoid hemorrhage lepirudin, 394 subconjunctival hemorrhage interferon alfa, 418 subcortical hemorrhage metamfetamine, 29 subcortical lesions heroin, 47 submandibular swelling infliximab, 428 suicidal behavior haloperidol, 60 suicidal depression levetiracetam, 92 suicidal ideation efavirenz, 334 isotretinoin, 172 levetiracetam, 93 topiramate, 98 suicide isotretinoin, 172 suicide attempts isotretinoin, 172 sulfone syndrome dapsone, 343 suppression of adrenal gland function fluticasone, 184–185 suppression of the hypothamicpituitary-adrenal axis

glucocorticoids, 169 supraventricular extra beats taxanes, 547 supraventricular tachycardia tiotropium bromide, 191 surgical wound complications sirolimus, 462–463 susceptibility factors adverse drug reactions, xxxi identifying, xxxii–xxxiii sweating calcium channel blockers, 219 cocaine, 40 heroin, 46 mercury, 249 naltrexone, 114 reboxetine, 15 sweating, reduced topiramate, 98 zonisamide, 101 Sweet’s syndrome epoetin, 378 isotretinoin, 172–173 quinupristin/dalfopristin, 285 rofecoxib, 132 swelling artemether + lumifantrine, 321 aspirin, 124 buprenorphine, 112 deferoxamine, 256 doxycycline, 271 ivermectin, 349 mercury, 249 pneumococcal vaccine, 360 sirolimus, 461 titanium, 251 vitamin D (calciferol), 388 swelling, facial minocycline, 272 symmetrical deep cerebellar lesions heroin, 46 syncope antithymocyte globulin, 373 venlafaxine, 20 syndrome of inappropriate antidiuretic hormone secretion (SIADH) ecstasy, 512 itraconazole + vincristine, 305 MDMA, 35 vinca alkaloids, 542 syndrome X described, 329 systemic anaphylaxis gentamicin, 275 T T cell depletion alemtuzumab, 434 tachycardia artesunate, 321 cocaine, 38 gabapentin, 90

657

Index of adverse effects iron, 247 isoniazid, 343 MDMA, 31, 32, 34, 35 mercury, 249 norclozapine, 67 reboxetine, 15 secretin, 409 tiotropium bromide, 191 vitamin D (calciferol), 388 tachypnea MDMA, 32 talipes cocaine, 43 tardive dyskinesia cisapride, 401 risperidone + topiramate, 74 taste, bitter secnidazole, 346 taste disturbance botulinum toxin A, 169 clarithromycin, 283 esomeprazole + clarithromycin + metronidazole, 405 gadobenate dimeglumine, 563 mangafodipir trisodium, 565 tear osmolarity isotretinoin, 172 telangiectasia manganese, 248 temper tantrums clonazepam, 53 tenderness aspirin, 124 tendinopathy levofloxacin, 279 norfloxacin, 279 tendon reflexes chloroquine, 316 tendon rupture ciprofloxicin, 277 levofloxacin, 279 testosterone concentrations Glycyrrhiza species, 577 valproate, 100 thiamine deficiency furosemide, 234 parenteral nutrition, 383 thoracic pain antimony, 245 interferon alfa, 417 throat tightness polygeline, 372 thrombocythemia antithymocyte globulin, 374 intravenous immunoglobulins, 372 thrombocytopenia 6-thioguanine, 465 acetazolamide, 233 ammonium chelators, 254 antithymocyte globulin, 373 co-trimoxazole, 286 eptifibatide, 398 erythropoietin and derivatives, 377

fusidic acid, 280 glucagon, 514 gold, 247 hydroxyurea, 170 indinavir, 335 inhibitors of phosphodiesterase type V, 224 interferon alfa, 421 interferon beta, 422 linezolid, 284 Lyme disease vaccine, 358 nimesulide, 132 oxazolidinones, 284 positive inotropic drugs, 199 quinine, 318, 319 recombinant factor VIII, 376 rofecoxib, 131 vancomycin, 281 vinca alkaloids, 543 thrombocytopenic purpura quinine, 318 thrombocytosis mesalazine, 409 thromboembolic complications oral contraceptives, 487 thromboembolic disease raloxifene, 491 thromboembolism anti-CD40 antibody, 435 blood transfusion, 369 diethylstilbestrol, 482 enoxaparin, 393 fondaparinux, 392 growth hormone, 529 intravenous immunoglobulins, 372 rofecoxib, 131 thrombophlebitis amiodarone, 205 topiramate, 97 thrombosis coagulation factors, 375, 376 erythropoietin and derivatives, 377 mesalazine, 409 recombinant factor VIIa, 376 sirolimus, 460 thrombotic complications bevacizumab, 436 tretinoin, 173 thrombotic microangiopathy sirolimus + tacrolimus, 462 thrombotic thrombocytopenic purpura interferon alfa, 417 quinine, 318 sirolimus, 463 tretinoin, 173 thrombus cocaine, 40 thyroid autoimmunity interferon alfa, 420 tick-borne diseases blood transfusion, 370

tics methadone, 48 time-courses of adverse drug reactions, xxviii, xxx–xxxi Tinea incognito tacrolimus, 463 tingling sensation insulin, 509 potassium salts, 249 tacrolimus, 464 tinnitus atovaquone + proguanil, 317 clarithromycin, 282 interferon alfa, 419 metronidazole, 323 tobramycin, 275 vinca alkaloids, 542 tiredness buspirone, 52 levetiracetam, 91, 92 tiredness in the legs parenteral nutrition, 384 titubation penicillamine, 257 toenails, ingrown indinavir, 335 tongue, sluggish zolpidem, 56 tonic-clonic seizures adenosine, 204 baclofen, 157 ciclosporin, 453 ciprofloxicin, 277 glyceryl trinitrate, 218 haloperidol + promethazine, 54 levobupivacaine, 151–152 MDMA, 32, 34 topiramate, 97 tonsils, swollen metamfetamine + morphine, 28 tooth abscess infliximab, 428 tooth fractures gallium, 246 torsade de pointes amiodarone, 206 droperidol, 69 levofloxacin + quinolone antibiotics, 303 loratadine, 181 methadone, 47–48, 108 moxifloxacin, 279 quinine, 319 roxithromycin, 283 sotalol, 218 summary table, 203 Tourette’s syndrome methadone, 48 toxic epidermal necrolysis carbamazepine, 87 ciprofloxacin, 277 co-trimoxazole, 286 lamotrigine, 88 leflunomide, 457–458 metronidazole, 323

658 mupirocin, 284 oxicams, 128 terbinafine, 294–295 valdecoxib, 132 toxic erythema terbinafine, 295 toxic myocarditis aspirin, 124 toxic optic neuropathy infliximab, 429 TPMT deficiency azathioprine, 452 tracheobronchitis anti-CD40 antibody, 435 tranfusion-related acute lung injury (TRALI) blood transfusion, 369 transfusion reactions blood transfusion, 370 transverse myelitis Japanese encephalitis vaccine, 363 transverse sinus thrombosis intravenous immunoglobulins, 372 trembling alprazolam, 52 tremor aciclovir, 328 co-trimoxazole, 287 droperidol, 69 gatifloxacin, 278 lamotrigine, 90 levetiracetam, 91 MDMA, 34 olanzapine, 70 parenteral nutrition, 384 penicillamine, 257 risperidone, 74 risperidone + topiramate, 74 tacrolimus, 464 valproate + lamotrigine, 90 triglyceride concentrations tamoxifen, 492 tuberculosis adalimumab, 427 tumor necrosis factor antagonists, 425–426 tubular acidosis liposomal amphotericin, 298 tubular damage aminoglycosides, 274 tenofovir, 333–334 tubular dysfunction deferoxamine, 256 tubular necrosis tenofovir, 333 tumor lysis syndrome methotrexate, 547 tumors antithymocyte globulin, 375 pegvisomant, 529 tumors, mammary SSRIs, 14

Index of adverse effects tricyclic antidepressants, 14 twitching potassium salts, 250 type I renal tubular acidosis liposomal amphotericin (L-AmB), 298 U ulceration cocaine, 40–41 contrast media, 560 interferon alfa, 417 ulcerative lesions cocaine, 40 ulceronecrotic process cocaine, 3 ulcers, digestive clindamycin, 281 ulcers, skin silver, 250 unconsciousness ivermectin, 349 parenteral nutrition, 384 sulfamethoxazole + celecoxib, 322 unsteadiness aspirin, 123 heroin, 46 upper respiratory tract infection valaciclovir, 329 uremia quinine, 319 ureteral obstruction furosemide, 234 uric acid concentration parathyroid hormone, 531 trimethoprim, 322 urinary incontinence diamorphine, 107 midazolam, 54 risperidone, 78 valproate + lamotrigine, 90 urinary retention buprenorphine, 113 MDMA, 35 risperidone, 75 tiotropium bromide, 191 vinca alkaloids, 541 urinary sedimentation quinine, 319 urinary tract infection MDMA, 31 mycophenolate mofetil, 459 risperidone, 75 urinoma furosemide, 234 urolithiasis indinavir, 336 zonisamide, 101 urothelial tumors Aristolochia species, 575 urticaria amfebutamone, 19

atovaquone + proguanil, 317 cephalosporins, 267 co-trimoxazole, 286 estrogens, 481 fosfomycin, 287 furosemide, 234 interferon alfa, 421 iron, 247 itraconazole, 308 Japanese encephalitis vaccine, 363 leucovorin, 387 liposomal amphotericin (L-AmB), 298 ramipril, 229 urticarial rash heparins, 392 uterine liposarcoma tamoxifen, 493 uterine rupture diethylstilbestrol, 482 V vaginal bleeding anastrozole, 490 estrogens, 481 valvular heart disease benfluorex, 7 variant Creutzfeldt–Jakob disease (vCJD) blood transfusion, 370 perfluorocarbons, 371 Varicella infection infliximab, 433 Varicella zoster pneumonia azathioprine, 451 vascular disruption defects cocaine, 43 vascular parenchymal atrophy chloroquine, 316 vascular purpura chloroquine, 316 vasculitis azathioprine, 450 chloroquine, 316 hydralazine, 230–231 infliximab, 430 levamisole, 350 MDMA, 32 tretinoin, 174 vasoconstriction cocaine, 39, 41 perfluorocarbons, 370 vasodilatation histamine hydrochloride, 424 vasogenic edema tacrolimus, 463 vasospasm lidocaine, 152 vCJD see variant Creutzfeldt-Jakob disease veno-occlusive disease cyclophosphamide, 456–457 gemtuzumab, 437

659

Index of adverse effects venous thromboembolism anastrozole, 490 asparaginase, 545 blood transfusion, 369 clozapine, 65 enoxaparin, 393 fondaparinux, 393 HRT, 486 ximelagatran, 395 venous thrombosis glucagon, 514 infliximab, 429 ventral polyradiculopathy cytarabine, 546 ventricular dysrhythmia amphotericin B deoxycholate (DAMB), 295 ventricular fibrillation potassium salts, 250 ventricular septum, defect penicillamine, 258 ventricular tachycardia adrenaline, 160 amiodarone, 205 vertigo gatifloxacin, 278 ICL670, 257 polyvinylpyrrolidone, 263 sodium phosphate, 407 sulfamethoxazole + celecoxib, 322 topiramate, 97 vinca alkaloids, 542 zolpidem, 56 vesicoureteral reflux suramin, 353 vesiculation buprenorphine, 112 vesiculopapular lesions antiepileptic drugs, 87 vestibular damage aminoglycosides, 274 vestibular dysfunction aspirin, 123 violence haloperidol, 60 viral infection coagulation factors, 375 mycophenolate mofetil, 460 rituximab, 440 viscerotropic disease yellow fever vaccine, 366 vision, blurred aspirin, 123 melatonin, 531 minocycline, 271 quinine, 318 vision disturbance contraceptive implants, 490 COX-2 inhibitors, 129 topiramate, 96 voriconazole, 308, 309 vision loss ergot alkaloids, 224

interferon alfa, 418 metronidazole, 323 visual field loss vigabatrin, 101 visual hallucinations cefepime, 269 mefloquine, 316 zonisamide, 101 vitamin B12 absorption metformin, 516–517 vitamin D intoxication vitamin D (calciferol), 388 vitiligo interferon alfa, 421 vitiligo-like depigmentation chloroquine, 316 vitritis interferon alfa, 419 vocal cord damage MDMA, 31 vocal cord paralysis local anesthesia, 146 Vogt–Koyanagi–Harada disease interferon alfa, 418–419 volume changes acetazolamide, 233 vomiting 6-thioguanine, 465 all-trans retinoic acid + fluconazole, 299 anti-CD3 antibody, 435 antiretroviral drugs, 330 antithymocyte globulin, 373 artemether + lumefantrine, 321 artesunate, 321 buprenorphine, 113 calcium salts, 245 ceftriaxone, 270 clindamycin, 282 co-trimoxazole, 286, 322 cocaine, 39 diethylcarbamazine, 348 dolasetron, 402 doxycycline, 270 ergot alkaloids, 224 famotidine, 403 fentanyl, 108 gabapentin, 90 indinavir, 335 interferon beta, 422 itraconazole, 306 ivermectin, 349 mangafodipir trisodium, 565 mannitol, 237 MDMA, 31, 32, 35 metformin, 517 moxidectin, 351 naltrexone, 114 ondansetron, 402 parenteral nutrition, 383 polyethylene glycol, 407 polyvinylpyrrolidone, 263 praziquantel, 351 probenecid, 326

quinine, 318, 319 sennoside calcium, 407 sertraline, 17 sevoflurane, 140 sodium phosphate, 407 sulfamethoxazole + celecoxib, 322 suramin, 353 terbinafine, 294 tropisetron, 401 valaciclovir, 329 venlafaxine, 20 vinorelbine, 543 voriconazole, 309 vulvo-vaginal candidiasis clindamycin, 282 W water intoxication MDMA, 35 weakness aluminium, 244 antimony, 245 antiretroviral drugs, 330 atovaquone + proguanil, 317 calcium channel blockers, 219 calcium salts, 245 colistin, 285 daptomycin, 287 droperidol, 69 fluconazole, 305 fluconazole + simvastatin, 304 gabapentin, 89 gold, 246 interferon alfa, 420 ivermectin, 349 levetiracetam, 91, 93 magnesium, 248 mercury, 249 metronidazole, 323 potassium salts, 249 risperidone, 75 sodium phosphate, 407 vinca alkaloids, 541 weakness, motor mesalazine, 408 weakness of the legs olanzapine, 70 weariness polyethylene glycol, 407 sennoside calcium, 407 weight changes contraceptive implants, 490 weight gain anabolic steroids, 496 cholelitholytic agents, 409–410 clobazam, 53 clozapine, 65, 66 granulocyte colony-stimulating factor (G-CSF), 415 interferon alfa, 420 levetiracetam, 92 olanzapine, 62, 70, 71, 72 oxcarbazepine, 95

660 pioglitazone, 520 risperidone, 74, 75, 77 rosiglitazone, 521 thiazolidinediones, 519 valproate, 99 ziprasidone, 79 weight loss antiepileptic drugs, 87 antiretroviral drugs, 330 glucagon, 514 hydralazine, 230 infliximab, 430 interferon alfa, 419 ribavirin + interferon, 327 risperidone + topiramate, 74

Index of adverse effects tacrolimus, 464 topiramate, 97 venlafaxine, 20 West Nile virus blood transfusion, 370 wheal-and-flare responses polyvinylpyrrolidone, 263 wheezing cocaine, 40 vinca alkaloids, 540 white exudate garenoxacin, 277 white nail beds parenteral nutrition, 384 wind

see flatulence withdrawal (physical) cocaine, 41 HRT, 486 Hypericum perforatum, 577 withdrawal (regulatory) DoTS guidance, xxxii X xerosis ribavirin + interferon, 327 xerostomia interferon alfa, 421 tiotropium bromide, 190